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<context> Our results show a high prevalence of RA in LAC women with a ratio of 5.2 women per man RA in LAC women is not only more common but presents with some clinical characteristics that differ from RA presentation in men. Some of those characteristics could explain the high rates of disability and worse prognosis observed in women with RA in LAC The expression and clinical course of RA are influenced by gender. In developed countries the prevalence of RA is 0,5 to 1.0%, with a male:female ratio of 1:3. women were found to have higher disease activity scores, more pain and greater loss of function, both in early and established disease Intense anti-CCP2 reaction was 19.8-fold higher in females vs. males, men (n = 67) and women (n = 225) Responses to treatment over time were better among men in this prebiologic era; women had worse progression despite similar treatment. BMI appears to be associated with RA disease activity in women, but not in men. A total of 5,161 RA patients (4,082 women and 1,079 men) In women the DAS28 was significantly higher than in men due to higher scores for general health and tender joints. Likewise, HAQ and VAS pain were rated significantly higher in women. 432 females, 125 males ESR significantly increased with age, independent of other variables of disease activity. This increase was more pronounced in male than in female patients Disease patterns in RA vary between the sexes; the condition is more commonly seen in women, who exhibit a more aggressive disease and a poorer long-term outcome. The mean age of the patients was 62 years (range 19–96 years) and 71% were female; The female to male ratio was 2.5:1 and the mean age at diagnosis was 49.4 +/- 14.9 years for women and 55.3 +/-15.6 years for men (P < 0.0003) in 244 female and 91 male patients with rheumatoid arthritis. </context> <question> Is Rheumatoid Arthritis more common in men or women? </question> <answer> Women </answer>
<context> Gene fusion is an important evolutionary process. It can yield valuable information to infer the interactions and functions of proteins. Aside from their novelty, proteins with BLAST hits to two or more proteins in other organisms have been posited as Rosetta Stones since the fusion of two or more catalytic domains as part of a metabolic or regulatory pathway has been used to infer the association of orthologous proteins containing single domains that exist as separate entities in other genomes Gene fusion also enforces the co-regulation of two domains and co-regulated genes in multienzyme complexes. We have developed a Bayesian framework to infer phosphorylation networks from time series measurements of phosphosite concentrations upon ligand stimulation. To increase the prediction accuracy we integrated different types of data, e.g., amino acid sequence data, genomic context data (gene fusion, gene neighborhood, and phylogentic profiles) It is assumed that two proteins, which are found to be transcribed by a single transcript in one (or several) genomes are likely to be functionally linked, for example by acting in a same metabolic pathway or by forming a multiprotein complex. This method is of particular interest for studying genes that exhibit no, or only remote, homologies with already well-characterized proteins. PLEX search results are accompanied by quantitative estimates of linkage confidence, enabling users to take advantage of coinheritance, operon and gene fusion-based methods for inferring gene function and reconstructing cellular systems and pathways. While phylogenomic profiles remain the central focus of Phydbac2, it now integrates chromosomal proximity and gene fusion analyses as two additional non-similarity-based indicators for inferring pairwise gene functional relationships. The gene-fusion approach relies on the observation that pairs of genes encoding proteins of known function (usually interacting or forming a complex) tend to be found in other species as a fused composite gene encoding a single multifunctional protein. the detection of a gene fusion in one (query) genome allows the prediction of functional association between corresponding homologous genes that remain separate in another (reference) genome detection of gene fusion events can contribute towards the elucidation of functional associations of proteins within entire genomes This fusion analysis (also known as "Rosetta stone" method) takes advantage of the study of genomic structures and sequence similarity to detect putative interacting protein pairs, which, importantly might not have been suspected based on current biochemical knowledge. Briefly, if a pair of non-homologous proteins which are found in different genomic regions in organism A, are found fused into a single ORF in organism B, this suggests that the two independent proteins in organism A may interact. These protein-protein interactions may be transient or more long-lived, either within a metabolic pathway, or as part of a multi-subunit protein complex. Two polypeptides A and B in one organism, are likely to interact if their homologues are expressed as a single polypeptide AB in another. The in silico method used to detect such protein fusions is called domain fusion analysis and the composite polypeptide AB, is referred to as a Rosetta Stone protein, as it gives information about a functional link between domains A and B. a number of methods were proposed for the inference of protein interactions, using whole-genome information from gene clusters, gene fusions and phylogenetic profiles. This structural and evolutionary view of entire genomes has provided a valuable approach for the functional characterization of proteins, especially those without sequence similarity to proteins of known function. Inference of gene function based on gene fusion events: the rosetta-stone method. inferred functional association networks obtained by gene fusion analysis Here we have applied gene fusion analysis to a number of recently sequenced protists, and in particular tried to infer interacting protein pairs in the pathogenic parasite Trypanosoma brucei. protein domain fusions in human protein interaction networks prediction Some proteins, involved in a common biological process and encoded by separate genes in one organism, can be found fused within a single protein chain in other organisms. By detecting these triplets, a functional relationship can be established between the unfused proteins. These results suggest that domain fusion is an appropriate method for predicting protein complexes. The detection of gene fusion events across genomes can be used for the prediction of functional associations of proteins, including physical interactions or complex formation. Interacting proteins encoded by separate genes in some species, may sometimes occur as a single, multi-domain fusion protein in other species. Detecting fusion of non-homologous proteins in another organism has been shown to be a significant predictor of functional association between genes These genomic constraints form the basis for a variety of techniques that employ systematic genome comparisons to predict functional associations among genes. The most powerful techniques to date are based on conserved gene neighborhood, gene fusion events, and common phylogenetic distributions of gene families Functional links between proteins can often be inferred from genomic associations between the genes that encode them: groups of genes that are required for the same function tend to show similar species coverage, are often located in close proximity on the genome (in prokaryotes), and tend to be involved in gene-fusion events. Recent progress in genome analysis has shown that it is possible to predict protein interactions or, more generally, functional associations of proteins using genome sequences alone [1,2,3]. These powerful methods rely on the observation that pairs of genes encoding proteins of known function (usually interacting or forming a complex) tend to be found in other species as a fused gene encoding a single multifunctional protein the detection of gene fusions in one genome (defined as 'composite' proteins) allows the prediction of functional associations between homologous genes that remain separate in another genome (defined as 'component' proteins). the accurate detection of a gene fusion event in one genome allows interactions to be predicted between many proteins in other genomes. It is this kind of one-to-many relationship that makes this method unique for discovering possible interactions or functional associations between proteins, even for those of unknown function. The exhaustive detection of gene fusion events in entire genome sequences allows the prediction of functionally associated components based merely on genome structure. Functional associations of proteins in entire genomes by means of exhaustive detection of gene fusions Genes linked by fusion events are generally of the same functional category a functional association between two genes can be derived from the existence of a fusion of the two as one continuous sequence in another genome Protein interaction maps for complete genomes based on gene fusion events Because there must be selective pressure for certain genes to be fused over the course of evolution, we are able to predict functional associations of proteins. We observed that gene fusion events are more related to physical interaction between proteins than to other weaker functional relationships such as participation in a common biological pathway. CONCLUSIONS: We illustrate the phylogenetic and functional diversity of gene fusion events across genomes, and their usefulness for accurate prediction of protein interaction and function. FusionDB provides a characterization of a large number of gene fusion events at hand of multiple sequence alignments. RESULTS: We present a novel method for identifying genes encoding for a specific metabolic function based on a local structure of metabolic network and multiple types of functional association evidence, including clustering of genes on the chromosome, similarity of phylogenetic profiles, gene expression, protein fusion events and others. Domain fusion analysis has been proposed recently to infer the functional association of the component proteins. BACKGROUND: It has recently been shown that the detection of gene fusion events across genomes can be used for predicting functional associations of proteins, including physical interaction or complex formation. Here we present a method that identifies gene-fusion events in complete genomes, solely based on sequence comparison. Finally, the domain fusion method [20,21,22,23] is based on the observation that distinct non-homologous genes are functionally related if their orthologs are fused in another organism Gene or domain fusion is one of several genome context methods which can be used to predict functional associations between pairs of proteins [1], [2]. Genome context methods allow inheritance of functional information between non-homologous proteins and are thus an orthogonal approach to homology-based methods of function prediction. Pairs of distinct genes that are fused in at least one genome have been termed fusion-linked [3]. A gene fusion is presumably fixed during evolution only when the partners cooperate functionally and, by inference, a functional link can be predicted to exist between fusion-linked genes. Identification of gene fusion events (F)Associations of genes can also be deduced with the Rosetta stone technique [13,14] by detecting gene fusion events. Two distinct genes of a given organism that are found fused as a continuous sequence (referred to as the Rosetta Stone sequence) in another genome tend to physically interact. Analysis of gene fusion/division events to infer functional relatedness, commonly known as the Rosetta Stone method, is illustrated in Figure 1, and has been described in detail elsewhere [17,18]. Proteins that carry out consecutive metabolic steps or are components of molecular complexes are often expressed as a single polypeptide chain to maximize kinetic or expression efficiency. The basis for domain fusion analysis is the observation that certain proteins found separately in a given organism, form one full-length protein in another organism through fusion events. The composite proteins are also known as Rosetta stones. The component proteins are expected to be linked functionally, if not also physically. Viewing multi-domain proteins as sequences of domains also enables the identification of gene fusion events, interacting proteins (7,8) and preferred domain associations (9–14), and the comparison of sequences of domains helps in obtaining clues about domain function. Because fused genes often have similar functions, identification of fusion events can aid in inferring gene functions. The Rosetta-Stone approach [6] is a method to predict function based on protein fusion events. Two polypeptides A and B in one organism are likely to interact if their homologs are expressed as a single polypeptide AB in another organism. For example, among the most reliable methods, the Rosetta stone technique [5,6] detects functional associations based on protein-domain fusion events. Two polypeptides A and B in one organism are likely to interact if their homologs are expressed as a single polypeptide AB in another. The latter polypeptide (AB) is called a Rosetta Stone protein, as it contains information about both A and B. </context> <question> How could we infer functional associations from gene fusion events? </question> <answer> </answer>
<context> De novo DNA methylation in Arabidopsis thaliana is catalyzed by the methyltransferase DRM2, a homolog of the mammalian de novo methyltransferase DNMT3. Three functional classes of DNA methyltransferase exist in A.thaliana; METHYLTRANSFERASE1 (MET1) (orthologous to mammalian Dnmt1) which maintains CG methylation, CHROMOMETHYLASE3 (CMT3) (plant specific) which maintains methylation in non-CG sequence contexts and DOMAINS REARRANGED METHYLTRANSFERASE2 (DRM2) (orthologous to Dnmt3a/Dnmt3b) which both de novo methylates DNA and maintains non-CG methylation redundantly with CMT3 [2]. The drm2 mutation blocks all de novo DNA methylation driven by repeat containing transgenes [15]–[17]. The mammalian DRM2 orthologs, Dnmt3a and Dnmt3b, are required to de novo methylate integrated retroviral sequences and imprinted genes [38], [39]. Here we describe DNA methyltransferase genes from both Arabidopsis and maize that show a high level of sequence similarity to Dnmt3, suggesting that they encode plant de novo methyltransferases. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity. The N termini of these methyltransferases contain a series of ubiquitin-associated (UBA) domains. BLASTX searches and phylogenetic analysis suggested that five cDNAs belonged to four classes (Dnmt1, Dnmt2, CMT and Dnmt3) of DNA methyltransferase genes. </context> <question> Are there any DNMT3 proteins present in plants? </question> <answer> yes </answer>
<context> ver the last few years, advances in methodology have made it possible to recover peptides from FFPE tissues that yield a reasonable representation of the proteins recovered from identical fresh or frozen specimens. Thus, laser capture microdissection of FFPE tissue coupled with downstream proteomic analysis is a valid approach Qualitative proteome profiling of formalin-fixed, paraffin-embedded (FFPE) tissue is advancing the field of clinical proteomics. Pressure-assisted protein extraction: a novel method for recovering proteins from archival tissue for proteomic analysis. provements in techniques such as mTRAQ have made relative quantitation of disease biomarkers in FFPE tissue possible. A variety of methods for profiling FFPE tissue have been employed recently. Some are practical for slide-mounted FFPE tissue, such as quantitative fluorescence imaging analysis (QFIA), which is reproducible and sensitive for specific standardized proteins,12−14 or MALDI-imaging mass spectrometry (MS).15−17 Other encouraging mass spectrometry (MS)-based proteomic studies of FFPE tissues have appeared in the recent literature;2−7,9,18−20 however, these investigations have typically been restricted to minute tissue specimens, such as those obtained by laser capture microdissection. Although the FFPE proteomic literature is still quite limited, it is not unreasonable to propose that the same situation applies to the proteomic analysis of FFPE tissues. The ability of elevated pressure to significantly improve the recovery of intact proteins from FFPE tissues over the use of heat alone has great potential for broad application to top-down proteomic studies for the identification of disease biomarkers. Toward deciphering proteomes of formalin-fixed paraffin-embedded (FFPE) tissues. Recent improvements in proteomics technologies, from the 2D gel analysis of intact proteins to the "shotgun" quantification of peptides and the use of isobaric tags for absolute and relative quantification (iTRAQ) method, have made the analysis of FFPE tissues possible. The ability to investigate the proteome of formalin-fixed, paraffin-embedded (FFPE) tissues can be considered a major recent achievement in the field of clinical proteomics. The label-free approach enables the quantitative measurement of radiation-induced alterations in FFPE tissue and facilitates retrospective biomarker identification using clinical archives. Proteomic analysis of formalin-fixed paraffin-embedded pancreatic tissue using liquid chromatography tandem mass spectrometry. We report that differentially expressed proteins can be identified among FFPE tissue specimens originating from individuals with different pancreatic histologic findings. Initial development and validation of a novel extraction method for quantitative mining of the formalin-fixed, paraffin-embedded tissue proteome for biomarker investigations. Formalin-fixed paraffin-embedded (FFPE) proteome analysis using gel-free and gel-based proteomics. This study will facilitate the development of future proteomic analysis of FFPE tissue and provide a tool for the validation in archival samples of biomarkers of exposure, prognosis and disease. The CAAR method presented here complements previously described antigen-retrieval protocols and is an important step in being able to fully analyze the proteome of archived FFPE tissue. Proteome, phosphoproteome, and N-glycoproteome are quantitatively preserved in formalin-fixed paraffin-embedded tissue and analyzable by high-resolution mass spectrometry. It has only recently been shown that proteins in FFPE tissues can be identified by mass spectrometry-based proteomics but analysis of post-translational modifications is thought to be difficult or impossible Results from the FFPE-FASP procedure do not indicate any discernible changes due to storage time, hematoxylin staining or laser capture microdissection. Thus, FFPE biobank material can be analyzed by quantitative proteomics at the level of proteins and post-translational modifications. A novel tissue microdissection technique has been developed and combined with a method to extract soluble peptides directly from FFPE tissue for mass spectral analysis of prostate cancer (PCa) and benign prostate hyperplasia (BPH). Hundreds of proteins from PCa and BPH tissue were identified, espite using tissue blocks stored for as many as 28 years, high confidence and comparative proteome analysis between the leiomyomas and the sarcoma is achieved. we expect that our conclusions regarding the equivalence of FFPE and frozen tissues apply to laser capture microdissected specimens. These results provide evidence that use of archival FFPE specimens for retrospective studies is possible. In 2005, Hood et al. (7) first described the successful application of shotgun proteome analysis to FFPE tissue. Using laser capture microdissected cells and an optimized extraction method, hundreds of proteins were identified from a cancerous prostate lesion and benign prostate hyperplasia, thus opening the door to comparative proteomic analyses of FFPE tissue. These findings demonstrate that formalin fixation, paraffin processing, and LCM do not negatively impact protein quality and quantity as determined by MS and that FFPE samples are amenable to global proteomic analysis. Protein extraction of formalin-fixed, paraffin-embedded tissue enables robust proteomic profiles by mass spectrometry. </context> <question> Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue? </question> <answer> yes </answer>
<context> Different cutaneous side effects have been described for anti-TNF-α therapy such as psoriasis Anti-TNF drug-induced alopecia is a less well-known side effect of this class of drugs. 3 patients who developed scalp alopecia Psoriasis and psoriatic arthritis induced in a patient treated with infliximab for Crohn's disease side effects appearing in about a fifth of the patients, including myelosuppression and liver toxicity Persistent corneal endothelial deposits associated with rifabutin therapy for Crohn's disease complained of alopecia 3 days after starting 6-mercaptopurine (6-MP) and then developed severe myelosuppression Leucopoenia was the more frequent side effect observed, occurring in 36 (34%) Nausea, vomit, although slight, occurred in 29 (27.4%) Nodular regenerative hyperplasia as a side effect of azathioprine in a patient with Crohn's disease The whole blood count revealed a pancytopenia, hyperbilirubinemia and slightly elevated transaminases Analysis of the liver histology was highly suggestive of an azathioprine-related, nodular regenerative hyperplasia 3 serious adverse events (SAEs) known to be associated with CD treatment (progressive multifocal leukoencephalopathy (PML), serious infections, and lymphoma) Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease A severe side effect is acute pancreatitis, which is specific for Crohn's disease Recurrent myopericarditis in association with Crohn's disease Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine Pancreatitis in a patient with Crohn disease treated with mesalazine and azathioprine Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease. resulted to watery stools, vomiting, and fever Eosionophilia was present and the lymphocyte stimulation test with mesalazine was positive Pericarditis as a side effect induced by sulfasalazine or 5-aminosalicylic acid The commonest side-effect was hyperaesthesia, but one patient developed nephrotoxicity and one developed hepatotoxicity The only troublesome side effect is paresthesia, which apparently is dose-related and not progressive The only major side effect observed was paresthesias. These occurred in 50% of the patients and developed in the patients at a mean of 6.5 mo after the onset of treatment. Hemolysis is not a rare side-effect of sulfasalazine therapy 17 of 40 (43%) patients with inflammatory bowel disease receiving sulfasalazine had evidence of hemolysis as detected by starch gel electrophoresis </context> <question> Which are the most widely reported side-effects in the treatment of Crohn's disease? </question> <answer> Leukopenia; paresthesia; psoriasis; alopecia; hemolysis; pancreatitis; liver toxicity; pericarditis </answer>
<context> Tissue kallikreins are a group of closely related serine proteinases that are represented by multigene families in mice and rats. Our map specifies the distance between genes to one base pair accuracy, the relative location, and the direction of transcription of all 15 genes. The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. The prognostic value of at least 11 out of 15 members of the human kallikrein family in ovarian cancer has been also published (Clements et al, 2004; Yousef et al, 2005; Prezas et al, 2006; Dorn et al, 2007). The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The 15 human and 24 mouse kallikreins have been implicated in pathophysiology of brain, kidney, and respiratory and reproductive systems and often are used as cancer biomarkers. Kallikrein gene families have been identified previously in genomes of the human, the mouse, and the rat, and individual kallikrein-like genes have been found in many more species. The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes. The tissue kallikrein gene family consists of 15 genes tandemly arranged on human chromosome 19q13.4. Human kallikreins are a cluster of 15 serine protease genes located in the chromosomal band 19q13.4, a non-randomly rearranged region in many solid tumors, including pancreatic cancer. Tissue kallikrein genes (KLKs) are found on chromosome 19q13.3-4 as a gene cluster encoding 15 different serine proteases. Kallikreins are a family of 15 genes clustered together on chromosome 19 (Yousef and Diamandis, 2001,2003) and encode for serine protease enzymes (Clements et al, 2001; Yousef and Diamandis, 2002b). The mRNA sequences of the 15 human kallikrein genes were used to identify unique sequence tags of UniGene clusters for each kallikrein (the GenBank reference sequences were used). Project to perform in silico analyses of the expression pattern of the 15 human KLK genes in normal and cancerous ovarian tissues and cell lines. Novel kallikrein genes were cloned recently, and it was shown that the human kallikrein family contains 15 genes tandemly aligned on chromosomal locus 19q13.3-q13.4. The human kallikrein gene family includes 15 serine protease genes, clustered on chromosome 19q13.4. The kallikrein genes, denoted KLK1–KLK15, are located on chromosome 19q13.4 and encode for corresponding kallikrein enzymes, hK1–hK15 (Diamandis et al, 2000a; Yousef et al, 2000b). The human kallikrein gene family consists of 15 serine proteases. We have recently characterized the human kallikrein gene locus on chromosome 19q13.4, which includes 15 kallikrein genes. The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. that forms the largest cluster of contiguous protease genes in the human genome. Amongst the genes in this region is a cluster of the kallikrein genes. Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases encoded by the largest uninterrupted cluster of protease-encoding genes within the human genome. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. The human tissue kallikrein gene family is the largest contiguous family of proteases in the human genome, containing 15 genes. Human tissue kallikrein genes represent the largest contiguous group of proteases within the human genome. Human tissue kallikreins (hKs), which are encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Human tissue kallikrein-related serine peptidases (KLKs) constitute a single family of 15 highly conserved trypsin- or chymotrypsin-like serine proteases encoded by the largest contiguous cluster of protease-encoding genes (KLK1-15) in the human genome mapped to chromosomal locus 19q13.4 [1]. These phylogenies suggest that, apart from the fifteen “conventional” KLK family members, three ‘orphan’ KLKs are present in anole lizard. The lizard KLK orphans appear to arise from the basal node (Figure 4) leading to the suggestion that they are the members of the KLK family that diverged earliest (“proto-KLKs”). </context> <question> How many tissue kallikrein genes are present in the human genome? </question> <answer> 15 </answer>
<context> The topologies of the trees were overall congruent: four monophyletic groups corresponding to the four plant C5-MTase families were clearly distinguished. In addition, sequence analyses of the plant C5-MTase target recognition domain sequences were performed and phylogenetic trees were reconstructed showing that there is good conservation among but not within the plant C5-MTase families. To determine the inheritance of DNA methyltransferase genes and their expression patterns we examined three major DNA methyltransferase families (MET1, CMT3 and DRM) from tobacco and the progenitor species. However, phylogenetic analysis indicates that the Dnmt3 and DRM protein families diverged independently in plants and mammals (Figure 1A). Although an intriguing parallel exists between the functional relationships of DRM2/DRM3 and Dnmt3a/Dnmt3L, phylogenetic analysis strongly suggests that these protein families diverged independently in plants and animals (Figure 1A). The comparative investigation of transcription levels of different genes of cytosine DNA methyltransferase family MET (MET1, MET2a, MET2b, MET3) and their methylation patterns shows that there may exist some mechanisms defending the most actively transcribed gene MET1 of this family from methylation mediated silencing. In contrast to DRM2 gene we could not find any adenine methylated GATC sites in the MET1 gene. Using the 1kb 3' terminal DNA fragment of the mouse methyltransferase cDNA as a probe and low stringent hybridisation conditions, a new potential methyltransferase (MTase) gene family was isolated from an Arabidopsis thaliana genomic DNA library. The Dnmt3 family of de novo DNA methyltransferases has recently been characterized in animals. Here we describe DNA methyltransferase genes from both Arabidopsis and maize that show a high level of sequence similarity to Dnmt3, suggesting that they encode plant de novo methyltransferases. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity. These results provide the first direct demonstration that DNA-METases of a higher eukaryote are encoded by a gene family. Here we show that Arabidopsis DNA methyltransferase2 (AtDNMT2) is localized in nucleus and associates with histone deacetylation. To explore possible relationships between DNA methylation level and accumulation of DNA-(cytosine-5) methyltransferase (DNMT) transcripts, the full-length coding sequences corresponding to three different DNMT families in oil palm, namely the MET, CMT, and DRM classes, have been isolated and characterized. In Arabidopsis a SWI2/SNF2 chromatin remodeling factor-related protein DDM1 and a cytosine methyltransferase MET1 are required for maintenance of genomic cytosine methylation. Relative to all known eukaryotic methyltransferases, these plant proteins contain a novel arrangement of the motifs required for DNA methyltransferase catalytic activity. In the present study, the isolation and characterization of two distinct cDNAs that code for carrot DNA (cytosine-5)-methyltransferase (DNA-METase) are reported. The Arabidopsis methylase has eight of the ten conserved sequence motifs found in prokaryote cytosine-5 methyltransferases and shows 50% homology to the murine enzyme in the methyltransferase domain. As deduced form the DNA sequence this protein contains all conserved sequence motifs specific for the 5m cytosine MTases. </context> <question> Which are the plant DNA (cytosine-5) methyltransferase families? </question> <answer> MET; CMT; DRM </answer>
<context> miR-21* and miR-203 were significantly dysregulated (P < 0.05) in PTC tissues with BRAFV600E. Expressions of miRNAs in papillary thyroid carcinoma and their associations with the BRAFV600E mutation. Levels of miRNA-21 (miR-21) and miR-106a in gastric cancer tissues were significantly higher compared with the levels in adjacent tissues (P = .006 and P = .001, respectively). Patients who had gastric cancer had significantly different levels of gastric juice miR-21 and miR-106a compared with patients who had benign gastric diseases (both P < .001). miR-21 levels in intestinal type gastric cancer specimens were higher than that in diffuse (P = .003) or mixed (P < .001) gastric cancer types. MiR-155 and miR-21 appeared significantly over-expressed in the colonic mucosa of IBD subjects without CRC, but also in neoplastic tissues of IBD patients compared to non-IBD controls (p<0.001). Importantly, in patients with IBD-CRCs, miR-155 and miR-21 over-expression extended to the distant non-neoplastic mucosa (p<0.001). Here we hypothesize that over-expression of miR-155 and miR-21, two inflammation-related miRNAs that target core MMR proteins, may constitute a pre-neoplastic event for the development of MSI IBD-CRCs. After administration, we determined the expressions of miR-21, miR-27a, miR-34a, miR-93, miR-143, miR-146a, miR-148a, miR-155, miR-196a, miR-203, miR-205, miR-221 and nuclear factor kappa-light-chain enhancer of activated B-cells-1 (Nfκb1), mitogen-activated protein kinase-8 (Mapk8) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) genes in the liver of mice. Programmed cell death 4 (PDCD4) is a tumor suppressor gene whose expression is controlled by miR-21. Consistently with PDCD4 downregulation, miR-21 was upregulated in neoplastic by comparison with nonneoplastic tissue samples. Expression of miR-21 (p=0.027), miR-181b (p=0.002), and miR-146b (p=0.021) in tumor tissue and miR-21 (p=0.003) in noncancerous tissue were associated with patients' overall survival. We analyzed the expression of nine miRNAs (miR-21, miR-127, miR-154, miR-224, miR-323, miR-370, miR-9, miR-183, and miR-375) by quantitative real-time-polymerase chain reaction in 34 cases of sMTC, 6 cases of hMTC, and 2 cases of C-cell hyperplasia (CCH). MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323, 6.1-fold for miR-370, 13-fold for miR-9, 6.7-fold for miR-183, and 10.1 for miR-375, p<0.0001). As demonstrated in Figure 3A, the five miRNAs (mir-21, mir-223, mir-224, mir-29A and mir-29B) were significantly up-regulated in CRC tissues, except for mir-27a due to non-efficient amplification (CT value in most of the samples was either higher than 35 or even cannot be defined). The most frequent changes in miRNAs in CLL cells included downregulation of miR-126, miR-572, miR-494, miR-923, miR-638, miR-130a, miR-181a and miR-181b and up-regulation of miR-29a, miR-660, miR-20a, miR-106b, miR-142-5p, miR-101, miR-30b, miR-34a, miR-let-7f, miR-21 and miR-155. Results: MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323 and 6.1-fold for miR-370, 13-fold for miR-9, 6.7-fold for miR-183 and 10.1 for miR-375, p<0.0001). We found that the onco-miRNAs miR-21 and miR-221 displayed upregulated expression while the liver-specific miR-122 was downregulated. The aim of the present review was to describe the mechanisms of several known miR, summarize recent studies on oncogenic miR (e.g. miR-21, miR-106a and miR-17), tumor suppressor miR (e.g. miR-101, miR-181, miR-449, miR-486, let-7a) and controversial roles of miR (e.g. miR-107, miR-126) for gastric cancer. MiR-15b and miR-21 were differentially expressed in CSF samples from patients with gliomas, compared to control subjects with various neurologic disorders, including patients with primary CNS lymphoma and carcinomatous brain metastases. Moreover, inclusion of miR-15b and miR-21 in combined expression analyses resulted in an increased diagnostic accuracy with 90% sensitivity and 100% specificity to distinguish patients with glioma from control subjects and patients with primary CNS lymphoma. Many aberrantly expressed miRNAs were related to various cancers (e.g., miR-125b, hepatocellular carcinoma; miR-21, leukemia; miR-16, chronic lymphocytic leukemia; miR-192, pituitary adenomas; miR-199a-3p, ovarian cancer; miR-34a, pancreatic cancer). Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. In addition, diet and carcinogen exposure modulated a number of microRNAs (miR-16, miR-19b, miR-21, miR26b, miR27b, miR-93, and miR-203) linked to canonical oncogenic signaling pathways. RESULTS: Elevated miR-21 (HR 2.06, 1.13-3.75), miR-17 (HR 2.00, 1.10-3.61), and miR-155 (HR 2.37, 1.27-4.42) was associated with worse cancer-specific mortality in the Maryland cohort. NF-κB targets miR-16 and miR-21 in gastric cancer: involvement of prostaglandin E receptors. Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. hese two miRNAs have previously been identified as being overexpressed in MCF-7 breast cancer cells, with miR-21 specifically implicated in down-regulating the tumor suppressor gene, tropomyosin-1. MicroRNA-21 is involved in ionizing radiation-promoted liver carcinogenesis. We showed here that among several hundred miRNAs, miR-21 was the only one that increased 6 folds in high-LET IR-promoted mouse liver tumors when compared with that in the non-irradiated liver tissues. We also showed that miR-21 was up-regulated in human or mouse hepatocytes after exposure to IR, as well as in liver tissues derived from whole body irradiated mice. After the non-irradiated, low-LET or high-LET irradiated human hepatocytes were over-expressed with miR-21, these cells became tumorigenesis in nude mice. Among others, the oncogenic microRNA miR-21 (hsa-miR-21) has been shown to specifically target the PDCD4 3′-UTR, which negatively regulates PDCD4 expression. 19–24 PDCD4 protein levels have been found to be inversely correlated with miR-21 expression in oesophageal squamous cell carcinoma cell lines,18 and we have shown that PDCD4 expression is significantly downregulated in oesophageal cancers (adenocarcinoma and squamous cell carcinoma histotypes) and it predicts patient outcome. Figure 4miR-21 is overexpressed in high-grade intraepithelial neoplasia (HG-IEN) and Barrett's adenocarcinoma (BAc). The nuclear-to-cytoplasm shift documented in preneoplastic/neoplastic lesions could theoretically result from epigenetic (and/or genetic) gene dysregulation.In oesophageal squamous carcinoma cell lines, Hiyoshi et al recently demonstrated that PDCD4 gene expression is regulated by miR-21. miR-21 is overexpressed in different human cancers, being causally linked to cell proliferation, apoptosis and migration. 14–19 miR-21 was also found to be upregulated in both oesophageal adenocarcinoma and squamous cell carcinoma,18 40 41 suggesting a major oncogenic function for miR-21 (acquired early in both of these oncogenic pathways). METHODS: We used this combined ISH/IHC assay to study a subset of cancer-associated miRNAs, including miRNAs frequently detected at low (miR-34a and miR-126) and high (miR-21 and miR-155) levels, in a panel of breast, colorectal, lung, pancreas, and prostate carcinomas. The miR-15a, miR-16, miR-143, miR-155, and miR-21 were upregulated in M059K, and the modulation of these miRNAs fluctuated in M059J cells in a time-dependent manner. Aberrantly increased expression of miR-21 plays a significant role in lung carcinogenesis and is a potential therapeutic target in both epidermal growth factor receptor-mutant and wild-type cases. Additionally, high miR-21 expression was associated with significantly decreased 5 year survival in patients (hazard ratio, 1.68; 95% CI: 1.04-2.77) in a model controlled for patient age, gender and tumor stage. ESULTS: In adenocarcinoma patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, whereas miR-203 expression was reduced in cancerous compared with noncancerous tissue. Significantly, elevated miR-21 expression in noncancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of adenocarcinoma patients with Barrett's were strongly associated with worse prognosis. miR-21, mir-31, miR-130a, miR-146b and miR-377 were consistently upregulated, whereas miR-1 and miR-143 were downregulated in lung tumors relative to normal lungs. In mice treated with VC and given I3C in the diet, levels of miR-21, mir-31, miR-130a, miR-146b and miR-377 were reduced relative to the level in mice treated with the carcinogen only. Further studies with miR-21 indicated that phosphatase and tensin homolog, programmed cell death 4 and rich protein with Kazal motifs are potential targets for the oncogenic effect of miR-21 and the chemopreventive activity of I3C. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined miR-21 expression. CONCLUSIONS: IRS and miR-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high-risk patients. Figure 4qRT-PCR analysis of miR-21 and miR-16 in three cancer and three normal tissues. Correlation with cancersquamous cell carcinoma vs normal cheek pouch tissuehsa-miR-212. Using miRNA microarray analysis, Chang et al. identified seven miRNAs that were up-regulated (mir-21, let-7, 18, 29c, 142-3p, 155, and 146b) and one miRNA that was down-regulated (mir-494) in HNSCC primary tissue and cell lines. Moreover, they demonstrated that cytochrome c release was decreased by mir-21 knockdown, which suggested mir-21 inhibited several mRNAs that then led to a cascade of events that prevented apoptosis and increased cellular proliferation [35] The most highly expressed miRNAs in gastric cancer tissues were miR-20b, miR-20a, miR-17, miR-106a, miR-18a, miR-21, miR-106b, miR-18b, miR-421, miR-340, miR-19a and miR-658. Recent findings report their involvement in hair follicle morphogenesis (ablation of miRNAs from keratinocytes causes several defects, such as evagination instead of invagination), in psoriasis (skin-specific expression of miR-203 and psoriasisspecific expression of miR-146a, miR-21 and miR-125b in the skin), in autoimmune diseases affecting the skin, such as SLE and ITP, in wound healing (changes in the expression of specific miRNA at specific phases of the regeneration process), and in skin carcinogenesis (a novel miRNA signature that includes induction of miR-21, a candidate oncogenic miRNA). An expression abundance analysis, based on a signal density ≥20,000, showed that both normal and cancerous cervical tissues had abundant expression of miR-23a, miR-23b, let-7a, let-7c, and let-7d, whereas high expression of miR-26a, miR-29a, miR-99a, miR-100, miR-125b, miR-143, miR-145, miR195, and miR-199a was only observed in normal cervical tissues, and high expression of miR-16, miR-21, miR-205, and let-7f was only observed in cervical cancer tissues, despite that relatively low levels of miR-16 and miR-21 were noticed from a homogeneous cell population in some cell lines (Fig. 2B). Although upregulation of miR-15a and miR-223 and downregulation of miR-218 and miR-424 were observed both in the rafts (pre-neoplastic lesions) and in cervical cancer tissues, the majority of the miRNA expression signatures showed no correlation between the two tissues (compare Fig. 4A to Fig. 3A). In contrast, a slight increased expression of miR-21 and miR-26b was observed in both the pre-neoplastic lesions (HPV-infected rafts) and cervical cancer tissues and thus their expression appears not cancer-specific (Fig. 5). Although both cervical cancer tissues and HPV-infected raft tissues with pre-neoplastic lesions showed an upregulation of miR-15a and miR-223 and downregulation of miR-143, miR-145, miR-218, and miR-424, the majority of the miRNA expression showed no correlation between the two tissues and might delineate the disease progression. RESULTS: Several microRNAs were differentially expressed in serous ovarian carcinoma compared with normal ovarian tissues, including miR-21, miR-125a, miR-125b, miR-100, miR-145, miR-16, and miR-99a, which were each differentially expressed in >16 patients. Selected for validation were miR-20a, miR-21, miR-106a, miR-181b, and miR-203, and all 5 were enriched in tumors from the validation cohort (P < .001). Higher miR-21 expression was present in adenomas (P = .006) and in tumors with more advanced TNM staging (P < .001). In situ hybridization demonstrated miR-21 to be expressed at high levels in colonic carcinoma cells. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growth-inhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that approximately 30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Conversely, expression of other miRNAs was detected at varying levels predominantly within luminal epithelial cells in normal tissue; expression of miR-21 was frequently increased, whereas that of let-7a was decreased in malignant cells. We describe a novel EMT-specific microRNA signature that includes induction of miR-21, a candidate oncogenic microRNA associated with carcinogenesis. Notable was the high expression of miR-21 and miR-205. Recently, microRNAs (miRNAs) have emerged as key actors in carcinogenesis and we demonstrated that microRNA-21 (miR-21), oncomiR is expressed early during PDA. These results indicated that miR-21 plays a role in the carcinogenesis and metastasis of O. viverrini-associated CCA by suppressing the function of PDCD4. Importantly, in patients with IBD CRCs, miR-155 and miR-21 overexpression extended to the distant non-neoplastic mucosa (P < 0.001). Ectopic overexpression of miR-21 promoted Akt activation and phosphorylation of EZH2, whereas inhibiting miR-21 by transfecting the cells with anti-miR-21 inhibited Akt activation and EZH2 phosphorylation. PDCD4 nuclear down-regulation (which parallels miR-21 up-regulation) is involved in the molecular pathway of IBD-associated carcinogenesis. The expression levels of miR-21 (p = 0.027), miR-181b (p = 0.002) and miR-146b (p = 0.021) in tumor tissue and miR-21 (p = 0.003) in noncancerous tissue were associated with overall survival of patients. For instance, Schetter and colleagues showed that miR-21 corresponded to colorectal cancer related mortality [15]. MiR-21 is an oncogenic microRNA with known roles in inflammation, cell proliferation and tumorigenesis. OBJECTIVE: As an important oncogenic miRNA, miR-21 has been reported to play crucial roles in glioblastoma (GBM) carcinogenesis. We further analyzed the expression of microRNA-21 (miR-21), an oncogenic noncoding RNA involved in oncogenic Ras signaling, by quantitative reverse-transcription polymerase chain reaction and in situ hybridization. MicroRNA-21 (miR-21) plays crucial roles in carcinogenesis and is considered as one of the most studied oncomiRNAs. Although microRNA-21 (miR-21) has been implicated in various aspects of carcinogenesis, its functions and molecular mechanisms in carcinogen-induced tumorigenesis are unclear. Substantial evidence indicates that microRNA-21 (miR-21) is a key oncomiR in carcinogenesis and is significantly elevated in multiple myeloma (MM). MicroRNA 21 (miR-21) has been implicated in various aspects of carcinogenesis. Conversely, pAkt and miR-21 expression was significantly up-regulated in the whole spectrum of preneoplastic/neoplastic lesions considered. Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. RESULTS: Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. MicroRNA 21 (miR-21) is overexpressed in virtually all types of carcinomas and various types of hematological malignancies. However, the potential novel target gene of miR-21 in radiation induced carcinogenesis is still unclear. As expected, miR-21 expression was significantly upregulated in preneoplastic/neoplastic samples, consistent with PDCD4 downregulation. Furthermore, miR-21 levels in the primary tumours correlated with disease stage (P < 0.0001). We found that miR-16 and miR-21 were upregulated upon nicotine stimulation, transfection with anti-miR-16 or anti-miR-21 significantly abrogated cell proliferation. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Although altered expressions of miR-21 and miR-34a were manifested within cancer cells, those of miR-126 and miR-155 were predominantly confined to endothelial cells and immune cells, respectively. However, the function of miR-21 in osteosarcoma is still unclear. Specifically, miR-21 is overexpressed in very diverse types of malignancy. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared with noncancerous tissue. miR-21, mir-31, miR-130a, miR-146b and miR-377 were consistently upregulated, whereas miR-1 and miR-143 were downregulated in lung tumors relative to normal lungs. Precancerous adenomas also frequently showed miR-21 up-regulation. Higher miR-21 expression was present in adenomas (P = .006) We aimed to identify whether four miRNAs (miR-223, miR-21, miR-218 and miR-25) closely associated with the tumorigenesis or metastasis of GC can serve as novel potential biomarkers for GC detection. Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some upregulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. OBJECTIVE: MicroRNA-21 (miR-21) is one of the miRNAs that are frequently and highly overexpressed in tumor tissue of colorectal cancer (CRC) patients; however, only a little is known about its functional role in CRC. Inhibition of microRNA-21 (mir‑21) induced upregulation of Spry2 and PTEN which underscores the importance of mir-21 in Spry2-associated tumorigenesis of the colon. During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. The microRNA miR-21, a known oncogenic miRNA, was found to be upregulated in papillary and clear cell carcinomas. Since microRNA-21 (miR-21) may contribute to tumorigenesis and chemoresistance in many cancer types, we aimed to investigate its efficacy in TCCs. In both HIV associated dementia in humans and its monkey model SIV encephalitis we find miR-21, a miRNA largely known for its link to oncogenesis, to be significantly upregulated in the brain. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some up-regulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. The aim of this study was to determine whether microRNA-21 (miR-21), a specific microRNA implicated in multiple aspects of carcinogenesis, impacts breast cancer invasion by regulating the tissue inhibitor of metalloproteinase 3 (TIMP3) gene. The microRNA-21 (miR-21) has been identified as the only miRNA overexpressed in a variety of cancers, including leukemia. Aberrant expression of microRNAs (miRNAs), including miR-21, and alteration of their target genes stability have been associated with cellular transformation and tumorigenesis. OBJECTIVE: The contribution of overexpressed microRNA-21 and -221 (miR-21 and miR-221) to the malignant phenotype was determined by inhibiting these miRNAs using antisense oligonucleotides. The microRNA-21(miR-21) has been identified as the only miRNA over-expressed in a wide variety of cancers, including cervical cancer. To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) targeting miR-21 (ASO-21) and/or miR-155 (ASO-155) in NK-cell lymphoma lines overexpressing one or both of these miRNAs. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., up-regulated miR-21) and unidentified (e.g., down-regulated miR-138) in those smoker cases. The oncogenic miRNA, microRNA-21 (miR-21), was found to be upregulated in laryngeal carcinoma tissues. OBJECTIVE: To better understand microRNA miR-21 function in carcinogenesis, we analyzed miR-21 expression patterns in different stages of colorectal cancer development using in situ hybridization (ISH). Of these miRNAs, miR-21 appears to be important in tumorigenesis given its up-regulation in almost all types of human cancer examined. The microRNA-21 gene (mir-21) has been identified as the only miRNA commonly overexpressed in solid tumors of the lung, breast, stomach, prostate, colon, brain, head and neck, esophagus and pancreas. RESULTS: Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis. To search for tumor-associated mutations that could affect processing and expression of mature miRNAs, a panel of 91 cancer-derived cell lines was analyzed for sequence variations in 15 miRNAs implicated in tumorigenesis by virtue of their known target transcripts (let-7 family targeting oncogenic Ras) or their localization to sites of frequent chromosomal instability (miR-143, miR-145, miR-26a-1, and miR-21). Volinia et al. (2006) conducted a large-scale microarray analysis on six solid tumors (including lung, breast, stomach, prostate, colon, and pancreatic tumors) and identified a common miRNA signature for solid tumors largely composed of overexpressed miRNAs, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155 (45). </context> <question> Is miR-21 related to carcinogenesis? </question> <answer> yes </answer>
<context> antifungal protein KP4 Killer protein 4 (KP4) is a well studied viral toxin secreted by the maize smut fungus Ustilago maydis that kills sensitive Ustilago strains as well as inhibits Fusarium and plant root growth by inhibiting calcium uptake. Our previous work on a virally encoded fungal toxin, KP4, from Ustilago maydis and subsequently with the plant defensin, MsDef1, from Medicago sativa demonstrated that some of these proteins specifically blocked calcium channels in both fungi and animals. The results presented here demonstrate that KP4 and three plant defensins, MsDef1, MtDef2, and RsAFP2, all inhibit root growth in germinating Arabidopsis seeds at low micromolar concentrations . There are three well-characterized killer toxins in U. maydis-KP1, KP4, and KP6-which are secreted by the P1, P4, and P6 subtypes, respectively. These killer toxins are small polypeptides encoded by segments of an endogenous, persistent double-stranded RNA (dsRNA) virus in each U. maydis subtype. The viral gene for the killer protein 4 (KP4) has been explored for its antifungal effect antifungal protein KP4 from Ustilago maydis-infecting virus The antifungal activity correlated with the presence of the KP4 transgene. These results suggest that KP4 may inhibit cell growth and division by blocking calcium-regulated signal transduction pathways. KP4 is a virally encoded fungal toxin secreted by the P4 killer strain of Ustilago maydis. KP4 is a virally encoded fungal toxin secreted by the P4 killer strain of Ustilago maydis. Our results defining the type of mammalian channel affected by this fungal toxin further support our contention that KP4 inhibits fungal growth by blocking transmembrane calcium flux through fungal calcium channels, Killer toxins are polypeptides secreted by some fungal species that kill sensitive cells of the same or related species. In the best-characterized cases, they function by creating new pores in the cell membrane and disrupting ion fluxes KP4 is a virally encoded and highly specific toxin that kills fungi closely related to the fungus Ustilago maydis. The P4 strain of the corn smut fungus, Ustilago maydis, secretes a fungal toxin, KP4, encoded by a fungal virus (UMV4) that persistently infects its cells. These results led to experiments demonstrating that the toxin specifically inhibits voltage-gated Ca2+ channels in mammalian cells. Ustilago maydis killer toxins are small polypeptides (7-14 kDa) which kill susceptible cells of closely related fungal species. The KP4 toxin is a single polypeptide subunit with a molecular weight of 11.1 kDa </context> <question> What is the function of the viral KP4 protein? </question> <answer> The virally encoded fungal toxin KP4 specifically blocks L-type voltage-gated calcium channels. </answer>
<context> higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Two of them received etanercept and the remainder adalimumab. with a possible differential risk between the three anti-TNF drugs: infliximab (INF) and adalimumab (ADA) (both monoclonal antibodies) having a higher risk than etanercept (ETA) 45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) During the period of recruitment, etanercept was administered as a subcutaneous injection either once (50 mg) or twice (25 mg) weekly and adalimumab was administered as a subcutaneous injection 40 mg fortnightly The suggested starting dose of infliximab was 3 mg/kg administered in conjunction with MTX Of these, 4458 (41%) started etanercept, 3956 (36%) infliximab and 2579 (23%) adalimumab as their first anti-TNF drug Second anti-TNF (n = 331)Etanercept (%)4445Infliximab (%)3717Adalimumab (%)1938 </context> <question> Which is the most widely used anti-TNF drug? </question> <answer> Etanercept </answer>
<context> The histone marks appeared mainly in generic regions and were enriched around the transcription start sites (TSSs) of genes Tri-methylated H3 lysine 4 (H3K4me3) is associated with transcriptionally active genes, but its function in the transcription process is still unclear However, the catalytic function is critically required for transcription as H3K4me3 levels determine the efficiency of transcription elongation In particular, tri-methyl H3K4 (H3K4me3) occurs at the transcription-start site (TSS) of active genes and is important for transcription activation Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised promoters. Histone H3 lysine 4 trimethylation (H3K4me3) is well known to occur in the promoter region of genes for transcription activation 3'-H3K4me3 is associated with ~15% of protein-coding genes in both tissues Furthermore, 3'-H3K4me3 modification levels correlate positively with the antisense expression levels of the associated sense genes, implying that 3'-H3K4me3 is involved in the activation of antisense transcription. indicated that H3K4me1, but not H3K4me3, was enriched around distal cis-elements for the E1A binding protein p300 (EP300), while both modifications were enriched at promoters Among these are forms of histone 3 that are mono- or tri-methylated at lysine 4 (H3K4me1 or H3K4me3, respectively), which bind preferentially to promoter and enhancer elements in the mammalian genome we find that H3K4me1 and H3K4me3 are enriched at transcriptional start sites in the genome H3K4me1 and H3K4me3 generally mark cis regulatory elements </context> <question> Is the H3K4me3 histone mark related to transcriptional initiation or elongation? </question> <answer> transcriptional initiation </answer>
<context> Using H3K4me2 as a mark for active enhancers Hyperacetylation of histones H3 and H4, a mark of active chromatin, is established broadly across target loci by enhancers that function over long distances The enhancer region itself was marked by mono-methylation at K4 and K9, distinguishing it from the methyl marks in the gene coding region H3K4 methylation to monovalent and bivalent domains </context> <question> Which are the main histone modifications associated with enhancers? </question> <answer> Histone 3 lysine 4 mono-methylation (H3K4me1); Histone 3 lysine 4 di-methylation (H3K4me2) </answer>
<context> In group 2 and 3, two anomalies, anorectal malformation and cystic fibrosis, were detected postnatally Six had chromosomal/genetic abnormalities, two had congenital cytomegalovirus, none had cystic fibrosis Primary bowel pathology is rare following the finding of FEB Maternal serology for cytomegalovirus (CMV) was performed in 49 (78%) cases Thirty-three pregnancies (53%) were tested for cystic fibrosis (CF) and 1 baby was confirmed to have CF postnatally This study reiterates the increased prevalence of aneuploidy, CMV, CF and fetal growth restriction in pregnancies complicated by the midtrimester sonographic finding of FEB Primary outcomes were IUGR, defined as birth weight less than the 10th percentile for gestational age and intrauterine fetal demise at 20 weeks or more of gestatio Analyses were repeated after excluding cases of aneuploidy, cytomegalovirus (CMV) infection, The presence of echogenic bowel on ultrasonography is independently associated with an increased risk for both IUGR and intrauterine fetal demise This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis A disorder was diagnosed in 32.2% of the fetuses, cystic fibrosis being the most commonly identified (7.6%). We also found digestive malformations (7.0%), chromosomal abnormalities (3.7%), and maternofetal infections (3.7%). A potential association with placental abnormalities and a low prevalence of viral infections was observed Our data suggests an inverse relationship between the maternal BMI and the detection of fetal EIF and/or EB Fetal echogenic bowel at 17 weeks' gestational age as the early and only sign of a very long segment of Hirschsprung disease. fetal ultrasound findings associated with intrauterine cytomegalovirus (CMV) infection the combination of hydrops fetalis, cerebral hemorrhage, and hyperechoic bowel should raise the possibility of a CMV infection strongly associated with adverse pregnancy outcome due to utero-placental insufficiency, particularly in women with elevated maternal serum alpha-fetoprotein concentration due to severe feto-maternal bleeding Congenital cytomegalovirus infection presenting with echogenic bowel and oligohydramnios. Five cases of trisomy 21 and one case of trisomy 18 were detected Brightly echogenic bowel in the second trimester was found to be associated with a significant risk of fetal aneuploidy. echogenic bowel does not uniformly herald an abnormal outcome. Echogenic bowel coexistent with other abnormalities (such as growth deficiency or structural malformations) may be a comarker for aneuploidy. Congenital cytomegalovirus infection with oligohydramnios and echogenic bowel at 14 weeks' gestation Parental CF carrier testing and amniocentesis to identify aneuploidy or fetal CF status has a high positive ascertainment rate in fetuses with echogenic bowel grades 2 and 3. Swallowing of amniotic fluid after intraamniotic bleeding seems implicated in the etiology of second-trimester echogenic bowel in both euploid and aneuploid fetuses Fetal echogenic bowel and a dilated loop of bowel associated with cystic fibrosis (CF) mutations delta F508 and 2183AA-->G Fifteen cases (19%) were associated with maternal vaginal bleeding Five fetuses (6.3%) had evidence of bowel obstruction or perforation not associated with cystic fibrosis (CF) Chromosomal aberrations were found in 5 fetuses (6.3%). Intrauterine infection with cytomegalovirus, herpes simplex virus, varicella-zoster virus, or parvovirus B-19 was documented in 5 patients (6.3%). Fetal echogenic bowel has been reported as a normal variant in the second trimester, and has also been associated with an adverse fetal outcome, including cystic fibrosis (CF) Intra-amniotic bleeding can lead to echogenic bowel 112 cases (57%) had a known etiology, which included chromosomal abnormality (7%), infection (4%), cystic fibrosis (1.5%), bowel abnormality (3%), bleeding or stained amniotic fluid (11%), Doppler abnormality (14%), malformation (16%) and miscellaneous (0.5%) </context> <question> Which are the main causes of fetal echogenic bowel? </question> <answer> Itramniotic bleeding; CMV infection; Cystic Fibrosis (CF); Fetal aneuploidy </answer>
<context> our analysis indicates that the association of CGIs with housekeeping genes is not as strong as previously estimated CpG islands are preferentially located at the start of transcription of housekeeping genes and are associated with tissue-specific genes It has been envisaged that CpG islands are often observed near the transcriptional start sites (TSS) of housekeeping genes. These regions represent about 1% of genomic DNA and are generally found in the promoter region of housekeeping genes. CpG islands are stretches of DNA sequence that are enriched in the (CpG)n repeat and are present in close association with all housekeeping genes as well as some tissue-specific genes in the mammalian genome. CpG islands, which are found almost exclusively at the 5'-end of housekeeping genes In housekeeping and many tissue-specific genes, the promoter is embedded in a so-called CpG island. All housekeeping and widely expressed genes have a CpG island covering the transcription start, whereas 40% of the genes with a tissue-specific or limited expression are associated with islands Methylation-free CpG clusters, so-called HTF islands, are most often associated with the promoter regions of housekeeping genes, whereas genes expressed in a single-cell type are usually deficient in these sequences. Unmethylated CpG rich islands are a feature of vertebrate DNA: they are associated with housekeeping and many tissue specific genes. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes. </context> <question> Are CpG islands located close to housekeeping genes? </question> <answer> yes </answer>
<context> the cannonical polyadenylation signal sequence AATAAA Two AATAAA motifs are coded in the last exon of this gene The results demonstrate that the intact AAUAAA is not required for RNA polyadenylation but is required for the cleavage step preceding polyadenylation to occur efficiently the early poly(A) consensus signal was mutated from AAUAAA to UGUAAA Functional polyadenylation [poly(A)] sites consist of two sequence elements, the AAUAAA and G/U box signals, that closely flank the site of mRNA 3'-end formation the appropriate spacing of the AAUAAA and G/U box signals is critical for poly(A) site function Two AATAAA hexanucleotide sequences are present in the 2092 nucleotide interval. The first one functions as the major polyA signal </context> <question> What is the most prominent sequence consensus for the polyadenylation site? </question> <answer> AATAAA; AAUAAA </answer>
<context> yeast origins are characterized by an asymmetric pattern of positioned nucleosomes flanking the ACS. The origin sequences are sufficient to maintain a nucleosome-free origin; however, ORC is required for the precise positioning of nucleosomes flanking the origin. ORC binds to Nucleosome free regions (NFRs) in both budding yeast and Drosophila (1,37,38), suggesting that nucleosome organization may be a defining feature of origins in all eukaryotes the presence of a well-positioned nucleosome adjacent to the origin NFR was shown to be essential for ORC to nucleate pre-RC assembly and for origin activity Together, our results demonstrate significant enrichment of pre-RC proteins at regions of generally low nucleosome occupancy that are found within a de-localized region of initiation Here, we identify nucleosome occupancy as a likely candidate to set up ORI distribution we demonstrate that open chromatin domains, characterized by nucleosome depletion, are preferentially permissive for replication Nucleosome assembly of the template prevented DNA replication. Replication of chromosomes was severely inhibited at more than two-thirds of physiological nucleosome density </context> <question> Are nucleosomes positioned at DNA replication origins? </question> <answer> no </answer>
<context> he etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain, although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses. Subacute thyroiditis is an inflammatory disorder of the thyroid caused probably by viruses. I We believe that the etiologic agent was the Epstein-Barr virus because heterophile and Epstein-Barr virus-specific antibodies were positive. ltogether, these results indicate that the mechanism of inhibition of Spumavirinae infection by interferon differs from that described for the other Retroviridae, and particularly for types B, C and D viruses. Our data is of therapeutic interest since Spumavirinae have been linked to pathological processes such as de Quervain thyroiditis. </context> <question> Are viruses involved in the etiology of human subacute thyroiditis? </question> <answer> yes </answer>
<context> we identified three interferon-stimulated genes (ISGs; Ifi27, Irg1 and Rsad2 (also known as Viperin)) that mediated the antiviral effects against different neurotropic viruses IRG1 is highly upregulated in murine ANA-1 macrophages by several proinflammatory cytokines and Toll-like receptor (TLR) agonists, as well as in spleen and lung of Listeria monocytogenes or Toxoplasma gondii infected mice, respectively The proinflammatory cytokine-induced IRG1 protein associates with mitochondria multiple genes induced by Borrelia burgdorferi in macrophages to regulate Lyme disease inflammation One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis. Murine immune-responsive gene 1 (IRG1) plays significant roles in embryonic implantation and neurodegeneration the IRG1 gene is differentially expressed in human fetal PBMCs and LPS-stimulated adult PBMCs. we identified the immune-responsive gene 1 (IRG1), which was expressed substantially higher in lipopolysaccharide (LPS)-stimulated than in MAP-infected murine macrophage cell lines. The inhibitor also blocked induction by LIF of several LIF-regulated genes in the LE including Irg1, which has been shown previously to be essential for implantation. Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. our studies identified Irg1 as a novel target of PR in the pregnant uterus and also revealed that it is a critical regulator of the early events leading to implantation This resulted in the identification of one novel P4-regulated gene that had been previously found in lipopolysaccharide-stimulated macrophages and called immune response gene-1 (Irg1) and which is the mammalian ortholog of the bacterial gene encoding methylcitrate dehydratase the mammalian ortholog of methylcitrate dehydratase (immune response gene 1) Here we report the isolation of a complementary DNA representing a novel gene, interferon-regulated gene 1 (IRG1). T Here we report the isolation of a complementary DNA representing a novel gene, interferon-regulated gene 1 (IRG1). This gene exhibits significant homology to interferon (IFN)-alpha/beta-inducible human genes p27 and 6-16, indicating that these genes may belong to the same family The level of IRG1 mRNA again rose transiently on day 4 immediately preceding implantation. Although the functional roles of IRG1 and p27 remain unclear, we describe for the first time, identification of a gene family regulated by IFNalpha in both rodent and human uteri Hence, the induction of IRG1 by LPS is mediated by tyrosine kinase and protein kinase C pathway. </context> <question> What is the function of the mammalian gene Irg1? </question> <answer> Human IRG1 and mouse Irg1 mediates antiviral and antimicrobial immune responses, without its exact role having been elucidated. Irg1 has been suggested to have a role in apoptosis and to play a significant role in embryonic implantation. Irg1 is reported as the mammalian ortholog of methylcitrate dehydratase. </answer>
<context> Putative HCNE peak targets are characterized by a tight association with particular promoter motifs, higher incidence of severe mutant phenotypes, and evidence of a more precise regulation of gene expression during important developmental transitions Much evidence suggests that CNEs are selectively constrained and not mutational cold-spots, and there is evidence that some CNEs play a role in the regulation of development. This result suggests that there is widespread adaptation in mammalian conserved noncoding DNA elements, some of which have been implicated in the regulation of crucially important processes, including development. Some characteristics of CNEs include their high frequency in mammalian genomes, their potential regulatory role in gene expression, and their enrichment in gene deserts nearby master developmental genes Animal genomes possess highly conserved cis-regulatory sequences that are often found near genes that regulate transcription and development. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish. HCNEs from the same area often drive overlapping patterns, suggesting that multiple regulatory inputs are required to achieve robust and precise complex expression patterns exhibited by developmental genes. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor. Further positional analysis of these conserved noncoding elements (CNEs) in the genome demonstrates that they cluster around genes involved in developmental regulation. Several lines of evidence indicate that these highly conserved noncoding elements (HCNEs) play a fundamental role in regulating animal development and constraining genome evolution The majority of tetrapod-specific UCEs are noncoding and associated with genes involved in regulation of transcription and development. Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development In 74% of cases, we were able to assign a specific set of paralogous genes with annotation relating to transcriptional regulation and/or development to each family HCNEs typically cluster around one particular gene in the region, most often encoding a transcription factor involved in the regulation of embryonic development and differentiation, referred to as the GRB target gene A GRB target gene, which is often a developmental transcription factor, is spanned by a synteny-maintaining array of HCNEs The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development The identification of a large number of putative novel regulatory elements in a subset of synaptic genes provides an important list of novel functional 'targets' for gene regulation during nervous system development and for dysregulation in disease CRCNE000111095 may show a more accurate representation of the function of the CNE with this CNE being responsible for enhancing limb development in human but having little enhancer activity in Fugu Functional assay of such elements in transgenic mouse and zebrafish have indeed indicated that a large number of them function as transcriptional enhancers directing tissue-specific expression of reporter genes during embryonic development This inference is in agreement with our previous findings that genes that are involved in development, in particular development of the central nervous system, are enriched with CNEs This suggests that CNE4 may be active in the central nervous system at some other stage of development highly conserved noncoding elements and their association with developmental regulatory genes Several lines of evidence indicate that these highly conserved noncoding elements (HCNEs) play a fundamental role in regulating animal development and constraining genome evolution HCNEs tend to cluster in the vicinity of developmental regulatory genes many HCNE sequences have shown the ability to induce part of the embryonic expression pattern of a developmental regulatory gene located in the genomic neighborhood of the endogenous HCNE These experiments have associated HCNEs and developmental genes Hundreds of HCNEs have now been characterized as developmental enhancers in transgenic mice, frogs or zebrafish, and the list is growing rapidly Plots of HCNE density along chromosomes highlight regions that harbor large HCNE arrays and, thus, are likely to contain key developmental regulatory genes and correspond to regulatory domains Since there is a strong association between HCNE arrays and developmental regulatory genes it is likely that most regions of high HCNE-density contain at least one developmental regulatory gene They found 41 of these regions to contain a gene known to be involved in embryonic development. Inspection of other HCNE-dense regions has revealed that several coincide with microRNA gene loci [18], a class of regulators implicated in multiple aspects of development the GRB of PAX7, a transcription factor gene implicated in muscle development [37] and situated within an array of HCNEs . A valuable section of CONDOR provides developmental expression patterns for about 100 HCNEs that have been investigated by reporter assays in zebrafish Ancora is a new web resource that provides data and tools for exploring HCNEs and their association with developmental regulatory genes The GRBs typically coincide with loci of developmental regulatory genes, for which HCNEs appear to act as enhancers </context> <question> Which is the process that Conserved noncoding elements mostly regulate? </question> <answer> Development </answer>
<context> experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis Therefore, a well characterized homogeneous animal model, experimental autoimmune encephalomyelitis (EAE), was selected for this study to obtain a sample of the inflammatory lesions using experimental allergic encephalomyelitis (EAE) in rats as a disease model for M Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE) the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS The aim of our study was to characterize the sensory abnormalities and in particular the clinical signs linked to persistent pain in two models of Experimental Autoimmune Encephalomyelitis (EAE) in the rat Experimental autoimmune encephalomyelitis (EAE) is an animal model for studying multiple sclerosis (MS) Theiler's murine encephalomyelitis virus (TMEV) infection of mice is an experimental model for multiple sclerosis (MS) experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) In this study we investigated whether in an animal model for MS, namely in experimental autoimmune encephalomyelitis (EAE), similar changes occur experimental autoimmune encephalomyelitis (EAE), the animal model of MS Experimental autoimmune encephalomyelitis (EAE), a widely recognized animal model of multiple sclerosis (MS) we utilized the Theiler's murine encephalomyelitis virus (TMEV) model of MS In a murine disease model, experimental autoimmune encephalomyelitis (EAE) mice lacking cyclophilin D (CyPD) experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis Theiler's murine encephalomyelitis virus (TMEV) Inflammatory diseases of the CNS, such as MS and its animal model EAE the strong impact of the classical MS model experimental autoimmune encephalomyelitis (EAE) an animal model of multiple sclerosis (MS): disease modifying activity on acute and chronic relapsing experimental allergic encephalomyelitis (EAE). The immunology of multiple sclerosis and its animal model, experimental allergic encephalomyelitis EAE is the best available model for the inflammatory processes that occur in MS, and for the disease process The present study addressed this question using the model of experimental allergic encephalomyelitis (EAE) The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE) To assess neurological impairments quantitatively in an animal model of multiple sclerosis (MS), we have used a targeted model of experimental autoimmune encephalomyelitis (EAE) Experimental autoimmune encephalomyelitis (EAE) is a well-studied disease in rodents that mimics many clinical and pathological features of MS, including central nervous system inflammation and demyelination The neuropathology of MS and its animal model, experimental autoimmune encephalomyelitis (EAE) Both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), its animal model, involve inflammatory attack on central nervous system (CNS) white matter both MS patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE) In the MS animal model experimental autoimmune encephalomyelitis (EAE) multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis inflammatory demyelination in multiple sclerosis (MS) lesions and experimental autoimmune encephalomyelitis (EAE) </context> <question> Which is the most widely used model for the study of multiple sclerosis (MS)? </question> <answer> Experimental autoimmune encephalomyelitis (EAE) </answer>
<context> transcriptional enhancers in developing mouse embryos, found that the enhancers directed reporter expression most frequently in the brain and neural tube. More recently, a similar association between ultraconserved noncoding elements (noncoding sequences exceedingly conserved in human, chimp and mouse) and genes that preferentially express in the central nervous system has been described [51]. Using the GNF Human GeneAtlas, this study found that nine out of the ten tissues that express genes most significantly associated with ultraconserved noncoding elements constitute various members of the central nervous system.10.1371/journal.pone.0020088.g007Figure 7TF-encoding genes predominantly expressed in the central nervous system are enriched with CNEs. In this study we have used evolutionary constraint as an indicator of putative enhancers in the vertebrate Lhx2 locus. Due to selective pressure, noncoding functional elements such as enhancers tend to evolve slowly compared to their neighboring sequences and hence can be identified as conserved noncoding elements in comparisons of related genomes. This strategy has been effectively used to identify a large number of putative enhancers conserved in distantly related vertebrates such as mammals and teleost fishes [26], [27], [28], [29]. Functional assay of such elements in transgenic mouse and zebrafish have indeed indicated that a large number of them function as transcriptional enhancers directing tissue-specific expression of reporter genes during embryonic development [26], [28], [29]. We have aligned sequences of the Lhx2 locus from human, mouse and pufferfish (fugu) genomes and predicted conserved noncoding elements (CNEs) in the locus. Functional assay of these CNEs in a transgenic mouse assay system showed that half of them function as tissue-specific enhancers at embryonic day 11.5. A CNE was classified as a transcriptional enhancer if it directed reproducible reporter gene expression in the same anatomical structure in at least three independent transgenic mouse embryos.CNE1CNE1 is a 76-bp sequence located approximately 619 kb upstream of human LHX2 within the 20th intron of DENND1A. We therefore concluded that CNE1 does not act as a transcriptional enhancer at stage E11.5.CNE2/3CNE2/3 is a combination of two CNEs, CNE2 and CNE3, which were tested together due to their close proximity to each other (41 bp apart). Hence, CNE4 is not an enhancer at E11.5.CNE5/6CNE5/6 is a combination of two CNEs, CNE5 and CNE6, that are 38 bp apart and are located approximately 269 kb upstream of human LHX2 within the fifth intron of DENND1A. This CNE does not act as an enhancer at E11.5, because no lacZ expression was detected in four out of the six (67%) transgenic embryos obtained for this developmental stage. Hence, CNE9 does not act as an enhancer at E11.5.CNE10CNE10 is a 145-bp element that has the highest percentage identity (∼90%) in human and fugu among all the CNEs assayed. Hence, CNE7 acts as a transcriptional enhancer at stage E11.5. Indeed, CNE10 was found to act as a transcriptional enhancer. Summary of the expression patterns of CNEsIn summary, four out of the eight elements (50%) that we assayed for enhancer activity in transgenic mouse embryos, directed reproducible reporter gene expression in specific tissues at E11.5 Finally, a third study searched 13 forebrain enhancers conserved in human and zebrafish and identified five hexamer motifs that were enriched [54]. Hence, through the mutation of the predicted motif, the enhancer activity of CNE2/3 was either significantly reduced or completely abolished. The four CNEs that were showed to be functional enhancers in our transgenic mouse assay directed expression, among other domains, to the midbrain and hindbrain. Out of the four CNEs that showed expression in the central nervous system and the dorsal root ganglia, three showed overlapping expression in the hindbrain and all showed similar expression in the neural tube. These overlapping expression patterns of the different enhancers suggest that they are either associated with different genes in this locus or alternatively, redundant enhancers of the same gene. Similar enhancers showing overlapping patterns of expression have been previously identified in the screening of mammal-chicken CNEs in the Sox10 locus [59] and in a 1-Mb region surrounding the Shh locus [61]. The aCNEs are rich in tissue-specific enhancers Transgenic zebrafish assay of some human CNE enhancers that have been lost in teleosts strong DNA sequence conservation of enhancers of developmental regulator genes [3-8] implies purifying selection to keep such regions preserved across species and functionally constrained in their cis-regulatory functions. The orthologous Otx2 enhancers FM and AM [24] and the HoxC8 early enhancer [25] revealed strong conservation in DNA sequence and in enhancer expression in mouse transgenic experiments. In our report, we demonstrate that the Latimeria menadoensis shh locus contains all conserved proximal enhancers shared nonuniformly by fishes and land vertebrates. We provide experimental verification for enhancer activity of the putative Latimeria enhancers in transgenic zebrafish and electroporated chick embryos. From DNA sequence comparison of the shh locus of different vertebrate lineages, we infer that Latimeria conserved noncoding elements represent the ancestral gnathostome set of enhancers that diverged variably during vertebrate evolution. Several noncoding conserved sequences were detected in intronic and upstream regions of shh, and the distribution and frequency of these conserved blocks followed recognizable patterns. They overlap with the previously characterized enhancer regions of zebrafish and mouse (Figure 2a). Furthermore, the ar-D enhancer is not conserved in pufferfishes (e.g., Takifugu rubripes) and medaka (Oryzias latipes). This result suggests that the ar-B enhancer has been lost independently in the different tetrapod lineages. In summary, Latimeria has retained conservation of all four putative enhancers that were previously described in the actinopterygian zebrafish. Conserved Latimeria enhancer sequences we examined the rates of divergence within conserved shh enhancer sequences among sarcopterygian species with the relative rate test [51]. Congruent to the overall conservation, the mammalian enhancer sequences showed elevated rates of divergence compared to chick or Latimeria, with opossum putative enhancer sequences at intermediate rates and the placental mammalian species at highest rates (Table 1). In conclusion, all CNEs that were previously identified either in mouse or in zebrafish are present in Latimeria and thus are candidate enhancers of shh expression in the Latimeria embryonic midline is too large to suggest that the CNE within contains the functional enhancer. The region that is responsible for the ar-D enhancer effect overlaps fully with a CNE that is present in all the other compared sarcopterygian sequences Conserved noncoding elements of Latimeria shh intron 1 located between exon 1 and the intronic enhancer ar-A did not drive specific reporter gene expression (data not shown). These results indicate that the CNE in the Latimeria upstream region is a functional midline enhancer which has similar but not identical activity in zebrafish to the zebrafish ar-D enhancer Conservation of Latimeria shh noncoding DNAThe shh genomic region of Latimeria menadoensis reveals conservation of all four actinopterygian shh midline enhancers, which indicates an ancestral-like and rather unchanged cis-regulatory architecture of Latimeria shh. The Latimeria orthologous Otx2 enhancers FM and AM [24] as well as the HoxC8 early enhancer [25] revealed strong DNA sequence conservation across vertebrates. Conservation of the four enhancers ar-A, ar-B, ar-C and ar-D in Latimeria and zebrafish reveals preservation of an ancestral set of enhancers that originated before the split between ray-finned and lobe-finned vertebrates The Latimeria menadoensis shh genomic region represents a locus with the ancestral set of enhancers that emerged before the split of lobe-finned and ray-finned fishes. Conserved noncoding elements (CNEs) in vertebrate genomes often act as developmental enhancers, In all four cases where the zebra fish and human CNE display a similar expression pattern in zebra fish, the human CNE also displays a similar expression pattern in mouse. This suggests that the endogenous enhancer activity of ∼30% of human CNEs can be determined from experiments in zebra fish If these ancient CNEs are indeed enhancers directing tissue-specific expression of Hox genes, divergence of their sequences in vertebrate lineages might have led to altered expression patterns and presumably the functions of their associated Hox genes. Comparisons of noncoding sequences of the elephant shark and human Hox clusters have identified a large number of conserved noncoding elements (CNEs), which represent putative cis-regulatory elements that may be involved in the regulation of Hox genes. Animal genomes possess highly conserved cis-regulatory sequences that are often found near genes that regulate transcription and development. We test 42 of our PCNEs in transgenic zebrafish assays--including examples from vertebrates and amphioxus--and find that the majority are functional enhancers. The genomes of vertebrates, flies, and nematodes contain highly conserved noncoding elements (CNEs). CNEs cluster around genes that regulate development, and where tested, they can act as transcriptional enhancers. , we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, Pan-vertebrate developmental cis-regulatory elements are discernible as highly conserved noncoding elements (HCNEs) and are often dispersed over large areas around the pleiotropic genes whose expression they control. HCNEs of both human and zebrafish function as specific developmental enhancers in zebrafish. several transcriptional enhancers are conserved between amphioxus and vertebrates--a very wide phylogenetic distance. The same was shown by Woolfe and coworkers [6] by using 1,373 regions extracted from a direct comparison of the genomes of human and fish. The same report also provided the first systematic experimental evidence of enhancer activity for a subset of these elements in zebrafish (see below). Recognition and testing of individual highly conserved noncoding elementsThere is mounting evidence for the regulatory role of HCNEs. Soon after their genome wide discovery, it was realized that a significant number of previously characterized developmental enhancers overlap with HCNEs. Göttgens and coworkers [31] reported the discovery of enhancers that are highly conserved between human and mouse, and some in chicken. several such elements conserved between human and fugu near the SOX9 gene, of which they considered at least three candidate enhancers. isolated two HCNEs upstream of the mouse Pax3 gene as enhancers the question of whether the conservation is essential for the transcription factor binding properties of those enhancers a large number of HCNEs from the vertebrate iroquois clusters were tested in zebrafish and Xenopus, and the majority of them were shown to act as specific enhancers tested 167 HCNEs in a mouse transgenic enhancer assay. Seventy-five (43%) of the tested elements exhibited enhancer activity wo equivalent regions of a genomic sequence in human and zebrafish are both able to act as an enhancer in zebrafish, Mechanism of enhancer activity of highly conserved noncoding elementsWe still have no adequate explanation for the mechanism by which HCNEs act as enhancers, Five conserved noncoding sequences (>80% human-mouse identity) were identified within the 17 kb intergenic sequence. That some of these enhancers are shared We recently described GRBs in vertebrates, where most HCNEs function as enhancers Besides developmental regulators that are likely targets of HCNE enhancers We identify and characterize highly conserved noncoding elements flanking the TNF gene, which undergo activation-dependent intrachromosomal interactions. These elements, hypersensitive site (HSS)-9 and HSS+3 (9 kb upstream and 3 kb downstream of the TNF gene, respectively), contain DNase I hypersensitive sites in naive, T helper 1, and T helper 2 primary T cells. Both HSS-9 and HSS+3 inducibly associate with acetylated histones, indicative of chromatin remodeling, bind the transcription factor nuclear factor of activated T cells (NFAT)p in vitro and in vivo, and function as enhancers We used the sequence signatures identified by this approach to successfully assign tissue-specific predictions to approximately 328,000 human-mouse conserved noncoding elements in the human genome. By overlapping these genome-wide predictions with a data set of enhancers validated in vivo, in transgenic mice, we were able to confirm our results with a 28% sensitivity and 50% precision. Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development. uncovered two anciently conserved noncoding sequences (CNS) upstream of COUP-TFII (CNS-62kb and CNS-66kb). Testing these two elements using reporter constructs in liver cells (HepG2) revealed that CNS-66kb, but not CNS-62kb, yielded robust in vitro enhancer activity. </context> <question> Do Conserved noncoding elements act as enhancers? </question> <answer> yes </answer>
<context> Thrombophilia does hardly increase the risk of IUGR/PMPC or if so, it can be prevented by LMWH for illustrative purposes, a patient presenting with combined thrombophilia--both genetic and acquired--will be discussed. This patient had suffered severe gestational complications that led to devastating obstetrical outcome Thrombophilias have been implicated in complications related to ischemic placental disease including recurrent pregnancy loss, intrauterine fetal demise, preeclampsia, fetal growth restriction, placental abruption, and preterm delivery Further information about the combined risk of aPC resistance and pregnancy is needed before guidance on the management of affected women can be formulated. Thrombotic risk during pregnancy and the puerperium is higher in asymptomatic women with than without thrombophilia Further studies are required to assess the thrombotic risk in women with preeclampsia as well as early or late recurrent pregnancy loss. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period Careful diagnosis, observation and monitoring can add significant benefit to LMWH therapy during pregnancy Pregnancy in healthy women is accompanied by hypercoagulable changes that may interact with thrombophilia risk factors and threaten pregnancy. Fifty-three (13 %) women had antiphospholipid antibodies (lupus anticoagulant and/or anti-beta2-glycoprotein 1 antibodies) mainly associated with the risk of spontaneous abortion during the first trimester thrombophilia was found to be considerably more common in women with pregnancy-associated complications in comparison with the general population, and most frequently in conjunction with venous thromboembolism during pregnancy and the postpartum period When counseling white women with a history of preeclampsia, screening for thrombophilia can be useful for preconceptional counseling and pregnancy management. knowledge combined with the appropriate use of thromboprophylaxis and treatment in women who have objectively confirmed VTE continue to improve maternal and perinatal outcomes The risk of having thrombophilia is doubled in men who have fathered pregnancies which ended in perinatal death as well as in the mothers of such pregnancies. The prevalence of thrombophilic variants is of possible public health significance for other morbidity; but perhaps not in relation to preeclampsia This study suggests that thrombophilia "mediates" in lowering of cardiovascular risk factors in women with a history of preeclampsia </context> <question> Is thrombophilia related to increased risk of miscarriage? </question> <answer> yes </answer>
<context> The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses GNAS, the gene for guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (gene for PHP1A), identified a de novo heterozygous 3 bp in frame deletion predicting a deletion of the asparagine residue at position 377 (deltaN377 craniosynostosis genes (FGFR2, FGFR3) Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication early fusion of cranial sutures commonly observed in the dup(5q) syndrome is caused by triplication of the MSX2 gene further evidence that extra copy of MSX2 gene leads to craniosynostosis Our results support the previous finding that distal 5q-trisomy together with an extra copy of the MSX2 gene leads to abnormal closure of sutures and craniosynostosis Craniosynostosis-associated gene nell-1 is regulated by runx2 We studied the transcriptional regulation of NELL-1, a craniosynostosis-related gene Runx2 directly binds to the OSE2 elements and transactivates the human NELL-1 promoter. These results suggest that Nell-1 is likely a downstream target of Runx2 The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes SOX6 mutation screening of another 104 craniosynostosis patients revealed one missense mutation leading to the exchange of a highly conserved amino acid (p.D68N) in a single patient and his reportedly healthy mother Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene Overexpression of Nell-1, a craniosynostosis-associated gene Mutations in five genes (FGFR1-, -2, -3, TWIST, and MSX2) causing craniosynostosis as the main clinical feature were described. One of the genes involved in craniosynostosis syndromes is the fibroblast growth factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor gene Most mutations in Crouzon, Pfeiffer, and Apert syndromes are in the extracellular, third immunoglobulin-like domain and adjacent linker regions (exons IIIa and IIIc) of the fibroblast growth factor receptor 2 (FGFR2) gene Familial craniosynostosis due to Pro250Arg mutation in the fibroblast growth factor receptor 3 gene. Apert (Ap) syndrome is characterized by premature cranial suture ossification caused by fibroblast growth factor receptor 2 (FGFR-2) mutations Recently, the substitution of proline 250 by arginine in the fibroblast growth factor receptor 3 (FGFR3) gene, has been identified in patients with craniosynostosis and defines a new syndrome on a molecular basis Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. A unique Pro250Arg mutation in fibroblast growth factor receptor 3 (FGFR3) was recently found in patients with non-syndromic craniosynostosis a possible mechanism for MSX2-mediated craniosynostosis in humans We found previously that a single amino acid substitution in the homeodomain of the human MSX2 gene is associated with the autosomal dominant disorder craniosynostosis, Boston type. Recently, a unique Pro250Arg point mutation in fibroblast growth factor receptor 3 (FGFR3) was reported in 61 individuals with coronal craniosynostosis from 20 unrelated families We identified a novel TWIST gene mutation in this patient, a Glu181Stop mutation predicting a premature termination of the protein carboxy-terminal to the helix 2 domain A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis </context> <question> Which human genes are more commonly related to craniosynostosis? </question> <answer> FGFR3; FGFR2; FGFR1; MSX2; NELL1; RUNX2; RECQL4; TWIST; SOX6; GNAS </answer>
<context> role of primary cilia in autosomal dominant polycystic kidney disease Recent research has focused on defects in signaling mediated by the primary cilia as the causative factor in ADPKD Interestingly, primary cilia concentrate p75NTR receptors in their membranes and are abnormally structured/damaged in transgenic (Tg) AD‑model mice, which could impact on the adult neurogenesis occurring in the dentate gyrus's subgranular zone (SGZ) that is necessary for new memory encoding, thereby favouring typical AD cognitive decline malformation of primary cilia, and in the collecting ducts of kidney tubules this is accompanied by development of autosomal recessive polycystic kidney disease (PKD) While PKD was one of the first diseases to be linked to dysfunctional primary cilia, defects in this organelle have subsequently been associated with many other phenotypes, including cancer, obesity, diabetes as well as a number of developmental defects mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease Although Glis3(zf/zf) mice form normal primary cilia, renal cysts contain relatively fewer cells with a primary cilium When ciliary function is perturbed, photoreceptors may die, kidney tubules develop cysts, limb digits multiply and brains form improperly. Here, we report that CP110 interacts with CEP290--a protein whose deficiency is implicated in human ciliary disease The cholangiociliopathies include but are not limited to cystic and fibrotic liver diseases associated with mutations Cysts in the kidney are among the most common inherited human pathologies, and recent research has uncovered that a defect in cilia-mediated signaling activity is a key factor that leads to cyst formation Multiple proteins whose functions are disrupted in cystic diseases have now been localized to the cilium or at the basal body at the base of the cilium Polaris has been shown to co-localize with primary cilia, and these structures have been implicated in the formation of renal cysts hus, polaris and primary cilia function are required for the maturation and maintenance of proper tissue organization in the pancreas In cultured renal cells, the PKHD1 gene product colocalized with polycystin-2, the gene product of autosomal dominant polycystic disease type 2, at the basal bodies of primary cilia. Mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene The autosomal recessive polycystic kidney disease protein is localized to primary cilia It is proposed that the pathogenesis of autosomal recessive polycystic kidney disease is linked to the dysfunction of primary cilia </context> <question> Which is the most common disease attributed to malfunction or absence of primary cilia? </question> <answer> Polycystic kidney disease (PKD) </answer>
<context> The allelic frequency of this variant was calculated to be 0.7% for this population The results of literature reviews, surveys, and registry analyses revealed a mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98 The age related prevalence of CF among the South Asian and general populations was: 0-14 years, 1:9200 versus 1:6600; 15-24 years, 1:13,200 versus 1:7600; older than 25 years, 1:56,600 versus 1:12,400. A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, our data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants) CF mutations were identified in 374 (4.0%) individuals. The aim of this study was to evaluate the screening policies of cystic fibrosis (CF) in the Jewish population. </context> <question> Which is the prevalence of cystic fibrosis in the human population? </question> <answer> 0.7–7/100000 inhabitants </answer>
<context> interactions with alpha-expansin in cell wall extension and polysaccharide degradation cell wall swelling may not be a significant event during the action of expansin and hydrolases To evaluate a putative implication of three newly identified expansin/family 45 endoglucanase-like (EEL) proteins in lignocellulose degradation Our results show that EglD is a conidial cell wall localized expansin-like protein, which could be involved in cell wall remodeling during germination Swollenin, a protein first characterized in the saprophytic fungus Trichoderma reesei, contains an N-terminal carbohydrate-binding module family 1 domain (CBD) with cellulose-binding function and a C-terminal expansin-like domain alpha-Expansins are extracellular proteins that increase plant cell-wall extensibility these wall-loosening proteins are directly involved in the accommodation of the fungus by infected cortical cells </context> <question> What is the biological role of expansins in fungi? </question> <answer> Expansins are extracellular proteins that increase plant cell-wall extensibility. These wall-loosening proteins are involved in cell wall extension and polysaccharide degradation. In fungi expansins and expansin-like proteins have been found to localize in the conidial cell wall and are probably involved in cell wall remodeling during germination. </answer>
<context> Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus. Influenza immunization or infection may cause subacute thyroiditis. Coxsackie virus has been reported to be one of the viruses associated with the disease. The etiology of subacute granulomatous thyroiditis (SAT) is obscure, although it is postulated to be associated with viral infections and genetic factors. The results suggest that SAT is not usually associated with acute infections No evidence was obtained to support the proposed role of enteroviruses as an important etiologic agent of SAT. The viral antibodies evaluated were those of Influenza A and B, Coxsackie A9, B1, B2, B3, B4, B5 and B6, Echo 3, 7, 11 and 12, Parainfluenza 1, 2, 3 and 4, and Adeno 8 virus. The following results were obtained: In class I HLA typing, the frequency of HLA-Bw35 in SAT was 67.4%, which was significantly (p less than 0.0001) higher than that in the control (14.1%). On the other hand, the frequency of Cw1 in SAT (14.6%) was significantly (p less than 0.01) lower than that of the control (32.1%), and that of Cw3 (65.2%) was significantly (p less than 0.01) higher than that of the control (46.5%). </context> <question> Is paramyxovirus involved in human subacute thyroiditis? </question> <answer> no </answer>
<context> Proton-pump inhibitors, antacids and a long list of drugs may decrease thyroxine absorption Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine. Pantoprazole did not influence endocrine function in healthy male volunteers during short-term treatment. PPIs should be added to the list of medications affecting the level of thyroid hormone in patients with hypothyroidism treated with LT4 replacement. Patients with hypothyroidism and normal TSH values during LT4 replacement therapy may need additional thyroid function testing after treatment with PPIs and may need adjustment of their LT4 dose. </context> <question> Do proton pump inhibitors affect thyroxine absorption? </question> <answer> yes </answer>
<context> ommonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine Hypothyroid patients taking sevelamer hydrochloride or chromium picolinate should be advised to separate the time of ingestion of these drugs from their thyroid hormone preparation by several hours. </context> <question> Which drugs may interfere thyroxine absorption? </question> <answer> bile acide sequestrant; ferrous sulphate; sucralfate; Calcium carbonate; aluminium-containing antacids; raloxifene; proton pump inhibithors; sevelamer; chromium picolinate </answer>
<context> Myocardial ischaemia/reperfusion (I/R)-induced remodelling generally includes cell death (necrosis and apoptosis), myocyte hypertrophy, angiogenesis, cardiac fibrosis, and myocardial dysfunction. I In addition, miR-21, -24, -133, -210, -494, and -499 appear to protect myocytes against I/R-induced apoptosis, whereas miR-1, -29, -199a, and -320 promote apoptosis Myocardial fibrosis can be regulated by the miR-29 family Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general. </context> <question> Is microRNA(miRNA) 29 involved in post-ischemic cardiac remodeling? </question> <answer> yes </answer>
<context> The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosi Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an attractive therapeutic target CTGF is importantly regulated by 2 major cardiac microRNAs (miRNAs), miR-133 and miR-30. the expression of both miRNAs was inversely related to the amount of CTGF in 2 rodent models of heart disease and in human pathological left ventricular hypertrophy. Second, in cultured cardiomyocytes and fibroblasts, knockdown of these miRNAs increased CTGF levels. Third, overexpression of miR-133 or miR-30c decreased CTGF levels, which was accompanied by decreased production of collagens. miR-30 importantly limit the production of CTGF miR-30 directly downregulate CTGF, a key profibrotic protein, and thereby establish an important role for these miRNAs in the control of structural changes in the extracellular matrix of the myocardium. </context> <question> Is microRNA(miRNA) 30 involved in post-ischemic cardiac remodeling? </question> <answer> yes </answer>
<context> GD orbital fibroblasts, which comprise a mixture of CD34(+) and CD34(-) cells, express much lower levels of Tg and TSHR Previously, we found that CD34(+) progenitor cells, known as fibrocytes, express functional TSHR, infiltrate the orbit, and comprise a large subset of orbital fibroblasts in TAO. TSH induced lipolysis in adipose tissues. TSH worked as a lipolytic factor in white adipose tissues, These fibrocytes infiltrate orbital connective tissues in thyroid-associated ophthalmopathy and express functional TSH receptor (TSHR). TSHR levels are higher than those in orbital fibroblasts. </context> <question> Which extra thyroid tissues have thyrotropin (TSH) receptors? </question> <answer> adipose tissue; fibrotic tissue </answer>
<context> T3-induced cardiac sprouting angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and downstream activation of Akt. L-T3 significantly increased angiogenesis and cell survival and enhanced the expression of nuclear-encoded transcription factors involved in these processes. T(3) administration restored TRbeta mRNA expression level in AAC hearts to the control level. Rbeta knockout and TRalpha/TRbeta double-knockout mice both exhibited significantly less capillary density in LV compared with wild-type mice. TRbeta in the coronary ECs regulates capillary density during cardiac development, and down-regulation of TRbeta results in coronary microvascular rarefaction during pathological hypertrophy. </context> <question> Does triiodothyronine (T3) has cardiac angiogenic effects? </question> <answer> yes </answer>
<context> The product of the dcm gene is the only DNA cytosine-C5 methyltransferase of Escherichia coli K-12; it catalyses transfer of a methyl group from S-adenosyl methionine (SAM) to the C-5 position of the inner cytosine residue of the cognate sequence CCA/TGG. Deoxycytosine methylase (Dcm) enzyme activity causes mutagenesis in vitro either directly by enzyme-induced deamination of cytosine to uracil in the absence of the methyl donor, S-adenosylmethionine (SAM), or indirectly through spontaneous deamination of [5-methyl]cytosine to thymine In the absence of DNA substrate, the DNA methyltransferase (MTase) M.BspRI can methylate itself using the methyl donor S-adenosyl-L-methionine (AdoMet). The methyl group is transferred to two Cys residues of the MTase. The reaction is fairly insensitive to the methyl donor in the reaction, S-adenosylmethionine. Formation of the complex was dependent upon the presence of the methyl donor S-adenosylmethionine, suggesting that it comprises an enzyme-linked 5-substituted dihydrocytosine moiety in DNA. The DNA (cytosine-5)-methyltransferase (m5C-MTase) M.BspRI is able to accept the methyl group from the methyl donor S-adenosyl-L-methionine (AdoMet) in the absence of DNA. Transfer of the methyl group to the enzyme is a slow reaction relative to DNA methylation. S Here, we report the structure of HhaI methyltransferase in complex with DNA containing a south-constrained abasic carbocyclic sugar at the target site in the presence of the methyl donor byproduct AdoHcy. </context> <question> What is the methyl donor of DNA (cytosine-5)-methyltransferases? </question> <answer> S-adenosyl-L-methionine </answer>
<context> Most luminal lysosomal proteins are synthesized as precursors containing mannose 6-phosphate (Man6-P) and a number of recent studies have conducted affinity purification of Man6-P containing proteins as a step toward defining the composition of the lysosome This chapter describes the process of production, purification, separation, and mass spectrometry identification of soluble lysosomal proteins. The rationale for purification of these proteins resides in their characteristic sugar, the mannose-6-phosphate (M6P), which allows an easy purification by affinity chromatography on immobilized M6P receptor (MPR ecretions of these cells were affinity purified using an affinity matrix derivatized with MPR46 and MPR300. In the protein fraction bound to the affinity matrix and eluted with mannose 6-phosphate, Proteins containing mannose 6-phosphate (Man6-P), a carbohydrate modification used for targeting resident soluble lysosomal proteins to the lysosome, were affinity-purified using immobilized Man6-P receptor. . We purified mannose 6-phosphorylated proteins by affinity chromatography Since lysosomal soluble proteins are characterized by the presence of mannose-6-phosphate, they were purified on an affinity support bearing mannose-6-phosphate receptor The most abundant lysosomal substrates of Acp2 and Acp5 were identified by Man6P affinity chromatography and mass spectrometry. urinary proteins were affinity purified on immobilized Man-6-P receptors, A number of proteomic studies have focused on lysosomal proteins, exploiting the fact that Man-6-P-containing forms can be purified by affinity chromatography on immobilized MPRs. In this study, we purified the Man-6-P glycoforms of proteins from human plasma by affinity chromatography on immobilized MPRs </context> <question> What kind of affinity purification would you use in order to isolate soluble lysosomal proteins? </question> <answer> The rationale for purification of the soluble lysosomal proteins resides in their characteristic sugar, the mannose-6-phosphate (M6P), which allows an easy purification by affinity chromatography on immobilized M6P receptors. </answer>
<context> The lysosomal storage disorder Fabry disease is characterized by excessive globotriaosylceramide (Gb3) accumulation in major organs such as the heart and kidney. Defective lysosomal alpha-galactosidase A (Gla) is responsible for excessive Gb3 accumulation, and one cell sensitive to the effects of Gb3 accumulation is vascular endothelium. Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Human alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A) is the lysosomal exoglycosidase responsible for the hydrolysis of terminal alpha-galactosyl residues from glycoconjugates and is the defective enzyme causing Fabry disease (McKusick 301500). Transgenic mice expressing a human mutant alpha-galactosidase with an R301Q substitution, which was found in a patient with a variant form of Fabry disease, were established. </context> <question> Which is the defective protein causing the lysosomal storage disease Fabry? </question> <answer> alpha-galactosidase A </answer>
<context> Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus </context> <question> What is known as the cause of subacute thyroiditis? </question> <answer> Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus </answer>
<context> Oral glucocorticoids are administered in moderate and severe cases of subacute thyroiditis (SAT) he treatment protocol that we employed had 15 mg/day of PSL as the initial dosage for the treatment of SAT, with tapering by 5 mg every 2 weeks </context> <question> What is the treatment of subacute thyroiditis? </question> <answer> Common treatment of subacute thyroiditis is with anti-inflammatory drug agents, namely corticosteroids </answer>
<context> myc regulates hepatic glycolysis increase in c-Myc protein was able to induce liver glucose utilization and accumulation, and suggested that c-Myc transcription factor is involved in the control in vivo of liver carbohydrate metabolism p53 regulates mitochondrial oxidative phosphorylation, glycolysis, glutamine metabolism, lipid metabolism, and antioxidant defense STAT3 is a negative regulator of aerobic glycolysis. HIF1 alpha-mediated switches in the energy production of tumor cells from OXPHOS to glycolysis NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation Hypoxia-inducible factor-1α (HIF-1α), which is a transcription factor that enhances glycolysis in cells in response to hypoxia CRP plays a major role in switch control between glycolysis and gluconeogenesis the inhibition of PDK4 expression by NF-κB is related to the shift towards increased glycolysis that is observed during cardiac pathological processes induced by pro-inflammatory stimuli, such as cardiac hypertrophy and heart failure The oxygen sensor HIF-1α is a highly unstable protein that becomes stabilized under hypoxia, leading to the activation of glycolysis and the down-regulation of mitochondrial respiration several reports have linked HIF-1α induction with STAT3 activation Functionally, we have shown that glycolysis, oxidative phosphorylation, and cellular respiratory systems are altered in response to changes in Ets-1 expression SIRT6 appears to function as a corepressor of the transcription factor Hif1alpha, a critical regulator of nutrient stress responses SIRT6-deficient cells exhibit increased Hif1alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration c-Myc regulates genes involved in the biogenesis of ribosomes and mitochondria, and regulation of glucose and glutamine metabolism Myc regulates gene expression either directly, such as glycolytic genes including lactate dehydrogenase A (LDHA) loss of the widely expressed transcription factor Oct1 induces a coordinated metabolic shift: mitochondrial activity and amino acid oxidation are increased, while glucose metabolism is reduced. PVHL is a regulator of glucose metabolism Carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in the glucose-mediated induction of gene products involved in hepatic glycolysis and lipogenesis Activation of NF-kappaB, by loss of p53, caused an increase in the rate of aerobic glycolysis and upregulation of Glut3 p53 restricts activation of the IKK-NF-kappaB pathway through suppression of glycolysis cells express hypoxia-inducible factor (HIF)-1alpha, a transcription factor that responds to oxygen tension and regulates glycolysis The HIF-1 dependent genic products are involved in tumoral angiogenesis, in the metabolic switch to anaerobic glycolysis and in prosurvival, proliferative and apoptotic mechanisms he hypoxia-inducible transcription factor (HIF) regulates the expression of genes involved in angiogenesis, erythropoiesis and glycolysis hypoxia-inducible factor-1, which activates a gene program associated with angiogenesis, glycolysis, and adaptation to pH ChREBP (carbohydrate response element-binding protein) was recently identified as a candidate transcription factor in the glucose-signaling pathway Hypoxia-inducible factor (HIF)-1 is a master transcription factor, which up-regulates glycolysis (Src) express HIF-1alpha protein under normoxia, which results in the expression of multiple HIF-1alpha target genes. HIF-1 alpha can then translocate to the nucleus and facilitate transcription of numerous target genes, the majority of which are involved in glycolysis and angiogenesis via heterodimerisation with the beta subunit (HIF-1 beta/ARNT) We previously observed that the c-Myc oncogenic transcription factor regulates lactate dehydrogenase A and induces lactate overproduction. We, therefore, sought to determine whether c-Myc controls other genes regulating glucose metabolism overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway HNF4alpha is critical for regulating glucose transport and glycolysis and in doing so is crucial for maintaining glucose homeostasis </context> <question> Which are the major transcription factors regulating glycolysis in mammals? </question> <answer> HIF1-alpha; c-Myc; Src; STAT3; SIRT6; NF-κB; Oct1; HNF4-alpha; PVHL </answer>
<context> Recent evidence indicates that CXCR2 signaling is crucial for cancer progression, and its antagonist SB225002 induces apoptosis in Wilms' tumor cells. CXCR2 small-molecule antagonist (SB225002) G31P, an antagonist against CXC chemokine receptors 1 and 2, inhibits growth of human prostate cancer cells in nude mice. The CXCR2 antagonist, SCH-527123, shows antitumor activity CXCR2 Antagonist SB225002 The use of a small selective antagonist for CXCR2 (SB225002) represents an attractive targeted therapeutic approach [26]. retreatment with the CXCR2 antagonist AZ10397767 The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. we report that targeting CXCR2 and CXCR1 activity using orally active small molecule antagonist (SCH-527123, SCH-479833) inhibits human colon cancer liver metastasis mediated by decreased neovascularization and enhanced malignant cell apoptosis. CXCR2-specific small molecule inhibitor (AZ10397767) to investigate the recruitment and function of human neutrophils in tumors </context> <question> The CXCR2 receptor is targeted in cancer. Name five antagonists. </question> <answer> SB225002; G31P; SCH-527123; AZ10397767; SCH-479833 </answer>
<context> In contrast, GeneView recognizes a broader set of entity types but not gene ontology terms, provides search facilities using unique database identifiers and also finds relationships between proteins in texts. It uses a multitude of state-of-the-art text-mining tools optimized for recognizing mentions from 10 different entity classes and for automatically identifying protein–protein interactions (PPI). GeneView offers all annotations as downloads to support the development of new applications by freeing developers of data analysis algorithms from the necessity to deal with a multitude of text-mining packages. PPI finder: a mining tool for human protein-protein interactions. One of the most important applications is mining correlations or associations such as protein-protein interactions (PPIs) from the literature [4], [5]. Plenty of PPI text mining approaches have been categorized into two groups, one is statistical calculation of the co-occurrence of genes or proteins, and the other is the computational linguistic method [2], [4]. In this study, we developed a novel algorithm by a frame-based approach for a web-based tool, PPI Finder, which can not only find the related genes of the gene of interest based on their co-occurrence frequencies but also extract the semantic descriptions of interactions from the co-occurring literature by computational linguistic methods. The PPI Finder system consists of two modules: Information Retrieval (IR module) and Information Extraction (IE module). Extracting interactions between proteins from the literature. In the meantime, there has been a great interest with scientific communities in text mining tools to find knowledge such as protein-protein interactions, which is most relevant and useful for specific analysis tasks. This paper provides a outline of the various information extraction methods in biomedical domain, especially for discovery of protein-protein interactions. PreBIND and Textomy--mining the biomedical literature for protein-protein interactions using a support vector machine. PreBIND and Textomy are two components of a literature-mining system designed to find protein-protein interaction information and present this to curators or public users for review and submission to the BIND database. For the purposes of this paper and the initial population of the BIND database, we have chosen to focus on extracting information from the literature that is sufficient for defining a simple protein-protein interaction record in BIND. Subsequent text-mining modules can be added to PreBIND in future that will help fill out other aspects of the BIND data model. PreBIND and Textomy differ from these methods by a combination of five factors.1) Support Vector Machine (SVM) technology is used to identify articles about biomolecular interactions and confirm sentences that mention specific protein-protein interactions. Discovering implicit protein-protein interactions in the cell cycle using bioinformatics approaches. In this paper we examine if P-P interactions in regenerating tissues and cells of the anuran Xenopus laevis can be discovered from biomedical literature using computational and literature mining techniques. P-P interactions that are implicitly appearing in literature can be effectively discovered using literature mining techniques. The developed BioMap system allows discovering implicit P-P interactions from large quantity of biomedical literature data. Also, bioinformatics techniques based on sequence, structural, or evolutionary information have been devised to predict binary protein interactions. How to link ontologies and protein-protein interactions to literature: text-mining approaches and the BioCreative experience. In particular, we will focus on the attempts that have been made to automatically extract protein–protein interaction (PPI) data taking advantage of ontologies, and to associate ontology terms to the interactions. One of the most common and challenging problem in biomedical text mining is to mine protein-protein interactions (PPIs) from MEDLINE abstracts and full-text research articles because PPIs play a major role in understanding the various biological processes and the impact of proteins in diseases. Extracting protein-protein interaction (PPI) from biomedical literature is an important task in biomedical text mining (BioTM). Automated extraction of protein-protein interactions (PPIs) from biomedical literatures is an important topic of biomedical text mining. Extraction of protein-protein interactions (PPIs) reported in scientific publications is one of the core topics of text mining in the life sciences. BACKGROUND: The automated extraction of gene and/or protein interactions from the literature is one of the most important targets of biomedical text mining research. The techniques used in text mining range from the very simple (e.g., the inference of relationships between genes from frequent proximity in documents) to the complex and computationally intensive (e.g., the analysis of sentence structures with parsers in order to extract facts about protein-protein interactions from statements in the text). A major challenge in text mining for biomedicine is automatically extracting protein-protein interactions from the vast amount of biomedical literature. One of the most common and challenging problem in biomedical text mining is to mine protein-protein interactions (PPIs) from MEDLINE abstracts and full-text research articles because PPIs play a major role in understanding the various biological processes and the impact of proteins in diseases. We have developed the Extracting Functional Impact of Phosphorylation (eFIP) text mining system, which combines several natural language processing techniques to find relevant abstracts mentioning phosphorylation of a given protein together with indications of protein-protein interactions (PPIs) and potential evidences for impact of phosphorylation on the PPIs. One of the most common and challenging problem in biomedical text mining is to mine protein-protein interactions (PPIs) from MEDLINE abstracts and full-text research articles because PPIs play a major role in understanding the various biological processes and the impact of proteins in diseases. In this paper, we present a tool called Protopia for searching for and integrating protein-protein interactions and the information about them contained in five different Protein Interaction Web Databases. It can be useful as a friendly search interface among different databases, as a validator of redundant information, as a network visualization tool and also as an export tool to SBML [15]. </context> <question> Which are the available biomedical text mining tools for the detection of protein-protein interactions? </question> <answer> GeneView; PPI finder; PreBIND', 'Textomy; BioMap; eFIP', 'Extracting Functional Impact of Phosphorylation; Protopia; STRING </answer>
<context> The paraspeckle component 1 (PSPC1) and non-POU-domain-containing octamer-binding protein (NONO) heterodimer is an essential structural component of paraspeckles, PSPC1-NONO heterodimer. Crystallization of a paraspeckle protein PSPC1-NONO heterodimer difficult heterodimeric complex of two human proteins, paraspeckle component 1 (PSPC1) and non-POU domain-containing octamer-binding protein (NONO), that are involved in gene regulation and the structural integrity of nuclear bodies termed paraspeckles is described. SFPQ (PSF) and NONO (p54) are nuclear proteins that interact with each other and have diverse roles in nucleic acids metabolism. The SFPQ/NONO heterodimer was previously found to enhance DNA strand break rejoining in vitro. We identified a heterodimer, p54nrb and PSF, P54nrb forms a heterodimer with PSP1 that localizes to paraspeckles in an RNA-dependent manner. e demonstrated that the PSF heterodimer partner, p54nrb (non-POU-domain-containing, octamer binding protein), can also function as a transcription corepressor, independent of PSF. The PSPC1/NONO heterodimer has a right-handed antiparallel coiled-coil Structure of the heterodimer of human NONO and paraspeckle protein component 1 </context> <question> The protein NONO forms heterodimers. With which proteins? </question> <answer> PSPC1; SFPQ </answer>
<context> , a mixture of five SILAC-labeled cell lines that accurately represents the tissue We describe a method to accurately quantify human tumor proteomes by combining a mixture of five stable-isotope labeling by amino acids in cell culture (SILAC)-labeled cell lines with human carcinoma tissue. the use of a mix of multiple SILAC-labeled cell lines as an internal standard, a technique called super-SILAC Equal amounts of the heavy lysates were mixed to generate the super-SILAC mix For accurate quantification we developed a super-SILAC mix from several labeled breast cancer cell lines and used it as an internal standard for all samples. For the preparation of super-SILAC mix (18) equal amounts of heavy lysates were mixed and then combined with nonlabeled cells as described in the RESULTS section to select five cell lines, chosen to be as dissimilar to each other as possible (Jurkat, HEK293, LnCap, HeLa, and K562).As expected from the high correlations, even the SILAC quantification experiments between binary combinations of heavy and light labeled cell lines resulted in narrow ratio distributions (Fig. 6A, 6B). This was further improved in the quantification of the heavy super-SILAC mix against a single cell line (Fig. 6C). These experiments also suggest a general strategy to construct super-SILAC mixes and to evaluate their suitability for quantifying any cell line (or tissue) of interes Knowledge of the overall similarities of the proteomes was used to construct a five cell line, heavy labeled “super-SILAC” reference standard. We developed and used a super-SILAC mix of labeled B-cell lymphoma cell lines as an internal standard to segregate subtypes of DLBCL. </context> <question> Super-SILAC is a method used in quantitative proteomics. What is the super-SILAC mix? (SILAC: Stable Isotopic labelling by aminoacids in cell culture) </question> <answer> The Super-SILAC mix consists of the combination of multiple SILAC-labeled cell lines. </answer>
<context> In this work, we propose a method based on radial basis networks for predicting the number of beta-strands in OMPs and identifying their membrane spanning segments. We have developed a web server, TMBETAPRED-RBF for predicting the transmembrane beta-strands from amino acid sequence and it is available at http://rbf.bioinfo.tw/~sachen/tmrbf.html. We have developed a prediction server, TMBETADISC-RBF, which is available at http://rbf.bioinfo.tw/~sachen/OMP.html. TMB finding pipeline: novel approach for detecting beta-barrel membrane proteins in genomic sequences. Interestingly, the present approach identified TMBs from all 15 families in TCDB. Nevertheless, we show that when several concurring paths are present, as in the case of our beta-barrel HMM, PV performs better than the others. A new decoding algorithm for hidden Markov models improves the prediction of the topology of all-beta membrane proteins. A new method is presented for identification of beta-barrel membrane proteins. It is based on a hidden Markov model (HMM) with an architecture obeying these proteins' construction principles. Once the HMM is trained, log-odds score relative to a null model is used to discriminate beta-barrel membrane proteins from other proteins. Prediction of beta-barrel membrane proteins by searching for restricted domains. Now, four alternative directions are used in order to newly identify β-barrel proteins out of a genomic/proteomic data set. In the first approach, sequence profile based HMMs for predicting β-barrel membrane proteins were developed [10-12]. The second methodology is based on the alternating hydrophobicity as a measure for β-barrel transmembrane segments [13]. Thirdly, the structural data of the β-barrel membrane proteins were statistically analyzed and certain criteria developed for a linear prediction [14,15]. The fourth methodology is based on a modified k-nearest neighbor algorithm of the whole sequence amino acid composition [16,17]. Recently, the combination of several independent procedures for β-barrel membrane protein prediction [18,19] or their combination with other procedures, e.g. signal sequence prediction [15,19], was employed to improve the prediction quality. PRED-TMBB: a web server for predicting the topology of beta-barrel outer membrane proteins. PRED-TMBB: a web server for predicting the topology of beta-barrel outer membrane proteins. We present here a web server (PRED-TMBB, http://bioinformatics.biol.uoa.gr/PRED-TMBB) which is capable of predicting the transmembrane strands and the topology of beta-barrel outer membrane proteins of Gram-negative bacteria. The method is based on a Hidden Markov Model, trained according to the Conditional Maximum Likelihood criterion. Predicting transmembrane beta-barrels in proteomes. Here we introduced the design, statistics and results of a novel profile-based hidden Markov model for the prediction and discrimination of TMBs. A Hidden Markov Model method, capable of predicting and discriminating beta-barrel outer membrane proteins. A sequence-profile-based HMM for predicting and discriminating beta barrel membrane proteins. RESULTS: We develop a HMM model, which can predict the topology of beta barrel membrane proteins using, as input, evolutionary information. . For the reasons mentioned above, there is clearly a need to develop computational tools for predicting the membrane spanning strands of those proteins, and also discriminating them from water-soluble proteins when searching entire genomes. OMPdb: a database of {beta}-barrel outer membrane proteins from Gram-negative bacteria. Given these facts, and because many β-barrel OMPs nowadays attract an increased medical interest, several approaches have been made towards the development of predictive algorithms for this type of proteins. These methods are based grossly on hydrophobicity (10) and statistical analysis (11,12), remote homology detection (13), Hidden Markov Models (HMMs) (14–18), feed-forward Neural Networks (19–21), radial basis function Neural Networks (22,23) and Support Vector Machines (24), whereas others like BOMP (25), TMB-Hunt (26,27) and the TMB-finding pipeline (28) are oriented towards genome scale discrimination of β-barrel membrane proteins. transFold: a web server for predicting the structure and residue contacts of transmembrane beta-barrels. In the last few years, various methods have addressed TM β-barrel structure prediction (1–6). The transFold program extends a method introduced previously by Waldispühl and Steyaert (8) for TM α-bundle proteins, and employs statistical potentials developed for the program BETAWRAP (9,10). Our software, named transFold, applies grammars to describe all potential β-barrel supersecondary structures and then computes the global minimum energy structure by dynamic programming. Evaluation of methods for predicting the topology of beta-barrel outer membrane proteins and a consensus prediction method. We have evaluated the currently available methods, for predicting the topology of β-barrel outer membrane proteins, using a non-redundant dataset of 20 proteins with structures known at atomic resolution. By using multivariate and univariate analysis of variance, we conclude that the HMM-based methods HMM-B2TMR, ProfTMB and PRED-TMBB perform significantly better than the other (mostly NN-based) methods, in both terms of per-residue and per-segment measures of accuracy. A consensus prediction method is for the first time been applied for the prediction of the transmembrane strands, of β-barrel outer membrane proteins. BOMP: a program to predict integral beta-barrel outer membrane proteins encoded within genomes of Gram-negative bacteria. This work describes the development of a program that predicts whether or not a polypeptide sequence from a Gram-negative bacterium is an integral beta-barrel outer membrane protein. The program, called the beta-barrel Outer Membrane protein Predictor (BOMP), is based on two separate components to recognize integral beta-barrel proteins. This work describes the development of a program that predicts whether or not a polypeptide sequence from a Gram-negative bacterium is an integral beta-barrel outer membrane protein. The program, called the beta-barrel Outer Membrane protein Predictor (BOMP), is based on two separate components to recognize integral beta-barrel proteins. On the basis of existing knowledge of beta-barrel outer-membrane proteins, several state of the art prediction methods, as well as a new in-house program (PROB) were employed for the systematic exploration of Mycobacterium tuberculosis predicted proteomes for potential beta-barrel structures. Computational identification of beta-barrel outer-membrane proteins in Mycobacterium tuberculosis predicted proteomes as putative vaccine candidates. BETAWARE: a machine-learning tool to detect and predict transmembrane beta-barrel proteins in prokaryotes. Recently, we developed two top-performing methods based on machine-learning approaches to tackle both the detection of TMBBs in sets of proteins and the prediction of their topology. Supersecondary structure prediction of transmembrane beta-barrel proteins. We introduce a graph-theoretic model for predicting the supersecondary structure of transmembrane β-barrel proteins--a particular class of proteins that performs diverse important functions but it is difficult to determine their structure with experimental methods. BOCTOPUS: improved topology prediction of transmembrane β barrel proteins. Here, we present BOCTOPUS; an improved method for the topology prediction of TMBs by employing a combination of support vector machines (SVMs) and Hidden Markov Models (HMMs). TMBHMM: a frequency profile based HMM for predicting the topology of transmembrane beta barrel proteins and the exposure status of transmembrane residues. We present here TMBHMM, a computational method based on a hidden Markov model for predicting the structural topology of putative TMBs from sequence. In addition to predicting transmembrane strands, TMBHMM also predicts the exposure status (i.e., exposed to the membrane or hidden in the protein structure) of the residues in the transmembrane region, which is a novel feature of the TMBHMM method. Furthermore, TMBHMM can also predict the membrane residues that are not part of beta barrel forming strands. We present BTMX (Beta barrel TransMembrane eXposure), a computational method to predict the exposure status (i.e. exposed to the bilayer or hidden in the protein structure) of transmembrane residues in transmembrane beta barrel proteins (TMBs). BTMX predicts the exposure status of known TM residues with an accuracy of 84.2% over 2,225 residues and provides a confidence score for all predictions. A method for discovering transmembrane beta-barrel proteins in Gram-negative bacterial proteomes. A web server based on the proposed method is available at http://yanbioinformatics.cs.usu.edu:8080/TMBKNNsubmit. This paper presents a k-nearest neighbor (K-NN) method for discriminating TMB and non-TMB proteins. TMBpro: secondary structure, beta-contact and tertiary structure prediction of transmembrane beta-barrel proteins. We develop a suite (TMBpro) of specialized predictors for predicting secondary structure (TMBpro-SS), beta-contacts (TMBpro-CON) and tertiary structure (TMBpro-3D) of transmembrane beta-barrel proteins. We compare our results to the recent state-of-the-art predictors transFold and PRED-TMBB using their respective benchmark datasets, and leave-one-out cross-validation. PROFtmb: a web server for predicting bacterial transmembrane beta barrel proteins. PROFtmb predicts TMBs from Gram-negative bacteria only. For each sequence, PROFtmb builds a PSI-BLAST profile and runs the prediction, attempting to find the best fit of the protein to its TMB-based architecture, indicated as a Z-value. A consensus algorithm to screen genomes for novel families of transmembrane beta barrel proteins. Here we describe a new algorithm combining composition and hidden Markov model topology based classifiers (called TMB-Hunt2), which achieves a crossvalidation accuracy of >95%, with 96.7% precision and 94.2% recall. Tools and datasets are made available through a website called TMB-Web (http://www.bioinformatics.leeds.ac.uk/TMB-Web/TMB-Hunt2). TMB-Hunt: a web server to screen sequence sets for transmembrane beta-barrel proteins. TMB-Hunt is a program that uses whole sequence amino acid composition to discriminate between TMB and non-TMB proteins. TMB-Hunt is extremely quick, and so the web server allows screening of up to 10 000 sequences in a single query. TMB-Hunt uses whole sequence amino acid composition to discriminate between TMB and non-TMB proteins. However, although studies of TMB protein composition have been made, whole sequence amino acid composition has not yet been applied to the discrimination problem.Because TMB-Hunt puts no emphasis on identification of TM β-strands, we were not dependent on sequences with resolved structures, thus allowing the use of training sets that were larger and more representative than those used for other predictors. sing the ‘leave homologues out’ cross-validation, without inclusion of evolutionary information and without differential amino acid weightings, the program was able to discriminate between TMB and NTM proteins with 85% accuracy, 83% sensitivity and 86.5% positive predictive value (PPV). </context> <question> What are the computational tools for the prediction of beta-barrel transmembrane proteins? </question> <answer> BETAWARE; BOCTOPUS; BOMP; BTMX; HMM-B2TMR; OMPdb; PRED-TMBB; PROB; ProfTMB; PV; TMB finding pipeline; TMBETADISC-RBF; TMBETAPRED-RBF; TMBHMM; TMB-Hunt', 'TMB-Hunt2; TMBKNN; TMBpro; transFold; TMBETA-NET </answer>
<context> Toward Single Cell Analysis by Plume Collimation in Laser Ablation Electrospray Ionization Mass Spectrometry. he advent of proteomics and genomics at a single-cell level has set the basis for an outstanding improvement in analytical technology and data acquisition. The new-generation technology of single-cell analysis is able to better characterize a cell's population, identifying and differentiating outlier cells, in order to provide both a single-cell experiment and a corresponding bulk measurement, through the identification, quantification and characterization of all system biology aspects (genomics, transcriptomics, proteomics, metabolomics, degradomics and fluxomics). The movement of omics into single-cell analysis represents a significant and outstanding shift. Laser ablation electrospray ionization (LAESI) is a novel method for the direct imaging of biological tissues by mass spectrometry. By performing ionization in the ambient environment, this technique enables in vivo studies with potential for single-cell analysis. Other approaches for MS-based chemical imaging and profiling include those based on near-field laser ablation and inductively-coupled plasma MS analysis, which offer complementary capabilities for subcellular chemical imaging and profiling. Mass spectrometry imaging and profiling of single cells. his is rapidly changing with the recent examples of single cell genomics, transcriptomics, proteomics and metabolomics. The rate of change is expected to accelerate owing to emerging technologies that range from micro/nanofluidics to microfabricated interfaces for mass spectrometry to third- and fourth-generation automated DNA sequencers Single-cell analysis (SCA) has been increasingly recognized as the key technology for the elucidation of cellular functions, which are not accessible from bulk measurements on the population level. Thus far, SCA has been achieved by miniaturization of established engineering concepts to match the dimensions of a single cell Single-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells. The amount of single proteins in single cells can be as low as one copy per cell and is for most proteins in the attomole range or below; usually considered as insufficient for proteomic analysis. n Arabidopsis thaliana, we have successfully identified nine unique proteins in a single-cell sample and 56 proteins from a pool of 15 single-cell samples from glucosinolate-rich S-cells by nanoLC-MS/MS proteomic analysis, thus establishing the proof-of-concept for true single-cell proteomic analysis A first step towards practical single cell proteomics: a microfluidic antibody capture chip with TIRF detection. </context> <question> Is single-cell analysis (SCA) possible in proteomics? </question> <answer> no </answer>
<context> In conjunction with the XFEL temporal profile and high-flux, it is a powerful tool for studying the dynamics of time-dependent systems. Photo-induced processes and fast catalytic reaction kinetics, ranging from femtoseconds to milliseconds, will be resolvable in a wide array of systems circumventing radiation damage. We discuss the pertinent physics of the intense X-ray-matter interactions, and illustrate the importance of electron-ion collisions. Detailed simulations of the interaction process conducted with a radiative-collisional code show good qualitative agreement with the experimental results. We obtain insights into the evolution of the charge state distribution of the system, the electron density and temperature, and the timescales of collisional processes. Our results should inform future high-intensity X-ray experiments involving dense samples, such as X-ray diffractive imaging of biological systems, material science investigations, and the study of matter in extreme conditions. employment of "exotic" systems, such as the Free Electron LASER (FEL), that are expected to focus on the fundamental processes of life, following chemical reactions and biological processes as they happen, on unprecedented time and size scales. New data analysis approaches are outlined for the correlated fluctuations in fast WAXS, for protein nanocrystals just a few molecules on a side, and for the continuous x-ray scattering from a single virus Research opportunities and techniques are reviewed for the application of hard x-ray pulsed free-electron lasers (XFEL) to structural biology. These include the imaging of protein nanocrystals, single particles such as viruses, pump--probe experiments for time-resolved nanocrystallography, and snapshot wide-angle x-ray scattering (WAXS) from molecules in solution. The use of femtosecond exposure times, rather than freezing of samples, as a means of minimizing radiation damage is shown to open up new opportunities for the molecular imaging of biochemical reactions at room temperature in solution New opportunities for solving the phase problem for XFEL data are outlined. A summary of the latest results is given, which now extend to atomic resolution for nanocrystals. Possibilities for time-resolved chemistry using fast WAXS (solution scattering) from mixtures is reviewed, toward the general goal of making molecular movies of biochemical processes. Molecular imaging using X-ray free-electron lasers. The recent development of X-ray free-electron laser sources has created new opportunities for the structural analysis of protein nanocrystals. X-ray free electron lasers hold the promise of enabling atomic-resolution diffractive imaging of single biological molecules. The emergence of femtosecond diffractive imaging with X-ray lasers has enabled pioneering structural studies of isolated particles, such as viruses, at nanometer length scales. In this paper we report room temperature X-ray diffraction data of PS II microcrystals obtained using ultrashort (< 50 fs) 9 keV X-ray pulses from a hard X-ray free electron laser, namely the Linac Coherent Light Source. High-resolution protein structure determination by serial femtosecond crystallography We applied serial femtosecond crystallography (SFX) using an x-ray free-electron laser (XFEL) to obtain high-resolution structural information from microcrystals (less than 1 micrometer by 1 micrometer by 3 micrometers) of the well-characterized model protein lysozyme. Time-resolved protein nanocrystallography using an X-ray free-electron laser We demonstrate the use of an X-ray free electron laser synchronized with an optical pump laser to obtain X-ray diffraction snapshots from the photoactivated states of large membrane protein complexes in the form of nanocrystals flowing in a liquid jet. We describe the experimental setup and obtain the first time-resolved femtosecond serial X-ray crystallography results from an irreversible photo-chemical reaction at the Linac Coherent Light Source. This technique opens the door to time-resolved structural studies of reaction dynamics in biological systems. X-ray free electron laser (X-FEL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology. Here we recorded interpretable diffraction data from micrometer-sized lipidic sponge phase crystals of the Blastochloris viridis photosynthetic reaction center delivered into an X-FEL beam Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source. Single mimivirus particles intercepted and imaged with an X-ray laser Femtosecond X-ray protein nanocrystallography Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. Hard X-ray free-electron lasers (XFELs) are currently under construction in Europe (http://xfel.desy.de/) and Japan (http://www-xfel.spring8.or.jp/) and the first American XFEL facility has recently reported lasing at 8 keV (http://lcls.slac.stanford.edu/). These fourth-generation X-ray sources promise extremely intense hard X-ray bursts of approximately 100 fs in duration, and will thereby create new opportunities for imaging of biological molecules from extremely small samples (Neutze et al., 2000 ▶, 2004 ▶).Within the realm of time-resolved pump–probe structural studies, the most obvious benefit of these emerging sources will be their remarkable capability to probe the structural dynamics of light-driven reactions with a temporal resolution of 100 fs These methods can be used to image biological and materials science samples at high resolution with x-ray undulator radiation and establishes the techniques to be used in atomic-resolution ultrafast imaging at x-ray free-electron laser sources. With the prospects of the x-ray free electron lasers, this approach could provide a major new opportunity for the high-resolution three-dimensional structure determination of single biomolecules. X-ray free-electron lasers (XFELs) generate sequences of ultra-short spatially coherent pulses of X-ray radiation. Diffractive imaging using the intense and coherent beam of X-ray free-electron lasers opens new perspectives for structural studies of single nanoparticles and biomolecules. The opening of hard X-ray free-electron laser facilities, such as the Linac Coherent Light Source (LCLS) at SLAC National Accelerator Laboratory in the United States, has ushered in a new era in structural determination. Where possible we also highlight areas that we think could push this field forward with emerging technologies, such as X-ray free electron lasers (X-feL), which could have a big impact on the membrane protein structural biology community. X-ray free electron lasers (XFELs) deliver short (<100 fs) and intense (∼10(12) photons) pulses of hard X-rays, making them excellent sources for time-resolved studies. Modern imaging techniques at the molecular scale rely on utilizing novel coherent light sources like X-ray free electron lasers for the ultimate goal of visualizing such objects as individual biomolecules rather than crystals. In single-particle coherent x-ray diffraction imaging experiments, performed at x-ray free-electron lasers (XFELs), samples are exposed to intense x-ray pulses to obtain single-shot diffraction patterns. The structure reveals the mechanism of native TbCatB inhibition and demonstrates that new biomolecular information can be obtained by the "diffraction-before-destruction" approach of x-ray free-electron lasers from hundreds of thousands of individual microcrystals. Coherent diffraction imaging (CDI) of single molecules at atomic resolution is a major goal for the x-ray free-electron lasers (XFELs). Ultrashort X-ray pulses from free-electron laser X-ray sources make it feasible to conduct small- and wide-angle scattering experiments on biomolecular samples in solution at sub-picosecond timescales. The short and intense pulses of the new X-ray free electron lasers, now operational or under construction, may make possible diffraction experiments on single molecule-sized objects with high resolution, before radiation damage destroys the sample. The recent development of x-ray free electron lasers providing coherent, femtosecond-long pulses of high brilliance and variable energy opens new areas of scientific research in a variety of disciplines such as physics, chemistry, and biology. The advent of light sources based on the X-ray free-electron laser (XFEL) principle, has opened the door to a multitude of experiments in various fields of science. X-ray free electron laser (X-FEL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology. X-ray free-electron lasers (FELs) show promise for revealing the structure of single molecules or nanocrystals, but the phase problem remains largely unsolved. Coherent diffractive imaging using x-ray free-electron lasers (XFELs) may provide a unique opportunity for high-resolution structural analysis of single particles sprayed from an aqueous solution into the laser beam. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. This work is directly relevant to the time-resolved imaging of magnetic dynamics using coherent and ultrafast radiation from x-ray free-electron lasers and also to broader classes of diffractive imaging experiments which suffer noisy data, missing data, or both. By combining serial nanocrystallography with x-ray free-electron laser sources in the future, it may be possible to produce molecular-resolution electron-density maps using membrane protein crystals that contain only a few hundred or thousand unit cells. Very strong soft X-ray free electron laser (FEL) pulses must be short to allow for investigations of ultra-fast wet chemistry, according to the principle of collect and destroy. </context> <question> Where is X-ray free electron laser used? </question> <answer> high resolution protein structure determination; molecular imaging', 'single-particle imaging; study of enzyme kinetics', 'time resolved protein crystallography </answer>
<context> Multiple endocrine neoplasia type 1 (MEN1; formerly known as Wermer syndrome) is a rare disorder characterized by the combined occurrence of two or more tumors involving parathyroid, pancreatic islets and anterior pituitary glands; some other tumors have also been described. Hyperparathyroidism is the most common feature of MEN1 (95% of patients), pancreatic islet tumors or pancreatic NET (neuroendocrine tumor) occur in 40-70% and pituitary tumors in 30-40% of MEN 1 patients In addition, other tumors, such as adrenal cortical tumors, carcinoid tumors, lipomas, angiofibromas, colagenomas and meningiomas may be present. the most important causes malignant pancreatic neuroendocrine tumors (NET) and thymic carcinoids. Multiple endocrine neoplasia type 1 (MEN1) is inherited in an autosomal dominant fashion and predisposes to the development of hyperplastic or neoplastic changes in the parathyroid and pituitary glands and the endocrine pancreas, along with numerous other characteristic tumors and features. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid and adrenocortical tumors, and neuroendocrine tumors (NETs) of the pancreas and pituitary. The pancreatic NETs are predominantly gastrinomas and insulinomas, and the pituitary NETs are mostly prolactinomas and somatotrophinomas. We address the potential role of miRNAs in the endocrine pancreas, the pituitary gland, and the parathyroid glands-areas where MEN 1 shows high penetrance. Moreover, studies have provided evidence that dysregulation of miRNAs was responsible for endocrine carcinogenesis, including pancreatic, pituitary, and parathyroid tumors. MEN1 and MEN2 are rare inherited cancer syndromes which express a variety of endocrine and nonendocrine tumors. Multiple endocrine neoplasia Type 1 (MEN1) is a rare hereditary tumor syndrome predisposing to tumor development in several endocrine organs. Its major manifestations include hyperparathyroidism, tumors of endocrine pancreas and pituitary. eside these three, several other endocrine (adrenocortical, foregut carcinoid) and nonendocrine (lipoma, angiofibroma, collagenoma, ependymoma, meningioma) tumors have been described to be associated with this syndrome Both familial and sporadic forms of the disease are known. The diagnosis of MEN1 can be established if two of the three major manifestations are found in the same patient, whereas the diagnosis of familial MEN1 requires one MEN1 patient and a first degree relative with at least one MEN1 manifestation. Both benign (parathyroid, anterior pituitary) and malignant (gastrinoma, glucagonoma) lesions may develop in MEN1 patients Multiple endocrine neoplasia type 1 (MEN1) is a classic hereditary tumor syndrome characterized by a genetic predisposition to develop a variety of neuroendocrine neoplasias and hormone excess syndromes. Multiple endocrine neoplasia type 1 (MEN 1) is a familial syndrome characterized by parathyroid, enteropancreatic and pituitary tumors. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited tumor syndrome characterized by the development of multiple endocrine tumors Multiple facial angiofibromas were observed in 28 (88%) of the patients with MEN1, with 16 patients (50%) having 5 or more. Angiofibromas were clinically and histologically identical to those in individuals with tuberous sclerosis. Collagenomas were observed in 23 patients (72%). Also observed were cafe au lait macules in 12 patients (38%), lipomas in 11 patients (34%), confetti-like hypopigmented macules in 2 patients (6%), and multiple gingival papules in 2 patients (6%) Multiple angiofibromas, collagenomas, lipomas, confetti-like hypopigmented macules and multiple gingival papules are cutaneous manifestations of MEN1 and should be looked for in both family members of patients with MEN1 and individuals with hyperparathyroidism of other MEN1-associated tumors. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder characterized by nodular proliferation of the parathyroid glands and tumors of the anterior pituitary gland, the endocrine pancreas, and the neuroendocrine cell system of the gut. We report here a genetic study of a female MEN1 patient with the association of nodular hyperplasia of two parathyroid glands, an insulinoma, multiple duodenal gastrinomas, a prolactinoma, and a gastric carcinoid. Multiple endocrine neoplasia type 1 (MEN1) is defined clinically by the combined occurrence of multiple tumors, typically of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. In support of previous findings in islet tumors, we found down-regulation of the cell-cycle regulator, p18, in both the pancreatic islet and pituitary adenomas, suggesting that reduced p18 levels may be important for Men1-related tumorigenesis in multiple tissues. Surprisingly, we identified increased p16 transcript in pancreatic islet and pituitary tumors. The patient was studied and diagnosed with a multiple endocrine neoplasia type I (MEN I), familiar (mother with MEN I). A scintigraphic study with 99mTc-MIBI was performed in order to localize hyperfunctioning parathyroid glands because of biochemical diagnosis of primary hyperparathyroidism. The tumor was removed and histologically confirmed as a carcinoid within a thymus in a MEN type I syndrome. MEN I patients can benefit from the examination with this agent which can potentially localize not only parathyroid endocrine pathology but also unknown associated tumors. Pancreatic endocrine tumors occur sporadically and as part of the multiple endocrine neoplasia type 1 (MEN 1) and von Hippel-Lindau (VHL) syndromes. We have analyzed 22 nonfamilial and 16 MEN 1-associated pancreatic endocrine tumors for loss of heterozygosity (LOH) at 3p, 11q13, and 18q. LOH at 3p was revealed in 45% and 36% of tumors from 31 patients with nonfamilial and MEN 1-associated disease, respectively. The data indicate involvement of tumor suppressor genes on 3p and 18q, in addition to the MEN1 gene at 11q13, in the tumorigenesis of both nonfamilial and MEN 1-associated pancreatic endocrine tumors. Multiple endocrine neoplasia type 1 (MEN1) is characterized by the development of endocrine tumors of the parathyroid and pituitary glands, pancreas, and duodenum. Less frequently occurring tumors associated with MEN1 include non-endocrine tumors such as lipomas and angiofibromas. An increased incidence of thyroid neoplasms, leiomyomas, adrenal cortical hyperplasia, hepatic focal nodular hyperplasia, and renal angiomyolipoma has been noted in the MEN1 population. A germline mutation of the MEN1 gene was detected, and deletions of the MEN1 gene were consistently detected in multiple neuroendocrine tumors involving the parathyroid glands and the pancreas and a hepatic neuroendocrine tumor metastasis, as predicted by Knudson's "two hit" hypothesis. Two hits of the MEN1 gene were also detected in esophageal leiomyoma tissue, suggesting that tumorigenesis was directly related to the patient's underlying MEN1. In contrast, follicular thyroid adenoma, papillary thyroid carcinoma, hepatic focal nodular hyperplasia, and adrenal cortical hyperplasia consistently showed retained heterozygosity of the MEN1 gene with flanking markers and an intragenic marker. Therefore, these tumors appear to develop along pathogenetic pathways that are different from classical MEN1-associated tumors. Twelve unrelated (German MEN1 families and their associated tumors (5 parathyroid tumors, 1 vipoma, 1 gastrinoma, 1 insulinoma) were characterized for MEN1 gene mutations by single-strand conformational variant (SSCV) analysis and DNA sequence analysis as well as for loss of heterozygosity on chromosome 11q13. Multiple endocrine neoplasia type 1 (MEN1) consists of benign, and sometimes malignant, tumors (often multiple in a tissue) of the parathyroids, enteropancreatic neuroendocrine system, anterior pituitary, and other tissues. Skin angiofibromas and skin collagenomas are common. </context> <question> Tumors of which three organs are classically associated with the multiple endocrine neoplasia type 1 syndrome? </question> <answer> parathyroid gland; pancreas; pituitary gland </answer>
<context> The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (LES), which are known to inhibit ICa and INa in bovine adrenal chromaffin cells, also significantly inhibited INa in SCLC cells. These results indicate that (i) action potentials in human SCLC cells result from the regenerative increase in voltage-gated Na+ channel conductance; (ii) fundamental characteristics of SCLC Na+ channels are the same as the classical sodium channels found in a variety of excitable cells; and (iii) in some LES patients, SCLC Na+ channels are an additional target of the pathological IgG present in the patients' sera. Clinical features were those of LES and occurred insidiously in this 68-year old man: proximal weakness predominant in the lower limbs, generalized areflexia, dryness of the mouth and partial right eye palsy. Investigations disclosed a small cell lung cancer. Voltage-gated Ca2+ channels may be important to the secretion of ectopic hormones and the etiology and pathogenesis of Lambert-Eaton syndrome, an autoimmune disorder of the motor nerve terminal in which autoantibodies directed against voltage-gated Ca2+ channels are produced. Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin which is often associated with anaplastic small-cell lung cancer. Small-cell lung cancer (SCLC) is the most common cause of LES. We report an unusual case of LES associated with large-cell neuroendocrine carcinoma (LCNEC) of the lung. The Lambert-Eaton syndrome is caused by antibodies against voltage-gated calcium channels and often occurs in patients with small cell lung cancer. A 53 year-old heavy smoker presented with a Lambert-Eaton myasthenic syndrome (LEMS). Bronchoscopy was normal but radiological examinations revealed a lymph node in site 4R. The pathological diagnosis after mediastinoscopy was negative. Twenty-five months later, an opacity on chest X-ray led to a biopsy which revealed a squamous cell carcinoma. LEMS is generally associated with small cell lung cancer occurring in three percent of cases. However, the case that we report shows the unusual association of LEMS with non small-cell lung cancer and highlights the difficulties associated in the management of this condition. LEMS has a high degree of coincidence (approximately 60%) with small cell lung cancer; the remaining 40% of patients with LEMS have no detectable tumor. BACKGROUND: To enhance the acknowledgement of Lambert-Eaton syndrome in patients with small cell lung cancer. There were 10 cases of Lambert-Eaton syndrome in 332 pathologically diagnosed small cell lung cancer Treatment of small cell lung cancer may improve the symptoms of Lambert-Eaton syndrome Improving the recognition of Lambert-Eaton syndrome may be helpful to identify early small cell lung cancer and improve the prognosis,as the symptom of muscular weakness usually appears early before the diagnosis of small cell lung cancer. The Lambert Eaton syndrome is a paraneoplastic manifestation of small-cell lung cancer in 50% of the cases unlike generalized myasthenia which apparently is never associated with small-cell lung cancer. Paraneoplastic Lambert-Eaton myasthenia syndrome is presented in two cases with small cell lung cancer. Human small-cell lung cancer (SCLC) cells are believed to express the antigens responsible for the production of pathological antibodies in the Lambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal transmitter release from the motor nerve terminal is impaired. Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder caused by an IgG-mediated reduction in number of presynaptic voltage-gated calcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases, the stimulus for antibody production may be VGCC on small cell lung cancer (SCLC) Also, there was no obvious band pattern distinguishing patients with LES from those with LES and concurrent SCLC. The cancer associated with LEMS was small-cell lung carcinoma (SCLC) in 15 cases and epidermoid lung carcinoma in 3 cases. Etiology of this disease is uncertain but in view of its frequent association with small cell lung cancer, this specific type of neoplasm may be implicated in the initiation of autoimmune response. Recent studies indeed support the possibility that the antigenic stimulus in the neoplastic form of LES may arise from voltage-dependent Ca2+ channels found in the lung cancer cells. In the majority of LEMS patients, those having detectable tumor, the disease is thought to occur as a result of immune response directed initially against voltage-gated Ca2+ channels found on the lung tumor cells. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. Physicians need to be aware that patients may develop PCD and LEMS associated with anti-VGCC antibody caused by small cell lung cancer, and a mass survey should be conducted and careful examinations performed. Biopsy revealed small cell lung cancer (SCLC) indicating the importance of repeated chest CT in LEMS even when an existing autoimmune-like disease and negative CT may suggest an autoimmune origin. BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. The detection of SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup. The presence of a particular symptom associated with LEMS did not predict the presence of SCLC, but in patients with rapidly progressive LEMS the possibility of underlying lung cancer should be of particular concern. We report a case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory failure in a 67-year-old man who initially presented with progressive limb weakness for 6 months and tachypnea with shallow breathing for 1 week. Using this protein, we demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The gene encoding the beta 2 protein, first described as a Lambert-Eaton myasthenic syndrome (LEMS) antigen in humans, is found close to a region that undergoes chromosome rearrangements in small cell lung cancer, which occurs in association with LEMS. We then tested sera from 72 LEMS patients' 25 with proven small cell lung cancer (SCLC) and 66 healthy or other neurological, SCLC or autoimmune disease controls in an immunoprecipitation assay using 125I-omega-CmTx-labelled (P/Q-type) VGCCs in human cerebellar extract. In the majority of patients LEMS is associated with small cell lung cancer (SCLC). Patients with small cell lung cancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in patients affected by LEMS. We present a 69-year-old woman who had preventive whole brain radiation after a diagnosis of paraneoplastic Lambert-Eaton syndrome related to small cell lung cancer Five months after radiation therapy, she developed radiation-induced leukoencephalopathy manifested by ataxia. Physicians need to be aware that patients may develop PCD and LEMS associated with anti-VGCC antibody caused by small cell lung cancer, and a mass survey should be conducted and careful examinations performed. Biopsy revealed small cell lung cancer (SCLC) indicating the importance of repeated chest CT in LEMS even when an existing autoimmune-like disease and negative CT may suggest an autoimmune origin. BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. The detection of SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome (LEMS) predicts the presence of small cell lung cancer and may be used to follow more closely those LEMS patients with no evidence of cancer at the initial workup. Among the symptoms of lung cancer LEMS can be seen, but it is very rare. The presence of a particular symptom associated with LEMS did not predict the presence of SCLC, but in patients with rapidly progressive LEMS the possibility of underlying lung cancer should be of particular concern. We report a case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory failure in a 67-year-old man who initially presented with progressive limb weakness for 6 months and tachypnea with shallow breathing for 1 week. Using this protein, we demonstrated that anti-beta-subunit antibodies are present in the sera of 23% of LEMS patients and only, in low titer, in 2% of small cell lung cancer patients without LEMS. The gene encoding the beta 2 protein, first described as a Lambert-Eaton myasthenic syndrome (LEMS) antigen in humans, is found close to a region that undergoes chromosome rearrangements in small cell lung cancer, which occurs in association with LEMS. We then tested sera from 72 LEMS patients' 25 with proven small cell lung cancer (SCLC) and 66 healthy or other neurological, SCLC or autoimmune disease controls in an immunoprecipitation assay using 125I-omega-CmTx-labelled (P/Q-type) VGCCs in human cerebellar extract. In the majority of patients LEMS is associated with small cell lung cancer (SCLC). Patients with small cell lung cancer (SCLC) in particular may develop LEMS, and SCLC is very often detected in patients affected by LEMS. A patient with the Lambert-Eaton syndrome (LES) and small cell lung cancer developed respiratory failure several hours after verapamil was given. Patients with LEMS have mostly small cell lung cancer (SCLC); other subtypes of lung cancer are extremely rare. </context> <question> Which type of lung cancer is the most strongly associated with Lambert-Eaton syndrome? </question> <answer> small-cell lung cancer </answer>
<context> Krabbe disease is a lethal, demyelinating condition caused by genetic deficiency of galactocerebrosidase (GALC) and resultant accumulation of its cytotoxic substrate, psychosine (galactosylsphingosine), primarily in oligodendrocytes (OLs). In this study, we report that accumulation of endogenous psychosine under GALC deficient Krabbe conditions impedes OL differentiation process both by decreasing the expression of myelin lipids and protein and by inducing the cell death of maturating OLs. In almost all individuals with Krabbe disease, galactocerebrosidase (GALC) enzyme activity is deficient (0%-5% of normal activity) in leukocytes isolated from whole heparinized blood or in cultured skin fibroblasts. This chapter describes in detail a practical procedure for the preparation of radiolabeled galactocerebroside and its use in the assay of galactocerebrosidase (GalCase), the enzyme deficient in globoid cell leukodystrophy (Krabbe disease). Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside beta-galactosidase. Krabbe disease is an extremely rare condition with an incidence of 1 in 1,00,000 live births. It is caused by deficient activity of the Iysosomal hydrolase galactosylceramide beta-galactosidase. Globoid cell leukodystrophy (Krabbe disease) is characterized by the accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is a substrate for the deficient enzyme (galactocerebroside beta-galactosidase). Krabbe disease (globoid-cell leukodystrophy; GLD) is caused by mutations in the GALC gene. Beta-galactocerebrosidase (GALC) is a specific beta-galactosidase which is defective in GLD. Both galactosylceramide beta-galactosidase (GALC-GC) and GALC-PS activities were reduced by at least 85% of the normal in all but 2 of the 10 GLD patients studied. Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC) activity. The disease can be diagnosed by detecting the deficiency of GALC activity (less than 5% of normal) in any available tissue sample. Globoid cell leukodystrophy, or Krabbe disease, is a severe disorder of the peripheral and central nervous system myelin caused by deficient galactocerebrosidase (GALC) activity. Globoid cell leukodystrophy (GCL or Krabbe disease) is a recessive disease caused by mutations of the lysosomal enzyme galactocerebrosidase (GALC) and twitcher is the murine model of GCL. Galactocerebrosidase (GALC) is the lysosomal enzyme deficient in human and certain animal species with globoid cell leukodystrophy (GLD) or Krabbe disease. Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of the myelin glycolipid galactocerebroside. Krabbe disease is an autosomal recessive inherited demyelinating disease, which is deficient in lysosomal enzyme, galactocerebrosidase. Galactocerebrosidase (GALC) activity is deficient in all patients with globoid cell leukodystrophy (GLD). Human galactocerebrosidase, the enzyme deficient in Krabbe disease, was purified, through several hydrophobic column steps and gel filtration, 22,650-fold from human lymphocytes Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. 6-Hexadecanoylamino-4-methylumbelliferyl-beta-D-galactopyranoside (HMGal) has been shown to be a specific fluorogenic substrate of galactocerebrosidase and to facilitate the simple enzymatic diagnosis of Krabbe disease in human patients and in twitcher mice. The inherited deficiency of galactosylceramide beta-galactosidase (E.C. 3.2.1.46: galactocerebrosidase) activity results in globoid cell leukodystrophy in humans (Krabbe disease) and in mice (twitcher mutant). The lack of complementation between Krabbe disease patient and twitcher mutant mouse cells provides further evidence that the twitcher mouse is an authentic murine model for Krabbe disease and supports the hypothesis that the mutations in both species are within the structural gene for the galactocerebrosidase enzyme. Galactosylceramide beta-galactosidase cross reacting material was demonstrated in brain, liver, and skin fibroblasts from patients with Krabbe disease. . In this study, LRs in the brain of the twitcher (TWI) mouse, a bona-fide model for infant variants of human globoid cell leukodystrophy or Krabbe disease, were investigated. This mouse has deficient activity of GALC (beta-galactosylceramidase) that leads to a progressive accumulation of some galactosyl-sphingolipids in the brain. A GALC genotype with one deleted and one polymorphic GALC activity-reducing allele can lead to enzymatic and clinical signs of LOGLD in the absence of marked GALC-PS deficiency. Galactocerebrosidase (GALC) is deficient in all tissues from human patients and animal models with globoid cell leukodystrophy (GLD) or Krabbe disease. The purification of GALC and the securing of amino acid sequence information will aid in the cloning of the GALC gene. This enzyme is deficient in human patients with Krabbe disease and several animal species. </context> <question> Which enzyme is deficient in Krabbe disease? </question> <answer> Galactocerebrosidase is an enzyme that is deficient in Krabbe disease (also known as globoid-cell leukodystrophy). This leads to accumulation of psychosine (galactosylsphingosine) primarily in oligodendrocytes. </answer>
<context> he miRNAs miR-126 and miR-508-5p are associated with the outcome of ICM and NICM patients with CHF. These two miRNAs could be useful in the diagnosis of CHF patients, and might provide novel targets for prevention and treatment of CHF. The plasma concentration of miR-126 was negatively correlated with age and NYHA class, and could be a useful biomarker for heart failure. In 10 patients with heart failure, plasma concentrations of miR-126 were up-regulated with improvement of the NYHA class from IV to III. </context> <question> Is miR-126 involved in heart failure? </question> <answer> yes </answer>
<context> Dabigatran etexilate is a novel oral direct thrombin inhibitor, which provides stroke risk reduction for patients with nonvalvular atrial fibrillation. Dabigatran is a potent reversible, competitive direct thrombin inhibitor which is available as the prodrug, Dabigatran etexilate. The recently introduced oral direct thrombin antagonist, dabigatran, has been shown in phase III clinical trials to be noninferior in efficacy to warfarin for the prevention of thromboembolic events in patients with atrial fibrillation, as well as in treatment of acute venous thromboembolism. Dabigatran is an oral, reversible direct thrombin inhibitor approved in Europe and in several other countries for the prevention of venous thromboembolism after elective knee and hip replacement surgery. This mechanism of action is different from that of other anticoagulants that have been or are currently used in clinical practice, such as warfarin (a vitamin K antagonist) [4], enoxaparin (an indirect thrombin/Factor Xa inhibitor) [5], [6], ximelagatran (now withdrawn) [7] and dabigatran (direct thrombin inhibitors) Dabigatran etexilate is a direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin. Direct inhibitors of FXa (rivaroxaban), FVIIa (BMS-593214), thrombin (dabigatran, argatroban) and FXIa (BMS-262084) were included for comparison. Two agents, the direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitor rivaroxaban, have recently been approved in the EU and several other countries for the prevention of VTE after total hip or knee replacement surgery. The direct thrombin inhibitor dabigatran is farthest along in development. Lastly, inhibitors of thrombin activity are composed of either indirect (UFH, LMWH), or direct thrombin (FIIa) inhibitors including: hirudin, argatroban, melagatran, ximelagatran, dabigatran, and bivalirudin. The effect of the oral direct activated factor X (factor Xa) inhibitor apixaban on tissue factor-induced thrombin generation in human plasma was investigated in vitro using the calibrated automated thrombogram (CAT) method and compared with the oral direct factor Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran. The DTI dabigatran etexilate was recently shown to provide superior risk reduction to warfarin for stroke and systemic embolism for patients with nonvalvular AF and recently gained US Food and Drug Administration approval for this indication. </context> <question> What is the mechanism of action of anticoagulant medication Dabigatran? </question> <answer> Dabigatran is orally administered, reverisble direct and competetive inhibitor of both free and bouded thrombin. </answer>
<context> In the intermediate-risk subgroup, the 70-gene signature could be useful to decide in elderly patients whether they may benefit from adjuvant chemotherapy or not. One of the new prognostic markers is the 70-gene prognostic signature (MammaPrint™; Agendia, Amsterdam, Netherlands) Analysis of gene expression patterns has led to the discovery of this prognostic gene signature [6]. This signature has been validated in many studies as a more powerful prognostic factor for distant metastasis and death than the current clinicopathological factors Many recent studies have shown that this signature can be used to classify postmenopausal women (older age women), neoadjuvant chemotherapy patients and node-positive patients [9,22,23]. this signature is a more powerful predictor of disease outcome than the currently used clinicopathological guidelines [7,9,10,19] using this signature could result in a substantial reduction of the number of patients who would be recommended for chemotherapy. Adjuvant assessment tools for prognosis and prediction of treatment benefit, including Adjuvant! Online, the St Gallen Consensus, Oncotype DX(®) and MammaPrint(®), aid clinical decision making The 70-gene MammaPrint prognosis profile accurately identified Japanese breast cancer patients at low risk of developing recurrences. In fact, 100% of the individuals in the low-risk category remained metastasis-free for the duration of the observation period. he probability of distant metastasis-free survival at five years was 100% for the low-risk group and 94% for the high-risk group. The 70-gene prognosis signature can accurately select postmenopausal patients at low risk of breast cancer-related death within 5 years of diagnosis and can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy. The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions A pCR is unlikely to be achieved in tumors that have a good prognosis-signature. Tumors with a poor prognosis-signature are more sensitive to chemotherapy. The EWG found adequate evidence to characterize the association of MammaPrint with future metastases, but inadequate evidence to assess the added value to standard risk stratification, and could not determine the population to which the test would best apply. he EWG found no evidence regarding the clinical utility of the MammaPrint and Quest H:I Ratio tests, and inadequate evidence regarding Oncotype DX. These technologies have potential for both benefit and harm MammaPrint, an oligonucleotide microassay performed on fresh-frozen tumor samples, analyzes the expression of 70 genes. Studies have found that MammaPrint allows young patients (<61 years) with early-stage breast cancer to be categorized as having a high or low risk of distant metastasis. High-risk patients may then be managed with more aggressive therapy. </context> <question> What is the clinical value of MammaPrint? </question> <answer> MammaPrint has a prognostic value for distant metastasis and death, as well as predictive value for response to adjuvant chemotherapy in patients with breast cancer. However, the EGAPP Working Group found no evidence regarding the clinical utility of the MammaPrint. </answer>
<context> Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation. Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase. These results suggest that JNK activation by H(2)O(2) plus PDTC resulted from the down-regulation of JNK phosphatases. M3/6 is a dual-specificity phosphatase selective for JNK Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite. Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK Both anisomycin and arsenite activate the JNK pathway and, in addition, inactivate the M3/6 phosphatase. M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins. . We suggest that reduction of HSP70 by expanded polyglutamine is implicated in aggregation and inhibition of M3/6 and in activation of JNK and AP-1. </context> <question> Which protein is affected by dusp8 activation? </question> <answer> JNK </answer>
<context> In 2008, the American Heart Association (AHA) recommended a 2-step screening method, consisting of the 2-item Patient Health Questionnaire (PHQ-2) followed by the 9-item Patient Health Questionnaire (PHQ-9), for identifying depression in cardiovascular patients. The American Heart Association (AHA) statement has recommended routine screening for depression in coronary artery disease with a 2-stage implementation of the Patient Health Questionnaire (PHQ). A recent American Heart Association (AHA) Prevention Committee report recommended depression screening of all coronary heart disease patients using 2- and 9-item instruments from the Patient Health Questionnaire (PHQ-2 and PHQ-9) to identify patients who may need further assessment and treatment. Patients were screened for depression using a protocol identical to the one endorsed by the AHA in a cardiology community clinic in Elmhurst (Queens, New York). Depression was assessed using the Patient Health Questionnaire. Depression screening in cardiac patients has been recommended by the American Heart Association, but the best approach remains unclear. OBJECTIVE: To evaluate nurse-administered versions of the Patient Health Questionnaire for depression screening in patients hospitalized for acute coronary syndrome. METHODS: Staff nurses in an urban cardiac care unit administered versions 2, 9, and 10 of the questionnaire to 100 patients with acute coronary syndrome. </context> <question> Which scales are recommended by the American Heart Association for depression screening in cardiovascular patients? </question> <answer> patient health questionnaire-2; patient health questionnaire-9 </answer>
<context> an FDA-cleared 70-gene signature of MammaPrint panel on MammaPrint, the first and only assay for breast cancer management that has been cleared by the FDA. The MammaPrint assay has the advantages of a 510(k) clearance by the US Food and Drug Administration, a larger gene number which may enhance further utility, and the potentially wider patient eligibility including lymph node-positive, ER-negative, MammaPrint from Agendia are the first FDA approved microarray-based tests for diagnostic applications. MammaPrint is the first FDA approved, gene expression-based prognostic test which assess patients’ risk for distant metastasis in women under age 61 with Stage I-II lymph node negative breast cancer. The Amsterdam 70-gene expression signature as breast cancer prognosis marker has been validated in follow-up studies [39,40], and a clinical assay MammaPrint® has recently been cleared by FDA. The MammaPrint assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node-positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy). </context> <question> Is Mammaprint approved by the United States Food and Drug Administration? </question> <answer> yes </answer>
<context> Pharmacogenetic studies have revealed that abacavir HSRs are highly associated with the major histocompatibility complex class I. Large studies established the effectiveness of prospective HLA-B57:01 screening to prevent HSRs to abacavir. Accordingly to these results the abacavir label has been modified: the European Medicines Agency (EMA) and the FDA recommend/suggested that the administration of abacavir must be preceded by a specific genotyping test. Pharmacogenomic tests offer a promising strategy to improve the safety and efficacy of drug treatment. Compelling examples, such as HLA-B5701 testing to identify patients at risk for abacavir-associated hypersensitivity, are already changing clinical care International HIV treatment guidelines recommend HLA-B57:01 typing before abacavir administration, in order to reduce the incidence of abacavir hypersensitivity reactions, the major cause of early therapy discontinuation. A fast, sensitive and specific test for HLA-B57:01 detection has been developed in the present study. The rollout of HLA-B∗5701 into routine clinical practice as a genetic screening test to prevent abacavir hypersensitivity provides a translational roadmap for other drugs. he aim of the session, using real-world examples (KRAS/panitumumab and HLA-B5701/abacavir), was to identify good scientific principles that would guide the design of studies to identify subgroups of responders during development programs (including marketed drugs), which could subsequently be used to guide treatment decisions. HLA-B5701 screening to prevent abacavir hypersensitivity syndrome is an example of a test now in widespread routine clinical use in the developed world. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA-B5701 screening to avoid hypersensitivity to the antiretroviral abacavir, Prospective pharmacogenetic screening for the human leucocyte antigen (HLA) B5701 allele can significantly reduce the number of cases of abacavir-related hypersensitivity among HIV-infected patients treated with this drug. development of HLA-B5701 genetic screening as a means of preventing drug hypersensitivity reactions caused by a commonly prescribed antiretroviral drug, abacavir. Abacavir hypersensitivity syndrome (AHS) is a potentially life-threatening illness occurring in 4-8% of those initiating the drug. Early studies identified a strong association between the MHC class I allele HLA-B5701 and AHS. These studies suggested that HLA-B5701 holds promise as a screening test to prevent AHS, but concern arose from HLA-B5701-negative cases with a clinical diagnosis of AHS, and particularly from early reports of apparently low sensitivities of HLA-B5701 for AHS in patients of non-White race. However, open screening studies suggested that HLA-B5701 screening can largely eliminate AHS Current HIV treatment guidelines have been revised to reflect the recommendation that HLA-B5701 screening be incorporated into routine care for patients who may require abacavir. The research approach applied to AHS has led to a genetic screening test being successfully implemented globally in primary HIV clinical practice. The clinical utility of prospective HLA-B5701 screening was demonstrated in a blinded randomized clinical trial and in open-label cohorts. Screening has been incorporated into clinical practice and the ABC HSR pharmacogenetics program has been highlighted as a success by pharmacogenetics researchers. Abacavir hypersensitivity (ABC HSR) is a treatment-limiting adverse event associated with the use of the antiretroviral medicine, abacavir. The major histocompatibility complex allele, HLA-B5701, was identified retrospectively and confirmed with independent sample sets. he most significant advance for clinical practice is the correlation between the presence of the HLA-B5701 allele and hypersensitivity reaction to abacavir. In particular, one clinical trial with a large number of patients from distinct ethnic groups found that the probability of not developing hypersensitivity reaction (immunologically confirmed) was 100% if the patient was HLA-B5701-negative. These data suggest the need to implement this test in daily clinical practice. The aim of the PREDICT-1 study was to determine the clinical utility of the pharmacogenetic test identifying HLA-B5701 to reduce the incidence of hypersensitivity reaction to abacavir, diagnosed clinically and with immunological confirmation, as well as to reduce unwarranted withdrawal of this drug the identification of HLA-B()5701 as a highly sensitive and specific predictive marker for abacavir treated patients who will develop hypersensitivity syndrome (HSS). Clinical consensus panels rapidly recommended abacavir as the preferred therapy along with HLA-B()5701 pre-testing, immediately increasing the market share of abacavir with respect to other reverse transcriptases that are associated with there own adverse events Pharmacogenetic testing for HLA-B5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment. HLA-B5701 testing remained the preferred strategy only if abacavir-based treatment had equal efficacy and cost less per month than tenofovir-based treatment. Results were also sensitive to the cost of HLA-B5701 testing and the prevalence of HLA-B5701. The strong association of the abacavir hypersensitivity reaction with HLA-B5701 permits testing patients for the allele, and if present avoiding the drug and therefore preventing the reaction. Although the human leukocyte antigen (HLA)-B5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B5701 positivity and risk of ABC HSRs in both races. A strong statistical association between the major histocompatibility complex allele, HLA-B5701, and clinically diagnosed ABC HSR was identified but varied between racial populations. In a randomized, prospective study evaluating the clinical utility of HLA-B5701 screening, avoidance of ABC in HLA-B5701-positive patients significantly reduced clinically diagnosed ABC HSR and eliminated patch test-positive ABC HSR. Finally, a retrospective PGx study supports the generalizability of the association across races. Prospective HLA-B5701 screening should greatly reduce the incidence of ABC HSR by identifying patients at high risk for ABC HSR before they are treated. Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B5701 allele HLA-B5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. For abacavir in particular, the use of HLA-B5701 as a screening test appears to be generalizable across racially diverse populations and has been supported by both observational, and blinded randomized controlled trials. HLA-B5701 screening to prevent abacavir hypersensitivity is currently the most relevant to clinical practice and highlights that the promise of cost-effective testing can be facilitated by robust laboratory methodology and quality assurance programs that can be applied to diverse treatment settings. the major histocompatibility complex HLA-B5701 allele has been associated with hypersensitivity to abacavir (ABC) by several independent researchers. The strong association between HLA-B5701 and abacavir hypersensitivity reaction shows promise for a genetic screening test to be feasibly incorporated into clinical practice. Abacavir hypersensitivity reaction (ABC HSR) is a potentially life-threatening adverse reaction that affects approximately 8% of patients that initiate this antiretroviral drug. Independent groups have shown a strong predictive association between ABC HSR and HLA-B5701, indicating that exclusion of HLA-B5701 positive individuals from abacavir treatment would largely prevent ABC HSR. Abacavir, a human immunodeficiency virus-1 (HIV-1) nucleoside-analogue reverse transcriptase inhibitor, causes severe hypersensitivity in 4-8% of patients. HLA B5701 is a known genetic risk factor for abacavir hypersensitivity in Caucasians. Abacavir hypersensitivity is associated with HLA B5701, and pre-prescription pharmacogenetic testing for this appears to be a cost-effective use of healthcare resources. </context> <question> Which pharmacogenetic test is available for abacavir? </question> <answer> HLA B*5701 genotyping </answer>
<context> Entacapone is a highly potent, reversible, peripherally acting catechol-O-methyl transferase (COMT) inhibitor that is used as an adjunct to L-dopa in the treatment of patients with Parkinson disease (PD). Stalevo is a combination tablet comprised of levodopa, carbidopa, and the COMT inhibitor entacapone. It is available in fixed-dose combinations of levodopa/carbidopa/entacapone, 50/12.5/200, 75/18.75/200, 100/25/200, 125/31.25/200, 150/37.5/200 and 200/50/200 mg. Stalevo is currently approved for use in Parkinson's disease patients with end-of-dose wearing off. Good news were marketing of ropinirole, a new non-ergot agonist, in December 2006 and entacapone, the first catechol-O-methyl transferase (COMT) inhibitor in Japan in April 2007. Having faced these new situations, Japanese Neurological Association has started revising "the Guideline 2002 for the treatment of Parkinson's disease". Stalevo (Orion) combines levodopa, the dopa-decarboxylase inhibitor carbidopa and the catechol-O-methyl transferase inhibitor entacapone in a single tablet. We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. The catechol-O-methyl transferase inhibitor entacapone is given in combination with levodopa/dopa decarboxylase inhibitor for Parkinson's disease (PD) patients experiencing end-of-dose wearing-off. Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. Sleep attacks in Parkinson's disease induced by Entacapone, a COMT-inhibitor. We present a patient who suffered from sleep attacks after starting entacapone in addition to levodopa. Entacapone, a catechol-O-methyl transferase inhibitor, alters the pharmacokinetics of levodopa, leading to increase of levodopa concentration in plasma and brain. Two COMT inhibitors, tolcapone and entacapone, have recently been made available as adjunctive agents to levodopa Two inhibitors of catechol-O-methyl transferase (COMT), tolcapone and entacapone, have recently been introduced as adjuncts to levodopa in the treatment of Parkinson's disease patients. Tolcapone, a peripheral and central COMT inhibitor, appears to be quite effective, producing a 47% reduction in 'off' time. . Entacapone, a purely peripheral COMT inhibitor with a lower potency than tolcapone, has also proved to be effective and has not been associated with liver damage, obviating the need for testing. Here we report that a treatment of the cerebral tissue with tolcapone, a central and peripheral inhibitor of COMT, does not change the membrane responses of midbrain dopamine neurons to dopamine and levodopa. Therefore, the therapeutic action of tolcapone in Parkinson's disease, might be dependent on the reduction of COMT activity in the extracerebral tissue. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. The novel and reversible inhibitors are the catechol-O-methyl-transferase (COMT) inhibitors, Ro 40-7592 (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), and the monoamine oxidase type-B (MAO-B) inhibitor, Ro 19-6327 (N-(2-aminoethyl)-5-chloro-2-pyridine carboxamide HC1). </context> <question> Which two catechol-O-methyl transferase (COMT) inhibitors can be used for treatment of Parkinson disease? </question> <answer> tolcapone; entacapone </answer>
<context> There are two identified genes that are responsible for the main proportion of the genetic effect: CYP2C9, which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, and VKORC1, which codes for warfarin's target, vitamin K epoxide reductase. We identified ORM1 as another polymorphic gene affecting warfarin dose requirements. ORM1 S carriers require lower maintenance doses to achieve and maintain an optimal level of anticoagulation. Many of these studies have identified significant associations with two genes in particular, the cytochrome-P450 gene CYP2C9 and the vitamin K epoxide reductase complex subunit 1 gene, VKORC1. it is widely accepted that genotype at CYP2C9 and VKORC1 affect dose requirements Variants in another gene, CYP4F2, have also been associated with warfarin dose requirements in several studies. The evidence base for the effect of CYP2C9 and VKORC1 genotype on response to warfarin is substantial Detecting genetic polymorphism of CYP2C9 and VKORC1 could guide clinical use of warfarin to reduce the risk of adverse reactions including bleeding in patients receiving chronic anticoagulation therapy The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements There are other genetic polymorphisms that may further explain the response to warfarin. The VKORC1 genotype is an important determinant of response to warfarin in Chinese, but some genetic variants found in other ethnic groups that have a large effect on warfarin response and dosing are not commonly found in Chinese the alleles rs1799853 (2) and rs1057910 (3) of the CYP2C9 gene, as well as rs9923231 of the VKORC1 gene were associated with warfarin dose required to achieve anticoagulation with INR of 2-3. Polymorphisms in the genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and the vitamin K epoxide reductase (VKORC1) are known to contribute to variability in sensitivity to coumarins. VKORC1 and CYP2C9 polymorphisms are important factors that influence warfarin dose response in Sudanese patients he response to the anticoagulant drug warfarin is greatly affected by genetic polymorphisms in the VKORC1 and CYP2C9 genes. The HDA-based assays demonstrated a clinically acceptable performance for genotyping the VKORC1 -1639G>A SNP and two SNPs (430C>T and 1075A>C) for the CYP2C9 enzyme (CYP2C92 and CYP2C9*3), all of which are relevant in warfarin pharmacogenentics. Genetic variability in the VKORC1 and CYP2C9 genes is associated with increased warfarin sensitivity CYP2C9 and VKORC1 polymorphisms known to affect warfarin response genetic variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant predictor variables for the maintenance dose of warfarin, explaining 26.6% of dose variability. CYP2C9 was the most important gene determining initial anticoagulant control, whereas VKORC1 was more important for stable anticoagulation. Novel associations with some clinical outcomes were found with single nucleotide polymorphisms in the cytochrome 450 genes CYP2C18 and CYP2C19, which were independent of the associations observed with CYP2C9 and in genes encoding CYP3A5, protein S and clotting factor V, although the variability explained by these genes was small. Warfarin pharmacogenetic studies demonstrated that variants in the CYP2C9 (Cytochrome P450 2C9) and VKORC1 (Vitamin K epoxide reductase complex subunit 1) genes account for approximately 50–60% of drug dosing variability hese last two are associated with decreased metabolic efficiency of the CYP2C9 enzyme and increased risk of bleeding when administrated initial dosages of warfarin [15]. A G>A variation at position 1639 in the promoter region of the VKORC1 gene results in decreased mRNA transcription and increased sensitivity to warfarin inhibition of hepatic synthesis of functional vitamin K-dependent coagulation factors [1 Polymorphisms within VKORC1, a target of warfarin inhibition, may explain 23% of this drug dosage variability [ Those who are CYP2C9 PMs may exhibit different pharmacokinetics than wild-type individuals if they are medicated with warfarin The metabolism of warfarin and the other coumarin anticoagulants is well understood, with the cytochrome P450 enzyme CYP2C9 having a major role in their phase I metabolism (reviewed in [3]). CYP2C9 is subject to a genetic polymorphism affecting its activity, and the fact that this polymorphism contributes to individual anticoagulant dose requirement is now well established, although its effect on phenprocoumon metabolism is less pronounced than that on either warfarin or acenocoumarol [2,4-7]. Coumarin anticoagulants exert their effect by inhibiting the enzyme vitamin K epoxide reductase, which regenerates vitamin K following its oxidation in the gamma glutamyl carboxylase reaction Polymorphisms in this gene's non-coding sequences have been shown to affect levels of gene expression, resulting in inter-individual variation in the amount of this protein present in hepatocytes A clear association between the G-1639A polymorphism and warfarin dose requirement has been reported in many independent studies [10,13,14], and similar associations for acenocoumarol and phenprocoumon also occu An important recent development is the inclusion of reference to genetic factors affecting response (both CYP2C9 and VKORC1) in the prescribing information for warfarin in the USA by the Food and Drug Administration (FDA) [18 ne possible exception to this is the cytochrome P450 CYP4F2 gene. This gene was shown to contribute to warfarin dose requirement in a study using the Affymetrix ADME gene chip, which includes a single nucleotide polymorphism (SNP) in CYP4F2 that is associated with the amino acid change V433M [22]. owever, its relevance to warfarin action is still unclear, although a role for CYP4F2 in vitamin K metabolism has been suggested [22] and it also remains possible that it contributes directly to warfarin metabolism The effect of CYP4F2 on warfarin dose requirement is biologically interesting, but the overall 1-2% contribution to dose requirement confirmed so far [22] may be too small for genotyping for the relevant SNP to be clinically useful. VKORC1 -1639 G>A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variabilit the CYP2C9 and VKORC1 genes have been demonstrated to be determinants of warfarin response. On the basis of these observations, the Food and Drug Administration (FDA) approved a labeling change for warfarin that includes the genetic information of VKORC1 and CYP2C9 as factors influencing interindividual variability in warfarin dosing. T the two key genes of interest, the cytochrome P450 2C9 gene, CYP2C9, and the vitamin K epoxide reductase complex 1 gene, VKORC1, on warfarin response The influence of CYP2C9 and VKORC1 genotypes on warfarin dose requirements has been consistently demonstrated in diverse racial and ethnic patient groups in observational studies and randomized clinical trials. genetic factors influencing drug pharmacokinetics (CYP2C9) and pharmacodynamic response (VKORC1). In particular, the discovery of polymorphisms in the VKORC1 gene that strongly impact oral anticoagulant dose has heightened expectations that genetic testing Our data suggest that CYP2C9 genotype, age and body size are important determinants of warfarin dose requirements in African-Americans. Our data further suggest that the VKORC1 G6853C polymorphism alone may not be useful for predicting warfarin dose requirements in this racial group. A strong association was found between genetic polymorphisms in six genes, including VKORC1, CYP2C9, PROC, EPHX1, GGCX, and ORM1, and interindividual variability in the anticoagulant effect of warfarin; the strongest predictors were VKORC1 and CYP2C9. Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001) These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin's actions. Clinical studies showed an increased plasma level of S-warfarin, decreased clearance of S-warfarin, increased frequency of bleeding, and prolongation of hospitalization in patients with variant CYP2C9 alleles. </context> <question> Which genes are involved in patient response to warfarin? </question> <answer> CYP2C9; VKORC1; ORM1; CYP4F2; EPHX1; CYP2C18; CYP2C19; CYP3A5; protein S; clotting factor V; PROC; GGCX </answer>
<context> The calcium channel blocker verapamil is the drug of choice for CH prevention. Other drugs that may be used for this purpose include lithium carbonate, topiramate, valproic acid, gabapentin, and baclofen. Recently, the therapeutic options for refractory CH patients have expanded with the emergence of both peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation. With the emergence of these novel treatments, the role of ablative surgery in CH has declined. The mainstay of prophylactic therapy is verapamil. Yet, other medications, including lithium, divalproex sodium, topiramate, methysergide, gabapentin, and even indomethacin, may be useful when the headache fails to respond to verapamil. For medically refractory patients, surgical interventions, occipital nerve stimulation, and deep brain stimulation remain an option. The objective of this open single-centre study was to evaluate the efficacy and tolerability of botulinum toxin type-A (BTX-A) as add-on in the prophylactic treatment of cluster headache (CH). These findings provide evidence that BTX-A may be beneficial as an add-on prophylactic therapy for a limited number of patients with chronic CH. There are a variety of different medications for abortive and prophylactic therapy, accompanied by a variable amount of evidence-based medicine. Most procedures are directed against the sensory trigeminal nerve and associated ganglia, eg, anesthetizing the sphenopalatine ganglion. The mainstay of prophylactic therapy is verapamil. Lithium, divalproex sodium, or topiramate may also be useful. Based on our clinical experience, we recommended the combination of nasal sumatriptan for acute attacks and verapamil 240 mg/day for prophylaxis. Topiramate also appears to be well tolerated and useful in the adjunctive treatment of cluster headache. The cornerstone of maintenance prophylaxis is verapamil, yet methysergide, lithium, and divalproex sodium may also be employed. In some patients, melatonin or topiramate may be useful adjunctive therapies. Prophylactic therapy in most cases consisted of verapamil, also with a good response. Patients with chronic cluster headache may achieve good results from long-term treatment with other therapies, including lithium carbonate, verapamil, and ketoprofen. </context> <question> What pharmacological and non-pharmacological interventions can be considered as prophylactic therapies in Cluster Headache patients? </question> <answer> Verapamil, a calcium channel blocker, is considered the mainstay of prophylactic therapy of Cluster Headache patients. Lithium carbonate, topiramate, valproic acid, gabapentin, baclofen, methysergide, melatonin, ketoprofen and indomethacin can also be tried for prophylactic therapy of Cluster Headaches patients. Non-pharmacological prophylactic measures, such as peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation, ablative surgery, and botulinum toxin type-A (BTX-A) injection, can be also considered. </answer>
<context> The recognition of sustained androgen dependence of CRPC has led to the identification of more potent and selective inhibitors of androgen synthesis and androgen-receptor signaling, such as abiraterone and enzalutamide, respectively. This review summarizes the rationale, mechanism of action and relevant clinical data of abiraterone acetate , an oral androgen biosynthesis inhibitor, in the management of CRPC. Sipuleucel-T, an immunotherapeutic vaccine, is now available in the US for patients with non-metastatic CRPC and abiraterone, an oral enzyme inhibitor of androgen biosynthesis, as well as cabazitaxel, a cytotoxic chemotherapeutic, have been approved for the treatment of metastatic CRPC. Abiraterone acetate was identified to be a potent and selective irreversible inhibitor of CYP17. Preclinical studies with abiraterone demonstrated reduction in androgen production downstream of CYP17 which resulted in decreased weight of the ventral prostate, testis, and seminal vesicles in mice. This could potentially be explained by the fact that although abiraterone blocks androgen synthesis at the CYP17 level, androgens upstream continue to accumulate and can potentially stimulate an altered androgen receptor. Recently, abiraterone acetate, which is a potent inhibitor of cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1), has been focused on for the treatment of CRPC. Abiraterone acetate is a potent, selective, and irreversible inhibitor of CYP17A1 (IC50, 2-4 nmol/l) Thus, the original rationale for the use of abiraterone acetate in CRPC is that a complete blockade of not only testicular but also adrenal androgen may beneficial in CRPC patients. Thus, abiraterone acetate has been expected to block not only testicular and adrenal androgenesis but also intratumoral de novo androgen synthesis. Abiraterone (17-(3-pyridyl)androsta-5,16-dien-3beta-ol, 1) is a potent inhibitor (IC50 4 nM for hydroxylase) of human cytochrome P45017alpha. Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer. </context> <question> What is the mechanism of action of abiraterone? </question> <answer> Abiraterone acts by inhibiting cytochrome P450 17α-hydroxylase (CYP17A1), a critical step in androgen biosynthesis, thus leading to inhibition of androgen biosynthesis. </answer>
<context> NF-1 is caused by loss of function mutations in the NF1 gene in 17q11.2. The von Recklinghausen neurofibromatosis (NF1) gene has been localized to the pericentromeric region of chromosome 17. Nine markers from the pericentromeric region of chromosome 17 were typed in 16 British and five South African families with neurofibromatosis type 1 (NF1). Inspection of recombinant events in families informative for several markers suggests that the NF1 gene is located between the markers EW301 (cen-p11.2) and EW206 (cen-q12) and possibly distal to pHHH202 (q11.2-q12). The gene for von Recklinghausen neurofibromatosis type 1 (NF1) has recently been mapped to the pericentromeric region of human chromosome 17. In addition to reporting, in accompanying papers, their individual analyses of mapping the neurofibromatosis type 1 (NF1) gene on chromosome 17, members of the International Consortium for NF1 Linkage contributed their data for our joint analysis to determine the exact sequence of flanking markers and to obtain precise estimates and confidence limits of the recombination fractions for the closest markers, in anticipation of clinical use. To better map the location of the von Recklinghausen neurofibromatosis (NF1) gene, we have characterized a somatic cell hybrid designated 7AE-11. This microcell-mediated, chromosome-transfer construct harbors a centromeric segment and a neo-marked segment from the distal long arm of human chromosome 17. The cosmids in the NF1 region will be an important resource for testing DNA blots of large-fragment restriction-enzyme digests from NF1 patient cell lines, to detect rearrangements in patients' DNA and to identify the 17;22 NF1 translocation breakpoint. The frequent LOH surrounding the NF1 locus and lack of neurofibromin expression in these tumors suggest that NF1 gene mutations may contribute to the development of adrenal gland neoplasms in patients with NF1. In the latter, the breakpoint in 17q occurred below the centromere and is at or in the region of the Neurofibromatosis Type 1 (NF1) gene. Neurofibromatosis type I (NF1) is an autosomal dominant condition associated with mutations in the long arm of chromosome 17, and characterised by neurofibromas, café-au-lait spots and axillary freckling. In addition, the mother's and maternal grandmother's genetic analysis showed identical mutations in the neurofibromatosis I gene on the long arm of chromosome 17, confirming the diagnosis of NF1. Duplicon-mediated microdeletions around the NF1 gene are frequently associated with a severe form of neurofibromatosis type I in a subgroup of patients who show an earlier onset of cutaneous neurofibromas, dysmorphic facial features, and lower IQ values. Neurofibromatosis had been diagnosed in infancy, and genetic testing showed that the patient had a mutation in chromosome 17, consistent with neurofibromatosis type I. Neurofibromatosis Type 1 (NF1) is one of the most common inherited diseases in humans. It is caused by a mutation in the NF1 gene on chromosome 17, and is associated with numerous central and peripheral nervous system manifestations. In 95% of NF1 individuals, a mutation is found in the NF1 gene, and in 5% of the patients, the germline mutation consists of a microdeletion that includes the NF1 gene and several flanking genes. Herein, we describe a unique case of anaplastic de novo astroblastoma-sarcoma, in essence a variant of gliosarcoma, occurring in a 50-year-old female with documented NF1. Genetic study (fluorescence in situ hybridization) demonstrated no chromosomal losses or gains. Testing for abnormalities of chromosomes 7, 9, 10, 12, 17, 19 and 20, including the EGFR, p16, PTEN, MDM2 and NF1 gene regions, we found the tumor to exhibit a deletion of PTEN, monosomy 17 and gains of chromosomes 19 and 20q. Neurofibromatosis type I (NF1) is an autosomal dominant disorder affecting 1 in 3000 people. The NF1 gene is located on chromosome 17q11.2, spans 350 kb of genomic DNA, and contains 60 exons. A patient with recurrent-remittent multiple sclerosis associated with neurofibromatosis type I is described. The case is interesting for two reasons: 1) the difficulty of evaluating MRI findings, since both entities involve similar anomalies and 2) the relation between the two entities, according to evidence from recent genetic studies showing that the myelin protein gene associated to oligodendrocytes is part of an intron of the neurofibromatosis-1 gene of chromosome 17. Neurofibromatosis type I (NFI) is a common autosomal dominant disorder with an increased risk for developing benign and malignant tumors. The NFI gene has been cloned and maps to 17q11.2, and the gene product acts as a tumor suppressor gene. Type 1 is caused by a genetic mutation in the NF1 gene (OMIM 613113) and symptoms can vary dramatically between individuals, even within the same family. Direct sequencing of the NF1 gene in tumor DNA identified the presence of an inactivating NF1 somatic mutation in 41% (25/61) of analyzed sporadic tumors, associated with loss of the wild-type allele in 84% (21/25) of cases. A novel mutation c.4821delA was identified in NF1 gene, which predicted truncation of neurofibromin (p.Leu1607fs). She had a genotype of heterozygous c.6709C>T mutation of NF1 gene. RESULTS: The mutational analysis of the NF1 gene revealed a novel frameshift insertion mutation in exon 4c (c.654 ins A) in all affected family members. Using lymphoblastoid, fibroblast, and buccal cell samples collected from both twins and from other family members in three generations, we discovered a pathogenic nonsense mutation in exon 40 of the NF1 gene. We also found a novel non-synonymous change in exon 16 of the NF1 gene that was transmitted from the unaffected mother to both twins and co-segregated with the pathogenic mutation in the ensuing generation. The disease gene of the Chinese NF1 family was linked to NF1 locus, and a nonsense mutation, G1336X in the NF1 gene was identified. The present study demonstrated that G1336X mutation in the NF1 gene cause Neurofibromatosis type I in the family. </context> <question> Mutation of which gene and which chromosome cause Neurofibromatosis type I? </question> <answer> NF1 gene; chromosome 17 </answer>
<context> A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC Arg(9) → Cys (R9C) and Arg(14) deletion (R14del) mutations in PLN are associated with lethal dilated cardiomyopathy in humans We previously reported the deletion of the highly conserved amino acid residue arginine 14 (nucleic acids 39, 40 and 41) in DCM patients. Mutations in the gene encoding PLN have been associated with idiopathic dilated cardiomyopathy; Mutations in the PLN gene are a rare cause of heart failure, present almost exclusively in patients with dilated cardiomyopathy etiology A missense mutation in PLN cytoplasmic domain (R9C) triggers dilated cardiomyopathy in humans, leading to premature death. Recently, a mutation of PLN in which one of the N-terminal di-arginine residues at positions 13 and 14 was deleted led to a severe, early onset dilated cardiomyopathy [4 Complete genetic and clinical analyses were performed in a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation. A candidate gene approach resulted in identification of a heterozygous deletion of arginine 14 in the gene encoding phospholamban (PLN-R14Del) segregating with dilated cardiomyopathy in the family pedigree. Mutation carriers suffered from familial dilated cardiomyopathy associated with cardiac death between the ages of 26 and 50 years. a family with familial dilated cardiomyopathy due to the PLN-R14Del mutation. For the phospholamban (PLN) and titin cap (TTN) genes, a direct mutation screening approach was used. DNA sequence analysis of all exons showed no evidence that these genes are involved in DCM in the Newfoundland dog. two human PLN mutations, associated with either absence or sustained dephosphorylation of PLN, were linked to dilated cardiomyopathy. Mutations in the gene encoding PLN have been associated with dilated cardiomyopathy characterized by early onset and the presence of lethal ventricular arrhythmias. The identical PLN mutation can be associated with both mild and severe forms of dilated cardiomyopathy. Additionally, PLN mutations should be considered in late onset cardiomyopathy Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No PLN gene mutation was found in patients with DCM in Chengdu. This result indicated that PLN gene mutation may not be a common cause for DCM in the Chinese population in Chengdu. none in PLN the recent discoveries of human PLN mutations leading to disease states. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. humans lacking PLN develop lethal dilated cardiomyopathy. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN) </context> <question> Can PLN mutations lead to dilated cardiomyopathy? </question> <answer> yes </answer>
<context> NGS sequencing data for a particular genomic region can be seen as the summation of all the individual sequences (reads) obtained for that region and no longer as the mean of this sum as it is the case for traditional Sanger sequencing. Hereby we present the proof of principle of a NGS based mutation screening procedure allowing the detection of inherited Alu insertions within any predefined sequence by investigating 2 cases: c.1739_1740insAlu in BRCA1 and c.156_157insAlu in BRCA2. Targeted sequence data of the BRCA1 and BRCA2 genes, generated using a PCR-based, multiplexed NGS approach using the SOLiD 4 (n = 24) and Ion Torrent PGM (n = 20) next-generation sequencers, The overall sensitivity for SOLiD and PGM were 97.8% (95% CI = 94.7 to 100.0) and 98.9% (95% CI = 96.8 to 100.0) respectively. The specificity for the SOLiD platform was high, at 100.0% (95% CI = 99.3 to 100.0). PGM correctly identified all 3 indels, but 68 false-positive indels were also called genes known to cause deafness sequenced by the Illumina NGS platform. Results demonstrated that targeted exons captured by our approach achieved specificity, multiplexicity, uniformity, and depth of coverage suitable for accurate sequencing applications by the NGS systems. Reliable genotype calls for various homozygous and heterozygous mutations were achieved. The method validated here could be readily expanded to include all-known deafness genes for applications such as genetic hearing screening in newborns applying this technology to von Willebrand disease 43 mutations, including 36 substitutions, 2 intronic splice site mutations, 2 indels, and 3 deletions. on the next-generation sequencing instrument, at least 350 patients and relatives per run can be simultaneously analyzed in a fast, inexpensive manner. The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa. ConclusionsIn conclusion, our HRM assay is a simple, robust and inexpensive method that allows multiple mutation hotspots to be rapidly screened and is thus highly suited to mutation detection in DNA derived from FFPE tissues. Ultra-deep pyrosequencing of KRAS amplicons with GS Junior 454 proved to be a highly sensitive and quantitative technique to analyse somatic mutations in cancer specimens, and which can also be used in a high-throughput assay. Moreover, the use of MIDs allowed massively parallel sequence analysis of multiple samples to be performed Not surprisingly, EGFR mutations have been identified in several types of cancer and it is a target of many anticancer therapies, including small-molecule TK inhibitors (e.g., gefitinib and erlotinib for lung cancer) and monoclonal antibodies (e.g., cetuximab and panitumumab for colon cancer). Moreover, the mutational status of EGFR and its downstream molecules have implications for the responsiveness to treatment and prognosis.Somatic mutations in the kinase domain of the EGFR gene (exons 18-21) are reportedly associated with sensitivity of lung cancers to TK inhibitors [1-5] Mutations in the KRAS gene occur early in the development of many cancers and are found in more than 90% of pancreatic adenocarcinomas, 40% of colorectal cancers (CRC) and 33% of non-small cell lung carcinomas (NSCLC) [8 BRAF mutations are found in many types of cancer, predominantly in up to 80% of melanoma and nevi [12]. V600E amino acid substitution in the activation segment accounts for 90% of BRAF mutations and is significantly associated with microsatellite instability [13]. Data from retrospective studies suggest that mutated BRAF, which is present in 5-10% of colorectal tumours, can affect the response to anti-EGFR monoclonal antibodies in patients with wild type KRAS [14-16], 40-60% of whom do not respond to such therapy [17].Current guidelines in the US state that patients with metastatic CRC being considered for EGFR-targeted therapies should be tested for KRAS and BRAF mutations [18], and recommend EGFR testing for patients with advanced NSCLC to predict response to first-line TK inhibitors [19,20]. a HRM assay to identify hotspot mutations in EGFR, KRAS and BRAF oncogenes, and investigate the potential application of ultra-deep amplicon pyrosequencing for somatic variation detection in clinical sample Mutations in the COL4A5 gene cause X-linked ATS. Mutations in COL4A4 and COL4A3 genes have been reported in both autosomal recessive and autosomal dominant ATS. To overcome these limitations, we designed a next-generation sequencing (NGS) protocol enabling simultaneous detection of all possible variants in the three genes. We used a method coupling selective amplification to the 454 Roche DNA sequencing platform (Genome Sequencer junior). The Marfan (MFS) and Loeys-Dietz (LDS) syndromes are caused by mutations in the fibrillin-1 (FBN1) and Transforming Growth Factor Beta Receptor 1 and 2 (TGFBR1 and TGFBR2) genes, respectively. We have tailored a cost-effective and reliable mutation discovery strategy using multiplex PCR followed by Next Generation Sequencing (NGS) We conclude that multiplex PCR of all coding exons of FBN1 and TGFBR1/2 followed by NGS analysis and MLPA is a robust strategy for time- and cost-effective identification of mutations To date, six genes have been commonly associated with MKS (MKS1, TMEM67, TMEM216, CEP290, CC2D2A and RPGRIP1L). H To explore the full genetic complexity of MKS, we performed exon-enriched next-generation sequencing of 31 ciliopathy genes in 12 MKS pedigrees using RainDance microdroplet-PCR enrichment and IlluminaGAIIx next-generation sequencing. o carry out exome sequencing of entire transcripts of the whole X chromosome to investigate a family with X linked leucoencephalopathy. Next-generation sequencing of all the transcripts of the X chromosome, Single-lane exome next-generation sequencing is sufficient to fully analyse all the transcripts of the X chromosome. This method is particularly suitable for mutation screening of X-linked recessive disorders and can avoid biases in candidate gene choice. diagnoses of inherited urea cycle disorders (UCDs) We used the Genome Sequencer FLX System (454 Life Sciences) </context> <question> Give examples of next-generation sequencing applications in mutation screening? </question> <answer> Next generation sequencing data for a particular genomic region can be seen as the summation of all the individual sequences (reads) obtained for that region and no longer as the mean of this sum as it is the case for traditional Sanger sequencing. NGS is introduced to an increasing number of mutation screening applications. An NGS based mutation screening procedure allowing the detection of inherited Alu insertions within any predefined sequence was used for the case of c.1739_1740insAlu in BRCA1 and c.156_157insAlu in BRCA2. Another NGS study screened BRCA1 and BRCA2 resulting in overall sensitivity for SOLiD and PGM of 97.8% (95% CI = 94.7 to 100.0) and 98.9% (95% CI = 96.8 to 100.0) respectively. The specificity for the SOLiD platform was high, at 100.0% (95% CI = 99.3 to 100.0). PGM correctly identified all 3 indels, but 68 false-positive indels were also called. Genes known to cause deafness were sequenced by the Illumina NGS platform. Results demonstrated that targeted exons captured by our approach achieved specificity, multiplexicity, uniformity, and depth of coverage suitable for accurate sequencing applications by the NGS systems. Reliable genotype calls for various homozygous and heterozygous mutations were achieved. In the context of von Willebrand disease 43 mutations, including 36 substitutions, 2 intronic splice site mutations, 2 indels, and 3 deletions were screened on the next-generation sequencing instrument. This demonstrated that at least 350 patients and relatives per run can be simultaneously analyzed in a fast, inexpensive manner. The Alport syndrome is caused by mutations in three key genes namely COL4A3, COL4A4 and COL4A5, each of which consists of approximately 50 exons, thus rendering mutations screening a highly time consuming and expensive endeavor. NGS is now being established for the simultaneous, fast and cost-effective detection of all possible variants in these three genes. NGS has also been used screening EGFR, KRAS and BRAF for mutations associated with cancer diagnosis and/or response to several anticancer therapies. NGS has also been used in mutation screening for hereditary spastic paraplegias, X linked leucoencephalopathy, retinitis pigmentosa, inherited urea cycle disorders, as well as the Marfan (MFS), Loeys-Dietz (LDS) and Meckel syndromes. </answer>
<context> This article discusses some of these unresolved issues, including the use of medications such as nimodipine, antifibrinolytics, statins, and magnesium; coiling or clipping for aneurysm securement; and the prevention and treatment of potential complications. The results of this study were as follows: nimodipine demonstrated benefit following aneurysmal SAH; other calcium channel blockers, including nicardipine, do not provide unequivocal benefit; triple-H therapy, fasudil, transluminal balloon angioplasty, thrombolytics, endothelin receptor antagonists, magnesium, statins, and miscellaneous therapies such as free radical scavengers and antifibrinolytics require additional study. The present results suggest that fasudil is equally or more effective than nimodipine for the prevention of cerebral vasospasm and subsequent ischemic injury in patients undergoing surgery for SAH. Three studies (2 meta-analyses and 1 randomized controlled trial) demonstrated that nimodipine use confers benefits (reduced morbidity and mortality) for patients with aneurysmatic subarachnoid hemorrhage. Nimodipine is the only preventative treatment that can be recommended. Nimodipine (Nimotop), HMG Co-A reductase inhibitor (statins) and enoxaparin (Lovenox) were the only drugs with level-1 evidence available for the treatment of vasospasm from aneurysmal subarachnoid hemorrhage as defined by the US Preventative Services Task Force. The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH). There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively). Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging. The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH. the risk of delayed cerebral ischemia is reduced with nimodipine and avoiding hypovolemia A major randomized controlled trial, the British aneurysm oral nimodipine trial, showed a significant reduction in the incidence of cerebral infarction and poor outcome at three months compared to placebo A recommendations (standard) for the prophylaxis and treatment of cerebral vasospasm with oral Nimodipine in good grade patients. Of the 75 patients initially considered for active treatment, 83% underwent surgery within 48 hours of rupture, all received nimodipine, 16% received tissue plasminogen activator to lyse subarachnoid or intraventricular clots, 40% underwent hypertensive treatment, and 7% underwent transluminal balloon angioplasty for vasospasm. All patients with aneurysmal SAH should be treated with the calcium antagonist nimodipine, and in certain circumstances patients should receive anticonvulsants. The following review gives an account of pathophysiological mechanisms; the importance of treatment with calcium antagonists, hypervolaemic haemodilution, and induced arterial hypertension is discussed in light of the current literature. Seven placebo-controlled clinical studies have shown that nimodipine improves the outcome of patients with severe neurological damage due to cerebral vasospasm. In a series of 100 individuals with a ruptured supratentorial aneurysm, who were subjected to aneurysm operation in the acute stage and who subsequently received intravenous treatment with the calcium channel blocker nimodipine, the occurrence of DID with FND was reduced to 5%. There are many possible successful treatment options for preventing vasospasm, delayed ischemic neurologic deficits, and poor neurologic outcome following aneurysmal subarachnoid hemorrhage; however, further multicenter RCTs need to be performed to determine if there is a significant benefit from their use. Nimodipine is the only treatment that provided a significant benefit across multiple studies. Absence of symptomatic vasospasm, occurrence of low density areas associated with vasospasm on CT, and occurrence of adverse events were similar between the two groups. The clinical outcomes were more favorable in the fasudil group than in the nimodipine group (p = 0.040). The proportion of patients with good clinical outcome was 74.5% (41/55) in the fasudil group and 61.7% (37/60) in the nimodipine group. Cerebral vasospasm is the classic cause of delayed neurological deterioration leading to cerebral ischemia and infarction, and thus, poor outcome and occasionally death, after aneurysmal subarachnoid hemorrhage (SAH). Advances in diagnosis and treatment, principally nimodipine, intensive care management, hemodynamic manipulations, and endovascular neuroradiology procedures, have improved the prospects for these patients, but outcomes remain disappointing. Nimodipine is a dihydropyridine that blocks calcium influx through the L-type calcium channels. It is the most rigorously studied and only drug approved by the US Food and Drug Administration for use in treatment of vasospasm. It is safe [12,59], cost-effective [60], and most importantly reduces the risk of poor outcome and secondary ischemia after aneurysmal SAH [7,10-12,61]. Cerebral vasospasm is the classic cause of delayed neurological deterioration after aneurysmal subarachnoid hemorrhage, leading to cerebral ischemia and infarction, and thus to poor outcome and occasionally death. Advances in diagnosis and treatment-principally the use of nimodipine, intensive care management, hemodynamic manipulations and endovascular neuroradiology procedures-have improved the prospects for these patients, but outcomes remain disappointing. Cerebral vasospasm and delayed cerebral ischemia remain common complications of aneurysmal subarachnoid hemorrhage (SAH), and yet therapies for cerebral vasospasm are limited. Despite a large number of clinical trials, only calcium antagonists have strong evidence supporting their effectiveness. The only proven therapy for vasospasm is nimodipine. nimodipine is indicated after SAH and tirilazad is not effective. Fasudil hydrochloride and nimodipine both showed inhibitory effects on cerebral vasospasm. The incidence of symptomatic vasospasm was five of 33 patients in the fasudil group and nine of 32 patients in the nimodipine group. Good recovery evaluated by the Glasgow Outcome Scale was achieved by 23 of 33 patients in the fasudil group and 19 of 34 patients in the nimodipine group. Both drugs significantly improved consciousness levels and neurological deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more than nimodipine. </context> <question> Is nimodipine recommended for prevention of vasospasm in aneurysmal subarachnoid hemorrhage patients? </question> <answer> yes </answer>
<context> Pyridostigmine is the most widely used acetylcholinesterase inhibitor. For more than 50 years the acetylcholinesterase inhibitor pyridostigmine bromide has been the drug of choice in the symptomatic therapy for myasthenia gravis. The switch to SR-Pyr ameliorated the total quantified myasthenia gravis (QMG) score from 0.9 ± 0.5 to 0.6 ± 0.4 (p<0.001) in all patients and in the younger subgroup. This was accompanied by a significant improvement in the quality of life parameters. The health status valued by EuroQoL questionnaire improved from 0.626 ± 0.286 to 0.782 ± 0.186 (p<0.001). Our results support the usefulness of SR-Pyr in an individualized therapeutic regimen to improve quality of life regardless of the patient's age in myasthenia gravis. This review focuses on treatment of MG, mainly on the use of the AChE inhibitor pyridostigmine. Despite a lack of data from well controlled clinical trials to support their use, AChE inhibitors, of which pyridostigmine is the most commonly used, are recommended as first-line therapy for MG. Novel AChE inhibitors with oral antisense oligonucleotides have been developed and preliminary results appear to be promising. Except for one small and inconclusive trial of intranasal neostigmine, no randomised controlled trial has been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis. Response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in the placebo arm of treatment would be difficult to justify. Current guidelines and recommendations for MG treatment are based largely on clinical experience, retrospective analyses and expert consensus. Available therapies include oral acetylcholinesterase (AChE) inhibitors for symptomatic treatment, and short- and long-term disease-modifying treatments. Pyridostigmine has been used as a treatment for MG for over 50 years and is generally considered safe. It is suitable as a long-term treatment in patients with generalized non-progressive milder disease, and as an adjunctive therapy in patients with severe disease who are also receiving immunotherapy. Acetylcholinesterase inhibitors provide temporary, symptomatic treatment for all forms of myasthenia gravis. In MG, the first-line option is symptomatic treatment with acetylcholinesterase inhibitors. Pyridostigmine bromide is the most commonly used drug. Other acetylcholinesterase inhibitors such as neostigmine are rarely used because of their poorer pharmacodynamic profiles and tolerability. In an observational study of 14 MG patients comparing pyridostigmine with neostigmine, it was concluded that over 1 year, pyridostigmine was more effective with less adverse events.5 Similar conclusions were reached in another observational study of 69 patients which compared the use of pyridostigmine with neostigmine </context> <question> Which acetylcholinesterase inhibitors are used for treatment of myasthenia gravis? </question> <answer> neostigmine; pyridostigmine </answer>
<context> The Center of Epidemiological Studies-Depression Scale (CESD) (sensitivity: 0.75; 95% CI 0.60 to 0.85; specificity: 0.88; 95% CI 0.71 to 0.95), the Hamilton Depression Rating Scale (HDRS) (sensitivity: 0.84; 95% CI 0.75 to 0.90; specificity:0.83; 95% CI 0.72 to 0.90) and the Patient Health Questionnaire (PHQ)-9 (sensitivity: 0.86; 95% CI 0.70 to 0.94; specificity: 0.79; 95% CI 0.60 to 0.90) appeared to be the optimal measures for screening measures. There are a number of possible instruments that may help in screening for poststroke depression but none are satisfactory for case-finding. Preliminary data suggests the CESD, HDRS or the PHQ-9 as the most promising options. The Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale-depression subscale (HADS-D), Hamilton Rating Scale for Depression (HAMD), and Montgomery-Asberg Depression Rating Scale (MADRS) were administered. The balance of sensitivity and specificity was assessed using receiver operating characteristics (ROC) analysis. RESULTS: Discriminating abilities of all the scales for major and all PSD were good (area under ROC values 0.88-0.93 and 0.88-0.92 at 2 weeks; and 0.93-0.96 and 0.89-0.91 at 1 year, respectively). We compared the Beck Depression Inventory, Hamilton Rating Scale for Depression, Visual Analogue Mood Scale, proxy assessment, and Clinical Global Impression of the nursing and study personnel, together with Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised diagnosis, in assessing depression after stroke in a follow-up study of 100 patients. The sensitivity and specificity against the Diagnostic and Statistical Manual of Mental Disorders criteria were acceptable with the Clinical Global Impression, Beck Depression Inventory, and Hamilton Rating Scale for Depression, mostly in the range of 0.70 to 1.00. The Visual Analogue Mood Scale was not a sensitive instrument (sensitivity, 0.20 to 0.60) and did not correlate with the Beck Depression Inventory during the first year after stroke. Beck Depression Inventory, Hamilton Rating Scale for Depression, and Clinical Global Impression assessment by professionals, in addition to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised diagnosis, are useful in assessing depression, but none of these instruments clearly stood apart from the others. Proxy ratings should be used with caution, and the use of the Visual Analogue Mood Scale among patients with aphasia and other cognitive impairments cannot be recommended. This study evaluated the diagnostic accuracy of the Poststroke Depression Rating Scale (PSDRS), a diagnostic tool specifically devised to assess depression after stroke, in comparison to the Hamilton Depression Rating Scale (Ham-D). At their optimum cut-off points, the Ham-D and PSDRS showed good sensitivity and specificity for MDL or MDL + MDDM; the PSDRS had a higher positive predictive value for MDL in respect of the Ham-D (78 vs. 59%). Furthermore, the diagnostic accuracy of the PSDRS was higher in respect of the Ham-D in aphasic patients. The Ham-D and PSDRS are both reliable diagnostic tools for the diagnosis of PSD. We suggest that the PSDRS could be a useful tool in clinical practice and in therapeutic trials. The psychiatrist classified 25/71 (35.2%) patients as depressed. Using the recommended cut-point of 2 or more on the Signs of Depression Scale, the nurse and carer respectively rated 27/71 (38.0%) and 18/30 (60.0%) patients as potentially depressed. The proportion of patients correctly identified as depressed by the test (sensitivity) when rated by nurses was 64%, and the proportion of patients not depressed who were correctly identified by the test (specificity) was 61%, whereas carers achieved sensitivity 90% and specificity 35%. The Signs of Depression Scale is easily completed by clinical staff, although we found the sensitivity when completed by nurses to be low. Information from carers shows potential to improve screening and it is important for nurses to value the knowledge and skills of carers in detecting depression following a stroke. Further refinement of the Signs of Depression Scale, with accompanying research, is required. The VAMS was not useful in screening for depression in Chinese stroke patients while both the HADS and the GDS demonstrated satisfactory accuracy in detecting depression in Chinese stroke patients. At their respective optimum cutoff values, the sensitivity of the self-rated scales varied between 80% and 90%, while the specificity was about 60%. For the observer-rated scale (Hamilton Depression Rating Scale), sensitivity was 78.1%, and specificity was 74.6%. The hypothesis was supported: in contrast to psychiatric interview (68% depressed) and self-report (Beck Depression Inventory, 50% depressed), none of the patients were described as depressed in chart notes by the rehabilitation team (excluding the psychiatrists). Although there were no marked differences in the screening abilities for PSD between the scales, differences were found in factors influencing misclassification. Assessment scales with less somatic items may be recommended for the screening of PSD, particularly at the acute phase of stroke. </context> <question> Which depression rating scales were shown to have acceptable psychometric properties for screening of poststroke depression? </question> <answer> The Center of Epidemiological Studies-Depression Scale, Hamilton Depression Rating Scale, and the Patient Health Questionnaire, The Beck Depression Inventory, Hospital Anxiety and Depression Scale-depression subscale, Montgomery-Asberg Depression Rating Scale, Poststroke Depression Rating Scale and Clinical Global Impression scale appeared to have acceptable psychometric properties for identifying depression in patients after stroke. Therefore, these scales can be used for screening of post-stroke depression. Signs of Depression Scale and Visual Analogue Mood Scale showed inferior psychometric properties and therefore should not be used for screening for post-stroke depression. </answer>
<context> BETAWARE: a machine-learning tool to detect and predict transmembrane beta-barrel proteins in prokaryotes Recently, we developed two top-performing methods based on machine-learning approaches to tackle both the detection of TMBBs in sets of proteins and the prediction of their topology. Here, we present our BETAWARE program that includes both approaches and can run as a standalone program on a linux-based computer to easily address in-home massive protein annotation or filtering. We introduce a graph-theoretic model for predicting the supersecondary structure of transmembrane β-barrel proteins--a particular class of proteins that performs diverse important functions but it is difficult to determine their structure with experimental methods. This ab initio model resolves the protein folding problem based on pseudo-energy minimization with the aid of a simple probabilistic filter. It also allows for determining structures whose barrel follows a given permutation on the arrangement of β-strands, and allows for rapidly discriminating the transmembrane β-barrels from other kinds of proteins. The majority of OMPs can be bioinformatically differentiated and predicted by using their amino acid compositions [12-14], specific protein modifications and sorting mechanisms [15,16], and unique sequences and structural patterns These predictors can be categorized into three groups: (1) subcellular localization or global predictors which can differentiate between proteins from different compartments; (2) transmembrane β-barrel protein predictors which distinguish β-barrel structures from transmembrane α-helical proteins predominantly found in the inner membrane; and (3) lipoprotein predictors which can discriminate between inner membrane and outer membrane lipoprotein signal peptides A combination of different predictors, together with consensus prediction, has been shown to increase the coverage and accuracy of the predicted outer membrane proteome [45,48] including that of transmembrane β-barrel proteins In the present study, we used 10 different predictors classified into three groups (subcellular localization, transmembrane β-barrel protein and lipoprotein predictors) to identify putative OMPs from two available P. multocida genomes BOCTOPUS: improved topology prediction of transmembrane β barrel proteins Improving the detection of transmembrane β-barrel chains with N-to-1 extreme learning machines we introduce a new machine learning approach for TMBB detection based on N-to-1 Extreme Learning Machines TMBHMM: a frequency profile based HMM for predicting the topology of transmembrane beta barrel proteins and the exposure status of transmembrane residues We present here TMBHMM, a computational method based on a hidden Markov model for predicting the structural topology of putative TMBs from sequence. In addition to predicting transmembrane strands, TMBHMM also predicts the exposure status (i.e., exposed to the membrane or hidden in the protein structure) of the residues in the transmembrane region, which is a novel feature of the TMBHMM method. Furthermore, TMBHMM can also predict the membrane residues that are not part of beta barrel forming strands. Prediction of the exposure status of transmembrane beta barrel residues from protein sequence We present BTMX (Beta barrel TransMembrane eXposure), a computational method to predict the exposure status (i.e. exposed to the bilayer or hidden in the protein structure) of transmembrane residues in transmembrane beta barrel proteins (TMBs). Combined prediction of transmembrane topology and signal peptide of beta-barrel proteins: using a hidden Markov model and genetic algorithms We present here, an HMM that combine a transmembrane barrel submodel and an SP submodel for both topology and SP predictions. A new genetic algorithm (GA) is presented here to training the model, at the same time the Posterior-Viterbi algorithm is adopted for decoding. HHomp--prediction and classification of outer membrane proteins Previous methods to predict the occurrence and topology (i.e. number and location of strands) of OMBBs from sequence data have mostly used analogous features such as amino acid composition or alternating hydrophobicity patterns (7,8), either implicitly, such as in neural network and SVM-based methods (9–11), or explicitly, such as in TMB-Hunt, which applies a k-nearest neighbour algorithm to the whole-sequence amino acid composition (12,13), or in BOMP, which employs C-terminal pattern recognition combined with a sliding window analysis of amino acids frequencies in alternating positions (14). TransFold is a topology prediction method that employs statistical pair potentials to predict inter-β-strand contacts The best-performing OMBB predictors, such as PROFtmb (18), have specially designed hidden Markov models (HMMs). HHomp shows excellent performance in assigning OMP sequences to the correct functional subgroups In this work, we propose a method based on radial basis networks for predicting the number of beta-strands in OMPs and identifying their membrane spanning segments. We have developed a web server, TMBETAPRED-RBF for predicting the transmembrane beta-strands from amino acid sequence and it is available at http://rbf.bioinfo.tw/~sachen/tmrbf.html We have developed a novel approach for dissecting transmembrane beta-barrel proteins (TMBs) in genomic sequences. The features include (i) the identification of TMBs using the preference of residue pairs in globular, transmembrane helical (TMH) and TMBs, (ii) elimination of globular/TMH proteins that show sequence identity of more than 70% for the coverage of 80% residues with known structures, (iii) elimination of globular/TMH proteins that have sequence identity of more than 60% with known sequences in SWISS-PROT, and (iv) exclusion of TMH proteins using SOSUI, a prediction system for TMH proteins. TMBpro: secondary structure, beta-contact and tertiary structure prediction of transmembrane beta-barrel proteins We develop a suite (TMBpro) of specialized predictors for predicting secondary structure (TMBpro-SS), beta-contacts (TMBpro-CON) and tertiary structure (TMBpro-3D) of transmembrane beta-barrel proteins. This paper presents a k-nearest neighbor (K-NN) method for discriminating TMB and non-TMB proteins. Beta barrel trans-membrane proteins: Enhanced prediction using a Bayesian approach This paper describes the construction of a predictor for a beta-barrel membrane protein topology, based on machine learning Bayesian Networks (BNs) In this paper, based on the concept of pseudo amino acid composition (PseAA) that can incorporate sequence-order information of a protein sequence so as to remarkably enhance the power of discrete models (Chou, K. C., Proteins: Structure, Function, and Genetics, 2001, 43: 246-255), cellular automata and Lempel-Ziv complexity are introduced to predict the TM regions of integral membrane proteins including both alpha-helical and beta-barrel membrane proteins, validated by jackknife test transFold: a web server for predicting the structure and residue contacts of transmembrane beta-barrels we present BOCTOPUS; an improved method for the topology prediction of TMBs by employing a combination of support vector machines (SVMs) and Hidden Markov Models (HMMs). The SVMs and HMMs account for local and global residue preferences, respectively. In this paper, we describe the transFold web server, which implements a novel method (7) to predict TMB architecture. The transFold program extends a method introduced previously by Waldispühl and Steyaert (8) for TM α-bundle proteins, and employs statistical potentials developed for the program BETAWRAP Our software, named transFold, applies grammars to describe all potential ��-barrel supersecondary structures and then computes the global minimum energy structure by dynamic programming.The space of all possible TMB structures is described using multi-tape S-attribute grammars (7)—a framework which extends that of classical context-free grammars TMB-Hunt: an amino acid composition based method to screen proteomes for beta-barrel transmembrane proteins numerous methods have recently been published for the identification of these proteins, most commonly focusing on identification of TM beta-strands. Methods include rule based approaches [12], an architecture based approach [13], Hidden Markov Models (HMMs) [14-18], a neural network based method [19], a combined neural network and support vector machine [20], composition of transmembrane beta strands combined with secondary structure prediction [21] and an approach based on architecture [13] combined with isoleucine and asparagine abundance This paper describes TMB-Hunt, an amino acid composition based program for the identification of bbtm proteins. A program called TMB-Hunt has been described which identifies bbtm proteins using the amino acid composition of entire sequences. TMB-Hunt uses a novel method for calibration of results from the k-NN algorithm and uses evolutionary information from close homologues to build composition profiles. Evaluation of methods for predicting the topology of beta-barrel outer membrane proteins and a consensus prediction method The first computational methods that were deployed for the prediction of the transmembrane strands were based on hydrophobicity analyses, using sliding windows along the sequence, in order to capture the alternating patterns of hydrophobic-hydrophilic residues of the transmembrane strands [10,11]. Other approaches included the construction of special empirical rules using amino-acid propensities and prior knowledge of the structural nature of the proteins [12,13], and the development of Neural Network-based predictors to predict the location of the Cα's with respect to the membrane [ During the last few years, other more refined methods, using larger datasets for training, appeared. These methods, include refined Neural Networks (NNs), [15,16], Hidden Markov Models (HMMs) [17-21] and Support Vector Machines (SVMs) predictors [22]. Other popular methods such as the method of Wimley [23] and BOMP [24] do not explicitly report the transmembrane strands, but instead they are oriented towards genome scale discrimination of β-barrel membrane proteins. We conclude, that the recently developed Hidden Markov Model methods HMM-B2TMR [17], ProfTMB [21] and PRED-TMBB [20], perform significantly better than the other available methods Finally, we developed a consensus prediction method, using as input the individual predictions of each algorithm, and we conclusively show that this approach performs better, in all the measures of accuracy, compared to each individual prediction method separately. By using multivariate and univariate analysis of variance, we conclude that the HMM-based methods HMM-B2TMR, ProfTMB and PRED-TMBB perform significantly better than the other (mostly NN-based) methods, in both terms of per-residue and per-segment measures of accuracy. PRED-TMBB: a web server for predicting the topology of beta-barrel outer membrane proteins We present here a web server (PRED-TMBB, http://bioinformatics.biol.uoa.gr/PRED-TMBB) which is capable of predicting the transmembrane strands and the topology of beta-barrel outer membrane proteins of Gram-negative bacteria. The method is based on a Hidden Markov Model, trained according to the Conditional Maximum Likelihood criterion. Prediction of transmembrane regions of beta-barrel proteins using ANN- and SVM-based methods his article describes a method developed for predicting transmembrane beta-barrel regions in membrane proteins using machine learning techniques: artificial neural network (ANN) and support vector machine (SVM). The ANN used in this study is a feed-forward neural network with a standard back-propagation training algorithm. We have also developed an SVM-based method using a primary sequence as input and achieved an accuracy of 77.4%. The SVM model was modified by adding 36 physicochemical parameters to the amino acid sequence information. Finally, ANN- and SVM-based methods were combined to utilize the full potential of both techniques. we have developed a Web server, TBBPred, for predicting transmembrane beta-barrel regions in proteins Predicting transmembrane beta-barrels in proteomes Here we introduced the design, statistics and results of a novel profile-based hidden Markov model for the prediction and discrimination of TMBs. All proteome predictions and the PROFtmb prediction method are available A Hidden Markov Model method, capable of predicting and discriminating beta-barrel outer membrane proteins A few approaches have been made, in the direction of predicting the transmembrane strands of outer membrane proteins and/or identifying those proteins when searching large data sets; they are based on study of the physicochemical properties of the β-strands, such as hydrophobicity and amphipathicity [3], statistical analyses based on the amino acid composition of the known structures [4], or machine learning techniques like neural network predictors [5,6], and Hidden Markov Models [4,7,8]. Recently, a method based on a sequence profile-based HMM [8], requiring as input evolutionary information derived from multiple alignments, achieved the highest accuracy.In this work we developed a Hidden Markov Model method based solely on the amino acid sequence, without the requirement of evolutionary information. We present here a novel method, based on a Hidden Markov Model, for the prediction of the transmembrane β-strands of the outer membrane proteins of Gram-negative bacteria, and for the discrimination of these proteins from globular proteins. To our knowledge, a Hidden Markov Model trained with a discriminative method is applied for the first time in molecular biology for such a task. The beta-barrel finder (BBF) program, allowing identification of outer membrane beta-barrel proteins encoded within prokaryotic genomes We here report computational analyses of six outer membrane proteins of known 3D structures with respect to (1) secondary structure, (2) hydropathy, and (3) amphipathicity. Using these characteristics, as well as the presence of an N-terminal targeting sequence, a program was developed allowing prediction of integral membrane beta-barrel proteins encoded within any completely sequenced prokaryotic genome. This program, termed the beta-barrel finder (BBF) program, was used to analyze the proteins encoded within the Escherichia coli genome. A sequence-profile-based HMM for predicting and discriminating beta barrel membrane proteins We develop a HMM model, which can predict the topology of beta barrel membrane proteins using, as input, evolutionary information. The model is cyclic with 6 types of states: two for the beta strand transmembrane core, one for the beta strand cap on either side of the membrane, one for the inner loop, one for the outer loop and one for the globular domain state in the middle of each loop. The development of a specific input for HMM based on multiple sequence alignment is novel. Prediction of the transmembrane regions of beta-barrel membrane proteins with a neural network-based predictor A method based on neural networks is trained and tested on a nonredundant set of beta-barrel membrane proteins known at atomic resolution with a jackknife procedure. The method predicts the topography of transmembrane beta strands with residue accuracy as high as 78% when evolutionary information is used as input to the network. A web server based on the proposed method is available at http://yanbioinformatics.cs.usu.edu:8080/TMBKNNsubmit. Predicting three-dimensional structures of transmembrane domains of β-barrel membrane proteins We have developed a computational method for predicting structures of the transmembrane (TM) domains of β-barrel membrane proteins. Based on physical principles, our method can predict structures of the TM domain of β-barrel membrane proteins of novel topology, including those from eukaryotic mitochondria. Our method is based on a model of physical interactions, a discrete conformational state space, an empirical potential function, as well as a model to account for interstrand loop entropy. exposure status classification of transmembrane beta barrel residues Several computational methods exist for the identification of transmembrane beta barrel proteins (TMBs) from sequence. Some of these methods also provide the transmembrane (TM) boundaries of the putative TMBs. The aim of this study is to (1) derive the propensities of the TM residues to be exposed to the lipid bilayer and (2) to predict the exposure status (i.e. exposed to the bilayer or hidden in protein structure) of TMB residues. The modified Mahalanobis Discriminant for predicting outer membrane proteins by using Chou's pseudo amino acid composition. In this study, a method that combines increment of diversity with modified Mahalanobis Discriminant, called IDQD, is presented to predict 208 OMPs, 206 transmembrane helical proteins (TMHPs) and 673 globular proteins (GPs) by using Chou's pseudo amino acid compositions as parameters. Predicting transmembrane beta-barrels and interstrand residue interactions from sequence A novel method using pairwise interstrand residue statistical potentials derived from globular (nonouter membrane) proteins is introduced to predict the supersecondary structure of transmembrane beta-barrel proteins. The algorithm transFold employs a generalized hidden Markov model (i.e., multitape S-attribute grammar) to describe potential beta-barrel supersecondary structures and then computes by dynamic programming the minimum free energy beta-barrel structure. Predicting the solvent accessibility of transmembrane residues from protein sequence In this study, we propose a novel method to predict the solvent accessible surface areas of transmembrane residues. For both transmembrane alpha-helix and beta-barrel residues, the correlation coefficients between the predicted and observed accessible surface areas are around 0.65. BOMP: a program to predict integral beta-barrel outer membrane proteins encoded within genomes of Gram-negative bacteria This work describes the development of a program that predicts whether or not a polypeptide sequence from a Gram-negative bacterium is an integral beta-barrel outer membrane protein. The program, called the beta-barrel Outer Membrane protein Predictor (BOMP), is based on two separate components to recognize integral beta-barrel proteins. The first component is a C-terminal pattern typical of many integral beta-barrel proteins. The second component calculates an integral beta-barrel score of the sequence based on the extent to which the sequence contains stretches of amino acids typical of transmembrane beta-strands. A HMM-based method to predict the transmembrane regions of beta-barrel membrane proteins A novel method is developed to model and predict the transmembrane regions of beta-barrel membrane proteins. It is based on a Hidden Markov model (HMM) with architecture obeying those proteins' construction principles. First, an algorithm that calculates the mean hydrophobicity of one side of putative beta-strands predicted the positions of 16 transmembrane segments, a structure common to known porins. Second, outer loops typical of porins were assigned using an artificial neural network trained to predict the topology of bacterial outer-membrane proteins with a predominance of beta-strands Prediction of the membrane-spanning beta-strands of the major outer membrane protein of Chlamydia Topology prediction of Brucella abortus Omp2b and Omp2a porins after critical assessment of transmembrane beta strands prediction by several secondary structure prediction methods Four porins of known structure were selected as test-cases and their secondary structure delineated. The specificity and sensitivity of 11 methods were separately evaluated. Our critical assessment shows that some secondary structure prediction methods (PHD, Dsc, Sopma) originally designed to predict globular protein structure are useful on porin topology prediction. The overall best prediction is obtained by combining these three "generalist" methods with a transmembrane beta strand prediction technique A knowledge-based potential highlights unique features of membrane α-helical and β-barrel protein insertion and folding In previous work, a depth-dependent insertion potential, E(z) , was derived for α-helical inner membrane proteins. We have generated an equivalent potential for TM β-barrel proteins. The similarities and differences between these two potentials provide insight into unique aspects of the folding and insertion of β-barrel membrane proteins. This potential can predict orientation within the membrane and identify functional residues involved in intermolecular interactions. Improved identification of outer membrane beta barrel proteins using primary sequence, predicted secondary structure, and evolutionary information We present an accurate sequence-based predictor of OMBBs, called OMBBpred, which utilizes a Support Vector Machine classifier and a custom-designed set of 34 novel numerical descriptors derived from predicted secondary structures, hydrophobicity, and evolutionary information. Predicting weakly stable regions, oligomerization state, and protein-protein interfaces in transmembrane domains of outer membrane proteins. We have also discovered that out-clamps, in-plugs, and oligomerization are 3 general mechanisms for stabilizing weakly stable TM regions. In addition, we have found that extended and contiguous weakly stable regions often signal the existence of an oligomer and that strands located in the interfaces of protein-protein interactions are considerably less stable. Based on these observations, we can predict oligomerization states and can identify the interfaces of protein-protein interactions for beta-barrel membrane proteins by using either structure or sequence information Recently, we developed two top-performing methods based on machine-learning approaches to tackle both the detection of TMBBs in sets of proteins and the prediction of their topology. We introduce a graph-theoretic model for predicting the supersecondary structure of transmembrane β-barrel proteins--a particular class of proteins that performs diverse important functions but it is difficult to determine their structure with experimental methods. Several computational methods have been developed to discriminate TMBBs from other types of proteins. To conquer this limitation, we developed a new computational model that can be used for predicting the ASA of both TM α-helix and β-barrel residues. Transmembrane beta barrel (TMB) proteins are found in the outer membranes of bacteria, mitochondria and chloroplasts. RESULTS: We present here, an HMM that combine a transmembrane barrel submodel and an SP submodel for both topology and SP predictions. Prediction of membrane spanning segments in beta-barrel outer membrane proteins (OMP) and their topology is an important problem in structural and functional genomics. In the simplest of these, the target "model" is another protein sequence, while the more elaborate methods group together the entire set of t ansmembrane helical or transmembrane beta-barrel proteins. A consensus prediction method is for the first time been applied for the prediction of the transmembrane strands, of β-barrel outer membrane proteins. Based on this study, we have developed a Web server, TBBPred, for predicting transmembrane beta-barrel regions in proteins (available at http://www.imtech.res.in/raghava/tbbpred). </context> <question> What are the computational methods for the prediction of beta-barrel transmembrane proteins? </question> <answer> BBF', 'beta-barrel finder; BETAWARE; BOCTOPUS; BOMP; BTMX', 'Beta barrel TransMembrane eXposure; HHomp; HMM-B2TMR; OMBBpred; PROFtmb; PRED-TMBB; TMB-Hunt; TBBPred; TMBETAPRED-RBF; TMBHMM; TransFold; TMBpro; TMBKNN; Wimley; TMBETA-NET </answer>
<context> We implemented, PPInterFinder--a web-based text mining tool to extract human PPIs from biomedical literature. PPInterFinder uses relation keyword co-occurrences with protein names to extract information on PPIs from MEDLINE abstracts PPInterFinder--a mining tool for extracting causal relations on human proteins from literature eFIP system for text mining of protein interaction networks of phosphorylated proteins We have developed the Extracting Functional Impact of Phosphorylation (eFIP) text mining system, which combines several natural language processing techniques to find relevant abstracts mentioning phosphorylation of a given protein together with indications of protein-protein interactions (PPIs) and potential evidences for impact of phosphorylation on the PPIs. eFIP integrates our previously developed tools, Extracting Gene Related ABstracts (eGRAB) for document retrieval and name disambiguation, Rule-based LIterature Mining System (RLIMS-P) for Protein Phosphorylation for extraction of phosphorylation information, a PPI module to detect PPIs involving phosphorylated proteins and an impact module for relation extraction. In this article, we present GeneView, a web-based application providing access to a comprehensively annotated version of ∼21 million PubMed abstracts and ∼271 000 openly available PubMed Central full texts. It uses a multitude of state-of-the-art text-mining tools optimized for recognizing mentions from 10 different entity classes and for automatically identifying protein–protein interactions (PPI). iHop (5) provides access to a subset of PubMed sentences containing at least two proteins in conjunction with interaction specific keywords eneView uses several inter-operating components: (i) named entity recognition and PPI extraction modules; GeneView recognizes a broader set of entity types but not gene ontology terms, provides search facilities using unique database identifiers and also finds relationships between proteins in texts GeneView uses a machine learning approach based on support vector machines for relationship extraction between recognized proteins (20). The final model is trained on the ensemble of five corpora annotated with PPIs (21). The method achieved very good results in a comprehensive evaluation of nine machine learning approaches for PPI extraction (22). In this study, we propose a novel algorithm for extracting PPIs from literature which consists of two phases. First, we automatically categorize the data into subsets based on its semantic properties and extract candidate PPI pairs from these subsets. Second, we apply support vector machines (SVMs) to classify candidate PPI pairs using features specific for each subset. The source code and scripts used in this article are available for academic use at http://staff.science.uva.nl/~bui/PPIs.zip PPI finder: a mining tool for human protein-protein interactions In this study, we developed a novel algorithm by a frame-based approach for a web-based tool, PPI Finder, which can not only find the related genes of the gene of interest based on their co-occurrence frequencies but also extract the semantic descriptions of interactions from the co-occurring literature by computational linguistic methods. If users are only interested in whether there is an interaction between a specific pair of genes or proteins, Paired-PPI Finder can be used in this situation The frontpage of PPI Finder includes two web applications: PPI Finder (searching one gene at a time) and Paired-PPI Finder (searching two genes at a time). Protein-protein interactionsThere are several approaches to the extraction of PPIs from text. A large number of systems uses hand-crafted pattern sets, such as [9] and [19]. Although these systems may reach very good precision, the effort necessary to obtain at least acceptable recall on the sentence level is very high. Another class of systems relies on pure machine learning and casts the extraction task as one of classifying a sentence (or an abstract); an example is the PreBind system [20] PIE: an online prediction system for protein-protein interactions from text In this article, we describe an online Web service–PIE (Protein interaction information extraction system)–for providing biologists with extracted PPI sentences from text. PIE does not use locally saved PPIs, but rather focuses on PPI sentence predictions from the biomedical literature such as user-provided papers and PubMed articles. This feature provides much flexibility for the biologists who are interested in summarizing unknown PPI information out of papers or abstracts. In addition, PIE implements keyword-based extraction, which is similar to the one in other PPI services. By accepting keywords from users, PIE retrieves PubMed database on-the-fly and processes all or part of articles to predict PPI sentences. After uploading abstracts or papers, the prediction results are displayed by highlighting potential PPI sentences. The PIE interface is carefully designed to help biologists and bio-system developers, featuring PDF and HTML support, customized PubMed searching, PPI visualization and network communication. The PIE system consists of several modules. ‘Article Filter’ and ‘Sentence Filter’ decide whether given articles or sentences contain PPI information. Article filterIn the first step, the article filter classifies whether a given text contains PPI-related information. In doing so, it should not miss any PPI relevant documents, even though a certain amount of irrelevant documents is included. In the article filter, the bag-of-words method is used to represent text because we presume that some specific words or a simple combination of the words are enough to evaluate their PPI relevance at the article level, i.e. as a co-occurrence model. The sentence filter identifies PPI-related sentences from documents classified as relevant by the article filter. Since most of PPI sentences tend to have unique grammatical structures (7), a parse tree information which represents a set of words and its structural information is used to classify the PPI sentences. The PPI-related sentences are obtained using the following procedure PIE allows multiple PubMed articles for PPI prediction in two ways When keywords are given in the ‘PubMed Search’ tool, relevant abstracts are listed and users can select one or more abstracts to find PPI-related sentences. PIE also supports an automatic extraction method to obtain PPI information Users can maintain predicted PPI sentences PPI sentences might appear in several places in a full document. Hence, PIE highlights the predicted PPI sentences on the original article predicted PPI sentences can be stored in a local computer Our focus in the PIE system is to develop an ML-based framework for automatically identifying PPI sentences. PIE is specialized to extract PPI sentences from text for summarizing or finding relevant information. Our methods for gene, protein, and species identification, and PPIs are available as part of the BioCreative Meta Services We describe a system for the detection of mentions of protein-protein interactions in the biomedical scientific literature. The original system was developed as a part of the OntoGene project Protein term co-occurrences at sentence level of scientific abstracts might be potentially useful for the prediction of literature-based protein-protein interactions. Therefore, we have tested the performance of LAITOR to find protein-protein interaction data in abstracts. Once LAITOR identifies a co-occurring protein pair in an abstract, this is considered to be positively (relevant) classified LAITOR's has been evaluated for correct classification of abstracts relevant to curation of protein-protein interactions STRING uses Natural Language Processing [38] to search for statistically relevant co-occurrences of gene names, and also extract a subset of semantically specified interactions. We aim to improve automatic PPI detection by combining multiple linguistic clues via machine learning. While systems using linguistic features achieve good performance in extracting social, part-of and locational relations between entities such as person, organization and location (Zhou et al., 2005), they have not been fully explored for identifying PPIs. We have built a system and applied it to find evidence for interactions in the Interologous Interaction Database (I2D, http://ophid.utoronto.ca/i2d; Brown and Jurisica, 2007). Our interaction detection system has been used to identify evidence for human PPIs in I2D By searching PubMed with our system, we found 58 489 pairs with the two interaction partners co-occurring in at least one abstract. In this article, we described a system for automatic PPI detection in the text. we also plan to integrate the analysis with BioCreative Meta Server (BCMS; Leitner et al., 2008, http://bcms.bioinfo.cnio.es/), to identify known PPIs from PubMed We applied our system for PPI detection to two tasks when only a few supporting abstracts are available, evidence can be found for ∼60% of the interactions with the two proteins co-occurring in at least one sentence using our automatic PPI detection approach Extracting Protein-Protein Interactions from MEDLINE using the Hidden Vector State model We have constructed an information extraction system based on the Hidden Vector State (HVS) model for protein-protein interactions. When applied in extracting protein-protein interactions, we found that it performed better than other established statistical methods The developed BioMap system allows discovering implicit P-P interactions from large quantity of biomedical literature data. In this paper we examine if P-P interactions in regenerating tissues and cells of the anuran Xenopus laevis can be discovered from biomedical literature using computational and literature mining techniques. Using literature mining techniques, we have identified a set of implicitly interacting proteins in regenerating tissues and cells of Xenopus laevis that may interact with Cdc2 to control cell division. P-P interactions that are implicitly appearing in literature can be effectively discovered using literature mining techniques. Such methods include systems that efficiently retrieve and classify documents in response to complex user queries, and beyond this, systems that carry out a deeper analysis of the literature to extract specific associations, such as protein-protein interactions and protein functions. This deeper analysis is called text-mining In addition, we are seeing the emergence of new tools to aid in massive extraction of information from both literature and biological databases (for example, WikiProfessional [5]) or on-demand extraction of information from the literature (Information Hyperlinked Over Proteins [iHOP] [6]). Physical protein-protein interactions have been studied extensively because of their crucial role in controlling central biological processes such as cell division and their implications in a range of human diseases including cancer. OpenDMAP has been applied in three domains: protein transport, protein-protein interaction and the expression of a gene in a particular cell type. OpenDMAP advances the state of the art for extracting protein-protein interaction predications from the full texts of biomedical research articles. To address this problem, we have been developing a group of biology-specific computational annotators that work in conjunction with our group's text analytic software, for the discovery of protein-protein relations in text.In this paper, we undertook a study that utilizes a combination of computational linguistics, statistics and domain-specific rules to detect protein-protein interactions in a set of Medline abstracts. The current version of this system is called TafTalent and operates in the Unstructured Information Management (UIMA) environment [9]. These requirements motivated us to develop just such a resource—called PolySearch.PolySearch is a web accessible tool that is designed specifically for extracting and analyzing text-derived relationships between human diseases, genes/proteins, mutations (SNPs), drugs, metabolites, pathways, tissues, organs and sub-cellular localizations. In this paper, we present a tool called Protopia for searching for and integrating protein-protein interactions and the information about them contained in five different Protein Interaction Web Databases. C) Annotation event detection: identifying and encoding annotatable events, such as descriptions of protein–protein interactions, characterizations of gene products in terms of their cellular location, their molecular function, biological process involvement and phenotypic effect. This step may also involve a prioritization or ranking of documents, with documents containing information on novel discoveries (genes, proteins interactions) assigned a higher priority. We can analyse part of a sentence, such as a subphrase describing a protein–protein interaction or part of a sentence containing a gene and a protein name, but we always run into Zipf's law whenever we write down the rules for how the extraction is done (Figure 2) [3]. A small number of patterns describe a reasonable portion of protein–protein interactions, gene names, or mutations, but many of those entities are described by a pattern of words that's only ever used once. PreBIND and Textomy are two components of a literature-mining system designed to find protein-protein interaction information and present this to curators or public users for review and submission to the BIND database. STRING [93] integrates many different types of evidence about PPIs, including literature co-occurrence, phylogenetic data and results from high-throughput experiments, and has been used to predict novel PPIs in other organisms by transferring annotations to orthologous protein pairs. As a demonstration of the potential effectiveness of integrating concept recognition, we have constructed a protein interaction relation extraction system, the components of which were generated through participation in several of the BioCreative II tasks.We took a modular approach to the BioCreative II tasks, building on system components from other tasks whenever possible. A key focus in our work, and for the protein-protein interaction extraction task (interaction pair subtask [IPS]) in particular, was the use of a concept recognition system being developed by our group. In this work, we describe a new PPI web database resource, Human Annotated Protein-Protein Interactions (HAPPI), located at . As of early 2008, HAPPI (version 1.1) contains 142,956 non-redundant, medium to high-confidence human protein interaction pairs among 10,592 human proteins identified by UniProt protein names. The HAPPI database aims to become the most comprehensive public compilation of human protein interaction information. </context> <question> Which are the available biomedical text mining tools for the detection of protein-protein interactions? </question> <answer> BioCreative Meta Server; BioMap; eFIP', 'Extracting Functional Impact of Phosphorylation; GeneView; Hidden Vector State model; iHop; LAITOR; OntoGene; PIE', 'Protein interaction information extraction system; PPI finder', 'Paired-PPI Finder; PPInterFinder; PPIs; PreBind', 'Textomy; STRING; TafTalent; PolySearch; Protopia; OpenDMAP; HAPPI </answer>
<context> MosaicFinder: Identification of fused gene families in sequence similarity networks This leads to an efficient formulation of previous methods of fused gene identification, which we implemented in the Python program FusedTriplets. We implemented this method in the C++ program MosaicFinder, which additionally uses local alignments to discard false positive candidates and indicates potential fusion points. we refer to the fused gene as a 'composite' protein, while the un-fused counterpart genes in the reference organism are referred to as 'component' proteins [1,3].The accuracy of this approach has previously been demonstrated [3,9], however the presence of so-called 'promiscuous domains' in eukaryotic species has made it problematic to apply this method across a broad phylogenetic spectrum. These widespread domains (e.g. WD40 or TPR) are present in a multitude of combinations in many eukaryotic proteins [10] and can confound gene-fusion detection by appearing to be multiple conserved examples of gene-fusion components [3]. For this reason, we have improved our detection method to filter highly promiscuous domains from predictions.Previously, we used sequence homology and clustering to attempt resolving this issue, however this approach is computationally intensive. For this analysis, we take a simpler approach based on the PFAM domain database [11]. By delineating the domain architecture of each protein involved in a fusion event, we are able to locate and filter those domains that appear to link an inordinate number of proteins together based on domain interaction graph connectivity analysis Sequence similarities for all proteins against each other was generated using NCBI BLASTp v2.0 [29] with an E-value threshold of E ≤ 1e-10. Two proteins will be considered as interacting partners of a gene fusion event if both were similar to a non-overlapping part of a third sequence and were not similar to each other. To check similarity between the interacting proteins, we used a Smith-Waterman dynamic programming alignment tool [30,31] (prss33) with a threshold p-value of 0.04.Promiscuous Domain FilteringWe calculated the domain architecture of all protein sequences using HMMER [32] against the PFAM (v15) database [11] as a reference, using an e-value threshold of E ≤ 1e-10. A frequency analysis was then performed on the connectivity of PFAM domains. Recently, an analysis similar in spirit but different in detail has also been published [33]. The distribution obtained is logarithmic, with a long tail. We assume that this tail indicates the presence of promiscuous domains. When these data are visualized as a network, using the BioLayout tool [34], most of the nodes (i.e. proteins) are connected (i.e. interacting) in a super-cluster, due to the presence of promiscuous domains. We use this domain connectivity graph in order to determine a threshold for the removal of promiscuous domains Inference of gene function based on gene fusion events: the rosetta-stone method. The basic idea is based on the principle of "guilt by association." It is assumed that two proteins, which are found to be transcribed by a single transcript in one (or several) genomes are likely to be functionally linked, for example by acting in a same metabolic pathway or by forming a multiprotein complex. This method is of particular interest for studying genes that exhibit no, or only remote, homologies with already well-characterized proteins This chapter uses the FusionDB database (http://www.igs.cnrs-mrs.fr/FusionDB/) as source of information. FusionDB provides a characterization of a large number of gene fusion events at hand of multiple sequence alignments. PLEX can be searched iteratively and also enables searches for chromosomal gene neighbors and Rosetta Stone linkages. While phylogenomic profiles remain the central focus of Phydbac2, it now integrates chromosomal proximity and gene fusion analyses as two additional non-similarity-based indicators for inferring pairwise gene functional relationships. Functional links between proteins can often be inferred from genomic associations between the genes that encode them: groups of genes that are required for the same function tend to show similar species coverage, are often located in close proximity on the genome (in prokaryotes), and tend to be involved in gene-fusion events. The database STRING is a precomputed global resource for the exploration and analysis of these associations. Functional associations of proteins in entire genomes by means of exhaustive detection of gene fusions These powerful methods rely on the observation that pairs of genes encoding proteins of known function (usually interacting or forming a complex) tend to be found in other species as a fused gene encoding a single multifunctional protein [4]. This type of event is known as gene fusion and is a well-known process in molecular evolution the detection of gene fusions in one genome (defined as 'composite' proteins) allows the prediction of functional associations between homologous genes that remain separate in another genome (defined as 'component' proteins).Although gene fusion events appear to be relatively rare, the accurate detection of a gene fusion event in one genome allows interactions to be predicted between many proteins in other genomes The exhaustive detection of gene fusion events in entire genome sequences allows the prediction of functionally associated components based merely on genome structure. The all-against-all species comparison is a necessary step because we have repeatedly observed fused, composite proteins in taxonomically lower organisms. All 24 genomes were filtered using the CAST compositional bias filtering algorithm [20], then compared against themselves and each of the other 23 genomes using the BLASTp [21] sequence similarity searching algorithm with a cut-off E-value of 1 × 10-10. The DifFuse algorithm [1] was then applied automatically to each genome in turn as a query against the other 23 (reference) genomes. Protein interaction maps for complete genomes based on gene fusion events Here we present a method that identifies gene-fusion events in complete genomes, solely based on sequence comparison. Gene fusions have been suggested to be useful characters for identifying evolutionary relationships because they constitute synapomorphies or cladistic characters. To investigate the fidelity of gene-fusion characters, we developed an approach for identifying differentially distributed gene fusions among whole-genome datasets: fdfBLAST. Genome-scale comparative analysis of gene fusions, gene fissions Based on these comparisons, we developed a new method to integrate the features used in all four methods. We named the method InPrePPI (an Integrated method for Prediction of Protein-Protein Interactions). InPrePPI first calculates a score for each protein-protein pair predicted by each method, then optimally weighs the score, and finally obtains an integrated score. Based on the integrated score, InPrePPI extracts the PPIs with high confidence from all of the predicted protein pairs. Our comparison of InPrePPI with the joint observation method and STRING indicates that InPrePPI in general outperforms the others. Finally, we implemented the four genomic context based methods and InPrePPI in a user-friendly platform-independent system. Genomic context information has been frequently used in the computational methods for PPI prediction. There are four major genomic context based methods: the phylogenetic profile method [14], the gene cluster method [3], the gene fusion method [15], and the gene neighbor method In this study, we first evaluated the prediction performance of the four major genomic context based methods (PPM, GCM, GFM, and GNM), then we developed a novel integrated method (InPrePPI) based on the comparisons of these four methods in three datasets (KEGG, EcoCyc, and DIP). In the gene fusion method, two or more proteins were identified to be functionally linked when they were not encoded by neighboring genes in E. coli but were uniquely homologous to a single protein in a reference organism Here we present Predictome, a database of predicted links between the proteins of 44 genomes based on the implementation of three computational methods--chromosomal proximity, phylogenetic profiling and domain fusion Pairs of genes that function together in a pathway or cellular system can sometimes be found fused together in another organism as a Rosetta Stone protein--a fusion protein whose separate domains are homologous to the two functionally-related proteins. Using the Rosetta Stone method and this scoring scheme, we find all significant functional linkages for proteins of E. coli, P. horikshii and S. cerevisiae, and measure the extent of the resulting protein networks. We considered the four most important mechanisms of modular rearrangements—fusion, fission, terminal deletion, and domain addition (Björklund et al. 2005; Pasek et al. 2006; Weiner et al. 2006; Buljan et al. 2010). The algorithm assigns a fusion event when two ancestral arrangements can be fused to form the gained arrangement. This fusion analysis (also known as "Rosetta stone" method) takes advantage of the study of genomic structures and sequence similarity to detect putative interacting protein pairs, which, importantly might not have been suspected based on current biochemical knowledge. Briefly, if a pair of non-homologous proteins which are found in different genomic regions in organism A, are found fused into a single ORF in organism B, this suggests that the two independent proteins in organism A may interact. We used a home-built software tool [42] based on the BLASTp search algorithm [43] to identify gene fusion links (Figure 6). The output of the program consists of pairs of non-homologous T. brucei proteins, which appear fusion-linked in other species, i.e. when queried against the proteome of another organism, both match the same protein as their best BLAST hit. The top scoring hits were verified by various criteria, such as the top scoring hit on the reverse BLAST process, the E-value threshold, the similarity and functionality of domain architecture between the component and composite proteins. The software algorithm was developed to exclude any homologues which are 85% identical over the whole sequence length. Hence, a protein with a similarity value of 85% or higher to a larger protein of the sameorganism, was deleted from the proteome. A fusion-linked protein was taken into consideration only if each component had a minimum DOMAIN length of 70 amino acids, along with a minimum of 27% identity with the composite protein, based on the BLAST alignment per domain.• We automatically excluded all results with an E-value higher than the threshold of 10-3, as not statistically significant.• Two proteins were considered to be fusion-linked only if each of them aligned with a minimum PROTEIN coverage of 70% to the same reference sequence (based on the protein annotation of the target organism). Fusion events between proteomes have been used to predict protein-protein interactions [12],[13] with some degree of success, in particular metabolic enzymes for which stable protein-protein interactions in one species could be advantageously substituted by the products of fusion events in other species. </context> <question> Which are the state-of-the-art computational tools for the prediction of gene fusion events? </question> <answer> fdfBLAST; FusionDB; InPrePPI', 'Integrated method for Prediction of Protein-Protein Interactions; MosaicFinder; Phydbac2; PLEX; Predictome; Rosetta Stone method; STRING </answer>
<context> we illustrate arrangement diversity within closely related organisms, estimate arrangement turnover frequency and establish, for the first time, branch-specific rate estimates for fusion, fission, domain addition and terminal loss. Rate and polarity of gene fusion and fission in Oryza sativa and Arabidopsis thaliana We have identified all differentially composite or split genes in 2 fully sequenced plant genomes, Oryza sativa and Arabidopsis thaliana Polarizing these events by outgroup comparison revealed differences in the rate of gene fission but not of gene fusion in the rice and Arabidopsis lineages. Gene fission occurred at a higher rate than gene fusion in the O. sativa lineage and was furthermore more common in rice than in Arabidopsis. Gene fusion and fission are thus rare and slow processes in higher plant genomes; they should be of utility to address deeper evolutionary relationships among plants--and the relationship of plants to other eukaryotic lineages--where sequence-based phylogenies provide equivocal or conflicting results. Primary factors correlating with fusion rates are the presence of transmembrane helices in HKs and the presence of DNA-binding domains in RRs, features that require correct (and separate) spatial location. In the absence of such features, there is a relative abundance of fused genes. We show that indels are the most frequent elementary events and that they occur in most cases at either the N- or C-terminus of the proteins. As revealed by the genomic neighbourhood/context of the corresponding genes, we show that a substantial number of these terminal indels are the consequence of gene fusions/fissions. We provide evidence showing that the contribution of gene fusion/fission to the evolution of multi-domain bacterial proteins is lower-bounded by 27% and upper-bounded by 64%. We conclude that gene fusion/fission is a major contributor to the evolution of multi-domain bacterial proteins. We found that fusion events are approximately four times more common than fission events, and we established that, in most cases, any particular fusion or fission event only occurred once during the course of evolution. Analyzing the most parsimonious pathways, we find 87% of architectures to gain complexity over time through simple changes, among which fusion events account for 5.6 times as many architectures as fission. Our aim is to understand the evolutionary dynamics by studying the frequency of individual modular events such as fusion, fission, or terminal loss. We considered the four most important mechanisms of modular rearrangements—fusion, fission, terminal deletion, and domain addition Fusion events makeup the largest proportion of exact solutions, followed by domain addition, fission, and terminal deletion. Fusion events occur with a frequency of 4.59/Myr, followed by fission with 1.98/Myr, and gain with 1.89/Myr. Recent rearrangements can mostly be explained by the fusion of two single or two domain proteins. The relative rates of fusion and fission are similar to previously reported rates (Kummerfeld and Teichmann 2005). The high retention rate of proteins that result from a fusion event might be explained by the conservation of at least one regulatory element in the upstream region, whereas after fission, one arising protein may lose a regulatory region and undergo pseudogenization followed by gene loss. Quantitative analyses have shown that fusions are more prevalent to fission (Snel et al. 2000) Lastly, for merge and split events, a comparison of their counts revealed a 0.86:1 merge-to-split ratio, which at first seemed inconsistent with previous studies suggesting that fusion occurs more often than fission by a factor of 2.6–5.6 (Snel et al. 2000, Kummerfeld and Teichmann 2005, Fong et al. 2007). However, one key difference in this analysis is that we measured individual events, as opposed to simply observing the presence of fused and fragmented extant genes, and we measured events over a smaller higher resolution time scale (the 62 My Drosophila clade vs. all three domains of life diverging over 3.5 billion years). by considering only “simple” merges and splits that are unaccompanied by generation, duplication, or loss events, the merge-to-split ratio became 5.28:1, which is much more comparable to previously determine ratios. For example, gene fissions are relatively rare events compared to fusions [11] These trees defined timelines of architectural discovery and revealed remarkable evolutionary patterns, including the explosive appearance of domain combinations during the rise of organismal lineages, the dominance of domain fusion processes throughout evolution, and the late appearance of a new class of multifunctional modules in Eukarya by fission of domain combinations We searched for examples which have arisen by one of the three postulated mechanisms: independent fusion/fission, "duplication/deletion," and plasmid-mediated "cut and paste." We conclude that all three mechanisms can be observed, with the independent fusion/fission being the most frequent. </context> <question> Is there a difference in the rate between gene fusion and gene fission? </question> <answer> yes </answer>
<context> The illicit drugs more commonly associated with stroke are psychomotor stimulants, such as amphetamine and cocaine. Less commonly implicated are opioids and psychotomimetic drugs, including cannabis. Among 326 patients (184 males), the most frequent stroke risk factors overall were dyslipidaemia (187), smoking (161), hypertension (105) and obesity (92). Fifty-one patients used illicit drugs, mostly comprising marijuana and amphetamines. Patients in Adelaide are more likely to be obese, to be misusing marijuana and amphetamines, to suffer a cardioembolic event and to have a stroke that concurrently affects both the anterior and posterior cerebral circulation. RCVS was spontaneous in 37% of patients and secondary in the 63% others, to postpartum in 5 and to exposure to various vasoactive substances in 37, mainly cannabis, selective serotonin-recapture inhibitors and nasal decongestants. We reported two cases of young stroke associated with drug misuse. Case 1 used amphetamine, cocaine, marijuana and LSD for few yaers, and developed occlusion of a middle cerebral artery. Case 2 presented aphasia shortly after marijuana smoking. Marijuana may have accelerated stroke onset, but essential cause of stroke in this case must be protein S mutation. Cannabis is the most widely consumed among the illicit drugs worldwide, but it has only exceptionally been associated to cerebrovascular disease. We here describe 2 young patients (26 and 29 years, respectively) who suffered from ischemic stroke in temporal relation with cannabis consumption. The review of the literature on this topic reveals another 18 patients with stroke in association to cannabis use. Although a causal relationship is difficult to establish due to the widespread use of cannabis, this drug may play an etiologic role in ischemic stroke. Marijuana may trigger a myocardial infarction and have a vasospastic effect. Despite the fact that cannabis is the most widely used illicit drug, there are only a few reports associating its use with cerebrovascular disease. We describe a patient who suffered three ischaemic strokes immediately after cannabis consumption. Cannabis use may be associated with ischaemic stroke in young patients, but its mechanism is unclear. A right occipital ischemic stroke occurred in a 37-year-old Albanese man with a previously uneventful medical history, 15 min after having smoked a cigarette with approximately 250 mg of marijuana. Therefore, as the family history for cerebrovascular events, blood pressure, clotting tests, examinations for thrombophilia, vasculitis, extracranial and intracranial arteries and cardiac investigations were normal or respectively negative, the stroke was attributed to the chronic cannabis consumption. Three adolescent males had similar presentations of headache, fluctuating level of consciousness or lethargy, visual disturbance, and variable ataxia after self-administration of marijuana. Episodic marijuana use may represent a risk factor for stroke in childhood, particularly in the posterior circulation. Although several mechanisms exist by which marijuana use might contribute to the development of chronic cardiovascular conditions or acutely trigger cardiovascular events, there are few data regarding marijuana/THC use and cardiovascular disease outcomes. Reported here is the case of a previously healthy young man who smoked marijuana on a daily basis and had an occipital lobe stroke; he was found to be heterozygous for factor V Leiden. This case suggests that marijuana smoking may increase the risk of arterial thrombosis in otherwise healthy individuals who are heterozygous for factor V Leiden. Thus, chronic abuse of marijuana might be a risk factor for stroke. A 22-year-old man with a five-year history of drug and alcohol abuse presented with a left hemiparesis preceded by three transient ischaemic attacks, two of which occurred whilst smoking cannabis. Substance abuse was the only identifiable risk factor for cerebrovascular disease. Chronic marijuana smoking, however, seems to reduce CBF. Research directions might include more studies of cardiovascular disease outcomes and relationships of marijuana with cardiovascular risk factors, studies of metabolic and physiologic effects of chronic marijuana use that may affect cardiovascular disease risk, increased understanding of the role of the cannabinoid receptor system in cardiovascular regulation, and studies to determine if there is a therapeutic role for cannabinoids in blood pressure control or for neuroprotection after stroke. </context> <question> Is marijuana use associated with increased risk for stroke? </question> <answer> yes </answer>
<context> Opioid overdose has a high mortality, but is often reversible with appropriate overdose management and naloxone (opioid antagonist). Training clinicians how to manage an opioid overdose and administer naloxone was effective. For patients who have ingested dextromethorphan and are sedated or comatose, naloxone, in the usual doses for treatment of opioid overdose, can be considered for prehospital administration, particularly if the patient has respiratory depression Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. Patients who received naloxone for known or presumed opioid overdose were formally evaluated one hour later for multiple potential predictor variables. Patients with presumed opioid overdose can be safely discharged one hour after naloxone administration To determine whether naloxone administered i.v. to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of <10 breaths/min. There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. Management of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid overdose, whether illicit or iatrogenic, requires the prompt and skillful use of opioid antagonists. The proportion of clinicians willing to use naloxone in an opioid overdose rose from 77% to 99% after training. Barriers to implementing training were clinician time and confidence, service resources, client willingness and naloxone formulation. Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. </context> <question> Which medication should be administered when managing patients with suspected acute opioid overdose? </question> <answer> naloxone </answer>
<context> Benzodiazepine (BZD) overdose (OD) continues to cause significant morbidity and mortality in the UK. Flumazenil is an effective antidote but there is a risk of seizures, particularly in those who have co-ingested tricyclic antidepressants. Flumazenil was administered to 80 patients in 4504 BZD-related enquiries, 68 of whom did not have ventilatory failure or had recognised contraindications to flumazenil. Flumazenil is used infrequently in the management of BZD OD in the UK. Flumazenil is a benzodiazepine antagonist. It is widely used as an antidote in comatose patients suspected of having ingested a benzodiazepine overdose. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose. Flumazenil is indicated for reversal of sedation from benzodiazepines administered during therapeutic or diagnostic procedures and during induction or maintenance of general anesthesia, as well as for benzodiazepine overdose. When measures are required to ensure adequate recovery of a patient's respiratory function and mental awareness, such as in patients with benzodiazepine toxicity, consideration of continuous-infusion flumazenil is warranted. Flumazenil is a potent benzodiazepine antagonist that competitively blocks the central effects of benzodiazepines. It can reverse the sedative effects of benzodiazepines occurring after diagnostic or therapeutic procedures or after benzodiazepine overdose. A 54-y-old man ingested 2 g of bulk laboratory diazepam and was treated with activated charcoal, enhanced diuresis and flumazenil infusion. Flumazenil is a specific and competitive antagonist at the central benzodiazepine receptor, reversing all effects of benzodiazepine agonists without tranquillising or anticonvulsant actions. Incremental intravenous bolus injections of flumazenil 0.1 to 0.3 mg are the most effective and well tolerated in the diagnosis and treatment of pure benzodiazepine overdose; additional boluses or an infusion (0.3 to 0.5 mg/h) can be given to prevent patients from relapsing into coma. Flumazenil is a competitive benzodiazepine antagonist that acts to reverse their sedative and hypnotic effects. It is indicated in the management of benzodiazepine overdose, but its role in the routine reversal of endoscopic conscious sedation has not been defined. To develop clinical rules for the safe and effective use of flumazenil in suspected benzodiazepine overdose. Unconscious patients (n = 110) suspected of benzodiazepine overdose, graded 2 to 4 on the Matthew and Lawson coma scale, were treated with flumazenil, the specific benzodiazepine receptor antagonist. Fourteen of 17 double-blind, flumazenil-treated patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients (p < .001). Seventy-five percent of the aggregated controlled and uncontrolled patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high benzodiazepine serum blood concentrations. Flumazenil is effective in preventing recurrence of benzodiazepine-induced coma. Flumazenil is best left for reversal of therapeutic conscious sedation and rare select cases of benzodiazepine overdose. Flumazenil interacts at the central benzodiazepine receptor to antagonize or reverse the behavioral, neurologic, and electrophysiologic effects of benzodiazepine agonists and inverse agonists. It improves the level of consciousness in patients with benzodiazepine overdose; however, resedation may occur within one to two hours after administration, so repeated doses or a continuous infusion may be required to maintain therapeutic efficacy. Flumazenil has been shown to reverse sedation caused by intoxication with benzodiazepines alone or benzodiazepines in combination with other agents, but it should not be used when cyclic antidepressant intoxication is suspected. Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. Flumazenil, a specific benzodiazepine antagonist, is useful in reversing the sedation and respiratory depression that often occur when benzodiazepines are administered to patients undergoing anesthesia or when patients have taken an intentional benzodiazepine overdose. Flumazenil rapidly and effectively reverses the clinical signs and symptoms of a BDZ overdose. Flumazenil is a benzodiazepine antagonist that is highly effective in reversing the central nervous system effects of benzodiazepine overdose. In the setting of isolated benzodiazepine overdose, flumazenil is capable of completely reversing coma within one to two minutes, with this effect lasting between one and five hours. Fifteen comatous patients with suspected sedatives/hypnotics overdose were included in this study and flumazenil 0.25 mg per dose was administrated intravenously. The average score of Glasgow Coma Scale increased from 7.13 +/- 2.92 to 10.93 +/- 3.67 after one dose of flumazenil. Clear consciousness was restored after multiple doses of flumazenil administration. We concluded that flumazenil is an excellent antidote for benzodiazepine overdose and valuable for differentiating the patients in comatose. Patients with benzodiazepine overdose who received 5 mg flumazenil regained consciousness about 1-2 min after the end of injection. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. Flumazenil is the first benzodiazepine antagonist which can be used in humans and is a well established for treatment of benzodiazepine overdose. Flumazenil, a 1,4-imidazobenzodiazepine, is a highly effective, specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be attenuated or terminated at short notice. Thus, flumazenil provides a safe and effective means of attenuating or reversing the CNS-depressant effects of benzodiazepines whenever indicated, e.g. following benzodiazepine-induced general anaesthesia, conscious sedation, or after benzodiazepine overdose, either alone or in combination with other agents. Flumazenil is safe when administered cautiously, even in patients with coma caused by a mixed overdose of benzodiazepine plus tricyclic antidepressants. The mean +/- SD CGIS score at ten minutes for BDZ-positive patients was 1.41 +/- 0.72 for patients who received flumazenil and 3.41 +/- 0.91 for the placebo group (P < .01). There was no difference in the mean CGIS score between the flumazenil (3.25 +/- 1.15) and placebo (3.75 +/- 0.69) groups in BDZ-negative patients. The GCS and NAS were also significantly better in patients who were BDZ-positive and received flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). The efficacy and safety of flumazenil were assessed in comparison to placebo in a double-blind randomised study of 31 adults intoxicated with benzodiazepines. The criteria of efficacy were the degree of sedation, and orientation in time and space. Patients who received flumazenil awoke within minutes but central depression returned partly one hour later, which reflects the short elimination half-life of the drug. Side effects were few and the results indicate that flumazenil is effective in the primary management of benzodiazepine overdose and in states where benzodiazepines have been taken with other drugs. Flumazenil (Ro 15-1788) proved to be a very efficacious competitive antagonist of benzodiazepines that reliably counteracts their pharmacological actions within 1-2 min as could be demonstrated in clinical and EEG studies. In intensive care medicine, the antagonist may be used in the treatment of benzodiazepine overdose as well as in the differential diagnosis of a coma of unknown origin. </context> <question> Which drug should be used as an antidote in benzodiazepine overdose? </question> <answer> flumazenil </answer>
<context> The Oncotype-DX Breast Cancer Assay (Genomic Health, Redwood City, CA) quantifies gene expression for 21 genes in breast cancer tissue by performing reverse transcription polymerase chain reaction (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tumour blocks that are obtained during initial surgery (lumpectomy, mastectomy, or core biopsy) of women with early breast cancer that is newly diagnosed. Oncotype DXtrade mark, is a diagnostic test comprised of a 21-gene assay applied to paraffin-embedded breast cancer tissue, which allows physicians to predict subgroups of hormone-receptor-positive, node-negative patients who may benefit from hormonal therapy alone or require adjuvant chemotherapy to attain the best survival outcome. Oncotype DX is a clinically validated, high-complexity, multianalyte reverse transcription-PCR genomic test that predicts the likelihood of breast cancer recurrence in early-stage, node-negative, estrogen receptor-positive breast cancer. We therefore investigated the analytical performance of the assay. Assays used a pooled RNA sample from fixed paraffin-embedded tissues to evaluate the analytical performance of a 21-gene panel with respect to amplification efficiency, precision, linearity, and dynamic range, as well as limits of detection and quantification. One such strategy is the 21-gene assay (Oncotype DX), which is currently in commercial use in the USA. One advantage of this test is the use of paraffin-embedded blocks instead of previous methods, which required fresh frozen tissue. We used paraffin-embedded core biopsies from a completed phase II trial to identify genes that correlate with response to primary chemotherapy. In addition to the individual genes, the correlation of the Oncotype DX Recurrence Score with pCR was examined RNA was extracted from paraffin blocks to develop the 21-gene Recurrence Score assay (Oncotype DX) </context> <question> Does the Oncotype DX test work with paraffin embedded tissues? </question> <answer> yes </answer>
<context> The 70-gene signature (MammaPrint™) The 70 gene-signature (MammaPrint(®)) is a prognostic profile of distant recurrence and survival of primary breast cancer (BC) The 70-gene signature was analysed using MammaPrint the prognostic value of the MammaPrint(TM) signature by the 70-gene signature the 70-gene signature n FDA-cleared 70-gene signature of MammaPrint panel MammaPrint (the commercial test of the 70 genes, marketed by Agendia, Amsterdam) 70-gene MammaPrint signature 70-gene signature MammaPrint genes indeed capture these six steps, we examined the biological functions of each of the 70 genes. The 70 genes that make up the MammaPrint signature 70-gene profile 70 gene profile the 70 MammaPrint genes a set of 70 genes the 70 genes in the MammaPrint profile in the MammaPrint 70 gene expression profile he MammaPrint 70-gene tumor expression profile the 70-gene prognosis signature (MammaPrint, Agendia Inc., Huntington Beach, CA, USA and Amsterdam, The Netherlands the 70-gene MammaPrint signature The 70-gene MammaPrint signature The 70-gene signature (MammaPrint) is a prognostic test used to guide adjuvant treatment decisions in patients with node-negative breast cancer. 70-gene signature. 70-gene signature 70-gene signature 70-gene signature the 70-gene MammaPrint signature for chemotherapy (CT) benefit the 70-gene MammaPrint signature The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions. the 70-gene profile the 70-gene prognosis signature (MammaPrint) for node-negative breast cancer patients. 70-gene signature. 70-gene signature The Amsterdam 70-gene expression signature as breast cancer prognosis marker has been validated in follow-up studies [39,40], and a clinical assay MammaPrint® has recently been cleared by FDA. The MammaPrint 70-gene signature </context> <question> How many genes are in the gene signature screened by MammaPrint? </question> <answer> 70 genes </answer>
<context> Prognostic and predictive markers Oncotype DX® currently allow avoidance of an over therapy or under therapy a high score on the Oncotype DX gene expression profile r poor-prognosis ER-positive breast cancers in need of more aggressive therapy luminal B class The 21-gene recurrence score (Oncotype DX: RS) appears to augment clinico-pathologic prognostication and is predictive of adjuvant chemotherapy benefit in node-negative (N-) and node-positive (N+), endocrine-sensitive breast cancer. Half of all breast cancers are early stage, lymph node negative, and hormone receptor positive. A 21-gene (Oncotype DX®; Genomic Health, Inc., Redwood City, CA) recurrence score (RS) is prognostic for recurrence and predictive of chemotherapy benefit. We hypothesized that a distinct network of immune function genes at the tumor site can predict a low risk versus high risk of distant relapse in breast cancer patients regardless of the status of ER, PR, or HER-2/neu in their tumors. Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes. Molecular tests such as the Oncotype DX(®) breast cancer test are proving to be more effective tools for individualized patient stratification and treatment planning than traditional methods such as patient demographic variables and histopathology indicators. Node-negative breast cancer does not automatically suggest a good prognosis, or the preclusion of chemotherapy benefits, and additional biomarkers are needed to help identify patients who do benefit from chemotherapy. The oncotype DX® genomic assay has also been used to help prognosis estimation and treatment decisions. The Oncotype DX Recurrence Score (RS) is a validated genomic predictor of outcome and response to adjuvant chemotherapy in ER-positive breast cancer. The Oncotype DX Breast Cancer Assay has met this standard as an analytically and clinically validated high complexity, multi-analyte, RT-PCR test to predict the likelihood of recurrence and response to chemotherapy in estrogen receptor-positive, node-negative and node-positive breast cancer patients [1,2]. the Oncotype DX Breast Cancer Assay has become standard of care for individualized treatment decision-making in early stage breast cancer [3-5] study of the 12 gene Oncotype DX Colon Cancer Assay [7], stage II colon cancer patients (particularly those with T3 disease and mismatch repair proficient (MMR-P) tumors) are now empowered to make more informed treatment decisions with quantitative, individualized recurrence risk information based on the molecular profile of their tumor.The seven cancer-related genes in the Oncotype DX Colon assay were selected from a panel of 761 genes for their consistent association with colon cancer recurrence in 4 large and independent development studies [6]. Oncotype DX, which produces a quantitative RS between 0 and 100, is a molecular assay that has been clinically validated to predict the likelihood of 10-year distant recurrence and the expected benefit from adjuvant chemotherapy for early-stage, ER+ BCa patients.[1] Prognosis and treatment in early stage ER+ BCa are often guided by the Oncotype DX genomic assay (Genomic Health, Inc.), which produces a quantitative recurrence score (RS) correlated with likelihood for recurrence.[1] Clinical ScenarioOncotype DX is used for profiling tumor gene expression in patients with Stage-II colon cancer to predict recurrence risk and inform treatment decisions following surgery. The 21-gene signature has been intensively studied and incorporated into major guidelines for treatment decision in early breast cancer. Among early-stage breast cancer patients who received Oncotype DX, we found low knowledge about many aspects of genomic recurrence risk testing. the gene expression signatures that define specific prognostic subtypes in other breast cancer datasets, such as luminal A and B, basal, normal-like, and ERBB2+, and prognostic signatures including MammaPrint and Oncotype DX, predicted genomic instability in our samples. This remarkable congruence suggests a biological interdependence of poor-prognosis gene signatures, breast cancer subtypes, genomic instability, and clinical outcome. The Oncotype DX assay is one of the molecular tests that provide predictive and prognostic information to breast cancer patients with estrogen receptor (ER)-positive and node-negative disease. This study evaluates the association of Forkhead-box protein A1 (FOXA1) and GATA-binding protein 3 (GATA3) expressions with Oncotype DX recurrences scores in 77 cases of patients with ER-positive node-negative breast carcinomas diagnosed at Indiana University. the use of the Oncotype DX assay in estrogen receptor-positive node-negative breast cancer patients were incorporated into guidelines from both the American Society of Clinical Oncology and the National Comprehensive Cancer Network. The Oncotype DX assay is a diagnostic test which measures changes in a set of 21 genes in order to predict the likelihood of disease recurrence and also to predict which patients are most likely to respond to chemotherapy. The EWG found adequate evidence regarding the association of the Oncotype DX Recurrence Score with disease recurrence and adequate evidence for response to chemotherapy. EWG) found insufficient evidence to make a recommendation for or against the use of tumor gene expression profiles to improve outcomes in defined populations of women with breast cancer. confirmed the clinical validity of the Oncotype DX breast cancer assay, not only as a way to predict recurrence but also as a tool for determining therapeutic benefit from adjuvant chemotherapy. Over several decades, investigators working through National Cancer Institute-sponsored Cooperative Groups have contributed to major advances in the endocrine treatment of breast cancer. Cooperative Group studies have contributed to the development of a molecular profiling test, Oncotype Dx, which identifies women who have an excellent prognosis with hormonal therapy alone. In this report we compare the prognostic and predictive utility of these two tools in node-negative, ER-positive breast cancer The Oncotype-DX Breast Cancer Assay (Genomic Health, Redwood City, CA) quantifies gene expression for 21 genes in breast cancer tissue by performing reverse transcription polymerase chain reaction (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tumour blocks that are obtained during initial surgery (lumpectomy, mastectomy, or core biopsy) of women with early breast cancer that is newly diagnosed. 78 women, treated for early-stage, estrogen receptor-positive breast cancer with 0-3 positive lymph nodes, whose medical records indicated they received Oncotype DX testing earlier. A retrospective chart review of 58 T1/T2, node-negative, estrogen-receptor positive breast cancer patients that underwent Oncotype DX gene assay testing between January and December 2006 was performed. </context> <question> Which diseases can Oncotype DX be used for? </question> <answer> breast cancer; colon cancer </answer>
<context> The clinical need for novel approaches to improve drug therapy derives from the high rate of adverse reactions to drugs and their lack of efficacy in many individuals that may be predicted by pharmacogenetic testing. the assessment of the human epidermal growth factor receptor (HER-2) expression for trastuzumab therapy of breast cancer HER2 positive breast cancer and the use of the drug Herceptin The dependence on gene copy number or expression levels of HER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. to explore informed consent issues surrounding the use of the drug Herceptin, widely cited as an example of a novel approach to drug development called pharmacogenetics. Drawing on qualitative semi-structured interviews with 25 UK-based breast cancer specialists, this paper explores Herceptin's disputed epistemological status, as an example of pharmacogenetics or as something out of the ordinary in terms of clinical practice. There have been several success stories in the field of pharmacogenetics in recent years, including the analysis of HER2 amplification for trastuzumab selection in breast cancer Trastuzumab is standard of care in the treatment of human epidermal growth factor receptor (HER)-2⁺ early and advanced breast cancer. HER-2 overexpression as a predictor of response to trastuzumab New evidence for the role of trastuzumab comes from the updated results of the M77001 study, showing 8-month median survival improvement in Her2-positive metastatic disease patients administered trastuzumab and docetaxel, compared with docetaxel alone. Pharmacogenomic analysis aspires to identify individuals with specific genetic characteristics in order to predict a positive response or reduce a negative response to a therapeutic modality. Assays are available to detect the HER2 protein receptor or copies of the HER2 gene sequence to determine eligibility for Herceptin treatment or adriamycin treatment in node positive patients, respectively. Determining the HER2 status of breast carcinomas is a prerequisite for the use of the monoclonal antibody trastuzumab (Herceptin), which has recently been licensed for the treatment of metastatic disease. Laboratory testing of HER2/neu in breast carcinoma has become vital to patient care following the approval of trastuzumab as the first therapy to target the HER2/neu oncoprotein. Immunohistochemical (IHC) analysis was performed with use of a diagnostic test for the assessment of HER2 overexpression, the HercepTest. To test for HER-2/neu overexpression in patients with non-Hodgkin's lymphoma and the possible role of the recombinant monoclonal anti-HER-2/neu antibody trastuzumab (Herceptin) in the treatment of non-Hodgkin's lymphoma. To evaluate concordance between local and central laboratory HER2 testing results in patients from the North Central Cancer Treatment Group (NCCTG) N9831 adjuvant trial of trastuzumab. These findings support the importance of using high-volume, experienced laboratories for HER2 testing to improve the process of selecting patients likely to benefit from trastuzumab therapy. we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum. Biotin-labeled trastuzumab (BiotHER) can be used to test for HER2 by immunohistochemistry. The results support a role for BiotHER testing in better tailoring trastuzumab-based treatments in patients with advanced HER2-amplified breast cancers. response to anti-human epidermal growth factor receptor 2 (HER2) therapy trastuzumab. Although breast cancers that overexpress human epidermal growth factor receptor-2 (HER2) are characterized by a poor prognosis [4,5], higher rates of complete responses are currently achieved in HER2+ patients by standard chemotherapy, mainly in association with trastuzumab [6,7], in comparison with HER2- patients. </context> <question> Is there a pharmacogenetic test for trastuzumab? </question> <answer> yes </answer>
<context> Functional connectivity in the default mode network (DMN) is known to be reduced in patients with disorders of consciousness, to a different extent depending on their clinical severity. Patients showed significant impairments in all of the pathways connecting cortical regions within this network, as well as the pathway connecting the posterior cingulate cortex/precuneus with the thalamus, relative to the healthy volunteers. Moreover, the structural integrity of this pathway, as well as that of those connecting the posterior areas of the network, was correlated with the patients' behavioral signs for awareness, being higher in EMCS patients than those in the upper and lower ranges of the MCS patients, and lowest in VS patients. These results provide a possible neural substrate for the functional disconnection previously described in these patients, and reinforce the importance of the DMN in the genesis of awareness and the neural bases of its disorders. At the same time, using fMRI analysis it has already been shown that DMN functional connectivity is absent in brain death [50], is extremely low in VS patients [50, 51] and is slightly decreased in MCS patients [50] when compared to healthy subjects. We observed a significant decrease (pcorrected < 0.05-0.01) in the average strength of EEG operational synchrony (measured by the ISS index) within the DMN in MCS patients and even stronger decrease (pcorrected < 0.01) in VS patients compared to healthy controls. There was also a significant difference between MCS and VS patients (pcorrected < 0.05-0.01). In the beta2 frequency band, while both MCS and VS patients demonstrated a decrease in the average strength of EEG operational synchrony compared to healthy volunteers, only the VS group showed a correspondingly significant decrease The MCS and VS patients differed significantly (pcorrected < 0.05) The first and most straightforwardly predicted finding was that EEG DMN operational synchrony in all three (alpha, beta1 and beta 2) frequency bands was highest in healthy fully self-conscious subjects, lowest or even absent in VS patients, and intermediate in MCS patients: VS < MCS ≤ NORM Considering that DMN has been shown to be involved in self-referential processing [12, 14-16, 20-22], these results suggest that the strength of EEG DMN operational synchrony could be a potential indicator of a patient’s expression of self-consciousness. It could differentiate VS patients who lacking self-consciousness from MCS patients who have partially preserved operational connectivity architecture of DMN. Fully conscious, healthy controls displayed a particular, relatively high level of operationally integrated DMN EEG architecture . Therefore, diminished or absent (like in the beta2 frequency band) operational synchrony4 within the DMN in patients with severe brain injuries suggests a disruption of this network, all the way down to complete absence of any self-awareness, as in the VS patients of this study A similar conclusion has been reached by Sarà et al. [104], who used EEG approximate entropy measure and found functional isolation and disconnection within the brain network in VS patients. This hypothesis was indeed confirmed: the anterior part of DMN was found to have the strongest decrease in the EEG operational synchrony compared with the posterior areas of the DMN (Table 1) in MCS and VS. The third finding was about negative values of the index of EEG operational synchrony within the DMN which increased from healthy subjects, to MCS patients and reached its maximum in VS patients: VS > MCS > NORM Here we propose that unstable operational interactions within the DMN may underlie cognitive fluctuations observed in MCS patients. More specifically, we demonstrated that the strength of EEG operational synchrony within DMN was smallest or even absent in patients in VS, intermediate in patients MCS and highest in healthy fully self-conscious subjects: VS < MCS ≤ NORM Decreased DMN, especially of the posterior cingulate cortex (PCC), is associated with different degrees of impaired cognition and consciousness In previous neuroimaging studies, deficits in the DMN have been reported in various neuropsychiatric disorders (18), including schizophrenia (10, 14), autism (19), ADHD (20-23), Alzheimer's-type dementia, and mild cognitive impairment (24-26). Although the functional significance of the default-mode network remains a matter of debate, it has been suggested to be a candidate for the network subserving basic functions related to consciousness. Despite resolution of corpus callosum lesion on magnetic resonance imaging (MRI) within 1 week, the patient persistently presented disturbance of consciousness. Resting-state functional MRI revealed that the posterior cingulate cortex/precuneus was functionally disconnected from other brain regions within the default-mode network. Our case report suggests that assessment of the functional connectivity in the resting-state default-mode network could be a useful marker of consciousness disturbance even in the presence of a reversible brain lesion. A present and intact DMN was observed in controls and those patients who subsequently regained consciousness, but was disrupted in all patients who failed to regain consciousness. The results suggest that the DMN is necessary but not sufficient to support consciousness. Clinically, DMN connectivity may serve as an indicator of the extent of cortical disruption and predict reversible impairments in consciousness. Second, Vanhaudenhuyse and colleagues [30] could demonstrate a reduced functional connectivity of the DMN and a correlation with the level of consciousness. The results of our study indicate that deactivation in medial regions of the DMN is reduced in MCS and absent in UWS compared with healthy control subjects. While investigation of DMN connectivity demonstrates a relation to the level of consciousness, it can still be identified in altered states of consciousness like in deeply anaesthetized monkeys [43], and in healthy subjects during light sedation [44] and during sleep [45]. In conjunction with the association between CRS-R scores and deactivation in the patient group, though, we conclude that there is indeed a relation between deactivation in the DMN and the level of consciousness. At group level, there is a correspondence between diagnosis and CRS-R scores, respectively, and deactivation in the DMN. Recent studies on resting state activity in DOC, measured with functional magnetic resonance imaging (fMRI) techniques, show that functional connectivity is disrupted in the task-negative or the default mode network. More recently, fMRI studies on the default/internal network confirmed a decreased cortico-cortical connectivity in patients with DOC (Boly et al., 2009; Cauda et al., 2009; Vanhaudenhuyse et al., 2010b) and an absence of connectivity in brain death Paralleling clinical experience, a non-linear correlation was found between this default/“internal” network connectivity and the level of consciousness ranging from healthy volunteers and pseudocoma/locked-in syndrome, to minimally conscious, vegetative/unresponsive, and comatose patients locked-in syndrome patients’ default/”internal” network connectivity was shown not to be significantly different from healthy control subjects. On the other hand, the connectivity between these primary cortices and “higher-order” associative cortices as well as connectivity inside the nodes of the default/“internal” network show a correlation decreasing consciousness in both coma and anesthesia. This report shows for the first time, in three patients, that the persistent vegetative state (PVS) is marked by a dysfunctional default mode network, with decreased connectivity in several brain regions, including the dorsolateral prefrontal cortex and anterior cingulated cortex, especially in the right hemisphere. </context> <question> How functional connectivity of the default mode network changes in patients with disorders of consciousness? </question> <answer> Functional connectivity in the default mode network (DMN) is reduced in patients with different disorders of consciousness, and correlates with the level of consciousness. \nSpecifically, functional connectivity in the default mode network was shown to be absent in brain death patients, extremely low in vegetative state patients and slightly decreased in minimally conscious state patients when compared to healthy subjects. Therefore, functional connectivity in the default mode network was suggested to be valuable in differentiating patients with different disorders of consciousness. Clinically, functional connectivity in the default mode network was also shown to be an indicator of the extent of cortical disruption and predict reversible impairments in consciousness. </answer>
<context> Psammoma bodies (PBs) are concentric lamellated calcified structures, observed most commonly in papillary thyroid carcinoma (PTC), meningioma, and papillary serous cystadenocarcinoma of ovary but have rarely been reported in other neoplasms and nonneoplastic lesions. Studies on serous cystadenocarcinoma of ovary and meningioma, however, revealed that collagen production by neoplastic cells and subsequent calcification was responsible for the formation of PBs. The existence of some precursor forms of PBs was reported in meningiomas and more recently in PTC, which were mostly in the form of extracellular hyaline globules surrounded by well-preserved neoplastic cells or in a smaller number of cases intracytoplasmic bodies liberated from intact tumor cells. Light microscopy revealed abundant microcysts of varied size throughout the tumor tissue with the presence of whorl formation and psammoma body, but no malignancy was indicated. Electron microscopy further demonstrated interdigitation of the neighboring cell membranes, desmosomes, and intracytoplasmic filaments, which are pathognomonic findings of meningiomas. Unlike SFT, FMs were glycogen-containing and variously exhibited a storiform pattern (13 of 20), psammoma body formation (9 of 20), and calcification of collagen (4 of 20). Immunoreactivities included vimentin (100%), focal to patchy EMA (80%), S-100 protein (80%), collagen IV (25%), and patchy, mild-to-moderate CD34 staining (60%). In contrast to the inner structure, three-dimensional structure of psammona bodies in meningiomas is not well defined. This study examined three cultured meningiomas, in which surface observation of psammoma bodies might be easier than in the tumor tissues since influence of interposing connective tissue is minimized in tissue culture. The results suggest that psammoma bodies in meningiomas arise in part from meningothelial whorls due to collagen production by tumor cells followed by obliteration and disappearance of tumor cell processes, although some of the alternative pathways for psammoma body formation proposed by other investigators cannot be ruled out by this study. To demonstrate that psammoma bodies in human meningiomas contain type VI collagen and laminin. This is the first report to describe the involvement of type VI collagen in psammoma bodies and whorl formations in meningiomas. Calcification such as psammoma body is sometimes found especially in spinal cord meningioma but ossification of the meningeal tumor was rarely observed. Histological diagnosis was transitional meningioma with psammoma body. In this study we analyzed the morphologic and ultrastructural characteristics of the psammoma bodies in ten meningiomas of different histologic subtypes, characterizing the components of the psammoma body and the elements of the tumor, such as the capillaries and degenerative cells that have been classically considered as initiators of the formation of these calcareous is structures. It is concluded that the mineralization of the psammoma bodies is induced principally by the collagen fibers synthesized by the meningocytes and that the form of mineralization is spherical and growth is radial, controlled by the tumoral cells. CSF cytology revealed benign fibroblastic or meningotheliomatous meningioma with whorl formation and psammoma body. Electron microscopic examination of the calculi showed membrane-bound vesicles and radially precipitated crystals that simulated hydroxyapatite of psammoma body in meningioma. Psammoma bodies in meningiomas resembled those in the choroid plexus stroma. The results of this study suggest that psammoma bodies in the choroid plexus, as in meningiomas, form by a process of dystrophic calcification associated with arachnoid cells and collagen fibres. An early stage of psammoma body formation was seen more frequently in these villous microcores than in the meningocytic whorls. Psammoma bodies in meningocytic whorls were investigated by electron microscopy. Psammoma body formation in the meningocytic whorls may represent degeneration in some whorls of the central cells which contain connective tissue fibers, producing cell debris such as membrane invested vesicles. Twenty human meningiomas were examined for IgG and IgM by the direct immunofluorescence of immunoperoxidase methods, or both. IgG was conspicuously found in and around the blood vessels, whorls, and psammoma bodies. It was also clearly present on the cytoplasmic membranes of the tumour cells. Significance of these findings is briefly discussed including possible humoral immune reactions in regard to whorl and psammoma body formation in meningioma. The fine structure of psammoma bodies was examined in four cases of fibroblastic meningioma. In general, large numbers of various-sized calcified bodies (psammoma bodies) were scattered among the interstitial fibers. These findings suggest that both matrix giant bodies and matrix vesicles may serve as initial nidus of calcification of psammoma bodies in fibroblastic meningioma. Psammoma body formation or dystrophic mineralization and gliosis of the intervening parenchyma was observed in all three cases. </context> <question> Are psammoma bodies characteristic to meningiomas? </question> <answer> yes </answer>
<context> Prolactinoma is the most common secreting pituitary adenoma. It is typically diagnosed in women of reproductive age and is common cause of infertility. Examination of the tissue excised by transsphenoidal excision of the mass showed a pituitary adenoma that stained strongly for FSH. RESULTS: Regular menses resumed soon after excision of the gonadotroph adenoma, followed by a spontaneous pregnancy. CONCLUSIONS: Gonadotroph adenoma should be suspected in a reproductive age woman with oligomenorrhea or amenorrhea, infertility, multiple preovulatory follicles, and a persistently elevated serum estradiol concentration. Hyperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis, occurring mostly in women and presenting most commonly with amenorrhea and galactorrhea. Causes of hyperprolactinemia include physiologic, pharmacologic and pathologic factors; pituitary adenoma is a common pathologic cause. Women may present with decreased libido, infertility, oligomenorrhea/amenorrhea and galactorrhea. When specific treatable underlying causes have been eliminated and in cases of severe hyperprolactinemia, the most likely cause is a prolactin (PRL)-secreting pituitary adenoma. Microadenomas should be treated medically, with a dopamine agonist, if there is an indication for therapy (such as amenorrhea, infertility or bothersome galactorrhea). Pregnancy in a woman with active acromegaly is very rare, because amenorrhea, due to hyperprolactinemia and disturbed pituitary gonadotropin secretion may cause infertility. Of the remaining six patients who had been investigated for infertility, no demonstrable cause of infertility was found in three. Of the other three patients, one showed evidence of bilateral tubal occlusion secondary to pelvic inflammatory disease, one has had a right ectopic pregnancy followed by two abortions, and the third patient was found to have a pituitary adenoma. Results in 136 hyperprolactinaemic women who presented with infertility, amenorrhoea, menstrual irregularities and/or galactorrhoea are reported. There was radiographic evidence of pituitary microadenoma in 21 (15.4%) patients and 5 (3.7%) had macroadenoma. Patients with pituitary adenoma had a significantly higher (p less than 0.001) baseline serum prolactin level (182 +/- 4.6 ng/ml) than those with no adenoma (59.2 +/- 4.2 ng/ml). All patients in the study were treated with bromocriptine (2.5-10 mg) to normalize serum prolactin or to achieve a pregnancy. There was no significant difference in the pregnancy rate between the patients with or without pituitary adenoma. Two hyperprolactinemic infertile women, one with and one without a pituitary adenoma, who were resistant to bromocriptine treatment, were treated orally with Hachimijiogan, a Chinese herbal medicine. Infertility caused by hyperprolactinemic amenorrhea may be complicated by pituitary adenoma. </context> <question> Which pituitary adenoma is common cause of infertility is women? </question> <answer> prolactinoma </answer>
<context> To evaluate the cost effectiveness of the four medications with a US FDA-approved indication for PMDD: fluoxetine, sertraline, paroxetine and drospirenone plus ethinyl estradiol (DRSP/EE). All SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and clomipramine) were effective in reducing premenstrual symptoms. Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults. Selective serotonin-reuptake inhibitors (SSRIs) have been proven safe and effective for the treatment of PMDD and are recommended as first-line agents when pharmacotherapy is warranted. Currently fluoxetine, controlled-release paroxetine, and sertraline are the only Food and Drug Administration-approved agents for this indication. When compared with placebo, patients treated with paroxetine 20 mg attained a significant reduction in irritability (difference in median percent change: -23.9, 95% CI = -51.3 to -6.2, p = .014; difference in mean absolute change: -18.6, 95% CI = -32.5 to -4.6, p = .007). A statistically significant difference was not observed when the patients treated with the lower dose of paroxetine (10 mg) were compared with placebo. Treatment was well tolerated with no unexpected side effects. Intermittent administration of paroxetine 20 mg significantly reduced irritability symptoms in patients with PMDD. All these women had significant improvements in the HAMA, HAMD, CGI, and PRISM calendar. The rate of response to paroxetine treatment lay between 50% and 78.6% in the continuous-treatment group, and 37.5-93.8% in the intermittent-treatment group, as determined at the study end-point. The present results indicate that paroxetine is effective in both continuous and intermittent treatment of oriental PMDD women, and that the effects of active treatment lasted for six consecutive treatment menstrual cycles. Paroxetine CR is approved for the treatment of major depression, social anxiety disorder, panic disorder and premenstrual dysphoric disorder in adults. Continuous treatment with paroxetine reduced premenstrual symptoms effectively with a response rate of 85%. Intermittent treatment was as effective as continuous treatment in reducing irritability, affect lability, and mood swings, but had a somewhat weaker effect on depressed mood and somatic symptoms. Daily Record of Severity of Problems scores were lower in the paroxetine group compared with the placebo group, although the differences were not statistically significant. However, the mean on-treatment Inventory of Depressive Symptomatology (clinician-rated) score for the paroxetine group was 17.9 +/- 8.3 compared with 31.5 +/- 11.2 in the placebo group (adjusted mean difference = 13.6, P = 0.009). Response (Clinical Global Impressions Scale score of 1 or 2) occurred in 70% of subjects randomized to paroxetine CR and 10% of those assigned to placebo (chi2(1) = 7.5, P = 0.006). The US Food and Drug Administration and Health Canada recently approved paroxetine for the treatment of premenstrual dysphoric disorder. Patients treated with either dose of paroxetine CR demonstrated significantly greater improvements on the primary efficacy measure (change from baseline in mean luteal phase VAS-Mood scores) and on the majority of secondary efficacy measures compared with patients randomly assigned to placebo. For the treatment of PMDD, luteal phase dosing with 12.5 mg and 25 mg of paroxetine CR is effective and generally well tolerated. A statistically significant difference was observed in favor of paroxetine CR 25 mg versus placebo on the VAS-Mood (adjusted mean difference = -12.58 mm, 95% CI = -18.40 to -6.76; p < .001) and for paroxetine CR 12.5 mg versus placebo (adjusted mean difference = -7.51 mm, 95% CI = -13.40 to -1.62; p = .013). Paroxetine CR doses of 12.5 mg/day and 25 mg/day are effective in treating PMDD and are well tolerated. At end point, subjects treated with paroxetine CR (12.5 mg and 25 mg) demonstrated significant improvement in VAS-Mood scores compared with those who received placebo (paroxetine CR 12.5 mg mean treatment difference vs. placebo, -8.7 mm; 95% CI, -15.7, -1.7; p =.015; paroxetine CR 25 mg mean treatment difference vs. placebo, -12.1 mm; 95% CI, -18.9, -5.3; p <.001). Both doses of paroxetine CR 12.5 mg and 25 mg daily are effective and well tolerated in patients who suffer from PMDD. Of these agents, sertraline, fluoxetine and paroxetine (as an extended-release formulation) are approved by the US FDA for luteal phase, as well as continuous, administration. In well designed placebo-controlled trials in patients with major depressive disorder (including a study in the elderly), social anxiety disorder or premenstrual dysphoric disorder (PMDD), paroxetine CR was consistently superior to placebo with regards to primary endpoints (i.e. mean Hamilton Rating Scale for Depression total score [major depressive disorder], Liebowitz social anxiety scale total score and Clinical Global Impressions-Global Improvement score [social anxiety disorder] and Visual Analogue Scale-Mood score [PMDD]). Paroxetine is a potent selective serotonin reuptake inhibitor (SSRI) with indications for the treatment of depression, obsessive- compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post-traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. Studies having compared the efficiency of antidepressants according to their serotonin activity (paroxetine or sertraline versus maprotiline, that is a selective noradrenaline re-uptake inhibitor), showed that serotonin re-uptake inhibitors were significantly more efficient on all symptoms than maprotiline, that was not more efficient than placebo. Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache. Preliminary data suggest that paroxetine has potential in the treatment of social phobia, premenstrual dysphoric disorder and chronic headache. The effects of active treatment were marked by the first active cycle with luteal phase 17-item Hamilton Rating Scale for Depression scores decreasing from 14.9 (+/- 5.3) to 8.2 (+/- 4.9) in the first, 7.8 (+/- 5.1) in the second, and 7.8 (+/- 6.8) in the third active treatment cycles (F[1,13] = 17.6; p < 0.0001). The most conservative measure, the Clinical Global Impression (CGI), revealed that 7 of 14 patients had a complete response (CGI = 1 or 2) whereas 4 patients had a partial response (CGI = 3). These open trial findings are consistent with the notion that paroxetine is effective in the acute phase for the treatment of PDD. The rating of premenstrual irritability, depressed mood, increase in appetite, and anxiety/tension was markedly lower during treatment with paroxetine than before, and this reduction in symptomatology appeared unabated for the entire treatment period. </context> <question> Is paroxetine effective for treatment of premenstrual dysphoric disorder? </question> <answer> yes </answer>
<context> During the subacute phase, the irreversible damage expands into the penumbra: multiple electrical and biological signals are triggered by periinfarct, spreading depression-like depolarizations leading to hypoxia and stepwise increase in lactate. Experimental and clinical studies indicate that waves of cortical spreading depolarization (CSD) appearing in the ischemic penumbra contribute to secondary lesion growth. Analysis of MCA occlusions (MCAOs) revealed a first CSD wave starting off during ischemic decline at the emerging core region, propagating concentrically over large portions of left cortex. Subsequent recurrent waves of CSD did not propagate concentrically but preferentially circled around the ischemic core. In the vicinity of the core region, CSDs were coupled to waves of predominantly vasoconstrictive CBF(LSF) responses, resulting in further decline of CBF in the entire inner penumbra and in expansion of the ischemic core. We conclude that CSDs and corresponding CBF responses follow a defined spatiotemporal order, and contribute to early evolution of ischemic territories. Astrocytes in the metabolically compromised ischemic penumbra-like area showed a long lasting swelling response to spontaneous spreading depolarizations despite rapid dendritic recovery in a photothrombotic occlusion model of focal stroke. Spontaneous spreading depolarizations (SDs) occur in the penumbra surrounding ischemic core. These SDs, often referred to as peri-infarct depolarizations, cause vasoconstriction and recruitment of the penumbra into the ischemic core in the critical first hours after focal ischemic stroke; however, the real-time spatiotemporal dynamics of SD-induced injury to synaptic circuitry in the penumbra remain unknown. We propose that metabolic stress resulting from recurring SDs facilitates acute injury at the level of dendrites and dendritic spines in metabolically compromised tissue, expediting penumbral recruitment into the ischemic core. Although the mechanism remains unknown, SDs show delayed electrophysiological recovery within the ischemic penumbra. Spreading depression-like peri-infarct depolarizations not only characterize but also worsen penumbra conditions in cortical border zones of experimental focal ischemia. We conclude that in focal ischemia, transient peri-infarct depolarizations emerge not only in cortical but also in striatal gray matter, thereby demonstrating the existence of subcortical zones of ischemic penumbra. Spreading depression (SD) has been demonstrated following focal ischemia, and the additional workload imposed by SD on a tissue already compromised by a marked reduction in blood flow may contribute to the evolution of irreversible damage in the ischemic penumbra. While the changes in the glucose-related metabolites persisted during recovery even in anterior portions of the cortex in both groups in the aftermath of the SD, the magnitude of the changes was greater in the penumbra than in the normal cortex. SD appears to impose an equivalent increase in energy demands in control and ischemic brain, but the ability of the penumbra to recover from the insult is compromised. Thus, increasing the energy imbalance in the penumbra after multiple SDs may hasten the deterioration of the energy status of the tissue and eventually contribute to terminal depolarization and cell death, particularly in the penumbra. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. Transient decreases of the apparent diffusion coefficient (ADC) of water as measured by fast diffusion-weighted imaging (DWI) in the ischemic border zone are thought to reflect cellular swelling associated with spreading depression. Severely delayed recovery time after spreading depression is thought to represent the ischemic penumbra. One current but controversial hypothesis is that this penumbra tissue often eventually dies because of the metabolic stress imposed by multiple cortical spreading depression (CSD) waves, that is, by ischemic depolarizations. After simulated infarction, the model displays the linear relation between final infarct size and the number of CSD waves traversing the penumbra that has been reported experimentally, although damage with each individual wave progresses nonlinearly with time. These findings support the hypothesis that CSD waves play an important causal role in the death of ischemic penumbra tissue. MCAO also triggers periodic periinfarction depolarizing waves (PIDs) in the ischemic penumbra, the territory of salvage. Here, the effects of SD at reduced flow conditions as encountered in the ischemic penumbra are examined. The experiments illustrate how peri-infarct depolarizations may detrimentally affect the penumbra. In the second series of experiments, periinfarct depolarizations (PIDs) were recorded with an extracellular DC electrode at two locations in the ischemic penumbra for the initial 3 h following MCAO. In vivo two-photon microscopy of green fluorescent protein-expressing neurons in this penumbra-like area at risk revealed that SDs were temporally correlated with rapid (<6 s) dendritic beading. </context> <question> Does cortical spreading depression appear in ischemic penumbra following ischemic stroke? </question> <answer> yes </answer>
<context> Here we show that the Orbitrap mass analyzer can be used to measure protein assemblies of molecular weights approaching one megadalton with sensitivity down to the detection of single ions. Using this relationship we show that we can determine masses of both 30S subunits and intact 2.3 MDa 70S ribosomes from Thermus thermophilus. We confirm the existence of these subpopulations using tandem mass spectrometry of intact 30S subunits. Overall, the results show that, rather than uniform particles, gas-phase ribosomes consist of a number of discrete populations. More generally, the results establish a rigorous procedure for accurate mass measurement and spectral analysis of heterogeneous macromolecular assemblies. </context> <question> Intact macromolecular assemblies are analysed by advanced mass spectrometry. How large complexes (in molecular weight) have been studied? </question> <answer> 2.3 megadalton </answer>
<context> Besides the baseline characteristics, daily interleukin-6 (IL-6), procalcitonin, C-reactive protein levels, and leukocyte counts were prospectively measured until day 14 after subarachnoid hemorrhage. Occurrence of infectious complications and application of therapeutic hypothermia were assessed as confounding factors. The primary end point was outcome after 3 months, assessed by Glasgow Outcome Scale; the secondary end point was the occurrence of DINDs. RESULTS: : During a 3-year period, a total of 138 patients were included. All inflammatory parameters measured were higher in patients with unfavorable outcome (Glasgow Outcome Scale score, 1-3). Twenty-three and 28 patients showed poor outcome and symptomatic vasospasm after SAH, respectively. Both preoperative and postoperative CRP levels were significantly higher in patients with a poor outcome compared with patients with a good outcome (P<0.05). e area under the receiver operating characteristic curve of CRP measured on postoperative day 1 or 2 (CRP POD1-2) for predicting a poor clinical outcome was 0.870, and its cutoff point of 4 mg/dL had a sensitivity of 0.826 and a specificity of 0.843. A high CRP level after aneurysm treatment was associated with severe neurological deterioration on admission, cerebral infarction, intracerebral hemorrhage, and surgical decompression (P<0.05). CRP POD1-2, and not the preoperative CRP, was an independent factor in predicting symptomatic vasospasm (P<0.05). In patients with symptomatic vasospasm, an increase in the postoperative CRP was associated with the time profile of developing symptomatic vasospasm. Postoperative CRP, especially CRP POD1-2, can be a useful prognostic factor for both poor outcome and symptomatic vasospasm in patients with aneurysmal SAH. Serum CRP levels were related to severity of aSAH. Patients with lower GCS scores and higher Hunt and Hess and Fisher grades presented statistically significant higher serum CRP levels. Patients with higher serum CRP levels had a less favorable prognosis. Increased serum CRP levels were strongly associated with worse clinical prognosis in this study. After SAH, the value of C-reactive protein (CRP)--an acute phase sensitive inflammatory marker--as a prognostic factor has been poorly studied, with conflicting results. Admission (18.0 ± 35.7 vs 8.5 ± 8.4 mg/l) and postoperative (41.0 ± 40.2 vs 21.1 ± 24.1 mg/l) CRP levels were higher (p < 0.001) in those with a poor outcome than in those with a favourable outcome, but CRP values did not predict delayed cerebral ischaemia or cerebral infarction. Higher increase in CRP level between admission and postoperative morning, however, independently predicted poor outcome (p = 0.004). CRP levels correlate with outcome but do not seem to predict delayed cerebral ischaemia or infarction after SAH. Systemic oxygen consumption is associated with hsCRP levels in the first 14 days after SAH and is an independent predictor of DCI. Intracranial hypertension was associated with an inflammatory response, indicating activation of the inflammatory cascade in the brain (ECF) and systemic circulation with high IL-6 and C-reactive protein (CRP) plasma levels after SAH, the latter associated with unfavourable outcome. Patients with angiographic vasospasm had higher CRP measurements in serum and CSF, in a statistically significant fashion (p < 0.0001). Additionally, patients with higher CRP levels in serum and CSF had less favorable outcome in this cohort. Furthermore, patients developing angiographically proven vasospasm demonstrated significantly elevated CRP levels in serum and CSF, and increased CRP measurements were strongly associated with poor clinical outcome in this cohort. Finally, serum concentrations of ICAM-1, VCAM-1, and hsCRP during the early (P = .0055, P = .0266, and P = .0266) and late (P = .0423, P = .0041, and P = .0004) period were significantly higher in patients with DIND than in patients without DIND. CONCLUSIONS: Serum levels of ICAM-1, VCAM-1 and hsCRP during the early and late period following SAH correlate with DIND CRP levels on days 5, 6, 7, and 8 were statistically significantly higher in the group of patients developing a DIND (P < 0.025, P < 0.016, P < 0.011, P < 0.0002). Overall CRP values were higher with increasing severity of the initial ictus according to the Hunt and Hess Scale and to the outcome according to the Glasgow Outcome Scale from day 3 on. The presented data do not prove that WBCs and CRP values have a direct contribution to the pathogenesis of ischemic complications following SAH, but it supports the assertion that inflammation may present a common pathogenic pathway in the development of such complications. The CRP and TGF-beta1 levels in CSF are strongly concerned with communicating hydrocephalus after SAH. </context> <question> Is there an association between c-reactive protein concentrations and outcomes of subarachnoid hemorrhage patients? </question> <answer> yes </answer>
<context> Before surgery 27 patients (35%) had BDI scores indicating the presence of depression. These scores were significantly higher in patients with a history of depression (p = 0.017) and in those with a lower functional outcome (p = 0.015). A lower functional status (KPS score < or = 70) in patients was significantly associated with high depression scores at the 3-month (p = 0.000) and 1-year (p = 0.005) assessments. At all follow-ups, depressed low-grade glioma patients had a significantly shorter survival time, 3.3-5.8 years, compared to non-depressed low-grade glioma patients, 10.0-11.7 years. The results suggest that depression and decreased QOL among low-grade glioma patients is related to shorter survival at long-term follow-up. The adverse impact of depression in relation to survival among cancer patients is currently a subject of great interest in research. In the subgroup of patients with low-grade gliomas, depressive patients had a significantly shorter survival time compared with nondepressive subjects (P = 0.031, Kaplan-Meier survival analysis). Preoperative depression seemed to be a significant prognostic factor for worse survival in low-grade glioma patients. Major depressive disorder was marginally associated with outcomes, while surgical interventions and radiotherapy did not show strong associations with test performances. </context> <question> Is depression associated with poor prognosis of brain tumor patients? </question> <answer> yes </answer>
<context> Reduced positive affect and depression/anxiety were associated with poor prognosis, but reduced positive affect was the only independent predictor of events. The incidence of death/MI in adequate versus reduced positive affect patients was 4% (29/663) vs. 11% (23/211); HR = 2.55 (95% CI 1.46-4.34, P = 0.001), adjusting for clinical variables. Reduced positive affect and diabetes were independent prognostic factors, and patients with one (HR = 2.84, 95% CI 1.58-5.10) or both (HR = 5.61, 95% CI 2.25-13.99) of these factors had a higher risk when compared with nondiabetic patients with adequate positive affect, P < or = 0.003. Reduced positive affect independently predicted death/MI following stent implantation, and improved risk stratification above and beyond diabetes. Reduced positive affect (anhedonia) predicts major clinical events following implantation of coronary-artery stents. Beyond Type D personality: reduced positive affect (anhedonia) predicts impaired health status in chronic heart failure. In established CHD, high levels of positive affect have been associated with less hospital readmissions [9], whereas low levels of positive affect, also referred to as anhedonia, increase the risk of major clinical events in patients following coronary-artery stenting [10]. Conflicting findings have been reported for associations between positive affect and survival in CHD (e.g. [11–13]). After controlling for demographic and clinical confounders, and mental health status at inclusion, both anhedonic non-Type D patients and Type D patients report lower levels of health status when compared with non-Type D patients without anhedoni In univariable analyses, both non-Type D patients with anhedonia and Type D patients reported lower levels of physical health status at 12-months, compared with the reference group of non-Type D patients without anhedonia In multivariable analyses, a trend was shown for non-Type D patients with anhedonia and Type D patients to report lower levels of physical health status at 12-month follow-up, when compared with the reference group In univariable analyses, non-Type D patients with anhedonia and Type D patients reported more cardiac symptoms at 12-month follow-up, when compared with the reference group of non-Type D patients without anhedonia In multivariable analyses, Type D remained associated with higher levels of cardiac symptoms, but the association between non-Type D patients with anhedonia and higher levels of cardiac symptoms at 12-month follow-up was no longer significant. Non-Type D patients with anhedonia and Type D patients reported more feelings of disability at 12-months, when compared with the reference group of non-Type D patients without anhedonia, in univariable analyses After controlling for demographic and clinical variables, and scores at inclusion, both non-Type D patients with anhedonia and Type D patients still reported more feelings of disability at 12-month follow-up. In the present study, we identified group of CHF patients reporting lower levels of health status at 12 months, namely those patients classified as having no Type D personality, but low on positive affect. This specific group of anhedonic non-Type D patients were shown to report lower levels of mental and physical health status, as well as more feelings of disability at 12-month follow-up, when compared with non-Type D patients high on positive affect. Furthermore, we were able to identify a subgroup of anhedonic patients reporting lower levels of patient-centred outcomes. These findings are in line with those of Hu and colleagues showing that older community dwelling persons diagnosed with chronic disease (i.e., arthritis, CVD, COPD, or diabetes) high on positive affect and low on negative affect had better mental and physical health status Other studies that have also shown that lack of positive affect is associated with worse clinical outcome in patients with established CAD In conclusion, we identified a specific group of CHF outpatients at risk for reporting impaired health outcomes, in the present study, namely those patients low on positive affect, and not classified as having a Type D personality. t follow-up, there were 176 clinical events (36 deaths, 8 MIs, 58 ACS, 55 hospital readmissions, 19 heart failures). Dimensional anhedonia and depression were associated with poor prognosis, but anhedonia was the only predictor of severe cardiac events and clinical events after adjusting for demographic and clinical variables. Contrary to depression, categorical anhedonia (PAS >23) was an independent and significant predictor of severe cardiac events after adjusting for clinical variables. The incidence of death/MI in hedonics vs anhedonics was 11.1% vs 22.1% (hazard ratio = 2.18; 95% confidence interval, 1.11-4.26). Dimensional and categorical anhedonias predicted independently severe cardiac events and clinical events after ACS. Only depressive symptoms of fatigue-sadness predicted prognosis in univariate (hazard ratio [HR]=1.8, 95% CI 1.1-3.0, P=.025) and multivariate analysis (HR=1.8, 95% CI 1.1-2.9, P=.025). Symptoms of anhedonia (HR=1.6, 95% CI 0.9-2.8, P=.102) and depressive cognitions (HR=1.3, 95% CI 0.7-2.2, P=.402) did not. Controlling for sex, age, and medical covariates, anhedonia (adjusted hazard ratio, 1.58; 95% confidence interval, 1.16-2.14; P < .01) was a significant predictor of combined MACE and ACM, but depressed mood was not. Anhedonia continued to significantly predict outcomes (P < .05) when additionally controlling for MDE diagnosis or depressive symptom severity. Anhedonia identifies risk of MACE and ACM beyond that of established medical prognostic indicators, including MDE and depressive symptom severity. Anhedonia (i.e. the lack of positive affect) has been shown to independently predict the combined endpoint of adverse clinical events and mortality 1 year after an acute coronary syndrome [17] and in patients following implantation of coronary-artery stents [18], even after controlling for clinical depression and severity of depressive symptoms The time by Anhedonia interaction effect was not significant, indicating that Anhedonia had a stable effect on health status over time (F(1,366) = 1.33, P = .25). However, anhedonic patients reported significantly poorer health status than non-anhedonic patients (F(1,366) = 64.53, P < .001). The time by anhedonia interaction effect was not significant, indicating that anhedonia had a stable effect on health status over time (F(1,357) = .23, P = .63). The between-subjects effect for anhedonia remained significant, showing that anhedonic and non-anhedonic patients differed on self-reported health status (F(1,357) = 34.80, P < .001). Anhedonia as a determinant of somatic and cognitive symptomsMANOVA with repeated measures yielded a significant main within-subjects effect for time, indicating a decrease in somatic and cognitive symptoms following CR (F(1,366) = 96.11, P < .001). The interaction effect for time by anhedonia was significant, showing that anhedonia did not exert a stable effect over time on somatic and cognitive symptoms (F(1,366) = 11.79, P < .001). Finally, the between-subjects main effect for anhedonia was significant, denoting that anhedonic and non-anhedonic patients reported different levels of somatic and cognitive symptoms (F(1,366) = 94.59, P < .001). To the best of our knowledge, this is the first study to demonstrate that anhedonic patients, i.e. the lack of positive affect, reported more impaired health status and higher levels of health complaints prior to and after CR attendance compared with non-anhedonic patients. However, in the present study, we were also able to identify a specific subgroup of patients—namely anhedonic patients—who consistently reported impaired health status and higher levels of somatic and cognitive symptoms despite CR attendance. he importance of anhedonia has been demonstrated previously in CAD, with anhedonia being a risk factor for major clinical adverse events following implantation of coronary-artery stents [18], and the combined endpoint of adverse clinical events and all-cause mortality [17]. The present study elaborates on these findings by showing that in a large sample of CR patients, patient-centered outcomes vary as a function of the level of anhedonia as well Anhedonia, or the lack of positive affect, independently predicted major clinical adverse events following implantation of coronary-artery stents [18], and the combined endpoint of MACE and all-cause mortality in post-MI patients [17] in previous studies. In conclusion, the present study showed that anhedonic CAD patients reported poorer health status and higher levels of somatic and cognitive symptoms prior to and after CR in comparison with non-anhedonic patients. The incidence of mortality in anhedonic patients was 22.7% (65/286) vs. 13.2% (121/920) in non-anhedonic patients (HR = 1.66, 95% CI [1.19-2.32], p = 0.003). Cumulative hazard functions were significantly different for anhedonic vs. non-anhedonic patients (log-rank χ(2) = 16.61, p < 0.001). n multivariable analysis, anhedonia remained independently associated with all-cause mortality (HR = 1.51, 95% CI [1.03-2.22], p = 0.036), after adjusting for socio-demographics, clinical characteristics, and negative and relaxed affect. Anhedonia was independently associated with a 1.5-fold increased risk for all-cause mortality in patients who survived the first 6 months post-PCI. Depressive symptoms related to lack of enjoyment or pleasure and physical or cognitive slowing, as measured by the HADS-D, predicted all-cause mortality at 8 years ACS patients, whereas other depressive and anxiety symptoms did not. </context> <question> What is the role of anhedonia in coronary disease patients? </question> <answer> Anhedonia is associated with poor prognosis in patients with coronary disease. Namely, in patients with coronary disease, anhedonia was associated with increased mortality, greater risk for major cardiac event, impaired physical health status, more cardiac symptoms, more feelings of disability. These associations were independent from clinical and demographic factors. </answer>
<context> Sildenafil citrate (SIL) generic sildenafil (Unison Laboratories, Thailand) was proved to have the same bioequivalent as in the original formula. The authors conducted a 12-week case series to study the efficacy and safety of Elonza (generic sildenafil) Viagra tablets or generic versions containing sildenafil citrate </context> <question> What are the generic versions of Viagra </question> <answer> Sildenafil Citrate and Elonza in Thailand are the generic versions of Viagra </answer>
<context> Treatment with sildenafil was less costly and resulted in a greater gain in quality-adjusted life-years (QALYs) compared with other treatments. Based on this model, sildenafil is a cost-effective treatment for PAH with a low price and a net increase in QALYs. Four treatment strategies, Viagra, Rivastigmine, statins, and lung transplants, are analysed with respect to whether either cost-effectiveness or need, or both, seem to have played a role in the decisions it seems that decisions are almost exclusively made with reference to the principle of need. In Sweden decisions on priority setting are almost solely based on the principle of need. This implies that the principle of cost-effectiveness is given very little space, which is a problem as this means an obvious risk of inefficient resource use. The case of Viagra, it concludes, holds out two general lessons: first, allow exceptions to total bans on reimbursement; second, involve the medical profession in the decision-making process. This paper analyzes the rationing strategies adopted in four countries (United States, Britain, Germany, and Sweden), the question whether statutory social health insurances are obliged to reimburse the costs for the treatment of erectile dysfunction. Coverage of sildenafil by health insurance plans is a contentious issue. coverage of Viagra and Zyban was limited predominantly through generalized exclusion or through restrictions on quantity or duration of use. Value judgments, rather than cost, seem to play a central, though largely unspoken, role in these coverage decisions. availability of orphan drugs and in patient access to them in 11 pharmaceutical markets: Australia, Canada, England, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Switzerland and the US. lthough the present study showed some variations between countries in selected indicators of availability and access to orphan drugs, virtually all of the drugs in question were available and accessible in our sample. However, substantial co-payments in the US and Canada represent important barriers to patient access, especially in the case of expensive treatments such as those analysed in this study. Using a large US health insurance claims database, we identified all patients with evidence of PAH (ICD-9-CM diagnosis codes 416.0, 416.8) who received sildenafil between 1/1/2005 and 9/30/2008. The mean cost of all PAH-related medication was $7139 during pretreatment and $14,095 during follow-up (sildenafil cost during follow-up= $5236); exclusive of PAH-related medications, however, total healthcare costs decreased modestly (from $30,104 to $27,605) (p<0.01 for all comparisons). CONCLUSIONS: The cost of sildenafil therapy may be partially offset by reductions in other healthcare costs. Adults with evidence of PAH from 1 January 2004 (commercial and Medicaid) or 1 July 2006 (Medicare Advantage) through 30 June 2008 were identified. Most patients (94%) initiated treatment with monotherapy (most commonly sildenafil or bosentan) Mean PAH-related healthcare costs were $6617 per patient per month, comprising 71% of all-cause costs. Retrospective claims database analysis of 706 patients with PAH enrolled in a large, geographically diverse US managed-care organization. Of the oral agents approved for treating PAH at the time of this study, sildenafil was most commonly prescribed as index therapy and was also associated with the lowest costs, largely due to significantly lower pharmacy costs. This study is characterized by limitations inherent to claims database analyses, Erectile dysfunction (ED) affects approximately 30 million men in the United States. The objectives of this study were to (1) assess the cost and utilization of sildenafil citrate (Viagra), an oral therapeutic agent for ED, in a large managed care organization (MCO) with a quantity limit of 6 units per 30-day supply and The total allowed charges for sildenafil pharmacy claims in 2001 were 3.56 million US dollars, of which patients paid 26.6% in average cost-share, and the net MCO cost per member per month (PMPM) was 0.18 US dollars. A total of 1,681 patients (8.3%) exceeded their quantity restrictions for sildenafil tablets in 2001, of which 1,362 (81.0%) paid cash and 319 (19.0%, or 1.6% of all sildenafil users) appealed and received approval from the MCO for additional sildenafil tablets beyond the restriction of 6 tablets per month A quantity limit of 6 tablets of sildenafil per 30-day period was associated with a drug cost to users and the MCO of 0.25 US dollars PMPM. Sildenafil users paid an average cost-share of 26.6%, resulting in a net drug cost of 0.18 US dollars PMPM to the MCO. Managed care companies are expected to counter runaway pharmacy costs for sildenafil by excluding it from coverage, imposing significant limitations, or requiring higher copayments. </context> <question> What is known about the reimbursement of Viagra </question> <answer> Coverage of Viagra/Sildenafil for erectile dysfunction by health insurance plans is a contentious issue in developed countries. There are data of the limitations (6 per month) and co-payments (26.6%) by patients in the US.\nThe costs for Viagra/Sildenafil for PAH (pulmonary artery hypertension) appear to be covered by health insurances in the US. </answer>
<context> Generic switch after ramipril patent expiry is not associated with decreased pharmacy refill compliance: a retrospective study using the DAPI database. The costs per DDD decreased for all three drugs and, as expected, these costs decrease more rapidly after patent expiry. Significant differences in the trend lines were found for enalapril and fluoxetine Our study demonstrated that prescription switching was from cheaper drugs to more expensive agents, and our patients, with a complexity of clinical conditions, were more likely to be treated with both drugs (subsequent or concurrent use of ACEI and ARB) than ACEIs alone. The implementation of Taiwan’s stepwise price adjustments, with different adjustment strategies applied to patented and off-patent drugs, has achieved cost savings for off-patent ACEIs, but not for patented ACEI, ARBs and overall renin-angiotensin drugs in the long term. Increases in incident ARB users and possible switching from ACEIs to ARBs have emerged. These results indicate that policy makers in Taiwan should reconsider the appropriateness of the current adjustment strategies applied to patented and off-patent products, since they result in a difference in the profit margin that physicians obtain from these two classes of drugs and affect physicians’ prescribing decisions. </context> <question> What is the influence of patent expiry on ACE inhibitor prescribing. </question> <answer> Patent expiry has different effects on prescribing in different systems. It leads to decreased cost but no decreased refill compliance in countries like Sweden, Germany etc. In countries like Taiwan, where doctors profit directly from dispensing, patients are switched to ARBs which are more costly. </answer>
<context> Of the 17 Paediatric Investigation Plans submitted, 14 have resulted in an EMA Decision, 3 were withdrawn by the applicants, 8 were granted a full waiver from development, and 1 resulted in a negative opinion. Decisions as issued included 15 clinical trials, with at least 1,282 children to be recruited into studies across five different products. Neonates were included in four of the products. CONCLUSIONS: The small number of submissions indicates a lack of new drugs being developed for the management of pain. Ethical concerns that too many vulnerable children will be recruited into clinical trials must be balanced against limiting the number of off-label prescribing and obtaining age-appropriate information on paediatric use. Paediatric Investigations Plans (PIPs) submitted with a Decision (outcome) reached between September 2007 and March 2010 were included in the analysis. </context> <question> How many clinical trials for off-label drugs in neonates are cited in the literature. </question> <answer> none' '0' 'zero </answer>
<context> The authors conducted a 12-week case series to study the efficacy and safety of Elonza (generic sildenafil) in PAH patients. SildenafilCavertaNot providedNot providedNot ProvidedNot ProvidedSan Diego, California, United Stateswww.worldexpress.comZenegra-100Mepro PharmZA 200202-03Mumbai, Maharashtra, IndiaMonterrey, Neuvo Leon, Mexicowww.viagrasecrets.comVega AsiaNot providedB1110210-04Not providedDelhi, Indiawww.blue-pills.netSuhagra-100Okasa LtdMR302501-06Pune, Maharashtra, IndiaIndiawww.viagrageneric.tripod.comVegaNot providedNot provided04-04Not providedManila, Phillippineswww.genericviagra.com </context> <question> What are the generic versions of Viagra? </question> <answer> Elonza; Caverta; Zenegra-100; Vega Asia; Suhagra-100; Vega </answer>
<context> Longitudinal analysis showed that in Eut men higher baseline FT4 was significantly (p = 0.02) predictive of a lower SPPB score at the 3-year follow-up Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men. Oral L-thyroxine treatment was started and at a 1-month follow-up examination, mental status and physical performance were improved In a population of independently living elderly men, higher FT4 and rT3 concentrations are associated with a lower physical function She had generalised weakness of muscles, cold intolerance and a reduced physical performance. Replacement therapy by oral administration of L-thyroxin resulted in a gradual improvement of the patient's state multivariate analysis revealed that total T3 was an independent predictor of VO2max changes in thyroid hormone were closely correlated to myocardial functional status in patients with heart failure. THR among patients with SCH is beneficial not only by improvement in lipid profile, as well as by improvement in cognitive and functional status, CONCLUSIONS: Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men. Subclinical hyperthyroidism (SH) may be responsible for many cardiovascular changes, including an impaired exercise performance. BACKGROUND: Physiological changes in thyroid hormone concentrations might be related to changes in the overall physical function in the elderly. </context> <question> Is physical performance influenced by thyroid hormone metabolism? </question> <answer> yes </answer>
<context> Mutations in the myotubularin 1 gene (MTM1) have been identified in the most of the patients with the X-linked recessive form. their conditions were diagnosed by genetic testing of MTM1. X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin As a gene for X linked MTM was recently identified in Xq28, we screened the obligatory carrier mothers for mutation. We found a 4 bp deletion in exon 4 of the MTM1 gene, X-linked Myotubular Myopathy has clearly shown the benefits to be gained from a multinational research consortium with a common interest in identifying and cloning the MTM1 gene. Myotubular myopathy (XLMTM, OMIM 310400) is the X-linked and most severe form of a group of muscular disorders, named centronuclear myopathies (CNM), characterized by the presence of hypotrophic myofibers with central nuclei in skeletal muscle (1). Myotubular myopathy, which affects one newborn male in 50 000 is caused by mutations in the ubiquitously expressed MTM1 gene that codes for a phosphoinositide phosphatase named myotubularin Myotubular myopathy (MTM1) is an X-linked disease, characterized by severe neonatal hypotonia and generalized muscle weakness, with pathological features suggesting an impairment in maturation of muscle fibres. The MTM1 gene encodes a protein (myotubularin) with a phosphotyrosine phosphatase consensus. myotubular myopathy (XLMTM), a severe congenital muscular disorder due to loss-of-function mutations in the MTM1 gene, We established a colony of dogs that harbor an X-linked MTM1 missense mutation.Muscle from affected male dogs exhibits reduction and altered localization of the MTM1 gene product, myotubularin, and provides a model analogous to X-linked myotubular myopathy (XLMTM) X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy, usually characterized by severe hypotonia and respiratory insufficiency at birth, in affected, male infants. The disease is causally associated with mutations in the MTM1 gene, coding for phosphatase myotubularin. XLMTM pathogenesis is due to a mutation in the MTM1 gene on Xq28;4,5 it encodes a phosphoinositide lipid phosphatase, which is known as myotubularin and appears to be important in muscle maintenance Mutations in the MTM1 gene encoding myotubularin cause X-linked myotubular myopathy (XLMTM), a well-defined subtype of human centronuclear myopathy. MTM1 gene sequencing revealed a unique exon 7 variant in all seven affected males, causing a nonconservative missense change, p.N155K, which haplotype data suggest derives from a recent founder in the local population. X-linked centronuclear myopathy (XLMTM), also called myotubular myopathy, is a severe congenital myopathy characterized by generalized hypotonia and weakness at birth and the typical histological finding of centralization of myo-nuclei. It is caused by mutations in the MTM1 gene encoding the 3-phosphoinositides phosphatase myotubularin. sequencing all MTM1 exons X-linked myotubular myopathy (XLMTM), a severe congenital disorder due to loss of function mutations in the MTM1 gene, encoding myotubularin, a phosphoinositide phosphatase thought to have a role in plasma membrane homeostasis and endocytosis. Mutations in the gene encoding the phosphoinositide phosphatase myotubularin 1 protein (MTM1) are usually associated with severe neonatal X-linked myotubular myopathy (XLMTM). However, mutations in MTM1 have also been recognized as the underlying cause of "atypical" forms of XLMTM in newborn boys, female infants, female manifesting carriers and adult men. X-linked myotubular myopathy (XLMTM), a recessive disorder, is caused by mutations affecting the myotubulatin (MTM1) gene located on the X chromosome. Most of the affected males die in the early postnatal period whereas female carriers are usually asymptomatic. The authors present a patient with the most severe X-linked recessive type (XLMTM). The diagnosis was confirmed and further specified by genetic analysis, revealing a novel frameshift mutation (1314-1315insT) of the myotubularin-coding MTM1 gene. X-linked myotubular myopathy (XLMTM) is a congenital muscle disorder caused by mutations in the MTM1 gene. MTM1, the gene encoding myotubularin (MTM1), is mutated in the X-linked myotubular myopathy (XLMTM), a severe genetic muscular disorder Myotubularin is a ubiquitously expressed phosphatase that acts on phosphatidylinositol 3-monophosphate [PI(3)P], a lipid implicated in intracellular vesicle trafficking and autophagy. It is encoded by the MTM1 gene, which is mutated in X-linked myotubular myopathy (XLMTM), a muscular disorder characterized by generalized hypotonia and muscle weakness at birth leading to early death of most affected males. The entire coding sequence of the gene was screened in 10 XLMTM patients using this technique. X-linked myotubular myopathy (XLMTM; OMIM# 310400) is a severe congenital muscle disease caused by mutations in the myotubularin (MTM1) gene. Mutations in the MTM1 gene cause X-linked recessive myotubular myopathy (XLMTM; MIM310400). We screened 29 independant patients with XLMTM phenotype and four with centronuclear myopathy. 87% (21/24) of patients with known MTM1 mutations showed abnormal myotubularin levels, including some with missense mutations. X-linked myotubular myopathy (XLMTM) characteristically causes severe or fatal muscle weakness in male infants. Mutations in the gene MTM1, encoding the protein myotubularin, can be identified in most families. X-linked myotubular myopathy (XLMTM) is a congenital muscular disease characterized by severe hypotonia and generalized muscle weakness, leading in most cases to early postnatal death. The gene responsible for the disease, MTM1, encodes a dual specificity phosphatase, named myotubularin, which is highly conserved throughout evolution. X-linked recessive myotubular myopathy (XLMTM) is a muscle disorder usually affecting newborn males. In the majority of cases, muscle weakness and hypotonia lead to a rapid demise at neonatal age. The responsible MTM1 gene is located in proximal Xq28. X-linked myotubular myopathy (XLMTM) is a severe congenital muscle disorder due to mutations in the MTM1 gene. X-linked recessive myotubular myopathy (XLMTM) is characterized by severe hypotonia and generalized muscle weakness, with impaired maturation of muscle fibres. The gene responsible, MTM1, was identified recently by positional cloning, and encodes a protein (myotubularin) with a tyrosine phosphatase domain (PTP). X-linked recessive myotubular myopathy (XLMTM; MTM1) is a severe neonatal disorder often causing perinatal death of the affected males. The responsible gene, designated MTM1, was localized to proximal Xq28 and recently isolated. The characterization of MTM1 allowed us to screen for causing mutations in three families, previously investigated by linkage analysis. Using exon amplification, single strand conformation polymorphism, and subsequent sequencing analysis, three new mutations and their mutational origin were characterized by analyzing 10 exons. </context> <question> Which gene test can be used for the X-linked myotubular myopathy? </question> <answer> MTM1 gene test </answer>
<context> patients receiving abacavir develop a hypersensitivity reaction, characterized by rash, fever and, occasionally, multisystemic involvement The predictors included any one of several specific symptoms commonly found with this reaction, a claims diagnosis of adverse effect of drug, anaphylactic shock or unspecified allergy, and a discontinuation in abacavir prior to completing a 90-day course of therapy. patients who receive abacavir develop an idiosyncratic hypersensitivity reaction. The most common symptoms are fever, skin rash and gastrointestinal disorders. Respiratory symptoms occurred in approximately 20% of patients who have hypersensitivity reaction. We describe the first case, to our knowledge, of hypesensitivity reaction characterized by enanthema and fever without skin rash promptly resolved after discontinuation of abacavir Abacavir is associated with an infrequent but potentially serious hypersensitivity reaction (HSR) that can include a wide range of signs and symptoms. Rash was associated with hypersensitivity (odds ratio [OR] = 13.1, P = 0.02) as was the presence of nausea (OR = 30, P < 0.001), vomiting (OR = 17.1, P = 0.001) or diarrhoea (OR = 22, P < 0.001). The number of gastrointestinal symptoms was also predictive of hypersensitivity reaction ( the number of gastrointestinal symptoms (OR = 8.6, P = 0.0032), cough (OR = 0.039, P = 0.02) and rash (OR = 16.9, P = 0.07). Abacavir hypersensitivity is strongly associated with gastrointestinal (GI) symptoms. </context> <question> What are the symptoms of abacavir hypersensitivity? </question> <answer> fever; enathema; skin rash; nausea; vomiting; diarrhea; cough; gastrointestinal disorders; anaphylactic shock; respiratory symptoms </answer>
<context> The histidine-rich Ca-binding protein (HRC) is a Ca-storage protein in cardiac sarcoplasmic reticulum. Recent transgenic studies revealed that this protein inhibits the maximal rates of sarcoplasmic reticulum Ca-transport, leading to cardiac dysfunction. In view of the role of sarcoplasmic reticulum Ca-cycling in myocardial ischemia/reperfusion injury, we designed this study to gain further insight into the role of HRC during ischemia/reperfusion. the genetic variant of Ser96Ala in HRC correlates with ventricular arrhythmogenesis and sudden death in DCM patients, suggesting that HRC may play a modifying role in the progression of this disease. Our findings suggest that increased cardiac HRC expression protects against ischemia/reperfusion injury in the heart, resulting in improved recovery of function and reduced infarction. The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients The HRC(S96A) mutant exacerbated the inhibitory effects of HRC(WT) on the amplitude of Ca(2+) transients, prolongation of Ca(2+) decay time, and caffeine-induced sarcoplasmic reticulum Ca(2+) release. Consistent with these findings, HRC(S96A) reduced maximal sarcoplasmic reticulum calcium uptake rate to a higher extent than HRC(WT). Furthermore, the frequency of spontaneous Ca(2+) sparks, which was reduced by HRC(WT), was increased by mutant HRC(S96A) under resting conditions although there were no spontaneous Ca(2+) waves under stress conditions. However, expression of the HRC(S96A) genetic variant in cardiomyocytes from a rat model of postmyocardial infarction heart failure induced dramatic disturbances of rhythmic Ca(2+) transients. These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers. Recent studies have shown that histidine-rich calcium (HRC)-binding protein, a 165 kDa sarcoplasmic reticulum (SR) protein, may regulate SR Ca cycling during excitation–contraction coupling. HRC may play a regulatory role in both SR Ca release and uptake. HRC mutations or polymorphisms may affect the SR Ca cycling and may be associated with depressed cardiac function and remodelling. </context> <question> What is the role of the histidine rich calcium binding protein (HRC) in cardiomyopathy? </question> <answer> The histidine-rich Ca-binding protein (HRC), a 165 kDa sarcoplasmic reticulum (SR) protein, regulates SR Ca cycling during excitation–contraction coupling. HRC mutations or polymorphisms lead to cardiac dysfunction. The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias and sudden death in idiopathic dilated cardiomyopathy (DCM). </answer>
<context> Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are promising therapies for patients with advanced non-small-cell lung cancer (NSCLC). Patients with somatic activating mutations in the EGFR gene have dramatic response initially, but would eventually develop resistance to these TKIs. NSCLCs with EGFR mutations (exon 19 deletions or the exon 21 L858R) attain responses to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, with improved response rate (RR), progression-free survival (PFS) and in some reports overall survival (OS) when compared with EGFR wildtype (WT) cases. Patients presenting with non-small cell lung cancer (NSCLC) and active EGFR mutation have a high response rate (60-70%) to EGFR tyrosine kinase inhibitors (TKI) with little immediate progression (primary resistance). Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. EGFR-TKI yields a long survival period in cases of non-small cell lung cancer (NSCLC), especially those with EGFR gene mutations, Efficacy of erlotinib was recognized in the cases in which disease control was obtained by initial treatment with gefitinib. Patients with lung adenocarcinoma who carry epidermal growth factor receptor (EGFR) gene mutations respond remarkably well to EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, or erlotinib. lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations respond to treatment with the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib; The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. Gefitinib- or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more resistance to gefitinib and erlotinib and acquired cross-resistance to other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this seemed to be the cause of drug resistance. Patients with advanced pulmonary adenocarcinoma exhibiting overexpression or mutation of epidermal growth factor receptor tend to respond better to targeted therapy with tyrosine kinase inhibitors such as gefitinib and erlotinib. Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small-cell lung cancer (NSCLC), especially in patients with adenocarcinoma and never smokers. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib, which are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are found in human lung adenocarcinomas and are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in lung adenocarcinomas that respond to the EGFR inhibitors gefitinib and erlotinib. Somatic gain-of-function mutations in exons encoding the epidermal growth factor receptor (EGFR) tyrosine kinase domain are found in about 10% of non-small cell lung cancers (NSCLCs) from the United States [1,2,3], with higher percentages observed in east Asia [2,4,5,6]. Some 90% of NSCLC-associated mutations occur as either multi-nucleotide in-frame deletions in exon 19, involving elimination of four amino acids, Leu-Arg-Glu-Ala, or as a single nucleotide substitution at nucleotide 2573 (T→G) in exon 21, resulting in substitution of arginine for leucine at position 858 (L858R). Both of these mutations are associated with sensitivity to the small-molecule kinase inhibitors gefitinib or erlotinib Epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor(TKI)(such as gefitinib or erlotinib)treatment of lung cancer harboring EGFR gene mutation is one of the prototypes of such therapies. patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). The evidence of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) such as gefitinib and erlotinib was first confirmed as the second-line treatment for non-selective patients with advanced NSCLC. patients with EGFR-mutated advanced NSCLC, the first-line treatment with gefitinib had achieved a significant prolongation of progression-free survival compared with standard platinum doublet chemotherapy in a few phase III trials, and became a new standard of care. Gefitinib is highly effective for patients with advanced NSCLC with EGFR mutation even if their performance status is poor, although one should always pay careful attention to fatal interstitial lung disease. The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are effective in non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) gene mutations. Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the responses to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with non-small-cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (gefitinib, erlotinib), which are molecularly targeted drugs, and it has now become possible to select treatment methods by choosing from a number of anticancer drugs. EGFR tyrosine kinase inhibitors have been demonstrated to have a very high cytoreductive effect on lung cancers that have EGFR gene mutations. EGFR gene mutations at kinase domain in non-small cell lung cancer (NSCLC) have been examined for their ability to predict sensitivity to gefitinib or erlotinib. responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. the epidermal growth factor receptor (EGFR) was a therapeutic target in non-small cell lung cancer (NSCLC) and other cancers led to development of the small-molecule receptor tyrosine kinase inhibitors gefitinib and erlotinib. There was a significant correlation between EGFR gene copy number, EGFR gene mutations, and gefitinib sensitivity. Epidermal growth factor receptor (EGFR) gene mutations have been found in a subset of non-small cell lung cancer (NSCLC) with good clinical response to gefitinib therapy. Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity such as gefitinib and erlotinib. Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity. </context> <question> Mutations in which gene determine response to both erlotinib and gefitinib? </question> <answer> epidermal growth factor receptor (EGFR) gene </answer>
<context> A strong association between human leukocyte antigen (HLA)-B1502 and CBZ-induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. found a strong association between HLA-B1502 and CBZ-induced SJS/TEN in the Han Chinese population from central and northern China. Combined with previous studies of the southern Han Chinese subpopulation, our results suggest that HLA-B1502 is strongly associated with CBZ-induced SJS/TEN in the whole Han Chinese population. A strong association between HLA-B1502 and carbamazepine-induced SJS/TEN has been identified in Chinese and Thai. In the present study, we conducted a pilot study to detect a possible association of oxcarbazepine (OXC)-induced MPE with HLA-B1502 allele in Chinese Han population. observed an increased frequency of HLA-B1502 allele in patients (44.44%) compared with tolerant controls (11.11%), although it failed to reach statistical significance (P=0.294). CONCLUSIONS: Our findings indicate that HLA-B1502 allele may contribute to the genetic susceptibility to OXC-induced MPE in Chinese Han population. A strong association between HLA-B1502 and CBZ-induced SJS/TEN has been reported in Han Chinese but not in Caucasian and Japanese populations. A case-control study was conducted to determine whether HLA-B1502 is a valid pharmacogenetic test for SJS/TEN caused by CBZ in a Thai population. Results from this study suggest that HLA-B1502 may be a useful pharmacogenetic test for screening Thai individuals who may be at risk for CBZ-induced SJS and TEN. A strong association has been reported between human leucocyte antigen (HLA)-B1502 and carbamazepine-induced SJS in Han Chinese patients. European studies suggested that HLA-B1502 is not a universal marker but is ethnicity-specific for Asians. the human leukocyte antigen HLA-B1502 is associated with Stevens-Johnson syndrome (SJS) induced by CBZ in Han Chinese. the HLA allele B1502 as a marker for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese, This allele is seen in high frequency in many Asian populations other than Han Chinese, but there are few data on whether the allele is a marker for this severe outcome in anyone other than Han Chinese. a strong association between HLA-B1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. A very strong association of carbamazepine-induced SJS with HLA-B1502 has recently been described in the Han Chinese population. there is a strong association in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B1502, and Stevens-Johnson syndrome induced by carbamazepine, a drug commonly prescribed for the treatment of seizures </context> <question> Which population has a high frequency of the HLA-B1502 allele? </question> <answer> Han Chinese and other Asian populations, except Japanese </answer>
<context> Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery remains the elective treatment. We retrospectively compared two group of patients, who underwent surgery for GIST before and after Imatinib advent in order to analyze the recurrence and survival rate. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST Prognostic factors such as tumor size, mitotic rate and presence of metastases may provide an indication for adjuvant imatinib mesylate (IM) treatment. Here we present a young patient with a large GIST with high-risk features who is in complete remission after surgical excision and adjuvant IM treatment. This patient is the only colon-located CD117-positive case where IM was administered. Imatinib is the first tyrosine kinase inhibitor to have achieved long term disease control in the majority of patients with CML. Imatinib mesylate is the sole BCR-ABL tyrosine kinase inhibitor approved as first-line treatment of accelerated-phase (AP) chronic myeloid leukemia (CML). imatinib mesylate could be a therapeutic target of strategies against osteosarcoma tumors. Following the success of the tyrosine kinase inhibitor (TKI) imatinib in chronic myeloid leukemia (CML), research focused on targeted therapy strategies for Ph-positive ALL and other ALL subtypes [9–13]. Imatinib has since become part of pre- and posttransplant treatment for patients with Ph-positive ALL [13, 14]. Allogeneic hematopoietic stem cell transplantation (HSCT) is well-established as a potentially curative treatment for patients who have chronic myeloid leukemia. The success of imatinib and other tyrosine kinase inhibitors (TKI) as initial therapy has changed the treatment paradigm for this disease. Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication. Ki67 correlated with time to recurrence (p=0.022). Ki67 >11% was taken as the indication to start imatinib chemotherapy (sensitivity 61.5%, specificity 92.0%, p=0.022). Significant pharmacokinetic interactions have already been shown between St. John's Wort (SJW) and the anticancer drugs imatinib and irinotecan. The search for a specific inhibitor of the BCR-ABL tyrosine kinase have resulted in the identification of the specific inhibitor imatinib mesylate (STI571), which has now become the standard first-line therapy in patients with CP-CML [10,11]. Imatinib, also known as Gleevec® (Novartis, Basel, Switzerland), is a selective inhibitor not only of ABL but also for Kit and PDGFR kinases and exerts significant antileukemic activity in the majority of CML patients. for CML we analysed imatinib, dasatinib and nilotinib. Imatinib mesylate, an orally administered kinase inhibitor that targets the Kit (CD117) protein, currently has 10 approved indications including treatment of chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GIST). The drugs were assessed according to clinical evidence on efficacy and safety, based on Micromedex categorization, on systematic reviews and meta-analyses. Indications present in the legal documentation were compared to the indications approved by regulatory agencies. RESULTS: Bevacizumab, capecitabine, cetuximab, erlotinib, rituximab, imatinib, and temozolomide Bcr-Abl, an oncogene responsible for CML Bcr-Abl-expressing cells showed resistance to death activated by spindle defects, reversed by imatinib. Imatinib, an oral tyrosine kinase inhibitor (TKI), is first-line treatment in patients with metastatic or unresectable GIST. Surgical indication for metastatic gastrointestinal stromal tumor (GIST) treated with imatinib is not yet established. Surgery of residual disease upon best clinical response seems associated with survival benefit compared with historical controls in similar patient collectives treated with imatinib alone. To explore the effect of preoperative imatinib mesylate (IM) in patients with unresectable or locally advanced primary gastrointestinal stromal tumor (GIST) In 2004, imatinib was approved for use as a first-line treatment for GIST after phase II and III clinical trials yielded overall response rates of approximately 50%, a 1-year survival rate greater than 80%, and a 2-year survival rate around 70% (Joensuu et al, 2001; Dagher et al, 2002; Demetri et al, 2002, 2005; Verweij et al, 2004). The patient had been diagnosed 14 months earlier and had been submitted to surgery, followed by adjuvant radiotherapy and temozolomide-based chemotherapy. On clinical suspicion of recurrence 5 months later, magnetic resonance imaging (MRI) revealed a lesion at the site of preceded surgery, which was treated by imatinib mesylate Radical surgery remains the most effective method of GIST treatment. In inoperable/metastatic lesion the treatment of choice is tyrosinase kinase inhibitor--imatinib. Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of chronic myeloid leukemia (CML) patients. Imatinib, an inhibitor of the tyrosine kinase activity of c-kit, was used as an adjuvant chemotherapy in two patients who underwent curative surgery for recurrent gastrointestinal stromal tumors. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery remains the elective treatment. We retrospectively compared two group of patients, who underwent surgery for GIST before and after Imatinib advent in order to analyze the recurrence and survival rate. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. </context> <question> Is imatinib an antidepressant drug? </question> <answer> no </answer>
<context> trastuzumab (Herceptin®) an antibody-based therapy exists which is successfully used clinically for targeting HER2 in metastatic HER2-positive breast cancer over-expression of HER2 is reported in approximately 20% of gastric tumours, challenging the use of targeted therapies. In patients with advanced gastric or gastro-oesophageal junction cancer, addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone. Addition of trastuzumab to chemotherapy did not increase the incidence of adverse events. treatment of HER2-overexpressing breast cancer: trastuzumab, Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. trastuzumabThe Panel unanimously supported the use of 1 year of trastuzumab as standard adjuvant treatment for patients with ‘HER2 positive’ disease, An example is the established benefit of trastuzumab as adjuvant therapy for breast cancer; a clear definition of HER2-positivity and the assay reproducibility have, however, remained unanswered. Trastuzumab is a monoclonal antibody targeted to the Her2 receptor and approved for treatment of Her2-positive breast cancer. Without contraindication HER2 protein overexpression (or HER2 gene amplification) represents the worldwide accepted rationale for antibody-targeted therapy using trastuzumab (Herceptin™). anti-HER2 monoclonal antibody trastuzumab (Tzb; Herceptin®), the first immunotherapeutic drug for the successful treatment of breast carcinomas overexpressing the HER2 (erbB-2) oncogene [ Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast cancers in which it is overexpressed. However, no approved anti-HER2/neu therapy is available for the majority of breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative). effective targeted therapies such as Trastuzumab (Herceptin), a monoclonal antibody to HER2, which are effective only in tumors with HER2 overexpression, The humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) is useful in the treatment of ErbB2-overexpressing breast cancers, HercepTestTM (DAKO A/S, Glostrup, Denmark) is an immunohistochemical assay that detects HER2/neu gene products, and evaluates the overexpression status of the HER2/neu protein in determining eligibility for the Trastuzumab (HerceptinR, Genentech, San Francisco, CA, USA) therapy. </context> <question> Does HER2 under-expression lead to favorable response to trastuzumab? </question> <answer> no </answer>
<context> polymorphisms in the CYP2C19 gene affect clopidogrel pharmacokinetics. This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420). Variants in the CYP2C19 gene influence the pharmacologic and clinical response to the standard 75-mg daily maintenance dose of the antiplatelet drug clopidogrel. OBJECTIVE: To test whether higher doses (up to 300 mg daily) improve the response to clopidogrel in the setting of loss-of-function CYP2C19 genotypes. polymorphisms in the CYP2C19 gene affect clopidogrel pharmacokinetics. These polymorphisms may be useful to identify clopidogrel nonresponders who may benefit from taking an alternative antiplatelet agent such as prasugrel and ticagrelor. Although both drugs have pharmacogenomic tests available for clinical use, This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420). The CYP2C192 allele is a common genetic variant associated with increased rates of major adverse events in individuals given clopidogrel after percutaneous coronary intervention (PCI). We used a novel point-of-care genetic test to identify carriers of the CYP2C192 allele and aimed to assess a pharmacogenetic approach to dual antiplatelet treatment after PCI The antiplatelet effect of clopidogrel has been linked to cytochrome P450 2C19 (CYP2C19) carrier status. The presence of loss of function and gain of function variants were found to have a gene-dose effect on clopidogrel metabolism. However, genotyping is only one aspect of predicting response to clopidogrel and several platelet function tests are available to measure platelet response. Variants in the CYP2C19 gene influence the pharmacologic and clinical response to the standard 75-mg daily maintenance dose of the antiplatelet drug clopidogrel. OBJECTIVE: To test whether higher doses (up to 300 mg daily) improve the response to clopidogrel in the setting of loss-of-function CYP2C19 genotypes. The cytochrome P450 (CYP) 2C192 loss-of-function allele has been associated with impaired clopidogrel response and worse prognosis in clopidogrel-treated patients. The present study was designed to evaluate the benefit of tailored therapy with a higher maintenance dose according to CYP2C19 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes. identify genes and mutations with known associations with disease and drug response. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, The cytochrome P450 (CYP) 2C19 isoenzyme plays an important role in clopidogrel metabolization. A recently explored CYP2C1917 allelic variant has been linked to increased transcriptional activity, resulting in extensive metabolization of CYP2C19 substrates, which may lead to an enhanced platelet response to clopidogrel treatment. To identify gene variants that influence clopidogrel response. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C192 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C192 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention. Coexisting polymorphisms of the genes affecting clopiogrel resistance may influence platelet activation. Genotyping revealed 7 carriers of both the C allele of P2Y12 and A allele of CYP2C19 (group 1), 14 carriers of the T allele of P2Y12 and A allele of CYP2C19 (group 2), 17 carriers of the C allele of P2Y12 and G allele of CYP2C19 (group 3) and 67 carriers of the T allele of P2Y12 and G allele of CYP2C19 (controls). to evaluate the effect of polymorphisms affecting the clopidogrel metabolism (CYP3A4 IVS10+12G/A and CYP2C192) and the P2Y12 receptor (P2Y12 T744C) on modulating platelet function in acute coronary syndrome patients on dual antiplatelet treatment. to test the influence of the CYP 2C192 allele on clopidogrel responsiveness. Genetic polymorphisms significantly influence responses to warfarin and clopidogrel. A recent clinical trial has demonstrated that patients with acute coronary syndromes (ACS) and the reduced function allele CYP2C192 (2 allele), who are treated with thienopyridines, have an increased risk of adverse cardiac events with clopidogrel, but not with prasugrel. </context> <question> What gene test is recommended for clopidogrel? </question> <answer> CYP2C19 genotyping </answer>

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