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Does replication timing affect the rate of somatic mutations?

['Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome', 'll classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage', 'We show that mutation rate varies 6-fold across a single chromosome, that this variation is correlated with replication timing, and we propose a model to explain this variation that relies on the temporal separation of two processes for replicating past damaged DNA: error-free DNA damage tolerance and translesion synthesis.', 'Recent studies revealed a long suspected replication-timing effect on mutation rate, but the mechanisms that regulate the increase in mutation rate as the genome is replicated remain unclear. ', 'DNA repair systems, in general, are less efficient in late replicating heterochromatic regions compared to early replicating euchromatic regions of the genome.', 'The mutational profile of the yeast genome is shaped by replication', 'the mutation rate increases with the replication timing by more than 30% between the earliest and the latest replicating regions.', 'Thus, we show that the leading replicating strands present an excess of C over G and of A over T in the genome of S. cerevisiae (reciprocally an excess of G + T over C + A in lagging strands)', 'Late-replicating domains have higher divergence and diversity in Drosophila melanogaster', 'Recent evidence also suggests that late replication is associated with high mutability in yeast.', 'Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence', 'The mutation rate for DNA mismatch repair null strains was approximately 1 mutation per genome per generation, 225-fold greater than the wild-type rate. The mutations were distributed randomly throughout the genome, independent of replication timing.', 'Many single-nucleotide substitutions in cancer genomes arise because of errors in DNA replication, which is spatio-temporally stratified.', 'Here we propose that DNA replication patterns help shape the mutational landscapes of normal and cancer genomes', 'Using data on five fully sequenced cancer types and two personal genomes, we determined that the frequency of intergenic single-nucleotide substitution is significantly higher in late DNA replication timing regions, even after controlling for a number of genomic features', 'we found that genomic regions in close spatial proximity to late-replicating domains display similar mutation spectra as the late-replicating regions themselves', 'In addition, certain chromosome rearrangements found in cancer cells and in cells exposed to ionizing radiation display a significant delay in replication timing of >3 hours that affects the entire chromosome(2,3). Recent work from our lab indicates that disruption of discrete cis-acting autosomal loci result in an extremely late replicating phenotype that affects the entire chromosome(4).', 'A conservative estimate is that at least 1-2% of new deleterious mutations affect some aspect of DNA replication, repair, or chromosome segregation. Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate.', 'Drake calculates that lytic RNA viruses display spontaneous mutation rates of approximately one per genome while most have mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline mutation rates among microbial species need not necessarily mean constancy of the somatic mutation rates.', 'A recent flurry of reports correlates replication timing (RT) with mutation rates during both evolution and cancer.', 'DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability.', 'Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate.', 'In addition, this method allows for the unambiguous identification of chromosomal rearrangements that correlate with changes in replication timing that affect the entire chromosome.']

['Mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome. All classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage. DNA repair systems, in general, are less efficient in late replicating heterochromatic regions compared to early replicating euchromatic regions of the genome. In yeast the mutation rate increases with the replication timing by more than 30% between the earliest and the latest replicating regions. Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence. In humans DNA replication patterns help shape the mutational landscapes of normal and cancer genomes.', 'Recent studies revealed a long suspected replication-timing effect on mutation rate, but the mechanisms that regulate the increase in mutation rate as the genome is replicated remain unclear. The mutations were distributed randomly throughout the genome, independent of replication timing. Here, we show that the mutation rate increases with the replication timing by more than 30% between the earliest and the latest replicating regions. Interestingly, 5% of the single base pair substitutions might represent double-slippage events that occurred at the junction of immediately adjacent repeats, resulting in a shift in the repeat boundary.', 'Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome']

['yes']

What is the effect of ivabradine in heart failure with preserved ejection fraction?

['Traditional agents with strong evidence in HFrEF have proved unsuccessful in HFpEF. Newer agents such as angiotensin receptor neprilysin inhibitor, sildenafil, and ivabradine have demonstrated benefits without improving mortality.', 'In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.', 'Selective HR reduction with IVA reduces DD and cardiac fibrosis in hypercholesterolemic rabbits. These beneficial effects of IVA support testing pure HR reduction in patients with diastolic heart failure.', 'Beside its use in therapy of coronary artery disease, I(f)-channel inhibition potentially exhibits beneficial effects in systolic and diastolic heart failure as well.', 'In patients with HFpEF, short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity.']

['I(f)-channel inhibition potentially exhibits beneficial effects in diastolic heart failure. In patients with heart failure with preserved ejection fraction (HFpEF), short-term treatment with ivabradine increased exercise capacity, with a contribution from improved left ventricular filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity. Ivabradine has demonstrated benefits in HFpEF without improving mortality.\tIn db/db, a model of HFpEF, ivabradine improved vascular stiffness, left ventricular contractility, and diastolic function. Furthermore, ivabradine reduces cardiac fibrosis in hypercholesterolemic rabbits.']

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Which genes/proteins have been found to inhibit cyclin dependent kinase 4 (CDK4)?

['Interestingly, the Cdk inhibitor p18(Ink4c) was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53.', 'Our finding that the Cdk4 inhibitor p18(Ink4c) is a tumor suppressor in cyclin D1-driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption.', 'Our previous studies showed that while both specific CDK4 inhibitor p16INK4A (P16) and gankyrin bind to cyclin-dependent kinase 4 (CDK4) in similar fashion, only P16 inhibits the kinase activity of CDK4.', 'Recent biological studies of Cyclin D1/Cdk4 have proposed that p21 C-terminal domain (p21(CT)) plays a key role as a potent Cdk4 inhibitor. ', 'Especially, our data suggests that the D(149)FYHSKRR(156) region of p21 is critical for Cdk4 binding, indicating that the major driving force for complex originates from hydrophobic interaction between p21 and Cdk4.', 'We show that c-Myc prevents induction of the cdk4 inhibitor p15(Ink4b) and the subsequent inhibition of G(1) cdks by TGF-beta.', 'CDK activity is modulated by inhibitors such as p15INK4b and p16INK4a. Loss of function of p15INK4b and p16INK4a (multiple tumor suppressor-I and CDK4 inhibitor) determines impairment in the control of the cell cycle and contributes to the transformation of several cell types. ', 'D-type cyclins, in association with the cyclin-dependent kinases CDK4 and CDK6, promote progression through the G1 phase of the cell cycle.', 'In the present study, we analyzed human ovarian carcinoma cell lines for abnormalities in the tumor suppressor gene Rb (retinoblastoma) and in cyclin-dependent kinase 4 (CDK4) inhibitor genes (p16INK4 and p15INK4B) using molecular biology techniques.', 'These data suggest that abnormalities of Rb and CDK4 inhibitor genes (p16INK4, p15INK4B) may be involved in human ovarian carcinogenesis.', 'The mutation, an arginine-to-cysteine exchange at residue 24, was part of the CDK4 peptide recognized by CTLs and prevented binding of the CDK4 inhibitor p16INK4a, but not of p21 or of p27KIP1. ', 'The p15 and p16 CDK4 inhibitor genes map within the chromosome band 9p21 region deleted frequently in malignant mesothelioma and other cancers.', 'The cyclin-dependent kinase 4 (cdk4) inhibitor (p16INK4/MTS1/CDKN2) gene has been recently identified as a putative tumor suppressor gene because of the high frequency of homozygous deletion observed in numerous human tumor cell lines, including leukemias. ', 'The identification of a cdk4 inhibitor, p16INK4, as a target for mutations in cultured tumor lines and primary tumors suggested that RB activity may be affected in these cells.', 'Roles of cyclin A-Cdk2 as a p27 target and cyclin D2-Cdk4 as a p27 reservoir may result from the differential ability of bound p27 to inhibit the kinase subunit in these complexes.', 'Role of the cyclin-dependent kinase 4 and 6 inhibitor gene family p15, p16, p18 and p19 in leukemia and lymphoma.', 'Identification of functional elements of p18INK4C essential for binding and inhibition of cyclin-dependent kinase (CDK) 4 and CDK6.', 'One of the INK4 molecules, p16, is also known as multiple tumor suppressor and has been found to be mutated or deleted in various tumors and cell lines. We have previously identified p18 as a member of the INK4 family.', 'Members of the INK4 family of cyclin-dependent kinase (CDK) inhibitors specifically bind and inhibit the G1-specific CDK molecules CDK4 and CDK6.', 'The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.']

['The p15(ink4b) and p16(ink4a) CDK4 inhibitor genes map within the chromosome band 9p21 region deleted frequently in various cancers.The Cdk4 inhibitor p18(Ink4c) is a tumor suppressor. Recent studies of Cyclin D1/Cdk4 have proposed that p21(Waf1/Cip1/Sdi1) plays a key role as a potent Cdk4 inhibitor. p27KIP1 is also a cdk4 ihibitor.']

['p16', 'p16INK4', 'p16INK4a', 'MTS1', 'CDKN2', 'p15', 'p15INK4B', 'p18(Ink4c)', 'p21(Waf1/Cip1/Sdi1)', 'p27KIP1']

Which drugs are utilized to treat amiodarone-induced thyroitoxicosis?

['good response to anti-thyroid drugs and steroid therapy', 'The disease course of amiodarone-induced thyrotoxicosis is usually benign and remits with timely administration of anti-thyroid medications, with or without corticosteroids.', 'RIT may be a safe and useful method of AIT therapy in patients with low RAIU, in whom other treatment methods are contraindicated.', 'Treatment consists in the use of a high dose of anti-thyroid drugs and steroids in an isolated form or in combination.', 'the addition of lithium carbonate to the two other drugs resulted in a successful and safety therapy in controlling amiodarone-induced thyrotoxicosis.', 'lithium is a useful and safe medication for treatment of iodine-induced thyrotoxicosis caused by amiodarone.', 'Two patients with amiodarone-induced thyrotoxicosis were treated successfully with potassium perchlorate and carbimazole while treatment with amiodarone was continued.', 'Amiodarone-induced thyrotoxicosis seems to be a transient condition that can be treated successfully with a short course of antithyroid drugs without stopping amiodarone treatment.', 'Both patients were successfully treated with propylthiouracil (PTU) and dexamethasone (DXT).']

['Amiodarone-induced thyrotoxicosis treatment includes anti-thyroid drugs and steroid therapy\nRadio Iodine Treatment (RIT) may be a safe and useful method of AIT therapy in patients with low RAIU, in whom other treatment methods are contraindicated.\nLithium is a useful and safe medication for treatment of iodine-induced thyrotoxicosis caused by amiodarone.\nThyrodectomy may be necessary in presence of unresponsiveness to standard medical treatments']

['Antithyroid drugs', 'Corticosteroids', 'Lithium', 'Radioiodine']

What is the role of LIMT lncRNA?

['LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer.', 'This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in\xa0vitro and tumor metastasis in\xa0vivo In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.', 'Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis.', 'Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter.', 'We also find that LIMT inhibits extracellular matrix invasion of mammary cells in\xa0vitro and tumor metastasis in\xa0vivo In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.', 'Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis.', 'LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer.', 'We also find that LIMT inhibits extracellular matrix invasion of mammary cells in\xa0vitro and tumor metastasis in\xa0vivo In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.']

['LINC01089 (LncRNA Inhibiting Metastasis; LIMT) is a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo.', 'LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer.']

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What is the role of the TSC1 and TSC2 genes in regulating the mTOR signaling pathway and cell growth?

['["The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2.", "The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently", "Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors", "Ten years ago, a mutation in the TSC2 gene was identified in the Eker rat at Fox Chase Cancer Center by Yeung and Knudson, and in Tokyo by Kobayashi and Hino.", "Here, we will review the clinical association of RCC in TSC, consider the factors that have led to its under-emphasis within the RCC field, address the cellular and biochemical mechanisms that may contribute to RCC in cells with TSC1 or TSC2 mutations, and finally discuss the ways in which the TSC signaling pathways may be linked to sporadic RCC in the general population.", "Either of two genes, TSC1 or TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype.", "The protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and tuberin (TSC2), have been discovered to play important roles in several cell-signaling pathways", "Knowledge regarding the function of the tuberin-hamartin complex has led to therapeutic intervention trials. ", "TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease.", "We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis.", "Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis", "The disease can be caused by mutations in either of two genes, TSC2, identified in 1993, and TSC1, only recently identified.", "Molecular genetic basis of renal carcinogenesis in the Eker rat model of tuberous sclerosis (Tsc2)", "We have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene (Tsc2), the gene predisposing to renal carcinoma (RC) in the Eker rat", "Tuberous sclerosis complex is a genetic disorder caused by mutations in either the TSC1 or TSC2 gene that can result in the growth of hamartomas in multiple organ systems", "Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway. ", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13.3) genes with the regulation of the Rheb/m-TOR/p70S6K pathway.", "In all these lesions, genetic alterations related to the tuberous sclerosis complex (TSC) have been demonstrated. Striking improvements in the understanding of the genetic basis of this autosomal dominant genetic disease are coupled to the understanding of the mechanisms that link the loss of TSC1 (9q34) or TSC2 (16p13."]']

The TSC1 and TSC2 genes act as negative regulators of the mTOR signaling pathway. Tuberin, a product of the TSC2 gene, coordinates inputs from growth factors and energy availability to control cell growth, proliferation, and survival. The TSC 1/2 complex may also modulate the activity of beta-catenin and TGFbeta, providing functional links between the TSC genes and other tumor suppressors.

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Can RG7112 inhibit MDM2?

['To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production.', 'RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2.', 'Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study.', 'We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection.', 'To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production.', 'Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.', 'RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development.', 'RG7112 binds MDM2 with high affinity (K(D) ~ 11 nmol/L), blocking its interactions with p53 in vitro.', 'RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis.', 'The effects of RG7112 and Peg-IFNα 2a on MPN progenitor cells were dependent on blocking p53-MDM2 interactions and activating the p53 pathway, thereby increasing MPN CD34(+) cell apoptosis', 'The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon α 2a target JAK2V617F-positive progenitor and stem cells', 'Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program', 'In this issue of Blood, Lu et al describe the cooperation between an orally bioavailable mouse double minute 2 (MDM2) antagonist (RG7112) and the pegylated interferon α (Peg-IFNα 2a) to target JAK2V617F hematopoietic progenitors and stem cells', 'MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.', 'Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis.', 'The orally bioavailable MDM2 antagonist RG7112 and pegylated interferon α 2a target JAK2V617F-positive progenitor and stem cells.', 'Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program.', 'The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC-1], and apoptosis). ', 'RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies.', 'However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development.', 'Treatment with low doses of RG7112, an orally available small-molecule inhibitor of p53-MDM2, both alone and combined with pegylated interferon α 2a (Peg-IFNα 2a), significantly decreased MPN colony-forming unit-granulocyte macrophage and burst-forming unit-erythroid numbers and preferentially eliminated the total number of JAKV617F(+) MPN hematopoietic progenitor cells. The effects of RG7112 and Peg-IFNα 2a on MPN progenitor cells were dependent on blocking p53-MDM2 interactions and activating the p53 pathway, thereby increasing MPN CD34(+) cell apoptosis.', 'RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.']

['Yes, RG7112 is a small molecule MDM2 antagonist.']

['yes']

Where do the Schwann cells and melanocytes originate from?

['The development of the nervous system involves cells remaining within the neural tube (CNS) and a group of cells that delaminate from the dorsal neural tube and migrate extensively throughout the developing embryo called neural crest cells (NCC). These cells are a mesenchymal highly migratory group of cells that give rise to a wide variety of cell derivatives: melanocytes, sensory neurons, bone, Schwann cells, etc. ', 'Cell types with neural crest ancestry consequently comprise a number of specialized varieties, such as ectodermal neurons, melanocytes and Schwann cells, as well as mesodermal osteoblasts, adipocytes and smooth muscle cells. ', 'Melanocytes, the pigmented cells of the skin, and the glial Schwann cells lining peripheral nerves are developmentally derived from an early and transient ectodermal structure of the vertebrate embryo, the neural crest, which is also at the origin of multiple neural and non-neural cell types. ', 'Later, SoxE proteins drive the formation of multiple neural crest derivatives including chondrocytes, melanocytes, and cells of the peripheral nervous system, particularly Schwann cells/peripheral glia. ', 'Melanocytes and Schwann cells are derived from the multipotent population of neural crest cells.', 'The present results suggest that the induced hamster melanomas originate from neural crest-derived cells which are able to differentiate into both melanocytes and Schwann cells.', 'Melanocytes and Schwann cells both arise from the neural crest during development, and some melanocytes arise directly from Schwann cell precursors lining developing spinal nerves', 'Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells', 'In the vertebrate embryo, Schwann cells lining the peripheral nerves originate from the neural crest (NC), a structure that also gives rise to ganglion satellite cells, most of the neurons of the peripheral nervous system, melanocytes, and part of the cranial mesenchyme', 'The present results suggest that the induced hamster melanomas originate from neural crest-derived cells which are able to differentiate into both melanocytes and Schwann cells', 'Thus, the nevus cells shared a common nature with epidermal melanocytes and Schwann cells which originate from the neural crest; however, the former cells were somewhat different from the latter two kinds and from benign and malignant tumors derived from these cells in the expression of these antigenic substances', 'Melanocytes, the pigmented cells of the skin, and the glial Schwann cells lining peripheral nerves are developmentally derived from an early and transient ectodermal structure of the vertebrate embryo, the neural crest, which is also at the origin of multiple neural and non-neural cell types', 'Furthermore, although both populations are initially part of the Foxd3 lineage, hypaxial melanocytes lose Foxd3 at late stages upon separation from the nerve, whereas we recently found that epaxial melanocytes segregate earlier from Foxd3-positive neural progenitors while still residing in the dorsal neural tube. ', 'Reversal of developmental restrictions in neural crest lineages: transition from Schwann cells to glial-melanocytic precursors in vitro.', 'Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells.', 'In the vertebrate embryo, Schwann cells lining the peripheral nerves originate from the neural crest (NC), a structure that also gives rise to ganglion satellite cells, most of the neurons of the peripheral nervous system, melanocytes, and part of the cranial mesenchyme.', 'Thus, the nevus cells shared a common nature with epidermal melanocytes and Schwann cells which originate from the neural crest; however, the former cells were somewhat different from the latter two kinds and from benign and malignant tumors derived from these cells in the expression of these antigenic substances.', 'Other already committed cells are the angioblasts forming the endothelial lining of the blood vessels, the neural crest cells differentiating into melanocytes and Schwann cells, and the blood-derived cells like chrondro- or osteoclasts.', 'The dorsal neural tube first generates neural crest cells that exit the neural primordium following an epithelial-to-mesenchymal conversion to become sympathetic ganglia, Schwann cells, dorsal root sensory ganglia, and melanocytes of the skin.', 'We show here that neural crest cells arising from the neural tube located at the level of somites 47-53 can differentiate both in vitro and in vivo into melanocytes and Schwann cells but not into neurons.', 'This capacity may be due to the common origin of Schwann cells and melanocytes in the neural crest.', 'Melanocytes and Schwann cells both arise from the neural crest during development, and some melanocytes arise directly from Schwann cell precursors lining developing spinal nerves.', 'In the vertebrate embryo, multiple cell types originate from a common structure, the neural crest (NC), which forms at the dorsal tips of the neural epithelium.']

['Schwann cells and melanocytes originate from the multipotent population of neural crest cells.']

['neural crest cells', 'NCC']

Does SCRIB deregulation promote cancer?

['human homologs of Drosophila dlg, scrib, and lgl are cancer-associated genes.', 'Aberrant overexpression of the cell polarity module scribble in human cancer.', 'we show that Scrib is nearly universally overexpressed in cultured tumor cell lines and genetically disparate cancer patient series compared with matched normal tissues in vivo. ', 'These data uncover a previously unrecognized exploitation of Scrib for aberrant tumor cell motility and invasion, thus potentially contributing to disease progression in humans.', 'oss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration and tumor cell invasiveness. ', 'Scrib levels predict tumor relapse in hepatocellular carcinoma patients.', 'Scrib heterozygosity predisposes to lung cancer', 'loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, l', 'Scribble, a product of a well-known tumor suppressor gene', 'CD74-dependent deregulation of the tumor suppressor scribble in human epithelial and breast cancer cells.', ' scribble (SCRIB) complexes) is intricately related to advanced stages of tumour progression and invasiveness. ', 'SCRIB expression is deregulated in human prostate cancer,', 'Scrib heterozygosity initiated prostate hyperplasia', 'The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer.', 'we demonstrate that scribble inhibits breast cancer formation and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death.', 'Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma.', 'loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system.', 'Scribble expression is decreased in many invasive human cancers.', 'Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling.']

['Yes, deregulation of scribble promotes cancer.']

['yes']

What is trichotillomania?

['Trichotillomania (hair pulling disorder, HPD) is characterized by significant psychological distress, childhood-onset, and, in adults, certain cognitive deficits such as inhibitory control. ', 'TRICHOTILLOMANIA (HAIR PULLING DISORDER)', 'Hair pulling disorder (HPD; trichotillomania) is thought to be associated with significant psychiatric comorbidity and functional impairment. ']

['Trichotillomania is a hair pulling disorder.']

['Trichotillomania is a hair pulling disorder.']

Which genes are known to be involved in Diamond-Blackfan anemia?

['Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents during the first year of life. The main features of the disease are normochromic and macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. The patients also present with growth retardation and craniofacial, upper limb, heart and urinary system congenital malformations in ~30-50 % of cases. The disease has been associated with point mutations and large deletions in ten ribosomal protein (RP) genes RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, and RPL26 and GATA1 in about 60-65 % of patients', 'This study was aimed to explore the mutations of ribosomal protein (RP) genes in patients with Diamond Blackfan anemia (DBA). Twenty-one cases of DBA admitted in our hospital from Dec 2008 to Aug 2012 were screened by PCR for mutations in the nine known genes associated with DBA: RPS19, RPS24, RPS17, RPL5, RPL11, RPS7, RPL35a, RPS10 and RPS26', 'The results found that 8 patients (38.1%) with DBA had mutations in the genes coding for ribosomal protein, in which RPS19 mutation was identified in 3 patients, RPS24, RPS7, RPL5, RPL11 and RPL35A mutations were identified respectively in 1 of the patient', 'Diamond-Blackfan anemia (DBA) is a hypoplastic anemia characterized by impaired production of red blood cells, with approximately half of all cases attributed to ribosomal protein gene mutations. We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1', 'As a proof of concept, we designed a multiplex ligation-dependent probe amplification assay targeted to screen the six genes that are most frequently mutated in Diamond-Blackfan anemia patients: RPS17, RPS19, RPS26, RPL5, RPL11, and RPL35A. Using this assay we showed that deletions represent approximately 20% of all mutations', 'DESIGN AND METHODS: We screened 49 Japanese patients with Diamond-Blackfan anemia (45 probands) for mutations in the six known genes associated with Diamond-Blackfan anemia: RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A.', 'Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases.', 'OBJECTIVE: Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia caused by mutations in ribosomal protein (RP) genes.', 'Fifty percent of Diamond-Blackfan anemia (DBA) patients possess mutations in genes coding for ribosomal proteins (RPs).', 'Mutations in the gene coding for the ribosomal protein RPS19 have been identified in 25% of patients with DBA, with resulting impairment of 18S rRNA processing and 40S ribosomal subunit formation', 'We screened 49 Japanese patients with Diamond-Blackfan anemia (45 probands) for mutations in the six known genes associated with Diamond-Blackfan anemia: RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A', 'Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases', 'The first ribosomal gene involved in DBA, ribosomal protein (RP) gene S19 (RPS19 gene), was identified in 1999', 'These data identify RPL15 as a new gene involved in DBA and further support the presence of large deletions in RP genes in DBA patients.']

['Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents during the first year of life. The disease has been associated with point mutations and large deletions in ten ribosomal protein (RP) genes RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, and RPL26, as well as in GATA1, in about 60-65 % of patients.']

['RPS19', 'RPS24', 'RPS17', 'RPL35A', 'RPL5', 'RPL11', 'RPS7', 'RPS10', 'RPS26', 'RPL26', 'GATA1']

List BRAF inhibitors that have been tested in clinical trials for treatment of melanoma patients

['Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor.', ' Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). ', 'This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. ', 'METHODS: All patients treated with the BRAF inhibitors vemurafenib or dabrafenib or combination BRAF inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor therapy at Westmead Hospital, Sydney, Australia underwent regular dermatological assessments for the duration of therapy.', 'We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. ', 'We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. ', 'However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities.', 'The BRAF inhibitor dabrafenib recently was approved for use in patients with BRAF V600-mutated metastatic melanoma.', 'His treatment course to date has included surgery, adjuvant radiotherapy, and interferon, metastasectomies, granulocyte-macrophage colony-stimulating factors, a clinical trial with the BRAF inhibitor vemurafenib (PLX-4032), clinical trial with combination BRAF plus MEK inhibition with vemurafenib plus GDC-0973, and combination targeted and immune therapy with vemurafenib plus the anti-CTLA4 antibody ipilimumab.', 'Thirty-one patients commenced dabrafenib therapy including six individuals who had progressed on a prior BRAF-inhibitor treatment.', 'Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites.', 'Dabrafenib is a BRAF kinase inhibitor indicated for the treatment of BRAF V600E mutation-positive melanoma. ', 'This was a prospective study of melanoma patients harboring the BRAF V600 mutation and treated with iBRAF within a clinical trial (dabrafenib) or as part of an expanded access program (vemurafenib).', 'We investigated the BRAF kinase inhibitor vemurafenib in patients with advanced melanoma with symptomatic brain metastases.', 'This discovery led to the development of BRAF kinase inhibitors like vemurafenib and dabrafenib. ', 'CONCLUSIONS: Dabrafenib joins vemurafenib to confirm the superior clinical outcome of the BRAF inhibitors when compared with dacarbazine in patients with BRAF(V600E)-positive advanced melanoma. ', 'Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436).', 'PURPOSE: Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. ', 'Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma.', 'PURPOSE: Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase.', 'Cutaneous squamous cell carcinoma (cSCC) is a concerning toxicity with BRAF inhibitors in the treatment for melanoma. While the two drugs shown to improve survival, vemurafenib, and dabrafenib, have similar efficacy, the reported rates of cSCC are quite different.', 'PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. ', 'BACKGROUND: The cobas 4800 BRAF V600 Mutation Test is a CE-marked and FDA-approved in vitro diagnostic assay used to select patients with metastatic melanoma for treatment with the selective BRAF inhibitor vemurafenib', 'The purpose of this study is to review the development of BRAF inhibitors, with emphasis on the trials conducted with dabrafenib (GSK2118436) and the evolving role of dabrafenib in treatment for melanoma patients.', 'Dabrafenib inhibits the mutant BRAF (BRAF(mut)) protein in melanomas with BRAF(V600E) and BRAF(V600K) genotypes.', 'To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.', 'Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma.', 'We conducted a systematic prospective dermatological review of all patients enrolled at a single institution in the phase I/II clinical trial of the mutant BRAF inhibitor dabrafenib (GSK2118436).', 'CONCLUSIONS: Administration of the mutant BRAF inhibitor dabrafenib is associated with induction of keratinocytic proliferation, which in some cases develops features of low-grade malignancy.', 'Neoplastic leptomeningitis presenting in a melanoma patient treated with dabrafenib (a V600EBRAF inhibitor): a case report.', 'For this reason, she was enrolled into another clinical trial with the GSK2118436 BRAF inhibitor, dabrafenib, as a second line of therapy.', 'BACKGROUND: The development of keratoacanthomas (KAs) and well-differentiated squamous cell carcinomas (SCCs) is a known adverse effect of novel BRAF inhibitors such as vemurafenib.', 'OBSERVATIONS: We describe a patient with stage IV melanoma who received the BRAF inhibitor vemurafenib (recently approved by the US Food and Drug Administration) as part of a clinical trial and developed numerous diffuse, pathology-proven KAs and SCCs. ', "CONCLUSIONS: Given vemurafenib's recent approval by the US Food and Drug Administration, we provide a timely case report on the effective use of PDT in the treatment of BRAF inhibitor-associated KAs and SCCs. ", 'The BRAF inhibitor, vemurafenib, has shown up to 78% objective response rates in melanoma patients harboring the BRAF-V600E mutation but not in patients lacking the mutation. ', 'The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. ', 'CONTEXT: A polymerase chain reaction-based companion diagnostic (cobas 4800 BRAF V600 Mutation Test) was recently approved by the US Food and Drug Administration to select patients with BRAF-mutant metastatic melanoma for treatment with the BRAF inhibitor vemurafenib. ', 'However, in the recent clinical trial of the BRAF inhibitor, vemurafenib (PLX4032), a significant percentage of BRAF V600E mutant melanoma patients did not meet the RECIST criteria for a response. ', 'Vemurafenib (RG7204/PLX4032), a small-molecule inhibitor of mutant BRAF, has shown striking clinical efficacy in BRAFV600 mutant melanoma, creating the need for a well-validated companion diagnostic to select patients for treatment.', 'BACKGROUND: Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.', 'Vemurafenib is the first molecularly targeted therapy to be licensed in the US and Europe for treatment of advanced melanoma', 'Clinical trials to test the efficacy of vemurafenib in combination with immunomodulatory agents, such as ipilimumab, and MAPK kinase (MEK) inhibitors, such as GDC-0973, in the treatment of advanced melanoma are currently underway']

['Vemurafenib and dabrafenib are BRAF inhibitors that have been tested in clinical trials for treatment of melanoma patients.']

['Vemurafenib', 'Dabrafenib']

Can vitamin B1 deficiency cause encephalopathy?

["Wernicke's encephalopathy (WE) is a severe neurological syndrome caused by thiamine (vitamin B1) deficiency and clinically characterized by the sudden onset of mental status changes, ocular abnormalities, and ataxia", 'Wernicke encephalopathy (or Wernicke-Korsakoff encephalopathy) is a rarely diagnosed neurological disorder, which is caused by vitamin B1 deficiency', "Wernicke's encephalopathy (WE) is a potentially reversible yet serious neurological manifestation caused by vitamin B1(thiamine) deficiency", 'Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency', 'Both the thyrotoxicosis and a catabolic state due to the hyperemesis were thought to have induced a vitamin B1 deficiency, causing the Wernicke encephalopathy.', 'Wernicke encephalopathy (or Wernicke-Korsakoff encephalopathy) is a rarely diagnosed neurological disorder, which is caused by vitamin B1 deficiency.', 'Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency.', "Wernicke's encephalopathy is a neurological disorder caused by thiamine (vitamin B1) deficiency characterized by vertigo, ataxia, and mental confusion.", "Wernicke's encephalopathy (WE) is caused by thiamine (vitamin B1) deficiency and most commonly found in individuals with chronic alcoholism and malnutrition.", "Wernicke's encephalopathy (WE) is an acute neurological disease resulting from thiamine (vitamin B1) deficiency.", 'Post-mortem findings demonstrate that thiamine (vitamin B1) deficiency sufficient to cause irreversible brain damage is not diagnosed ante mortem in 80-90% of these patients.', "Wernicke's encephalopathy is an acute neuropsychiatric disorder, due to thiamine (vitamin B1) deficiency.", "Wernicke's encephalopathy (WE) is a severe neurological syndrome caused by thiamine (vitamin B1) deficiency and clinically characterized by the sudden onset of mental status changes, ocular abnormalities, and ataxia.", "Wernicke's encephalopathy, a pathology caused by vitamin B1 (thiamin) deficiency, is often difficult to diagnose and can lead to severe cognitive sequels if left untreated.", "Wernicke's encephalopathy-Korsakoff syndrome (WE-KS) is common in alcoholics, caused by thiamine deficiency (TD; vitamin B1) and associated with lesions to the thalamus (THAL).", 'Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency', 'Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke's encephalopathy (WE)', "Wernicke's encephalopathy is caused by thiamin deficiency and can be recognized by severe neurological symptoms that are occasionally accompanied by systemic signs. ", "INTRODUCTION: Wernicke's encephalopathy, a pathology caused by vitamin B1 (thiamin) deficiency, is often difficult to diagnose and can lead to severe cognitive sequels if left untreated. ", 'OBSERVATION: We report a case of encephalopathy due to dual vitamin deficiency of both thiamine (vitamin\xa0B1) and niacin (vitamin\xa0PP) in an 80-year-old women, hospitalized for severe sepsis caused by aspiration pneumonia. ', "Acute Wernicke's encephalopathy (WE) is caused by profound vitamin B1 (thiamine) deficiency and commonly presents with the classic clinical triad of mental confusion, ataxia, and ophthalmoplegia. ", '[Wernicke´s encephalopathy and polyneuropathy associated with vitamin B complex deficiency after a bariatric surgery].', "BACKGROUND: Thiamine deficiency in patients who abuse alcohol can cause Wernicke's encephalopathy (WE). ", 'Wernicke encephalopathy--a debilitating acute or subacute neurological disorder-is caused by a deficiency in thiamine (vitamin B(1)). ', "Wernicke's encephalopathy is a serious neurological manifestation of vitamin B1 deficiency.", 'Both the thyrotoxicosis and a catabolic state due to the hyperemesis were thought to have induced a vitamin B1 deficiency, causing the Wernicke encephalopathy.', 'Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency.', 'Wernicke encephalopathy (or Wernicke-Korsakoff encephalopathy) is a rarely diagnosed neurological disorder, which is caused by vitamin B1 deficiency.', "Wernicke's encephalopathy is a neurological disorder caused by thiamine (vitamin B1) deficiency characterized by vertigo,", 'Post-mortem findings demonstrate that thiamine (vitamin B1) deficiency sufficient to cause irreversible brain damage is not diagnosed ante mortem in 80-90% of these patients. The causes of vitamin deficiency are reviewed with special attention to the inhibition of oral thiamine hydrochloride absorption in man caused by malnutrition present in alcoholic patients or by the direct effects of ethanol on intestinal transport.', "Wernicke's encephalopathy is a serious neurologic disorder caused by vitamin-B1 or thiamine deficiency.", "Wernicke's encephalopathy results from thiamine (vitamin B1) deficiency. Common causes include alcoholism and gastric disorders.", "Wernicke's encephalopathy is a neurological disorder caused by thiamine (vitamin B1) deficiency characterized by vertigo, ataxia, and mental confusion.", "Wernicke's encephalopathy (WE) is caused by thiamine (vitamin B1) deficiency and most commonly found in individuals with chronic alcoholism and malnutrition.", 'Post-mortem findings demonstrate that thiamine (vitamin B1) deficiency sufficient to cause irreversible brain damage is not diagnosed ante mortem in 80-90% of these patients.', "Wernicke's encephalopathy, a pathology caused by vitamin B1 (thiamin) deficiency, is often difficult to diagnose and can lead to severe cognitive sequels if left untreated."]

["Wernicke's encephalopathy (WE) is a severe neurological syndrome caused by thiamine (vitamin B1) deficiency and clinically characterized by the sudden onset of mental status changes, ocular abnormalities, and ataxia. It is commonly associated with heavy alcohol consumption. Other clinical associations are with hyperemesis gravidarum (HG), starvation, and prolonged intravenous feeding.", "Wernicke's encephalopathy (WE) is a severe neurological syndrome caused by thiamine (vitamin B1) deficiency and clinically characterized by the sudden onset of mental status changes, ocular abnormalities, and ataxia"]

['yes']

Describe mechanism of action of Eteplirsen?

['Eteplirsen (Exondys\xa051) is an antisense oligonucleotide designed to induce exon 51 skipping that is developed by Sarepta Therapeutics. Intravenous eteplirsen has received accelerated approval from the US FDA for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping.', 'The first AON (eteplirsen) has recently received accelerated approval by the Food and Drug Administration in the US.', 'Currently, the most promising potential drugs are the exon-skipping agents eteplirsen and drisapersen.', 'OBJECTIVE: In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51.', 'We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. ', 'Exon skipping quantification by quantitative reverse-transcription polymerase chain reaction in Duchenne muscular dystrophy patients treated with the antisense oligomer eteplirsen.', 'We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection. ', 'To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD).', 'In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51.', "The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT).DMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n\u2009=\u20094/group).", 'Here we describe the development of a Taqman quantitative (q)RT-PCR assay to quantify exon skipping and highlight its use to determine the levels of exon skipping in DMD patients treated intramuscularly with a morpholino AO to skip exon 51, eteplirsen (AVI-4658).', 'The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.<CopyrightInformation>© 2016 The Authors.', 'We previously conducted a proof of principle; dose escalation study in Duchenne muscular dystrophy (DMD) patients using the morpholino splice-switching oligonucleotide AVI-4658 (eteplirsen) that induces skipping of dystrophin exon 51 in patients with relevant deletions, restores the open reading frame and induces dystrophin protein expression after intramuscular (i.m.) injection.']

['Eteplirsen (Exondys 51) is an antisense oligonucleotide designed to induce exon 51 skipping. Eteplirsen is approved for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene amenable to exon 51 skipping.']

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List features of the Perry syndrome.

['BACKGROUND: Depression, parkinsonism, and hypoventilation (Perry syndrome) or familial motor neuron disease have been linked to mutations in dynactin P150(Glued) (DCTN1).', 'BACKGROUND: Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation.', 'CONCLUSIONS AND RELEVANCE: Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. ', 'OBJECTIVES: Perry syndrome consists of autosomal dominant Parkinsonism, depression, weight loss, and central hypoventilation.', 'A patient with a mood disorder and a Parkinsonian syndrome with frontal cognitive impairment thought to resemble progressive supranuclear palsy defied precise diagnosis until the development of respiratory compromise, prompting consideration of the diagnosis of Perry syndrome.', 'Perry syndrome is a familial parkinsonism associated with central hypoventilation, mental depression, and weight loss. ', 'Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation', 'Perry syndrome is a familial parkinsonism associated with central hypoventilation, mental depression, and weight loss', 'Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure', 'Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. ']

['Perry syndrome is a familial parkinsonism associated with central hypoventilation, mental depression, and weight loss.']

['parkinsonism', 'central hypoventilation', 'depression', 'weight loss']

Which is the mechanism used for synthesis of a highly functional N-truncated dystrophin isoform that attenuates dystrophinopathy?

['Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice', 'amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible', 'However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin.', 'Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice.', 'We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice.', 'However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin', 'We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice', 'However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. ', 'We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. ', 'However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin.', 'We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice.', 'amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin.', 'However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin.', 'Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice.']

['Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice', 'Alternative translation initiation beginning in DMD exon 6 with the use of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible leads to expression of a highly functional N-truncated dystrophin isoform which is able to ameliorate disease severity.', 'Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice ']

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How is MicroRNA let-7a potentially useful as a marker for selection of paclitaxel in ovarian cancer management?

[' in the carcinogenesis of ovarian cancer through deregulation of cell proliferation. They may be novel biomarkers for early detection or therapeutic targets of ovarian cancer", "MicroRNA let-7a: a potential marker for selection of paclitaxel in ovarian cancer management", " The study suggests that the beneficial impact of the addition of paclitaxel on EOC survival was significantly linked to let-7a levels, and that miRNAs such as let-7a may be a useful marker for selection of chemotherapeutic agents in EOC management", "miR-200c has potential as a predictor of survival, and is a biomarker of relapse, in stage I EOC", "MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancer", " our results strongly suggest that let-7i might be used as a therapeutic target to modulate platinum-based chemotherapy and as a biomarker to predict chemotherapy response and survival in patients with ovarian cancer", "miRNAs-21, 92 and 93 are known oncogenes with therapeutic and biomarker potential", "Serum miR-132, miR-26a, let-7b, and miR-145 could be considered as potential candidates as novel biomarkers in serous ovarian cancer"]']

The study suggests that the beneficial impact of the addition of paclitaxel on EOC survival was significantly linked to let-7a levels, and that miRNAs such as let-7a may be a useful marker for selection of chemotherapeutic agents in EOC management

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Which is the protein (antigen) targeted by anti-Vel antibodies in the Vel blood group?

['Anti-Vel is an uncommon antibody to a high-prevalence antigen. Its clinical significance and management in the prenatal setting are not well characterized.', 'Haemolytic disease of the newborn because of rare anti-Vel.', 'A haemolytic anti-Vel was detected in the tube test. In contrast, the particular commercial gel test kit used did not reveal the haemolytic property or specificity of the antibody.']

['Disruption of SMIM1 causes the Vel- blood type. The protein carrying the Vel blood group antigen was biochemically purified from red blood cell membranes. Mass spectrometry-based de novo peptide sequencing identified this protein to be small integral membrane protein 1 (SMIM1), a previously uncharacterized single-pass membrane protein. Expression of SMIM1 cDNA in Vel- cultured cells generated anti-Vel cell surface reactivity, confirming that SMIM1 encoded the Vel blood group antigen. (PMID: 23505126)', 'SMIM1']

['SMIM1']

Is NADPH oxidase 5 expressed in rodents?

['Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5(pod+)). ', 'The NADPH oxidase 5 (NOX5) gene is present in humans but not rodents. ', 'The data document that the NOX5 gene was expressed in cells of lagomorphs unlike rodents, making the rabbit an interesting model to study NOX5 functions.', 'Nox5 was lost in rodents, and Nox3, which functions in the inner ear in gravity perception, emerged the most recently, corresponding to full-time adaptation of vertebrates to land. ', 'NOX expression patterns in animals are complex and ancestral NOXes, NOX5-like isoforms and DUOXes are generally found. But there are exceptions; for example rodents lack NOX5 and Caenorhabditis elegans expresses only DUOXes.', 'The NADPH oxidase 5 (NOX5) gene is present in humans but not rodents.', 'The NADPH oxidase 5 (NOX5) gene is present in humans but not rodents', 'NADPH oxidases are the major sources of reactive oxygen species in cardiovascular, neural, and kidney cells. The NADPH oxidase 5 (NOX5) gene is present in humans but not rodents.', 'But there are exceptions; for example rodents lack NOX5 and Caenorhabditis elegans expresses only DUOXes.', 'Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5(pod+)).', 'The data document that the NOX5 gene was expressed in cells of lagomorphs unlike rodents, making the rabbit an interesting model to study NOX5 functions.', 'The most recently identified member of the Nox family, Nox5, has for the most part been overlooked in renal disease, partly owing to its absence from the rodent genome.']

['No, NADPH oxidase 5 is not expressed in rodents, because the gene is absent.']

['no']

Please list 2 treatments for a torn rotator cuff

['To compare clinical outcomes between conventional en masse repair and separate double-layer double-row repair for the treatment of delaminated rotator cuff tears', ' To systematically review and evaluate the effectiveness of grafts in the augmentation of large-to-massive rotator cuff repairs', 'To evaluate the effectiveness of arthroscopic debridement (DB), partial (PR), and complete repair (CR) for massive rotator cuff tears (mRCT) ', 'The purpose was to investigate whether surgical repair earlier or later than 3\xa0months after injury may result in similar outcomes and patient satisfaction', 'double-row (DR) and knotless transosseous-equivalent (KL-TOE)', ' arthroscopic subacromial decompression and rotator-cuff debridement; the other comparable group of 23 patients had open repair and acromioplasty']

['to compare clinical outcomes between conventional en masse repair and separate double-layer double-row repair for the treatment of delaminated rotator cuff tears.', 'Surgical repair earlier or later than 3 months after injury may result in similar outcomes and patient satisfaction.']

['early surgery', 'later surgery(3 months after injury)', 'en masse repair', 'double-layer double-row repair', 'arthroscopic', 'open', 'knotless transosseous-equivalent']

What is the role of RhoA in bladder cancer?

['Alterations in RhoA, RhoB, RhoC, Rac1 and Cdc42 expression play a significant role in the genesis and progression of UCC of the urinary bladder.', 'Published reports suggest that elevated RhoA/Rho-kinase signaling plays a role in the development of benign prostatic hyperplasia, erectile dysfunction, kidney failure, ejaculation disorders, prostate and bladder cancer initiation, and eventual metastasis.', 'The suppressive effect of Rho kinase inhibitor, Y-27632, on oncogenic Ras/RhoA induced invasion/migration of human bladder cancer TSGH cells', 'Our results provide evidence that Ras-induced RhoA and NF-kappaB activation was involved in the invasion/migration of bladder cancer.', 'Increased RHOA expression was more common in grade 3 than in grade 2 tumors (P = 0.016).', 'RhoA, RhoC, and ROCK were more abundant in tumors and metastatic lymph nodes than in nontumor bladder and uninvolved lymph nodes (P < 0.0001).', 'High RhoA, RhoC, and ROCK expression were related to poor tumor differentiation (P < 0.05, P < 0.01, and P < 0.01, respectively), muscle invasion (P < 0.001), and lymph node metastasis (P < 0.05).', 'Kaplan-Meier plots linked high RhoA, RhoC, and ROCK protein expression to shortened disease-free and overall survival (P < 0.0001).', 'By univariate analysis, high RhoA, RhoC, and ROCK protein expression predicted shortened disease-free and overall survival (P < 0.0001).', 'Overall survival in tumors invading muscle (T2 to T4; 44 patients) was significantly influenced by RhoA, RhoC, and ROCK in a Kaplan-Meier analysis (P < 0.0001, P < 0.0001, and P < 0.01, respectively).']

['In urinary bladder cancer, RhoA was more commonly found to be activated in the later stages of the disease. This activation was related to poor tumor differentiation, muscle invasion, lymph node metastasis, and shortened disease-free and overall survival.']

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What is the the Menzerath-Altmann law?

['Recently, a random breakage model has been proposed to explain the negative correlation between mean chromosome length and chromosome number that is found in many groups of species and is consistent with Menzerath-Altmann law, a statistical law that defines the dependency between the mean size of the whole and the number of parts in quantitative linguistics', 'The random breakage and variants keeping genome size and chromosome number independent raise no serious objection to the relevance of correlations consistent with Menzerath-Altmann law across taxonomic groups and the possibility of a connection between human language and genomes through that law', 'The random breakage and variants keeping genome size and chromosome number independent raise no serious objection to the relevance of correlations consistent with Menzerath-Altmann law across taxonomic groups and the possibility of a connection between human language and genomes through that law.', 'Recently, a random breakage model has been proposed to explain the negative correlation between mean chromosome length and chromosome number that is found in many groups of species and is consistent with Menzerath-Altmann law, a statistical law that defines the dependency between the mean size of the whole and the number of parts in quantitative linguistics.', 'The random breakage and variants keeping genome size and chromosome number independent raise no serious objection to the relevance of correlations consistent with Menzerath-Altmann law across taxonomic groups and the possibility of a connection between human language and genomes through that law.']

['Recently, a random breakage model has been proposed to explain the negative correlation between mean chromosome length and chromosome number that is found in many groups of species and is consistent with Menzerath-Altmann law, a statistical law that defines the dependency between the mean size of the whole and the number of parts in quantitative linguistics. The random breakage and variants keeping genome size and chromosome number independent raise no serious objection to the relevance of correlations consistent with Menzerath-Altmann law across taxonomic groups and the possibility of a connection between human language and genomes through that law. ', 'Recently, a random breakage model has been proposed to explain the negative correlation between mean chromosome length and chromosome number that is found in many groups of species and is consistent with Menzerath-Altmann law, a statistical law that defines the dependency between the mean size of the whole and the number of parts in quantitative linguistics', 'Menzerath-Altmann law is a statistical law that defines the dependency between the mean size of the whole and the number of parts in quantitative linguistics.', 'Recently, a random breakage model has been proposed to explain the negative correlation between mean chromosome length and chromosome number that is found in many groups of species and is consistent with Menzerath-Altmann law, a statistical law that defines the dependency between the mean size of the whole and the number of parts in quantitative linguistics ']

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What is the connection between furin and hepcidin?

['Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. ', 'Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin.', 'Analysis of primary hepatocytes from mice lacking furin, PC5, PACE4, or PC7 revealed that hepcidin, which limits iron availability in the circulation, is specifically generated by furin and not by PC7. ', 'Among the PC family members, only furin activates hepcidin in hepatocytes, and uniquely the full-length membrane-bound PC7 can directly shed hTfR1 by cleavage at Arg100 ↓.', 'The human hepcidin gene contains three exons that encode a 72-aa precursor (pro-hepcidin) with a characteristic furin cleavage site immediately N-terminal to the 25-aa major hepcidin species found in plasma and urine [3]', 'Pro-hepcidin is unable to degrade the iron exporter ferroportin unless maturated by a furin-dependent process.', 'The iron-regulatory peptide hepcidin is synthesized in the liver as an 84-aa pre-pro-hormone maturated by proteolysis through a consensus furin cleavage site to generate the bioactive 25-aa peptide secreted in the circulation. This peptide regulates iron export from enterocytes and macrophages by binding the membrane iron exporter, ferroportin, leading to its degradation. ', 'Our results demonstrate that pro-hepcidin lacks biological activity, unless fully maturated by a furin-dependent process to yield the bioactive 25-aa peptide.', 'Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin.', 'Hepcidin is encoded as an 84 amino acid prepropeptide containing a typical N-terminal 24 amino acid endoplasmic reticulum targeting signal sequence, and a 35 amino acid proregion (pro) with a consensus furin cleavage site immediately followed by the C-terminal 25 amino acid bioactive iron-regulatory hormone (mature peptide). ', 'In conclusion, the hepatic prohormone convertase furin mediates the posttranslational processing of hepcidin.', 'In conclusion, the hepatic prohormone convertase furin mediates the posttranslational processing of hepcidin.', 'Furin in turn may control hepcidin expression.', 'Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7.', 'BACKGROUND/AIMS: The iron-regulatory peptide hepcidin is synthesized in the liver as an 84-aa pre-pro-hormone maturated by proteolysis through a consensus furin cleavage site to generate the bioactive 25-aa peptide secreted in the circulation.', 'Furin activity was also modulated using furin inhibitor or siRNA-mediated furin mRNA knockdown.RESULTS: We found that pro-hepcidin could fully induce ferroportin degradation, but only when processed by furin to generate the mature hepcidin-25 form.', 'Furin activity was also modulated using furin inhibitor or siRNA-mediated furin mRNA knockdown.We found that pro-hepcidin could fully induce ferroportin degradation, but only when processed by furin to generate the mature hepcidin-25 form', 'CONCLUSIONS: These results demonstrate the key role of the convertases Furin, PACE4, PC5 and/or PC7 in the generation and secretion of active hepcidin and suggest that the control of hepcidin processing as a potential therapeutic/diagnostic strategy in hepcidin-related disorders such as haemochromatosis, inflammatory diseases, anaemia and cancer.', 'BACKGROUND/AIMS: The iron-regulatory peptide hepcidin is synthesized in the liver as an 84-aa pre-pro-hormone maturated by proteolysis through a consensus furin cleavage site to generate the bioactive 25-aa peptide secreted in the circulation. ', 'CONCLUSIONS: Our results demonstrate that pro-hepcidin lacks biological activity, unless fully maturated by a furin-dependent process to yield the bioactive 25-aa peptide.', 'The iron-regulatory peptide hepcidin is synthesized in the liver as an 84-aa pre-pro-hormone maturated by proteolysis through a consensus furin cleavage site to generate the bioactive 25-aa peptide secreted in the circulation.', 'Furin activity was also modulated using furin inhibitor or siRNA-mediated furin mRNA knockdown.We found that pro-hepcidin could fully induce ferroportin degradation, but only when processed by furin to generate the mature hepcidin-25 form.', 'Furin in turn may control hepcidin expression.', 'Analysis of primary hepatocytes from mice lacking furin, PC5, PACE4, or PC7 revealed that hepcidin, which limits iron availability in the circulation, is specifically generated by furin and not by PC7.', 'Furthermore, the mutated version of pro-hepcidin was completely inefficient at degrading ferroportin in macrophages.CONCLUSIONS: Our results demonstrate that pro-hepcidin lacks biological activity, unless fully maturated by a furin-dependent process to yield the bioactive 25-aa peptide.', 'However, the activity of the pro-peptide on ferroportin degradation has never been addressed.METHODS: To answer this question, we produced recombinant pro-hepcidin, both the wild-type form and a furin cleavage site mutant, and tested their activity on ferroportin levels in macrophagic J774 cells.', 'Furin in turn may control hepcidin expression..', 'We found that pro-hepcidin could fully induce ferroportin degradation, but only when processed by furin to generate the mature hepcidin-25 form.', 'Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin.', 'Implication of the proprotein convertases in iron homeostasis: proprotein convertase 7 sheds human transferrin receptor 1 and furin activates hepcidin.', 'Pro-hepcidin is unable to degrade the iron exporter ferroportin unless maturated by a furin-dependent process.', 'These results demonstrate the key role of the convertases Furin, PACE4, PC5 and/or PC7 in the generation and secretion of active hepcidin and suggest that the control of hepcidin processing as a potential therapeutic/diagnostic strategy in hepcidin-related disorders such as haemochromatosis, inflammatory diseases, anaemia and cancer..']

['The iron-regulatory peptide hepcidin is synthesized in the liver as an 84-aa pre-pro-hormone maturated by proteolysis through a consensus furin cleavage site to generate the bioactive 25-aa peptide secreted in the circulation. The hepatic prohormone convertase furin mediates the posttranslational processing of hepcidin.']

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Which peak calling algorithm employs mixture model clustering under the hood?

["We developed JAMM (Joint Analysis of NGS replicates via Mixture Model clustering): a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks. JAMM is a universal peak finder that is applicable to different types of datasets. We show that JAMM is among the best performing peak finders in terms of site detection accuracy and in terms of accurate determination of enrichment sites widths. In addition, JAMM's replicate integration improves peak spatial resolution, sorting and peak finding accuracy."]

['JAMM (Joint Analysis of NGS replicates via Mixture Model clustering) is a peak finder that can integrate information from biological replicates, determine enrichment site widths accurately and resolve neighboring narrow peaks. JAMM is a universal peak finder that is applicable to different types of datasets.']

['JAMM']

List drugs withdrawn from the market for cardiovascular adverse events.

[' rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk.', 'A common over-the-counter (OTC) non-opioid antitussive drug, clobutinol, was recently withdrawn from the market due to its potential to induce cardiac arrhythmias by a blockade of the potassium channel coded by the human ether-à-go-go-related gene (hERG).', 'n. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events', 'Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity.', 'Sibutramine was associated with an increase in major adverse cardiovascular events in the Sibutramine Cardiovascular Outcomes (SCOUT) trial and it was withdrawn from the market in 2010', 'The safety of the most popular agent, aprotinin, has been challenged, and it was withdrawn from world markets in May 2008 because of concerns that it increased the risk of cardiovascular complications and death.To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood cell (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death.We searched: the Cochrane Injuries Groups Specialised Register (July 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 1980 to July 2010.', 'The safety of the most popular agent, aprotinin, has been challenged, and it was withdrawn from world markets in May 2008 because of concerns that it increased the risk of cardiovascular complications and death.To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood cell (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death.We searched: the Cochrane Injuries Groups Specialised Register (July 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 1980 to July 2010.', 'Rofecoxib and valdecoxib have been withdrawn from the market worldwide due to safety concerns (most importantly for cardiovascular adverse events) and lumiracoxib has been withdrawn in many countries due to liver toxicity', 'In the SCOUT (Sibutramine Cardiovascular OUTcomes) study, sibutramine increased serious cardiovascular events, such as stroke or myocardial infarction, compared with placebo, and was consequently withdrawn from the market', 'Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. ', 'Rofecoxib and valdecoxib have been withdrawn from the market worldwide due to safety concerns (most importantly for cardiovascular adverse events) and lumiracoxib has been withdrawn in many countries due to liver toxicity.', 'Sertindole , first withdrawn from the market for cardiovascular safety concerns, is currently available in many countries.', 'In the SCOUT (Sibutramine Cardiovascular OUTcomes) study, sibutramine increased serious cardiovascular events, such as stroke or myocardial infarction, compared with placebo, and was consequently withdrawn from the market. The lesson learnt from this is the importance of patient selection, limiting the duration of treatment and stopping treatment in non-responders. Currently, phentermine and amfepramone (diethylpropion) are approved for short-term treatment of obesity (up to 3 months) and orlistat is approved for longer-term treatment; however, the gastrointestinal adverse effects of orlistat may be intolerable for some patients.', 'BACKGROUND: Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events.', 'In the SCOUT (Sibutramine Cardiovascular OUTcomes) study, sibutramine increased serious cardiovascular events, such as stroke or myocardial infarction, compared with placebo, and was consequently withdrawn from the market.', 'Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity.', ' Rofecoxib, a selective cyclo-oxygenase (COX)-2 inhibitor, was a widely marketed drug that was used for relief of pain and inflammation in arthritic conditions. It was withdrawn from the market worldwide in September 2004 because of an increased risk of cardiovascular events. ']

['Over the years, a number of different drugs have been withdrawn for Cardiotoxicity. Drugs like Clobutinol, that induce cardiac arrhythmias by a blockade of the potassium channel coded by the hERG channel, sibutramine for weight loss and Cox2 inhibitors, Rofecoxib and Valdecoxib have been withdrawn from the market.']

['Rofecoxib', 'Valdecoxib', 'Sibutramine', 'Clobutinol', 'Sertindole', 'aprotinin']

What is the functional role of the protein Drp1?

['dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission,', 'dynamin-related protein 1 (DRP1), a protein required for mitochondrial network division.', 'dynamin-related protein 1 (Drp1)-mediated mitochondrial fission', 'Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1),', 'Drp1 is a dynamin-like GTPase that mediates mitochondrial and peroxisomal division in a process dependent on self-assembly and coupled to GTP hydrolysis. ', 'Mitochondrial fission requires the dynamin GTPase Drp1, which assembles in a ring around the mitochondrion and appears to constrict both outer and inner mitochondrial membranes.', 'DRP1; a mitochondrial fission protein', 'Mitochondrial morphology is primarily controlled by the activation of dynamin-related proteins including dynamin-related protein 1 (Drp1), which promotes mitochondrial fission. ', 'The change in mitochondrial morphology was caused by downregulation of the expression of Fis1 and Drp1, two proteins regulating mitochondrial fission.', 'Furthermore, overexpression of the fission protein Drp1 (dynamin-related protein 1) or knocking down of the fusion protein OPA1 (optical atrophy 1) suppressed PINK1 RNAi-induced mitochondrial morphological defect, and overexpression of PINK1 or Parkin suppressed the elongated mitochondria phenotype caused by Drp1 RNAi.', 'These results collectively indicate that ER-specific BNIP1 plays an important role in mitochondrial dynamics by modulating the mitochondrial fission protein Drp1 in a BH3 domain-dependent fashion.', 'In the present study, we found a marked upregulation of mitochondrial fission protein dynamin-related protein 1 (Drp1) expression in human invasive breast carcinoma and metastases to lymph nodes.', 'Mitochondrial remodeling was associated with increased proximity between Rab11a and mitochondrial membranes, changes in fusion-fission dynamics, and mitochondrial relocalization of the fission factor dynamin-related protein 1 (Drp1), which was regulated by the Rab11a effector protein FIP1/RCP.', 'Functional analysis demonstrated that BNIP1 expression increased dynamin-related protein 1 (Drp1) expression followed by the mitochondrial translocation of Drp1 and subsequent mitochondrial fission.', 'Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.', 'In this study the role of the mitochondrial fission protein, Drp1 during Shigella infection in HeLa cells was examined', 'In this study, we investigate the role of mitochondrial fission factor dynamin-related protein 1 (Drp1) in myogenic differentiation', 'Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus', 'Functional analysis demonstrated that BNIP1 expression increased dynamin-related protein 1 (Drp1) expression followed by the mitochondrial translocation of Drp1 and subsequent mitochondrial fission', 'These results collectively indicate that ER-specific BNIP1 plays an important role in mitochondrial dynamics by modulating the mitochondrial fission protein Drp1 in a BH3 domain-dependent fashion', 'Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1.', 'Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1.', 'This novel function for DRP1 is distinct from its recognized role in regulating mitochondrial fission. ', "Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage.", 'SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle.', 'Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1.', 'We highlight posttranslational modifications of the mitochondrial fission protein Drp1, for which these regulatory mechanisms are best characterized.', 'Furthermore, overexpression of the fission protein Drp1 (dynamin-related protein 1) or knocking down of the fusion protein OPA1 (optical atrophy 1) suppressed PINK1 RNAi-induced mitochondrial morphological defect, and overexpression of PINK1 or Parkin suppressed the elongated mitochondria phenotype caused by Drp1 RNAi. Functionally, PINK1 knockdown and overexpression had opposite effects on dendritic spine formation and neuronal vulnerability to excitotoxicity.', 'In this study the role of the mitochondrial fission protein, Drp1 during Shigella infection in HeLa cells was examined.']

['Drp1 is involved in the regulation of mitochondrial fission.', 'Dynamin-related protein 1 (Drp1) mediates mitochondrial fission.']

['mitochondrial fission']

List two most common symptoms of Aagenaes syndrome.

['Aagenaes syndrome, also called lymphoedema cholestasis syndrome 1 (LSC1), is characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age and severe chronic lymphoedema, mainly affecting the lower extremities. ', 'In this study, 17 out of 20 Norweigian adult patients with lymphedema cholestasis syndrome 1 (LCS1)/Aagenaes syndrome were examined. The patients exhibited lymphedema and sporadic cholestasis.', 'BACKGROUND: Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb.', 'The disease was thought to be caused by a congenital cholestatic syndrome associated with intermittent oedema in childhood, resembling the rare Aagenaes syndrome.', 'Do patients with lymphoedema cholestasis syndrome 1/Aagenaes syndrome need dietary counselling outside cholestatic episodes?', 'BACKGROUND & AIMS: Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic.', 'Aagenaes syndrome, also called Lymphedema Cholestasis Syndrome (LSC 1), is a form of idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities. ', 'Aagenaes syndrome, also called Lymphedema Cholestasis Syndrome (LSC 1), is a form of idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities.', 'Parent-child transmission of infantile cholestasis with lymphoedema (Aagenaes syndrome).', 'Mapping of the locus for cholestasis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromosome 15q.', 'Lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome) is the only known form of hereditary lymphedema associated with cholestasis. ', 'OBJECTIVE: To investigate the prognosis of liver disease in Aagenaes syndrome (lymphoedema cholestasis syndrome 1 (LCS1)), which is an autosomal recessive inherited syndrome consisting of neonatal cholestasis with intermittent cholestatic episodes in childhood into adulthood and development of lymphoedema. ', 'BACKGROUND: Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. ', '[Aagenaes syndrome--lymphedema and intrahepatic cholestasis].', 'Parent-child transmission of infantile cholestasis with lymphoedema (Aagenaes syndrome).', 'Hereditary lymphedema, characteristics, and variations in 17 adult patients with lymphedema cholestasis syndrome 1/Aagenaes syndrome.', 'Lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome) is the only known form of hereditary lymphedema associated with cholestasis.']

['Aagenaes syndrome, also called lymphoedema cholestasis syndrome 1, is characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age and severe chronic lymphoedema, mainly affecting the lower extremities.']

['intrahepatic cholestasis', 'lymphoedema']

What is the genomic structure of the FAA (FANCA) gene?

['In the present study we describe the genomic structure of the FAA gene. The gene contains 43 exons spanning approximately 80 kb as determined by the alignment of four cosmids and the fine localization of the first and the last exons in restriction fragments of these clones. Exons range from 34 to 188 bp', "Sequence analysis of the 5' region upstream of the putative transcription start site showed no obvious TATA and CAAT boxes, but did show a GC-rich region, typical of housekeeping genes"]

["The FAA (FANCA) gene contains 43 exons spanning approximately 80 kb. Exons range from 34 to 188 bp, whereas sequence analysis of the 5' region upstream of the putative transcription start site showed no obvious TATA and CAAT boxes, but did show a GC-rich region, typical of housekeeping genes."]

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what is the role of erythropoietin in cardiac regeneration after myocardial infarction?

['EPO in patients with STEMI treated with PCI is associated with an increase in diameter stenosis that is not associated with circulating progenitor cells.', 'The cytokines granulocyte colony-stimulating factor, erythropoietin, and stem cell factor may play a role in helping to stimulate cell regeneration under normal physiologic conditions and in patients with myocardial injury. ', 'In preclinical study, G-CSF and erythropoietin improved cardiac function and perfusion by angiomyogenesis and protection of cardiomyocytes in myocardial infarction. However, results from recent clinical trials did not support beneficial effects of cytokine therapy with G-CSF or erythropoietin alone in patients with myocardial infarction.', 'Epo overexpression enhances the cellular regenerative properties of MSCs by both autocrine and paracrine pathways.', 'Transplantation of MSC combined with cytokine EPO is superior to either of the monotherapy approach for angiomyogenesis and cardiac function recovery.']

['In preclinical studies, erythropoietin improved cardiac function and perfusion by angiomyogenesis and protection of cardiomyocytes in myocardial infarction indicating that erythropoietin may play a role in the stimulation of cell regeneration under normal physiologic conditions and in patients with myocardial injury. Epo overexpression was found to enhance the cellular regenerative properties of MSCs by both autocrine and paracrine pathways. However, results from recent clinical trials did not support beneficial effects of cytokine therapy with erythropoietin in patients with myocardial infarction.']

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What tissue is commonly affected in Marfan's syndrome

['Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents ', 'Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome.', 'Marfans syndrome is an Autosomal dominant disorder of the connective tissues resulting in abnormalities of the musculoskeletal system, cardiovascular system and eyes.', 'Marfan syndrome (MFS) is a systemic disorder of the connective tissue with pleiotropic manifestations due to heterozygous FBN1 mutations and consequent upregulation of TGFβ signaling in affected tissues', 'Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling', 'Marfan syndrome is an autosomal dominant connective tissue disorder commonly due to mutation of the fibrillin-1 (FBN-1) gene that causes disruption of elastic fibers in large- and medium-size arteries and predisposes to aneurysm formation and arterial dissection', 'Children affected by the Marfan syndrome carry a mutation in one of their two copies of the gene that encodes the connective tissue protein fibrillin-1', "Marfan's syndrome is an autosomal dominant disorder of connective tissue, commonly involving the cardiovascular, ocular, and skeletal systems. ", 'Marfan syndrome is an autosomal dominant connective tissue disorder commonly due to mutation of the fibrillin-1 (FBN-1) gene that causes disruption of elastic fibers in large- and medium-size arteries and predisposes to aneurysm formation and arterial dissection. ', "Marfan's syndrome is an autosomal dominant disorder of connective tissue, commonly involving the cardiovascular, ocular, and skeletal systems.", "Marfan's syndrome is a heritable connective tissue disorder that has been associated with intracranial aneurysms.", "Marfan's syndrome is an inherited disorder of connective tissue associated with characteristic abnormalities of the skeletal, ocular, and cardiovascular systems.", "Therefore, Marfan's syndrome is termed a fibrillinopathy, along with other connective tissue disorders with subtle differences in clinical manifestations.", 'The Marfan syndrome is an inherited disorder of the connective tissue which is mainly caused by a mutation in the fibrillin-1 gene. ', 'Marfan syndrome is an inherited multisystemic connective-tissue disease that is caused by a mutation of the fibrillin-1 gene. ', ' Mutations in the fibrillin-1 gene give rise to Marfan syndrome, a connective tissue disorder with clinical complications in the cardiovascular, skeletal, ocular and other organ systems.']

['Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents ', 'Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents', 'Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents. ', 'Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents.', 'marfan syndrome (ms) is a connective tissue disorder that affects thousands of adolescents .']

['connective tissue']

Which domain of TIA-1 is necessary for stress granule assembly?

['Tia1/Pub1 is a stress granule component carrying a Q/N-rich prion domain', 'Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival', 'We report an unanticipated link between stress granules and the serine/threonine kinase RSK2. In stressed breast cells, endogenous RSK2 colocalizes in granules with TIA-1 and poly(A)-binding protein 1, and the sequestration of RSK2 and TIA-1 exhibits codependency. The RSK2 N-terminal kinase domain controls the direct interaction with the prion-related domain of TIA-1', 'Stress granule assembly is mediated by prion-like aggregation of TIA-1', 'TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells', 'The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs', 'Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress', 'Stress granule assembly is mediated by prion-like aggregation of TIA-1.', ' TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD).']

['TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells.']

['The glutamine-rich prion-related domain (PRD)']

Which disease(s) are caused by HEX A deficiency?

['Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder due to mutations in the HEXA gene resulting in a beta-hexosaminidase A (Hex A) deficiency. ', 'Rapid identification of HEXA mutations in Tay-Sachs patients.', 'Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A (HEX A) deficiency and neuronal accumulation of GM2 ganglioside.', 'Tay-Sachs disease is a genetically determined neurodegenerative disorder, resulting from mutations of the hexosaminidase (Hex) A gene coding for the alpha-subunit of beta-D-N-acetyl-hexosaminidase.', 'Tay-Sachs disease (TSD) results from mutations in HEXA that cause Hex A deficiency. ', 'Mutations in the HEX A gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), are the cause of Tay-Sachs disease as well as of juvenile, chronic, and adult GM2 gangliosidoses.']

['Mutations in the HEX A gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), are the cause of Tay-Sachs disease as well as of juvenile, chronic, and adult GM2 gangliosidoses.']

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Is thrombophilia related to increased risk of miscarriage?

['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']

['Thrombophilia has been 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. In particular there is an increased risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. When counseling white women with a history of preeclampsia, screening for thrombophilia can be useful for preconceptional counseling and pregnancy management.']

['yes']

Which R / bioconductor package is used for performing SNP enrichment analysis?

['traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals', 'Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD', 'we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD', 'Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD.', 'traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals.', 'traseR: an R package for performing trait-associated SNP enrichment analysis in genomic intervals.', 'Here, we present traseR, an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD.', 'The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor [email protected] Supplementary data are available at Bioinformatics online..']

['traseR is an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD.']

['traseR']

Which genes have been associated with Cerebral Cavernous Malformation?

['Cerebral cavernous malformations associated to meningioma: High penetrance in a novel family mutated in the PDCD10 gene', 'we outline a consistent association between PDCD10 mutations and a syndrome of CCMs with multiple meningiomas', 'Cerebral cavernous malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1, CCM2 or CCM3', 'To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients.METHODS: We analyzed the CCM1, CCM2, and CCM3 genes', 'Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 (also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs)', 'Surveying genetic variants and molecular phylogeny of cerebral cavernous malformation gene, CCM3/PDCD10', 'The three cerebral cavernous malformations (CCMs) genes namely CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 have been identified for which mutations cause cerebral cavernous malformations', 'At least 45% of families affected with cerebral cavernous malformations harbour a mutation in Krev interaction trapped-1 (Krit1) gene (cerebral cavernous malformation gene-1, CCM1).', 'Mutations in Krev1 interaction trapped gene 1 (KRIT1) cause cerebral cavernous malformation, an autosomal dominant disease featuring malformation of cerebral capillaries resulting in cerebral hemorrhage, strokes, and seizures.', 'KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.', 'Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.', 'Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations.', 'Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations.', 'These findings document a de novo germline mutation in Kritl gene that causes cerebral cavernous malformations.', 'Cerebral cavernous malformation is a common human vascular disease that arises due to loss-of-function mutations in genes encoding three intracellular adaptor proteins, cerebral cavernous malformations 1 protein (CCM1), CCM2, and CCM3.', 'Cerebral cavernous malformation is a common human vascular disease that arises due to loss-of-function mutations in genes encoding three intracellular adaptor proteins, cerebral cavernous malformations 1 protein (CCM1), CCM2, and CCM3', 'Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1).', 'Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene.', 'Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs).', 'Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10).', 'At least 45% of families affected with cerebral cavernous malformations harbour a mutation in Krev interaction trapped-1 (Krit1) gene (cerebral cavernous malformation gene-1,', 'Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.', 'A novel CCM1 mutation associated with multiple cerebral and vertebral cavernous malformations.', 'These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10).', 'CCM1 is caused by a mutation in the KRIT1 gene and CCM2 is caused by a mutation in the MGC4607 gene, while the gene for CCM3 is not yet identified.', 'Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1).', 'At least 45% of families affected with cerebral cavernous malformations harbour a mutation in Krev interaction trapped-1 (Krit1) gene (cerebral cavernous malformation gene-1, CCM1).', 'KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.']

['Loss-of-function mutations in genes encoding CCM1 (also known as KRIT1), CCM2 (also known as OSM and malcavernin) or CCM3 (also known as PDCD10) cause cerebral cavernous malformations (CCMs).']

['CCM1/KRIT1', 'CCM2/OSM/Malcavernin', 'CCM3/PDCD10']

List the components of a Replisome Progression Complex (RPC).

['This interaction requires the RPC components Mrc1 and Ctf4, both of which associate with a tetratricopeptide repeat (TPR) domain located at the amino terminus of Dia2', 'Here we show that SCF(Dia2) associates with the replisome progression complex (RPC) that assembles around the MCM2-7 helicase at DNA replication forks', 'We found previously that many regulatory proteins assemble around the MCM2-7 helicase at yeast replication forks to form the replisome progression complex (RPC), which might link MCM2-7 to other replisome components', 'Here, we show that the RPC associates with DNA polymerase alpha that primes each Okazaki fragment during lagging strand synthesis. Our data indicate that a complex of the GINS and Ctf4 components of the RPC is crucial to couple MCM2-7 to DNA polymerase alpha', 'Others have found recently that the Mrc1 subunit of RPCs binds DNA polymerase epsilon, which synthesises the leading strand at DNA replication forks', 'we show that the GINS (go ichi ni san) complex allows the MCM (minichromosome maintenance) helicase to interact with key regulatory proteins in large replisome progression complexes (RPCs) that are assembled during initiation and disassembled at the end of S phase', 'RPC components include the essential initiation and elongation factor, Cdc45, the checkpoint mediator Mrc1, the Tof1-Csm3 complex that allows replication forks to pause at protein-DNA barriers, the histone chaperone FACT (facilitates chromatin transcription) and Ctf4, which helps to establish sister chromatid cohesion. RPCs also interact with Mcm10 and topoisomerase I', 'During initiation, GINS is essential for a specific subset of RPC proteins to interact with MCM. GINS is also important for the normal progression of DNA replication forks, and we show that it is required after initiation to maintain the association between MCM and Cdc45 within RPCs', 'We found previously that many regulatory proteins assemble around the MCM2-7 helicase at yeast replication forks to form the replisome progression complex (RPC), which might link MCM2-7 to other replisome components.', 'Here we show that SCF(Dia2) associates with the replisome progression complex (RPC) that assembles around the MCM2-7 helicase at DNA replication forks [6].', 'Compared with wild type, hydroxyurea-treated ctf18жд cells exhibited increased chromatin association of replisome progression complex components including Cdc45, Ctf4, and GINS complex subunits, the polymerase processivity clamp PCNA and the single-stranded DNA-binding complex RPA.', 'The amino-terminal TPR domain of Dia2 tethers SCF(Dia2) to the replisome progression complex.', 'Ctf4 is a protein conserved in eukaryotes and a constituent of the replisome progression complex.', 'Eukaryotic GINS also links with other key proteins at the fork to maintain an active replisome progression complex.', 'Dia2 has previously been implicated in the control of replication and genome stability via its interaction with the replisome progression complex.', 'The Cdc45-MCM-GINS complex could constitute the core of a larger macromolecular structure that has been termed the "replisome progression complex".', 'FACT does not associate with the Mcm2-7 helicase at replication origins during G1 phase but is subsequently incorporated into the replisome progression complex independently of histone binding and uniquely among histone chaperones.', 'Our data indicate that a complex of the GINS and Ctf4 components of the RPC is crucial to couple MCM2-7 to DNA polymerase alpha.', 'Replisome progression complex links DNA replication to sister chromatid cohesion in Xenopus egg extracts.', 'On the basis of the physical interactions between AND-1 and DNA polymerases, we discuss a model to describe how replisome progression complex establishes sister chromatid cohesion.', 'The components of the replisome that preserve genomic stability by controlling the progression of eukaryotic DNA replication forks are poorly understood.', 'RPC components include the essential initiation and elongation factor, Cdc45, the checkpoint mediator Mrc1, the Tof1-Csm3 complex that allows replication forks to pause at protein-DNA barriers, the histone chaperone FACT (facilitates chromatin transcription) and Ctf4, which helps to establish sister chromatid cohesion.']

['RPC components include the essential initiation and elongation factor, Cdc45, the checkpoint mediator Mrc1, the Tof1-Csm3 complex that allows replication forks to pause at protein-DNA barriers, the histone chaperone FACT (facilitates chromatin transcription) and Ctf4, which helps to establish sister chromatid cohesion. RPCs also interact with Mcm10 and topoisomerase I.', 'RPCs also interact with Mcm10 and topoisomerase I. Others have found recently that the Mrc1 subunit of RPCs binds DNA polymerase epsilon, which synthesises the leading strand at DNA replication forks. Here, we show that the RPC associates with DNA polymerase alpha that primes each Okazaki fragment during lagging strand synthesis. During initiation, GINS is essential for a specific subset of RPC proteins to interact with MCM. GINS is also important for the normal progression of DNA replication forks, and we show that it is required after initiation to maintain the association between MCM and Cdc45 within RPCs. This interaction requires the RPC components Mrc1 and Ctf4, both of which associate with a tetratricopeptide repeat (TPR) domain located at the amino terminus of Dia2. RPC components include the essential initiation and elongation factor, Cdc45, the checkpoint mediator Mrc1, the Tof1-Csm3 complex that allows replication forks to pause at protein-DNA barriers, the histone chaperone FACT (facilitates chromatin transcription) and Ctf4, which helps to establish sister chromatid cohesion. ']

['Cdc45', 'Mrc1', 'Tof1-Csm3 complex', 'FACT', 'Ctf4']

Can ferric carboxymaltose be used to treat anemia in inflammatory bowel disease patients?

['Intravenous iron should be preferred where oral iron is poorly tolerated or where it has failed in moderate to severe anemia, and in combination with erythropoietin', 'Ferric carboxymaltose is much more convenient, and has been shown to be more effective than iron sucrose in a large randomized tria', 'nemia and iron deficiency anemia are very common in inflammatory bowel disease (IBD', 'Ferric carboxymaltose was associated with cost savings of 30-44\xa0% per patient per treatment cycle compared to iron sucrose. ', 'Iron deficiency is common in pregnancy, postpartum, inflammatory bowel disease, chronic kidney disease, chronic heart failure, heavy uterine bleeding, cancer and following surgery. We estimate the budget impact (BI) on the Swiss mandatory health insurance associated with substituting iron sucrose (standard) with ferric carboxymaltose (new treatment) using real-life data.', 'reating iron deficiency involves substantial costs to the Swiss MHI which may be reduced by substituting iron sucrose with ferric carboxymaltose.', 'e aim of this study was to observe, in a non-interventional way, how Swedish gastroenterologists adhere to guidelines in IBD outpatients treated with intravenous ferric carboxymaltose (FCM), and the result of treatment', 'FCM lowers platelet counts and platelet activation in patients with IBD-associated secondary thrombocytosis.', 'We performed a randomized, single-blinded placebo-controlled trial testing the effect of ferric carboxymaltose (FCM) in patients with IBD with secondary thrombocytosis (platelets > 450 G/L)', 'e performed a randomized, placebo-controlled trial to determine if administration of ferric carboxymaltose (FCM) prevents anemia in patients with IBD and low levels of serum ferritin', 'FCM prevents recurrence of anemia in patients with IBD, compared with placebo. ', ' A subgroup was analyzed regarding efficacy and side effects of iron supplementation with ferric carboxymaltose.', 'Iron deficiency and anemia are frequent in IBD patients. Treatment with ferric carboxymaltose is efficious, safe and well tolerated in iron-deficient IBD patients.', ' Intravenous iron avoids these concerns, especially with the development of ferric carboxymaltose, which allow up to 1000mg to be given rapidly.', 'What is the optimal treatment for anemia in inflammatory bowel disease?', 'We compared the efficacy and safety of a novel fixed-dose ferric carboxymaltose regimen (FCM) with individually calculated iron sucrose (IS) doses in patients with inflammatory bowel disease (IBD) and IDA', 'Study drugs were well tolerated and drug-related adverse events were in line with drug-specific clinical experience', ' The simpler FCM-based dosing regimen showed better efficacy and compliance, as well as a good safety profile, compared with the Ganzoni-calculated IS dose regimen.', 'Ferric carboxymaltose can be rapidly administered in doses of 15 mg/kg body weight, up to a ceiling dose of 1000 mg. A test dose is not required, and it can be used more widely across a spectrum of iron deficiency and iron deficiency anemia indication', ' Intravenous iron offers a rapid means of iron repletion and is superior to oral iron in many circumstances, especially in the presence of anemia of chronic disease, where it appears to overcome the block to absorption of iron from the gastrointestinal tract and immobilization of stored iron. The clinical situations where high doses of iron are commonly required are reviewed. These include nondialysis-dependent chronic kidney disease, inflammatory bowel disease, obstetrics, menorrhagia, and anemia associated with cancer and its treatment. ', 'Ferric carboxymaltose can be administered at 15 mg/kg body weight to a maximum dose of 1000 mg, whereas iron isomaltoside 1000 can be administered at 20 mg/kg body weight. The ability to give high doses of iron is important in the context of managing iron deficiency anemia in a number of clinical conditions where demands for iron are high (including chronic blood loss associated with inflammatory bowel disease, menorrhagia, and chronic kidney disease)', 'erric carboxymaltose (FCM, Ferinject) was effective and well tolerated in the treatment of iron-deficiency anemia (IDA) in nine, Phase III, randomized, controlled, multicenter trials in a diverse range of indications, including patients with inflammatory bowel disease (IBD), post-partum anemia (PPA) or abnormal uterine bleeding (AUB), chronic heart failure (CHF), non-dialysis-dependent chronic kidney disease (CKD) and those undergoing hemodialysis (HD', 'In patients with IBD or PPA, improvements in Hb levels were more rapid with FCM than with FeSulf. ', 'CM improved patient quality of life to an equivalent extent to oral FeSulf in patients with IBD or PPA, and to a greater extent than oral FeSulf in women with AUB', 'Four different products are principally used in clinical practice, which differ in their pharmacokinetic properties and safety profiles: iron gluconate and iron sucrose (lower single doses), and iron dextran and ferric carboxymaltose (higher single doses).', 'he prevalence of anemia across studies on patients with inflammatory bowel disease (IBD) is high (30%).', ' novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial.', 'FeCarb is effective and safe in IBD-associated anemia. It is noninferior to FeSulf in terms of Hb change over 12 wk, and provides a fast Hb increase and a sufficient refill of iron stores.', 'Treatment-related adverse events (AEs) occurred in 28.5% of the FeCarb and 22.2% of the FeSulf groups, with discontinuation of study medication due to AEs in 1.5% and 7.9%, respectively.', 'The median Hb improved from 8.7 to 12.3 g/dL in the FeCarb group and from 9.1 to 12.1 g/dL in the FeSulf group, demonstrating noninferiority (P= 0.6967). ', 'Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease.', 'Ferric carboxymaltose (FCM, Ferinject) was effective and well tolerated in the treatment of iron-deficiency anemia (IDA) in nine, Phase III, randomized, controlled, multicenter trials in a diverse range of indications, including patients with inflammatory bowel disease (IBD), post-partum anemia (PPA) or abnormal uterine bleeding (AUB), chronic heart failure (CHF), non-dialysis-dependent chronic kidney disease (CKD) and those undergoing hemodialysis (HD).', 'Ferric carboxymaltose (FCM, Ferinject) was effective and well tolerated in the treatment of iron-deficiency anemia (IDA) in nine, Phase III, randomized, controlled, multicenter trials in a diverse range of indications, including patients with inflammatory bowel disease (IBD), post-partum anemia (PPA) or abnormal uterine bleeding (AUB), chronic heart failure (CHF), non-dialysis-dependent chronic kidney disease (CKD) and those undergoing hemodialysis (HD)']

['Ferric carboxymaltose can be used to treat anemia in patients with inflammatory bowel disease, and prevents recurrence of anemia in these patients, compared with placebo. Treatment with ferric carboxymaltose is efficious, safe and well tolerated in iron-deficient IBD patients.']

['yes']

How does phospholamban (PLN) regulate cardiac contractility through its modulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity?

['["Phospholamban (PLN) is a small integral membrane protein, which binds and inhibits in a yet unknown fashion the Ca(2+)-ATPase (SERCA) in the sarcoplasmic reticulum.", "SR calcium uptake is mediated by a Ca(2+)-ATPase (SERCA2), whose activity is reversibly regulated by phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA and phosphorylation of PLN relieves this inhibition. ", "Regulation of the SERCA calcium pump by phospholamban (PLB) is largely due to interactions between their respective transmembrane domains. In spite of numerous mutagenesis and kinetic studies, we still do not have a clear mechanistic picture of how PLB influences the calcium transport cycle of SERCA. ", "Phospholamban (PLN) regulates cardiac contractility via its modulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity. Impairment of this regulatory process causes heart failure.", "Based on structural and dynamics data, we propose a model in which PLN undergoes allosteric activation upon encountering SERCA.", "The membrane protein complex between the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and phospholamban (PLN) controls Ca(2+) transport in cardiomyocytes, thereby modulating cardiac contractility. \\u03b2-Adrenergic-stimulated phosphorylation of PLN at Ser-16 enhances SERCA activity via an unknown mechanism.", "We found that the allosteric regulation of SERCA depends on the conformational equilibrium of PLN, whose cytoplasmic regulatory domain interconverts between three different states: a ground T state (helical and membrane associated), an excited R state (unfolded and membrane detached), and a B state (extended and enzyme-bound), which is noninhibitory. Phosphorylation at Ser-16 of PLN shifts the populations toward the B state, increasing SERCA activity.", "Phospholamban (PLN) is a type II membrane protein that inhibits the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), thereby regulating calcium homeostasis in cardiac muscle."]']

Phospholamban (PLN) regulates cardiac contractility via its modulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity. Impairment of this regulatory process causes heart failure.

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Where is the protein CLIC1 localized?

['CLIC1 expression was obtained in the cytoplasm and plasma membrane of cells in both cell lines.', 'CLIC1, an intracellular chloride ion channel,', 'Like NCC27/CLIC1, CLIC3 is predominantly localized in the nucleus ', 'the nuclear localization pattern of CLIC1 was remarkably changed by insulin stimulation']

['CLIC1 is an intracellular chloride ion channel that is localized both to the nucleus and to the cytolasm.']

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Which eye condition is managed by the athens protocol?

['Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol).', 'The Athens Protocol to arrest keratectasia progression and improve corneal regularity demonstrates safe and effective results as a keratoconus management option. Progressive potential for long-term flattening validates using caution in the surface normalization to avoid overcorrection.', 'The management of cornea blindness from severe corneal scarring, with the Athens Protocol (transepithelial topography-guided PRK therapeutic remodeling, combined with same-day, collagen cross-linking).', ' To evaluate the safety and efficacy of combined transepithelial topography-guided photorefractive keratectomy (PRK) therapeutic remodeling, combined with same-day, collagen cross-linking (CXL). This protocol was used for the management of cornea blindness due to severe corneal scarring.', 'Management of corneal ectasia after LASIK with combined, same-day, topography-guided partial transepithelial PRK and collagen cross-linking: the athens protocol.', 'Corneal refractive power and symmetry changes following normalization of ectasias treated with partial topography-guided PTK combined with higher-fluence CXL (the Athens Protocol).', 'To compare epithelial remodeling in keratoconic eyes that had photorefractive keratectomy and corneal collagen crosslinking (Athens protocol) with that in untreated keratoconic eyes and healthy eyes.', 'To evaluate a series of patients with corneal ectasia after LASIK that underwent the Athens Protocol: combined topography-guided photorefractive keratectomy (PRK) to reduce or eliminate induced myopia and astigmatism followed by sequential, same-day ultraviolet A (UVA) corneal collagen cross-linking (CXL).', 'PURPOSE: To compare epithelial remodeling in keratoconic eyes that had photorefractive keratectomy and corneal collagen crosslinking (Athens protocol) with that in untreated keratoconic eyes and healthy eyes.SETTING: Private clinical practice, Athens, Greece.DESIGN: Comparative case series.METHODS: Fourier-domain anterior segment optical coherence tomography (AS-OCT) was used to obtain in vivo 3-dimensional epithelial thickness maps and center, superior, inferior, maximum, minimum, mean, midperipheral, and variability data.RESULTS: Group A comprised 175 treated keratoconic eyes (Athens protocol); Group B, 193 untreated keratoconic eyes; and Group C, 160 healthy eyes. ', 'CONCLUSIONS: The Athens Protocol to arrest keratectasia progression and improve corneal regularity demonstrates safe and effective results as a keratoconus management option. ', 'To compare epithelial remodeling in keratoconic eyes that had photorefractive keratectomy and corneal collagen crosslinking (Athens protocol) with that in untreated keratoconic eyes and healthy eyes. Private clinical practice, Athens, Greece.', 'To compare epithelial remodeling in keratoconic eyes that had photorefractive keratectomy and corneal collagen crosslinking (Athens protocol) with that in untreated keratoconic eyes and healthy eyes.']

['The athens protocol (transepithelial topography-guided PRK therapeutic remodeling, combined with same-day, collagen cross-linking) was developed for the management of cornea blindness due to severe corneal scarring.']

['Keratoconus', 'cornea blindness due to severe corneal scarring']

Which molecule is targeted by the drug Gevokizumab?

['Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties.', 'Gevokizumab is a potent anti-IL-1β antibody being developed as a treatment for diseases in which IL-1β has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1β signaling through an allosteric mechanism. ', 'These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1β signaling that may offer an alternative to current therapies for IL-1β-associated autoinflammatory diseases.', 'Most recently, rising evidence reports on the use of adalimumab, etanercept, and golimumab, while use of anti-interleukin (IL)-1 agents (anakinra, canakinumab, gevokizumab), IL-6 blockers (tocilizumab), and rituximab (depleting anti-CD20 antibody) is also increasing.', 'One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β.', 'Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. ', 'Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. ', 'In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.', 'Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody. ', "Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study.", "This pilot study aimed to evaluate the safety, pharmacokinetics and clinical activity of XOMA 052 (gevokizumab), a recombinant humanised anti-interleukin 1β antibody, in Behçet's disease patients with uveitis. ", 'Gevokizumab, an anti-IL-1β mAb for the potential treatment of type 1 and 2 diabetes, rheumatoid arthritis and cardiovascular disease.', 'XOMA is developing gevokizumab (XOMA-052), an IgG2 humanized mAb against human IL-1β, for the potential treatment of these diseases. Gevokizumab has a high affinity for IL-1β and a long t1/2, which would allow for once-monthly dosing and offer a considerable advantage for patients over agents requiring more frequent dosing.', 'To meet these challenges, we developed XOMA 052 (gevokizumab), a potent anti-IL-1β neutralizing antibody that was designed in silico and humanized using Human Engineering™ technology. ', 'In the present study, we measured the impact of gevokizumab on the IL-1β system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1β for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II).', 'Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies.', 'Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody.', 'Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies', 'Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody']

['Gevokizumab is an allosteric anti-IL-1β monoclonal antibody.']

['IL-1β']

What is the role of Lysine 2-hydroxyisobutyrylation?

['Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark.', 'We report the identification of a new type of histone mark, lysine 2-hydroxyisobutyrylation (Khib), and identify the mark at 63 human and mouse histone Khib sites, including 27 unique lysine sites that are not known to be modified by lysine acetylation (Kac) and lysine crotonylation (Kcr). This histone mark was initially identified by MS and then validated by chemical and biochemical methods. Histone Khib shows distinct genomic distributions from histone Kac or histone Kcr during male germ cell differentiation. Using chromatin immunoprecipitation sequencing, gene expression analysis and immunodetection, we show that in male germ cells, H4K8hib is associated with active gene transcription in meiotic and post-meiotic cells. In addition, H4K8ac-associated genes are included in and constitute only a subfraction of H4K8hib-labeled genes. The histone Khib mark is conserved and widely distributed, has high stoichiometry and induces a large structural change. These findings suggest its critical role on the regulation of chromatin functions.', 'We report the identification of a new type of histone mark, lysine 2-hydroxyisobutyrylation (Khib), and identify the mark at 63 human and mouse histone Khib sites, including 27 unique lysine sites that are not known to be modified by lysine acetylation (Kac) and lysine crotonylation (Kcr).', 'Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark', 'We report the identification of a new type of histone mark, lysine 2-hydroxyisobutyrylation (Khib), and identify the mark at 63 human and mouse histone Khib sites, including 27 unique lysine sites that are not known to be modified by lysine acetylation (Kac) and lysine crotonylation (Kcr)', 'We report the identification of a new type of histone mark, lysine 2-hydroxyisobutyrylation (Khib), and identify the mark at 63 human and mouse histone Khib sites, including 27 unique lysine sites that are not known to be modified by lysine acetylation (Kac) and lysine crotonylation (Kcr). ', 'The histone Khib mark is conserved and widely distributed, has high stoichiometry and induces a large structural change.', 'Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark.']

['Lysine 2-hydroxyisobutyrylation (Khib) is a widely distributed active histone mark. This histone mark was initially identified by MS and then validated by chemical and biochemical methods. Histone Khib shows distinct genomic distributions from histone Kac or histone Kcr during male germ cell differentiation. In male germ cells, H4K8hib is associated with active gene transcription in meiotic and post-meiotic cells. In addition, H4K8ac-associated genes are included in and constitute only a subfraction of H4K8hib-labeled genes. The histone Khib mark is conserved and widely distributed, has high stoichiometry and induces a large structural change.']

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Which pharmacogenetic test is available for abacavir?

['Pharmacogenomic tests offer a promising strategy to improve the safety and efficacy of drug treatment. Compelling examples, such as HLA-B*5701 testing to identify patients at risk for abacavir-associated hypersensitivity, are already changing clinical care', 'International HIV treatment guidelines recommend HLA-B*57:01 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-B*57:01 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-B*5701/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-B*5701 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-B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir,', 'Prospective pharmacogenetic screening for the human leucocyte antigen (HLA) B*5701 allele can significantly reduce the number of cases of abacavir-related hypersensitivity among HIV-infected patients treated with this drug.', 'development of HLA-B*5701 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-B*5701 and AHS. These studies suggested that HLA-B*5701 holds promise as a screening test to prevent AHS, but concern arose from HLA-B*5701-negative cases with a clinical diagnosis of AHS, and particularly from early reports of apparently low sensitivities of HLA-B*5701 for AHS in patients of non-White race. However, open screening studies suggested that HLA-B*5701 screening can largely eliminate AHS', 'Current HIV treatment guidelines have been revised to reflect the recommendation that HLA-B*5701 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-B*5701 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-B*5701, 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-B*5701 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-B*5701-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-B*5701 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-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment.', 'HLA-B*5701 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-B*5701 testing and the prevalence of HLA-B*5701.', 'The strong association of the abacavir hypersensitivity reaction with HLA-B*5701 permits testing patients for the allele, and if present avoiding the drug and therefore preventing the reaction.', 'Although the human leukocyte antigen (HLA)-B*5701 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-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races.', 'A strong statistical association between the major histocompatibility complex allele, HLA-B*5701, and clinically diagnosed ABC HSR was identified but varied between racial populations.', 'In a randomized, prospective study evaluating the clinical utility of HLA-B*5701 screening, avoidance of ABC in HLA-B*5701-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-B*5701 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-B*5701 allele', 'HLA-B*5701 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-B*5701 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-B*5701 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-B*5701 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-B*5701 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-B*5701, indicating that exclusion of HLA-B*5701 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 B*5701 is a known genetic risk factor for abacavir hypersensitivity in Caucasians.', 'Abacavir hypersensitivity is associated with HLA B*5701, and pre-prescription pharmacogenetic testing for this appears to be a cost-effective use of healthcare resources.']

['The pharmacogenetic test recommended prior to abacavir administration is the HLA B*5701 genotyping.']

['HLA B*5701 genotyping']

Which are the subunits of the IkB protein kinase (IKK)?

['NEMO (NF-κB essential modulator) associates with catalytic subunits IKKα and IKKβ to form the IκB kinase (IKK) complex and is a key regulator of NF-κB pathway signaling.', 'All known NF-κB activators converge on the IkappaB kinase (IKK) complex to activate the canonical and non-canonical NF-κB pathways. The IKK complex contains two catalytic subunits (IKKα and IKKβ) and a regulatory subunit NEMO/IKKγ that regulates the canonical NF-κB pathway, whereas IKKα regulates the non-canonical pathway.', ' The IKK protein complex is comprised of IKKα, IKKβ and NEMO subunits, with IKKβ thought to play the dominant role in modulating NF-κB activity. ', 'The IκB kinase (IKK) complex plays a crucial role in the activation of the transcription factor NF-κB by phosphorylating an inhibitory molecule IκBα. Recently, we showed that IKK2 (also called IKKβ), a catalytic subunit of the IKK complex, induces immunoglobulin E-mediated degranulation in mast cells by phosphorylating SNAP-23, the target-membrane soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptor (SNARE).', 'The depletion of any of the three subunits of the inhibitor of NFκB (IκB) kinase (IKKα, IKKβ, IKKγ/NEMO), each of which is essential for the canonical NFκB activation pathway, limits autophagy induction by physiological or pharmacological triggers, while constitutive active IKK subunits suffice to stimulate autophagy. ', 'NF-κB activation is tightly regulated by the IκB kinase (IKK) complex, which is composed of two catalytic subunits IKKα and IKKβ, and a regulatory subunit IKKγ/NEMO.', 'Activation of the classical NF-κB pathway is mediated through the activity of the IKK kinase complex, which consists of a heterotrimer of IKKα, IKKβ, and IKKγ subunits. ', 'NF-kB is a key regulator of inflammation and immunity in cancer development. The IkB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ. ', 'Activation of NF-κB involves the IκB kinase (IKK)-complex composed of two catalytic subunits, IKKα and IKKβ, and a regulatory scaffold protein, IKKγ.', 'The IKK kinase complex is the core element of the NF-kappaB cascade. It is essentially made of two kinases (IKKalpha and IKKbeta) and a regulatory subunit, NEMO/IKKgamma.', 'Additional components may exist, transiently or permanently, but their characterization is still unsure.', 'Activation of NF-kappaB subunits is regulated by the upstream IkappaB kinase (IKK) complex which contains IKKalpha, IKKbeta, and IKKgamma; the latter also known as NF-kappaB essential modulator (NEMO).', 'Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO).', 'Inhibition of NF-kappaB by suppressing the canonical NF-kappaB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-kappaB (I kappaB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. ', 'The IkappaB-Kinase (IKK) complex is a multisubunit protein complex crucial for signal-induced phosphorylation of the IkappaB proteins and thus controls the activity of the transcription factor NF-kappaB. Besides the two kinases IKKalpha and IKKbeta, the IKK complex contains NEMO/IKKgamma, an additional subunit with regulatory and adaptor functions.', 'Activation of a large multisubunit protein kinase, called the inhibitor kappaB kinase (IKK) complex, is central to the induction of the family of transcription factors nuclear factor kappaB. IKK is comprised of two catalytic subunits, IKKalpha and IKKbeta, and a regulatory IKKgamma subunit.', 'The IkB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ']

['Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO).Additional components may exist, transiently or permanently, but their characterization is still unsure.', 'The IKK kinase complex is the core element of the NF-kappaB cascade. It is essentially made of two kinases (IKKalpha and IKKbeta) and a regulatory subunit, NEMO (NF-kB Essential Modulator)/IKKgamma. Additional components may exist, transiently or permanently, but their characterization is still unsure.', ' The IKK protein complex is comprised of IKKα, IKKβ and NEMO subunits, with IKKβ thought to play the dominant role in modulating NF-κB activity. The IkappaB-Kinase (IKK) complex is a multisubunit protein complex crucial for signal-induced phosphorylation of the IkappaB proteins and thus controls the activity of the transcription factor NF-kappaB. Besides the two kinases IKKalpha and IKKbeta, the IKK complex contains NEMO/IKKgamma, an additional subunit with regulatory and adaptor functions. ']

['IKKalpha', 'IKKα', 'IKK1', 'IKKbeta', 'IKKβ', 'IKK2', 'IKKgamma', 'IKKγ', 'NEMO']

What is the function of the protein tafazzin?

['Tafazzin is a transacylase that transfers acyl chains with unsaturated fatty acids from phospholipids to monolysocardiolipin to generate cardiolipin with unsaturated fatty acids.', 'Tafazzin (EC 2.3.1.23) is a Phospholipid Transacylase involved in Cardiolipin remodeling on mitochondrial membrane and coded by TAZ gene (Cytogenetic Location: Xq28) in human.', 'Tafazzin is a transacylase that affects cardiolipin fatty acid composition and mitochondrial function. ', 'Tafazzin is a mitochondrial phospholipid transacylase, and its mutations cause Barth syndrome (BTHS). ', 'Tafazzin (TAZ) is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. ', 'Tafazzin expression induced a new enzymatic function in Sf9 cell mitochondria, namely 1-palmitoyl-2-[14C]linoleoyl-phosphatidylcholine:monolysocardiolipin linoleoyltransferase.', 'Among the human isoforms, only full-length tafazzin (FL) and tafazzin lacking exon 5 (Delta5) had transacylase activity, and only these two isoforms were able to restore a normal cardiolipin pattern, normal respiratory activity of mitochondria, and male fertility in tafazzin-deficient flies.', 'Tafazzin is a mitochondrial transacylase required for cardiolipin remodeling.', 'Tafazzin is a putative enzyme that is involved in cardiolipin metabolism, it may carry mutations responsible for Barth syndrome.', 'Tafazzin is an enzyme that remodels saturated fatty acyl chains within CL to unsaturated fatty acyl chains, loss of function mutations in the TAZ gene encoding tafazzin are causal for the inherited cardiomyopathy Barth syndrome', 'The tafazzin gene encodes a phospholipid-lysophospholipid transacylase involved in cardiolipin metabolism, but it is not known why it forms multiple transcripts as a result of alternative splicing.', 'Furthermore, the data show that the expression of human tafazzin in flies creates cardiolipin with a Drosophila pattern, suggesting that the characteristic fatty acid profile of cardiolipin is not determined by the substrate specificity of tafazzin.', 'Tafazzin is a transacylase that affects cardiolipin fatty acid composition and mitochondrial function.']

['Tafazzin is a phospholipid transacylase that transfers acyl chains with unsaturated fatty acids from phospholipids to monolysocardiolipin to generate cardiolipin with unsaturated fatty acids on mitochondrial membrane.']

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List 3 features of IRVAN syndrome.

['Fluorescein photodiagnosis of idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome: A case report and long-term outcome of photocoagulation therapy.', 'Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome is a disease characterized by multiple retinal macroaneurysms, neuroretinitis and peripheral capillary non-perfusion, leading to irreversible visual loss.', '[Early treatment of idiopathic vasculitis, aneurysms and neuroretinitis (IRVAN). A case report].', 'CASE REPORT: A 55 year old woman presented with retinal vasculitis, multiple aneurysms, macular exudation and widespread retinal nonperfusion and was diagnosed with IRVAN.', 'A 7-year-old girl with IRVAN (idiopathic retinal vasculitis, aneurysms, and neuroretinitis) syndrome was monitored for 9 years.', 'Vision loss associated with the idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome most commonly occurs from macular edema or complications related to neovascularization. ', 'PURPOSE: To report a case of idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN) syndrome associated with positive perinuclear antineutrophil cytoplasmic antibody (P-ANCA).', 'PURPOSE: We report our experience in treating 2 patients of idiopathic retinal vasculitis, aneurysm, and neuroretinitis (IRVAN) syndrome with antitumor necrosis factor agent, infliximab, who showed a very favorable response to treatment', 'Fluorescein angiography delineated saccular aneurysms of the retinal arteriolar vasculature, and IRVAN syndrome was diagnosed.', 'The authors describe the clinical feature of ten patients with a new syndrome characterized by the presence of retinal vasculitis, multiple macroaneurysms, neuro-retinitis, and peripheral capillary nonperfusion.The authors evaluated ten patients identified to have clinical features compatible with the syndrome of idiopathic retinal vasculitis, aneurysms and neuroretinits (IRVAN)', 'The authors evaluated ten patients identified to have clinical features compatible with the syndrome of idiopathic retinal vasculitis, aneurysms and neuroretinits (IRVAN).']

['Idiopathic retinal vasculitis, aneurysms, and neuroretinitis is coined as IRVAN syndrome.']

['Idiopathic retinal vasculitis', 'Aneurysms', 'Neuroretinitis']

Are BBS mutations involved in syndromic Hirschsprung disease?

['Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease', 'Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease', 'Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.', 'Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease.', 'Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays', 'Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease', 'Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays']

['In 3 families with Bardet-Biedl syndrome (BBS) and Hirschsprung disease (HSCR), concomitant mutations in BBS genes and regulatory RET elements have been identified. Analysis of the data suggests that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease.']

['yes']

Is the abnormal dosage of ultraconserved elements disfavored in cancer cells?

['Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells.', 'We begin by showing that depletion for UCEs characterizes the most recent large-scale human CNV datasets and then find that even newly formed de novo CNVs, which have passed through meiosis at most once, are significantly depleted for UCEs. In striking contrast, CNVs arising specifically in cancer cells are, as a rule, not depleted for UCEs and can even become significantly enriched. This observation raises the possibility that CNVs that arise somatically and are relatively newly formed are less likely to have established a CNV profile that is depleted for UCEs. Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state. In support of this latter explanation, somatic CNVs that are not associated with disease are depleted for UCEs. Finally, we show that it is possible to observe the CNVs of induced pluripotent stem (iPS) cells become depleted of UCEs over time, suggesting that depletion may be established through selection against UCE-disrupting CNVs without the requirement for meiotic divisions.', 'Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state.']

['No. Abnormal dosage of ultraconserved elements is highly disfavored in healthy cells but not cancer cells.']

['no']

Can SUMO affect calcium homeostasis?

['Increasing SUMOylation levels correlated inversely with calcium influx in sensory neurons.', 'CRMP2 deSUMOylation by SUMO proteases SENP1 and SENP2 normalized calcium influx to those in the CRMP2AAA mutant.', 'Thus, our results identify a novel role for SUMO modification in CRMP2/CaV2.2 signaling pathway', 'Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca(2+) decay.', ' RIM1α SUMOylation at lysine residue K502 facilitates\xa0the clustering of CaV2.1 calcium channels and\xa0enhances the Ca(2+) influx necessary for vesicular release, whereas non-SUMOylated RIM1α participates in the docking/priming of synaptic vesicles and maintenance of active zone structure. ', 'Identification and characterization of a SUMO-1 conjugation system that modifies neuronal calcium/calmodulin-dependent protein kinase II in Drosophila melanogaster.']

['Yes, SUMO proteins can affect calcium homeostasis.']

['yes']

Which disease is treated with semaglutide?

['INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer.METHODS: A MEDLINE search (2010-2015) identified publications that discussed longer-acting GLP-1 RAs. Search terms included GLP-1 receptor agonists, liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide, albiglutide, efficacy, safety, pancreatitis, pancreatic cancer, and thyroid cancer.', ' Seven trials have been published that have established CV safety for three DPP-4 inhibitors (alogliptin, saxagliptin, and sitagliptin), three GLP-1 receptor agonists (liraglutide, lixisenatide, and semaglutide), and one sodium-glucose cotransporter-2 inhibitor (empagliflozin). Three of those studies also established superiority with liraglutide, empagliflozin, and semaglutide at reducing the composite primary endpoint of major CV events (CV death, nonfatal myocardial infarction, and nonfatal stroke). ', 'RECENT FINDINGS: In response to guidance issued by the Food and Drug Administration, thousands of patients have been enrolled in large randomized trials evaluating the cardiovascular effects of the three newest diabetes drug classes: glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose cotransporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. Two studies of GLP-1 receptor agonists-one of liraglutide and one of semaglutide-have shown cardiovascular benefit relative to placebo, and one study of the SGLT-2 inhibitor empagliflozin has shown benefit.', 'New antidiabetic drugs are being developed today that expand the range of pharmacological intervention, in particular for patients with type 2 diabetes (imeglimin, semaglutide, dulaglutide, FGF 21 analogue).', 'The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. ', 'Conclusions In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide.', 'Postmenopausal women with T2D (n\u2009=\u200943) on diet/exercise\u2009±\u2009metformin received ethinylestradiol (0.03\u2009mg)/levonorgestrel (0.15\u2009mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0\u2009mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25\u2009mg 4 weeks; 0.5\u2009mg 4 weeks; 1.0\u2009mg 5 weeks).', 'Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.']

['Semaglutide is glucagon-like peptide-1 receptor agonist that is being used for the treatment of type 2 diabetes mellitus.']

['Type 2 diabetes mellitus', 'TYPE 2 DIABETES']

A common problem in proteomics is the contamination of samples with exogenous proteins (often from other species). These proteins can be found in specific databases. List some contaminants.

['protease autolysis or keratin contaminants.', 'Most of the interfering masses originate from trypsin autolysis and human keratins.', '5-15% FBS. Contamination by bovine proteins is difficult to avoid because of adherence to the plastic vessel and the cultured cells.', 'The main disadvantage of traditional IP and co-IP is that the conditions used to elute the precipitated antigen also release the antibody thus contaminating the antigen', 'MaConDa: a publicly accessible mass spectrometry contaminants database.']

['Some common contaminants in proteomics are proteases (used for the digestion of the proteins), keratins (usually from the skin), proteins originated from the serum of the culture media and antibodies if used in the experiment.']

['Proteases', 'Keratins', 'Bovine serum proteins', 'Antibodies']

Can chronological age be predicted by measuring telomere length?

['Human somatic cells gradually lose telomeric repeats with age. This study investigated if one could use a correlation between telomere length and age, to predict the age of an individual from their DNA.', 'Therefore, telomere length measurement by real-time quantitative PCR cannot be used to predict age of a person, due to the presence of large inter-individual variations in telomere lengths.', 'ur results provide the first clear and unambiguous evidence of a relationship between telomere length and mortality in the wild, and substantiate the prediction that telomere length and shortening rate can act as an indicator of biological age further to chronological age when exploring life history questions in natural conditions.']

['No, telomere length measurement by real-time quantitative PCR cannot be used to predict age of a person, due to the presence of large inter-individual variations in telomere lengths.']

['no']

Are people with blood group O protected against severe Malaria?

['Differential carbonylation of cytoskeletal proteins in blood group O erythrocytes: potential role in protection against severe malaria.', '. Our findings indicate a possible correlation between the protection against severe malaria in blood group O individuals and a specific pattern of 4-HNE-carbonylation of cytoskeleton proteins.', 'There is a predominance of blood group O in malaria-endemic regions, and several lines of evidence suggest that ABO blood groups may influence the outcome of P. falciparum infection', 'These data provide the first evidence that ABO blood group antigens influence macrophage clearance of P. falciparum-infected erythrocytes and suggest an additional mechanism by which blood group O may confer resistance to severe malaria.', 'Blood group phenotypes A and B are risk factors for cerebral malaria in Odisha, India.', 'type O is significantly associated with protection against CM, patients with type A and B group had increased risk for developing CM.', 'Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting.', 'Malaria has been a major selective force on the human population, and several erythrocyte polymorphisms have evolved that confer resistance to severe malaria. Plasmodium falciparum rosetting, a parasite virulence phenotype associated with severe malaria, is reduced in blood group O erythrocytes compared with groups A, B, and AB, but the contribution of the ABO blood group system to protection against severe malaria has received little attention', 'We hypothesized that blood group O may confer resistance to severe falciparum malaria through the mechanism of reduced rosetting.', 'It appears that individuals who are of blood-group O are relatively resistant to the severe disease caused by P. falciparum infection.']

['It appears that individuals who are of blood-group O are relatively resistant to the severe disease caused by P. falciparum infection.']

['yes']

Is there an increased risk for cancer in Dyskeratosis Congenita?

['People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis', 'Clinical progression of the disease can lead to aplastic anemia (86% of all patients) and to pulmonary or hepatic complications. These patients also have an increased risk of cancer.', 'Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST)', 'Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients', 'The findings demonstrate that both FA and DC are major cancer susceptibility syndromes', 'People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis', 'Patients with dyskeratosis congenita (DC) have an increased risk of cancer, but also exhibit heightened radiation sensitivity.', 'Dyskeratosis congenita (DC) is characterized by the clinical triad of reticular skin pigmentation, oral leukoplakia, and nail dystrophy associated with bone marrow failure (BMF) and an high risk to develop cancer and pulmonary complications.', 'CONCLUSION: Dyskeratosis congenita is a rare condition; however, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients.', 'Point mutations in the DKC1 gene that encodes dyskerin cause the rare inherited syndrome called X-linked dyskeratosis congenita, characterized by a failure of proliferating tissues and increased susceptibility to cancer.', 'Dyskeratosis Congenita (DC) also known as Zinsser-Engman-Cole syndrome is a rare multi-system bone marrow failure syndrome characterised by mucocutaneous abnormalities and an increased predisposition to cancer".', 'Dyskeratosis congenita is an inherited syndrome characterised by mucocutaneous features, bone marrow failure, an increased risk of malignancy and other somatic abnormalities.', 'Dyskeratosis congenita is a rare condition; however, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients.', 'Epidermal atrophy, hair growth defects, bone marrow failure and increased risk of cancer are also common in DC patients.', 'Telomere dysfunction and tumor suppression responses in dyskeratosis congenita: balancing cancer and tissue renewal impairment.', 'Patients with dyskeratosis congenita (DC) have an increased risk of cancer, but also exhibit heightened radiation sensitivity', 'Dyskeratosis congenita is a rare condition; however, it is vital to recognise the increased risk of upper aerodigestive tract cancers in these patients', 'Dyskeratosis congenita is an inherited syndrome characterised by mucocutaneous features, bone marrow failure, an increased risk of malignancy and other somatic abnormalities', 'While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients', 'As in Fanconi anemia and dyskeratosis congenita, DBA is both an inherited bone marrow failure syndrome and a cancer predisposition syndrome; cancer risks appear lower in DBA than in Fanconi anemia or dyskeratosis congenita', 'Severe pancytopenia frequently causes early mortality of DC patients, who have an increased risk of developing oropharyngeal squamous cell carcinoma', 'Here different aspects of telomere biology, concerning adult stem cells senescence, tumor suppression and cancer are considered in the context of DC, resulting in two translational models: late onset of DC symptoms in telomere-related mutations carriers is a potential indicator of increased cancer risk and differences in tumor suppression capacities among the genetic subgroups are (at least partial) causes of different clinical manifestations of the disease', 'Point mutations in the DKC1 gene that encodes dyskerin cause the rare inherited syndrome called X-linked dyskeratosis congenita, characterized by a failure of proliferating tissues and increased susceptibility to cancer', 'Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.']

['People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis ', 'Yes. Clinical progression of the disease can lead to aplastic anemia (86% of all patients) and to pulmonary or hepatic complications. These patients also have an increased risk of cancer. Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST)', 'People with Dyskeratosis Congenita are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis.']

['yes']

How has the study of ancient DNA (aDNA) been impacted by the use of refined sampling methods such as the inner part of petrous bones and the cementum layer in teeth roots?

['["Large-scale genomic analyses of ancient human populations have become feasible partly due to refined sampling methods. The inner part of petrous bones and the cementum layer in teeth roots are currently recognized as the best substrates for such research.", "Ancient DNA (aDNA) research involves invasive and destructive sampling procedures that are often incompatible with anthropological, anatomical, and bioarcheological analyses requiring intact skeletal remains. The osseous labyrinth inside the petrous bone has been shown to yield higher amounts of endogenous DNA than any other skeletal element; however, accessing this labyrinth in cases of a complete or reconstructed skull involves causing major structural damage to the cranial vault or base.", "first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones,"]']

The study of ancient DNA (aDNA) has been impacted by the use of refined sampling methods such as the inner part of petrous bones and the cementum layer in teeth roots by making large-scale genomic analyses of ancient human populations feasible. These substrates are recognized as the best for such research, allowing for the extraction of genetic material from petrous bones of Anatolian Neolithic farmers.

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Which is the target of bortezomib used in cancer therapy?

['The ubiquitin-proteasome system (UPS) degrades 80 - 90% of intracellular proteins. Cancer cells take advantage of the UPS for their increased growth and decreased apoptotic cell death. Thus, the components that make up the UPS represent a diverse group of potential anti-cancer targets. The success of the first-in-class proteasome inhibitor bortezomib not only proved that the proteasome is a feasible and valuable anti-cancer target, but also inspired researchers to extensively explore other potential targets of this pathway.', 'The ubiquitin-proteasome pathway has been identified as a potential molecular target for cancer therapy. In this study, we investigated the effect of the proteasome inhibitor bortezomib on anaplastic thyroid carcinoma (ATC) characterized by complete refractoriness to multimodal therapeutic approaches.', 'The ubiquitin-proteasome pathway regulates many basic cellular processes and has been proven to be a promising target for cancer therapy. Bortezomib is the first U.S. Food and Drug Administration (FDA) approved proteasome inhibitor used in the treatment of newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and mantle cell lymphoma.', 'This review summarizes the current status of bortezomib as well as several other proteasome inhibitors that are currently under clinical and preclinical investigation.', 'Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target.', 'The ubiquitin-proteasome system (UPS) is a conserved pathway regulating numerous biological processes including protein turnover, DNA repair, and intracellular trafficking.', 'The development of bortezomib (Velcade(®)) as a treatment for multiple myeloma and mantle cell lymphoma has verified this and suggests that targeting other components of the UPS may be a viable strategy for the treatment for cancer.', 'The proteasome inhibitor bortezomib is now in the clinic to treat multiple myeloma and mantle cell lymphoma.', 'In this study, we investigated the transcriptome-wide effects of the proteasome inhibitor bortezomib on estrogen-regulated transcription in MCF7 human breast cancer cells and showed that bortezomib caused a specific global decrease in estrogen-induced gene expression.', 'The clinical efficacy of the proteasome inhibitor bortezomib toward multiple myeloma and other hematologic malignancies provides the "proof of concept" that targeting the proteasome is a promising strategy for cancer treatment.', "It has previously been suggested that the excess proteins not targeted to the proteasome, or that accumulate when the proteasome is inhibited through the use of chemically active agents such as bortezomib, are linked to impaired cell survival, and that their packaging in the form of an aggresome somehow minimizes their 'proteotoxicity' allowing these toxic proteins to be sequestered away from normal cellular machinery.", 'The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma.', 'Bortezomib (PS-341) is a potent and specific reversible proteasome inhibitor, which has shown strong in vitro antitumor activity as single agent and in combination with other cytotoxic drugs in a broad spectrum of hematological and solid malignancies.', 'In addition to the development and clinical validation of proteasome inhibitor, bortezomib, in myeloma therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination enzymes.', 'Bortezomib as first-in-class proteasome inhibitor has proven to be highly effective in some hematological malignancies, overcomes conventional chemoresistance, directly induces cell cycle arrest and apoptosis, and also targets the tumor microenvironment. It has been granted approval by the FDA for relapsed multiple myeloma, and recently for relapsed mantle cell lymphoma.', 'Validation of the ubiquitin-proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care.', 'Cells were cultured, exposed to proteasome inhibitors (bortezomib, ALLN, MG-132 and epoxomicin) and then assayed for cell cycle and cell death analyses.', 'The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM).', 'Bortezomib is the first proteasome inhibitor to enter clinical use, and received approval by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma, therefore validating inhibition of the proteasome as an anticancer target.', 'Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma.', 'Preclinical evidence using bortezomib, the only proteasome inhibitor to enter clinical trials, suggests that proteasome inhibition may be effective in the treatment of hematologic and solid malignancies by promoting apoptosis, retarding angiogenesis, and inhibiting tumor cell adhesion and production of growth factors by acting on molecules such as nuclear factor-kappaB.', 'Bortezomib was recently approved for the treatment of multiple myeloma. It is currently being investigated, both as a single agent and in combination, in phase I and II trials in a variety of tumor types.', 'Protein degradation pathways are also targets for cancer therapy, as shown by the successful introduction of bortezomib, an inhibitor of the 26S proteasome.', 'Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy.', 'The potent and selective proteasome inhibitor bortezomib (VELCADE; formerly known as PS-341) is particularly promising as a potential anticancer agent.', 'Inhibitors of the proteasome impact on cells in part through down-regulation of nuclear factor kappaB, but also through modulation of cell cycle proteins and other pro- and antiapoptotic pathways. Bortezomib (VELCADE; formerly PS-341), the first such inhibitor to undergo clinical testing, has demonstrated impressive antitumor activity and manageable toxicities in Phase I and II trials both as a single agent, and in combination with other drugs.', 'Although targeting E3 ubiquitin ligases is still in its infancy, speedy approval of the general proteasome inhibitor, Velcade (bortezomib) by the FDA for the treatment of relapsed and refractory multiple myeloma suggests the promise of specific E3 inhibitors in anti-cancer therapy.']

['Bortezomib is a potent and specific reversible ubiquitin/proteasome pathway inhibitor, which has shown strong in vitro antitumor activity as single agent and in combination with other cytotoxic drugs in a broad spectrum of hematological and solid malignancies.']

['The ubiquitin/proteasome pathway']

Which is the main difference between Alu and B1 repeats?

['The mouse B1 sequence is congruent to 130 nucleotides long and shows homology with the monomeric units of the dimeric 300-nucleotide primate sequence. ', 'Here we show that some members of the mouse B1 Alu sequence family encode a small cytoplasmic RNA', 'Alus and B1s are short interspersed repeat elements (SINEs) derived from the 7SL RNA gene. Alus and B1s exist in the cytoplasm as non-coding RNA indicating that they are actively transcribed, but their function, if any, is unknown.', 'B1 (Alu-equivalent) is a murine short interspersed element whose amplification probably involved an RNA intermediate', 'The data demonstrate that a limited set of B1 sequences are expressed as processed RNA polymerase III-transcripts of a high degree of structural conservation. ', 'B1 is a murine homolog of the human SINE Alu', 'These RNAs have conserved a secondary structure motif also present in signal recognition particle (SRP) RNA despite substantial sequence divergence, whereas random B1 and Alu sequences have not.', 'The modern B1 elements are similar to the left Alu monomer, but with a 9 bp deletion and a 29 bp duplication.', 'A master sequence related to a free left Alu monomer (FLAM) at the origin of the B1 family in rodent genomes.', ' The core sequences of these elements contain pol III promoters but must rely on fortuitous downstream oligo(dT) tracts for terminator function. We show that a B1-Alu gene differs markedly from a classical pol III gene (tRNAiMet) in terminator sequence requirements', 'Most human Alu and murine B1 repeats are unique.', 'Alu and b1 repeats have been selectively retained in the upstream and intronic regions of genes of specific functional classes', 'Alu and B1 repeats are mobile elements that originated in an initial duplication of the 7SL RNA gene prior to the primate-rodent split about 80 million years ago and currently account for a substantial fraction of the human and mouse genome, respectively', 'we present evidence that Alu and B1 elements have been selectively retained in the upstream and intronic regions of genes belonging to specific functional classes.', 'Finally, the unexpected finding that Alu and B1 elements show similar biases in their distribution across functional classes, despite having spread independently in their respective genomes, further supports our claim that the extant instances of Alu and B1 elements are the result of positive selection.', 'Furthermore, the presence of Alu-like structural motifs supports the hypothesis of the monophyletic origin of Alu and B1 repeats, i.e., from a common 7SL RNA-derived retroposing monomeric element.', 'Furthermore, the presence of Alu-like structural motifs supports the hypothesis of the monophyletic origin of Alu and B1 repeats, i.e., from a common 7SL RNA-derived retroposing monomeric element.', 'A statistically reliable slowing down in the evolutionary rates of one of two monomers for the human Alu repeats has been proved.', 'Furthermore, the presence of Alu-like structural motifs supports the hypothesis of the monophyletic origin of Alu and B1 repeats, i.e., from a common 7SL RNA-derived retroposing monomeric element.']

['B1 is a murine homolog of the human SINE Alu. B1 (Alu-equivalent) is a murine short interspersed element whose amplification probably involved an RNA intermediate. The modern B1 elements are similar to the left Alu monomer, but with a 9 bp deletion and a 29 bp duplication.', 'The mouse B1 sequence is congruent to 130 nucleotides long and shows homology with the monomeric units of the dimeric 300-nucleotide primate sequence. ']

['it is the mouse homolog to the left Alu monomer']

What memory problems are reported in the " Gulf war syndrome"

['memory loss', 'loss of memory,', ' loss of memory', 'dysmnesia', 'memory problems', '"impaired cognition," characterized by problems with attention, memory, and reasoning, as well as insomnia, depression, daytime sleepiness, and headaches']

['memory loss']

['memory loss']

Which gene mutations are predictive of response to anti-TNF therapy in Rheumatoid Arthritis patients?

['Genetic Variations in Pattern Recognition Receptor Loci Are Associated with Anti-TNF Response in Patients with Rheumatoid Arthritis', 'Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1-2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1-7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4-1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response. The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4-16.3),p = 0.0002,q = 0.024). ', 'Variation at FCGR2A and functionally related genes is associated with the response to anti-TNF therapy in rheumatoid arthritis', 'We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response.', 'A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274.', ' Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression.', 'We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001).', 'We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040).', 'In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042).']

['Μutations in TLR5 and TLR1 genes contribute to differential response to anti-TNF treatment in RA. Variation at FCGR2A and functionally related genes such as DHX32 and RGS12 is also associated with the response to anti-TNF therapy in rheumatoid arthritis.']

['TLR5', 'TLR1', 'FCGR2A', 'DHX32', 'RGS12']

How can Human Hsp70 Disaggregase potentially reverse Parkinson's-linked α-Synuclein amyloid fibrils, given the need for therapeutic agents to address neurodegenerative disorders caused by protein misfolding and aggregation, and the role of disaggregases in resolubilizing protein aggregates?

['["Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson\'s disease (PD), and Alzheimer\'s disease (AD).", "Human Hsp70 Disaggregase Reverses Parkinson\'s-Linked \\u03b1-Synuclein Amyloid Fibrils.", "Disaggregases, molecular chaperones that resolubilize protein aggregates.", "The structural basis by which Hsp104 dissolves disordered aggregates and prions is unknown."]']

Human Hsp70 Disaggregase can potentially reverse Parkinson's-linked α-Synuclein amyloid fibrils by resolubilizing protein aggregates. Disaggregases, such as Hsp70, are molecular chaperones that can dissolve protein aggregates, including those linked to neurodegenerative disorders like Parkinson's disease. This process is crucial in addressing the protein misfolding and aggregation that underlie conditions such as ALS, PD, and AD.

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What kind of affinity purification would you use in order to isolate soluble lysosomal proteins?

['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']

['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.']

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Is NSD-1015 an inhibitor of Aromatic L-Amino Acid Decarboxylase?

['When pretreated with a central AADC inhibitor (NSD-1015), further application of l-dopa failed to increase the motoneuron activity although the expression of DA in the AADC cells was not completely inhibited. ', 'Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. ', 'We evaluated this in vivo by reverse dialysis of the aromatic-l-amino-acid decarboxylase (EC 4.1.1.28) inhibitor NSD-1015 (20μM) and selected concentrations of l- or d-tyrosine. ', 'Neurochemical study of effects of the new anxiolytic drugs afobazol and ladasten on the synthesis and metabolism of monoamines and their metabolites in the brain structures of Wistar rat on the model of monoamine synthesis blockade induced by aromatic amino acid decarboxylase inhibitor NSD-1015', 'To establish the neurotransmitter role(s) of L-3,4-dihydroxyphenylalanine (DOPA) in its own right, we attempted to clarify whether i.p. injection of a DOPA antagonist, DOPA cyclohexyl ester (CHE), would antagonize the behavioral responses of conscious rats to DOPA in the presence of 3-hydroxybenzylhydrazine (NSD-1015) (100 mg/kg i.p.), a central aromatic L-amino acid decarboxylase (AADC) inhibitor.', 'TH and TPH activities were determined in tissue extracts by measuring the accumulation of L-Dopa and 5-HTP respectively, following the administration of the aromatic L-amino acid decarboxylase inhibitor, NSD-1015. ', 'Results of a neurochemical study of the effects of the new anxiolytic drugs afobazole and ladasten on the synthesis and metabolism of monoamines and their metabolites determined by HPLC on the model of monoamine synthesis blockade induced by NSD-1015 (aromatic L-amino acid decarboxylase) in the brain structures of Wistar rats are reported. ', '. When pretreated with a central AADC inhibitor (NSD-1015)', 'NSD 1015 (general AADC inhibitor)', 'monoamine synthesis blockade induced by NSD-1015 (aromatic L-amino acid decarboxylase) ', 'the aromatic-l-amino-acid decarboxylase (EC 4.1.1.28) inhibitor NSD-1015', 'An accumulation of L-dihydroxyphenylalanine (DOPA) in the median eminence of female rats treated with 3-hydroxybenzylhydrazine (NSD 1015), and inhibitor of aromatic L-amino acid decarboxylase (DOPA decarboxylase) activity, was associated with a decreased concentration of dopamine in the median eminence and pronounced reduction in the release of dopamine into hypophysial portal blood.', '6S-BH4 increased extracellular DOPA levels in the presence of NSD 1015, an inhibitor of aromatic L-amino acid decarboxylase (an index of in vivo tyrosine hydroxylase activity), to an extent similar to the increase induced by 6R-BH4.', '5-HT synthesis was estimated by measuring the accumulation of the 5-HT precursor, 5-hydroxytryptophan (5-HTP), in the neurointermediate lobe of male Long-Evans rats following the administration of NSD 1015, an inhibitor of aromatic L-amino acid decarboxylase.', 'Monoamine synthesis was studied in different parts of the brain by measuring the accumulated dopa and 5-hydroxytryptophan (5-HTP), 30 min after NSD 1015 (3-hydroxybenzylhydrazine HCl, 100 mg/kg) an inhibitor of aromatic L-amino-acid decarboxylase, given i.p.', 'HPLC coupled with electrochemical detection was used to make concurrent measurements of the rate of accumulation of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine in selected brain regions (striatum, nucleus accumbens, septum, medial periventricular hypothalamus) and thoracic spinal cords of rats treated with NSD 1015, an inhibitor of aromatic-L-amino-acid decarboxylase.', 'The activity of 5-hydroxytryptaminergic neurons has been estimated from measurements of: concentrations of 5-hydroxyindoleacetic acid; the ratio of the concentrations of 5-hydroxyindoleacetic acid to 5-hydroxytryptamine; the rate of accumulation of 5-hydroxytryptophan following the administration of an aromatic L-amino acid decarboxylase inhibitor (e.g., NSD 1015); the rate of accumulation of 5-hydroxytryptamine, and the rate of decline of 5-hydroxyindoleacetic acid following the administration of a monoamine oxidase inhibitor (e.g., pargyline).', 'The accumulation of dopa (3,4-dihydroxyphenylalanine) after administration of NSD 1015 to inhibit aromatic l-amino acid decarboxylase was determined as an index of NE synthesis.', 'The central aromatic amino acid DOPA decarboxylase inhibitor, NSD-1015, does not inhibit L-DOPA-induced circling in unilateral 6-OHDA-lesioned-rats.', 'The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA.', 'The aromatic amino acid decarboxylase inhibitor, NSD-1015, increases release of dopamine: response characteristics.', 'The aromatic amino acid decarboxylase inhibitor NSD 1015 markedly increased the dopa concentration.', 'Using a microdialysis technique, the rat striatum was perfused with NSD-1015, an inhibitor of aromatic L-amino acid decarboxylase, and the amount of L-3,4-dihydroxyphenylalanine (L-DOPA) and 5-hydroxytryptophan (5-HTP) accumulating in dialysate was measured as an index of in vivo activities of tyrosine hydroxylase and tryptophan hydroxylase.', 'Also, we studied the effect of MnCl2 on extracellular levels of l-Dopa in the presence of aromatic amino acid decarboxylase (AADC) inhibitor 3-hydroxybencilhydracine-HCl (NSD 1015).', 'The role of L-DOPA itself was investigated by administering several doses of an aromatic L-amino acid decarboxylase inhibitor, NSD 1015, prior to 100 mg/kg L-DOPA to 5-day-old rats.', 'An accumulation of L-dihydroxyphenylalanine (DOPA) in the median eminence of female rats treated with 3-hydroxybenzylhydrazine (NSD 1015), and inhibitor of aromatic L-amino acid decarboxylase (DOPA decarboxylase) activity, was associated with a decreased concentration of dopamine in the median eminence and pronounced reduction in the release of dopamine into hypophysial portal blood. ', '[Neurochemical study of effects of the new anxiolytic drugs afobazol and ladasten on the synthesis and metabolism of monoamines and their metabolites in the brain structures of Wistar rat on the model of monoamine synthesis blockade induced by aromatic amino acid decarboxylase inhibitor NSD-1015].', 'DOPA was measured in the anterior pituitary and hypothalamic-hypophysial portal blood after treatment with NSD-1015, a DOPA decarboxylase inhibitor. ', 'Central action of an inhibitor of brain dopa-decarboxylase, NSD-1015, on cyanamide-induced alcohol drinking in rats.', 'The role of L-DOPA itself was investigated by administering several doses of an aromatic L-amino acid decarboxylase inhibitor, NSD 1015, prior to 100 mg/kg L-DOPA to 5-day-old rats. ', 'The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. ', 'Furthermore, the ethanol-induced enhancement of 3,4-dihydroxyphenylalanine accumulation in the mesolimbic dopamine terminal area after NSD 1015 (an inhibitor of l-aromatic amino acid decarboxylase) was completely antagonized by mecamylamine in doses (3.0 and 6.0 mg/kg) that exerted no effects per se.', 'The acetylcholinesterase inhibitor physostigmine (0.5 mg/kg s.c.) enhanced L-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in both the corpus striatum and limbic areas (nucleus accumbens) after inhibition of aromatic amino acid decarboxylase with NSD-1015, indicating an enhanced synthesis of dopamine in these brain regions.', 'Estradiol benzoate-treated rats had significantly lower anterior pituitary DOPA accumulation after intraperitoneal administration of 3,4-hydroxybenzyl-hydrazine dihydrochloride (NSD-1015), an irreversible inhibitor of L-aromatic amino acid decarboxylase whereas methylene blue did not affect anterior pituitary DOPA accumulation when compared to controls.', 'The accumulation of dihydroxyphenylalanine (DOPA) following administration of the L-aromatic amino acid decarboxylase inhibitor, NSD 1015, was used to estimate DA synthesis.', 'Inhibition of PE synthesis by i.p. injection of the aromatic L-amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19-6327.', 'After 42 hr of abstinence, rats were challenged with either cocaine (15 mg/kg, ip) or saline, followed by the aromatic L-amino acid decarboxylase inhibitor 3-hydroxybenzylhydrazine (NSD-1015; 100 mg/kg, ip).', 'Following motor activity observations, the cerebral aromatic L-amino acid decarboxylase inhibitor NSD-1015 (100 mg kg-1 intraperitoneally) was administered and 30 min. later the animals were decapitated for subsequent analysis of the accumulated forebrain DOPA and 5-HTP levels, as an estimate of the rate of monoamine synthesis.', 'The utility of this technique was demonstrated by comparing the effects on the scans of halothane and pentobarbital anesthesia and by the administration of NSD 1015, a peripheral and central inhibitor of L-aromatic amino-acid decarboxylase, between back-to-back scans.', 'Addition of the aromatic amino acid decarboxylase inhibitor, 3-hydroxybenzylhydrazine (NSD 1015), prevented the formation of N-acetylcompounds from L-[3H]tyrosine, without resulting in an accumulation of label in L-DOPA.', 'The effects of the peripheral aromatic amino acid decarboxylase (AADC) inhibitors, carbidopa and benserazide, and the central AADC inhibitor, 3-hydroxybenzylhydrazine (NSD-1015) on peripheral and brain monoamine oxidase (MAO) A and B activity were investigated in the rat.', 'Although the putative role of NSD-1015 is as an aromatic amino acid decarboxylase inhibitor, the present results demonstrate that, either as a result of this function and/or in addition to this role, NSD-1015 is a potent activator of the release of dopamine.', 'The aromatic amino acid decarboxylase inhibitor, NSD-1015, increases release of dopamine: response characteristics.', 'The central aromatic amino acid DOPA decarboxylase inhibitor, NSD-1015, does not inhibit L-DOPA-induced circling in unilateral 6-OHDA-lesioned-rats.', 'The L-aromatic amino acid decarboxylase inhibitor, NSD-1015 (3-hydroxybenzylhydrazine dihydrochloride) was then given ICV twice daily in a volume of 5.0 microliters in the following doses: 0.005, 0.01, 0.1 and 1.0 micrograms.', 'Although the putative role of NSD-1015 is as an aromatic amino acid decarboxylase inhibitor, the present results demonstrate that, either as a result of this function and/or in addition to this role, NSD-1015 is a potent activator of the release of dopamine..']

['Yes, NSD-1015 is an ihnibitor of Aromatic L-Amino Decarboxylase.']

['yes']

Which anticancer drugs target human topoisomerase II?

['Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA', 'benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity', 'F14512, a polyamine-containing inhibitor of DNA topoisomerase II', 'F14512, an epipodophyllotoxin derivative equipped with a spermine moiety, is selectively taken up by the polyamine transport system over-active in tumor cells', 'F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a water-soluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS', 'Twenty previously synthesized fused heterocyclic DNA-topoisomerase II (Topo II)-inhibiting compounds were investigated for their potential efficacy in various human cancer cell lines that were derived from different tumor entities', 'In conclusion, compounds BD 13, BD 14, BD 16, D 23 and D 24 may be useful for the treatment of different multidrug-resistant cancer cells with cross resistance against "classical" Topo II-targeting drugs.', 'ATPase domain of eukaryotic DNA topoisomerase II. Inhibition of ATPase activity by the anti-cancer drug bisdioxopiperazine and ATP/ADP-induced dimerization', 'We tested the effects of two DNA topoisomerase II poisons, etoposide and doxorubicin', 'the bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF-187', 'Bisdioxopiperazine drugs such as ICRF-187 are catalytic inhibitors of DNA topoisomerase II, with at least two effects on the enzyme: namely, locking it in a closed-clamp form and inhibiting its ATPase activity', 'These findings suggest that the difference in drug sensitivities to doxorubicin and etoposide in human lung cancer cell lines might not be explainable by the topoisomerase II alpha levels and topoisomerase II catalytic activity', 'Reduced expression of DNA topoisomerase II confers resistance to etoposide (VP-16) in small cell lung cancer cell lines', 'topoisomerase II-targeting anticancer agents, etoposide (VP-16) and teniposide (VM-26)', 'the anti-cancer DNA topoisomerase II poison etoposide (VP-16', 'New DNA topoisomerase II inhibitors less prone to redox reactions, such as mitoxantrone and more recently the anthrapyrazoles, were developed to circumvent this toxicity', 'Two anthrapyrazoles currently in clinical evaluation, DuP 941 (Losoxantrone) and DuP 937, were compared to other topoisomerase II inhibitors', 'Among topoisomerase II inhibitors, the cytostatic potency was by decreasing order: mitoxantrone; doxorubicin, which was slightly greater than DuP 941, azatoxin; DuP 937; and amsacrine, which was much greater than VP-16', 'n an attempt to clarify the role of drug-induced protein-associated DNA breaks (i.e., DNA topoisomerase II-mediated DNA cleavage) in the cytotoxic activity of doxorubicin and etoposide', "The effect of combinations of the anthracycline aclarubicin and the topoisomerase II targeting drugs 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16) and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) was investigated in a clonogenic assay", 'Antagonistic effect of aclarubicin', 'The effect of combinations of the anthracyclines aclarubicin and daunorubicin was investigated in a clonogenic assay using the human small cell lung cancer cell line OC-NYH and a multidrug-resistant (MDR) murine subline of Ehrlich ascites tumor (EHR2/DNR+)', 'the DNA topoisomerase II inhibitors doxorubicin and etoposide in both types of cancer cell lines', 'the DNA topoisomerase II inhibitors doxorubicin and etoposide in human lung cancer cell lines', 'cells are cross-resistant to some drugs that interact with topoisomerase II but not mitoxantrone', 'suramin decreases the phosphorylation of Topo II mediated by PKC. This effect of suramin might cause the inhibition of Topo II activity resulting in the growth inhibition of tumor cells.']

['Etoposide (VP-16) and Teniposide (VM-26) are effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Doxorubicin, Daunorubicin and Aclarubicin are anthracyclins that act as DNA topoisomerase II inhibitors and may be used in combination. Benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity. F14512 is a polyamine-containing epipodophyllotoxin derivative that acts as an inhibitor of DNA topoisomerase II. Bisdioxopiperazine drugs such as ICRF-187 are catalytic inhibitors of DNA topoisomerase II. \nAmong topoisomerase II inhibitors, the cytostatic potency was by decreasing order: mitoxantrone; doxorubicin, which was slightly greater than DuP 941, azatoxin; DuP 937; and amsacrine, which was much greater than VP-16']

['Etoposide (VP-16)', 'Teniposide (VM-26)', 'Doxorubicin', 'Daunorubicin', 'Aclarubicin', 'Mitoxantrone', 'Amsacrine (m-AMSA)']

Is Mycobacterium avium less susceptible to antibiotics than Mycobacterium tuberculosis?

['The prevalence of MAC lung infection in two inner city hospitals was four times higher than that of TB.', 'Most patients with combined infection were clinically consistent with MTB and responded to anti MTB treatment alone.', 'The triplex PCR developed by us could be used to detect and differentiate M. tuberculosis, M. avium and other mycobacteria in a single reaction tube.', 'Twelve (15%) of the 80 blood cultures were positive for mycobacteria, with Mycobacterium avium being identified in 7 (8.8%) samples and M. tuberculosis in 5 (6.2%). ', 'The antimycobacterial activities of RS-112997, RS-124922 and RS-118641, three capuramycin analogues that inhibit phospho-N-acetylmuramyl-pentapeptide translocase, were tested against clinical isolates of Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare', 'The MIC50/90 (mg/L) results for RS-118641 were: M. tuberculosis, 1/2; multidrug-resistant (MDR) M. tuberculosis, 0.5/2; M. avium, 4/8; and M. intracellulare, 0.06/0.5', 'These results suggest that capuramycin analogues exhibit strong antimycobacterial potential and should be considered for further evaluation in the treatment of M. tuberculosis and M. avium-M. intracellulare complex infections in humans.', 'Mycobacterium avium causes disseminated infection in patients with acquired immune deficiency syndrome.', 'Overall incidences of Mycobacterium tuberculosis (TB) and Mycobacterium avium complex (MAC) were 0.8 and 1.4 cases/100 person-years of follow-up (PYF), decreasing from 1.8 (TB) and 3.5 cases/100 PYF (MAC) before September 1995 to 0.3 and 0.2 cases/100 PYF after March 1997.', 'Because M tuberculosis disease is preventable and curable and yet communicable, physicians should maintain a high degree of suspicion for tuberculosis in HIV-infected adults. In comparison, the goal of treating M avium complex in patients with advanced HIV disease is to reduce constitutional symptoms and improve survival.', 'MAC pulmonary disease should be considered in the differential diagnosis of SPNs, even when encountered in geographic regions with a high prevalence of pulmonary tuberculosis.', 'From April 2001 to February 2002, 80 blood samples from patients who were suspected to have disseminated mycobacterial infection, presenting fever and (preferably) a CD4 T cell count<100.0 cell/mL were investigated', 'IL-10 underlies distinct susceptibility of BALB/c and C57BL/6 mice to Mycobacterium avium infection and influences efficacy of antibiotic therapy.', 'Clinical utility of rifabutin 1 (RBT), a potent antibiotic used in multidrug regimens for tuberculosis (TB) as well as for infections caused by Mycobacterium avium complex (MAC), has been hampered due to dose-limiting toxicity. ', 'Effective therapeutic regimens exist that are limited by the emergence of drug resistance and the inability of antibiotics to kill dormant organisms. ', 'Clinical utility of rifabutin 1 (RBT), a potent antibiotic used in multidrug regimens for tuberculosis (TB) as well as for infections caused by Mycobacterium avium complex (MAC), has been hampered due to dose-limiting toxicity.', 'a potent antibiotic used in multidrug regimens for tuberculosis (TB) as well as for infections caused by Mycobacterium avium complex (MAC),', 'Clinical utility of rifabutin 1 (RBT), a potent antibiotic used in multidrug regimens for tuberculosis (TB) as well as for infections caused by Mycobacterium avium complex (MAC), has been hampered due to dose-limiting toxicity.', 'tuberculosis appear to have different genetic mechanisms for resisting the effects of these antibiotics, with pks12 playing a relatively more significant role in MAC.']

['Mycobacterium avium causes disseminated infection in patients with acquired immune deficiency syndrome. M tuberculosis disease is preventable and curable and yet communicable, physicians should maintain a high degree of suspicion for tuberculosis in HIV-infected adults. In comparison, the goal of treating M avium complex in patients with advanced HIV disease is to reduce constitutional symptoms and improve survival. Patients who were suspected to have disseminated mycobacterial infection, presenting fever and (preferably) a CD4 T cell count<100.0 cell/mL were investigated. Twelve (15%) of the 80 blood cultures were positive for mycobacteria, with Mycobacterium avium being identified in 7 (8.8%) samples and M. tuberculosis in 5 (6.2%). The antimycobacterial activities of RS-112997, RS-124922 and RS-118641, three capuramycin analogues that inhibit phospho-N-acetylmuramyl-pentapeptide translocase, were tested against clinical isolates of Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare. The MIC50/90 (mg/L) results for RS-118641 were: M. tuberculosis, 1/2; multidrug-resistant (MDR) M. tuberculosis, 0.5/2; M. avium, 4/8; and M. intracellulare, 0.06/0.5']

['yes']

What is the CEGA catalog?

['CEGA--a catalog of conserved elements from genomic alignments.', 'To facilitate the study of such CNCs/UCEs, we present our resource of Conserved Elements from Genomic Alignments (CEGA), accessible from http://cega.ezlab.org. Harnessing the power of multiple species comparisons to detect genomic elements under purifying selection, CEGA provides a comprehensive set of CNCs identified at different radiations along the vertebrate lineage. Evolutionary constraint is identified using threshold-free phylogenetic modeling of unbiased and sensitive global alignments of genomic synteny blocks identified using protein orthology. We identified CNCs independently for five vertebrate clades, each referring to a different last common ancestor and therefore to an overlapping but varying set of CNCs with 24 488 in vertebrates, 241 575 in amniotes, 709 743 in Eutheria, 642 701 in Boreoeutheria and 612 364 in Euarchontoglires, spanning from 6 Mbp in vertebrates to 119 Mbp in Euarchontoglires. The dynamic CEGA web interface displays alignments, genomic locations, as well as biologically relevant data to help prioritize and select CNCs of interest for further functional investigations.', 'To facilitate the study of such CNCs/UCEs, we present our resource of Conserved Elements from Genomic Alignments (CEGA), accessible from http://cega.ezlab.org.', 'To facilitate the study of such CNCs/UCEs, we present our resource of Conserved Elements from Genomic Alignments (CEGA), accessible from http://cega.ezlab.org', 'CEGA--a catalog of conserved elements from genomic alignments', 'CEGA--a catalog of conserved elements from genomic alignments.', 'To facilitate the study of such CNCs/UCEs, we present our resource of Conserved Elements from Genomic Alignments (CEGA), accessible from http://cega.ezlab.org.']

['CEGA is a catalog of conserved elements from genomic alignments. Harnessing the power of multiple species comparisons to detect genomic elements under purifying selection, CEGA provides a comprehensive set of CNCs identified at different radiations along the vertebrate lineage. Evolutionary constraint is identified using threshold-free phylogenetic modeling of unbiased and sensitive global alignments of genomic synteny blocks identified using protein orthology. The dynamic CEGA web interface displays alignments, genomic locations, as well as biologically relevant data to help prioritize and select CNCs of interest for further functional investigations.']

[]

Which are the thyroid hormone analogs utilized in human studies?

["Here, we evaluate the therapeutic potential of the TH analog 3,5,3',5'-tetraiodothyroacetic acid (tetrac) as a replacement for T(4) in brain development. ", 'This treatment was sufficient to promote TH-dependent neuronal differentiation in the cerebellum, cerebral cortex, and striatum but was ineffective in suppressing hypothalamic TRH expression. ', 'In the current study, we investigated the effect of a natural thyroid hormone analogue - 3, 3?, 5-triiodo-thyroacetic acid (TRIAC) on regulating proliferation and differentiation and its possible molecular mechanism in normal human epidermal keratinocytes and C57BL/6 mice.', 'TRIAC was effective and safe in ameliorating the effects of hyperthyroidism and ADHD symptoms in a child with known genetic RTH.']

['TRIAC and TETRAC are two different thyroid hormone analogs utilized in human studies']

['TRIAC', 'TETRAC']

Has vitamin D has been shown to reduce incidence of falls in older people in clinical trials?

['However, apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly, causality remains yet unproven in randomized controlled trials (RCTs). ', 'The rate of falls and the number of fallers was significantly reduced in two studies evaluating the effect of medication on preventing falls; one study (85 participants) compared vitamin D versus placebo in institutionalised women after stroke with low vitamin D levels, and the other study (79 participants) evaluated alendronate versus alphacalcidol in hospitalised people after stroke.', 'Two studies testing vitamin D versus placebo and alendronate versus alphacalcidol found a significant reduction in falls and the number of people falling', '.Overall, vitamin D supplementation does not appear to reduce falls but may be effective in people who have lower vitamin D levels before treatment.', 'Overall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment.', 'Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly.', 'We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96)', 'This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D.', 'Vitamin D combined with calcium reduces the risk of falls.', 'The majority of the evidence is derived from trials enrolling elderly women.', 'Studies of vitamin D and calcium for fracture prevention have produced inconsistent results, as a result of different vitamin D status and calcium intake at baseline, different doses and poor to adequate compliance.', 'Despite significant increases in the provision of hip protectors and use of vitamin D supplementation in both intervention and control facilities, there was no difference in the number of falls or falls injuries between the intervention and control groups, nor a reduction in falls overall.', 'Beyond fall and fracture prevention, vitamin D may also reduce overall morbidity by multiple mechanisms. ', 'There is evidence to suggest that these agents may reduce the incidence of nonvertebral fractures and falls; however, their benefit on vertebral fracture reduction may depend on the type of active vitamin D. ']

['The rate of falls and the number of fallers was significantly reduced in two studies evaluating the effect of medication on preventing falls; one study (85 participants) compared vitamin D versus placebo in institutionalised women after stroke with low vitamin D levels, and the other study (79 participants) evaluated alendronate versus alphacalcidol in hospitalised people after stroke.\nTwo studies testing vitamin D versus placebo and alendronate versus alphacalcidol found a significant reduction in falls and the number of people falling.\nOverall, vitamin D did not reduce rate of falls (RaR 1.00, 95% CI 0.90 to 1.11; seven trials; 9324 participants) or risk of falling (RR 0.96, 95% CI 0.89 to 1.03; 13 trials; 26,747 participants), but may do so in people with lower vitamin D levels before treatment.\nWe found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96)']

['yes']

Which protein phosphatases have been found to dephosphorylate phospholamban?

['The protein phosphatases which dephosphorylate native, sarcoplasmic reticulum (SR)-associated phospholamban were studied in cardiac muscle extracts and in a Triton fraction prepared by detergent extraction of myofibrils, the latter fraction containing 70-80% of the SR-associated proteins present in the tissue. At physiological concentrations of free Mg2+ (1 mM), protein phosphatase 1 (PP1) accounted for approximately 70% of the total phospholamban phosphatase activity in these fractions towards either Ser-16 (the residue labelled by cAMP-dependent protein kinase, PK-A) or Thr-17 (the residue phosphorylated by an SR-associated Ca2+/calmodulin-dependent protein kinase). Protein phosphatase 2A (PP2A) and protein phosphatase 2C (PP2C) accounted for the remainder of the activity.', 'These results are consistent with the views that protein phosphatase 1 is capable of dephosphorylating membrane-associated phospholamban when it is phosphorylated by protein kinase A, but not by calcium/calmodulin kinase, and that under certain conditions, calcium/calmodulin-stimulated protein phosphatase (protein phosphatase 2B) is also able to dephosphorylate PLN phosphorylated by protein kinase A. Additionally, the observations show that protein phosphatase 1 is extremely active against the three protein kinase A substrates (M(r) 23, 19 and 17 kDa) that were present in the isolated microsomes and whose state of phosphorylation was particularly affected in the presence of dimethylsulfoxide.', 'These results are consistent with the views that protein phosphatase 1 is capable of dephosphorylating membrane-associated phospholamban when it is phosphorylated by protein kinase A, but not by calcium/calmodulin kinase, and that under certain conditions, calcium/calmodulin-stimulated protein phosphatase (protein phosphatase 2B) is also able to dephosphorylate PLN phosphorylated by protein kinase A', 'These results are consistent with the views that protein phosphatase 1 is capable of dephosphorylating membrane-associated phospholamban when it is phosphorylated by protein kinase A, but not by calcium/calmodulin kinase, and that under certain conditions, calcium/calmodulin-stimulated protein phosphatase (protein phosphatase 2B) is also able to dephosphorylate PLN phosphorylated by protein kinase A']

['The protein phosphatases which dephosphorylate native, sarcoplasmic reticulum (SR)-associated phospholamban were studied in cardiac muscle extracts and in a Triton fraction prepared by detergent extraction of myofibrils, the latter fraction containing 70-80% of the SR-associated proteins present in the tissue. At physiological concentrations of free Mg2+ (1 mM), protein phosphatase 1 (PP1) accounted for approximately 70% of the total phospholamban phosphatase activity in these fractions towards either Ser-16 (the residue labelled by cAMP-dependent protein kinase, PK-A) or Thr-17 (the residue phosphorylated by an SR-associated Ca2+/calmodulin-dependent protein kinase). Protein phosphatase 2A (PP2A) and protein phosphatase 2C (PP2C) accounted for the remainder of the activity. ', 'The protein phosphatases which dephosphorylate native, sarcoplasmic reticulum (SR)-associated phospholamban were studied in cardiac muscle extracts and in a Triton fraction prepared by detergent extraction of myofibrils, the latter fraction containing 70-80% of the SR-associated proteins present in the tissue. At physiological concentrations of free Mg2+ (1 mM), protein phosphatase 1 (PP1) accounted for approximately 70% of the total phospholamban phosphatase activity in these fractions towards either Ser-16 (the residue labelled by cAMP-dependent protein kinase, PK-A) or Thr-17 (the residue phosphorylated by an SR-associated Ca2+/calmodulin-dependent protein kinase). Protein phosphatase 2A (PP2A) and protein phosphatase 2C (PP2C) accounted for the remainder of the activity.']

['Protein Phosphatase 1', 'PP1', 'Protein phosphatase 2A', 'PP2A', 'Protein Phosphatase 2C', 'PP2C', 'Protein Phosphatase 2B', 'PP2B']

Is the PTPN22 gene a biomarker for rheumatoid arthritis?

['TPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease', '21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL', 'he HLA locus, particularly HLA-DRB1, is its strongest genetic risk determinant across ethnicities. Several other genes, including PTPN22 and PADI4, show modest association with RA. ', 'Several alleles in the epitope-recognition part of the HLA molecule that show the highest association with RA susceptibility, also share a common string of amminoacid residues (the so-called shared-epitope hypothesis). Other variants in potentially pathogenic genes located in non-MHC regions have been implicated by recently performed genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, STAT4. ', 'n particular, genome-wide association studies (GWAS) have provided supportive evidence that RA is a disease with a strong genetic background. Interestingly, a series of candidate genes have been identified outside of the classical major histocompatibility (MHC) locus, which had long been regarded as the major contributor to the pathogenesis of this disease. Among these genes, PTPN22 plays an outstanding role.', 'ssociation of the PTPN22 gene (-1123G > C) polymorphism with rheumatoid arthritis in Chinese patients', 'Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis', 'Recent genome-wide association studies (GWAS) on RA identified known and novel susceptibility genes like HLA-DRB1, PTPN22, STAT4, TRAF1/C5, OLIG3/TNFAIP3, CD40, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, IL2RB, and KIF5A-PIP4K2C. ', 'This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort', 'After initial completion of the Human Genome Project on the 16th February 2001, significant progress has been made in identifying other than HLA genome regions linked to the increased RA susceptibility. As an effect several new genes have been recognized as an HLA-independent genetic risk factors of RA. PTPN22 gene polymorphism, C5/TRAF1 genes region polymorphism and TNFAIP3-OLIG3 genes region polymorphism(s) are among newly identified and already confirmed genetic risk factors', 'As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA.', 'Recent advances have led to novel identification of genetic polymorphisms that are associated with susceptibility to rheumatoid arthritis (RA). Currently, 5 loci (HLA, PTPN22, TRAF1/C5, TNFAIP3, and STAT4) have been consistently reported, whereas others have been observed less systematically', 'However, inconsistent results of the contributions of non-HLA susceptibility genes have been described, with the exception of a few genes repeatedly associated with RA-susceptibility, such as PTPN22 gene in populations of European ancestry and PADI4 gene in populations of Asian ancestry, revealing the presence of genetic heterogeneity in RA. ', 'In conclusion, we have confirmed that PTPN22 620W allele is associated with Tunisian RA but does not constitute a factor influencing clinical manifestations. ', 'After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts', 'We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P=.00002), using previously untested EIRA samples.', 'Although HLA-DRB1 is the main RA gene, it accounts for only part of the familial risk for RA. HLA-DRB1 alleles are neither necessary nor sufficient to cause the development of RA in a given individual. Several genome scans conducted in populations from France, Japan, North America and UK have confirmed the role of the HLA region and suggested several other susceptibility loci. Association studies support a role for several genes, including TNFR2, PADI4, SLC22A4, RUNX1, and PTPN22.', 'the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis', 'PTPN22, PADI-4, and CTLA-4 have been associated with risk for rheumatoid arthritis (RA)', 'progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele', 'In this Dutch cohort of UA-patients, the PTPN22 1858T allele does not markedly improve individual decision-making to predict RA-development', 'challenges in identifying genetic polymorphisms that influence the susceptibility to rheumatoid arthritis are the same as those faced in most complex diseases', 'Recently a number of convincing candidate genes have begun to emerge and an update has been provided for three of these: PTPN22']

['Most association studies have indeed confirmed an association between mutations at the PTPN22 gene and rheumatoid arthritis']

['yes']

Can aspirin be used in cancer prevention?

[' Evidence for an association between aspirin or other nonsteroidal antiinflammatory drug (NSAID) use and basal cell carcinoma (BCC) has been inconsistent.', ' We report for the first time, in a typical risk US clinical population, a lack of protective association of aspirin for polyps among active smokers. Future prospective studies are recommended to confirm this mitigating effect in order to improve the precision of the growing evidence base about the chemopreventive benefit of aspirin in colorectal cancer.', 'The most serious side effect of prolonged aspirin treatment is haemorrhage, especially from the GI tract. This is likely to be less of a problem with chemoprevention at lower doses. One also needs to consider the impact if aspirin resistance, an increasingly recognised clinical entity.', 'Overall, our results do support the hypothesis that use of NSAIDs or statins may reduce the odds of developing pancreatic cancer.', 'Understanding is growing of the possible mechanisms by which aspirin exerts its anticancer effects. ', 'Long-term aspirin use was associated with a modest but significantly reduced risk for overall cancer, especially gastrointestinal tract tumors. Regular aspirin use may prevent a substantial proportion of colorectal cancers and complement the benefits of screening.']

['Long-term aspirin use was associated with a modest but significantly reduced risk for overall cancer, especially gastrointestinal tract tumors. Regular aspirin use may prevent a substantial proportion of colorectal cancers and complement the benefits of screening.']

[]

What is the effect of ranolazine in diastolic heart failure?

['Data from in vitro and animal studies indicate that ranolazine improves diastolic function by inhibiting the late sodium current. ', 'Ranolazine is an innovative anti-ischemic and antianginal agent that inhibits the late Na current, thereby reducing the Na-dependent Ca-overload, which improves diastolic tone and oxygen handling during myocardial ischemia. In addition, ranolazine seems to exert beneficial effects on diastolic cardiac function. ', 'Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity', 'Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.', 'Ranolazine (10 microM) significantly reduced the PC-induced increase in LVEDP by 72 +/- 6% (n = 6, p < 0.001), reduced left ventricular wall stiffness, and attenuated the PC-induced increase of CPP by 53 +/- 10% (n = 6-7, p < 0.05). ', ' Ranolazine, a specific inhibitor of late INa, reduces Na influx and hence ameliorates disturbed Na and Ca homeostasis.', 'New clinical and experimental studies even point to potential antiarrhythmic effects, beneficial effects in diastolic heart failure, and under hyperglycemic conditions.']

['Data from in vitro and animal studies indicate that ranolazine improves diastolic function by inhibiting the late sodium current. Ranolazine is an innovative anti-ischemic and antianginal agent that reduces the Na-dependent Ca-overload, which improves diastolic tone and oxygen handling during myocardial ischemia. Furthermore, ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.']

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Is tirilazad effective for treatment of aneurysmal subarachnoid haemorrhage?

['There was no significant difference between the two groups at the end of follow up for the primary outcome, death (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.74 to 1.06), or in poor outcome (death, vegetative state or severe disability) (OR 1.04, 95% CI 0.90 to 1.21). During the treatment period, fewer patients developed delayed cerebral ischaemia in the tirilazad group than in the control group (OR 0.80, 95% CI 0.69 to 0.93). Subgroup analyses did not demonstrate any significant difference in effects of tirilazad on clinical outcomes. ', "AUTHORS' CONCLUSIONS: There is no evidence that tirilazad, in addition to nimodipine, reduces mortality or improves poor outcome in patients with aneurysmal SAH.", 'This clinical trial suggest that tirilazad mesylate, at a dosage of 6 mg/kg/day, improves overall outcome in aneurysmal subarachnoid hemorrhage patients.', 'Tirilazad is ineffective.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', 'Findings from previous multicenter clinical trials have suggested that tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH).', 'This clinical trial suggest that tirilazad mesylate, at a dosage of 6 mg/kg/day, improves overall outcome in aneurysmal subarachnoid hemorrhage patients.']

['No. Based on meta-analysis, there is no evidence that tirilazad, in addition to nimodipine, reduces mortality or improves poor outcome in patients with aneurysmal subarachnoid haemorrhage.']

['no']

What do nerve-associated peripheral glial progenitors give rise to?

['Parasympathetic neurons originate from nerve-associated peripheral glial progenitors.', 'We show that the parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites.', 'Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors.', 'Parasympathetic neurons originate from nerve-associated peripheral glial progenitors', 'Neurodevelopment. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors.']

['Nerve-associated peripheral glial progenitors give rise to parasympathetic neurons. The parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites.', 'Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites.', 'Parasympathetic neurons originate from nerve-associated peripheral glial progenitors.']

['Parasympathetic neurons']

Which is the subcellular localization of ERAP2?

['The human endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 proteins ', 'They are categorized as a unique class of proteases based on their subcellular localization on the luminal side of the endoplasmic reticulum. ', 'endoplasmic reticulum aminopeptidase 2 (ERAP2) ', 'ERAP2 is a proteolytic enzyme set in the endoplasmic reticulum (ER) ', 'both A-LAP and L-RAP are retained in the endoplasmic reticulum']

['Endoplasmic reticulum aminopeptidase 2 (ERAP2) is localized to the luminal side of the endoplasmic reticulum.']

['luminal side of the endoplasmic reticulum']

Is PUVA therapy indicated for eczema treatment?

['With bath PUVA treatment, the best results were found in patients with hyperkeratotic eczema (17/22; 77% good clinical response) followed by patients with palmoplantar psoriasis (26/41; 63%) and patients with dyshidrotic eczema (8/16; 50%). ', 'Oral vs. bath PUVA using 8-methoxypsoralen for chronic palmoplantar eczema.', 'Both oral and bath PUVA with 8-methoxypsoralen (8-MOP) have been shown to be effective in the treatment of chronic palmoplantar eczema. ', 'Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema.', 'Treatment of hand eczema is dominated by the administration of topical glucocorticosteriods. If topical treatment fails, the best second-line option is ultraviolet (UV) therapy alone or as combination therapy. UVB and PUVA (psoralen plus UVA) therapy is effective and has relatively few side effects. ', 'Although local PUVA has been proven to be effective in the treatment of chronic hand eczema, little is known about the efficacy and safety of local narrowband UVB (TL-01) for this condition.', 'Local narrowband UVB phototherapy regimen is as effective as paint-PUVA therapy in patients with chronic hand eczema of dry and dyshidrotic types.', 'Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved.', 'Treatment of chronic palmoplantar eczema with local bath-PUVA therapy.', 'Bath-PUVA therapy has been described as successful treatment for palmoplantar eczema.', 'Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema.', 'A new psoralen-containing gel for topical PUVA therapy: development, and treatment results in patients with palmoplantar and plaque-type psoriasis, and hyperkeratotic eczema.', 'These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema.', 'In order to evaluate environmental influences possibly having an impact on the efficacy of this therapy, smokers and non-smokers suffering from palmoplantar eczema treated with bath-PUVA therapy were compared.', 'Does smoking influence the efficacy of bath-PUVA therapy in chronic palmoplantar eczema?', 'PUVA therapy caused acute aggravation of the eczema.', 'Hyperkeratotic eczema cleared significantly better with oral than with bath PUVA (P=0.03).CONCLUSION: Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema.', 'BACKGROUND: Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema.', 'These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema.', 'Vitiligo (60.9%) was the commonest skin disorder treated with PUVA, followed by psoriasis (20.9%), endogenous eczema (11.3%), mycosis fungoides (3.5%), lichen amyloidosis (2.6%) and prurigo nodularis (0.9%).', 'bath PUVA using 8-methoxypsoralen for chronic palmoplantar eczema.', 'A 36-year-old female patient was treated with PUVA for dyshidrotic eczema that had not shown sufficient response to topical therapy over the previous months.', 'BACKGROUND: Both oral and bath PUVA with 8-methoxypsoralen (8-MOP) have been shown to be effective in the treatment of chronic palmoplantar eczema.', 'One patient with hand eczema consistently had detectable 8-MOP levels 1 hour after topical PUVA treatments.CONCLUSION: This report indicates that there is minimal, if any, systemic absorption of 8-MOP after topical PUVA treatment of patients with palmoplantar psoriasis.', 'In the narrowband UVB-treated side, the tolerance of all the patients to the treatment was good all patients well-tolerated the treatment with the exception of mild xerosis that responded to topical emollients.Local narrowband UVB phototherapy regimen is as effective as paint-PUVA therapy in patients with chronic hand eczema of dry and dyshidrotic types', 'Bath-PUVA therapy has been described as successful treatment for palmoplantar eczema', 'Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved', 'Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema', 'However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema.Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment.After fungal or bacterial infection had been excluded in all patients, hands or feet or both were soaked for 15 minutes in warm water containing 1 mg/L 8-methoxypsoralen', 'No phototoxic reactions were observed.Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment', 'Treatment of chronic palmoplantar eczema with local bath-PUVA therapy', 'Bath-PUVA therapy has been described as successful treatment for palmoplantar eczema. ', 'Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved.', 'OBJECTIVE: Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment. ', 'CONCLUSION: Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment. ', 'Topical PUVA therapy for chronic hand eczema.', 'However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema.Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment.After fungal or bacterial infection had been excluded in all patients, hands or feet or both were soaked for 15 minutes in warm water containing 1 mg/L 8-methoxypsoralen.', 'No phototoxic reactions were observed.Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment.', 'Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved.', 'However, our own observations showed that patients with palmoplantar eczema of the dyshidrotic or hyperkeratotic type responded only partially to bath-PUVA therapy.', 'In the narrowband UVB-treated side, the tolerance of all the patients to the treatment was good all patients well-tolerated the treatment with the exception of mild xerosis that responded to topical emollients.Local narrowband UVB phototherapy regimen is as effective as paint-PUVA therapy in patients with chronic hand eczema of dry and dyshidrotic types.', 'Comparison of localized high-dose UVA1 irradiation versus topical cream psoralen-UVA for treatment of chronic vesicular dyshidrotic eczema.', 'No phototoxic reactions were observed.CONCLUSION: Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment.', 'These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema..', 'Treatment of chronic palmoplantar eczema with local bath-PUVA therapy.', 'Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema..', 'Does smoking influence the efficacy of bath-PUVA therapy in chronic palmoplantar eczema?', 'Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment.', 'However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema.', 'A new psoralen-containing gel for topical PUVA therapy: development, and treatment results in patients with palmoplantar and plaque-type psoriasis, and hyperkeratotic eczema.', 'Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved..', 'In order to investigate the effectiveness of topical PUVA-bath therapy (PUVA-soak therapy) on chronic palmoplantar dermatoses, 30 patients with plaque-type psoriasis, pustular psoriasis, endogenous eczema, dyshidrotic eczema and hyperkeratotic dermatitis of the palms and soles were treated over 8 weeks with PUVA-soak using 8-MOP.', 'Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment.']

['Yes, PUVA (psoralen plus UVA) therapy is effective for eczema treatment and has relatively few side effects.']

['yes']

Which genes does thyroid hormone receptor alpha1 regulate in the liver?

['Mice expressing the mutant thyroid hormone receptor TRalpha1R384C, which has a 10-fold reduced affinity to the ligand T(3), exhibit hypermetabolism due to an overactivation of the sympathetic nervous system. To define the consequences in the liver, we analyzed hepatic metabolism and the regulation of liver genes in the mutant mice. Our results showed that hepatic phosphoenolpyruvate-carboxykinase was up-regulated and pyruvate kinase mRNA down-regulated, contrary to what observed after T(3) treatment', 'Remarkably, there was an obligatory requirement for a TR, whether TRbeta or TRalpha1, for any detectable D1 expression in liver.', 'Liver and kidney D1 mRNA and activity levels were reduced in TRbeta(-/-) but not TRalpha1(-/-) mice']

['phosphoenolpyruvate-carboxykinase"//\n"pyruvate kinase"//\n"D1", "deiodinase 1"//']

['phosphoenolpyruvate-carboxykinase', 'pyruvate kinase', 'D1', 'deiodinase 1']

Which proteins participate in the formation of the Notch transcriptional activation complex?

['The Notch intracellular domain (NICD) forms a transcriptional activation complex with the DNA-binding factor CSL and a transcriptional co-activator of the Mastermind family (MAML). The "RAM" region of NICD recruits Notch to CSL, facilitating the binding of MAML at the interface between the ankyrin (ANK) repeat domain of NICD and CSL.', 'Inappropriate release of the intracellular domain of Notch (N(ICD)) from the plasma membrane results in the accumulation of deregulated nuclear N(ICD) that has been linked to human cancers, notably T-cell acute lymphoblastic leukemia (T-ALL). Nuclear N(ICD) forms a transcriptional activation complex by interacting with the coactivator protein Mastermind-like 1 and the DNA binding protein CSL (for CBF-1/Suppressor of Hairless/Lag-1) to regulate target gene expression.', 'Although it is well understood that N(ICD) forms a transcriptional activation complex, little is known about how the complex is assembled.', 'Canonical Notch signaling is initiated when ligand binding induces proteolytic release of the intracellular part of Notch (ICN) from the cell membrane. ICN then travels into the nucleus where it drives the assembly of a transcriptional activation complex containing the DNA-binding transcription factor CSL, ICN, and a specialized co-activator of the Mastermind family. A consensus DNA binding site motif for the CSL protein was previously defined using selection-based methods, but whether subsequent association of Notch and Mastermind-like proteins affects the DNA binding preferences of CSL has not previously been examined.', 'We report here the crystal structure of a Notch transcriptional activation complex containing the ankyrin domain of human Notch1 (ANK), the transcription factor CSL on cognate DNA, and a polypeptide from the coactivator Mastermind-like-1 (MAML-1). ', 'Ligand binding by Notch receptors triggers a series of proteolytic cleavages that liberate the intracellular portion of Notch (ICN) from the cell membrane, permitting it to translocate to the nucleus. Nuclear ICN binds to a highly conserved DNA-binding transcription factor called CSL (also known as RBP-Jkappa, CBF1, Suppressor of Hairless, and Lag-1) and recruits Mastermind-like transcriptional co-activators to form a transcriptional activation complex.', 'On the basis of our results, we present a working structural model for the organization of the MAML1.ICN.CSL.DNA complex.', 'The requirement for cooperative assembly of the MAML1.ICN.CSL.DNA complex suggests that a primary function of ICN is to render CSL competent for MAML loading.', 'We report here that the astrogliogenic role of Notch is in part mediated by direct binding of the Notch intracellular domain to the CSL DNA binding protein, forming a transcriptional activation complex onto the astrocyte marker gene, glial fibrillary acidic protein (GFAP).', 'Importantly, although the classical CSL-dependent Notch signaling pathway is intact and able to activate the Notch canonical target promoter during the neurogenic phase, it is unable to activate the GFAP promoter during neurogenesis.', 'Mastermind (Mam) is a component of Notch pathway signaling. In combination with the intracellular domain of Notch and Suppressor of Hairless, Mam forms a transcriptional activation complex.', 'High levels of Notch-mediated transcriptional activation require the formation of a ternary complex consisting of NotchICD, CSL (CBF-1, suppressor of hairless, LAG-1) and a Mastermind family member.', 'This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA.', 'This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA', 'High levels of Notch-mediated transcriptional activation require the formation of a ternary complex consisting of NotchICD, CSL (CBF-1, suppressor of hairless, LAG-1) and a Mastermind family member', 'NotchIC, together with the transcriptional coactivator Mastermind, form a ternary complex with CSL that activates transcription from genes that are responsive to Notch signaling', 'Nuclear N(ICD) forms a transcriptional activation complex by interacting with the coactivator protein Mastermind-like 1 and the DNA binding protein CSL (for CBF-1/Suppressor of Hairless/Lag-1) to regulate target gene expression', 'Nuclear ICN binds to a highly conserved DNA-binding transcription factor called CSL (also known as RBP-Jkappa, CBF1, Suppressor of Hairless, and Lag-1) and recruits Mastermind-like transcriptional co-activators to form a transcriptional activation complex']

['The Notch intracellular domain (NICD) forms a transcriptional activation complex with the DNA-binding factor CSL and a transcriptional co-activator of the Mastermind family (MAML). ICN binds to a highly conserved DNA-binding transcription factor called CSL (also known as RBP-Jkappa, CBF1, Suppressor of Hairless, and Lag-1) and recruits Mastermind-like transcriptional co-activators to form a transcriptional activation complex.', 'Although it is well understood that N(ICD) forms a transcriptional activation complex, little is known about how the complex is assembled. The Notch intracellular domain (NICD) forms a transcriptional activation complex with the DNA-binding factor CSL and a transcriptional co-activator of the Mastermind family (MAML).']

['Notch intracellular domain (NICD)', 'NICD', 'Intracellular part of Notch', 'ICN', 'NIC', 'Transcription factor CSL', 'RBP-Jkappa', 'CBF1', 'Suppressor of Hairless', 'Lag-1', 'The coactivator protein Mastermind-like 1', 'MAML-1']

Is RET the major gene involved in Hirschsprung disease?

['The RET proto-oncogene is the major gene associated to HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology', 'The RET proto-oncogene is the major gene for HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology', 'The rearranged during transfection gene (RET) is considered the major gene in HSCR', 'RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology', 'While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease', ' The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease.', 'The RET proto-oncogene is the major gene involved in the complex genetics of Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative loss-of-function mutations in 15-30% of the sporadic cases.', 'The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET.', 'The RET proto-oncogene is considered to be the major susceptibility gene involved in Hirschsprung disease.', ' Hirschsprung disease (HSCR), a developmental disorder characterized by the absence of enteric neurons in distal segments of the gut, shows a complex pattern of inheritance, with the RET protooncogene acting as a major gene and additional susceptibility loci playing minor roles.', ' Traditional RET germline mutations account for a small subset of Hirschsprung disease patients, but several studies have shown that there is a specific haplotype of RET associated with the sporadic forms of Hirschsprung disease.', 'PURPOSE: The RET proto-oncogene is considered to be the major susceptibility gene involved in Hirschsprung disease.', 'The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut.', 'While rare variants (RVs) in the coding sequence (CDS) of several genes involved in ENS development lead to disease, the association of common variants (CVs) with HSCR has only been reported for RET (the major HSCR gene) and NRG1.', 'The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease.', 'The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7.', 'Hirschsprung disease (HSCR), a developmental disorder characterized by the absence of enteric neurons in distal segments of the gut, shows a complex pattern of inheritance, with the RET protooncogene acting as a major gene and additional susceptibility loci playing minor roles.', 'BACKGROUND: The RET gene encodes a tyrosine kinase receptor involved in different human neurocristopathies, such as specific neuroendocrine tumours and Hirschsprung disease (HSCR).', 'The first major susceptibility gene for Hirschsprung disease is the RET proto-oncogene on 10q11.2.', 'The developmental abnormalities apparent in these mice, together with the observation that the major tissues affected in MEN 2 and Hirschsprung disease have a common origin in the embryonal neural crest, suggest that RET encodes a receptor for a developmental regulator involved in the genesis of a variety of neural crest derivatives, and in the organogenesis of the kidney.', 'RET is the major gene involved in HSCR.', 'Recent advances show that the RET gene is a major locus involved in the pathogenesis of HSCR.', 'Although with several genes involved in its pathogenesis, the major HSCR gene is the RET proto-oncogene.', 'In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model.', 'The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut', 'The RET proto-oncogene is the major gene involved in the complex genetics of Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative loss-of-function mutations in 15-30% of the sporadic cases', 'The RET proto-oncogene is considered to be the major susceptibility gene involved in Hirschsprung disease', 'Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations', 'RET is the major gene involved in HSCR', 'Although with several genes involved in its pathogenesis, the major HSCR gene is the RET proto-oncogene', 'While rare variants (RVs) in the coding sequence (CDS) of several genes involved in ENS development lead to disease, the association of common variants (CVs) with HSCR has only been reported for RET (the major HSCR gene) and NRG1', 'The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease', 'Recent advances show that the RET gene is a major locus involved in the pathogenesis of HSCR', 'In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model', 'We report on mutation analysis of five genes involved in the receptor tyrosine kinase (RET) or the endothelin-signalling pathways in 28 sporadic Japanese patients with Hirschsprung disease', 'In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease', 'The RET gene is the major HSCR gene, although reduced penetrance of RET mutations and variable expression of HSCR phenotype indicates that more than one gene is required']

['The RET proto-oncogene is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology.', 'RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology ']

['yes']

Have gnotobiotic animal models been used for the study of bowel disease?

['Host gene expression in the colon of gnotobiotic interleukin-2-deficient mice colonized with commensal colitogenic or noncolitogenic bacterial strains: common patterns and bacteria strain specific signatures.', ' Specific pathogen-free (SPF), but not germfree (GF), interleukin (IL)-2-deficient (IL-2-/-) mice develop inflammatory bowel disease (IBD) at 10 to 15 weeks of age. Gnotobiotic IL-2-/- mice monocolonized with E. coli mpk develop IBD at 25 to 33 weeks of age but not B. vulgatus mpk, E. coli Nissle 1917, or mice cocolonized with both E. coli mpk and B. vulgatus', 'Lactobacillus reuteri promotes Helicobacter hepaticus-associated typhlocolitis in gnotobiotic B6.129P2-IL-10(tm1Cgn) (IL-10(-/-) ) mice.', 'To model inflammatory bowel disease, we assessed infection with Helicobacter hepaticus 3B1 (ATCC 51449) and a potential probiotic Lactobacillus reuteri (ATCC PTA-6475) in gnotobiotic B6.129P2-IL-10(tm1Cgn) (IL-10(-/-) ) mice. No typhlocolitis developed in germ-free controls (n=21) or in L. reuteri (n=8) or H. hepaticus (n=18) mono-associated mice for 20 weeks post-infection. As positive controls, three specific pathogen-free IL-10(-/-) mice dosed with H. hepaticus developed severe typhlocolitis within 11 weeks. ', 'These data support that the development of typhlocolitis in H. hepaticus-infected IL-10(-/-) mice required co-colonization with other microbiota and in this study, required only L. reuteri. ', 'When transferred to gnotobiotic mice, gut microbiomes from mice with active disease versus treatment-induced remission elicited varying degrees of colitis. ', 'The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases.', 'The immunomodulatory effects of microbiota and probiotics for inflammatory bowel diseases and the role of bacteria in their etiologies are being studied in gnotobiotic systems.', 'To model inflammatory bowel disease, we assessed infection with Helicobacter hepaticus 3B1 (ATCC 51449) and a potential probiotic Lactobacillus reuteri (ATCC PTA-6475) in gnotobiotic B6.129P2-IL-10(tm1Cgn) (IL-10(-/-) ) mice.', 'Gnotobiotic piglets may be used as a suitable animal model to study colitis induced by C. jejuni', 'The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases', 'We investigated the changes in renal expression of Kl as a consequence of colitis. METHODS: We studied 3 mouse models of IBD: colitis induced by trinitrobenzene sulfonic acid, colitis induced by microflora (in gnotobiotic interleukin-10(-/-)), and colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells. ', 'METHODS: We studied 3 mouse models of IBD: colitis induced by trinitrobenzene sulfonic acid, colitis induced by microflora (in gnotobiotic interleukin-10(-/-)), and colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells. ']

['Yes, gnotobiotic animals (e.g. mice) have been used for the study of bowel disease (e.g. inflammatory bowel disease).']

['yes']

Do conserved noncoding elements co-occur with matrix-attachment regions?

["We hypothesized that some of these regions might be matrix-scaffold attachment regions, MARs (or S/MARs). MARs comprise one of the few classes of eukaryotic noncoding DNA with an experimentally characterized function, being involved in the attachment of chromatin to the nuclear matrix, chromatin remodeling and transcription regulation. To test our hypothesis, we analyzed the co-occurrence of predicted MARs with highly conserved noncoding DNA regions in human-mouse genomic alignments. We found that 11% of the conserved noncoding DNA consists of predicted MARs. Conversely, more than half of the predicted MARs co-occur with one or more independently identified conserved sequence blocks. An excess of conserved predicted MARs is seen in intergenic regions preceding 5' ends of genes, suggesting that these MARs are primarily involved in transcriptional control", 'A significant fraction of conserved noncoding DNA in human and mouse consists of predicted matrix attachment regions.', 'To test our hypothesis, we analyzed the co-occurrence of predicted MARs with highly conserved noncoding DNA regions in human-mouse genomic alignments.', 'To test our hypothesis, we analyzed the co-occurrence of predicted MARs with highly conserved noncoding DNA regions in human-mouse genomic alignments']

["Yes. It is estimated that 11% of the conserved noncoding DNA consists of predicted MARs. Conversely, more than half of the predicted MARs co-occur with one or more independently identified conserved sequence blocks. An excess of conserved predicted MARs is seen in intergenic regions preceding 5' ends of genes, suggesting that these MARs are primarily involved in transcriptional control."]

['yes']

Which enzyme deficiency can cause GM1 gangliosidoses?

['GM1 and GM2 gangliosidosis are associated with deficiency of β-galactosidase and β-hexosaminidase respectively', 'The total content and distribution of retinal glycosphingolipids was studied for the first time in control mice and in Sandhoff disease (SD) and GM1 gangliosidosis mice', 'The GSL abnormalities in the SD and the GM1 retinas reflect significant reductions in beta-hexosaminidase and beta-galactosidase enzyme activities, respectively', 'In the absence of macular or retinal degeneration, organomegaly, and somatic-facial features suggesting mucopolysaccharidosis, the presence of hyperacusis together with sea-blue histiocytes in bone marrow biopsies and deficient beta-galactosidase activity but normal glucosidase, hexosaminidase, and neuraminidase activity on lysosomal enzyme assays constitutes the clinical-pathologic-biochemical profile of GM1 gangliosidosis type 2. This is a rare, late infantile onset, progressive gray-matter disease in which beta-galactosidase deficiency is largely localized to the brain, though it can be demonstrated in leukocytes and cultured skin fibroblasts', 'GM1-gangliosidosis (genetic beta-galactosidase deficiency)', 'GM1-gangliosidosis is a genetic neurological disorder caused by mutations in the lysosomal acid beta-galactosidase gene', 'GM1-gangliosidosis is a rare neurovisceral storage disease caused by an inherited deficiency of acid beta-galactosidase', 'A female infant with early-onset GM1-gangliosidosis type I was investigated. The lymphocytes, transformed lymphocytes and cultured skin fibroblasts of the patient were demonstrated to have severe beta-D-galactosidase deficiency', 'Only 1 individual was found to have about 50% of normal beta-galactosidase activity; presumably he is a carrier for beta-galactosidase deficiency (GM1 gangliosidosis).', 'GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme β-d-galactosidase', 'GM1 gangliosidosis is a genetic disease with lysosomal beta-galactosidase deficiency caused by mutations of the gene coding for this enzyme', 'GM1 gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid beta-galactosidase (beta-gal), the enzyme that catabolyzes GM1 within lysosomes', 'Correction of acid beta-galactosidase deficiency in GM1 gangliosidosis human fibroblasts by retrovirus vector-mediated gene transfer: higher efficiency of release and cross-correction by the murine enzyme', 'Review of the data is presented on the hereditary disease gangliosidosis GM1 and on the enzyme beta-galactosidose, deficiency of which is responsible for this disease', 'GM1 gangliosidosis and Morquio B disease are distinct disorders both clinically and biochemically yet they arise from the same beta-galactosidase enzyme deficiency', 'Heterogeneous patterns of biosynthesis, posttranslational processing, and degradation were demonstrated for mutant enzymes in three clinical forms of beta-galactosidase deficiency (beta-galactosidosis): juvenile GM1-gangliosidosis, adult GM1-gangliosidosis, and Morquio B disease.', 'GM1 gangliosidosis and Morquio B disease are distinct disorders both clinically and biochemically yet they arise from the same beta-galactosidase enzyme deficiency.', 'Cerebral lipids of patients with GM1-gangliosidoses, infantile, juvenile, and chronic type which are caused by deficiency of beta-galactosidase, were examined and compared to each other.', 'In the autosomal recessive disease GM1-gangliosidosis caused by a beta-gal deficiency and in galactosialidosis, associated with a combined deficiency of lysosomal neuraminidase and beta-gal, precursor forms of the latter enzyme are found in RER, Golgi and some labeling is present at the cell surface. The lysosomes remain unlabeled, indicative for the absence of enzyme molecules in this organelle.', 'In the lysosomes virtually all beta-gal exists as a high molecular weight multimer of mature enzyme. In the autosomal recessive disease GM1-gangliosidosis caused by a beta-gal deficiency and in galactosialidosis, associated with a combined deficiency of lysosomal neuraminidase and beta-gal, precursor forms of the latter enzyme are found in RER, Golgi and some labeling is present at the cell surface.', 'In the autosomal recessive disease GM1-gangliosidosis caused by a beta-gal deficiency and in galactosialidosis, associated with a combined deficiency of lysosomal neuraminidase and beta-gal, precursor forms of the latter enzyme are found in RER, Golgi and some labeling is present at the cell surface.', 'GM1 and GM2 gangliosidosis are associated with deficiency of β-galactosidase and β-hexosaminidase respectively.']

['GM1 gangliosidoses are associated with deficiency of β-galactosidase.']

['β-galactosidase']

Is there a relation between ANP and transcapillary albumin escape?

['Thus, in a large ethnically homogeneous cohort of diabetic subjects, our data show: (1) a significant association of C708/T polymorphism with microalbuminuria in long-term diabetes and with both lower plasma ANP levels and widespread albumin leakage', 'hese results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes.', 'Moreover, the increased susceptibility of the glomerular capillaries in diabetics to ANP seems to be part of a more generalized capillary abnormality, because ANP also increases the transcapillary escape of albumin.', 'In summary, low dose ANP infusion in healthy subjects caused a shift of plasma water and electrolytes from the circulation, with albumin escape as a secondary phenomenon.']

['A possible role of ANP gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes is present.\nANP infusion in healthy subjects caused a shift of plasma water and electrolytes from the circulation, with albumin escape as a secondary phenomenon']

['yes']

Which enzyme is targeted by the drug Imetelstat?

['Imetelstat (a telomerase antagonist) exerts off‑target effects on the cytoskeleton.', "imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. ", 'In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length.', 'We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells', 'Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths', ' Telomerase extension is less processive during the first few weeks following the reversal of long-term treatment with the telomerase inhibitor Imetelstat (GRN163L), a time when Cajal bodies fail to deliver telomerase RNA to telomeres.', 'The role of telomerase as an immunotherapy, as a gene therapy approach using telomerase promoter driven oncolytic viruses and as a small oligonucleotide targeted therapy (Imetelstat) will be discussed', 'We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo. R', 'e telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines', 'In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited.', 'Telomerase activity is required for the maintenance of normal adult stem cells, and we examined the activity of the telomerase inhibitor imetelstat against MM CSC.', 'Human MM CSC were isolated from cell lines and primary clinical specimens and treated with imetelstat, a specific inhibitor of the reverse transcriptase activity of telomerase. Two weeks of exposure to imetelstat resulted in a significant reduction in telomere length and the inhibition of clonogenic MM growth both in vitro and in vivo. ', "Short oligonucleotide N3'-->P5' thio-phosphoramidate conjugated to 5'-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor", 'etelstat (GRN163L)--telomerase-based cancer therapy.', 'Imetelstat (GRN163L) is a potent and specific telomerase inhibitor and so far the only drug of its class in clinical trials.', 'e telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth.', 'The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo. ', 'Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC(50) 0.45 micromol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells.', ' We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. ', 'Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor.']

["Imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models."]

['Human Telomerase']

LY450139 is investigational name of which drug?

['The outcomes of the clinical trials of the γ-secretase inhibitor Semagacestat (LY-450139) and the γ-secretase modulator (GSM) Tarenflurbil were disappointing, but may not represent the end of the γ-secretase era. ', 'A selective BACE inhibitor and the γ-secretase inhibitor LY450139 (semagacestat) were used to inhibit respective secretase.', 'ACS chemical neuroscience molecule spotlight on semagacestat (LY450139).', "Semagacestat (LY450139) is a novel γ-secretase inhibitor currently in late-stage development by Eli Lilly and Company as a potential treatment for Alzheimer's disease (AD). ", ' The γ-secretase inhibitor LY450139 (semagacestat) lowers plasma Aβ(1-40) and Aβ(1-42) in a dose-dependent manner but has no clear effect on the CSF level of these isoforms. ', 'TRODUCTION: LY450139 (semagacestat) inhibits gamma-secretase, a key enzyme for generation of amyloid beta (Abeta), the peptide deposited in plaques in Alzheimer disease (AD).', 'Two potent gamma-secretase inhibitors (GSIs), DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) and LY450139 (hydroxylvaleryl monobenzocaprolactam), were found to reduce the density of dendritic spines in wild-type mice. ', "velopment of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease.", 'OBJECTIVE: This paper reviews the pharmacology and chemical efficacy of an A beta-lowering agent, semagacestat (LY450139).', 'ACS chemical neuroscience molecule spotlight on semagacestat (LY450139).', ' A selective BACE inhibitor and the γ-secretase inhibitor LY450139 (semagacestat) were used to inhibit respective secretase.']

["LY450139 is investigational name of Semagacestat. It is a γ-secretase inhibitor developed for treatment for Alzheimer's disease. Chemical name of LY450139 is hydroxylvaleryl monobenzocaprolactam."]

['semagacestat']

Does ghrelin play a role in ischemic stroke?

['Recent evidence suggests that ghrelin may also be neuroprotective after injury in animal models of cerebral ischemia.', 'Overall, these experiments point to a neurodegenerative but antiapoptotic effect of endogenous ghrelin in this model of global ischemia, highlighting that further research is essential before we can apply ghrelin treatments to neurodegenerative insults in the clinic.', ' The serum ghrelin level was higher in the MCAO group when compared with the control group (P < 0.05). ', 'Our results showed that higher level of serum ghrelin decreased gastrointestinal motility and damage to the intestinal mucosa existed in rats with MCAO.', 'Leptin, adiponectin and ghrelin, new potential mediators of ischemic stroke.', 'RESULTS: Significantly higher levels of leptin and lower levels of adiponectin and ghrelin were confirmed in the stroke group.', 'Ghrelin levels correlated mildly with triglyceride levels, and were dominant in men with cardioembolic stroke.', 'CONCLUSIONS: Adipokines and ghrelin play an important role in ischemic stroke, but their function in stroke subtypes seems to be different and sex influenced.', 'Ghrelin suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve.', 'Compared with vehicle treatment, human ghrelin treatment in vagus nerve-intact rats after MCAO showed marked reduction in neurological deficit by 57% and infarct size by 25%. ', 'Human ghrelin treatment in vagus nerve-intact rats significantly decreased the above measurements. Human ghrelin treatment also improved 7-day survival and significantly decreased neurological deficit over the entire 7 days after MCAO in vagus nerve-intact rats compared with vehicle. ', 'Human ghrelin is thus a neuroprotective agent that inhibits inflammation, nNOS activity, and apoptosis in focal cerebral ischemia through a vagal pathway.', 'Ghrelin is known to promote neuronal defense and survival against ischemic injury by inhibiting apoptotic processes. ', 'Our data indicate that des-acyl ghrelin, as well as ghrelin, protect cortical neurons against ischemic injury through the inhibition of Par-4 expression and apoptotic molecules in mitochondrial pathway.', 'In conclusion, it is considered that ghrelin as well as S-100B can be a useful marker for the prediction of stoke after CPB. ', 'Adipokines and ghrelin play an important role in ischemic stroke, but their function in stroke subtypes seems to be different and sex influenced.', 'In this review we discuss pre-clinical evidence suggesting ghrelin may be a useful therapeutic in protecting the brain against injury after ischemic stroke.', 'Both ghrelin and des-acyl ghrelin protected cortical neurons from ischemic injury.', 'Our data indicate that des-acyl ghrelin, as well as ghrelin, protect cortical neurons against ischemic injury through the inhibition of Par-4 expression and apoptotic molecules in mitochondrial pathway.', 'Adipokines and ghrelin play an important role in ischemic stroke, but their function in stroke subtypes seems to be different and sex influenced.', 'In this review we discuss pre-clinical evidence suggesting ghrelin may be a useful therapeutic in protecting the brain against injury after ischemic stroke', 'Human ghrelin is thus a neuroprotective agent that inhibits inflammation, nNOS activity, and apoptosis in focal cerebral ischemia through a vagal pathway', 'Both ghrelin and des-acyl ghrelin protected cortical neurons from ischemic injury', 'Overall, these experiments point to a neurodegenerative but antiapoptotic effect of endogenous ghrelin in this model of global ischemia, highlighting that further research is essential before we can apply ghrelin treatments to neurodegenerative insults in the clinic', 'In the present study, we investigated the role of prostate apoptosis response-4 (Par-4), a proapoptotic gene the expression of which is increased after ischemic injury, in ghrelin-mediated neuroprotection during middle cerebral artery occlusion (MCAO)', 'Adipokines and ghrelin play an important role in ischemic stroke, but their function in stroke subtypes seems to be different and sex influenced']

['Yes. It has been shown that serum ghrelin levels are reduced after ischemic stroke and ghrelin is associated with stroke type. Ghrelin can be a useful marker for the prediction of stoke after cardiopulmonary bypass. Ghrelin may be neuroprotective after injury in animal models of cerebral ischemia by inhibiting apoptotic processes, inflammation, nNOS activity and modulating gastrointestinal motility.']

['yes']

What is Creutzfeldt-Jakob Disease (CJD)?

['Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive, and fatal neurodegenerative disease affecting the central nervous system', 'Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)', 'The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc).', 'Creutzfeldt-Jakob disease (CJD) is a progressive, fatal, neurodegenerative disease classified under transmissible spongiform encephalopathies (TSE) or prion diseases', 'Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans', 'Creutzfeldt-Jakob disease (CJD) is a rare, degenerative and fatal brain disease that appears to be caused by an abnormal form of a protein called a prion.', 'Creutzfeldt-Jakob disease (CJD) is presumably caused by a slow infectious pathogen or prion. The principal clinical features of Creutzfeldt-Jakob disease are dementia, pyramidal and extrapyramidal symptoms and signs, cerebellar dysfunction, and myoclonus.', 'Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, neurodegenerative disorder causing dramatic neuromuscular symptoms, profound dementia, and death.', 'Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disorder.', 'Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative condition with a rapid disease course and a mortality rate of 100%.', 'Creutzfeldt-Jakob disease is a rare, but rapidly progressive, up to now untreatable and fatal neurodegenerative disorder', 'Creutzfeldt-Jakob disease is a rare neurodegenerative disease that belongs to the group of human spongiform encephalopathies and usually affects elderly people.', 'Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy']

['Creutzfeldt-Jakob disease (CJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)). The origin of CJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc).', 'Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive, and fatal neurodegenerative disease affecting the central nervous system Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)', 'Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive, and fatal neurodegenerative disease affecting the central nervous system']

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Which are the different proteins/isoforms encoded but the ASPH (aspartate beta-hydroxylase) gene in humans?

['The single genomic locus, AbetaH-J-J, encodes three functionally distinct proteins aspartyl beta-hydroxylase, junctin and junctate by alternative splicing.', 'The human AbetaH-J-J locus is a genomic sequence which generates three functionally distinct proteins, the enzyme aspartyl-beta-hydroxylase (AbetaH), the structural protein of sarcoplasmic reticulum junctin, and the membrane-bound calcium binding protein junctate.', 'Aspartyl (asparaginyl)-beta-hydroxylase (AAH) hydroxylates Asp and Asn residues within EGF-like domains of Notch and Jagged, which mediate cell motility and differentiation. This study examines the expression, regulation and function of AAH, and its related transcripts, Humbug and Junctin, which lack catalytic domains, using SH-Sy5y neuroblastoma cells.', 'Alternative splicing of the locus AbetaH-J-J generates three functionally distinct proteins: an enzyme, AbetaH (aspartyl-beta-hydroxylase), a structural protein of the sarcoplasmic reticulum membrane (junctin), and an integral membrane calcium binding protein (junctate).', 'Junctate is a newly identified integral ER/SR membrane calcium binding protein, which is an alternative splicing form of the same gene generating aspartyl beta-hydroxylase and junctin.', 'Screening a mouse heart cDNA library using canine junctin cDNA as a probe yielded three complete mouse heart cDNAs. One of the cDNAs is homologous to the previously reported human junctate.', 'Screening a cDNA library from human skeletal muscle and cardiac muscle with a cDNA probe derived from junctin led to the isolation of two groups of cDNA clones. The first group displayed a deduced amino acid sequence that is 84% identical to that of dog heart junctin, whereas the second group had a single open reading frame that encoded a polypeptide with a predicted mass of 33 kDa, whose first 78 NH(2)-terminal residues are identical to junctin whereas its COOH terminus domain is identical to aspartyl beta-hydroxylase, a member of the alpha-ketoglutarate-dependent dioxygenase family. We named the latter amino acid sequence junctate.', 'Our study shows that alternative splicing of the same gene generates the following functionally distinct proteins: an enzyme (aspartyl beta-hydroxylase), a structural protein of SR (junctin), and a membrane-bound calcium binding protein (junctate).', 'Junctin is a calsequestrin binding protein detected in junctional sarcoplasmic reticulum of striated muscles. In the present study, the human cardiac junctin cDNA has been cloned by human heart cDNA library screening and RT-PCR, and the cDNA sequence has been determined. The deduced amino acid sequence of human junctin (210 aa) has 84% sequence identity to that of canine junctin identified previously. A human junctin isoform (isoform 1, 225 aa) was also identified and characterized. The isoform 1 has a 15 aa insertion at the amino acid residue 55 of the human junctin. Northern blot analysis revealed that the human junctin was present both in cardiac and skeletal muscles, and the sizes of the transcripts were approximately 3.0 and 4.2kb. Amino acid residues 6-78 of human junctin and 35-107 of human aspartyl beta-hydroxylase (hAspH) overlapped perfectly.', "The mouse aspartyl beta-hydroxylase gene (Asph, BAH) has been cloned and characterized. The mouse BAH gene spans 200 kilobase pairs of genomic DNA and contains 24 exons. Of three major BAH-related transcripts, the two largest (6,629 and 4,419 base pairs) encode full-length protein and differ only in the use of alternative polyadenylation signals. The smallest BAH-related transcript (2,789 base pairs) uses an alternative 3' terminal exon, resulting in a protein lacking a catalytic domain. Evolutionary conservation of this noncatalytic isoform of BAH (humbug) is demonstrated in mouse, man, and Drosophila.", 'The single genomic locus, AbetaH-J-J, encodes three functionally distinct proteins aspartyl beta-hydroxylase, junctin and junctate by alternative splicing', 'Multiple levels of control of the expression of the human A beta H-J-J locus encoding aspartyl-beta-hydroxylase, junctin, and junctate.', 'A human junctin isoform (isoform 1, 225 aa) was also identified and characterized']

["Alternative splicing of the locus AbetaH-J-J (asparetyl-beta-hydroxylase) generates three functionally distinct proteins: an enzyme, AbetaH (aspartyl-beta-hydroxylase), a structural protein of the sarcoplasmic reticulum membrane (junctin), and an integral membrane calcium binding protein (junctate). Aspartyl (asparaginyl)-beta-hydroxylase (AAH), has also two related transcripts, Humbug and Junctin, which lack catalytic domains. The smallest BAH-related transcript (2,789 base pairs) uses an alternative 3' terminal exon, resulting in a protein lacking a catalytic domain. Evolutionary conservation of this noncatalytic isoform of BAH (humbug) is demonstrated in mouse, man, and Drosophila. A human junctin isoform (isoform 1, 225 aa) was also identified and characterized. The isoform 1 has a 15 aa insertion at the amino acid residue 55 of the human junctin."]

['Aspartyl-beta-hydroxylase', 'Aspartyl (asparaginyl)-beta-hydroxylase', 'AbetaH', 'AAH', 'BAH', 'humbug', 'junctate', 'junctin', 'junctin isoform']

Is calcium overload involved in the development of diabetic cardiomyopathy?

['High-glucose treatment resulted in increased intracellular calcium ([Ca2+]i) which was mobilized to the mitochondria. Concomitant intra-mitochondrial calcium ([Ca2+]m) increase resulted in enhanced reactive oxygen and nitrogen species generation. These events led to mitochondrial dysfunction and apoptosis.', 'The novel findings of the study reveal that high glucose induces apoptosis by both mitochondria-dependent and independent pathways via concomitant rise in intracellular calcium.', 'Diabetes-induced myocardial dysfunction has been attributed, in part, to calcium overload within individual myocytes.', 'It seems that intracellular calcium overload is intimately involved in the development of diabetic cardiomyopathy;', 'BACKGROUND: It has been suggested that intracellular Ca2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy.', 'The results from the alloxan-rat model of diabetes support the view that membrane abnormalities with respect to Ca2+ handling may lead to the occurrence of intracellular Ca2+ overload and the development of diabetic cardiomyopathy.', 'It seems that intracellular calcium overload is intimately involved in the development of diabetic cardiomyopathy; however, a concentrated research effort is required to understand the primary biochemical lesion in the pathogenesis of cardiac dysfunction in diabetes.', 'It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction.']

['Yes.']

['yes']

List the off-label use of SSRIs

['The present analysis evaluates the prevalence and medication use in inpatients with depression during childhood and adolescence', 'Fluoxetine and mirtazapine were the most frequently prescribed substances. Sertraline, escitalopram, and citalopram were also prescribed. CONCLUSION: A reserved medical treatment can be observed in child and adolescence psychiatry. Off-label use seems to be nearly unavoidable due to the lack of newly authorized medicine. Moreover, the numerous prescriptions for fluoxetine, the only SSRI currently approved for this age group in Germany, lead to the question of possible unauthorized alternatives.', 'Premature ejaculation (PE) is a common sexual dysfunction affecting 20% to 30% of men worldwide', 'Treatment of PE typically involves pharmacotherapy, particularly when lifelong. Although there are numerous reports on the off-label use of selective serotonin reuptake inhibitors (SSRIs) and other compounds, only 2 treatments have been evaluated in randomized controlled phase 3 clinical trials: PSD502 and dapoxetine (SSRI)', 'Drug therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline].', 'Amitriptyline and-in case of comorbid depressive disorder or generalized anxiety disorder-duloxetine are recommended. Off-label use of duloxetine and pregabalin can be considered in case of no comorbid mental disorder.', 'Trazodone is an antidepressant belonging to the class of serotonin receptor antagonists and reuptake inhibitors. It is approved by the FDA for the treatment of depression. Insomnia is the most frequent reason for prescription of trazodone. It has also been proven useful in the treatment of anxiety disorders. Other off-label uses include the treatment of bulimia, benzodiazepine/alcohol dependence, fibromyalgia, central nervous system degenerative diseases (behavioral disorders in dementia and other organic disorders), schizophrenia, chronic pain disease and diabetic neuropathy, sexual dysfunction.', 'symptoms of vasomotor dysregulation (hot flashes) associated with the menopausal transition and sex hormone deprivation. Implication of changes in central neurotransmission in the pathogenesis of hot flashes has prompted the off-label use of serotonergic and γ-aminobutyric acid-ergic drugs as a therapeutic alternative,', 'Sertraline was the most prescribed antidepressant for the treatment of major depressive disorder, followed by fluvoxamine and tianeptine. Fluvoxamine was the most prescribed antidepressant for the treatment of anxiety disorders and mixed disorders of emotions and conduct. Off-label prescribing of antidepressants was found in 85.6% of young patients.', 'Our results suggest that duloxetine is a possible alternative treatment of postprostatectomy established stress urinary incontinence.', 'Pharmacological treatment of fibromyalgia.', 'different classes of drugs with different mechanisms of action are used off-label, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs)', 'Gynaecological cancer patients generally suffer from an earlier and more severe menopausal syndrome than the general female population. Hormone replacement therapy is often contraindicated and there are non-hormonal treatments that are proven to be more effective than placebo in randomized controlled trials, e.g., some antidepressants, gabapentine and clonidine. The main limits to the use of these drugs in controlling hot flashes are the off-label use for this purpose,', 'ymptomatic therapy for patients with erectile dysfunction.', 'a oral daily off label use therapy with selective serotonin re-uptake inhibitors (paroxetine, fluoxetine, sertraline) can be offered.', 'Without the Food and Drug Administration approval, dapoxetine, as well as other SSRIs in PE, is an off-label drug for PE.', 'the treatment of PE consists of primarily off-label use of oral selective serotonin reuptake inhibitors (SSRIs) via either on-demand or daily delivery. ', 'The results of this off-label use show that Duloxetine is effective in men with SUI after prostate surgery even if standard pelvic floor exercises have failed.', 'Preliminary results on the off-label use of duloxetine for the treatment of stress incontinence after radical prostatectomy or cystectomy.', 'the number of children and adolescents whose visits involved prescription of antidepressants, particularly SSRIs, has increased markedly through 2002. Although fluoxetine remained the most commonly prescribed, other SSRIs were increasingly prescribed through 2002. These trends raise concerns regarding the widespread off-label use of antidepressants lacking reliable evidence of safety and efficacy for use in children and adolescents.', 'Given the presumed efficacy of these new compounds and the off-label use of the current SSRIs, one might conclude that psychotherapy\\behavior therapy for rapid ejaculation is an obsolete and antiquated intervention', 'The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding:', 'The use of selective serotonin reuptake inhibitors during pregnancy or lactation is, to date, not promoted because of lack of safety documentation. However, the off-label use of these drugs has been common for several years. In the treatment of mood and anxiety disorders during pregnancy, the serotonin reuptake inhibitors are often preferred over tricyclic antidepressants because of their relatively few adverse effects and safety in overdose. ', 'The last few years have seen a remarkable rise in the off-label use of trazodone for inducing sleep in nondepressed patients, to a degree that it is prescribed for this purpose as commonly as the leading hypnotic', 'Since the mid-1980s there has been a rapid rise in the off-label use of antidepressants, particularly trazodone, for treating insomnia.']

['depression during childhood and adolescence\nPremature ejaculation (PE)\nerectile dysfunction\nInsomnia\npostprostatectomy established stress urinary incontinence.\nmood and anxiety disorders during pregnancy and breast feeding\nsymptoms of vasomotor dysregulation (hot flashes) associated with the menopausal transition and sex hormone deprivation\n..off-label uses include the treatment of bulimia, benzodiazepine/alcohol dependence, fibromyalgia, central nervous system degenerative diseases (behavioral disorders in dementia and other organic disorders), schizophrenia, chronic pain disease and diabetic neuropathy, sexual dysfunction.']

['depression during childhood and adolescence', 'Premature ejaculation', 'PE', 'erectile dysfunction', 'Insomnia', 'postprostatectomy established stress urinary incontinence', 'SUI', 'mood and anxiety disorders during pregnancy and breast feeding', 'hot flashes', 'postmenopausal symptoms', 'bulimia', 'benzodiazepine/alcohol dependence', 'fibromyalgia', 'behavioral disorders in dementia', 'schizophrenia', 'chronic pain disease', 'diabetic neuropathy']

Describe the usefulness of the SPIKE database in human signaling pathways

['The rapid accumulation of knowledge on biological signaling pathways and their regulatory mechanisms has highlighted the need for specific repositories that can store, organize and allow retrieval of pathway information in a way that will be useful for the research community. SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction. To make database population and pathway comprehension straightforward, a simple yet informative data model is used, and pathways are laid out as maps that reflect the curator’s understanding and make the utilization of the pathways easy. The database currently focuses primarily on pathways describing DNA damage response, cell cycle, programmed cell death and hearing related pathways. Pathways are regularly updated, and additional pathways are gradually added. The complete database and the individual maps are freely exportable in several formats. The database is accompanied by a stand-alone software tool for analysis and dynamic visualization of pathways.', 'SPIKE: a database of highly curated human signaling pathways.', 'SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction.', 'SPIKE--a database, visualization and analysis tool of cellular signaling pathways.', 'SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction. ', 'SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&amp;~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction.']

['The rapid accumulation of knowledge on biological signaling pathways and their regulatory mechanisms has highlighted the need for specific repositories that can store, organize and allow retrieval of pathway information in a way that will be useful for the research community. SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction. To make database population and pathway comprehension straightforward, a simple yet informative data model is used, and pathways are laid out as maps that reflect the curator’s understanding and make the utilization of the pathways easy. The database currently focuses primarily on pathways describing DNA damage response, cell cycle, programmed cell death and hearing related pathways. Pathways are regularly updated, and additional pathways are gradually added. The complete database and the individual maps are freely exportable in several formats. The database is accompanied by a stand-alone software tool for analysis and dynamic visualization of pathways.']

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List all articles on network meta-analysis for smoking cessation

['Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis.', 'Pharmacological interventions for smoking cessation: an overview and network meta-analysis.', 'Effectiveness and cost-effectiveness of computer and other electronic aids for smoking cessation: a systematic review and network meta-analysis.', 'network meta-analysis on interventions for smoking cessation including over 100 trials', 'Smoking cessation interventions in COPD: a network meta-analysis of randomised trials.']

['Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis.\nPharmacological interventions for smoking cessation: an overview and network meta-analysis\nEffectiveness and cost-effectiveness of computer and other electronic aids for smoking cessation: a systematic review and network meta-analysis.\nSmoking cessation interventions in COPD: a network meta-analysis of randomised trials.']

['Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis.', 'Pharmacological interventions for smoking cessation: an overview and network meta-analysis', 'Effectiveness and cost-effectiveness of computer and other electronic aids for smoking cessation: a systematic review and network meta-analysis.', 'Smoking cessation interventions in COPD: a network meta-analysis of randomised trials.']

What is the suggested clinical management of Fanconi anemia?

['Hematopoietic stem cell transplantation is the only proven cure for the hematopoietic manifestations of FA and aggressive lifelong surveillance for solid tumors is essential.', 'Bone marrow surveillance is an important part of the clinical management of FA and often reveals cytogenetic aberrations', 'In patients with FA, there is a high incidence of aggressive HNSCC at a young age. Surgery remains the mainstay of treatment because patients with FA tolerate radiation therapy and chemotherapy poorly, with significant morbidity']

['Hematopoietic stem cell transplantation is the only proven cure for the hematopoietic manifestations of FA and aggressive lifelong surveillance for solid tumors is essential.In patients with FA, there is a high incidence of aggressive HNSCC at a young age. Surgery remains the mainstay of treatment because patients with FA tolerate radiation therapy and chemotherapy poorly, with significant morbidity', 'Hematopoietic stem cell transplantation is the only proven cure for the hematopoietic manifestations of FA and aggressive lifelong surveillance for solid tumors is essential. Surgery remains the mainstay of treatment because patients with FA tolerate radiation therapy and chemotherapy poorly, with significant morbidity. In patients with FA, there is a high incidence of aggressive HNSCC at a young age. Bone marrow surveillance is an important part of the clinical management of FA and often reveals cytogenetic aberrations. ', 'Hematopoietic stem cell transplantation is the only proven cure for the hematopoietic manifestations of FA and aggressive lifelong surveillance for solid tumors is essential.', 'Surgery remains the mainstay of treatment because patients with FA tolerate radiation therapy and chemotherapy poorly, with significant morbidity. In patients with FA, there is a high incidence of aggressive HNSCC at a young age. Hematopoietic stem cell transplantation is the only proven cure for the hematopoietic manifestations of FA and aggressive lifelong surveillance for solid tumors is essential. Bone marrow surveillance is an important part of the clinical management of FA and often reveals cytogenetic aberrations. ']

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Which genes are associated with Ehlers-Danlos syndrome type I/II?

['It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively', 'In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen', 'A smaller proportion of patients harbor a structural mutation in COL5A1 or COL5A2, causing the production of a functionally defective type V collagen protein', 'Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlos syndrome type I', 'Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele', 'We identified a novel splice-acceptor mutation (IVS4-2A-->G) in the N-propeptide-encoding region of COL5A1, in one patient with EDS type I', 'Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce ehlers-danlos syndrome type I', 'We have identified mutations of the COL5A2 gene, which encodes the alpha2(V) chain of type V collagen, in two unrelated patients with the severe type I form of EDS', 'Our findings show that heterozygous mutations of the COL5A2 gene can produce the EDS type I phenotype', 'A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro alpha 1(V) chains results in the gravis form of the Ehlers-Danlos syndrome (type I)', 'We report that genomic polymorphisms at the pro alpha 1(V) gene (COL5A1) locus cosegregated with the gravis form of Ehlers-Danlos syndrome (EDS) (type I) in a three generation family', 'Since exon 65 encodes 78 residues of the carboxyl propeptide, the expected result of this mutation is reduced efficiency in incorporating mutant pro alpha 1(V) chains into type V collagen molecules and reduced type V collagen synthesis', 'These studies indicate that heterozygous mutations in COL5A1 can result in EDS type I', 'The gene encoding collagen alpha1(V)(COL5A1) is linked to mixed Ehlers-Danlos syndrome type I/II', 'Recently, genetic linkage has been demonstrated between the COL5A1 gene, which encodes the alphal chain of type V collagen, and EDS type II in a large British kindred', 'Using a polymorphic intragenic simple sequence repeat at the COL5A1 locus, we now demonstrate tight linkage to EDS type I/II in a three-generation family', 'The variation in expression in this family suggests that EDS types I and II are allelic, and the linkage data support the hypothesis that mutation in COL5A1 can cause both phenotypes.', 'Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II).', 'Recently mutations have been found in the genes for type V collagen in a small number of people with the most common forms of EDS, types I and II', 'The gene encoding collagen alpha1(V)(COL5A1) is linked to mixed Ehlers-Danlos syndrome type I/II.', 'Linkage of the gene that encodes the alpha 1 chain of type V collagen (COL5A1) to type II Ehlers-Danlos syndrome (EDS II).', 'Genetic linkage to the collagen alpha 1 (V) gene (COL5A1) in two British Ehlers-Danlos syndrome families with variable type I and II phenotypes.']

['It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively', 'Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively ', 'It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively.', 'Ehlers-Danlos syndrome (EDS) type I (the classical variety) is a dominantly inherited, genetically heterogeneous connective-tissue disorder. Mutations in the COL5A1 and COL5A2 genes, which encode type V collagen, have been identified in several individuals. Most mutations affect either the triple-helical domain of the protein or the expression of one COL5A1 allele ']

['COL5A1', 'COL5A2']

Which technique is used for detection of EWS/FLI1 fusion transcripts?

['We evaluated the feasibility and usefulness of reverse transcriptase-polymerase chain reaction (RT-PCR) on fine-needle aspirates for categorization of small blue round cell tumors (SBRCTs). A total of 51 cases, including 25 Ewing sarcoma/peripheral primitive neuroectodermal tumors (PNETs), 11 rhabdomyosarcomas, 13 neuroblastomas, and 2 desmoplastic small round cell tumors (DSRCTs) were analyzed. The detection of the EWS-FLI1 (20/25) and EWS-ERG (4/25) fusion transcripts resolved 24 of 25 cases of Ewing sarcoma/PNET', 'Molecular detection of EWS-FLI1 chimeric transcripts in Ewing family tumors by nested reverse transcription-polymerase chain reaction', 'To assess the feasibility and reliability of the molecular detection of the transcript originating from the chimeric gene in paraffin-embedded tumor specimens, we performed a nested reverse transcription-polymerase chain reaction (RT-PCR)-based assay to detect the EWS-FLI1 chimeric message in a series of Ewing family tumors. Of 24 paraffin-embedded tumor specimens from 23 cases analyzed, the chimeric message was detectable in 20 (83%) specimens from 20 cases (87%) by this nested RT-PCR assay, whereas none of 7 small round cell tumors not from this family (3 alveolar rhabdomyosarcomas, 2 neuroblastomas, 2 malignant lymphomas) showed detectable chimeric messages', "Using our different sets of exon specific primer pairs, it was possible to detect 4 different breakpoints of ews/fli1 fusion transcripts and the ews/erg fusion by RT-PCR in RNA isolates from formalin-fixed, paraffin-embedded Ewing's tumor tissue.", 'Molecular detection of EWS-Fli1 fusion transcripts in formalin-fixed paraffin-embedded material by nested RT-PCR is feasible and is useful for the diagnosis and differential diagnosis of ES/pPNETs.', 'We established a novel RT-PCR method, using 3 different exon specific sets of PCR primer pairs, selected according to the coding ews and fli1 nucleotide sequences (NCBI database), suitable for RT-PCR identification of variant ews/fli1 fusion transcripts in RNA isolated from formalin-fixed, paraffin-embedded tissue.', 'In this study, we evaluated reverse transcriptase-polymerase chain (RT-PCR) for EWS-FLI1 fusion transcripts in 18 neurally derived small round cell tumours.', 'We performed a clinical and pathologic analysis of 112 patients with ES in which EWS-FLI1 fusion transcripts were identified by reverse-transcriptase polymerase chain reaction (RT-PCR).', 'Molecular detection of EWS-Fli1 fusion transcripts in formalin-fixed paraffin-embedded material by nested RT-PCR is feasible and is useful for the diagnosis and differential diagnosis of ES/pPNETs.', 'RT-PCR confirmed that SK-NEP-1 expresses EWS-FLI1 gene fusion transcripts characteristic of Ewing sarcoma, and DNA sequencing demonstrated the joining of exon 7 of EWS with exon 5 of FLI1 for these transcripts.', 'Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts', 'The aims of this study were (1) to present the diverse clinicopathological and molecular profile of EFTs in our settings, (2) to identify a pragmatic approach for diagnosing EFTs, especially for application of ancillary techniques, namely RT-PCR for specific transcripts (EWS-FLI1, EWS-ERG) and FISH for EWSR1 gene rearrangement, in certain cases and (3) to show the utility of tissue microarray in establishing a new FISH test', "[Detection of EWS-FLI1 fusion transcript in Ewing's sarcoma/peripheral primitive neuroectodermal tumors by one-step RT-PCR using paraffin-embedded tissues].", 'Molecular detection of EWS-Fli1 fusion transcripts in formalin-fixed paraffin-embedded material by nested RT-PCR is feasible and is useful for the diagnosis and differential diagnosis of ES/pPNETs.', 'We established a novel RT-PCR method, using 3 different exon specific sets of PCR primer pairs, selected according to the coding ews and fli1 nucleotide sequences (NCBI database), suitable for RT-PCR identification of variant ews/fli1 fusion transcripts in RNA isolated from formalin-fixed, paraffin-embedded tissue', 'Molecular detection of EWS-FLI1 chimeric transcripts in Ewing family tumors by nested reverse transcription-polymerase chain reaction: application to archival paraffin-embedded tumor tissues.']

['Molecular detection of EWS-FLI1 chimeric transcripts in Ewing family tumors is carried out by reverse transcription-polymerase chain reaction (RT-PCR).']

['Reverse transcription - polymerase chain reaction (RT-PCR)']

Have microRNAs been implicated in pharmacogenomics?

["A major discovery is the ability of miRNAs to determine the efficacy of drugs, which has given rise to the field of 'miRNA pharmacogenomics' through 'Pharmaco-miRs'. miRNAs play a significant role in pharmacogenomics by down-regulating genes that are important for drug function.", 'The potential modulation of toxicology-related changes in miRNA expression, the role of miRNA in immune-mediated drug-induced liver injuries, the use of circulating miRNAs in body fluids as potential toxicological biomarkers, and the link between miRNA-related pharmacogenomics and adverse drug reactions are highlighted.', 'Single nucleotide polymorphisms (SNPs) in the miRNA target sequences may affect or impair the binding of miRNAs. Studies have shown that SNPs in miRNA target sites (miR-TS-SNPs) have a great influence on diverse biological functions, including pharmacogenomics and disease susceptibilities in human.', 'Pharmacogenomics genes can be divided into drug target genes termed as pharmacodynamics genes (PD) and genes involved in drug transport and metabolism termed as pharmacokinetics genes (PK). To clarify the regulatory potential of miRNAs in pharmacogenomics, we have examined the potential regulation by miRNAs of PK and PD genes.', 'Our analysis identify a striking difference in the level of miRNA regulation between PK and PD genes, with the former having less than half predicted conserved miRNA binding sites compared with the latter. Importantly, this finding is reflected in a highly significant difference in the shift in expression levels of PD versus PK genes after depletion of miRNAs. CONCLUSIONS: Our study emphasizes an intrinsic difference between PK and PD genes and helps clarify the role of miRNAs in pharmacogenomics.', 'Pharmacogenomics, toxicogenomics, and small RNA expression analysis are three of the most active research topics in the biological, biomedical, pharmaceutical, and toxicological fields. All of these studies are based on gene expression analysis, which requires reference genes to reduce the variations derived from different amounts of starting materials and different efficiencies of RNA extraction and cDNA synthesis.', 'In contrast, hTBCA and small RNAs are more stable during drug treatment, and they are better reference genes for pharmacogenomics and toxicogenomics studies.', 'Polymorphisms of genes involved in the pharmacokinetic and pharmacodynamic processes underlie the divergent drug responses among individuals.', 'A panel of drug-response genes was constructed, which contains 923 pharmacokinetic genes, 703 pharmacodynamic genes and 720 miRNAs.', 'miRNA variations can affect drug resistance, efficacy, and metabolism, opening new avenues of pharmacogenomics research.', '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.', 'n 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. Ten of those microRNAs have already been implicated in cancer biology. Our results support a substantial role for microRNAs in anticancer drug response, suggesting novel potential approaches to the improvement of chemotherapy.', 'The NCI-60 has also been profiled for mRNA and protein expression, mutational status, chromosomal aberrations, and DNA copy number, generating an unparalleled public resource for integrated chemogenomic studies.', 'To complement the existing NCI-60 data sets, we have measured expression levels of microRNAs in the NCI-60 and incorporated the resulting data into the CellMiner program package for integrative analysis.', '. Comparison of microRNA expression patterns and compound potency patterns showed significant correlations, suggesting that microRNAs may play a role in chemoresistance. Combined with gene expression and other biological data using multivariate analysis, microRNA expression profiles may provide a critical link for understanding mechanisms involved in chemosensitivity and chemoresistance.', 'This study reports on miRNAs implicated in SSRI sensitivity of LCLs.', 'these miRNAs as tentative SSRI response biomarkers awaits validation with lymphocyte samples of major depression patients.']

['Yes. MicroRNAs have been implicated in pharmacogenomics.']

['yes']

Is Rheumatoid Arthritis related to myopathy?

['Prevalence of risk factors for statin-induced myopathy in rheumatoid arthritis patients', 'we describe a patient with rheumatoid arthritis and respiratory failure associated with proximal myopathy secondary to HCQ', 'Occurrence of chloroquine-induced myopathy after low-dose treatment of rheumatoid arthritis for seven years', 'a 75 year old female with rheumatoid arthritis treated with daily doses of 250 mg of chloroquine for four years. The patient visited because of several months history of predominantly proximal progressive tetraparesis with areflexia', 'Myopathy and neuropathy in rheumatoid arthritis', 'with rheumatoid arthritis (RA) have clinical or subclinical evidence of peripheral neuropathy or myopathy', 'The study reveals an increased prevalence of neurogenic but not myogenic changes in patients with RA compared with controls']

['Vacuolar myopathy and statin-induced myopathy have been reported in rheumatoid arthritis patients, but this association may be due to the anti-malarial treatment received. An increased prevalence of neurogenic but not myogenic changes in patients with RA compared with controls has been reported.']

['yes']

What is the function of 6SRNA in bacteria?

['Qbeta replicase lacking subunit alpha (R-alpha) is capable of replicating templates other than (+) strand, such as (--), "6S" RNA, poly(C) etc., in the absence of the host factor.', 'Escherichia coli 6S RNA gene is part of a dual-function transcription unit.', 'The DNA sequence results confirm the accuracy of the previously established RNA sequence and, with genomic hybridization data, reveal that there is only one copy of the 6S DNA in the chromosome. Consistent with its relaxed mode of expression, the promoter region of the 6S RNA gene was found to lack the hypothetical GC-rich discriminator domain common to other stable RNA genes under stringent control. The sequence results also revealed the occurrence of a 540-base-pair open reading frame immediately downstream from the 6S RNA coding region.', '6S RNA function enhances long-term cell survival.', '6S RNA-deficient cells are at a disadvantage for survival in stationary phase, a time when 6S RNA regulates transcription.', '6S RNA inhibition of sigma(70)-dependent transcription was not ubiquitous, in spite of the fact that the vast majority of sigma(70)-RNA polymerase is bound by 6S RNA during stationary phase.', 'The sigma(70)-dependent promoters inhibited by 6S RNA contain an extended -10 promoter element, suggesting that this feature may define a class of 6S RNA-regulated genes.', ' a secondary effect of 6S RNA in the activation of sigma(S)-dependent transcription at several promoters.', '6S RNA regulation of both sigma(70) and sigma(S) activities contributes to increased cell persistence during nutrient deprivation.', 'Escherichia coli 6S RNA represents a non-coding RNA (ncRNA), which, based on the conserved secondary structure and previous functional studies, had been suggested to interfere with transcription. ', 'Preferred binding of 6S RNA to Esigma(70) was confirmed, however weaker binding to Esigma(38) was also observed.', 'Moreover, we show for the first time that 6S RNA acts as a template for the transcription of defined RNA molecules in the absence of DNA. In conclusion, this study reveals new aspects of 6S RNA function.', '6S RNA, first described as a ncRNA in E. coli, mimics an open promoter structure, which has a large bulge with two hairpin/stalk structures that regulate transcription through interactions with RNA polymerase', 'The release reaction depends on a characteristic property of 6S RNAs, namely to act as template for the de novo synthesis of small RNAs, termed pRNAs.Here, we used limited hydrolysis with structure-specific RNases and in-line probing of isolated 6S RNA and 6SRNA ∼ pRNA complexes to investigate the molecular details leading to the release reaction', 'The release reaction depends on a characteristic property of 6S RNAs, namely to act as template for the de novo synthesis of small RNAs, termed pRNAs.Here, we used limited hydrolysis with structure-specific RNases and in-line probing of isolated 6S RNA and 6SRNA ∼ pRNA complexes to investigate the molecular details leading to the release reaction. ', 'The release reaction depends on a characteristic property of 6S RNAs, namely to act as template for the de novo synthesis of small RNAs, termed pRNAs.Here, we used limited hydrolysis with structure-specific RNases and in-line probing of isolated 6S RNA and 6SRNA ∼ pRNA complexes to investigate the molecular details leading to the release reaction.']

['6S RNA, first described as a ncRNA in E. coli, mimics an open promoter structure, which has a large bulge with two hairpin/stalk structures that regulate transcription through interactions with RNA polymerase. Escherichia coli 6S RNA represents a non-coding RNA (ncRNA), which, based on the conserved secondary structure and previous functional studies, had been suggested to interfere with transcription. The carboxy terminus containing the Arg-Gly-Gly (RGG) repeat domains in these proteins are necessary for cis-repression of transcription activation and HAT activity by the N-terminal glutamine-rich domain.', 'Escherichia coli 6S RNA represents a non-coding RNA (ncRNA), which, based on the conserved secondary structure and previous functional studies, had been suggested to interfere with transcription. 6S RNA-deficient cells are at a disadvantage for survival in stationary phase, a time when 6S RNA regulates transcription. 6S RNA regulation of both sigma(70) and sigma(S) activities contributes to increased cell persistence during nutrient deprivation. 6S RNA acts as a template for the transcription of defined RNA molecules in the absence of DNA. 6S RNA, first described as a ncRNA in E. coli, mimics an open promoter structure, which has a large bulge with two hairpin/stalk structures that regulate transcription through interactions with RNA polymerase.', '6S RNA function enhances long-term cell survival. ']

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What is ceritinib?

['We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. ', 'The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC).', 'Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response.', 'The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs.', 'Ceritinib is effective and approved for ALK-positive NSCLC in the acquired resistance setting. ', 'Ceritinib is an oral, potent, second-generation ALK inhibitor recently approved by the U.S. Food and Drug Administration', 'Preclinical data showed impressive antitumor activity against crizotinib-resistant clones, and based on available data, ceritinib could represent a suitable option in crizotinib-resistant NSCLC.', 'In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented.', 'In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.SIGNIFICANCE: The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. ', 'The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.', 'Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease. The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib.', 'The accelerated approval of potent ALK inhibitors, such as crizotinib and more recently ceritinib (LDK378), based on the well designed phase I/II trials has been a landmark success in clinical cancer research and contributes a new era of oncogenic targeted therapy characterized by elegant clinical trial design. In this review, we aim to present the current knowledge on acquired resistance of crizotinib known as a first-in-class ALK inhibitor and potential solutions to improve the cost-effectiveness, and to review the difference between ceritinib and crizotinib; preclinical data and results of the elegant early clinical trial of ceritinib which promoted its accelerated approval, pharmacokinetics, safety profile, and tolerability, the updated results (eg, efficacy on brain metastases), and robust design of ongoing phase II/III trials, and future directions of ceritinib to be a potent alternative to crizotinib for ALK-rearranged non-small-cell lung cancer are also presented.']

['Ceritinib is a second generation tyrosine kinase inhibitor, that serves as an effective and approved oral therapy for patients with ALK-rearranged non-small cell lung cancer.']

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What genes are drug targets for Fibrodysplasia Ossificans Progressiva (FOP)?

[' Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. ', 'Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP).', 'Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date.', 'By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189', 'Here, it is noted that if B cells are found to be the lymphocytes responsible for excess BMP-4 production in FOP, use of Rituximab, a monoclonal anti-CD20 antibody which effectively targets B cells, could be a less permanent and less risky treatment alternative for FOP.', 'A new mutation of the Noggin gene in a French Fybrodysplasia ossificans progressiva (FOP) family: Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of the muscles.', 'Localization of the gene for fibrodysplasia ossificans progressiva (FOP) to chromosome 17q21-22.', 'A new mutation of the noggin gene in a French Fibrodysplasia ossificans progressiva (FOP) family.', 'Rarely occurring mutation of ACVR1 gene in Moroccan patient with fibrodysplasia ossificans progressiva.', 'A new mutation of the Noggin gene in a French Fybrodysplasia ossificans progressiva (FOP) family: Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of the muscles', 'Mutations in the ACVR1 gene are associated with Fibrodysplasia Ossificans Progressiva (FOP), a rare and extremely disabling disorder characterized by congenital malformation of the great toes and progressive heterotopic endochondral ossification in muscles and other non-skeletal tissues', 'Mutations of the noggin (NOG) and of the activin A type I receptor (ACVR1) genes in a series of twenty-seven French fibrodysplasia ossificans progressiva (FOP) patients', 'ACVR1, a therapeutic target of fibrodysplasia ossificans progressiva, is negatively regulated by miR-148a.', 'These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.', 'In this study, we examined downstream signaling targets to study the BMP-Smad and BMP-p38 mitogen-activated protein kinase (MAPK) pathways in FOP. ', 'Mutations in the ACVR1 gene are associated with Fibrodysplasia Ossificans Progressiva (FOP), a rare and extremely disabling disorder characterized by congenital malformation of the great toes and progressive heterotopic endochondral ossification in muscles and other non-skeletal tissues. ', 'Linkage exclusion and mutational analysis of the noggin gene in patients with fibrodysplasia ossificans progressiva (FOP).', 'Fibrodysplasia ossificans progressiva (FOP), a rare disorder characterized by progressive ossification of connective tissue, is caused by an activating mutation in Acvr1 (the gene that encodes ACVR1/ALK2).', 'This gene encodes the type I bone morphogenic protein receptor ALK2, with the residues affected identical to those that, when mutated in the germline, give rise to the congenital malformation syndrome fibrodysplasia ossificans progressiva (FOP), resulting in the transformation of soft tissue into bone.', 'ACVR1, a therapeutic target of fibrodysplasia ossificans progressiva, is negatively regulated by miR-148a.', 'A new mutation of the noggin gene in a French Fibrodysplasia ossificans progressiva (FOP) family.', 'Neofunction of ACVR1 in fibrodysplasia ossificans progressiva.', 'The discovery of the FOP gene establishes a crucial milestone in understanding FOP, reveals a highly conserved target in the BMP signaling pathway for drug development and specifically stimulates therapeutic approaches for the development of inhibitors for ACVR1/ALK2 signaling.', 'The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved druggable target in the TGF-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for activin-like kinase-2.']

[' Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. ', 'here, it is noted that if b cells are found to be the lymphocytes responsible for excess bmp-4 production in fop, use of rituximab, a monoclonal anti-cd20 antibody which effectively targets b cells, could be a less permanent and less risky treatment alternative for fop.', 'Inhibitors of ALK2(ACVR1) are used for the treatment of FOP. Current therapies for FOP are Dorsomorphin analogues which function as BMP inhibitor. if B cells control excess BMP-4 production in FOP, use of Rituximab, a monoclonal which targets B cells, could be a treatment alternative for FOP.']

['ALK2', 'BMP']

Which histone modifications distinguish between promoters and enhancers?

['Here, we used chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to measure genome-wide changes in histone H3 acetylation at lysine 27 (H3K27ac), a marker of active enhancers, in unstimulated HUVECs and HUVECs stimulated with VEGFA for 1, 4, and 12 h.', 'Here we use whole-transcriptome analysis coupled with genome-wide profiling of H3K27ac and H3K27me3 to map chromatin states and enhancers in mouse embryonic forelimb and hindlimb.', 'Using H3K27ac profiles, we identified 28,377 putative enhancers, many of which are likely to be limb specific based on strong enrichment near genes highly expressed in the limb and comparisons with tissue-specific EP300 sites and known enhancers. ', 'a chromatin state signature associated with active developmental enhancers, defined by high levels of H3K27ac marking, nucleosome displacement, hypersensitivity to sonication, and strong depletion of H3K27me3', 'We also find that some developmental enhancers exhibit components of this signature, including hypersensitivity, H3K27ac enrichment, and H3K27me3 depletion, at lower levels in tissues in which they are not active.', 'At some locations, H3K27 monomethylation was also found to be associated with chromatin signatures of gene enhancers.', 'Individual chromatin marks, such as H3K27ac and H3K27me3, have been identified to distinguish active from inactive enhancers. ', 'We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements containing H3K4me1 alone. ', 'Although certain chromatin features, such as the histone acetyltransferase P300 and the histone modification H3K4me1, indicate the presence of enhancers, only a fraction of enhancers are functionally active. Individual chromatin marks, such as H3K27ac and H3K27me3, have been identified to distinguish active from inactive enhancers.', 'We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements containing H3K4me1 alone.']

['H3K27ac is a marker of active enhancers. An enhancer chromatin state signature associated with active developmental enhancers may be defined by high levels of H3K27ac marking, nucleosome displacement, hypersensitivity to sonication, and strong depletion of H3K27me3.']

['H3K27ac enrichment', 'H3K27me3 depletion']