Respond with exceptions, completions and modifications or revisions done before completion
. PS1 defined as following: Human PSEN1 wild-type allele is located in the vicinity of 14q24.3 and is approximately 87 kb in length. This allele, which encodes presenilin-1 protein, is involved in the modulation of proteolytic processing. Mutation of the gene is associated with early-onset Alzheimer disease and frontotemporal dementia.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary..", "label": "yes"} {"id": "converted_1182", "sentence1": "Is macroautophagy a selective degradation process?", "sentence2": "Selective autophagy, Macroautophagy (autophagy) is a bulk degradation system for cytoplasmic components and is ubiquitously found in eukaryotic cells, Here we show that selective autophagy downregulates Ty1 transposition, We propose that selective autophagy safeguards genome integrity against excessive insertional mutagenesis caused during nutrient starvation by transposable elements in eukaryotic cells., Moreover, it is becoming apparent that proteins, organelles, and pathogens can be targeted for autophagic clearance by selective mechanisms, Cell spreading required ref(2)P, the Drosophila p62 multiadaptor, implicating selective autophagy as a novel mechanism for modulating cortical dynamics, The selective macroautophagic degradation, There is growing evidence that macroautophagic cargo is not limited to bulk cytosol in response to starvation and can occur selectively for substrates, including aggregated proteins., It remains unclear, however, whether starvation-induced and selective macroautophagy share identical adaptor molecules to capture their cargo. Here, we report that Alfy, a phosphatidylinositol 3-phosphate-binding protein, is central to the selective elimination of aggregated proteins., We propose that Alfy plays a key role in selective macroautophagy by bridging cargo to the molecular machinery that builds autophagosomes., Thus, cytoplasmic NBR1 might be important to maintain basal levels of selective macroautophagy in these neurons., we could show that Smatg8 and Smatg4 are not only required for nonselective macroautophagy, but for selective macropexophagy as well., The latter is performed by proteasome-mediated degradation, chaperone-mediated autophagy (CMA), and selective macroautophagy,, Here we demonstrate a role for PtdIns 4-kinases and PtdIns4P 5-kinases in selective and nonselective types of autophagy in yeast., Macroautophagy (hereafter autophagy) is a degradative cellular pathway that protects eukaryotic cells from stress, starvation, and microbial infection., Previously, we showed that macroautophagy is necessary for conidiation in the rice-blast fungus Magnaporthe oryzae. Here, we analyzed the physiological function(s) of selective autophagy in Magnaporthe, Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins., Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins., Whole organelle turnover is mediated through macroautophagy, a process by which autophagosomes deliver mitochondria to the lysosome for hydrolytic degradation. While mitochondrial autophagy can occur as part of a nonselective upregulation of autophagy, selective degradation of damaged or unneeded mitochondria (mitophagy) is a rapidly growing area in development, cancer, and neurodegeneration, particularly with regard to Parkinson's disease, BAG3 was recently described as a mediator of a novel macroautophagy pathway that uses the specificity of heat shock protein 70 (HSP70) to misfolded proteins and also involves other protein partners, such as HSPB8., two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy), Here we show that whole mitochondria are turned over via macroautophagy., Does Huntingtin play a role in selective macroautophagy?, In the discussion here I suggest that Htt may have a normal function in the lysosomal mechanism of selective macroautophagy involved in its own degradation, Macroautophagy induced by ethanol seemed to be selective for damaged mitochondria and accumulated lipid droplets, but not long-lived proteins, which could account for its protective effects, Although macroautophagy can be nonspecific, there are many examples of selective sequestration including pexophagy, mitophagy and the cytoplasm to vacuole targeting (Cvt) pathway., Mitochondria autophagy (mitophagy) is the process of selective degradation of mitochondria that has an important role in mitochondrial quality control., One of the genes identified, YLR356W, is required for mitophagy, but not for macroautophagy or other types of selective autophagy., A genomic screen for yeast mutants defective in selective mitochondria autophagy., Mitophagy is the process of selective mitochondrial degradation via autophagy, which has an important role in mitochondrial quality control., Analysis of this set of targeted deletion mutants demonstrated that loss of any of the 16 genes necessary for nonselective macroautophagy renders the fungus unable to cause rice blast disease, due to impairment of both conidial programmed cell death and appressorium maturation. In contrast, genes necessary only for selective forms of autophagy, such as pexophagy and mitophagy, are dispensable for appressorium-mediated plant infection., This gene is not required for other types of selective autophagy or for nonspecific macroautophagy., However, in contrast to the core autophagy genes such as atg5 and atg7, expression of ulk1 is not essential for induction of macroautophagy in response to nutrient deprivation or for survival of newborn mice. Together, these data suggest that the ATG1 homologue, Ulk1, is a component of the selective autophagy machinery that leads to the elimination of organelles in erythroid cells rather that an essential mechanistic component of autophagy., Growing evidence supports an active role for dysregulated macroautophagy (autophagic stress) in neuronal cell death and neurodegeneration. Alterations in mitochondrial function and dynamics are also strongly implicated in neurodegenerative diseases. Interestingly, whereas the core autophagy machinery is evolutionarily conserved and shared among constitutive and induced or selective autophagy, recent studies implicate distinct mechanisms regulating mitochondrial autophagy (mitophagy) in response to general autophagic stimuli., We discovered that activation of the UPR in yeast also induces a new branch of macroautophagy that selectively targets the ER. We term this process \"ER-phagy\", in analogy to pexophagy and mitophagy, the two other known forms of organelle-specific marcoautophagy. ER-phagy involves the generation of autophagosomes that selectively include ER membranes and whose delimiting double membranes also derive, at least in part, from the ER., This suggests that in fungi an organism-specific form of selective autophagy may occur, for which specialized Atg proteins have evolved., ransfer of Y. lipolytica cells from oleate/ethylamine to glucose/ammonium chloride medium leads to selective macroautophagy of peroxisomes., Insulin-dependent signaling regulates azurophil granule-selective macroautophagy in human myeloblastic cells., We show that insulin-dependent signals regulate azurophil granule-selective macroautophagy in human myeloid cells., By contrast, other organelles, including the mitochondria, endoplasmic reticulum, and Golgi apparatus remained intact, indicating that the macroautophagy selectively targeted azurophil granules., Thus, insulin-dependent signals are responsible for the control of azurophil granule-selective macroautophagy via Akt-dependent pathways, Eukaryotic cells have the ability to degrade proteins and organelles by selective and nonselective modes of micro- and macroautophagy., For example, pexophagy is a selective process for the regulated degradation of peroxisomes by autophagy., We have characterized biochemically, morphologically, and genetically two distinct pathways for the selective degradation of peroxisomes in Pichia pastoris. These pathways are independently regulated and analogous to microautophagy and macroautophagy that have been defined in mammalian cells., If we are willing to slightly modify our definition of autophagy, with a focus on \"degradation of a cell's own components through the lysosomal/vacuolar machinery,\" we can include a newly documented process, programmed nuclear destruction (PND)., Autophagy is a lysosomal degradation pathway that can sequester cytosolic material, including organelles, nonspecifically in a process called nonselective macroautophagy, or target specific protein aggregates designated for destruction in a process called selective autophagy., Selective macroautophagy uses double-membrane vesicles, termed autophagosomes, to transport cytoplasmic pathogens, organelles and protein complexes to the vacuole for degradation., Autophagy (macroautophagy), a highly conserved eukaryotic mechanism, is a non-selective degradation process, helping to maintain a balance between the synthesis, degradation and subsequent recycling of macromolecules to overcome various stress conditions., Whole organelle turnover is mediated through macroautophagy, a process by which autophagosomes deliver mitochondria to the lysosome for hydrolytic degradation., Macroautophagy is a catabolic process by which the cell degrades cytoplasmic components through the lysosomal machinery., Macroautophagy maintains cellular homeostasis through targeting cytoplasmic contents and organelles into autophagosomes for degradation., Macroautophagy is a catabolic process by which cytosolic components are sequestered by double membrane vesicles called autophagosomes and sorted to the lysosomes/vacuoles to be degraded., Macroautophagy (hereafter autophagy) is a cellular degradation process, which in yeast is induced in response to nutrient deprivation., Macroautophagy was thought to be an unspecific bulk degradation process., Autophagy is a highly regulated intracellular degradation process by which cells remove cytosolic long-lived proteins and damaged organelles, and can be monitored by imaging the incorporation of microtubule-associated light chain 3 (LC3) fused to a fluorescent protein (GFP or mCherry) into nascent autophagosomes., Beside macroautophagy, there are several forms of selective autophagy, including chaperone-mediated autophagy (CMA), cytoplasm to vacuole targeting (Cvt), pexophagy and mitophagy., Macroautophagy (commonly referred to as autophagy) is the process by which intact organelles and/or large portions of the cytoplasm are engulfed within double-membraned autophagic vacuoles for degradation., This analysis demonstrated that Atg proteins required for non-selective macroautophagy are conserved from yeast to man, stressing the importance of this process in cell survival and viability., Part of the degradation of intracellular proteins occurs in the lysosomes and is mediated by macroautophagy.[SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. genome defined as following: Anatomical set of genes in all the chromosomes.. ulk1 defined as following: Serine/threonine-protein kinase ULK1 (1050 aa, ~113 kDa) is encoded by the human ULK1 gene. This protein is involved in protein phosphorylation that mediates the autophagocytotic process.. organelle defined as following: Cell part which consists of macromolecules aggregated into discrete structures in the protoplasm. (Digital Anatomist Foundational Model). yeast defined as following: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as \"baker's\" or \"brewer's\" yeast. The dried form is used as a dietary supplement.. GFP defined as following: Protein analogs and derivatives of the Aequorea victoria green fluorescent protein that emit light (FLUORESCENCE) when excited with ULTRAVIOLET RAYS. They are used in REPORTER GENES in doing GENETIC TECHNIQUES. Numerous mutants have been made to emit other colors or be sensitive to pH.. mitochondria defined as following: Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed). peroxisomes defined as following: Microbodies which occur in animal and plant cells and in certain fungi and protozoa. They contain peroxidase, catalase, and allied enzymes. (From Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology, 2nd ed). transposable elements defined as following: Discrete segments of DNA which can excise and reintegrate to another site in the genome. Most are inactive, i.e., have not been found to exist outside the integrated state. DNA transposable elements include bacterial IS (insertion sequence) elements, Tn elements, the maize controlling elements Ac and Ds, Drosophila P, gypsy, and pogo elements, the human Tigger elements and the Tc and mariner elements which are found throughout the animal kingdom.. erythroid cells defined as following: The series of cells in the red blood cell lineage at various stages of differentiation.. atg7 defined as following: This gene plays a role in both autophagy and the transport of cytoplasmic molecules to vacuoles.. ER defined as following: A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed). ethanol defined as following: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in ALCOHOLIC BEVERAGES.. macroautophagy defined as following: The major inducible pathway for the general turnover of cytoplasmic constituents in eukaryotic cells, it is also responsible for the degradation of active cytoplasmic enzymes and organelles during nutrient starvation. Macroautophagy involves the formation of double-membrane-bounded autophagosomes which enclose the cytoplasmic constituent targeted for degradation in a membrane-bounded structure. Autophagosomes then fuse with a lysosome (or vacuole) releasing single-membrane-bounded autophagic bodies that are then degraded within the lysosome (or vacuole). Some types of macroautophagy, e.g. pexophagy, mitophagy, involve selective targeting of the targets to be degraded. [PMID:11099404, PMID:12914914, PMID:15798367, PMID:16973210, PMID:20159618, PMID:9412464]. neurons defined as following: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.. insertional mutagenesis defined as following: Mutagenesis where the mutation is caused by the introduction of foreign DNA sequences into a gene or extragenic sequence. This may occur spontaneously in vivo or be experimentally induced in vivo or in vitro. Proviral DNA insertions into or adjacent to a cellular proto-oncogene can interrupt GENETIC TRANSLATION of the coding sequences or interfere with recognition of regulatory elements and cause unregulated expression of the proto-oncogene resulting in tumor formation.. lysosome defined as following: A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes MEMBRANE FUSION. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).. cytosolic defined as following: Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.. CMA defined as following: The autophagy process which begins when chaperones and co-chaperones recognize a target motif and unfold the substrate protein. The proteins are then transported to the lysosome where they are degraded. [GOC:pad, GOC:PARL, PMID:22743996, PMID:23434281]. Cvt defined as following: Congenital severe form of flatfoot involving dislocation of the NAVICULAR BONE OF FOOT on the TALUS.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. Huntingtin defined as following: Huntingtin (3144 aa, ~348 kDa) is encoded by the human HTT gene. This protein may be involved in the regulation of vesicular transport.. atg5 defined as following: This gene plays a role in autophagy and may play a role in apoptosis.. Parkin defined as following: E3 ubiquitin-protein ligase parkin (465 aa, ~52 kDa) is encoded by the human PRKN gene. This protein may play a role in the ubiquitination of proteins targeted for proteasomal degradation.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. LC3 defined as following: A protein family whose members bind to microtubule-associated protein 1A and 1B and are involved in the formation of autophagosomes.. ATG1 defined as following: Human ULK1 wild-type allele is located in the vicinity of 12q24.3 and is approximately 29 kb in length. This allele, which encodes serine/threonine-protein kinase ULK1 protein, plays a role in both serine/threonine protein phosphorylation and the modulation of autophagy.. eukaryotic cells defined as following: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane.. HSP70 defined as following: A family of structurally related proteins that are involved in both protein folding and cellular stress responses. The members of this family are approximately 70 kDa.. macropexophagy defined as following: The selective autophagy process in which a peroxisome is degraded by macroautophagy. [GOC:autophagy, PMID:12914914, PMID:16973210]. PtdIns 4-kinases defined as following: An enzyme that catalyzes the conversion of phosphatidylinositol (PHOSPHATIDYLINOSITOLS) to phosphatidylinositol 4-phosphate, the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate.. Serine defined as following: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.. cytoplasm defined as following: The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990). Htt defined as following: Human SLC6A4 wild-type allele is located in the vicinity of 17q11.2 and is approximately 42 kb in length. This allele, which encodes sodium-dependent serotonin transporter protein, plays a role in serotonin uptake. Polymorphism in the promoter region affects gene expression and lower gene expression is associated with depression. Coding region variations are associated with genetic susceptibility to both obsessive-compulsive disorder and alcoholism.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. Parkinson's disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75). heat shock protein 70 defined as following: A recombinant peptide that is chemically identical to or similar to the endogenous 70-kD heat shock protein (HSP70). HSP70 is a molecular chaperone that prevents physiologic stress-induced cell death by inhibiting both caspase-dependent and caspase-independent apoptosis. Because this peptide is often overexpressed in tumor cells, autologous vaccination with HSP70 derived from tumor cells may stimulate the host immune system to mount a tumoricidal cytotoxic T lymphocyte (CTL) response. (NCI04). vacuole defined as following: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. ubiquitinated proteins defined as following: Proteins covalently modified with UBIQUITINS or UBIQUITIN-LIKE PROTEINS.. PD defined as following: A score of 4 or 5 on a 5-point PET scale with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end of treatment assessment.. BAG3 defined as following: BAG family molecular chaperone regulator 3 (575 aa, ~62 kDa) is encoded by the human BAG3 gene. This protein is involved in both protein chaperone activity modulation and the negative regulation of apoptosis.. autophagosomes defined as following: A double-membrane-bounded compartment that engulfs endogenous cellular material as well as invading microorganisms to target them to the lytic vacuole/lysosome for degradation as part of macroautophagy. [GOC:autophagy, ISBN:0198547684, PMID:11099404]. mitochondrial defined as following: The distribution of mitochondria, including the mitochondrial genome, into daughter cells after mitosis or meiosis, mediated by interactions between mitochondria and the cytoskeleton. [GOC:mcc, PMID:10873824, PMID:11389764]. HSPB8 defined as following: Heat shock protein beta-8 (196 aa, ~22 kDa) is encoded by the human HSPB8 gene. This protein plays a role in the regulation of autophagy and as a protein chaperone.. cargo defined as following: The activity of a gene product that interacts with a cargo receptor and initiates endocytosis. [PMID:15797858]. neuronal cell death defined as following: The process of cell death in a neuron. [GOC:BHF, GOC:mah]. organelles defined as following: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the MITOCHONDRIA; the GOLGI APPARATUS; ENDOPLASMIC RETICULUM; LYSOSOMES; PLASTIDS; and VACUOLES.. human defined as following: Members of the species Homo sapiens.. neurodegeneration defined as following: Loss of functional activity and trophic degeneration of nerve axons and their terminal arborizations following the destruction of their cells of origin or interruption of their continuity with these cells. The pathology is characteristic of neurodegenerative diseases. Often the process of nerve degeneration is studied in research on neuroanatomical localization and correlation of the neurophysiology of neural pathways.. fungus defined as following: Confirmatory presence of fungal microorganisms.. molecule defined as following: An aggregate of two or more atoms in a defined arrangement held together by chemical bonds.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. microautophagy defined as following: A type of autophagy in which the cytoplasmic entities, such as parts of CELL NUCLEI; damaged MITOCHONDRIA; and lipid droplets, are taken up by small vesicles such as VACUOLES or MULTIVESICULAR BODIES, and degraded by lysosomal digestion.. ER-phagy defined as following: The selective autohagy process in which parts of the endoplasmic reticulum are loaded into autophagosomes, delivered to the vacuole, and degraded in response to changing cellular conditions. [GOC:autophagy, GOC:dph, PMID:22481944, PMID:24060720, PMID:26040717].", "label": "yes"} {"id": "converted_1526", "sentence1": "Is there an association between presenteeism and depression?", "sentence2": "Presenteeism was positively associated with severity of depression (Health and Work Performance Questionnaire, P < 0.0001; WPAI, P < 0.0001)., Statistically significant correlations (0.32-0.53) were found between presenteeism and increasing disability, fatigue, depression, anxiety, and reduced quality of life. , Presenteeism was associated with increasing fatigue, depression, anxiety, and reduced quality of life., Factors with less contribution to presenteeism included physical limitations, depression or anxiety, inadequate job training, and problems with supervisors and coworkers. , BACKGROUND: Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism)., Two major causes of worker presenteeism (reduced on-the-job productivity as a result of health problems) are musculoskeletal pain and mental health issues, particularly depression. , Pain and depression were significantly associated with presenteeism. Pr, Survey adjusted multivariable logistic regression assessed classification of 12-month, depression-related presenteeism on the basis of socio-demographic, financial, work and health factors. , RESULTS: The LPT from absenteeism and presenteeism (reduced performance while present at work) was significantly higher among the MDD group., BACKGROUND: Depression is reported to be a major cause of illness-related sub-optimal work performance (presenteeism). , BACKGROUND: It is amply documented that mood disorders adversely affect job satisfaction, workforce productivity, and absenteeism/presenteeism. , The difference in productivity loss due to impaired presenteeism was significantly different between the two groups, but the productivity loss due to absenteeism was not. , Disease activity (OR 3.24, 95% CI 1.11-9.48) and depression (OR 3.22, 95% CI 1.22-8.48) were associated with absenteeism, while depression (OR 5.69, 95% CI 1.77-18.27, disease activity (OR 3.97, 95% CI 1.76-8.98), anxiety (OR 3.90, 95% CI 1.83-8.31), self-efficacy (OR 0.71, 95% CI 0.58-0.86), and increasing age (OR 1.04 per year, 95% CI 1.00-1.08) were associated with presenteeism. , Depression, in particular, appears to be associated with employment, absenteeism, and presenteeism, and should therefore be prioritized in clinical practice., Depression frequently causes unemployment, absenteeism, and presenteeism, which results in significantly reduced productivity., Presenteeism and absenteeism were significantly worse for the depression group at each time point (p < or = .001). In cross-sectional models, presenteeism was associated with more severe depression symptoms, poorer general physical health, psychologically demanding work, the interaction ofpsychologically demanding work with depression, and less job control (r2 range = .33-.54)., Chronic conditions such as depression/anxiety, obesity, arthritis, and back/neck pain are especially important causes of productivity loss. Comorbidities have significant non-additive effects on both absenteeism and presenteeism., RESULTS: At baseline, all presenteeism measures were sensitive to differences between those with (N=69) and without (N=363) depression/anxiety., Depression and anxiety were more consistently associated with \"presenteeism\" (that is, lost productivity while at work) than with absenteeism, whether this was measured by cutback days or by direct questionnaires., RESULTS: Substantial research exists about anxiety and depression costs, such as performance and productivity, absenteeism, presenteeism, disability, physical disability exacerbation, mental health treatment, increased medical care costs, exacerbating of physical illness, and studies of mental health care limitations and cost-offset., The author discusses the etiology and potential solutions for managing this new component in the productivity equation and in addressing depression, the major contributor to presenteeism., For employees who are currently depressed, recent research evidence has demonstrated that pharmacotherapy can have a dramatic and positive effect on lost productivity, absenteeism, and presenteeism., Among participants who were still employed, those with depression had significantly more job turnover, presenteeism, and absenteeism. , Only depression affected both absenteeism-presenteeism and critical incidents. , CONCLUSIONS: Depressive disorders in the workplace persist over time and have a major effect on work performance, most notably on \"presenteeism,\" or reduced effectiveness in the workplace. , The negative effects of depression include those on patients' occupational functioning, including absenteeism, presenteeism, and reduced opportunities for educational and work success. , The remitted group demonstrated a significant improvement in productivity (particularly presenteeism) when compared with the new visit group (Z = -3.29, p = 0.001)., Depression in workers leads to significant absenteeism, \"presenteeism\" (diminished capacity due to illness while still present at work), and significantly increased medical expenses in addition to the costs of psychiatric care. , Significant predictors of presenteeism and activity impairment at follow-up (controlled for gender, age, spondyloarthritis subgroups and presenteeism at baseline) were presenteeism at baseline, poor quality of life, worse disease activity, decreased physical function, lower self-efficacy pain and symptom, higher scores of anxiety, depression, smoking and low education level, and for activity impairment also female sex. , \" Pain and depression were significantly associated with presenteeism., Only depression affected both absenteeism-presenteeism and critical incidents., Factors with less contribution to presenteeism included physical limitations, depression or anxiety, inadequate job training, and problems with supervisors and coworkers.[SEP]Definitions: arthritis defined as following: Acute or chronic inflammation of JOINTS.. MDD defined as following: Disorder in which five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Symptoms include: depressed mood most of the day, nearly every daily; markedly diminished interest or pleasure in activities most of the day, nearly every day; significant weight loss when not dieting or weight gain; Insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate, or indecisiveness, nearly every day; or recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt. (DSM-5). musculoskeletal pain defined as following: Discomfort stemming from muscles, LIGAMENTS, tendons, and bones.. Depressive disorders defined as following: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent.. depressed defined as following: An emotional state characterized by feelings of sadness, emptiness, and/or tearfulness.. anxiety defined as following: Persistent and disabling ANXIETY.. fatigue defined as following: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.. illness defined as following: A state of ill health, bodily malfunction, or discomfort.. presenteeism defined as following: Reporting for work despite feeling ill.. mood disorders defined as following: Those disorders that have a disturbance in mood as their predominant feature..", "label": "yes"} {"id": "converted_983", "sentence1": "Have mutations in the ZEB2 gene been found in any human syndrome?", "sentence2": "Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene, Mowat-Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene., owat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene, MWS is caused by de novo heterozygous mutations in the ZEB2 gene, The cause of MWS is a de novo mutation in the ZEB2 gene, owat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene, MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B,, human Mowat-Wilson syndrome, we suggest that deletion of ZEB2, is responsible for most of the effects of the mutation, Mutations at the hZeb2 locus cause Mowat-Wilson syndrome (MWS), Mowat-Wilson syndrome and a mutation in ZEB2, owat-Wilson syndrome (MWS) is caused by a heterozygous mutation or deletion of the ZEB2 gene, The syndrome is caused by mutations or deletions of the ZEB2 gene, owat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome, single-copy ZEB2 gene deletion at 2q22.3 consistent with Mowat-Wilson syndrome, Mowat-Wilson syndrome, confirmed by molecular analysis as a heterozygous deletion of the ZEB2 gene., deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, Six patients had deletions in the ZEB2 gene, ZEB2 gene analysis for Mowat-Wilson syndrome, Mowat-Wilson syndrome (MWS) like appearance was noted. The disease is caused by mutation or deletion of ZEB2 gene, owat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, owat-Wilson syndrome (MWS) is an autosomal dominant developmental disorder with mental retardation and variable multiple congenital abnormalities due to mutations of the ZEB2 (ZFHX1B) , MWS is caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1), owat-Wilson syndrome (MWS) is a multiple congenital anomaly-mental retardation complex caused by mutations in the Zinc Finger Homeobox 1 B gene (ZFHX1B), the ZFHX1B gene, which is known to be involved in the Mowat-Wilson syndrom, de novo heterozygous mutations or deletions of the ZFHX1B gene located at 2q22, owat-Wilson syndrome (MWS) is a recently delineated mental retardation (MR)-multiple congenital anomaly syndrome, FHX1B mutations in patients with Mowat-Wilson syndrome, Mutations leading to haploinsufficiency of the ZFHX1B gene, mutation in the ZFHX1B gene associated with an atypical Mowat-Wilson syndrome phenotype, ZFHX1B mutation associated with a mild Mowat-Wilson syndrome, Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS), Heterozygous mutations or deletions involving the gene ZFHX1B (previously SIP1) [OMIM 605802] have recently been found to cause MWS, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS, Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B), mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1), ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the \"Mowat-Wilson\" syndrome, ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects, mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome, syndrome is the result of heterozygous deletions or truncating mutations of the ZFHX1B (SIP1) gene, humans with Zfhx1b mutations (Mowat-Wilson syndrome, syndrome occurs as a result of heterozygous mutations or deletions in the zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1), owat-Wilson syndrome (MWS) is a recently delineated mental retardation;, Mowat-Wilson syndrome is a congenital syndrome caused by a defect of the transcriptional repressor ZFHX1B (SIP1), Mowat-Wilson syndrome patients, and all siblings had the same E87X nonsense mutation in ZFHX1B[SEP]Definitions: OMIM defined as following: This database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere, and developed for the World Wide Web by NCBI, the National Center for Biotechnology Information. The database contains textual information and references. It also contains copious links to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere.. 2q22 defined as following: A chromosome band present on 2q.. ZFHX1B defined as following: Human ZEB2 wild-type allele is located in the vicinity of 2q22 and is approximately 132 kb in length. This allele, which encodes zinc finger E-box-binding homeobox 2 protein, is involved in regulation of transcription. Mutations in this gene are associated with Mowat-Wilson syndrome.. ZEB2 defined as following: This gene is involved in regulation of transcription.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. Smad-interacting protein 1 defined as following: A transcription factor that consists of 8 CYS2-HIS2 ZINC FINGERS flanking a central HOMEOBOX. It binds to the 5'-CACCT-3' DNA sequence located within E-BOX ELEMENTS of many genes essential for embryonic growth and development and regulates their activity; it represses transcription of the E-CADHERIN gene. Mutations in the ZEB2 gene are associated with MOWAT-WILSON SYNDROME.. deletions defined as following: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.. congenital abnormalities defined as following: Malformations of organs or body parts during development in utero.. Mowat-Wilson syndrom defined as following: A rare autosomal dominant syndrome caused by mutations in the ZEB2 gene. It is characterized by mental retardation, and a distinctive facial appearance (wide set eyes, uplifted earlobes, broad nasal bridge, prominent chin, and a smiling expression). The majority of patients have Hirschsprung disease (colonic enlargement and constipation due to intestinal blockage).. MWS defined as following: An autoinflammatory disease caused by mutations in the NLRP3 gene which encodes cryopyrin. It is characterized by recurrent episodes of urticaria and fever which develop in infancy. It may lead to sensorineural hearing loss and/or amyloidosis.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. intellectual disabilities defined as following: Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28). MR defined as following: Backflow of blood from the LEFT VENTRICLE into the LEFT ATRIUM due to imperfect closure of the MITRAL VALVE. This can lead to mitral valve regurgitation.. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. humans defined as following: Members of the species Homo sapiens.. syndrome defined as following: Book syndrome is a rare autosomal dominant ectodermal dysplasia syndrome reported in a Swedish family (25 cases from 4 generations), and one isolated case. The syndrome has characteristics of premolar aplasia, hyperhidrosis, and premature graying of the hair. Additional features reported in the isolated case include a narrow palate, hypoplastic nails, eyebrow anomalies, a unilateral simian crease, and poorly formed dermatoglyphics.. ZEB2 gene defined as following: This gene is involved in regulation of transcription.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA..", "label": "yes"} {"id": "converted_1302", "sentence1": "Does thyroid hormone signaling affect microRNAs expression in the heart?", "sentence2": "e show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a., On the other hand, T₃ treatment increased miR-350 expression., Through a bioinformatics screening using TargetScan, we identified thyroid hormone receptor β1 (TRβ1), which negatively regulates β-MHC transcription, as a target of miR-27a, hese findings suggested that miR-27a regulates β-MHC gene expression by targeting TRβ1 in cardiomyocytes., We found that a cardiac-specific microRNA (miR-208) encoded by an intron of the alphaMHC gene is required for cardiomyocyte hypertrophy, fibrosis, and expression of betaMHC in response to stress and hypothyroidism., Moreover, miR-27a was demonstrated to modulate β-MHC gene regulation via thyroid hormone signaling and to be upregulated during the differentiation of mouse embryonic stem (ES) cells or in hypertrophic hearts in association with β-MHC gene upregulation.[SEP]Definitions: fibrosis defined as following: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.. thyroid hormone defined as following: Natural hormones secreted by the THYROID GLAND, such as THYROXINE, and their synthetic analogs.. MED13 defined as following: This gene is involved in mediator complex-dependent transcriptional regulation.. intron defined as following: Sequences of DNA in the genes that are located between the EXONS. They are transcribed along with the exons but are removed from the primary gene transcript by RNA SPLICING to leave mature RNA. Some introns code for separate genes.. nuclear hormone receptors defined as following: Nuclear hormone receptors constitute a superfamily of structurally related ligand binding transcription factors that includes the steroid receptors, thyroid hormone receptors, vitamin D and retinoid receptors, and orphan receptors for which ligands have not yet been found.. Mediator complex defined as following: A protein complex that is involved in the initiation of transcription. This complex is composed of over 30 protein subunits, which binds to the RNA polymerase II holoenzyme complex and facilitates the interaction of transcription factors with the polymerase.. thyroid hormone receptor β1 defined as following: Specific high affinity binding proteins for THYROID HORMONES in target cells. They are usually found in the nucleus and regulate DNA transcription. These receptors are activated by hormones that leads to transcription, cell differentiation, and growth suppression. Thyroid hormone receptors are encoded by two genes (GENES, ERBA): erbA-alpha and erbA-beta for alpha and beta thyroid hormone receptors, respectively.. hypothyroidism defined as following: A syndrome that results from abnormally low secretion of THYROID HORMONES from the THYROID GLAND, leading to a decrease in BASAL METABOLIC RATE. In its most severe form, there is accumulation of MUCOPOLYSACCHARIDES in the SKIN and EDEMA, known as MYXEDEMA. It may be primary or secondary due to other pituitary disease, or hypothalamic dysfunction.. cardiomyocytes defined as following: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).. microRNAs defined as following: Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing..", "label": "yes"} {"id": "converted_680", "sentence1": "Is signal transducer and activator of transcription-3 (STAT3) critical for tumor angiogenesis progression?", "sentence2": " (STAT3) is critical for cancer progression by regulating tumor cell survival, proliferation, and angiogenesis. Herein, we investigated the regulation of STAT3 activation and the therapeutic effects of Icaritin, a prenyl flavonoid derivative from Epimedium Genus, in renal cell carcinoma (RCC). , Overall, these results suggest that Icaritin strongly inhibits STAT3 activation and is a potentially effective therapeutic option for the treatment of renal cell carcinoma, we have reviewed important signaling pathways that are closely related to radiosensitization, such as cell cycle arrest, tumor angiogenesis, JAK/STAT3 signaling pathway and Mismatch repair, Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial-mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis., The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype., STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases, EESB treatment could significantly suppress the activation of several CRC-related pathways, including STAT3, Erk, and p38 signalings in tumor tissues, and alter the expression of multiple critical target genes such as Bcl-2, Bax, Cyclin D1, CDK4, and p21. These molecular effects lead to the induction of cancer cell apoptosis and inhibition of cell proliferation. Our findings demonstrate that SB possesses a broad range of antitumor activities because of its ability to affect multiple intracellular targets, Western immunoblotting analyses of mouse lung tissues indicated significantly lower level of pSTAT3 and Mcl-1 in the carcinogen plus DMAPT group relative to the group treated with the carcinogen only. Given the evidence that STAT3 is activated in more than half of lung cancers and it regulates genes involved in cell proliferation, survival and angiogenesis, DMAPT is a promising agent for lung cancer chemoprevention in subjects who are at high risk of developing this devastating disease., (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis, STAT3) signaling pathway plays important roles in oncogenesis, angiogenesis, immunity, and tumor cell invasion. In the present study, we investigated the association of interleukin , Phosphorylated STAT3 (pSTAT3) regulates many genes that are necessarily expressed in cancer initiation, development, and progression, being involved in proliferation, anti-apoptosis, invasion, angiogenesis, and immune surveillance evasion[SEP]Definitions: STAT1 defined as following: Signal transducer and activator of transcription 1-alpha/beta (750 aa, ~87 kDa) is encoded by the human STAT1 gene. This protein plays a role in signal transduction, immune responses and transcriptional regulation.. RCC defined as following: A malignant epithelial neoplasm of the kidney characterized by the presence of lipid-containing clear cells within a vascular network. The tumor may metastasize to unusual sites and late metastasis is common.. Bcl-2 defined as following: The B-cell leukemia/lymphoma-2 genes, responsible for blocking apoptosis in normal cells, and associated with follicular lymphoma when overexpressed. Overexpression results from the t(14;18) translocation. The human c-bcl-2 gene is located at 18q24 on the long arm of chromosome 18.. STAT3 defined as following: Signal transducer and activator of transcription 3 (770 aa, ~88 kDa) is encoded by the human STAT3 gene. This protein plays a role in cytokine signaling and gene expression.. JAK defined as following: A family of intracellular tyrosine kinases that participate in the signaling cascade of cytokines by associating with specific CYTOKINE RECEPTORS. They act upon STAT TRANSCRIPTION FACTORS in signaling pathway referred to as the JAK/STAT pathway. The name Janus kinase refers to the fact the proteins have two phosphate-transferring domains.. Cyclin D1 defined as following: Protein encoded by the bcl-1 gene which plays a critical role in regulating the cell cycle. Overexpression of cyclin D1 is the result of bcl-1 rearrangement, a t(11;14) translocation, and is implicated in various neoplasms.. Erk defined as following: A superfamily of PROTEIN SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).. p21 defined as following: A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.. Bax defined as following: Apoptosis regulator BAX (192 aa, ~21 kDa) is encoded by the human BAX gene. This protein plays a role in both apoptosis and protein-protein interactions.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. CDK4 defined as following: Cyclin-dependent kinase 4 is a key regulator of G1 PHASE of the CELL CYCLE. It partners with CYCLIN D to phosphorylate RETINOBLASTOMA PROTEIN. CDK4 activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P16.. cancer cell defined as following: Cells of, or derived from, a malignant tumor.. tumor cell defined as following: Cells of, or derived from, a tumor.. interleukin defined as following: A recombinant therapeutic agent which is chemically identical to or similar to the endogenous cytokine interleukin-1 (IL-1). Produced mainly by monocytes, endogenous IL-1 plays a role in hematopoiesis, is a potent stimulator of T-cell activity, may promote or inhibit tumor growth, depending on tumor type. (NCI04). cell surface receptors defined as following: Cell surface proteins that bind signalling molecules external to the cell with high affinity and convert this extracellular event into one or more intracellular signals that alter the behavior of the target cell (From Alberts, Molecular Biology of the Cell, 2nd ed, pp693-5). Cell surface receptors, unlike enzymes, do not chemically alter their ligands.. Icaritin defined as following: A metabolite of icariin, a principal flavonoid glycoside in Herba Epimedii (a traditional Chinese medicine herb used in treating osteoporosis) with potential antineoplastic activity. ERa36 modulator icaritin selectively binds to a novel variant of estrogen receptor alpha, a36, and mediates a membrane-initiated \"nongenomic\" signaling pathway, which is linked to activate signaling pathways like the MAPK/ERK and the PI3K/Akt pathways. This agent induces cell cycle arrest at G1, or G2/M arrest depending upon the dose. Consistently with G1 arrest, icaritin increases protein expressions of pRb, p27(Kip1) and p16(Ink4a), while decreasing phosphorylated pRb, Cyclin D1 and CDK4. 40% of ER-negative breast cancer tumors express high levels of ERa36, and this subset of patients is less likely to benefit from tamoxifen treatment compared with those with ERa66-positive/ERa36-negative tumors.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. SB defined as following: A metallic element that has the atomic symbol Sb, atomic number 51, and atomic weight 121.75. It is used as a metal alloy and as medicinal and poisonous salts. It is toxic and an irritant to the skin and the mucous membranes.. lung cancers defined as following: A primary or metastatic malignant neoplasm involving the lung.. Mcl-1 defined as following: This gene is a regulator of apoptosis and plays a role in differentiation.. nucleus defined as following: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). tumor tissues defined as following: A tumor sample, or entire tumor that is removed for microscopic examination..", "label": "yes"} {"id": "converted_831", "sentence1": "Have 5q35 microdeletions been implicated in Sotos syndrome development?", "sentence2": "Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID), We observed a novel 3.5 Mb 5q subtelomeric deletion in a 3-year-old girl with developmental delay, hypotonia and multiple minor anomalies. Comparison of her phenotype with the few published patients with terminal 5q35 deletions revealed several overlapping features, but also showed remarkable differences such as shortness of stature versus macrosomia. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. We demonstrated that the deletion in our patient is immediately adjacent to the reported Sotos syndrome deletion site, Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions., Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome., After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes., Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations., Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia., Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos., Alu-related 5q35 microdeletions in Sotos syndrome., Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions., Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome, Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations, Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos, A case of Sotos syndrome with 5q35 microdeletion and novel clinical findings., Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. , There are two types of mutations that cause NSD1 haploinsufficiency: mutations within the NSD1 gene (mutation type) and a 5q35 submicroscopic deletion encompassing the entire NSD1 gene (deletion type). , aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome., Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome., Switch in FGFR3 and -4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions., A case of Sotos syndrome with 5q35 microdeletion and novel clinical findings., Most cases of Sotos syndrome are caused by intragenic NSD1 mutations or 5q35 microdeletions., aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome., Alu-related 5q35 microdeletions in Sotos syndrome.[SEP]Definitions: NSD1 defined as following: Histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specific (2696 aa, ~297 kDa) is encoded by the human NSD1 gene. This protein is involved in histone methylation.. FGFR3 defined as following: Fibroblast growth factor receptor 3 (806 aa, ~88 kDa) is encoded by the human FGFR3 gene. This protein is involved in fibroblast growth factor signaling and skeletal development.. 5q35.3 defined as following: A chromosome band present on 5q. Sos defined as following: Spondylo-ocular syndrome is a very rare association of spinal and ocular manifestations that is characterized by dense cataracts, and retinal detachment along with generalized osteoporosis and platyspondyly. Mild craniofacial dysphormism has been reported including short neck, large head and prominent eyebrows.. fibroblast growth factor receptor 4 defined as following: A fibroblast growth factor receptor with specificity for FIBROBLAST GROWTH FACTORS; HEPARAN SULFATE PROTEOGLYCAN; and NEURONAL CELL ADHESION MOLECULES. Several variants of the receptor exist due to multiple ALTERNATIVE SPLICING of its mRNA. Fibroblast growth factor receptor 1 contains three extracellular IMMUNOGLOBULIN C2-SET DOMAINS and is a tyrosine kinase that transmits signals through the MAP KINASE SIGNALING SYSTEM.. 5q35 defined as following: A chromosome band present on 5q. human defined as following: Members of the species Homo sapiens.. terminal defined as following: Being or situated at an end; occurring at or forming an end.. NSD1 gene defined as following: This gene is involved in the mediation of histone methylation.. FGFR4 defined as following: This gene plays a role in mitogenesis and differentiation.. macrocephaly defined as following: A congenital abnormality in which the occipitofrontal circumference is greater than two standard deviations above the mean for a given age. It is associated with HYDROCEPHALUS; SUBDURAL EFFUSION; ARACHNOID CYSTS; or is part of a genetic condition (e.g., ALEXANDER DISEASE; SOTOS SYNDROME).. hypercalcemia defined as following: Abnormally high level of calcium in the blood.. deletions defined as following: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus.. BACs defined as following: A standardized rating scale developed by Keefe et al in 2004 to assess cognitive function and impairment in patients with schizophrenia. This instrument consists 6 tests in the following areas: verbal memory, working memory, motor speed, verbal fluency, attention, and executive function.. hypotonia defined as following: A diminution of the skeletal muscle tone marked by a diminished resistance to passive stretching.. macrosomia defined as following: A fetus or infant who is larger than expected for the age or gender, or who has a birth weight greater than the 90th percentile.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. intellectual disability defined as following: Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28).", "label": "yes"} {"id": "converted_160", "sentence1": "Is there any software for automated analysis of FISH images?", "sentence2": "he study demonstrated the feasibility of automated FISH signal analysis that applying a CAD scheme to the automated generated 2-D projection images., A color imaging technique, multiplex fluorescent in situ hybridization (M-FISH), has been developed to ease the analysis of the process. Using an M-FISH technique each chromosome class (1,2, …,22,X,Y) is stained with a unique color. However, significant variations between images are observed due to a number of factors such as uneven hybridization and spectral overlap among channels. These types of variations influence the pixel classification accuracy of image classification methods which are supervised and require a set of annotated images for training. In this paper, we present a fully unsupervised M-FISH chromosome image classification methodology. Our main contributions are 1) the assumption that the intensity of a chromosome pixel is sampled from multiple Gaussian components [Gaussian mixture model (GMM)] such that each component corresponds to one chromosome class, and 2) the initialization of the GMM model using the emission information of each chromosome class. This is feasible since prior to the M-FISH image acquirement, we already know which chromosome class is emitting to each of the five M-FISH image channels. The method has been tested on a large number of M-FISH images and an overall accuracy of 89.85% is reported. Our method is unsupervised and presents higher classification accuracy even when it is compared with common supervised based methods., hybridization (FISH) tests provide promising molecular imaging biomarkers to more accurately and reliably detect and diagnose cancers and genetic disorders. Since current manual FISH signal analysis is low-efficient and inconsistent, which limits its clinical utility, developing automated FISH image scanning systems and computer-aided detection (CAD) schemes has been attracting research interests. To acquire high-resolution FISH images in a multi-spectral scanning mode, a huge amount of image data with the stack of the multiple three-dimensional (3-D) image slices is generated from a single specimen. Automated preprocessing these scanned images to eliminate the non-useful and redundant data is important to make the automated FISH tests acceptable in clinical applications. In this study, a dual-detector fluorescence image scanning system was applied to scan four specimen slides with FISH-probed chromosome X. A CAD scheme was developed to detect analyzable interphase cells and map the multiple imaging slices recorded FISH-probed signals into the 2-D projection images. CAD scheme was then applied to each projection image to detect analyzable interphase cells using an adaptive multiple-threshold algorithm, identify FISH-probed signals using a top-hat transform, and compute the ratios between the normal and abnormal cells. To assess CAD performance, the FISH-probed signals were also independently visually detected by an observer. The Kappa coefficients for agreement between CAD and observer ranged from 0.69 to 1.0 in detecting/counting FISH signal spots in four testing samples., In this paper we developed a sparse representation-based classification (SRC) algorithm based on L1-norm minimization for classifying chromosomes from multicolor fluorescence in situ hybridization (M-FISH) images. The algorithm has been tested on a comprehensive M-FISH database that we established, demonstrating improved performance in classification. When compared with other pixel-wise M-FISH image classifiers such as fuzzy c-means (FCM) clustering algorithms and adaptive fuzzy c-means (AFCM) clustering algorithms that we proposed earlier the current method gave the lowest classification error. In order to evaluate the performance of different SRC for M-FISH imaging analysis, three different sparse representation methods, namely, Homotopy method, Orthogonal Matching Pursuit (OMP), and Least Angle Regression (LARS), were tested and compared. Results from our statistical analysis have shown that Homotopy based method is significantly better than the other two methods. , Fluorescence in situ hybridization (FISH) is used to study the organization and the positioning of specific DNA sequences within the cell nucleus. Analyzing the data from FISH images is a tedious process that invokes an element of subjectivity. Automated FISH image analysis offers savings in time as well as gaining the benefit of objective data analysis. While several FISH image analysis software tools have been developed, they often use a threshold-based segmentation algorithm for nucleus segmentation. As fluorescence signal intensities can vary significantly from experiment to experiment, from cell to cell, and within a cell, threshold-based segmentation is inflexible and often insufficient for automatic image analysis, leading to additional manual segmentation and potential subjective bias. To overcome these problems, we developed a graphical software tool called FISH Finder to automatically analyze FISH images that vary significantly. By posing the nucleus segmentation as a classification problem, compound Bayesian classifier is employed so that contextual information is utilized, resulting in reliable classification and boundary extraction. This makes it possible to analyze FISH images efficiently and objectively without adjustment of input parameters. Additionally, FISH Finder was designed to analyze the distances between differentially stained FISH probes., The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining. Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell. METHODS: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion. RESULTS: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217., The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining.Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell. METHODS: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion. RESULTS: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. There was no significant difference between CD133 positive tumour and CD133 negative tumour cells. , The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining.Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell.Methods: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion.Results: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. There was no significant difference between CD133 positive tumour and CD133 negative tumour cells.[SEP]Definitions: cell nucleus defined as following: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). CD133 defined as following: Prominin-1 (865 aa, ~97 kDa) is encoded by the human PROM1 gene. This protein may play a role in hematopoiesis, but an exact function has yet to be elucidated. The protein has been implicated in tumor pathogenesis and formation in several cancers, including retinoblastoma, hemangioma, and glioblastoma phenotypes. Additionally, the protein has been used as a marker to distinguish cells that have the potential to become cancerous from the larger normal cell population.. SRC defined as following: Proto-oncogene tyrosine-protein kinase Src (536 aa, ~60 kDa) is encoded by the human SRC gene. This protein is involved in both receptor-mediated signal transduction and tyrosine phosphorylation.. DNA sequences defined as following: The sequence of nucleotide residues along a DNA chain.. chromosomes defined as following: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification.. colorectal cancers defined as following: A malignant epithelial neoplasm that arises from the colon or rectum and invades through the muscularis mucosa into the submucosa. The vast majority are adenocarcinomas.. MYC defined as following: Myc proto-oncogene protein (439 aa, ~49 kDa) is encoded by the human MYC gene. This protein plays a role in the regulation of transcription and cell proliferation.. ZNF217 defined as following: Zinc finger protein 217 (1048 aa, ~115 kDa) is encoded by the human ZNF217 gene. This protein plays a role in the negative regulation of transcription.. DNA probes defined as following: Species- or subspecies-specific DNA (including COMPLEMENTARY DNA; conserved genes, whole chromosomes, or whole genomes) used in hybridization studies in order to identify microorganisms, to measure DNA-DNA homologies, to group subspecies, etc. The DNA probe hybridizes with a specific mRNA, if present. Conventional techniques used for testing for the hybridization product include dot blot assays, Southern blot assays, and DNA:RNA hybrid-specific antibody tests. Conventional labels for the DNA probe include the radioisotope labels 32P and 125I and the chemical label biotin. The use of DNA probes provides a specific, sensitive, rapid, and inexpensive replacement for cell culture techniques for diagnosing infections.. colon cancer defined as following: A primary or metastatic malignant neoplasm that affects the colon. Representative examples include carcinoma, lymphoma, and sarcoma.. Chromosome 6 defined as following: A specific pair GROUP C CHROMSOMES of the human chromosome classification.. abnormal cells defined as following: An abnormal human cell type which can occur in either disease states or disease models.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. MYC oncogene defined as following: A viral and cellular gene. A proto-oncogene, identified in several avian tumors, encoding a nuclear protein with a leucine zipper motif..", "label": "yes"} {"id": "converted_4214", "sentence1": "Are there antimicrobial proteins in royal jelly?", "sentence2": "Jellein, a peptide derived from royal jelly of honeybee has been shown to have promising effect against several bacterial and fungal species. , It is also the most studied bee product, aimed at unravelling its bioactivities, such as antimicrobial, antioxidant, anti-aging, immunomodulatory, and general tonic action against laboratory animals, microbial organisms, farm animals, and clinical trials, Jelleines, isolated as novel antibacterial peptides from the Royal Jelly (RJ) of bees, exhibit broad-spectrum protection against microbial infections., The study showed significant antimicrobial activity from several proteins present in the honey of M. beecheii.[SEP]Definitions: peptide defined as following: Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein..", "label": "yes"} {"id": "converted_2788", "sentence1": "Is pembrolizumab effective against Ewing's sarcoma?", "sentence2": "None of the 13 patients with Ewing's sarcoma had an objective response. , Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). [SEP]Definitions: Ewing's sarcoma defined as following: A small round cell bone tumor that lacks morphologic, immunohistochemical, and electron microscopic evidence of neuroectodermal differentiation. It represents one of the two ends of the spectrum called Ewing sarcoma/peripheral neuroectodermal tumor. It often affects the diaphysis or metaphyseal-diaphyseal portion of long bones. Clinical findings include pain and a mass in the involved area. Fever, anemia, leukocytosis, and an increased sedimentation rate are often seen. X-ray examination reveals osteolytic lesions. The prognosis depends on the stage, anatomic location, and size of the tumor..", "label": "no"} {"id": "converted_572", "sentence1": "Is phospholamban phosphorylated by Protein kinase A?", "sentence2": "cAMP-dependent protein kinase (PKA) phosphorylation of PLB, phosphorylation of PLN, at either Ser(16) by PKA , Activation of cardiac muscle sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) by beta1-agonists involves cAMP- and PKA-dependent phosphorylation of phospholamban (PLB), which relieves the inhibitory effects of PLB on SERCA2a. , Phospholamban (PLB) is a sarcoplasmic reticulum (SR) protein that when phosphorylated at Ser16 by PKA, phosphorylation of PLB by the Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein kinase (PKA). , cAMP-dependent protein kinase (PKA)-mediated phospholamban (PLB) phosphorylation at serine-16, Phospholamban (PLB) is a major target of the beta-adrenergic cascade in the heart, functioning to modulate contractile force by altering the rate of calcium re-sequestration by the Ca-ATPase. Functionally, inhibition by PLB binding is manifested by shifts in the calcium dependence of Ca-ATPase activation toward higher calcium levels; phosphorylation of PLB by PKA reverses the inhibitory action of PLB., phosphorylation of both PLB residues (Ser16, PKA site, and Thr17, CaMKII site) , Phosphorylation of Ser(16) by PKA, stabilization of the structure of PLB following phosphorylation of Ser(16), Phospholamban (PLB) inhibits the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, and this inhibition is relieved by cAMP-dependent protein kinase (PKA)-mediated phosphorylation. , Two-dimensional tryptic peptide maps of phosphorylated phospholamban indicated that cAMP-dependent protein kinase phosphorylates at a single site, A, and Ca2+-calmodulin-dependent protein kinase phosphorylates at sites C1 and C2 in the low molecular weight form, where A is different from C1 but may be the same as C2., Because SR function is regulated by phosphorylation of phospholamban (PLB), a SR protein phosphorylated by cAMP-dependent protein kinase (PKA) at Ser(16)and Ca(2+)-calmodulin-dependent protein kinase (CaMKII) at Thr(17), the phosphorylation of these residues during ischemia and reperfusion was examined in Langendorff-perfused rat hearts, These changes were associated with reduced protein expression of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and protein kinase A phosphorylated phospholamban (PLB), which was reduced in HF, but essentially abolished in VD-HF, The data indicate that 1) phosphorylation of phospholamban at Ser16 by cAMP-dependent protein kinase is the main regulator of beta-adrenergic-induced cardiac relaxation definitely preceding Thr17 phosphorylation and 2) the beta-adrenergic-mediated phosphorylation of Thr17 by Ca2+-calmodulin-dependent protein kinase required influx of Ca2+ through the L-type Ca2+ channel, Here we extend this model to explain the reversal of SERCA2a inhibition that occurs after phosphorylation of PLB at Ser(16) by protein kinase A (PKA) and after binding of the anti-PLB monoclonal antibody 2D12, which recognizes residues 7-13 of PLB, Phospholamban is phosphorylated in heart by cAMP-dependent protein kinase, cGMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II (CM-kinase-II) and in smooth muscle cells by cGMP-dependent protein kinase, Phospholamban, the cardiac sarcoplasmic reticulum proteolipid, is phosphorylated by cAMP-dependent protein kinase, by Ca2+/phospholipid-dependent protein kinase, and by an endogenous Ca2+/calmodulin-dependent protein kinase, the identity of which remains to be defined[SEP]Definitions: Phospholamban defined as following: free sarcoplasmic reticulum polymeric proteolipid which modulates sarcoplasmic reticulum function; phosphorylated by cAMP-dependent, calcium-calmodulin-dependent, and calcium-phospholipid-dependent protein kinases.. calcium defined as following: A dietary supplement containing the mineral calcium.. ischemia defined as following: A surgical procedure during which the blood supply to an organ or tissue is interrupted and then later reestablished.. C2 defined as following: Complement C2 (752 aa, ~83 kDa) is encoded by the human C2 gene. This protein is involved in post-translational protein processing and complement activity.. SR defined as following: Human SNCG wild-type allele is located within10q23.2-q23.3 and is approximately 13 kb in length. This allele, which encodes gamma-synuclein protein, plays a role in the modulation of axonal architecture and neurofilament integrity. This gene is highly expessed in advanced breast carcinomas, suggesting a correlation between SNCG overexpression and breast tumor development.. smooth muscle cells defined as following: An elongated spindle-shaped contractile cell, peculiar to an involuntary muscle, containing a single nucleus and longitudinally arranged myofibrils.. protein kinase A defined as following: A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.. rat defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. sarcoplasmic reticulum defined as following: A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.. CaMKII defined as following: A multifunctional calcium-calmodulin-dependent protein kinase subtype that occurs as an oligomeric protein comprised of twelve subunits. It differs from other enzyme subtypes in that it lacks a phosphorylatable activation domain that can respond to CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE.. calcium/calmodulin-dependent protein kinase II defined as following: A CALMODULIN-dependent enzyme that catalyzes the phosphorylation of proteins. This enzyme is also sometimes dependent on CALCIUM. A wide range of proteins can act as acceptor, including VIMENTIN; SYNAPSINS; GLYCOGEN SYNTHASE; MYOSIN LIGHT CHAINS; and the MICROTUBULE-ASSOCIATED PROTEINS. (From Enzyme Nomenclature, 1992, p277). cGMP-dependent protein kinase defined as following: A group of cyclic GMP-dependent enzymes that catalyze the phosphorylation of SERINE or THREONINE residues of proteins.. sarcoplasmic reticulum Ca(2+)-ATPase defined as following: Calcium-transporting ATPases that catalyze the active transport of CALCIUM into the SARCOPLASMIC RETICULUM vesicles from the CYTOPLASM. They are primarily found in MUSCLE CELLS and play a role in the relaxation of MUSCLES.. HF defined as following: Abnormal accumulation of serous fluid in two or more fetal compartments, such as SKIN; PLEURA; PERICARDIUM; PLACENTA; PERITONEUM; AMNIOTIC FLUID. General fetal EDEMA may be of non-immunologic origin, or of immunologic origin as in the case of ERYTHROBLASTOSIS FETALIS.. Protein kinase A defined as following: A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition..", "label": "yes"} {"id": "converted_172", "sentence1": "Is cytisine superior to nicotine replacement therapy for smoking cessation?", "sentence2": "The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men., CONCLUSIONS: When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events.[SEP]", "label": "yes"} {"id": "converted_1520", "sentence1": "Is there any data to suggest that TRH (thyrotropin releasing hormone) administration can improve symptom severity of amyotrophic lateral sclerosis patients?", "sentence2": "These central nervous system (CNS)-mediated effects provide the rationale for use of TRH and its analogs in the treatment of brain and spinal injury, and CNS disorders like schizophrenia, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, depression, shock and ischemia., The Effect of TRH to correct the abnormal F responses in SSP might be consistent with effects of TRH to reduce spasticity in amyotrophic lateral sclerosis described previously, Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue., Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system., The results of the clinical evaluation at the beginning and end of the treatment as well as after patient follow up demonstrated that beneficial effects do not occur equally in all patients but rather are transitory and do not improve the natural evolution of the disease., The neurological evaluation after acute TRH-T treatment showed an objective improvement in 3 of the 8., The outcome of the study, in agreement with some and at variance with other studies, was that TRH induced a statistically significant neurological improvement in 17 of the 23 ALS patients but little or none in the other ALS patients and in patients with other neurological diseases., [A case of amyotrophic lateral sclerosis with disturbance of vertical ocular movement responding to thyrotropin releasing hormone (TRH)]., TRH injections resulted in improvement of disturbance of vertical ocular movement, but no effect was seen on the weakness of the limb., 13 patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous infusion of thyrotropin-releasing hormone (TRH). , Similar improvements in speech, swallowing and in tongue and jaw movements were seen after iv and oral administration in nine, five and eight patients respectively. , No clinical improvement was detected. , A trial of Thyrotropin Releasing Hormone (TRH) 5.0 mg/kg body weight subcutaneously every other day for two weeks produced transient increased tone in muscles, along with other (side-) effects in patients with Amyotrophic Lateral Sclerosis (ALS)., Although the mechanism is not known, several reports of the effectiveness of thyrotropin releasing hormone (TRH) in ALS were recently published., Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). , Clinical studies have shown that response to TRH is state dependent, that is, it depends on whether the patient has bulbar or nonbulbar signs and is male or female. Future studies must take into consideration this state dependence as a specific feature of the pharmacological action of TRH and its analogues., Three of the studies showed a transient, statistically significant effect in at least some muscles. The two studies that demonstrated no such effect both used TRH in very small doses. It therefore seems reasonable to conclude that the effect of TRH in ALS is a definite, acute, and transient response. , It was found that in only 3 out of 14 patients with moderately progressed disease no improvement was achieved, while in 11 cases the improvement was from 10 to 20%. However, the improvement was transient, and TRH treatment failed to stop the progression of the disease., Only 3 patients noted subjective improvement of strength., In 6 of the 9, TRH induced a significant increase in vibratory inhibition. This suggests that the TRH-induced reduction of spasticity might be due to an increase in presynaptic inhibition acting on Ia fibres., However, 2 mg DN-1417, IM twice a day for 1 month in an open-label trial, produced no objective improvement of strength in nine patients with ALS. , Our experience suggests that this approach is safe, has high patient acceptance, and is worthy of more careful evaluation., Focal, small-to-moderate and transient improvement occurred in the muscle strength and function of patients with ALS who received TRH in dose-response and screening studies. In a small pilot study of 12 patients, 3 months administration of TRH at 10 mg per kg on alternate days resulted in localized increased strength of jaw muscles as well as significant improvement in lower extremity function. Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH. , Mild to moderate improvement was found in 9 (56%) of 16 patients. , We thought such action of TRH to be useful to the therapy of ALS., With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials., A temporary increase in the strength of some muscles was detected following the administration of TRH, but no change in functional performance was noted. Neither the patients nor the investigators believed the effects were of any marked clinical significance., Nevertheless, statistically significant improvement was seen only in dynametric strength 1 hour after subcutaneous injection (p less than 0.05). Significant improvement occurred, in one patient only, on subjective speech testing during IV infusion of TRH. In none of six other ratings was there a significant difference between TRH and placebo. Subjective improvement was noted by 11 of 12 patients., Significant improvement, as shown by statistical analysis, was noted in muscle strength in the 9 patients by 5 infusions over a 4-week period and a sub-group of 5 patients treated by 8 infusions over 10 weeks., The progressive course of this disease, manifested by increasing atrophy, paralysis and disability score, was not altered. , Very high intravenous doses (2-19 mg/min) of thyrotropin-releasing hormone (TRH, L-pyroglutamyl-L-histidyl-L-prolinamide) given to 12 patients with amyotrophic lateral sclerosis (ALS) produced a moderate to marked improvement of functions caused by deficiency of lower motor neurons (weakness) and upper motor neurons (spasticity). The improvement was sustained throughout the infusion and for about 1 h thereafter; sometimes a slight improvement was evident 20 h after infusion., Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH[SEP]Definitions: CNTF defined as following: A neurotrophic factor that promotes the survival of various neuronal cell types and may play an important role in the injury response in the nervous system.. thyrotropin releasing hormone defined as following: Thyrotropin-releasing hormone (3 aa, ~0.4 kDa) is encoded by the human TRH gene. This protein plays a role in the positive regulation of thyrotropin (thyroid-stimulating hormone; TSH) production and release.. Protirelin defined as following: A tripeptide that stimulates the release of THYROTROPIN and PROLACTIN. It is synthesized by the neurons in the PARAVENTRICULAR NUCLEUS of the HYPOTHALAMUS. After being released into the pituitary portal circulation, TRH (was called TRF) stimulates the release of TSH and PRL from the ANTERIOR PITUITARY GLAND.. amyotrophic lateral sclerosis defined as following: An inherited form of amyotrophic lateral sclerosis, usually inherited in an autosomal dominant pattern, caused by mutation(s) in the SOD1 gene, encoding superoxide dismutase.. ischemia defined as following: A surgical procedure during which the blood supply to an organ or tissue is interrupted and then later reestablished.. shock defined as following: A pathological condition manifested by failure to perfuse or oxygenate vital organs.. branched-chain amino acids defined as following: Amino acids which have a branched carbon chain.. TRH defined as following: Thyrotropin-releasing hormone (3 aa, ~0.4 kDa) is encoded by the human TRH gene. This protein plays a role in the positive regulation of thyrotropin (thyroid-stimulating hormone; TSH) production and release.. spasticity defined as following: A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a \"free interval\") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54). epilepsy defined as following: A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313). muscles defined as following: Contractile tissue that produces movement in animals.. paralysis defined as following: A general term most often used to describe severe or complete loss of muscle strength due to motor system disease from the level of the cerebral cortex to the muscle fiber. This term may also occasionally refer to a loss of sensory function. (From Adams et al., Principles of Neurology, 6th ed, p45). Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65.. Focal defined as following: Limited to a specific area.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. atrophy defined as following: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes.. tongue defined as following: A muscular organ in the mouth that is covered with pink tissue called mucosa, tiny bumps called papillae, and thousands of taste buds. The tongue is anchored to the mouth and is vital for chewing, swallowing, and for speech.. analogs defined as following: A synthetic chemical which structurally or functionally resembles a naturally occurring compound.. Parkinson's disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75).", "label": "yes"} {"id": "converted_2571", "sentence1": "Can gas vesicles be detected by ultrasound?", "sentence2": "Gas vesicles-genetically encoded protein nanostructures isolated from buoyant photosynthetic microbes-have recently been identified as nanoscale reporters for ultrasound., Here, we demonstrate that genetic engineering of gas vesicles results in nanostructures with new mechanical, acoustic, surface, and functional properties to enable harmonic, multiplexed, and multimodal ultrasound imaging as well as cell-specific molecular targeting. [SEP]Definitions: surface defined as following: The extended two-dimensional outer boundary of a three-dimensional object..", "label": "yes"} {"id": "converted_2605", "sentence1": "Does verubecestat activate BACE?", "sentence2": "Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. [SEP]Definitions: Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65.. BACE1 defined as following: Beta-secretase 1 (501 aa, ~56 kDa) is encoded by the human BACE1 gene. This protein plays a role in the proteolysis of ectodomains of membrane proteins..", "label": "no"} {"id": "converted_2357", "sentence1": "Is Kummell’s disease an avascular necrosis of the vertebral body?", "sentence2": " Kummell's disease is an avascular necrosis of the vertebral body, secondary to a vertebral compression fracture. This entity is characterised by the gradual development in time of a vertebral body collapse following a trivial spinal trauma, involving a worsening back pain associated with a progressive kyphosis., Kummell's disease is a rare spinal disorder characterized as avascular necrosis of a vertebral body occurring in a delayed fashion after minor trauma., Kummell's disease is a spinal disorder characterized by delayed post-traumatic collapse of a vertebral body with avascular necrosis., Kummell disease, or avascular necrosis of a vertebral body, presents as vertebral osteonecrosis typically affecting a thoracic vertebra with compression deformity, intravertebral vacuum cleft, and exaggerated kyphosis weeks to months after a minor traumatic injury., INTRODUCTION Kummell's disease is an avascular necrosis of the vertebral body, secondary to a vertebral compression fracture., Kummel disease is the eponym for avascular necrosis of the vertebral body after a vertebral compression fracture., kummell s disease delayed post traumatic osteonecrosis of the vertebral body, Kummell's disease, caused by osteonecrosis of the vertebral body, is a cause of vertebral collapse., Kummell's disease is a post-traumatic vertebral body collapse, Kummell's disease is a rare, delayed posttraumatic collapse of a vertebral body that can occur several months or even years after an osteoporotic compression fracture. , Avascular necrosis of a vertebral body, a relatively uncommon entity, is caused by malignancy, infection, radiation, systemic steroid treatment, trauma, and the like.1 Vertebral osteonecrosis induced by trauma is called Kvmell's disease[SEP]Definitions: trauma defined as following: Nurses in this specialty provide emergency care to patients of all ages. These nurses work to maintain vital signs and prevent complications and death. malignancy defined as following: A malignant tumor at the original site of growth.. infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. osteonecrosis defined as following: Death of a bone or part of a bone, either atraumatic or posttraumatic.. steroid defined as following: A group of polycyclic compounds closely related biochemically to TERPENES. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (STEROLS), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. (From Hawley's Condensed Chemical Dictionary, 11th ed). traumatic injury defined as following: Damage inflicted on the body as the direct or indirect result of an external force, with or without disruption of structural continuity.. thoracic vertebra defined as following: A group of twelve VERTEBRAE connected to the ribs that support the upper trunk region.. kyphosis defined as following: Deformities of the SPINE characterized by an exaggerated convexity of the vertebral column. The forward bending of the thoracic region usually is more than 40 degrees. This deformity sometimes is called round back or hunchback..", "label": "yes"} {"id": "converted_1267", "sentence1": "Does HER2 under-expression lead to favorable response to trastuzumab?", "sentence2": "over-expression of HER2 is reported in approximately 20% of gastric tumours, challenging the use of targeted therapies. , In patients with advanced gastric or gastro-oesophageal junction cancer, addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone. Addition of trastuzumab to chemotherapy did not increase the incidence of adverse events., treatment of HER2-overexpressing breast cancer: trastuzumab,, Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. , An example is the established benefit of trastuzumab as adjuvant therapy for breast cancer; a clear definition of HER2-positivity and the assay reproducibility have, however, remained unanswered. , Trastuzumab is a monoclonal antibody targeted to the Her2 receptor and approved for treatment of Her2-positive breast cancer., Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast cancers in which it is overexpressed. However, no approved anti-HER2/neu therapy is available for the majority of breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative)., The humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) is useful in the treatment of ErbB2-overexpressing breast cancers,, HercepTestTM (DAKO A/S, Glostrup, Denmark) is an immunohistochemical assay that detects HER2/neu gene products, and evaluates the overexpression status of the HER2/neu protein in determining eligibility for the Trastuzumab (HerceptinR, Genentech, San Francisco, CA, USA) therapy. [SEP]Definitions: breast cancer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. HER2 defined as following: Human ERBB2 wild-type allele is located in the vicinity of 17q21.1 and is approximately 29 kb in length. This allele, which encodes receptor tyrosine-protein kinase erbB-2 protein, plays a role in EGF receptor signal transduction pathways and cellular growth. Amplification or overexpression of this gene is involved in the progression of several forms of cancer, including breast and ovarian tumors.. breast defined as following: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.. Her2-positive breast cancer defined as following: A biologic subset of breast carcinoma defined by high expression of HER2, GRB7, and TRAP100, and by lack of expression of estrogen receptor (ER).. trastuzumab defined as following: A humanized monoclonal antibody against the ERBB-2 RECEPTOR (HER2). As an ANTINEOPLASTIC AGENT, it is used to treat BREAST CANCER where HER2 is overexpressed.. monoclonal antibody defined as following: A humanized monoclonal antibody directed against parathyroid hormone-related protein (PTH-rP). As a poly-hormone with diverse biological roles, PTH-rP is expressed by normal tissues, acting in local tissue environments in a variety of ways; it is commonly overexpressed by breast, prostate, and other cancers, acting systemically by promoting bone resorption, inhibiting calcium excretion from the kidney, inducing hypercalcemia, and possibly playing a role in the formation of bony metastases. By blocking the effects of PTH-rP on calcium metabolism, monoclonal antibody CAL may inhibit cancer-related hypercalcemia. (NCI04).", "label": "no"} {"id": "converted_1475", "sentence1": "Is aganglionic megacolon a feature of Down syndrome?", "sentence2": "Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS, Of the 17 patients with HD who were studied, 10 were isolated (58.8%) and seven (41.1%) were associated to other structural abnormalities and psychomotor retardation. Three of the cases in this latter group were due to chromosome pathology (trisomy 21, Down syndrome), The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy. The patient condition improved after a colostomy performed in the setting of the treatment of Hirschprung disease, Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age, Intestinal microvillous atrophy in a patient with Down syndrome and aganglionic megacolon., The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy., The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy., The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy[SEP]Definitions: HD defined as following: A malignant disease characterized by progressive enlargement of the lymph nodes, spleen, and general lymphoid tissue. In the classical variant, giant usually multinucleate Hodgkin's and REED-STERNBERG CELLS are present; in the nodular lymphocyte predominant variant, lymphocytic and histiocytic cells are seen.. diarrhea defined as following: An increased liquidity or decreased consistency of FECES, such as running stool. Fecal consistency is related to the ratio of water-holding capacity of insoluble solids to total water, rather than the amount of water present. Diarrhea is not hyperdefecation or increased fecal weight.. aganglionosis defined as following: Congenital MEGACOLON resulting from the absence of ganglion cells (aganglionosis) in a distal segment of the LARGE INTESTINE. The aganglionic segment is permanently contracted thus causing dilatation proximal to it. In most cases, the aganglionic segment is within the RECTUM and SIGMOID COLON.. Down syndrome defined as following: A chromosome disorder associated either with an extra CHROMOSOME 21 or an effective TRISOMY for chromosome 21. Clinical manifestations include HYPOTONIA, short stature, BRACHYCEPHALY, upslanting palpebral fissures, epicanthus, Brushfield spots on the iris, protruding tongue, small ears, short, broad hands, fifth finger clinodactyly, single transverse palmar crease, and moderate to severe INTELLECTUAL DISABILITY. Cardiac and gastrointestinal malformations, a marked increase in the incidence of LEUKEMIA, and the early onset of ALZHEIMER DISEASE are also associated with this condition. Pathologic features include the development of NEUROFIBRILLARY TANGLES in neurons and the deposition of AMYLOID BETA-PROTEIN, similar to the pathology of ALZHEIMER DISEASE. (Menkes, Textbook of Child Neurology, 5th ed, p213). duodenal atresia defined as following: A congenital malformation characterized by the absence of a normal opening in a part of the duodenum.. jejunal biopsy defined as following: Removal of tissue from the jujunum for microscopic examination, using an endoscope.. intellectual disability defined as following: Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28).", "label": "yes"} {"id": "converted_1754", "sentence1": "Could BRCA gene test used for breast and ovarian cancer risk?", "sentence2": "Participation of Korean families at high risk for hereditary breast and ovarian cancer in BRCA1/2 genetic testing., The prevalence of BRCA1/2 mutations in Korean ovarian cancer patients irrespective of the family history was significantly higher than previously reported. Possible founder mutations in Korean ovarian cancer patients were identified., Germline Mutations of BRCA1 and BRCA2 in Korean Ovarian Cancer Patients: Finding Founder Mutations., The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. , Maximising survival: the main concern of women with hereditary breast and ovarian cancer who undergo genetic testing for BRCA1/2., Little is known about how women with hereditary breast and/or ovarian cancer who test positive for a BRCA gene manage the impact of a positive test result on their everyday lives and in the longer term. This study defined the experience and needs of women with hereditary breast and ovarian cancer and a positive BRCA test over time., The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3))., Female BRCA (breast cancer gene)-1 and BRCA-2 mutations are significantly associated with risk of developing breast and ovarian cancers, in turn, associated with female infertility. , Large BRCA1 and BRCA2 genomic rearrangements in Polish high-risk breast and ovarian cancer families., BRCA1 and BRCA2 are two major genes associated with familial breast and ovarian cancer susceptibility., Until 2006, she supervised a diagnostic unit for BRCA gene testing at the Interdisciplinary Center for Hereditary Breast Cancer (Max Delbrück Center, Berlin, Germany). , Inherited BRCA gene mutations convey a high risk for breast and ovarian cancer, but current guidelines limit BRCA mutation testing to women with early-onset cancer and relatives of mutation-positive cases. , Women who carry a BRCA1 or BRCA2 gene mutation face a risk of developing breast or ovarian cancer at an earlier age than women without such a mutation., In 2006, participants were recruited from Web sites for women with breast cancer or BRCA gene mutations. , About 20 % of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes. Since BRCA1 and BRCA2 mutations may be spread throughout the gene, genetic testing is usually performed by direct sequencing of entire coding regions., Suggestion of an association between BRCA2 c.7806-2A>G and risk of breast cancer in males has emerged. , The presence of deleterious mutations in breast cancer (BRCA)-1 or BRCA-2 gene has a decisive influence on the development of various types of neoplasms, such as breast, ovarian, tubal, and peritoneal cancers. , OBJECTIVE: Female BRCA (breast cancer gene)-1 and BRCA-2 mutations are significantly associated with risk of developing breast and ovarian cancers, in turn, associated with female infertility., BRCA1 and BRCA2 genes are responsible for 5-10% of breast and ovarian cancer cases., She was daughter of a woman, a carrier of BRCA 1 gene mutation, with early onset of breast cancer and positive family history.CONCLUSIONS: BRCA 1 and BRCA 2 gene mutations are of particular importance in the increasing risk of ovarian cancer and early onset of breast cancer as well as some other malignancies., BACKGROUND: Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages., We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2., Germline BRCA gene mutations are reportedly associated with hereditary breast and ovarian cancers., [Detection and occurrence of BRCA 1 gene mutation in patients with carcinoma of the breast and ovary]., We investigated the relationship between BRCA mutations and the distribution of familial cancers other than breast or ovary in high-risk breast cancer patients.PATIENTS WITH BREAST CANCER WHO HAD AT LEAST ONE OF THE FOLLOWING RISK FACTORS WERE ENROLLED: reported family history of breast or ovarian cancer; 40 years of age or younger age at diagnosis; bilateral breast cancer; or male gender, Mutations in breast cancer susceptibility genes (BRCA1 and BRCA2) are associated with increased risks for breast, ovarian, and other types of cancer.To review new evidence on the benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women.MEDLINE and PsycINFO between 2004 and 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews from 2004 through the second quarter of 2013, Health Technology Assessment during the fourth quarter of 2012, Scopus, and reference lists.English-language studies about accuracy of risk assessment and benefits and harms of genetic counseling, genetic testing, and interventions to reduce cancer incidence and mortality., The objective of this study was to assess the incidence of primary breast cancer (PBC) and contralateral breast cancer (CBC) in patients who had BRCA1/BRCA2-associated epithelial ovarian cancer (OC).From the database of the Rotterdam Family Cancer Clinic, patients who had BRCA-associated OC without a history of unilateral breast cancer (BC) (at risk of PBC; n = 79) or with a history of unilateral BC (at risk of CBC; n = 37) were selected, Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer-identified and ovarian cancer-identified families.Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations, The USPSTF also reviewed interventions aimed at reducing the risk for BRCA-related cancer in women with potentially harmful BRCA mutations, including intensive cancer screening, medications, and risk-reducing surgery.This recommendation applies to asymptomatic women who have not been diagnosed with BRCA-related cancer.The USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2), If a woman bearing a mutation develops cancer in one breast, her risk of developing cancer in the other breast depends on the particular gene that is mutated and on her age at the onset of disease.About half of all monogenically determined carcinomas of the breast and ovary are due to a mutation in one or the other of the highly penetrant BRCA genes (BRCA1 and BRCA2), A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer, This study defined the experience and needs of women with hereditary breast and ovarian cancer and a positive BRCA test over time.METHODS: A grounded theory approach was taken using qualitative interviews (n = 49) and reflective diaries. , Little is known about how women with hereditary breast and/or ovarian cancer who test positive for a BRCA gene manage the impact of a positive test result on their everyday lives and in the longer term., This study defined the experience and needs of women with hereditary breast and ovarian cancer and a positive BRCA test over time.A grounded theory approach was taken using qualitative interviews (n = 49) and reflective diaries., Women with a harmful mutation in the BReast CAncer (BRCA) gene are at significantly increased risk of developing hereditary breast and ovarian cancer (HBOC) during their lifetime, compared to those without., Genetic testing for BRCA genes, associated with hereditary breast-ovarian cancer risk, is an accepted cancer control strategy., Younger patients, those with a family history of breast or ovarian cancer, and those diagnosed more recently were more likely to be BRCA tested., Mutations in BRCA genes elevate risk for breast and ovarian cancer., Observational studies of prophylactic surgeries report reduced risks for breast and ovarian cancer in mutation carriers.No data describe the range of risk associated with BRCA mutations, genetic heterogeneity, and moderating factors; studies conducted in highly selected populations contain biases; and information on adverse effects is incomplete.A primary care approach to screening for inherited breast and ovarian cancer susceptibility has not been evaluated, and evidence is lacking to determine benefits and harms for the general population., We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer)., Truncated proteins are easily discriminated from full size.RESULTS: Three BRCA 1 gene alterations were identified in the investigated group of women suffering from ovarian or breast cancer. One asymptomatic person--carrier of BRCA 1 gene mutation--was identified in this study. She was daughter of a woman, a carrier of BRCA 1 gene mutation, with early onset of breast cancer and positive family history.CONCLUSIONS: BRCA 1 and BRCA 2 gene mutations are of particular importance in the increasing risk of ovarian cancer and early onset of breast cancer as well as some other malignancies., Germline BRCA gene mutations are reportedly associated with hereditary breast and ovarian cancers. Identification of BRCA mutations greatly improves the preventive strategies and management of breast cancer., Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer-identified and ovarian cancer-identified families.CONCLUSIONS: Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations., Truncated proteins are easily discriminated from full size.RESULTS: Three BRCA 1 gene alterations were identified in the investigated group of women suffering from ovarian or breast cancer., However, some single risk factors without family histories (early-onset breast cancer, male breast cancer, or multiple organ cancers) may limit the utility of BRCA gene testing in the Korean population., BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk., Because infertility is associated with breast and ovarian cancer risks, we hypothesized that the mutations in the BRCA gene may be associated with low response to fertility treatments., Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis., Among the 554 women who underwent genetic testing for BRCA mutation, 78 were found to have a deleterious mutation in the BRCA1 gene, and 54 had a mutation in the BRCA 2 gene., Frequent recurrent mutations in the breast and ovarian cancer susceptibility (BRCA) genes BRCA1 and BRCA2 among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 exon 9-12 deletion [ex9-12del]), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economic screening for hereditary breast and ovarian cancer in Mexico., Individuals who carry a BRCA gene mutation have increased lifetime risks of developing hereditary breast and ovarian cancer syndrome-related cancers., BRCA gene mutations have been well described to carry an increased risk of both breast and ovarian cancer., Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2., Women who were BRCA carriers, women who had a history of breast cancer, DCIS, or breast biopsy, or had a family history of ovarian cancer were more likely to have undergone surgery for cancer risk reduction., Genetic testing for breast cancer susceptibility became a reality after two cancer predisposition genes, BRCA1 and BRCA2, were identified., Germline mutations in BRCA genes are associated with breast and ovarian cancer susceptibility., We used person-years at risk to assess ovarian cancer rates in the study population, subdivided by genetic status (BRCA1, BRCA2, BRCA negative, BRCA untested) compared with the general population.[SEP]Definitions: Breast defined as following: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.. ovarian cancers defined as following: A primary or metastatic malignant neoplasm involving the ovary. Most primary malignant ovarian neoplasms are either carcinomas (serous, mucinous, or endometrioid adenocarcinomas) or malignant germ cell tumors. Metastatic malignant neoplasms to the ovary include carcinomas, lymphomas, and melanomas.. cancer defined as following: A malignant tumor at the original site of growth.. BRCA 2 gene defined as following: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6). BReast CAncer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. DNA glycosylase defined as following: A family of DNA repair enzymes that recognize damaged nucleotide bases and remove them by hydrolyzing the N-glycosidic bond that attaches them to the sugar backbone of the DNA molecule. The process called BASE EXCISION REPAIR can be completed by a DNA-(APURINIC OR APYRIMIDINIC SITE) LYASE which excises the remaining RIBOSE sugar from the DNA.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. PBC defined as following: An autoimmune inflammatory disorder characterized by destruction of the small intrahepatic bile ducts. It affects predominantly females and it may lead to cirrhosis and liver failure. Patients have antimitochondrial and antinuclear antibodies in the peripheral blood.. BRCA1 gene defined as following: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.. OGG1 defined as following: N-glycosylase/DNA lyase (345 aa, ~39 kDa) is encoded by the human OGG1 gene. This protein is involved in nucleotide excision repair.. carcinoma of the breast defined as following: A carcinoma arising from the breast, most commonly the terminal ductal-lobular unit. It is the most common malignant tumor in females. Risk factors include country of birth, family history, menstrual and reproductive history, fibrocystic disease and epithelial hyperplasia, exogenous estrogens, contraceptive agents, and ionizing radiation. The vast majority of breast carcinomas are adenocarcinomas (ductal or lobular). Breast carcinoma spreads by direct invasion, by the lymphatic route, and by the blood vessel route. The most common site of lymph node involvement is the axilla.. neoplasms defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. breast biopsy defined as following: Removal of tissue from the breast for microscopic examination.. bilateral breast cancer defined as following: Carcinoma that affects both breasts in a simultaneous or non-simultaneous manner.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. peritoneal cancer defined as following: A primary or metastatic malignant neoplasm involving the peritoneum. Representative examples include carcinoma and malignant mesothelioma.. DCIS defined as following: A noninvasive (noninfiltrating) carcinoma of the breast characterized by a proliferation of malignant epithelial cells confined to the mammary ducts or lobules, without light-microscopy evidence of invasion through the basement membrane into the surrounding stroma.. gene mutation defined as following: A change in the nucleotide sequence of the TAF1 gene.. Germline mutations defined as following: Any detectable and heritable alteration in the lineage of germ cells. Mutations in these cells (i.e., \"generative\" cells ancestral to the gametes) are transmitted to progeny while those in somatic cells are not.. infertility defined as following: Complete inability to conceive or induce conception.. carcinomas defined as following: A malignant neoplasm made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. It is a histological type of neoplasm and not a synonym for \"cancer.\". BRCA genes defined as following: newly discovered protooncogene; mutation is responsible for about half of the inherited cases of breast cancer; implicated in esophageal, head, and neck cancer.. CBC defined as following: A conserved heterodimeric protein complex that binds to the 5' terminal cap structure m7G(5')ppp(5')N of nascent eukaryotic RNA polymerase II transcripts such as pre-mRNA and U snRNA. The consists of proteins known as CBP20 and CBP80, binds to cap structures in the nucleus, and is involved in pre-mRNA splicing, 3'-end formation, and RNA nuclear export. [PMID:16043498]. breast defined as following: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.. ovarian cancer defined as following: A primary or metastatic malignant neoplasm involving the ovary. Most primary malignant ovarian neoplasms are either carcinomas (serous, mucinous, or endometrioid adenocarcinomas) or malignant germ cell tumors. Metastatic malignant neoplasms to the ovary include carcinomas, lymphomas, and melanomas..", "label": "yes"} {"id": "converted_672", "sentence1": "Is TREM2 associated with Alzheimer's disease?", "sentence2": "Absence of TREM2 polymorphisms in patients with Alzheimer's disease and Frontotemporal Lobar Degeneration, These data demonstrate that TREM2 coding region is highly conserved, implying a crucial role of this receptor. Further studies, including a functional analysis, are certainly required to clarify the role of TREM2 in neurodegenerative processes, Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4, We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain, None of the rare variants individually reached significant association, but the frequency of p.R47H was increased ~ 3-fold in both AD and FTD patients compared to controls, in line with previous reports, Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general., non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD), These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD., Higher levels of TREM2 mRNA (p = 0.002) and protein (p < 0.001) were identified in AD patients, Our results indicate that TREM2 might serve as a novel noninvasive biomarker for AD diagnosis, studies have identified the rs75932628 (R47H) variant in TREM2 as an Alzheimer's disease risk factor with estimated odds ratio ranging from 2.9 to 5.1, This study replicates the association between R47H and Alzheimer's disease risk in a large, population-based sample, and estimates the population frequency and attributable risk of this rare variant, Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms, A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland, We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers, Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes, rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD), These results confirm the association between this variant and AD and underline its involvement in early-onset cases, recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD), Rs75932628-T is a rare nonsynonymous variant (p.R47H) that confers a high risk of AD with an effect size similar to that of the APOE ɛ4 allele, Here, we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD, works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer's disease (AD), with an odds ratio similar to that of the apolipoprotein E ε4 allele, The reduced function of TREM2 was speculated to be the main cause in the pathogenic effects of this risk variant, and TREM2 is highly expressed in white matter, as well as in the hippocampus and neocortex, which is partly consistent with the pathological features reported in AD brain, indicating the possible involvement of TREM2 in AD pathogenesis, Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons, TREM2 also participates in the regulation of phagocytic pathways that are responsible for the removal of neuronal debris, Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment, Under the hypothesis that low-prevalence variants showing moderate-to-high effect size may be associated with risk for sAD, two independent research groups have demonstrated that a rare variant (rs75932628, encoding a substitution of arginine by histidine at residue 47 (R47H), in the TREM2 gene, which encodes the triggering receptor expressed on myeloid cells 2) is significantly associated with an increased susceptibility to sAD, Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD, TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk, evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease, These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease, The association of TREM2 variants with AD brings innate immune signaling into the light, affirming innate immunity's role as a significant factor in AD pathogenesis, The purpose of this paper is to discuss these recent developments including the potential role that TREM2 normally plays and how loss of function may contribute to AD pathogenesis by enhancing oxidative stress and inflammation within the CNS, Even though we are more at the beginning than at the end of sAD genetics, there is some reason for optimism given the recent identification of novel risk or protective variants (such as rare TREM2 and APP mutations) showing strong statistical associations with sAD[SEP]Definitions: neocortex defined as following: The largest portion of the CEREBRAL CORTEX in which the NEURONS are arranged in six layers in the mammalian brain: molecular, external granular, external pyramidal, internal granular, internal pyramidal and multiform layers.. variant defined as following: An alteration or difference from a norm or standard.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. histidine defined as following: An essential amino acid that is required for the production of HISTAMINE.. sAD defined as following: A syndrome characterized by depressions that recur annually at the same time each year, usually during the winter months. Other symptoms include anxiety, irritability, decreased energy, increased appetite (carbohydrate cravings), increased duration of sleep, and weight gain. SAD (seasonal affective disorder) can be treated by daily exposure to bright artificial lights (PHOTOTHERAPY), during the season of recurrence.. APOE defined as following: A class of protein components which can be found in several lipoproteins including HIGH-DENSITY LIPOPROTEINS; VERY-LOW-DENSITY LIPOPROTEINS; and CHYLOMICRONS. Synthesized in most organs, Apo E is important in the global transport of lipids and cholesterol throughout the body. Apo E is also a ligand for LDL receptors (RECEPTORS, LDL) that mediates the binding, internalization, and catabolism of lipoprotein particles in cells. There are several allelic isoforms (such as E2, E3, and E4). Deficiency or defects in Apo E are causes of HYPERLIPOPROTEINEMIA TYPE III.. neurons defined as following: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.. myeloid cells defined as following: The classes of BONE MARROW-derived blood cells in the monocytic series (MONOCYTES and their precursors) and granulocytic series (GRANULOCYTES and their precursors).. TREM2 defined as following: Triggering receptor expressed on myeloid cells 2 (230 aa, ~25 kDa) is encoded by the human TREM2 gene. This protein plays a role in macrophage and dendritic cell immune responses.. allele defined as following: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.. region defined as following: The continents and countries situated on those continents; the UNITED STATES and each of the constituent states arranged by region; CANADA and each of its provinces; AUSTRALIA and each of its states; the major bodies of water and major islands on both hemispheres; and selected major cities.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65.. arginine defined as following: An essential amino acid that is physiologically active in the L-form.. FTD defined as following: The most common clinical form of FRONTOTEMPORAL LOBAR DEGENERATION, this dementia presents with personality and behavioral changes often associated with disinhibition, apathy, and lack of insight.. domain defined as following: A taxonomic category above that of Kingdom.. neurodegenerative disease defined as following: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures.. polymorphisms defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.. TREM2 gene defined as following: This gene plays a role in the activation of immune responses.. dementia defined as following: The presence of dementia in an individual younger than age sixty five.. CNS defined as following: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.. exons defined as following: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. substitution defined as following:Definition: Indicates that the subject Act has undergone or should undergo substitution of a type indicated by Act.code.
Rationale: Used to specify \"allowed\" substitution when creating orders, \"actual\" susbstitution when sending events, as well as the reason for the substitution and who was responsible for it.
.", "label": "yes"} {"id": "converted_885", "sentence1": "Does thyroid hormone receptor beta1 affect insulin secretion?", "sentence2": "We demonstrated that thyroid hormone T3 rapidly induces Akt activation in pancreatic beta cells rRINm5F and hCM via thyroid hormone receptor (TR) beta1., The silencing of TRbeta1 expression through RNAi confirmed this receptor to be crucial for the T3-induced activation of Akt., T3 is able to specifically activate Akt in the islet beta cells rRINm5F and hCM through the interaction between TRbeta1 and PI3K p85alpha, demonstrating the involvement of TRbeta1 in this novel T3 non-genomic action in islet beta cells.[SEP]Definitions: hCM defined as following: A form of CARDIAC MUSCLE disease, characterized by left and/or right ventricular hypertrophy (HYPERTROPHY, LEFT VENTRICULAR; HYPERTROPHY, RIGHT VENTRICULAR), frequent asymmetrical involvement of the HEART SEPTUM, and normal or reduced left ventricular volume. Risk factors include HYPERTENSION; AORTIC STENOSIS; and gene MUTATION; (FAMILIAL HYPERTROPHIC CARDIOMYOPATHY).. thyroid hormone receptor defined as following: Specific high affinity binding proteins for THYROID HORMONES in target cells. They are usually found in the nucleus and regulate DNA transcription. These receptors are activated by hormones that leads to transcription, cell differentiation, and growth suppression. Thyroid hormone receptors are encoded by two genes (GENES, ERBA): erbA-alpha and erbA-beta for alpha and beta thyroid hormone receptors, respectively.. Akt defined as following: Expressed in diverse tissues, Protein Kinase B (AKT/RAC Family) is a group (Alpha, Beta and Gamma) of cytoplasmic serine/threonine enzymes that covalently transfer the terminal, gamma phosphate group from ATP to a variety of substrate proteins and regulate cell signaling responses to insulin, PDGF, and IGF1 (through PI3K) involved in cell survival, cell proliferation, differentiation, apoptosis, glycogen synthesis, and glucose uptake.. pancreatic beta cells defined as following: A cell that composes the bulk of the islets of Langerhans and secretes insulin.. T3 defined as following: This gene plays a regulatory role in the production and utilization of ATP.. thyroid hormone defined as following: Natural hormones secreted by the THYROID GLAND, such as THYROXINE, and their synthetic analogs..", "label": "no"} {"id": "converted_129", "sentence1": "Is amantadine effective for treatment of disorders conciousness?", "sentence2": "We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes in the neurological status in patients, leading sometimes to dramatic improvements., Pharmaceuticals that act in the oxygen based amino acid systems of the brain include the GABAergic medications zolpidem and baclofen, while those that act in the monoamine axes include the dopaminergic medications L Dopa, amantadine, bromocriptine, apomorphine and methylphenidate, and the noradrenergic and serotonergic medications desipramine, amitriptyline, protriptyline and fluoxetine. , Sporadic cases of recovery from a DOC have been reported after the administration of various pharmacological agents (baclofen, zolpidem, amantadine etc.)., Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery., During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P=0.007), indicating a benefit with respect to the primary outcome measure. , Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness., Sporadic cases of dramatic recovery from DOC after the administration of various pharmacological agents, such as baclofen, zolpidem and amantadine, have been recently supported by intriguing scientific observations. , According to the 16 eligible studies, medical management by dopaminergic agents (levodopa, amantadine), zolpidem and median nerve stimulation, or surgical management by deep brain stimulation, extradural cortical stimulation, spinal cord stimulation and intrathecal baclofen have shown to improve the level of consciousness in certain cases. , Higher exposure of amantadine (average concentration of amantadine during 6 mg/kg/day > 1.5 mg/L) may be associated with better recovery of consciousness. , Based on the preliminary data, higher dosing may be considered in the setting of brain injury., Patients treated with PK-Merz exhibited the more significant restoration of consciousness and better dynamics (regress) of neurological deficit with the most intensive restoration of neurological deficit in the first day that allows to recommend the use of amantadine sulfate in the first hours of ischemic stroke and for the prevention of reperfusion damage in recanalisation therapy of ischemic stroke., There was no significant difference in the slopes of recovery during either arm for the Coma/Near-Coma Scale (P = 0.24) or the Coma Recovery Scale-Revised (P = 0.28), although improvements in consciousness were noted by the physician during weeks when amantadine was given (P = 0.02). , This study suggests that amantadine facilitates recovery of consciousness in pediatric acquired brain injury and provides important information necessary to design future more definitive studies., The study has shown a positive effect of this drug at coma emergence, which manifested itself as clinical improvement and a better outcome of the disease., This article will review the evidence for the use of psychostimulants (methylphenidate), antidepressants (amitriptyline, selective serotonin reuptake inhibitors, and buproprion), Parkinson's medications (amantadine, bromocriptine, carbidopa/levodopa), anticonvulsants (valproic acid), modafinil (Provigil), lactate, hyperbaric oxygen chamber, electroconvulsive therapy, and transmagnetic stimulation, in patients following a head injury., Of the psychoactive medications, amantadine hydrochloride was associated with greater recovery and dantrolene sodium was associated with less recovery, in terms of the DRS score at 16 weeks but not the time until commands were followed.[SEP]Definitions: amantadine hydrochloride defined as following: The hydrochloride salt of amantadine, a synthetic tricyclic amine with antiviral, antiparkinsonian, and antihyperalgesic activities. Amantadine appears to exert its antiviral effect against the influenza A virus by interfering with the function of the transmembrane domain of the viral M2 protein, thereby preventing the release of infectious viral nucleic acids into host cells; furthermore, this agent prevents virus assembly during virus replication. Amantadine exerts its antiparkinsonian effects by stimulating the release of dopamine from striatal dopaminergic nerve terminals and inhibiting its pre-synaptic reuptake. This agent may also exert some anticholinergic effect through inhibition of N-methyl-D-aspartic acid (NMDA) receptor-mediated stimulation of acetylcholine, resulting in antihyperalgesia.. baclofen defined as following: A GAMMA-AMINOBUTYRIC ACID derivative that is a specific agonist of GABA-B RECEPTORS. It is used in the treatment of MUSCLE SPASTICITY, especially that due to SPINAL CORD INJURIES. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission.. Amantadine defined as following: An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake.. protriptyline defined as following: Tricyclic antidepressant similar in action and side effects to IMIPRAMINE. It may produce excitation.. amantadine sulfate defined as following: The sulfate salt of amantadine, a synthetic tricyclic amine with antiviral, antiparkinsonian, and antihyperalgesic activities. Amantadine appears to exert its antiviral effect against the influenza A virus by interfering with the function of the transmembrane domain of the viral M2 protein, thereby preventing the release of infectious viral nucleic acids into host cells; furthermore, this agent prevents virus assembly during virus replication. Amantadine exerts its antiparkinsonian effects by stimulating the release of dopamine from striatal dopaminergic nerve terminals and inhibiting its pre-synaptic reuptake. This agent may also exert some anticholinergic effect through inhibition of N-methyl-D-aspartic acid (NMDA) receptor-mediated stimulation of acetylcholine, resulting in antihyperalgesia.. modafinil defined as following: A benzhydryl acetamide compound, central nervous system stimulant, and CYP3A4 inducing agent that is used in the treatment of NARCOLEPSY and SLEEP WAKE DISORDERS.. carbidopa/levodopa defined as following: An orally available combination of carbidopa, an inhibitor of aromatic amino acid decarboxylation, and levodopa, an inert, metabolic precursor to dopamine, with dopaminergic and antiparkinsonian properties. Upon oral administration, levodopa crosses the blood-brain barrier (BBB) and is decarboxylated to dopamine via dopa decarboxylase in the brain, promoting increased activation of dopamine receptors. Carbidopa inhibits dopa decarboxylase in the periphery, thereby preventing decarboxylation of levodopa in extracerebral tissues and increasing the delivery of dopamine to the central nervous system (CNS). As carbidopa does not cross the BBB, it does not interfere with CNS levodopa metabolism.. brain injury defined as following: Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.. lactate defined as following: The determination of the amount of lactic acid present in a sample.. levodopa defined as following: The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system.. drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. traumatic brain injury defined as following: A form of acquired brain injury which occurs when a sudden trauma causes damage to the brain.. ischemic stroke defined as following: An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of brain tissue.. amitriptyline defined as following: Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines.. zolpidem defined as following: An imidazopyridine derivative and short-acting GABA-A receptor agonist that is used for the treatment of INSOMNIA.. bromocriptine defined as following: A semisynthetic ergotamine alkaloid that is a dopamine D2 agonist. It suppresses prolactin secretion.. neurological deficit defined as following: Loss of movement function.. apomorphine defined as following: A derivative of morphine that is a dopamine D2 agonist. It is a powerful emetic and has been used for that effect in acute poisoning. It has also been used in the diagnosis and treatment of parkinsonism, but its adverse effects limit its use.. fluoxetine defined as following: The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants.. valproic acid defined as following: A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of EPILEPSY and BIPOLAR DISORDER. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GAMMA-AMINOBUTYRIC ACID levels in the brain or by altering the properties of VOLTAGE-GATED SODIUM CHANNELS.. dopaminergic agents defined as following: Any drugs that are used for their effects on dopamine receptors, on the life cycle of dopamine, or on the survival of dopaminergic neurons.. antidepressants defined as following: Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems.. head injury defined as following: Traumatic injuries involving the cranium and intracranial structures (i.e., BRAIN; CRANIAL NERVES; MENINGES; and other structures). Injuries may be classified by whether or not the skull is penetrated (i.e., penetrating vs. nonpenetrating) or whether there is an associated hemorrhage.. methylphenidate defined as following: A central nervous system stimulant used most commonly in the treatment of ATTENTION DEFICIT DISORDER in children and for NARCOLEPSY. Its mechanisms appear to be similar to those of DEXTROAMPHETAMINE. The d-isomer of this drug is referred to as DEXMETHYLPHENIDATE HYDROCHLORIDE.. dantrolene sodium defined as following: The sodium salt form of dantrolene, a hydantoin derivative and direct-acting skeletal muscle relaxant. Dantrolene depresses excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor 1, and decreasing intracellular calcium concentration. Ryanodine receptors mediate the release of calcium from the sarcoplasmic reticulum, an essential step in muscle contraction.. reperfusion damage defined as following: Adverse functional, metabolic, or structural changes in tissues that result from the restoration of blood flow to the tissue (REPERFUSION) following ISCHEMIA.. coma defined as following: Ocular motor apraxia, Cogan type is characterised by impairment of voluntary horizontal eye movements and compensatory head thrust. Around 50 cases have been described so far. The oculomotor manifestations tend to improve with age but the syndrome may also be associated with learning and speech difficulties, or, in some cases, cerebral malformations. Both sporadic and familial forms have been described, with sporadic forms being more frequent. The mode of transmission of the familial form has not yet been clearly established. A gene located on the long arm of chromosome 2, near to the <i>NPHP1</i> gene involved in nephronophthisis, may be associated with ocular motor apraxia, Cogan type.. amantadine defined as following: An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake..", "label": "yes"} {"id": "converted_2911", "sentence1": "Are there ultraconserved regions in the budding yeast (Saccharomyces cerevisiae)?", "sentence2": "The systematic analysis of ultraconserved genomic regions in the budding yeast., In the evolution of species, a kind of special sequences, termed ultraconserved sequences (UCSs), have been inherited without any change, which strongly suggests those sequences should be crucial for the species to survive or adapt to the environment. However, the UCSs are still regarded as mysterious genetic sequences so far. Here, we present a systematic study of ultraconserved genomic regions in the budding yeast based on the publicly available genome sequences, in order to reveal their relationship with the adaptability or fitness advantages of the budding yeast.Results: Our results indicate that, in addition to some fundamental biological functions, the UCSs play an important role in the adaptation of Saccharomyces cerevisiae to the acidic environment, which is backed up by the previous observation. Besides that, we also find the highly unchanged genes are enriched in some other pathways, such as the nutrient-sensitive signaling pathway. To facilitate the investigation of unique UCSs, the UCSC Genome Browser was utilized to visualize the chromosomal position and related annotations of UCSs in S.cerevisiae genome., Here, we present a systematic study of ultraconserved genomic regions in the budding yeast based on the publicly available genome sequences, in order to reveal their relationship with the adaptability or fitness advantages of the budding yeast., Motivation\nIn the evolution of species, a kind of special sequences, termed ultraconserved sequences (UCSs), have been inherited without any change, which strongly suggests those sequences should be crucial for the species to survive or adapt to the environment., The systematic analysis of ultraconserved genomic regions in the budding yeast.Supernumerary mandibular left lateral primary incisor
. dyspnea defined as following: Difficult or labored breathing.. IgA Nephropathy defined as following: A chronic form of glomerulonephritis characterized by deposits of predominantly IMMUNOGLOBULIN A in the mesangial area (GLOMERULAR MESANGIUM). Deposits of COMPLEMENT C3 and IMMUNOGLOBULIN G are also often found. Clinical features may progress from asymptomatic HEMATURIA to END-STAGE KIDNEY DISEASE.. oliguria defined as following: Decreased URINE output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0.5 or 1 ml/kg/hr depending on the age.. hypoalbuminemia defined as following: A condition in which albumin level in blood (SERUM ALBUMIN) is below the normal range. Hypoalbuminemia may be due to decreased hepatic albumin synthesis, increased albumin catabolism, altered albumin distribution, or albumin loss through the urine (ALBUMINURIA).. steroid-resistant nephrotic syndrome defined as following: A form of nephrotic syndrome that does not respond to treatment with steroid medication, defined as persistent proteinuria despite 60mg/m2 or 2mg/kg for 8 weeks, after insuring no infection or non-adherence to medication. [Eurenomics:ewuehl, ORCID:0000-0002-2234-4248, PMID:29910038]. proteinuria defined as following: The presence of proteins in the urine, an indicator of KIDNEY DISEASES.. renal failure defined as following: A severe irreversible decline in the ability of kidneys to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism.. pituitary gland defined as following: A small, unpaired gland situated in the SELLA TURCICA. It is connected to the HYPOTHALAMUS by a short stalk which is called the INFUNDIBULUM.. eyes defined as following: The organ of sight constituting a pair of globular organs made up of a three-layered roughly spherical structure specialized for receiving and responding to light.. AA amyloidosis defined as following: Extracellular tissue deposition of fibrils that are composed of fragments of and/or intact serum amyloid A protein, a hepatic acute phase reactant. [ORCID:0000-0003-3411-9598, PMID:29261990]. abdominal pain defined as following: Sensation of discomfort, distress, or agony in the abdominal region.. infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. hypertension defined as following: Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.. hypercholesterolemia defined as following: A laboratory test result indicating an increased amount of cholesterol in the blood.. Nephrotic syndrome defined as following: A condition characterized by severe PROTEINURIA, greater than 3.5 g/day in an average adult. The substantial loss of protein in the urine results in complications such as HYPOPROTEINEMIA; generalized EDEMA; HYPERTENSION; and HYPERLIPIDEMIAS. Diseases associated with nephrotic syndrome generally cause chronic kidney dysfunction.. diabetic retinopathy defined as following: Disease of the RETINA as a complication of DIABETES MELLITUS. It is characterized by the progressive microvascular complications, such as ANEURYSM, interretinal EDEMA, and intraocular PATHOLOGIC NEOVASCULARIZATION.. hyperlipoproteinemia defined as following: Conditions with abnormally elevated levels of LIPOPROTEINS in the blood. They may be inherited, acquired, primary, or secondary. Hyperlipoproteinemias are classified according to the pattern of lipoproteins on electrophoresis or ultracentrifugation.. hyperlipidemia defined as following: Conditions with excess LIPIDS in the blood.. nephrotic syndrome defined as following: A condition characterized by severe PROTEINURIA, greater than 3.5 g/day in an average adult. The substantial loss of protein in the urine results in complications such as HYPOPROTEINEMIA; generalized EDEMA; HYPERTENSION; and HYPERLIPIDEMIAS. Diseases associated with nephrotic syndrome generally cause chronic kidney dysfunction..", "label": "yes"} {"id": "converted_891", "sentence1": "Is NOD1 activated in inflammation?", "sentence2": "Nod1 and Nod2 control bacterial infections and inflammation, The Nod proteins Nod1 and Nod2 are two NLR family members that trigger immune defense in response to bacterial peptidoglycan, Nod proteins fight off bacterial infections by stimulating proinflammatory signaling and cytokine networks and by inducing antimicrobial effectors, such as nitric oxide and antimicrobial peptides., Nod1 is also critically implicated in shaping adaptive immune responses towards bacterial-derived constituents., Together, Nod1 and Nod2 represent central players in the control of immune responses to bacterial infections and inflammation., The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis., we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor-related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability., The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice., Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development., NOD1 protein is expressed in the eye and promotes ocular inflammation in a dose- and time-dependent fashion. , NOD1 expression in the eye and functional contribution to IL-1beta-dependent ocular inflammation in mice, Polymorphisms in NOD1 are associated with autoinflammatory diseases characterized by uveitis such as Crohn's disease and sarcoidosis, NOD1 is homologous to NOD2, which is responsible for an autosomal dominant form of uveitis. Nonetheless, the role of NOD1 in intraocular inflammation has not been explored., Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model, mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue, The present study has demonstrated an unexpected role of Nod1 in the development of site-specific vascular inflammation, especially coronary arteritis., Nod1 ligands induce site-specific vascular inflammation, Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease, The present study analyzed Nod1 and Nod2 double deficient (Nod1/2 DKO) mice under physiological and inflammatory conditions, Several inflammatory disorders, such as Crohn's disease and asthma, are linked to genetic changes in either Nod1 or Nod2., Systematic analysis of Nod1/2 DKO mice revealed a possible role of Nod1/2 in the development of renal disease during systemic inflammation., NOD1 and NOD2 Signaling in Infection and Inflammation, NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. , In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. , This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock., NOD1 expression elicited by iE-DAP in first trimester human trophoblast cells and its potential role in infection-associated inflammation, This study aimed to investigate the expression and function of NOD1 in first trimester trophoblast cells, and evaluate the potential role of trophoblast cells in infection-associated inflammation, NOD1 may have a role in mediating infection-associated inflammation. Once iE-DAP is recognized by NOD1, the inflammatory response may be induced via NOD1-RICK-NF-κB-mediated pathways., NOD1/2(-/-) mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance., In contrast, Nod1 gene-deficient mice developed enhanced joint inflammation with concomitant elevated levels of proinflammatory cytokines and cartilage damage, consistent with a model in which Nod1 controls the inflammatory reaction., These data indicate that the NLR family members Nod1 and Nod2 have different functions in controlling inflammation, and that intracellular Nod1-Nod2 interactions may determine the severity of arthritis in this experimental model., Whereas the lymphotoxin pathway was critical for the induction of the B cell chemoattractant CXCL13 in response to Nod1 agonists, B cell accumulation within the spleen following Nod1-induced systemic inflammation was independent of the lymphotoxin pathway., The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed., Nonetheless, the role of NOD1 in intraocular inflammation has not been explored., A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses., We previously demonstrated that human first-trimester trophoblasts express Nod1 and Nod2, which trigger inflammation upon stimulation., In addition, recent studies have revealed a role for intracellular NOD1 receptors in the regulation of vascular inflammation and metabolism., In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM., Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease., Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor., The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor κB (NFκB). , Nod1 ligands induce site-specific vascular inflammation., The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. , CONCLUSIONS: We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. , Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model., In particular, muramyl peptides trigger inflammation, contribute to host defense against microbial infections, and modulate the adaptive immune response to antigens. , Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand-injected mice. , CONCLUSIONS: We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. , Interferon-gamma (IFN gamma), which is a potent pro-inflammatory cytokine in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in a time- and dose-dependent manner and results in augmentation of CARD4/NOD1 protein in SW480 cells., These studies suggest that the Th1 cytokine, IFN gamma, activates CARD4/NOD1 transcription and regulate innate immune mechanisms in the condition of intestinal mucosal inflammation., NOD1 activation triggers inflammation,, In contrast to enhanced leptin mRNA by LPS and TNFα, NOD1 activation suppressed leptin mRNA in adipocytes, suggesting the differential effects of NOD1 activation in adipocytes. Overall, our results suggest that NOD1 represents a novel target for adipose inflammation in obesity., NOD1 activation triggers inflammation, antimicrobial mechanisms and autophagy in both epithelial cells and murine macrophages., NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure., Bacterial NOD1 activation is positioned as a component of metabolic endotoxemia that can contribute to hyperlipidemia, systemic inflammation and insulin resistance by acting directly on adipocytes., NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1(-/-), mice., We conclude that NOD1 activation reduced AHR in allergen-induced lung inflammation, which was accompanied by a reduction of allergen-specific T-cell proliferation., The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed., Interferon-gamma (IFN gamma), which is a potent pro-inflammatory cytokine in intestinal mucosal inflammation, activates CARD4/NOD1 mRNA transcription in a time- and dose-dependent manner and results in augmentation of CARD4/NOD1 protein in SW480 cells.[SEP]Definitions: epithelial cells defined as following: Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells.. Nod1 defined as following: This gene plays a role in both apoptosis and immunity.. chemically defined as following: A substance with a defined atomic or molecular structure that results from, or takes part in, reactions involving changes in its structure, composition, or properties.. adipocytes defined as following: Cells in the body that store FATS, usually in the form of TRIGLYCERIDES. WHITE ADIPOCYTES are the predominant type and found mostly in the abdominal cavity and subcutaneous tissue. BROWN ADIPOCYTES are thermogenic cells that can be found in newborns of some species and hibernating mammals.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. MAPK defined as following: A superfamily of PROTEIN SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).. RIP2 defined as following: Human RGNEF wild-type allele is located in the vicinity of 5q13.2 and is approximately 316 kb in length. This allele, which encodes Rho-guanine nucleotide exchange factor protein, plays a role in the modulation of integrin and growth factor receptor signaling.. leptin defined as following: A 16-kDa peptide hormone secreted from WHITE ADIPOCYTES. Leptin serves as a feedback signal from fat cells to the CENTRAL NERVOUS SYSTEM in regulation of food intake, energy balance, and fat storage.. NOD2 defined as following: This gene is involved in immune responses and cell death.. peptidoglycan defined as following: A structural polymer of the bacterial cell envelope consisting of sugars and amino acids which is responsible for both shape determination and cellular integrity under osmotic stress in virtually all bacteria.. endothelium defined as following: A layer of epithelium that lines the heart, blood vessels (ENDOTHELIUM, VASCULAR), lymph vessels (ENDOTHELIUM, LYMPHATIC), and the serous cavities of the body.. renal disease defined as following: Pathological processes of the KIDNEY or its component tissues.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. nitric oxide defined as following: A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.. B cell defined as following: Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation.. NFKB defined as following: Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA.. AHR defined as following: approximately 280kD soluble protein complex; binds and mediates carcinogenesis by polycyclic aromatic hydrocarbons, heterocyclic amines, and chlorinated aromatic compounds.. Th1 defined as following: Human NELFCD wild-type allele is located in the vicinity of 20q13 and is approximately 14 kb in length. This allele, which encodes negative elongation factor C/D protein, plays a role in the inhibition of transcriptional elongation.. hepatocytes defined as following: The main structural component of the LIVER. They are specialized EPITHELIAL CELLS that are organized into interconnected plates called lobules.. vasculature defined as following: Organ region cluster which consists of regions of arterial, venous and lymphatic trees and the capillary beds that connect them. Examples: Vasculature of head, vasculature of brain.. intestinal defined as following: The section of the alimentary canal from the STOMACH to the ANAL CANAL. It includes the LARGE INTESTINE and SMALL INTESTINE.. septic shock defined as following: Sepsis associated with HYPOTENSION or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include but are not limited to LACTIC ACIDOSIS; OLIGURIA; or acute alteration in mental status.. Infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. Polymorphisms defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.. GDM defined as following: Diabetes mellitus induced by PREGNANCY but resolved at the end of pregnancy. It does not include previously diagnosed diabetics who become pregnant (PREGNANCY IN DIABETICS). Gestational diabetes usually develops in late pregnancy when insulin antagonistic hormones peaks leading to INSULIN RESISTANCE; GLUCOSE INTOLERANCE; and HYPERGLYCEMIA.. uveitis defined as following: Inflammation of part or all of the uvea, the middle (vascular) tunic of the eye, and commonly involving the other tunics (sclera and cornea, and the retina). (Dorland, 27th ed). ocular inflammation defined as following: Inflammation of the eye, parts of the eye or the periorbital region. [HPO:sdoelken]. insulin defined as following: A synthetic or animal-derived form of insulin used in the treatment of diabetes mellitus. Therapeutic insulin is formulated to be short-, intermediate- and long-acting in order to individualize an insulin regimen according to individual differences in glucose and insulin metabolism. Therapeutic insulin may be derived from porcine, bovine or recombinant sources. Endogenous human insulin, a pancreatic hormone composed of two polypeptide chains, is important for the normal metabolism of carbohydrates, proteins and fats and has anabolic effects on many types of tissues.. preterm labor defined as following: Regular uterine activity with associated cervical change prior to 37 weeks gestation.. bacterial infections defined as following: Infections by bacteria, general or unspecified.. TLR4 defined as following: Human TLR4 wild-type allele is located within 9q32-q33 and is approximately 11 kb in length. This allele, which encodes toll-like receptor 4 protein, is involved in pathogen recognition, signal transduction and innate immunity. Mutations in the gene are associated with differences in LPS responsiveness.. NOD defined as following: A rare, autosomal dominant inherited progressive neurodegenerative disorder. It is caused by a mutation in the ATN1 gene, resulting in a combined degeneration of the dentatorubral and pallidoluysian systems. It can appear at any age, but it usually affects individuals between 20 and 30 years and leads to death within 10-15 years. The clinical presentation depends on the age of the affected individual; juvenile patients develop severe progressive myoclonus epilepsy and cognitive decline, whereas adult patients develop ataxia, choreoathetosis and dementia.. asthma defined as following: A form of bronchial disorder with three distinct components: airway hyper-responsiveness (RESPIRATORY HYPERSENSITIVITY), airway INFLAMMATION, and intermittent AIRWAY OBSTRUCTION. It is characterized by spasmodic contraction of airway smooth muscle, WHEEZING, and dyspnea (DYSPNEA, PAROXYSMAL).. WT defined as following: A designation used to describe a wild-type zebrafish line that is of unknown stock.. LPS defined as following: A rare autosomal dominant syndrome caused by mutations in the IRF6 gene. It is characterized by a cleft palate and/or pits on the lower lip. Other signs and symptoms include absent teeth, palate and tongue deformities.. nuclear factor κB defined as following: A family of proteins that contain 1 DWA/MH1 domain and bind 5'-TTGGCNNNNNGCCAA-3' DNA palindromes in viral and cellular promoters as homodimeric factors capable of activating transcription and replication.. colitis defined as following: Inflammation of the COLON section of the large intestine (INTESTINE, LARGE), usually with symptoms such as DIARRHEA (often with blood and mucus), ABDOMINAL PAIN, and FEVER.. CXCL13 defined as following: A CXC chemokine that is chemotactic for B-LYMPHOCYTES. It has specificity for CXCR5 RECEPTORS.. peptides defined as following: Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS.. arthritis defined as following: Acute or chronic inflammation of JOINTS.. human defined as following: Members of the species Homo sapiens.. mucosal tissue defined as following: An EPITHELIUM with MUCUS-secreting cells, such as GOBLET CELLS. It forms the lining of many body cavities, such as the DIGESTIVE TRACT, the RESPIRATORY TRACT, and the reproductive tract. Mucosa, rich in blood and lymph vessels, comprises an inner epithelium, a middle layer (lamina propria) of loose CONNECTIVE TISSUE, and an outer layer (muscularis mucosae) of SMOOTH MUSCLE CELLS that separates the mucosa from submucosa.. hyperlipidemia defined as following: Conditions with excess LIPIDS in the blood.. NOD1 defined as following: This gene plays a role in both apoptosis and immunity..", "label": "yes"} {"id": "converted_3788", "sentence1": "Is Semagacestat effective for Alzheimer's Disease?", "sentence2": "However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. , BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD)., CONCLUSION: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. , INTRODUCTION: The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes., A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all γ-secretases causes serious toxicity. , ESULTS: Semagacestat treatment was associated with increased reporting of suspected Notch-related adverse events (gastrointestinal, infection, and skin cancer related). Other relevant safety findings associated with semagacestat treatment included cognitive and functional worsening, skin-related TEAEs, renal and hepatic changes, increased QT interval, and weight loss. , CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability., RESULTS: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board., The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). , Recently disclosed Phase III findings on semagacestat indicated that Alzheimer's disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo., The recent failure of semagacestat in two large Phase III studies questions the value of γ-secretase inhibitors in treating Alzheimer's disease., ntly disclosed Phase III findings on semagacestat indicated that Alzheimer's disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo. Since, ts from Phase III studies showed that semagacestat failed to slow disease progression, and it was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Furthermore, sem, rge Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effect of the drug. These detrimental ef, BACKGROUND: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's d, However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects., However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD.[SEP]Definitions: drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. renal defined as following: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.. NPS defined as following: A syndrome of multiple abnormalities characterized by the absence or hypoplasia of the PATELLA and congenital nail dystrophy. It is a genetically determined autosomal dominant trait.. skin cancer defined as following: A primary or metastatic malignant neoplasm involving the skin. Primary malignant skin neoplasms most often are carcinomas (either basal cell or squamous cell carcinomas) or melanomas. Metastatic malignant neoplasms to the skin include carcinomas and lymphomas.. toxicity defined as following: The finding of bodily harm due to the poisonous effects of something.. bapineuzumab defined as following: A humanized monoclonal antibody (IgG1) raised against amyloid beta peptides with Alzheimer disease treatment application. Bapineuzumab recognizes and binds the N-terminal amino acids 1-5 of the amyloid beta peptide, and may be used in a passive immunotherapy treatment.. Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65.. cognitive deficits defined as following: Disorders characterized by disturbances in mental processes related to learning, thinking, reasoning, and judgment.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. weight loss defined as following: The measured decrease in body weight over a specified period of time..", "label": "no"} {"id": "converted_1778", "sentence1": "Is NADPH oxidase 5 expressed in rodents?", "sentence2": "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.[SEP]Definitions: NADPH oxidases defined as following: A family of membrane-associated flavoprotein NADPH-dependent oxidoreductases that catalyze the univalent reduction of OXYGEN to create SUPEROXIDES. Structurally, they are characterized by six N-terminal transmembrane ALPHA-HELICES, a FLAVIN-ADENINE DINUCLEOTIDE (FAD)-binding region, and a C-terminal NADPH-binding region. They are expressed primarily by EPITHELIAL CELLS in gut, kidney, colon, and smooth muscle tissues, as well as GRANULOCYTES and function to transfer electrons across membranes to molecular oxygen. Defects in the production of superoxide ions by some NADPH oxidases result in GRANULOMATOUS DISEASE, CHRONIC.. rodents defined as following: A mammalian order which consists of 29 families and many genera.. reactive oxygen species defined as following: Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of SIGNAL TRANSDUCTION and GENE EXPRESSION, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.. humans defined as following: Members of the species Homo sapiens.. kidney cells defined as following: any of the cells comprising the kidney, functioning in filtering the blood.. renal disease defined as following: Pathological processes of the KIDNEY or its component tissues.. lagomorphs defined as following: An order of small mammals comprising two families, Ochotonidae (pikas) and Leporidae (RABBITS and HARES). Head and body length ranges from about 125 mm to 750 mm. Hares and rabbits have a short tail, and the pikas lack a tail. Rabbits are born furless and with both eyes and ears closed. HARES are born fully haired with eyes and ears open. All are vegetarians. (From Nowak, Walker's Mammals of the World, 5th ed, p539-41). neural defined as following: Of or relating to neurons or the nervous system.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. Caenorhabditis elegans defined as following: A species of nematode that is widely used in biological, biochemical, and genetic studies.. transgenic mice defined as following: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.. vertebrates defined as following: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes..", "label": "no"} {"id": "converted_3501", "sentence1": "Do MAIT cells have a role in multiple myeloma?", "sentence2": "hus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies., Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors, Newly diagnosed MM patient MAIT cells had reduced IFNγ production and CD27 expression, suggesting an exhausted phenotype, although IFNγ-producing capacity is restored in relapsed/refractory patient samples. , We describe recent observations with regard to functional exhaustion of iNKT and MAIT cells in MM pathology and discuss the potential application of checkpoint inhibition as an attractive target for prolonged activation of these immunomodulatory T cells in the treatment of MM., Enumeration, functional responses and cytotoxic capacity of MAIT cells in newly diagnosed and relapsed multiple myeloma., Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies.[SEP]Definitions: CD27 defined as following: Human CD27 wild-type allele is located in the vicinity of 12p13 and is approximately 7 kb in length. This allele, which encodes CD27 antigen protein, plays a role in regulating B-cell activation and immunoglobulin synthesis.. multiple myeloma defined as following: A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY.. MM defined as following: A unit of concentration (molarity unit) equal to one thousandth of a mole (10E-3 mole) of solute per one liter of solution.. MAIT cell defined as following: A T-cell subtype bearing a semi-invariant T-cell receptor and restricted by the major histocompatibility complex related molecule MR1. These cells occupy peripheral tissues and are noted for their reactivity against various microorganisms of either bacterial or fungal origin.. IFNγ defined as following: A recombinant therapeutic agent which is chemically identical to or similar to the endogenous lymphokine interferon gamma (IFN-gamma) with antineoplastic, immunoregulatory, and antiviral activities. Therapeutic IFN-gamma binds to and activates the cell-surface IFN-gamma receptor, stimulating antibody-dependent cytotoxicity and enhances natural killer cell attachment to tumor cells. This agent also activates caspases, thereby inducing apoptosis in malignant cells. (NCI04). disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. malignancies defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas..", "label": "yes"} {"id": "converted_436", "sentence1": "Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data?", "sentence2": "BACKGROUND: Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. , The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS: Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials., BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. , There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). , CONCLUSIONS: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. , Numerous studies, however, show that progesterone has substantial pleiotropic properties as a neuroprotective agent in both animal models and humans., RESULTS: There was a better recovery rate and GOS score for the patients who were given progesterone than for those in the control group in a 3-months follow-up period (50% vs. 21%); subgroup analysis showed a significant difference in the percentage of favorable outcome between the two groups with GCS of 5-8 (p=0.03). CONCLUSION: The use of progesterone may significantly improve neurologic outcome of patients suffering severe TBI up to 3 months after injury, especially those with 5≤GCS≤8, providing a potential benefit to the treatment of acute severe TBI patients. Considering this drug had no significant side effects, so progesterone could be used in patients with severe TBI as a neuro-protective drug., While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending., All three studies reported the effects of progesterone on mortality. The pooled risk ratio (RR) for mortality at end of follow-up was 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone to be 0.77, 95% CI 0.62 to 0.96., AUTHORS' CONCLUSIONS: Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required., GOS was classified to 2 main categories of favorable and unfavorable recovery, of which, favorable recovery in placebo, progesterone, and progesterone-vitamin D was 25%, 45%, and 60%, respectively which showed a statistical significant difference among the groups (P-value = 0.03). CONCLUSION: The results showed that recovery rate in patients with severe brain trauma in the group receiving progesterone and vitamin D together was significantly higher than that of progesterone group, which was in turn higher than that of placebo group., The pooled relative risk (RR) for mortality at end of follow-up is 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone was 0.77, 95% confidence interval (CI) 0.62 to 0.96., AUTHORS' CONCLUSIONS: Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required., Clinical trials have shown that short-and long-term progesterone treatment induces a significant improvement in the level of disability among patients with brain injury. , Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial., CONCLUSION: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug. , The modified Functional Independence Measure scores in the progesterone group were higher than those in the placebo group at both 3-month and 6-month follow-up (P < 0.05 and P < 0.01). The mortality rate of the progesterone group was significantly lower than that of the placebo group at 6-month follow-up (P < 0.05). , CONCLUSION: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug. , These data, combined with the results of the previously published ProTECT trial, show progesterone to be safe and potentially efficacious in the treatment of TBI. Larger phase III trials will be necessary to verify results prior to clinical implementation., CONCLUSION: It indicated that successive early application of PG will benefit the patients with acute severe head injury by improving the recovery and reducing the disability, which may be related to its alleviating inflammatory and lipid peroxidation response., Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). , However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. CONCLUSION: In this small study, progesterone caused no discernible harm and showed possible signs of benefit., After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries., After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries, A US National Institutes of Health-sponsored, nationwide Phase III clinical trial is now evaluating progesterone for moderate-to-severe TBI in 1200 patients, An industry-sponsored Phase III international trial is also under way, and planning for a trial using progesterone to treat pediatric brain injury has begun, More than two decades of pre-clinical research and two recent clinical trials have shown that progesterone (PROG) and its metabolites exert beneficial effects after traumatic brain injury (TBI) through a number of metabolic and physiological pathways that can reduce damage in many different tissues and organ systems, After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries, RESULTS: Analysis of these reviews yielded meanfuling observations: (1) The effectiveness of most ordinary treatments in TBI is inconclusive except that corticosteroids are likely to be ineffective or harmful, and tranexamic acid, nimodipine and progesterone show a promising effect in bleeding trauma, traumatic subarachnoid hemorrhage, TBI or severe TBI., Laboratory data strongly show that progesterone treatment after TBI reduces edema, improves outcomes, and restores blood-brain barrier function. Clinical studies to date agree with these data, and there are ongoing human trials for progesterone treatment after TBI.[SEP]Definitions: drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. GOS defined as following: A 6-item patient-reported outcome used to evaluate patient empowerment after they have received genetic counseling and testing services.. vitamin D defined as following: Vitamin D2, a fat-soluble vitamin important for many biochemical processes including the absorption and metabolism of calcium and phosphorus. In vivo, ergocalciferol is formed after sun (ultraviolet) irradiation of plant-derived ergosterol, another form of vitamin D. Ergocalciferol is the form of vitamin D usually found in vitamin supplements. (NCI04). nimodipine defined as following: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure.. humans defined as following: Members of the species Homo sapiens.. tranexamic acid defined as following: Antifibrinolytic hemostatic used in severe hemorrhage.. traumatic brain injury defined as following: A form of acquired brain injury which occurs when a sudden trauma causes damage to the brain.. ciclosporin defined as following: A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).. tissues defined as following: Collections of differentiated CELLS, such as EPITHELIUM; CONNECTIVE TISSUE; MUSCLES; and NERVE TISSUE. Tissues are cooperatively arranged to form organs with specialized functions such as RESPIRATION; DIGESTION; REPRODUCTION; MOVEMENT; and others.. brain injury defined as following: Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.. thrombophlebitis defined as following: Inflammation of a vein associated with a blood clot (THROMBUS).. Phlebitis defined as following: Inflammation of a vein, often a vein in the leg. Phlebitis associated with a blood clot is called (THROMBOPHLEBITIS).. lipid peroxidation defined as following: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an electron acceptor.. metabolites defined as following: Any substance involved in metabolism, either as a product of metabolism or as necessary for metabolism..", "label": "no"} {"id": "converted_3183", "sentence1": "Are protamines ubiquitously expressed?", "sentence2": "Protamines are nuclear proteins which are specifically expressed in haploid male germ cells.[SEP]Definitions: Protamines defined as following: A group of simple proteins that yield basic amino acids on hydrolysis and that occur combined with nucleic acid in the sperm of fish. Protamines contain very few kinds of amino acids. Protamine sulfate combines with heparin to form a stable inactive complex; it is used to neutralize the anticoagulant action of heparin in the treatment of heparin overdose. (From Merck Index, 11th ed; Martindale, The Extra Pharmacopoeia, 30th ed, p692). nuclear proteins defined as following: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.. germ cells defined as following: The reproductive cells in multicellular organisms at various stages during GAMETOGENESIS.. protamines defined as following: A group of simple proteins that yield basic amino acids on hydrolysis and that occur combined with nucleic acid in the sperm of fish. Protamines contain very few kinds of amino acids. Protamine sulfate combines with heparin to form a stable inactive complex; it is used to neutralize the anticoagulant action of heparin in the treatment of heparin overdose. (From Merck Index, 11th ed; Martindale, The Extra Pharmacopoeia, 30th ed, p692).", "label": "no"} {"id": "converted_1623", "sentence1": "Is the Histidine-Rich Calcium Binding protein (HRC) related to arrhythmias and cardiac disease?", "sentence2": "A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy. , These findings suggest that aberrant SR Ca2+ release and increased susceptibility to delayed afterdepolarizations underlie triggered arrhythmic activity in human Ala96 HRC carriers., The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers., These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers., HRC plays an important role in myocyte differentiation and in antiapoptotic cardioprotection against ischemia/reperfusion induced cardiac injury. Interestingly, HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy., This review summarizes studies, which have established the critical role of HRC in Ca(2+)-homeostasis, suggesting its importance in cardiac physiology and pathophysiology., HRC is a SR luminal Ca(2+) binding protein known to associate with both triadin and the sarcoplasmic reticulum Ca(2+)-ATPase, and may thus mediate the crosstalk between SR Ca(2+) uptake and release. Indeed, evidence from genetic models of JCN and HRC indicate that they are important in cardiophysiology as alterations in these proteins affect SR Ca(2+) handling and cardiac function. In addition, downregulation of JCN and HRC may contribute to Ca(2+) cycling perturbations manifest in the failing heart, where their protein levels are significantly reduced., The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM., AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure., Chronic overexpression of HRC that may disrupt intracellular Ca(2+) homeostasis is implicated in pathogenesis of cardiac hypertrophy, Ablation of HRC showed relatively normal phenotypes under basal condition, but exhibited a significantly increased susceptibility to isoproterenol-induced cardiac hypertrophy, Our results present evidence that down-regulation of HRC could deteriorate cardiac function in TAC-FH through perturbed SR-mediated Ca(2+) cycling, However, AAV9-mediated HRC-KD in TAC-FH was associated with decreased fractional shortening and increased cardiac fibrosis compared with control., Histidine-rich calcium binding protein (HRC) is a high capacity, low affinity Ca(2+) binding protein, specifically expressed in striated muscles of mammals. In rabbit skeletal and cardiac muscles, HRC binds to sarcoplasmic reticulum (SR) membranes via triadin, a junctional SR protein. Recently, a potential role in heart failure and arrhythmogenesis has been assigned to HRC due to its activity as regulator of SR Ca(2+) uptake and Ca(2+) release., In addition, HRC null mice displayed a significantly exaggerated response to the induction of cardiac hypertrophy by isoproterenol compared to their wild-type littermates. The exaggerated response of HRC knockout mice to the induction of cardiac hypertrophy is consistent with a regulatory role for HRCBP in calcium handling in vivo and suggests that mutations in HRC, in combination with other genetic or environmental factors, might contribute to pathological hypertrophy and heart failure., We observed that the levels of HRC were reduced in animal models and human heart failure., Collectively, these data indicate that alterations in expression levels of HRC are associated with impaired cardiac SR Ca homeostasis and contractile function., Abnormal calcium cycling and cardiac arrhythmias associated with the human Ser96Ala genetic variant of histidine-rich calcium-binding protein., The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy., Interestingly, HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy[SEP]Definitions: calcium defined as following: A dietary supplement containing the mineral calcium.. variant defined as following: An alteration or difference from a norm or standard.. ventricular arrhythmias defined as following: A disorder characterized by an electrocardiographic finding of an atypical cardiac rhythm resulting from a pathologic process in the cardiac ventricles.. heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs.. cardiac arrhythmias defined as following: Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.. genetic defined as following: Having to do with information that is passed from parents to offspring through genes in sperm and egg cells.. sudden death defined as following: The abrupt cessation of all vital bodily functions, manifested by the permanent loss of total cerebral, respiratory, and cardiovascular functions.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. isoproterenol defined as following: Isopropyl analog of EPINEPHRINE; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant.. sarcoplasmic reticulum defined as following: A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.. dilated cardiomyopathy defined as following: Cardiomyopathy which is characterized by dilation and contractile dysfunction of the left and right ventricles. It may be idiopathic, or it may result from a myocardial infarction, myocardial infection, or alcohol abuse. It is a cause of congestive heart failure.. SR defined as following: Human SNCG wild-type allele is located within10q23.2-q23.3 and is approximately 13 kb in length. This allele, which encodes gamma-synuclein protein, plays a role in the modulation of axonal architecture and neurofilament integrity. This gene is highly expessed in advanced breast carcinomas, suggesting a correlation between SNCG overexpression and breast tumor development.. sarcoplasmic reticulum Ca(2+)-ATPase defined as following: Calcium-transporting ATPases that catalyze the active transport of CALCIUM into the SARCOPLASMIC RETICULUM vesicles from the CYTOPLASM. They are primarily found in MUSCLE CELLS and play a role in the relaxation of MUSCLES.. cardiac hypertrophy defined as following: Enlargement of the HEART due to chamber HYPERTROPHY, an increase in wall thickness without an increase in the number of cells (MYOCYTES, CARDIAC). It is the result of increase in myocyte size, mitochondrial and myofibrillar mass, as well as changes in extracellular matrix.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. DCM defined as following: A chlorinated methotrexate derivative. Dichloromethotrexate inhibits the enzyme dihydrofolate reductase, thereby preventing the synthesis of purine nucleotides and thymidylates and inhibiting DNA and RNA synthesis. This agent is metabolized and excreted by the liver. (NCI04). cardiac muscles defined as following: The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.. myocyte defined as following: Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal (MUSCLE FIBERS, SKELETAL), cardiac (MYOCYTES, CARDIAC), and smooth (MYOCYTES, SMOOTH MUSCLE). They are derived from embryonic (precursor) muscle cells called MYOBLASTS.. mammals defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. human defined as following: Members of the species Homo sapiens.. transverse aorta defined as following: The curved section of the aorta between the ascending and the descending tracts. The brachiocephalic, left common carotid and left subclavian arteries branch from the aorta at this section.. polymorphism defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.. cardiac disease defined as following: Pathological conditions involving the HEART including its structural and functional abnormalities.. arrhythmias defined as following: Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction..", "label": "yes"} {"id": "converted_1466", "sentence1": "Is the HRC Ser96Ala variant associated with sudden cardiac death in patients with dilated cardiomyopathy?", "sentence2": "The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM., The Ser96Ala (S96A) mutation within the histidine rich Ca(2+) binding protein (HRC) has recently been linked to cardiac arrhythmias in idiopathic dilated cardiomyopathy patients, potentially attributable to an increase in spontaneous Ca(2+) release events., A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy., The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers., HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy., A human genetic variant (Ser96Ala) in the sarcoplasmic reticulum (SR) histidine-rich Ca(2+)-binding (HRC) protein has been linked to ventricular arrhythmia and sudden death in dilated cardiomyopathy, The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM., The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers, The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy., These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers.[SEP]Definitions: ventricular arrhythmia defined as following: An electrocardiographic finding of an atypical cardiac rhythm resulting from a pathologic process in the cardiac ventricles.. variant defined as following: An alteration or difference from a norm or standard.. human defined as following: Members of the species Homo sapiens.. sarcoplasmic reticulum defined as following: A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.. dilated cardiomyopathy defined as following: Cardiomyopathy which is characterized by dilation and contractile dysfunction of the left and right ventricles. It may be idiopathic, or it may result from a myocardial infarction, myocardial infection, or alcohol abuse. It is a cause of congestive heart failure.. polymorphism defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.. ventricular arrhythmias defined as following: A disorder characterized by an electrocardiographic finding of an atypical cardiac rhythm resulting from a pathologic process in the cardiac ventricles.. cardiac arrhythmias defined as following: Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.. sudden death defined as following: The abrupt cessation of all vital bodily functions, manifested by the permanent loss of total cerebral, respiratory, and cardiovascular functions.. DCM defined as following: A chlorinated methotrexate derivative. Dichloromethotrexate inhibits the enzyme dihydrofolate reductase, thereby preventing the synthesis of purine nucleotides and thymidylates and inhibiting DNA and RNA synthesis. This agent is metabolized and excreted by the liver. (NCI04). sudden cardiac death defined as following: Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as CHEST PAIN and CARDIAC ARRHYTHMIAS, particularly VENTRICULAR TACHYCARDIA, can lead to the loss of consciousness and cardiac arrest followed by biological death. (from Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., 2005).", "label": "yes"} {"id": "converted_2324", "sentence1": "Are mutations in the nf1 gene associated with memory?", "sentence2": "We hypothesized that NF1 mutations disturb the expression of genes important for memory formation, Our previous work has shown that defective cAMP signaling leads to the learning phenotype in Drosophila Nf1 mutants. In the present report, our experiments showed that in addition to learning, long-term memory was also abolished in Nf1 mutants. , Distinct functional domains of neurofibromatosis type 1 regulate immediate versus long-term memory formation.[SEP]Definitions: NF1 defined as following: An autosomal dominant inherited disorder (with a high frequency of spontaneous mutations) that features developmental changes in the nervous system, muscles, bones, and skin, most notably in tissue derived from the embryonic NEURAL CREST. Multiple hyperpigmented skin lesions and subcutaneous tumors are the hallmark of this disease. Peripheral and central nervous system neoplasms occur frequently, especially OPTIC NERVE GLIOMA and NEUROFIBROSARCOMA. NF1 is caused by mutations which inactivate the NF1 gene (GENES, NEUROFIBROMATOSIS 1) on chromosome 17q. The incidence of learning disabilities is also elevated in this condition. (From Adams et al., Principles of Neurology, 6th ed, pp1014-18) There is overlap of clinical features with NOONAN SYNDROME in a syndrome called neurofibromatosis-Noonan syndrome. Both the PTPN11 and NF1 gene products are involved in the SIGNAL TRANSDUCTION pathway of Ras (RAS PROTEINS).. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. nf1 gene defined as following: Tumor suppressor genes located on the long arm of human chromosome 17 in the region 17q11.2. Mutation of these genes is thought to cause NEUROFIBROMATOSIS 1, Watson syndrome, and LEOPARD syndrome..", "label": "yes"} {"id": "converted_2549", "sentence1": "Are stress granules membraneous?", "sentence2": "PMLOs are different in size, shape, and composition, and almost invariantly contain intrinsically disordered proteins (e.g., eIF4B and TDP43 in stress granules,, Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules., Stress granules (SG) are membrane-less compartments involved in regulating mRNAs during stress., In addition to membrane delimited organelles, proteins and RNAs can organize themselves into specific domains. Some examples include stress granules and subnuclear bodies. [SEP]Definitions: proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. RNAs defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). organelles defined as following: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the MITOCHONDRIA; the GOLGI APPARATUS; ENDOPLASMIC RETICULUM; LYSOSOMES; PLASTIDS; and VACUOLES.. membrane defined as following: A device that is made from or resembles a thin flexible sheet of material.. TDP43 defined as following: Human TARDBP wild-type allele is located in the vicinity of 1p36.22 and is approximately 13 kb in length. This allele, which encodes TAR DNA-binding protein 43, plays a role in the mediation of both mRNA splicing and DNA transcription. Mutation of the gene is associated with amyotrophic lateral sclerosis type 10.. RNA-binding proteins defined as following: Proteins that bind to RNA molecules. Included here are RIBONUCLEOPROTEINS and other proteins whose function is to bind specifically to RNA.. stress granules defined as following: A dense aggregation in the cytosol composed of proteins and RNAs that appear when the cell is under stress. [GOC:ans, PMID:17284590, PMID:17601829, PMID:17967451, PMID:20368989].", "label": "no"} {"id": "converted_3660", "sentence1": "Is Impetigo a viral infection that affects the skin?", "sentence2": "Importance: Ozenoxacin, a novel topical antibacterial agent with potent bactericidal activity against gram-positive bacteria, has been developed as a cream with 1% active drug for the treatment of impetigo, a highly contagious bacterial skin infection, : To compare the in vitro activity of the anti-impetigo agent, ozenoxacin, and other antimicrobial agents against Gram-positive clinical isolates from skin and soft tissue infections, Streptococcus pyogenes is responsible for a wide variety of cutaneous infections ranging from superficial impetigo to fulminant invasive necrotizing fasciitis., Impetigo is a highly contagious bacterial skin infection and is one of the most common skin infections in children, Impetigo is a superficial bacterial infection that most commonly affects the face and extremities of children., Impetigo is the most common bacterial skin infection of children., Impetigo is the most common bacterial skin infection in children two to five years of age., BACKGROUND Impetigo can result from Staphylococcus aureus (S. aureus)., Impetigo , cellulitis , and abscess comprise the majority of childhood bacterial skin infections and are treated with topical or systemic antibiotics that cover group A Streptococcus and Staphylococcus aureus . , BACKGROUND\nImpetigo can result from Staphylococcus aureus (S. aureus)., Impetigo is a superficial bacterial infection that most commonly affects the face and extremities of children., Impetigo is a superficial, but contagious, bacterial infection of the skin that predominantly affects children and is common in primary care., Impetigo is a common, superficial, bacterial infection of the skin characterized by an inflamed and infected epidermis., Impetigo, a bacterial skin infection that involves the superficial layers of the skin, is one of the most common skin infections in children ages 2 to 5 but can occur in individuals across the lifespan., Impetigo contagiosa is a common, superficial, bacterial infection of the skin characterised by an inflamed and infected epidermis caused by Staphylococcus aureus, Streptococcus pyogenes or both.[SEP]Definitions: Streptococcus pyogenes defined as following: A species of gram-positive, coccoid bacteria isolated from skin lesions, blood, inflammatory exudates, and the upper respiratory tract of humans. It is a group A hemolytic Streptococcus that can cause SCARLET FEVER and RHEUMATIC FEVER.. epidermis defined as following: Cells from the outermost, non-vascular layer (EPIDERMIS) of the skin.. antimicrobial agents defined as following: Generically, any agent that destroys microbes. However, usage of the term is increasingly being confined to agents that prevent or reduce the transmission of SEXUALLY TRANSMITTED DISEASES.. bacterial infection defined as following: Infections by bacteria, general or unspecified.. Impetigo defined as following: A common superficial bacterial infection caused by STAPHYLOCOCCUS AUREUS or group A beta-hemolytic streptococci. Characteristics include pustular lesions that rupture and discharge a thin, amber-colored fluid that dries and forms a crust. This condition is commonly located on the face, especially about the mouth and nose.. cellulitis defined as following: An acute, diffuse, and suppurative inflammation of loose connective tissue, particularly the deep subcutaneous tissues, and sometimes muscle, which is most commonly seen as a result of infection of a wound, ulcer, or other skin lesions.. superficial defined as following: Of little substance or significance; involving only a surface.. cutaneous infections defined as following: Infections of the skin that happen multiple times. [HPO:curators]. skin infections defined as following: Skin diseases caused by bacteria, fungi, parasites, or viruses.. S. aureus defined as following: Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications..", "label": "no"} {"id": "converted_4", "sentence1": "Is RANKL secreted from the cells?", "sentence2": "Osteoprotegerin (OPG) is a soluble secreted factor that acts as a decoy receptor for receptor activator of NF-κB ligand (RANKL) , Osteoprotegerin (OPG) is a secreted glycoprotein and a member of the tumor necrosis factor receptor superfamily. It usually functions in bone remodeling, by inhibiting osteoclastogenesis through interaction with a receptor activator of the nuclear factor κB (RANKL)., e RANKL/OPG ratio secreted by osteoblasts increased and RANK expression by osteoclasts increased, leading to increased osteoclastogenesis, Osteoprotegerin (OPG) is an essential secreted protein in bone turnover due to its role as a decoy receptor for the Receptor Activator of Nuclear Factor-kB ligand (RANKL) in the osteoclasts, thus inhibiting their differentiation, We identify a TNFSF11 transcript variant that extends the originally identified transcript encoding secreted RANKL., Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL., OPG, on the other hand, is secreted by osteoblast as a decoy receptor for RANKL, prevents RANKL from binding to RANK and thus prevents bone resorption, Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) are cytokines predominantly secreted by osteoblasts and play a central role in differentiation and functional activation of osteoclasts, Although B. abortus-activated T cells actively secreted the pro-osteoclastogenic cytokines RANKL and IL-17, osteoclastogenesis depended on IL-17, because osteoclast generation induced by Brucella-activated T cells was completely abrogated when these cells were cultured with BMMs from IL-17 receptor knockout mice. , osteoclastogenesis and bone destruction in autoimmune arthritis. We isolated human fibroblasts from RA, pyrophosphate arthropathy (PPA) and osteoarthritis (OA) patients and analyzed their RANKL/OPG expression profile and the capacity of their secreted factors to induce osteoclastogenesis., Osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) are cytokines predominantly secreted by osteoblasts and play critical roles in the differentiation and function of osteoclasts. [SEP]Definitions: osteoblasts defined as following: Bone-forming cells which secrete an EXTRACELLULAR MATRIX. HYDROXYAPATITE crystals are then deposited into the matrix to form bone.. osteoclast defined as following: A large multinuclear cell associated with the BONE RESORPTION. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in CEMENTUM resorption.. RANKL defined as following: Human TNFSF11 wild-type allele is located within 13q14 and is approximately 45 kb in length. This allele, which encodes tumor necrosis factor ligand superfamily member 11 protein, plays a role in osteoclast differentiation and activation. This allele also is involved in apoptotic signal transduction and regulation.. decoy receptor defined as following: Tumor necrosis factor receptor superfamily member 10C (259 aa, ~27 kDa) is encoded by the human TNFRSF10C gene. This protein is involved in both binding to tumor necrosis factor ligand superfamily member 10 and the inhibition of apoptosis.. IL-17 defined as following: A proinflammatory cytokine produced primarily by T-LYMPHOCYTES or their precursors. Several subtypes of interleukin-17 have been identified, each of which is a product of a unique gene.. OPG defined as following: Extraoral body-section radiography depicting an entire maxilla, or both maxilla and mandible, on a single film.. Osteoprotegerin defined as following: A secreted member of the TNF receptor superfamily that negatively regulates osteoclastogenesis. It is a soluble decoy receptor of RANK LIGAND that inhibits both CELL DIFFERENTIATION and function of OSTEOCLASTS by inhibiting the interaction between RANK LIGAND and RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-KAPPA B.. PPA defined as following: A sympathomimetic that acts mainly by causing release of NOREPINEPHRINE but also has direct agonist activity at some adrenergic receptors. It is most commonly used as a nasal vasoconstrictor and an appetite depressant.. RA defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.. transcript defined as following: The initial RNA molecule produced by transcription.. IL-17 receptor defined as following: Cell surface receptors for INTERLEUKIN-17. Several subtypes of receptors have been found, each with its own in specificity for interleukin-17 subtype.. TNFSF11 defined as following: Tumor necrosis factor ligand superfamily member 11 (317 aa, ~35 kDa) is encoded by the human TNFSF11 gene. This protein is involved in osteoclast differentiation and activation and the regulation of the interactions between T-cells and dendritic cells.. RANK defined as following: Human TNFRSF11A wild-type allele is located in the vicinity of 18q22.1 and is approximately 61 kb in length. This allele, which encodes tumor necrosis factor receptor superfamily member 11A protein, plays a role in the regulation and maintenance of bone density.. osteoarthritis defined as following: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans.. nuclear factor κB defined as following: A family of proteins that contain 1 DWA/MH1 domain and bind 5'-TTGGCNNNNNGCCAA-3' DNA palindromes in viral and cellular promoters as homodimeric factors capable of activating transcription and replication.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. tumor necrosis factor receptor defined as following: Cell surface receptors that bind TUMOR NECROSIS FACTORS and trigger changes which influence the behavior of cells..", "label": "yes"} {"id": "converted_1408", "sentence1": "Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death?", "sentence2": "Here we refine our approach, and apply it to novel variants found in 2266 patients across two large cohorts with inherited sudden death syndromes, namely catecholaminergic polymorphic ventricular tachycardia (CPVT) or Brugada syndrome (BrS)., Calsequestrin-associated catecholaminergic polymorphic ventricular tachycardia (CPVT2) can cause sudden death in young individuals in response to stress. , Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic cardiac disorder characterized by life-threatening arrhythmias induced by physical or emotional stress, in the absence structural heart abnormalities. The arrhythmias may cause syncope or degenerate into cardiac arrest and sudden death which usually occurs during childhood, In many cases the cause of death can be elucidated by medico-legal autopsy, however, a significant number of these cases remain unexplained despite a detailed postmortem investigation and are labeled as sudden unexplained death (SUD). Post-mortem genetic testing, so called molecular autopsy, revealed that primary arrhythmogenic disorders including long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a certain number of these cases., We report a family with repeat events of sudden cardiac death and recurrent ventricular fibrillation in a teenage girl, where autopsy data and clinical investigations were inconclusive. The diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was established only following finding a gene mutation in the cardiac ryano, Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. , In conclusion, patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective., Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) yield no evidence to be found at autopsy, leaving coroners, medical examiners, and forensic pathologists only to speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD)., Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood., We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome., Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF)., Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease that manifests as syncope or sudden death during high adrenergic tone in the absence of structural heart defects., Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy characterized by altered intracellular calcium handling resulting in ventricular arrhythmias and high risk of cardiac sudden death in young cases with normal structural hearts, Early detection of CPVT is crucial because opportune medical intervention prevents sudden cardiac death. , If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. Sudden death may be the first manifestation of the disease. , Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young, Patients with CPVT present with exercise-induced syncope and sudden cardiac death but normal resting electrocardiograms., Although structural cardiovascular abnormalities explain most cases of sudden cardiac death in young people, the cause of death remains unexplained after autopsy in 10% to 30% of cases. Potentially lethal ion channel disorders (channelopathies) such as the long QT syndromes (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and the Brugada syndrome (BrS) may account for at least one-third of these unexplained cases. , Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death., The inherited arrhythmogenic diseases associated with the transmembranous ionic channels, anchoring proteins or intracellular calcium regulating proteins are thought to be responsible for sudden cardiac death in infants, children, and young adults who have structurally normal hearts. Recent genetic analyses have identified congenital diseases such as the long-QT syndrome (LQTS), the Jervell and Lange-Nielsen syndrome (JLNS), the Brugada syndrome (BrS), the short-QT syndrome (SQTS), the arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2), and the catecholamine-induced polymorphic ventricular tachycardia (CPVT) /familial polymorphic ventricular tachycardia (FPVT). , At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT[SEP]Definitions: BrS defined as following: A scale developed by Smith, et al, designed to assess an individual's ability to recover from stressful circumstances.. cardiac abnormalities defined as following: Developmental abnormalities involving structures of the heart. These defects are present at birth but may be discovered later in life.. CPVT2 defined as following: An autosomal recessive condition caused by mutation(s) in the CASQ2 gene, encoding calsequestrin-2. It is characterized by a relative resting bradycardia and a slight prolongation of the QTc interval. Polymorphic ventricular tachycardia may be induced with exercise stress testing or isoproterenol infusion.. arrhythmia defined as following: Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction.. epilepsy defined as following: A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313). ICDs defined as following: Implantable devices which continuously monitor the electrical activity of the heart and automatically detect and terminate ventricular tachycardia (TACHYCARDIA, VENTRICULAR) and VENTRICULAR FIBRILLATION. They consist of an impulse generator, batteries, and electrodes.. ventricular arrhythmias defined as following: A disorder characterized by an electrocardiographic finding of an atypical cardiac rhythm resulting from a pathologic process in the cardiac ventricles.. sudden death defined as following: The abrupt cessation of all vital bodily functions, manifested by the permanent loss of total cerebral, respiratory, and cardiovascular functions.. cardiac arrest defined as following: Cessation of heart beat or MYOCARDIAL CONTRACTION. If it is treated within a few minutes, heart arrest can be reversed in most cases to normal cardiac rhythm and effective circulation.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. HCM defined as following: A form of CARDIAC MUSCLE disease, characterized by left and/or right ventricular hypertrophy (HYPERTROPHY, LEFT VENTRICULAR; HYPERTROPHY, RIGHT VENTRICULAR), frequent asymmetrical involvement of the HEART SEPTUM, and normal or reduced left ventricular volume. Risk factors include HYPERTENSION; AORTIC STENOSIS; and gene MUTATION; (FAMILIAL HYPERTROPHIC CARDIOMYOPATHY).. sudden cardiac death defined as following: Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as CHEST PAIN and CARDIAC ARRHYTHMIAS, particularly VENTRICULAR TACHYCARDIA, can lead to the loss of consciousness and cardiac arrest followed by biological death. (from Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., 2005). polymorphic defined as following: The quality or state of being able to assume different forms.. SQTS defined as following: Ventricular tachyarrhythmias occurring in association with short QT syndrome.. congenital diseases defined as following: existing at, and usually before, birth; referring to conditions that are present at birth, regardless of their causation; inborn metabolism disorders are generally not treed here.. arrhythmogenic right ventricular cardiomyopathy defined as following: A congenital cardiomyopathy that is characterized by infiltration of adipose and fibrous tissue into the RIGHT VENTRICLE wall and loss of myocardial cells. Primary injuries usually are at the free wall of right ventricular and right atria resulting in ventricular and supraventricular arrhythmias.. cardiovascular abnormalities defined as following: Congenital, inherited, or acquired anomalies of the CARDIOVASCULAR SYSTEM, including the HEART and BLOOD VESSELS.. calcium defined as following: A dietary supplement containing the mineral calcium.. long QT syndrome defined as following: A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.. ventricular tachycardia defined as following: An electrocardiographic finding of three or more consecutive complexes of ventricular organ with a rate greater than a certain threshold (100 or 120 beats per minute are commonly used). The QRS complexes are wide and have an abnormal morphology. (CDISC). ventricular fibrillation defined as following: An electrocardiographic finding of a rapid grossly irregular ventricular rhythm with marked variability in QRS cycle length, morphology, and amplitude. The rate is typically greater than 300 bpm. (CDISC). Brugada syndrome defined as following: An autosomal dominant defect of cardiac conduction that is characterized by an abnormal ST-segment in leads V1-V3 on the ELECTROCARDIOGRAM resembling a right BUNDLE-BRANCH BLOCK; high risk of VENTRICULAR TACHYCARDIA; or VENTRICULAR FIBRILLATION; SYNCOPAL EPISODE; and possible sudden death. This syndrome is linked to mutations of gene encoding the cardiac SODIUM CHANNEL alpha subunit.. sudden cardiac arrest defined as following: Sudden suspension of cardiac activity that is usually due to ARRHYTHMIA, in contrast to heart attack (MYOCARDIAL INFARCTION) which occurs due to blockage. The sudden suspension of cardiac activity generally requires RESUSCITATION.. variants defined as following: An alteration or difference from a norm or standard.. gene mutation defined as following: A change in the nucleotide sequence of the TAF1 gene.. cardiac channelopathy defined as following: A disorder that affects the myocardial ion channels, altering the electrical properties of the heart and changing the ECG and/or predisposing the subject to pro-arrhythmic events.. channelopathies defined as following: A variety of neuromuscular conditions resulting from MUTATIONS in ION CHANNELS manifesting as episodes of EPILEPSY; HEADACHE DISORDERS; and DYSKINESIAS.. LQTS defined as following: A rare group of genetic, cardiac rhythm diseases characterized by a prolongation of the QT interval at basal electrocardiography (ECG) and by a high risk of life-threatening arrhythmias.. CPVT defined as following: An electrocardiographic finding of ventricular tachycardia that is associated with syncope and/or cardiac arrest triggered by emotion or exercise in patients whose baseline ECG is normal. (ACC). Lange-Nielsen syndrome defined as following: A form of long QT syndrome that is associated with congenital deafness. It is characterized by abnormal cardioelectrophysiology involving the VOLTAGE-GATED POTASSIUM CHANNEL. It results from mutation of KCNQ1 gene (Subtype 1 or JLN1) or the KCNE1 gene (Subtype 2 or JLN2).. Ventricular Tachycardia defined as following: An electrocardiographic finding of three or more consecutive complexes of ventricular organ with a rate greater than a certain threshold (100 or 120 beats per minute are commonly used). The QRS complexes are wide and have an abnormal morphology. (CDISC).", "label": "yes"} {"id": "converted_3145", "sentence1": "Can TAD disruption lead to disease?", "sentence2": "its perturbation will lead to human disease, highlighting the accumulating evidence that links the diverse 3D genome architecture components to a multitude of human diseases and the emerging mechanisms by which 3D genome derangement causes disease phenotypes., TAD boundaries are insulators of genomic neighborhoods. In this issue, Sun et al. show that disease-associated tandem repeats are located to TAD boundaries and affect their insulation. , Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs, Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers., the disruption of these structures by genomic rearrangements can result in gene misexpression and disease., TAD disruption as oncogenic driver., Recent studies have shown that TAD disruption is often found in cancer cells and contributes to oncogenesis through two mechanisms., Disruption of TAD boundaries results in aberrant gene expression by exposing genes to inappropriate regulatory elements., However, it is not clear to which extent TAD regions are conserved in evolution and whether disruption of TADs by evolutionary rearrangements can alter gene expression., Disruption of this organization by structural variations can lead to ectopic interactions between enhancers and promoters, and to alteration of genes expression patterns., Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers., Deletion in 2q35 excluding the IHH gene leads to fetal severe limb anomalies and suggests a disruption of chromatin architecture., We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. , Disruption of TAD boundaries results in aberrant gene expression by exposing genes to inappropriate regulatory elements. , Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers. , Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. , Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. , Recent studies have shown that TAD disruption is often found in cancer cells and contributes to oncogenesis through two mechanisms. , Disruption of this organization by structural variations can lead to ectopic interactions between enhancers and promoters, and to alteration of genes expression patterns. , Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. , However, it is not clear to which extent TAD regions are conserved in evolution and whether disruption of TADs by evolutionary rearrangements can alter gene expression. [SEP]Definitions: TADs defined as following: Tietz syndrome is a genetic hypopigmentation and deafness syndrome characterized by congenital profound bilateral sensorineural hearing loss and generalized albino-like hypopigmentation of skin, eyes and hair.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. pathogenic defined as following: A genetic variant that is known to directly contribute to the development of disease.. genome defined as following: Anatomical set of genes in all the chromosomes.. human defined as following: Members of the species Homo sapiens.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. promoters defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. oncogene defined as following: Genes whose gain-of-function alterations lead to NEOPLASTIC CELL TRANSFORMATION. They include, for example, genes for activators or stimulators of CELL PROLIFERATION such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of \"v-\" before oncogene symbols indicates oncogenes captured and transmitted by RETROVIRUSES; the prefix \"c-\" before the gene symbol of an oncogene indicates it is the cellular homolog (PROTO-ONCOGENES) of a v-oncogene.. IHH gene defined as following: This gene is involved in growth, patterning and morphogenesis..", "label": "yes"} {"id": "converted_3356", "sentence1": "Is golimumab effective for sarcoidosis?", "sentence2": "Introduced monoclonal antibodies (infliximab, etanercept, adaluimumab, golimumab, rituximab), tested for efficacy in other pathologies associated with the formation of granulomas, have a limited application in patients with SA. , Although treatment was well tolerated, neither ustekinumab nor golimumab demonstrated efficacy in pulmonary sarcoidosis. , Although treatment was well tolerated, neither ustekinumab nor golimumab demonstrated efficacy in pulmonary sarcoidosis.[SEP]Definitions: granulomas defined as following: A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents.. rituximab defined as following: A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS.. golimumab defined as following: A human monoclonal antibody directed against the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-a) with immunosuppressive activity. Golimumab binds to TNF-a, thereby preventing TNF-a-mediated immune responses. TNF-a production is dysregulated in various auto-immune diseases and in cancer.. etanercept defined as following: A recombinant version of soluble human TNF receptor fused to an IgG FC fragment that binds specifically to TUMOR NECROSIS FACTOR and inhibits its binding with endogenous TNF receptors. It prevents the inflammatory effect of TNF and is used to treat RHEUMATOID ARTHRITIS; PSORIATIC ARTHRITIS and ANKYLOSING SPONDYLITIS..", "label": "no"} {"id": "converted_3466", "sentence1": "Is Hemochromatosis type 4 is caused by a mutation in a recessive gene?", "sentence2": " severely affect iron homeostasis causing type 4 hereditary hemochromatosis, an autosomal dominant iron overload condition with variable phenotypic manifestations, Hemochromatosis type 4, also known as ferroportin disease, is an autosomal dominant genetic disorder caused by pathogenic mutations in the SLC40A1 gene, which encodes ferroportin 1 (FPN1)., Hemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1)., Type 4 hemochromatosis follows an autosomal dominant trait; the corresponding mutation affects the basolateral iron carrier ferroportin 1., Type 4 hemochromatosis follows an autosomal dominant trait; the corresponding mutation affects the basolateral iron carrier ferroportin 1, Type 4 hemochromatosis follows an autosomal dominant trait; the corresponding mutation affects the basolateral iron carrier ferroportin 1.[SEP]Definitions: gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. Hemochromatosis type 4 defined as following: A form of rare hereditary hemochromatosis, a group of diseases characterized by excessive tissue iron deposition of genetic origin. Type 4 is less rare than the other rare forms of hereditary hemochromatosis. The disease is phenotypically heterogeneous with two sub-types. Ferroportin disease form A is the usual form and is generally asymptomatic with no tissue damage and further complications. Ferroportin disease form B is rarer and resembles hemochromatosis type 1, but can affect children. Ferroportin disease is due to mutations in the SLC40A1 gene located on chromosome 2, which encodes for ferroportin (FPN), an iron exporter negatively regulated by the hepcidin hormone. Transmission is autosomal dominant.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. autosomal defined as following: Any chromosome other than a sex chromosome. [GOC:mah]. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. recessive gene defined as following: Genes that influence the PHENOTYPE only in the homozygous state..", "label": "no"} {"id": "converted_1854", "sentence1": "Is vortioxetine effective for treatment of depression?", "sentence2": "Vortioxetine is the most recently approved medication for the treatment of major depressive disorder (MDD). , [Vortioxetine: a new antidepressant to treat depressive episodes]., Vortioxetine is a new antidepressant, which mechanism of action is multimodal, targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin transporter (5-HTT). , In short-term studies (8 weeks), vortioxetine is more efficacious than placebo in decreasing depressive symptoms as measured by the MADRS total score, response rate (vortioxetine: 53.2% vs placebo: 35.2%) and remission rate (vortioxetine: 29.2% vs placebo: 19.3%). In a long-term study (52 weeks), vortioxetine is also superior to placebo in preventing relapses and recurrences. Moreover, in second line treatment, after failure of a first line selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrin reuptake inhibitor (SNRI), vortioxetine is superior to agomelatine in improving depressive symptoms and achieving response and remission. , Against this background, we feature the novel antidepressants vortioxetine, vilazodone and milnacipran/levomilnacipran with regard to their serotonin receptor targets such as the 5-HT1A, 5-HT3 and 5-HT7 which may account for their specific effects on certain symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile., CONCLUSION: Vortioxetine dominated venlafaxine XR in South Korea and is a relevant treatment option for MDD patients initiating or switching therapy., Vortioxetine: a New Treatment for Major Depressive Disorder., INTRODUCTION: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD)., EXPERT OPINION: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. , The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option., Clinical studies indicate that vortioxetine is effective in the treatment of major depression, though there is no suggestion of superiority over active comparators., Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day., Vortioxetine was significantly more effective than was placebo, with a standardized mean difference (SMD) of -0.118 (95% CIs, -0.203 to -0.033, P = 0.007)., Vortioxetine for the treatment of depression., Vortioxetine for the treatment of major depression., Vortioxetine (Lu-AA-21004; 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide) is a novel orally active molecule that is being investigated by Lundbeck and Takeda for the treatment of major depression and generalized anxiety disorders., Vortioxetine (Lu AA21004) is a multi-modal antidepressant in clinical development for the treatment of major depressive disorder (MDD)., A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder., Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day., Secondary endpoints included response and remission rates, anxiety symptoms(Hamilton Anxiety Rating Scale), Clinical Global Impression, overall functioning (Sheehan Disability Scale), health-related quality of life(EuroQol 5 Dimensions), productivity (work limitation questionnaire) and family functioning (Depression and Family Functioning Scale).RESULTS: Primary endpoint noninferiority was established and vortioxetine (n = 252) was superior to agomelatine (n = 241) by 2.2 MADRS points (p<0.01)., Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter.To evaluate the efficacy of vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder.This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR).Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, or placebo once daily for 8 weeks., Vortioxetine (Lu AA21004) is a new antidepressant that combines a number of neurotransmitter reuptake and receptor effects that have been thought to predict efficacy as a treatment for depressive and anxiety disorders.This review summarizes the pharmacology and neurobiology of vortioxetine, In the study of elderly patients, vortioxetine 5 mg (n = 136) improved 12-item Health Status Questionnaire scores significantly more than placebo (n = 148) for the domains of health perception (10.4, P < 0.0001, SES of 0.54), mental health (7.9, P < 0.001, SES of 0.44), and energy (6.4, P < 0.05, SES of 0.28) (FAS, mixed model for repeated measures).Vortioxetine yielded significant, meaningful HRQoL improvements in 6 MDD studies of 6 to 8 weeks duration., All references included were published between 1999 and 2014.All studies that included humans and were published in English, with data describing vortioxetine for the treatment of MDD, were reviewed.Vortioxetine is a novel multimodal antidepressant agent, which inhibits the 5-HT transporter protein, acts as a 5-HT3 antagonist, 5-HT1A receptor agonist, 5-HT7 receptor antagonist, and a partial agonist of the 5-HT1B receptor, Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day, Vortioxetine is an antidepressant with multimodal activity which has shown efficacy in major depressive disorder (MDD) patients in six of ten short-term, randomized, placebo-controlled trials (completed end 2012).We performed meta-regression analyses to indirectly compare vortioxetine to seven marketed antidepressants with different mechanisms of action, Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years.Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d, Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies.This double-blind, placebo-controlled study assessed the efficacy and tolerability of vortioxetine in subjects with a primary diagnosis of generalized anxiety disorder.Subjects (n = 457) were randomized 1:1:1 to treatment with placebo or vortioxetine 2.5 or 10 mg once daily, There was a significant difference for nausea between the two groups (OR=3.01, 95 % CI=2.22-4.09, Z=7.08, P=0.00001), but no significant differences were observed for the other four adverse effects.CONCLUSIONS: For the treatment of major depressive disorder, our results show that a dose of 5 mg/day vortioxetine was more effective, but more easily induced nausea, compared to placebo., The efficacy and safety of 5 mg/d Vortioxetine compared to placebo for major depressive disorder: A meta-analysis., Vortioxetine: a meta-analysis of 12 short-term, randomized, placebo-controlled clinical trials for the treatment of major depressive disorder., Vortioxetine in the treatment of adult patients with major depressive disorder: a meta-analysis of randomized double-blind controlled trials., Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day. , Clinical studies indicate that vortioxetine is effective in the treatment of major depression, though there is no suggestion of superiority over active comparators., The incidence of treatment-emergent adverse events was significantly higher in the duloxetine group than in the vortioxetine group.Duloxetine was more effective but less well-tolerated than vortioxetine in MDD., There was no significant difference in discontinuation rates between vortioxetine and comparators owing to inefficacy (OR 0.983, 95% CI 0.585 to 1.650), whereas discontinuation owing to AEs was significantly less common in the vortioxetine than in the comparator group (OR 0.728, 95% CI 0.554 to 0.957).Studies examining the role of vortioxetine in the treatment of MDD are limited.Although our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a l, We performed a meta-analysis to increase the statistical power of these studies and enhance our current understanding of the role of vortioxetine in the treatment of MDD.We performed an extensive search of databases and the clinical trial registry., BACKGROUND: Vortioxetine is a recently approved multimodal antidepressant with anxiolytic properties in preclinical studies.OBJECTIVE: This double-blind, placebo-controlled study assessed the efficacy and tolerability of vortioxetine in subjects with a primary diagnosis of generalized anxiety disorder.METHODS: Subjects (n = 457) were randomized 1:1:1 to treatment with placebo or vortioxetine 2.5 or 10 mg once daily., Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms., Furthermore, a statistically significant number of patients with MDD who were on vortioxetine have achieved a greater than or equal to 50% reduction in depression symptoms from baseline., BACKGROUND: Vortioxetine is a novel multimodal compound that has recently been approved by the FDA for the treatment of major depressive disorder (MDD)., Although our results suggest that vortioxetine may be an effective treatment option for MDD, they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of heterogeneous RCTs.., Vortioxetine is an effective agent for the treatment of MDD, but it does not have any clear advantages over other available treatment options.., Vortioxetine was significantly more effective than placebo for acute treatment of major depressive disorder (MDD)., Duloxetine was more effective but less well-tolerated than vortioxetine in MDD., Vortioxetine is an orally administered small molecule developed by Lundbeck A/S for the once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Vortioxetine received its first global approval for MDD in the USA in September 2013 and regulatory approval for its use in this indication in the EU (where it has received a positive opinion) and Canada is awaited. , This article summarizes the milestones in the development of vortioxetine leading to this first approval for MDD., Vortioxetine was efficacious and well tolerated in the treatment of patients with major depressive disorder., On the primary efficacy endpoint, both vortioxetine doses were statistically significantly superior to placebo, with a mean difference to placebo (n=158) of -5.5 (vortioxetine 15 mg, P<0.0001, n=149) and -7.1 MADRS points (vortioxetine 20 mg, P<0.0001, n=151)., The change in the severity of depressive and anxiety symptoms was maintained throughout the study as reflected by a 24-item Hamilton Depression Scale total score of 8.2 at week 52 (from 17.6 at open-label baseline) in the observed case data set., Vortioxetine is a multi-modal antidepressant that functions as a human 5-HT3A and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist, and inhibitor of the serotonin transporter. , Approval for the treatment of MDD was based on a clinical development programme that included six positive 6-8 week studies, including one study in elderly people, and one positive maintenance study in adults., Vortioxetine represents another option for the treatment of MDD. , The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction., Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT1A-R agonist properties with SERT blockade., Novel drugs in development include those that combine multiple simultaneous pharmacologic mechanisms in addition to SERT inhibition within the same molecule, such as vilazodone (combining 5HT1A partial agonism with SERT inhibition), triple reuptake inhibitors (combining norepinephrine and dopamine reuptake inhibition with SERT inhibition), and vortioxetine, a multimodal antidepressant combining actions at the G protein receptor mode (5HT1A and 5HT1B partial agonism and 5HT7 antagonism), at the ion channel mode (5HT3 antagonism) as well as the neurotransmitter transporter mode (SERT inhibition). , In this study of adults with MDD treated for 8 weeks with vortioxetine 2.5 mg or 5 mg per day, reductions in depression symptoms were not statistically significant compared with placebo. , However, on the basis of these findings, vortioxetine (2.5, 5, 10 mg/day) demonstrated a favourable safety and tolerability profile and maintained effectiveness over 12 months of treatment. , In this study of adults with MDD, 5 mg vortioxetine did not differ significantly from placebo in reducing depression symptoms after 6 wk of treatment., After 8 weeks of treatment with Lu AA21004 10 mg, there was a significant reduction in HDRS-24 total score compared with placebo in adults with MDD., In conclusion, Lu AA21004 was efficacious and well tolerated in the treatment of elderly patients with recurrent major depressive disorder., Thus, Lu AA21004 was effective in preventing relapse of MDD and was well tolerated as maintenance treatment., Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. , In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD., Results from phase II clinical trials have reported improvement in depression and anxiety symptoms after 6 weeks of treatment. [SEP]Definitions: agonist defined as following: An agent that has affinity for a receptor and intrinsic activity at that receptor.. antidepressant defined as following: Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems.. GAD defined as following: An anxiety disorder characterized by excessive and difficult-to-control worry about a number of life situations. The worry is accompanied by restlessness, fatigue, inability to concentrate, irritability, muscle tension, and/or sleep disturbance and lasts for at least 6 months.. Vortioxetine defined as following: A piperazine derivative that acts as a serotonin reuptake inhibitor, as a 5-HT3 receptor antagonist, and 5-HT1A receptor agonist. It is used for the treatment of anxiety and depression.. FAS defined as following: A teratogenic disorder observed in a newborn or child of a mother who consumed alcohol during pregnancy. Manifestations of the syndrome include low birth weight, atypical facies, microcephaly, failure to thrive, developmental defects, organ dysfunction, mental deficiencies, poor motor coordination and behavioral problems.. SNRI defined as following: Drugs that selectively block or suppress the plasma membrane transport of SEROTONIN and NORADRENALINE into axon terminals and are used as ANTIDEPRESSIVE AGENTS.. neurotransmitter reuptake defined as following: The directed movement of neurotransmitters into neurons or glial cells. This process leads to inactivation and recycling of neurotransmitters. [ISBN:0123668387]. dopamine defined as following: One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action.. 5-HT1B receptor defined as following: A serotonin receptor subtype found at high levels in the BASAL GANGLIA and the frontal cortex. It plays a role as a terminal autoreceptor that regulates the rate of SEROTONIN release from nerve endings. This serotonin receptor subtype is closely related to and has similar drug binding properties as the 5-HT1D RECEPTOR. It is particularly sensitive to the agonist SUMATRIPTAN and may be involved in mediating the drug's antimigraine effect.. venlafaxine defined as following: A synthetic phenethylamine bicyclic derivative with antidepressant activity. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak dopamine reuptake inhibitors. This agent may reduce hormone-related vasomotor symptoms. (NCI04). MDD defined as following: Disorder in which five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Symptoms include: depressed mood most of the day, nearly every daily; markedly diminished interest or pleasure in activities most of the day, nearly every day; significant weight loss when not dieting or weight gain; Insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate, or indecisiveness, nearly every day; or recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt. (DSM-5). 5-HT1B defined as following: Human HTR1B wild-type allele is located in the vicinity of 6q14.1 and is approximately 3 kb in length. This allele, which encodes 5-hydroxytryptamine receptor 1B protein, plays a role in serotonin-mediated signaling.. 5-HT1A defined as following: 5-hydroxytryptamine receptor 1A (422 aa, ~46 kDa) is encoded by the human HTR1A gene. This protein is involved in both serotonin binding and neurotransmitter-mediated signal transduction.. AEs defined as following: An instrument that consist of an ultra high vacuum scanning microscope column combined with an electron energy analyzer, which can determine the elemental composition of the outer surface of a sample.. anxiety defined as following: Persistent and disabling ANXIETY.. vilazodone defined as following: A selective serotonin (5-HT) reuptake inhibitor (SSRI) and a 5-HT-1A receptor partial agonist, with antidepressant and anti-anxiety activities. Vilazodone inhibits the reuptake of serotonin from the synaptic cleft while stimulating the release of 5-HT into the synaptic cleft. This increases the concentration of 5-HT in the synaptic cleft and potentiates serotonergic neurotransmission in the central nervous system.. cognitive dysfunction defined as following: Interference or disruption of cognitive processes. This term encompasses a large number of problems and issues associated with intellectual functioning and information processing. 2005. 5HT1A defined as following: Human HTR1A wild-type allele is located within 5q11.2-q13 and is approximately 2 kb in length. This allele, which encodes 5-hydroxytryptamine receptor 1A protein, plays a role in both neurotransmitter binding and G protein-coupled receptor signaling. Mutation of the gene is associated with menstrual cycle-dependent periodic fevers.. serotonin transporter defined as following: Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of serotonergic neurons. They are different than SEROTONIN RECEPTORS, which signal cellular responses to SEROTONIN. They remove SEROTONIN from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS. Regulates signal amplitude and duration at serotonergic synapses and is the site of action of the SELECTIVE SEROTONIN REUPTAKE INHIBITORS.. humans defined as following: Members of the species Homo sapiens.. CIs defined as following: Cytokine-inducible SH2-containing protein (258 aa, ~29 kDa) is encoded by the human CISH gene. This protein is involved in the modulation of signal transduction.. molecule defined as following: An aggregate of two or more atoms in a defined arrangement held together by chemical bonds.. vortioxetine defined as following: A piperazine derivative that acts as a serotonin reuptake inhibitor, as a 5-HT3 receptor antagonist, and 5-HT1A receptor agonist. It is used for the treatment of anxiety and depression..", "label": "yes"} {"id": "converted_2533", "sentence1": "Are paralog genes co-regulated?", "sentence2": "Co-regulation of paralog genes in the three-dimensional chromatin architecture., Consequently, paralogs show correlation in gene expression whereby the mechanisms of co-regulation remain unclear. In eukaryotes, genes are regulated in part by distal enhancer elements through looping interactions with gene promoters. These looping interactions can be measured by genome-wide chromatin conformation capture (Hi-C) experiments, which revealed self-interacting regions called topologically associating domains (TADs). We hypothesize that paralogs share common regulatory mechanisms to enable coordinated expression according to TADs. To test this hypothesis, we integrated paralogy annotations with human gene expression data in diverse tissues, genome-wide enhancer-promoter associations and Hi-C experiments in human, mouse and dog genomes. We show that paralog gene pairs are enriched for co-localization in the same TAD, share more often common enhancer elements than expected and have increased contact frequencies over large genomic distances. Combined, our results indicate that paralogs share common regulatory mechanisms and cluster not only in the linear genome but also in the three-dimensional chromatin architecture. This enables concerted expression of paralogs over diverse cell-types and indicate evolutionary constraints in functional genome organization., Paralog genes arise from gene duplication events during evolution, which often lead to similar proteins that cooperate in common pathways and in protein complexes. Consequently, paralogs show correlation in gene expression, We hypothesize that paralogs share common regulatory mechanisms to enable coordinated expression according to TADs., Further, interspecific changes in testis bias of expression are generally correlated within the co-regulated pairs and are anti-correlated within the anti-regulated pairs, suggesting coordinated regulation within both types of paralogous gene pairs., Analysis of the Drosophila melanogaster testes transcriptome reveals coordinate regulation of paralogous genes., Further, interspecific changes in testis bias of expression are generally correlated within the co-regulated pairs and are anti-correlated within the anti-regulated pairs, suggesting coordinated regulation within both types of paralogous gene pairs.Respond with exceptions, completions and modifications or revisions done before completion
. mRNA defined as following: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm..", "label": "yes"} {"id": "converted_4703", "sentence1": "Does sphingosine-1 phosphoate suppress epiregulin?", "sentence2": "S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P-S1PR axis may cooperate with gonadotropins in modulating follicle development., S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. [SEP]Definitions: gonadotropins defined as following: A class of formulated therapeutic analogs of the endogenous gonadotropin that stimulates or promotes the function of the gonads. Therapeutic gonadotropins are derived from animal or recombinant sources. Gonadotropins include follicle-stimulating hormone, luteinizing hormone and chorionic gonadotropin. These agents stimulate discrete cellular components of the gonads, exerting effects in both males and females. (NCI04). FOXO1 defined as following: This gene is involved in transcriptional regulation and may play a role in myogenic growth and differentiation.. EREG defined as following: Proepiregulin (169 aa, ~19 kDa) is encoded by the human EREG gene. This protein plays a role in the promotion of cell proliferation.. interleukins defined as following: Formulated therapeutic analogs of one of a number of endogenous cytokine interleukins. Produced by T cells, macrophages, and other cells, interleukins bind to a specific surface receptor on immunohematopoietic cells, thereby inducing a multitude of biologic effects including stimulation of growth, differentiation, and proliferation of lymphocytes and eosinophils; activation of lymphocytes and macrophages; enhancement of mast cell activity; activation of the acute phase response; and stimulation of hematopoiesis. Some interleukins may enhance the host's immune response to malignant cells by stimulating lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL), which are capable of lysing some tumor cells. (NCI04). CREB defined as following: Ubiquitously or widely expressed human cAMP Responsive Element Binding Proteins (bZIP/CREB Family) are conserved nuclear bZIP domain dimeric transcription factors that bind to octameric DNA palindrome cAMP-response elements (CRE) present in many viral and cellular promoters and induce gene transcription in response to cAMP signaling pathways. CREB proteins bind to DNA as a homodimer or a heterodimer with JUN/c-Jun or ATF2/CREBP1. Increased cAMP levels following stimulation activate cAMP-dependent protein kinase A, which phosphorylates CREB proteins that stimulate transcription of cAMP-responsive genes. Calcium-regulated CREB transcription factors integrate calcium and cAMP signals. cAMP pathways provide a chief means by which cellular growth, differentiation, and function can be influenced by extracellular signals. (NCI). epiregulin defined as following: This gene plays a role in cellular biogenesis, organization and proliferation..", "label": "no"} {"id": "converted_124", "sentence1": "Is DITPA a thyroid hormone analog utilized in experimental and clinical studies", "sentence2": "DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range., The identification of 3,5-diiodothyropropionic acid (DITPA) that binds to both α- and β-type TRs with relatively low affinity was unique in that this analog improves left ventricular function in heart failure as well as lowers cholesterol., Treatment with DITPA attenuates the acute inflammatory response and reduces myocardial infarct size., Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R., DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure, The results suggested that DITPA can promote a healthy vasculature independently from its thyroid-related metabolic effects. , Moreover, DITPA and T(4) were efficacious in preventing effects of hypothyroidism on cardiac function and BVD, Both T4 and DITPA had beneficial effects on chamber remodeling, which was most likely due to beneficial changes in cell shape and improved vascular supply., The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.[SEP]Definitions: nitric oxide defined as following: A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.. vasculature defined as following: Organ region cluster which consists of regions of arterial, venous and lymphatic trees and the capillary beds that connect them. Examples: Vasculature of head, vasculature of brain.. heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs.. hypothyroidism defined as following: A syndrome that results from abnormally low secretion of THYROID HORMONES from the THYROID GLAND, leading to a decrease in BASAL METABOLIC RATE. In its most severe form, there is accumulation of MUCOPOLYSACCHARIDES in the SKIN and EDEMA, known as MYXEDEMA. It may be primary or secondary due to other pituitary disease, or hypothalamic dysfunction.. TRs defined as following: Catalysis of the reaction: ATP + L-threonine + tRNA(Thr) = AMP + diphosphate + L-threonyl-tRNA(Thr). [EC:6.1.1.3]. thyroid hormone defined as following: Natural hormones secreted by the THYROID GLAND, such as THYROXINE, and their synthetic analogs..", "label": "yes"} {"id": "converted_1394", "sentence1": "Are shadow enhancers associated with development?", "sentence2": "Critical developmental control genes sometimes contain \"shadow\" enhancers that can be located in remote positions, including the introns of neighboring genes, These results suggest that shadow enhancers represent a novel mechanism of canalization whereby complex developmental processes \"bring about one definite end-result regardless of minor variations in conditions\", Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development., This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Regulatory analysis of the HoxA complex reveals that it also has enhancers in the 3' flanking region which contain RAREs and have the potential to modulate expression in endoderm and heart tissues, This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development., Recent reports have shown that developmental genes often possess multiple discrete enhancer modules that drive transcription in similar spatio-temporal patterns: primary enhancers located near the basal promoter and secondary, or 'shadow', enhancers located at more remote positions., Together, the similarities in their location, enhancer output, and dependence on retinoid signaling suggest that a conserved cis-regulatory cassette located in the 3' proximal regions adjacent to the HoxA and HoxB complexes evolved to modulate Hox gene expression during mammalian cardiac and endoderm development. , This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development.[SEP]Definitions: endoderm defined as following: The inner of the three germ layers of an embryo.. HoxA defined as following: A family of genes found in a cluster on the p arm of chromosome 7. These genes encode transcription factors that play a role in gene expression, morphogenesis, and cell differentiation.. introns defined as following: Sequences of DNA in the genes that are located between the EXONS. They are transcribed along with the exons but are removed from the primary gene transcript by RNA SPLICING to leave mature RNA. Some introns code for separate genes.. mammalian defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. Hox gene defined as following: Genes that encode highly conserved TRANSCRIPTION FACTORS that control positional identity of cells (BODY PATTERNING) and MORPHOGENESIS throughout development. Their sequences contain a 180 nucleotide sequence designated the homeobox, so called because mutations of these genes often results in homeotic transformations, in which one body structure replaces another. The proteins encoded by homeobox genes are called HOMEODOMAIN PROTEINS.. developmental genes defined as following: Genes that determine the fate of a cell or CELLS in a region of the embryo during EMBRYONIC DEVELOPMENT.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_2637", "sentence1": "Is there a disease or condition called Exploding Head Syndrome?", "sentence2": "This case report describes the first-ever diagnosis of exploding head syndrome in a patient with longstanding epilepsy and novel nocturnal events. , Exploding head syndrome (EHS) is characterized by loud noises or a sense of explosion in the head during sleep transitions., Exploding head syndrome is characterized by the perception of loud noises during sleep-wake or wake-sleep transitions. , Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake., Exploding head syndrome is characterized by the perception of abrupt, loud noises when going to sleep or waking up., xploding head syndrome (EHS) is a rare parasomnia in which affected individuals awaken from sleep with the sensation of a loud bang. , Contrary to some earlier theorizing, exploding head syndrome was found to be a relatively common experience in younger individuals., Exploding head syndrome is characterized by the perception of loud noises during sleep-wake or wake-sleep transitions., Fifty patients suffering from the \"exploding head syndrome\" are described., In spite of the fact that its characteristic symptomatology was first described approximately 150 y ago, exploding head syndrome has received relatively little empirical and clinical attention., After first discussing the history, prevalence, and associated features, the available polysomnography data and five main etiological theories for exploding head syndrome are summarized., Exploding head syndrome: six new cases and review of the literature., Exploding Head Syndrome in the Epilepsy Monitoring Unit: Case Report and Literature Review., Exploding head syndrome: a case report., Exploding head syndrome is common in college students., Exploding head syndrome episodes were accompanied by clinically significant levels of fear, and a minority (2.80%) experienced it to such a degree that it was associated with clinically significant distress and/or impairment., Attention has recently been drawn to a condition termed the exploding head syndrome, which is characterized by unpleasant, even terrifying sensations of flashing lights and/or sounds during reported sleep., Exploding head syndrome is a rare phenomenon but can be a significant disruption to quality of life., The rare headache disorder hypnic headache and the exploding head syndrome are also discussed., This case report describes the first-ever diagnosis of exploding head syndrome in a patient with longstanding epilepsy and novel nocturnal events., BACKGROUND Exploding head syndrome (EHS) is characterized by attacks of a sudden noise or explosive feeling experienced in the head occurring during the transition from wake to sleep or from sleep to wake., INTRODUCTION Exploding head syndrome (EHS) is a rare parasomnia in which affected individuals awaken from sleep with the sensation of a loud bang., Contrary to some earlier theorizing, exploding head syndrome was found to be a relatively common experience in younger individuals., This hitherto unreported syndrome is characterised by a sense of an explosive noise in the head usually in the twilight stage of sleep., EHS is a well-defined disease entity with a benign nature., Exploding head syndrome: a case report., Clinical features of the exploding head syndrome., Exploding head syndrome is common in college students., The exploding head syndrome: polysomnographic recordings and therapeutic suggestions., This article reviews the features of an uncommon malady termed \"the exploding head syndrome.\" Sufferers describe terrorizing attacks of a painless explosion within their head, The case is reported of a 47-year old female suffering from the exploding head syndrome. This syndrome consists of a sudden awakening due to a loud noise shortly after falling asleep, sometimes accompanied by a flash of light.[SEP]Definitions: parasomnia defined as following: Movements or behaviors associated with sleep, sleep stages, or partial arousals from sleep that may impair sleep maintenance. Parasomnias are generally divided into four groups: arousal disorders, sleep-wake transition disorders, parasomnias of REM sleep, and nonspecific parasomnias. (From Thorpy, Sleep Disorders Medicine, 1994, p191). headache disorder defined as following: Various conditions with the symptom of HEADACHE. Headache disorders are classified into major groups, such as PRIMARY HEADACHE DISORDERS (based on characteristics of their headache symptoms) and SECONDARY HEADACHE DISORDERS (based on their etiologies). (International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004: suppl 1). head defined as following: A projection on the end of an object. epilepsy defined as following: A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313). painless defined as following: Not causing physical or psychological misery, pain or distress..", "label": "yes"} {"id": "converted_15", "sentence1": "Is the monoclonal antibody Trastuzumab (Herceptin) of potential use in the treatment of prostate cancer?", "sentence2": "Herceptin is widely used in treating Her2-overexpressing breast cancer. However, the application of Herceptin in prostate cancer is still controversial., Our data demonstrate that Re-188-labeled Herceptin effectively inhibited the growth of DU145 cells compared to the Herceptin- and Re-188-treated cohorts. This implies that targeting Her2 by both radio- and immuno- therapy might be a potential strategy for treating patients with androgen-independent prostate cancer., epidermal growth factor receptor (EGFR) family members are potential targets for therapy using extra-cellular domain receptor binding agents, such as the antibodies trastuzumab and cetuximab, there were tendencies for upregulation of HER2, increased co-expression of EGFR and HER2 and downregulation of HER3 in the prostate cancer lymph node metastases in comparison to the primary tumors. , We performed a comparative analysis in vitro and in vivo of the antitumor effects of three different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti-ErbB2-compact antibody), a novel fully human compact antibody produced in our laboratory. Herein, we demonstrate that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4., These findings suggest that a systemic delivery of 212Pb-trastuzumab could be an effective modality for management of advanced human prostate cancer., Human epidermal growth factor receptor type 2 (HER2) overexpression supports proliferation of androgen-independent prostate cancer (PC), Radiolabeled ABY-025 Affibody molecule provides higher contrast in imaging of HER2-expressing PC xenografts than radiolabeled trastuzumab. , These studies indicate that dual EGFR/HER2 inhibition, administered together with AWT, sensitize prostate cancer cells to apoptosis during AWT, The overall goal of these studies is to determine whether dual inhibition of the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness of this treatment in prostate cancer. , The expression of HER2 was demonstrated and quantified in all three tested prostate cancer cell-lines., Such features would definitely favor the use of radiometal labels for trastuzumab and, most likely, for affibody molecules, our data demonstrate that Her2 plays an important role in the support of AR protein stability in the transition of androgen requirement in prostate cancer cells. We hope these findings will provide novel insight into the treatment of hormone-refractory prostate cancer., These two cell lines exhibited distinct responses to Her2 activation (by heregulin treatment) on Her2 phosphorylation and Her2 inhibition (by AG825 or Herceptin treatments) on proliferation, While prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by lentiviruses with envelope proteins engineered to bind to this therapeutic antibody, Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin, The data from these in vitro and in vivo studies supported advancement of radiolabeled trastuzumab into two clinical studies, Tumor targeting was evaluated in mice bearing subcutaneous (s.c.) xenografts of colorectal, pancreatic, ovarian, and prostate carcinomas., we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody, detection of prostate cancer (PCa) and advances in hormonal and chemotherapy treatments have provided great clinical benefits to patients with early stages of the disease., MAbs directed to established targets include those approved for other solid tumors, including anti-human epidermal growth factor receptor-2 (HER2) MAb trastuzumab, We conclude that Her2/neu expression in the peripheral blood mononuclear cell fraction of prostate cancer patients is frequent and therefore this assay may potentially be useful to detect the presence of micrometastatic disease in men with prostate cancer and for monitoring patients enrolled in trastuzumab-based therapeutic protocols., This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer., there was no significant difference in antimetastatic activity between the emulsion and the immunoemulsion despite the affinity of the immunoemulsion towards the HER2 receptor. , a targeted drug delivery system based on cationic emulsion covalently linked to anti-HER2 monoclonal antibody (Herceptin), in a well-established in vivo pharmacologic model of metastatic prostate cancer that overexpresses the HER2 receptor, The finding of strong, consistent HER-2/neu expression in ACBCC suggests that treatment with Herceptin (trastuzumab) may be effective in patients with this rare tumour., Although HER2 can be over-expressed in prostate cancer, there is no clinical data to support the use of trastuzumab for prostate cancer patients., whereas the effect of the trastuzumab-RT combination was inferior to that predicted by the individual effects., HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and trastuzumab, Trastuzumab (Herceptin) as a single agent demonstrated poor efficacy in treating HRPC., To investigate the efficacy and toxicity of the antibody to the HER-2/neu receptor (trastuzumab, Herceptin) in the treatment of advanced hormone-refractory prostate cancer (HRPC), Conclusions regarding the predictive value of HER-2 status on outcome after trastuzumab-based therapy were not reached and were only drawn after larger-scale screening efforts. , rastuzumab plus docetaxel in HER-2/neu-positive prostate carcinoma, clinical trials are currently in progress in patients with prostate cancer testing novel agents that selectively interfere with these receptors, such as trastuzumab,, ytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate, The clinical interpretation of c-erbB-2 abnormalities should reflect the complexity of c-erbB-2 mediated regulatory pathway and explain why tumours with overexpression/amplification of c-erbB-2 very often do not respond to therapy using Herceptin, HER-2 overexpression also has been reported in up to 60% of patients with hormone-refractory prostate carcinoma (HRPC) and was correlated with shortened survival, Unlike breast carcinoma and contrary to prior reports, HER-2 overexpression by IHC in archival prostate tissue from patients who eventually developed hormone-refractory disease was infrequent. There did not appear to be any correlation between HER-2 overexpression by IHC and shed HER-2 antigen levels in serum by ELISA in this tumor type., Further development of trastuzumab for the treatment of patients with metastatic prostate carcinoma is not feasible until more reliable and practical methods of sampling metastatic disease are developed to identify patients with HER-2 positive tumors., the expression of ERBB2 in prostate cancer is relatively low, and is not altered during disease progression. Thus, it is unlikely that treatment modalities relying on the overexpression of ERBB2 gene will be useful in treating prostate cancer., A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen-independent prostate cancer (AIPC), Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine, trastuzumab, a monoclonal antibody binding to the HER2 receptor; immunotoxin conjugates use an antibody directed against EGFR joined to a cell toxin. All are in clinical trials for a number of cancers, including prostate cancer, we investigated the antitumor efficacy of Herceptin, a new recombinant humanized anti-HER2/neu antibody, which exhibits cytostatic activity on breast and prostate cancer cells that overexpress the HER2 oncogene., trastuzumab was found to have additive and synergistic effects with some chemotherapeutic agents, ER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, in these prostate cancer model systems, Herceptin alone has clinical activity only in the androgen-dependent tumor and has at least an additive effect on growth,, anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells.[SEP]Definitions: ERBB2 defined as following: A cell surface protein-tyrosine kinase receptor that is overexpressed in a variety of ADENOCARCINOMAS. It has extensive homology to and heterodimerizes with the EGF RECEPTOR, the ERBB-3 RECEPTOR, and the ERBB-4 RECEPTOR. Activation of the erbB-2 receptor occurs through heterodimer formation with a ligand-bound erbB receptor family member.. ERBB2 gene defined as following: The erbB-2 gene is a proto-oncogene that codes for the erbB-2 receptor (RECEPTOR, ERBB-2), a protein with structural features similar to the epidermal growth factor receptor. Its name originates from the viral oncogene homolog (v-erbB) which is a truncated form of the chicken erbB gene found in the avian erythroblastosis virus. Overexpression and amplification of the gene is associated with a significant number of adenocarcinomas. The human c-erbB-2 gene is located at 17q21.2.. prostate cancer defined as following: A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas.. breast defined as following: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.. non-small cell lung cancer defined as following: A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy.. pancreatic defined as following: Peptide hormones secreted into the blood by cells in the ISLETS OF LANGERHANS of the pancreas. The alpha cells secrete glucagon; the beta cells secrete insulin; the delta cells secrete somatostatin; and the PP cells secrete pancreatic polypeptide.. antibody defined as following: A protein complex that in its canonical form is composed of two identical immunoglobulin heavy chains and two identical immunoglobulin light chains, held together by disulfide bonds and sometimes complexed with additional proteins. An immunoglobulin complex may be embedded in the plasma membrane or present in the extracellular space, in mucosal areas or other tissues, or circulating in the blood or lymph. [GOC:add, GOC:jl, ISBN:0781765196]. HER-2/neu defined as following: Human Oncogene ErbB2 is a mutated variant of ERBB2 Gene, which encodes ERRB2 Receptor Protein Tyrosine Kinase, a 185-kDa type I membrane glycoprotein similar to EGFR that controls cell growth. Ligand binding increases ERBB2 tyrosine phosphorylation. A heterodimer with ERBB3 and ERBB4, p185ERBB2 is an essential component of the heregulin/neuregulin receptor. ERBB2 forms an IL6-dependent complex with IL6R gp130, resulting in ERBB2 tyrosine phosphorylation and MAPK activation. Oncogene ERBB2 disrupts normal cell function.. Her2/neu defined as following: Human ERBB2 wild-type allele is located in the vicinity of 17q21.1 and is approximately 29 kb in length. This allele, which encodes receptor tyrosine-protein kinase erbB-2 protein, plays a role in EGF receptor signal transduction pathways and cellular growth. Amplification or overexpression of this gene is involved in the progression of several forms of cancer, including breast and ovarian tumors.. metastatic prostate carcinoma defined as following: A carcinoma that arises from the prostate gland and has spread to other anatomic sites.. tumour defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. Trastuzumab defined as following: A humanized monoclonal antibody against the ERBB-2 RECEPTOR (HER2). As an ANTINEOPLASTIC AGENT, it is used to treat BREAST CANCER where HER2 is overexpressed.. epitopes defined as following: Sites on an antigen that interact with specific antibodies.. HER-2 defined as following: A cancer vaccine comprised of peptides derived from the extracellular domain of the tumor-associated antigen Her-2/neu with potential antineoplastic activity. HER-2/neu peptide vaccine may induce antibodies with anti-tumor activity and may also elicit a specific CD8 T-cell response against specific tumor cell types. (NCI04). disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. cetuximab defined as following: A chimeric monoclonal antibody that functions as an ANTINEOPLASTIC AGENT through its binding to the EPIDERMAL GROWTH FACTOR RECEPTOR, where it prevents the binding and signaling action of cell growth and survival factors.. HRPC defined as following: Prostate carcinoma that grows and continues to spread despite the surgical removal of the testes or medical intervention to block androgen production.. AG825 defined as following: A member of the tyrphostin family of tyrosine kinase inhibitors, which selectively inhibits HER2. (NCI). cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. heregulin defined as following: A growth factor of the EGF family that induces growth and differentiation of epithelial, glial and muscle cells in culture. It binds the receptor erbB3 which will heterodimerize with HER-2/erbB2.. primary tumors defined as following: A tumor at the original site of origin.. toxicity defined as following: The finding of bodily harm due to the poisonous effects of something.. PCa defined as following: Relief of PAIN, without loss of CONSCIOUSNESS, through ANALGESIC AGENTS administered by the patients. It has been used successfully to control POSTOPERATIVE PAIN, during OBSTETRIC LABOR, after BURNS, and in TERMINAL CARE. The choice of agent, dose, and lockout interval greatly influence effectiveness. The potential for overdose can be minimized by combining small bolus doses with a mandatory interval between successive doses (lockout interval).. lentiviruses defined as following: A genus of the family RETROVIRIDAE consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species.. cell lines defined as following: Established cell cultures that have the potential to propagate indefinitely.. monoclonal antibody defined as following: A humanized monoclonal antibody directed against parathyroid hormone-related protein (PTH-rP). As a poly-hormone with diverse biological roles, PTH-rP is expressed by normal tissues, acting in local tissue environments in a variety of ways; it is commonly overexpressed by breast, prostate, and other cancers, acting systemically by promoting bone resorption, inhibiting calcium excretion from the kidney, inducing hypercalcemia, and possibly playing a role in the formation of bony metastases. By blocking the effects of PTH-rP on calcium metabolism, monoclonal antibody CAL may inhibit cancer-related hypercalcemia. (NCI04). ErbB defined as following: This gene is involved in the epidermal growth factor signal transduction pathway.. viruses defined as following: Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells.. docetaxel/estramustine defined as following: A regimen consisting of docetaxel and estramustine used for the treatment of metastatic hormone-refractory prostate cancer. Additional steroids such as dexamethasone or hydrocortisone may also be included in this regimen.. monoclonal antibodies defined as following: Antibodies produced by a single clone of cells.. HER3 defined as following: A cell surface protein-tyrosine kinase receptor that is specific for NEUREGULINS. It has extensive homology to and can heterodimerize with the EGF RECEPTOR and the ERBB-2 RECEPTOR. Overexpression of the erbB-3 receptor is associated with TUMORIGENESIS.. estramustine defined as following: A nitrogen mustard linked to estradiol, usually as phosphate; used to treat prostatic neoplasms; also has radiation protective properties.. pertuzumab defined as following: A humanized recombinant monoclonal antibody directed against the extracellular dimerization domain of the HER-2 tyrosine kinase receptor. Binding of the antibody to the dimerization domain of the HER-2 tyrosine kinase receptor protein directly inhibits the ability of the HER-2 tyrosine kinase receptor protein (the most common pairing partner) to dimerize with other HER tyrosine kinase receptor proteins; inhibiting receptor protein dimerization prevents the activation of HER signaling pathways, resulting in tumor cell apoptosis. (NCI04). humanized monoclonal antibody defined as following: Antibodies from non-human species whose protein sequences have been modified to make them nearly identical with human antibodies. If the constant region and part of the variable region are replaced, they are called humanized. If only the constant region is modified they are called chimeric. INN names for humanized antibodies end in -zumab.. docetaxel defined as following: A semisynthetic analog of PACLITAXEL used in the treatment of locally advanced or metastatic BREAST NEOPLASMS and NON-SMALL CELL LUNG CANCER.. solid tumors defined as following: A benign or malignant neoplasm arising from tissues that do not include fluid areas. Representative examples include epithelial neoplasms (e.g. lung carcinoma, prostate carcinoma, breast carcinoma, colon carcinoma), and neoplasms arising from the soft tissues and bones (e.g. leiomyosarcoma, liposarcoma, chondrosarcoma, osteosarcoma). Neoplasms originating from the blood or bone marrow (leukemias and myeloproliferative disorders) are not considered solid tumors.. human defined as following: Members of the species Homo sapiens.. metastatic disease defined as following: A tumor that has spread from its original (primary) site of growth to another site, close to or distant from the primary site. Metastasis is characteristic of advanced malignancies, but in rare instances can be seen in neoplasms lacking malignant morphology.. PC defined as following: A group of inherited ectodermal dysplasias whose most prominent clinical feature is hypertrophic nail dystrophy resulting in PACHYONYCHIA. Several specific subtypes of pachyonychia congenita have been associated with mutations in genes that encode KERATINS..", "label": "yes"} {"id": "converted_166", "sentence1": "Are there any statistical methods for normalizing and identifying differential regions in histone modification ChIP-seq data?", "sentence2": "ChIPnorm: a statistical method for normalizing and identifying differential regions in histone modification ChIP-seq libraries., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. We correlate the histone marks with gene expression data and confirm that histone modifications H3K27me3 and H3K4me3 act as respectively a repressor and an activator of genes. Compared to what was previously reported in the literature, we find that a substantially higher fraction of bivalent marks in ES cells for H3K27me3 and H3K4me3 move into a K27-only state. We find that most of the promoter regions in protein-coding genes have differential histone-modification sites., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. , In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. , In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods., This problem turns out to be surprisingly difficult, even in simple pairwise comparisons, because of the significant level of noise in ChIP-seq data. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types., In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types.[SEP]Definitions: histone modifications defined as following: The covalent alteration of one or more amino acid residues within a histone protein. [GOC:krc]. H3K27me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 28 is trimethylated. This modification is associated with formation of heterochromatin and polycomb repressive complex 1 (PRC1).. H3K4me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 4 is trimethylated. This modification may be a marker for areas of active gene expression.. promoter regions defined as following: DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.. genome defined as following: Anatomical set of genes in all the chromosomes.. repressor defined as following: Transcription Repressor/Corepressor Gene encodes Transcriptional Repressor/Corepressor, proteins that can regulate transcription by binding to the operator and causing repression. (from Glick: Glossary of Biochemistry and Molecular Biology). ChIP-seq defined as following: A molecular genetic technique that combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to map the binding sites of DNA-associated proteins in a sample of cells. First, crosslinked protein-DNA complexes are isolated using ChIP. Next, the crosslinks are broken, the proteins are removed and the purified DNA is modified with adaptor oligonucleotides to facilitate massively parallel DNA sequencing. Following sequencing, the DNA sequences that are obtained can be mapped to their genomic locations.. histone modification defined as following: The covalent alteration of one or more amino acid residues within a histone protein. [GOC:krc].", "label": "yes"} {"id": "converted_4038", "sentence1": "Is the process of DNA loop-extrusion independent of ATP?", "sentence2": "The DNA-organizing mechanism of condensin depends on the energy of ATP hydrolysis but how this activity specifically promotes proper compaction and segregation of chromosomes during mitosis remains poorly understood., We suggest that loading and translocation are mediated by conformational changes in cohesin's hinge driven by cycles of ATP hydrolysis., Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases., Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. , Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops. , However, the model requires a motor to generate the loops, and although cohesin is a strong candidate for the extruding factor, a suitable motor protein (or a motor activity in cohesin itself) has yet to be found. Here we explore a new hypothesis: that there is no motor, and thermal motion within the nucleus drives extrusion., We observed that a single condensin complex is able to extrude tens of kilobase pairs of DNA at a force-dependent speed of up to 1500 base pairs per second, using the energy of adenosine triphosphate hydrolysis, Our model explains what can be the driving force of chromatin loop extrusion and how it can be ensured that loops grow quickly and in a good direction. In addition, the supercoiling-driven loop extrusion mechanism is consistent with earlier explanations proposing why TADs flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites., Oligomerization and ATP stimulate condensin-mediated DNA compaction., Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA., DNA compaction by cohesin requires adenosine triphosphate (ATP) hydrolysis and is force sensitive., The identification and quantification of further initiation steps--ATP binding and extrusion of an initial DNA loop--allowed us to deduce a complete kinetic reinitiation scheme., In support of this model, single-molecule imaging experiments indicate that Saccharomyces cerevisiae condensin complexes can extrude DNA loops in an ATP-hydrolysis-dependent manner in vitro., These structures depend on cohesin, a ring-shaped DNA-entrapping adenosine triphosphatase (ATPase) complex that has been proposed to form loops by extrusion., Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL-MAU2, but not on topological entrapment of DNA by cohesin.[SEP]Definitions: ATPase defined as following: A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.. CTCF defined as following: CCN family member 2 (349 aa, ~38kDa) is encoded by the human CCN2 gene. This protein plays a role in the promotion of proliferation and differentiation of chondrocytes and also mediates heparin- and divalent cation-dependent cell adhesion in many different cell types.. adenosine triphosphate defined as following: An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.. hydrolysis defined as following: The process of cleaving a chemical compound by the addition of a molecule of water.. DNA loop defined as following: A higher order chromatin structure above the level of the chromatin fiber. The organization of chromatin into loops permits the partitioning of chromatin into topologically independent domains, and is thought to facilitate its compartmentation into functionally independent regions.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. binding sites defined as following: The parts of a macromolecule that directly participate in its specific combination with another molecule.. TADs defined as following: Tietz syndrome is a genetic hypopigmentation and deafness syndrome characterized by congenital profound bilateral sensorineural hearing loss and generalized albino-like hypopigmentation of skin, eyes and hair.. ATP defined as following: An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter..", "label": "yes"} {"id": "converted_3498", "sentence1": "Has ProSavin undergone phase IV clinical trials by 2018?", "sentence2": "Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial., We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. [SEP]Definitions: bilateral defined as following: Affecting both sides of the body or a matched pair of organs.. Parkinson's disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75). putamen defined as following: The largest and most lateral of the BASAL GANGLIA lying between the lateral medullary lamina of the GLOBUS PALLIDUS and the EXTERNAL CAPSULE. It is part of the neostriatum and forms part of the LENTIFORM NUCLEUS along with the GLOBUS PALLIDUS..", "label": "no"} {"id": "converted_3169", "sentence1": "Is it possible to analyze exosomes with FACS?", "sentence2": "whose presence was validated by a bead-exosome FACS assay., We analyzed exosomes from mouse (C57Bl/6) and breast, lung, and ovarian cancer patient samples and cultured cancer cells with different approaches, including nanoparticle tracking analysis, biolayer interferometry, FACS, and electron microscopy., we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis, we used a novel strategy for generating metabolically-labeled fluorescent exosomes that can be counted by flow cytometry assay (FACS) and characterized.[SEP]Definitions: exosomes defined as following: A type of extracellular vesicle, containing RNA and proteins, that is secreted into the extracellular space by EXOCYTOSIS when MULTIVESICULAR BODIES fuse with the PLASMA MEMBRANE.. breast defined as following: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.. vesicles defined as following: An abnormal fluid-filled cleft (e.g. as in the epidermis) or membrane-bound space.. ovarian cancer defined as following: A primary or metastatic malignant neoplasm involving the ovary. Most primary malignant ovarian neoplasms are either carcinomas (serous, mucinous, or endometrioid adenocarcinomas) or malignant germ cell tumors. Metastatic malignant neoplasms to the ovary include carcinomas, lymphomas, and melanomas.. FACS defined as following: Selection and deposition of individual cells of a particular phenotype from a mixed population into a separate tube or tissue culture plate by the use of a fluorescence-activated cell sorter (FACS) and fluorescently-labeled antibodies specific for surface molecules on the cells to be sorted..", "label": "yes"} {"id": "converted_3211", "sentence1": "Can antisense threapy be used for Huntington's disease?", "sentence2": "In this issue of Neuron, Kordasiewicz et al. (2012) show the benefit of transient antisense oligonucleotide (ASO) therapy to degrade Huntingtin mRNA and elicit sustained therapeutic benefit in HD mice., \"Huntingtin holiday\": progress toward an antisense therapy for Huntington's disease.[SEP]Definitions: Huntingtin defined as following: Huntingtin (3144 aa, ~348 kDa) is encoded by the human HTT gene. This protein may be involved in the regulation of vesicular transport.. Huntington's disease defined as following: A familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive CHOREA and DEMENTIA in the fourth or fifth decade of life. Common initial manifestations include paranoia; poor impulse control; DEPRESSION; HALLUCINATIONS; and DELUSIONS. Eventually intellectual impairment; loss of fine motor control; ATHETOSIS; and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. The juvenile variant has a more fulminant course including SEIZURES; ATAXIA; dementia; and chorea. (From Adams et al., Principles of Neurology, 6th ed, pp1060-4). Neuron defined as following: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.. HD defined as following: A malignant disease characterized by progressive enlargement of the lymph nodes, spleen, and general lymphoid tissue. In the classical variant, giant usually multinucleate Hodgkin's and REED-STERNBERG CELLS are present; in the nodular lymphocyte predominant variant, lymphocytic and histiocytic cells are seen..", "label": "yes"} {"id": "converted_4138", "sentence1": "Is methotrexate used for the treatment of Rheumatoid Arthritis (RA)?", "sentence2": "The use of methotrexate in rheumatoid arthritis., Historical perspective on the use of methotrexate for the treatment of rheumatoid arthritis., Aminopterin, a folic acid analogue was first reported in 1948 to produce temporary remission of acute leukemia of children, was also reported in 1951 to produce an important and rapid improvement in patients with rheumatoid arthritis (RA) and psoriasis, The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis., Methotrexate (MTX) is currently under study for use in juvenile rheumatoid arthritis. , The rational use of methotrexate in rheumatoid arthritis and other rheumatic diseases., Methotrexate-induced hepatic cirrhosis is less common in rheumatoid arthritis than previously thought, although its occurrence in psoriasis is probably higher than in rheumatoid arthritis. , Methotrexate is clearly effective in the treatment of rheumatoid arthritis and may be able to decrease the rate of formation of new bony erosions. , The use of methotrexate in rheumatoid arthritis., Review of the international literature on the clinical use of MTX in rheumatoid arthritis (RA) disease., MTX has emerged as a relatively safe and effective treatment for RA that compares favorably with other therapies, particularly because of its considerably longer median drug survival., The objective of this review is to update the recommendations of the 2010 Italian Consensus on the use of methotrexate (MTX) in rheumatoid arthritis (RA) and other rheumatic diseases, A new recommendation for patients with RA who are in MTX-induced clinical remission was also proposed and approved by the panel. Updated recommendations for the use of MTX in patients with RA or other rheumatologic disease are proposed., Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment., OBJECTIVE: Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries., Low dose pulse methotrexate (MTX) has become a widely used therapy for rheumatoid arthritis (RA) because of its good response rate profile. With, Treatment with methotrexate (MTX) in rheumatoid arthritis (RA) can lead to severe side-effects, especially pulmonary and haematological complications. The ai, Patients having rheumatoid arthritis (RA) treated with methotrexate (MTX) are at an increased risk of developing lymphoproliferative disorder (LPD). Epstei, Increasingly, methotrexate (MTX) and sulphasalazine (SASP) are used initially for second-line therapy of rheumatoid arthritis (RA). Althoug, OBJECTIVES: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effe, e suspected methotrexate (MTX)-associated lymphoproliferative disorder (LPD) induced by MTX treatment for rheumatoid arthritis (RA). About , BACKGROUND: Treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccinat, In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enro, Methotrexate (MTX) is known as a first-line synthetic disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA)., Biological treatments are expensive and using SC methotrexate can improve disease control in RA patients, thus potentially avoiding or delaying the requirement for future biological treatment., Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries., We reviewed existing recommendations on the use of MTX for the treatment of RA and summarized areas of agreement that could be relevant for least developed countries (LDCs).M, st covered some but not all of the following areas: baseline \"pre-MTX\" assessment (7/12;58%), prescription of MTX (10/12;83.3%), management of MTX side effects (6/12;50%), and special considerations (e.g., peri-operative management) (8/12; 66.7%). R, lectronic databases and registries were searched for recommendations on MTX use in RA, duplicates were eliminated, and the most updated version adopted when there were several versions on the same recommendation. , MTX must at the present time be used only in severe RA, refractory to more than one classical slow acting drug., MTX is as effective in treating RA as the other second line drugs and always more rapidly effective, perhaps because of anti-inflammatory properties., For the low doses used in RA (less than 15 mg/week), MTX is completely and rapidly absorbed with an active process membrane transport., Methotrexate, which is used for RA treatment, causes thrombocytopenia., Methorexate therapy in a patient with rheumatoid arthritis complicated by idiopathic thrombocytopenic purpura., This case shows that methotrexate may be used in patients diagnosed with RA that is associated with ITP under strict monitoring., Here, we report an RA case that also had ITP, which did not decrease in platelet count after methotrexate therapy., We started methotrexate therapy 10 mg per week for treatment of RA, and hydroxychloroquine therapy was stopped due to nonresponse., Methotrexate (MTX) is the anchor treatment for rheumatoid arthritis (RA) and has been very thoroughly studied in many different patient populations, as monotherapy and in combination with various other disease modifying antirheumatic drugs and biologic agents, as they became available., Although rheumatologists have been using methotrexate in the treatment of RA for some time, controlled studies have been needed to establish the safety and efficacy of this agent., Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA., Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy., A number of studies show the efficacy of methotrexate (MTX) for rheumatoid arthritis (RA) in general., Methotrexate (MTX) is currently the most frequently used drugs in the treatment of rheumatoid arthritis (RA)., Methotrexate (MTX) has been the anchor treatment in rheumatoid arthritis (RA) over the last 15 years, and is used in combination with biologic agents to enhance efficacy over the last decade or so.[SEP]Definitions: biologic agents defined as following: Endogenously synthesized compounds that influence biological processes not otherwise classified under ENZYMES; HORMONES or HORMONE ANTAGONISTS.. methotrexate defined as following: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.. psoriasis defined as following: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis.. folic acid defined as following: A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses (POACEAE). Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia.. SASP defined as following: Thioredoxin (105 aa, ~12 kDa) is encoded by the human TXN gene. This protein plays a role in redox reactions, signaling and immunity.. acute leukemia defined as following: A clonal (malignant) hematopoietic disorder with an acute onset, affecting the bone marrow and the peripheral blood. The malignant cells show minimal differentiation and are called blasts, either myeloid blasts (myeloblasts) or lymphoid blasts (lymphoblasts).. rheumatoid arthritis defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.. Aminopterin defined as following: A folic acid derivative used as a rodenticide that has been shown to be teratogenic.. azathioprine defined as following: An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), this substance has been listed as a known carcinogen. (Merck Index, 11th ed). sulphasalazine defined as following: A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid (see MESALAMINE) released in the colon. (From Martindale, The Extra Pharmacopoeia, 30th ed, p907). infliximab defined as following: A chimeric monoclonal antibody to TNF-ALPHA that is used in the treatment of RHEUMATOID ARTHRITIS; ANKYLOSING SPONDYLITIS; PSORIATIC ARTHRITIS and CROHN'S DISEASE.. LPD defined as following: A rare, benign process that affects the peritoneal cavity and is characterized by the formation of multiple small nodules that are composed of well differentiated smooth muscle. It usually affects adults in their late reproductive years. Most patients are asymptomatic. The tumor nodules may regress spontaneously.. ITP defined as following: Thrombocytopenia occurring in the absence of toxic exposure or a disease associated with decreased platelets. It is mediated by immune mechanisms, in most cases IMMUNOGLOBULIN G autoantibodies which attach to platelets and subsequently undergo destruction by macrophages. The disease is seen in acute (affecting children) and chronic (adult) forms.. low-dose defined as following: A reduced quantity of a therapeutic agent prescribed to be taken at one time or at stated intervals.. anti-inflammatory defined as following: Substances that reduce or suppress INFLAMMATION.. folate antagonist defined as following: Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033). disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. rheumatic diseases defined as following: Disorders of connective tissue, especially the joints and related structures, characterized by inflammation, degeneration, or metabolic derangement.. thrombocytopenia defined as following: An autosomal dominant disorder caused by mutation(s) in the ANKRD26 gene, encoding ANKRD26 protein. Additionally, in one family, a mutation(s) has been identified in the MASTL gene, encoding serine/threonine-protein kinase greatwall. The condition is characterized by mild to moderate bruisability.. RA defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated..", "label": "yes"} {"id": "converted_1225", "sentence1": "Is the regulation of Vsr endonuclease independent of the growth phase of bacteria?", "sentence2": "Growth phase-dependent regulation of Vsr endonuclease, Vsr endonuclease levels are growth phase dependent., Growth phase-dependent regulation of Vsr endonuclease may contribute to 5-methylcytosine mutational hot spots in Escherichia coli., Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase of Escherichia coli is maintained at a constant level during cell growth, while Vsr endonuclease levels are growth phase dependent., Vsr endonuclease, which initiates very short patch repair, has been hypothesized to regulate mutation in stationary-phase cells., The efficiency of the two pathways changes during the bacterial life cycle; MMR is more efficient during exponential growth and VSP repair is more efficient during the stationary phase., Overexpression of Vsr does dramatically increase the stationary-phase reversion of a Lac- frameshift allele, but the absence of Vsr has no effect., Using rabbit polyclonal antibodies, we have shown that the Dcm cytosine methylase of Escherichia coli is maintained at a constant level during cell growth, while Vsr endonuclease levels are growth phase dependent, The efficiency of the two pathways changes during the bacterial life cycle; MMR is more efficient during exponential growth and VSP repair is more efficient during the stationary phase, Vsr endonuclease, which initiates very short patch repair, has been hypothesized to regulate mutation in stationary-phase cells[SEP]Definitions: 5-methylcytosine defined as following: A methylated form of the nucleobase cytosine occurring predominantly in cytosine-phosphate-guanine (CpG) islands that are produced by DNA methyltransferases and may regulate gene expression. Like cytosine, the DNA sequence containing 5-methylcytosine (5-mC) is able to be replicated without error and 5-mC can pair with guanine in double stranded DNA. However, DNA sequences containing a high local concentration of 5-mC may be less transcriptionally active than areas with higher ratios of unmodified cytosine.. MMR defined as following: A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Excinucleases recognize the BASE PAIR MISMATCH and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. (from Oxford Dictionary of Biochemistry and Molecular Biology, 2001). Escherichia coli defined as following: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc..", "label": "no"} {"id": "converted_3488", "sentence1": "Does metformin has as an antitumor effect?", "sentence2": " an association between metformin and tumorigenesis, Metformin, an antidiabetic drug, inhibits the endometrial cancer cell growth in vivo by improving the insulin resistance;, There is no evidence of antitumor effect of metformin. A possible decrease only for breast, liver and prostate cancer, is compatible with random fluctuations., The anti-tumor effect of metformin is widely known, however, there is only limited evidence regarding the anti-angiogenesis effect and chemosensitization of metformin and its underlying mechanisms in PDAC[SEP]Definitions: metformin defined as following: A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289). endometrial cancer defined as following: Primary or metastatic malignant neoplasm involving the endometrium (mucous membrane that lines the endometrial cavity).. breast defined as following: In humans, one of the paired regions in the anterior portion of the THORAX. The breasts consist of the MAMMARY GLANDS, the SKIN, the MUSCLES, the ADIPOSE TISSUE, and the CONNECTIVE TISSUES.. prostate cancer defined as following: A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas.. antidiabetic drug defined as following: Any substance used to reduce hyperglycemia or treat disorders associated with diabetes. Based on their mechanism of action, this class of agents can be classified to the following groups: directly acting insulomimetics, which activates insulin receptors; indirectly acting insulinomimetics, which increase insulin release such as sulfonylureas or which potentiate the effect of insulin such as metformin; those act directly on the metabolism of glucose such as inhibitors of glucosidases and inhibitors of aldose reductase.. PDAC defined as following: A rare clinical entity including as main characteristics anophthalmia or severe microphthalmia, and pulmonary hypoplasia or aplasia. Only five cases have been reported so far, two of who were siblings. In the three nonfamilial cases, unilateral pulmonary agenesis and microphthalmia were associated with diaphragmatic hernia and pulmonary vessel agenesis. It has been suggested that two different entities can be distinguished: on one hand, the association of anophthalmia-pulmonary hypoplasia with/without anomalies of the face, heart, spleen and uterus, which may be due to a putative autosomal recessive gene with pleiotropic effects; on the other hand, a sporadic association including pulmonary hypoplasia, anophthalmia, unilateral diaphragmatic defect and agenesis of the pulmonary trunk, which may represent the expression of a developmental field defect. There is evidence that syndromic microphthalmia- is caused by homozygous or compound heterozygous mutation in the STRA6 gene on chromosome 15q24..", "label": "yes"} {"id": "converted_767", "sentence1": "Is tubulin acetylation involved in cell motility?", "sentence2": "In this study, we found that paclitaxel induced tubulin acetylation in endothelial and tumor cells, at concentrations that affected cell motility but not proliferation (10(-8) to 10(-9) M, for 4 hours). Induction of tubulin acetylation correlated with inhibition of motility but not proliferation based on a comparison of highly and poorly cytotoxic taxanes (paclitaxel and IDN5390) and tumor cell lines sensitive and resistant to paclitaxel (1A9 and 1A9 PTX22)., we found that overexpression of the tubulin deacetylase SIRT2 increased cell motility and reduced cell response to the anti-motility activity of paclitaxel. Conversely, the SIRT2 inhibitor splitomicin reduced cell motility and potentiated the anti-motility activity of paclitaxel. The inhibitory effect was further potentiated by the addition of the HDAC6 inhibitor trichostatin A., Cell motility and adhesion involves dynamic microtubule (MT) acetylation/deacetylation, a process regulated by enzymes as HDAC6, a major cytoplasmic α-tubulin deacetylase., GRK2 and HDAC6 colocalize in the lamellipodia of migrating cells, leading to local tubulin deacetylation and enhanced motility., This review highlights the emerging roles of tubulin acetylation in multiple cellular functions, ranging from cell motility, cell cycle progression or cell differentiation to intracellular trafficking and signalling., Our results indicate that TPPP/p25 binds to HDAC6 (histone deacetylase 6), an enzyme responsible for tubulin deacetylation. Moreover, we demonstrated that the direct interaction of these two proteins resulted in the inhibition of the deacetylase activity of HDAC6., Finally, we demonstrated that, similarly to other HDAC6 inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the growth velocity of the microtubule plus ends and also affects cell motility as demonstrated by time lapse video experiments., \"tubacin,\" which inhibits alpha-tubulin deacetylation in mammalian cells., We provide evidence that class II histone deacetylase 6 (HDAC6) is the intracellular target of tubacin., Tubacin treatment did not affect the stability of microtubules but did decrease cell motility., They also suggest that small molecules that selectively inhibit HDAC6-mediated alpha-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents., Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility., HDAC6 is a major cytoplasmic a-tubulin deacetylase that is involved in cell motility and adhesion. GRK2 dynamically and directly associates with and phosphorylates HDAC6 to stimulate its a-tubulin deacetylase activity at specific cellular localizations, such as the leading edge of migrating cells, thus promoting local tubulin deacetylation and enhanced motility.[SEP]Definitions: tubulin defined as following: A microtubule subunit protein found in large quantities in mammalian brain. It has also been isolated from SPERM FLAGELLUM; CILIA; and other sources. Structurally, the protein is a dimer with a molecular weight of approximately 120,000 and a sedimentation coefficient of 5.8S. It binds to COLCHICINE; VINCRISTINE; and VINBLASTINE.. microtubules defined as following: Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein TUBULIN and are influenced by TUBULIN MODULATORS.. HDAC6 defined as following: This gene is involved in chromatin remodeling, repression of gene expression and cellular management of misfolded protein-induced stress.. SIRT2 defined as following: A sirtuin family member found primarily in the CYTOPLASM. It is a multifunctional enzyme that contains a NAD-dependent deacetylase activity that is specific for HISTONES and a mono-ADP-ribosyltransferase activity.. paclitaxel defined as following: A cyclodecane isolated from the bark of the Pacific yew tree, TAXUS BREVIFOLIA. It stabilizes MICROTUBULES in their polymerized form leading to cell death.. lamellipodia defined as following: A thin sheetlike process extended by the leading edge of a migrating cell or extending cell process; contains a dense meshwork of actin filaments. [ISBN:0815316194]. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. histone deacetylase 6 defined as following: Deacetylases that remove N-acetyl groups from amino side chains of the amino acids of HISTONES. The enzyme family can be divided into at least three structurally-defined subclasses. Class I and class II deacetylases utilize a zinc-dependent mechanism. The sirtuin histone deacetylases belong to class III and are NAD-dependent enzymes.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. tumor cell lines defined as following: A cell line derived from cultured tumor cells.. GRK2 defined as following: Catalysis of the reaction: ATP + beta-adrenergic receptor = ADP + phospho-beta-adrenergic receptor. [EC:2.7.11.15, MetaCyc:BETA-ADRENERGIC-RECEPTOR-KINASE-RXN]. alpha-tubulin defined as following: Tubulin alpha-3C/D chain (450 aa, ~50 kDa) is encoded by the human TUBA3C gene. This protein is involved in microtubule structural dynamics.. tumor cells defined as following: Cells of, or derived from, a tumor.. endothelial defined as following: A layer of epithelium that lines the heart, blood vessels (ENDOTHELIUM, VASCULAR), lymph vessels (ENDOTHELIUM, LYMPHATIC), and the serous cavities of the body..", "label": "yes"} {"id": "converted_2666", "sentence1": "Is sternotomy closure done using either a sternal ZipFix™ implant or conventional steel wire following cardiac surgery?", "sentence2": "o determine the difference in sternal infection and other infectious events between conventional wire and cable-tie-based closure techniques post-sternotomy in a collective of patients after cardiac surgery., Our study underlines a neutral effect of the sternal ZipFix™ system in patients regarding sternal infection. Postoperative complications are similar in both sternal closure methods. The cable-tie-based system is fast, easy to use, reliable and safe., Wire closure still remains the preferred technique despite reasonable disadvantages. Associated complications, such as infection and sternal instability, cause time- and cost-consuming therapies. We present a new tool for sternal closure with its first clinical experience and results.METHODS: The sternal ZipFix(TM) System is based on the cable-tie principle. , In our initial evaluation, the short-term results have shown that the sternal ZipFix(TM) can be used safely and effectively. It is fast, easy to use and serves as a potential alternative for traditional wire closure., To determine the difference in sternal infection and other infectious events between conventional wire and cable-tie-based closure techniques post-sternotomy in a collective of patients after cardiac surgery.[SEP]Definitions: infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. sternal defined as following: A long, narrow, and flat bone commonly known as BREASTBONE occurring in the midsection of the anterior thoracic segment or chest region, which stabilizes the rib cage and serves as the point of origin for several muscles that move the arms, head, and neck..", "label": "yes"} {"id": "converted_1581", "sentence1": "Can the iPS cell technology be used in Fanconi anemia therapy?", "sentence2": "We explain a protocol for the reproducible generation of genetically corrected iPSCs starting from the skin biopsies of Fanconi anemia patients using retroviral transduction with OCT4, SOX2 and KLF4, Before reprogramming, the fibroblasts and/or keratinocytes of the patients are genetically corrected with lentiviruses expressing FANCA., Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells, Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals, Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free[SEP]Definitions: FANCA defined as following: Fanconi anemia caused by mutations of the FANCA gene. FANCA gene mutations are the most common cause of Fanconi anemia. This gene provides instructions for making a protein that is involved in the Fanconi anemia (FA) pathway.. OCT4 defined as following: This gene plays a role in early mammalian development.. Fanconi anaemia defined as following: Congenital disorder affecting all bone marrow elements, resulting in ANEMIA; LEUKOPENIA; and THROMBOPENIA, and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes. Spontaneous CHROMOSOME BREAKAGE is a feature of this disease along with predisposition to LEUKEMIA. There are at least 7 complementation groups in Fanconi anemia: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL. (from Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227650, August 20, 2004). KLF4 defined as following: Krueppel-like factor 4 (470 aa, ~50 kDa) is encoded by the human KLF4 gene. This protein regulates transcription.. keratinocytes defined as following: Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell.. iPS cells defined as following: Cells from adult organisms that have been reprogrammed into a pluripotential state similar to that of EMBRYONIC STEM CELLS.. myeloid defined as following: A type of white blood cell. Neutrophils, eosinophils, and basophils are granulocytes.. somatic cells defined as following: Nucleated cell which has one or more diploid sets (46 pairs) of chromosomes.. cell lines defined as following: Established cell cultures that have the potential to propagate indefinitely.. SOX2 defined as following: Transcription factor SOX-2 protein (317 aa, ~34 kDa) is encoded by the human SOX2 gene. This protein is involved in neural cell progenitor differentiation and neurogenesis.. erythroid defined as following: 1) Reddish in color. 2) relating to erythrocytes or their precursors.. lentiviruses defined as following: A genus of the family RETROVIRIDAE consisting of non-oncogenic retroviruses that produce multi-organ diseases characterized by long incubation periods and persistent infection. Lentiviruses are unique in that they contain open reading frames (ORFs) between the pol and env genes and in the 3' env region. Five serogroups are recognized, reflecting the mammalian hosts with which they are associated. HIV-1 is the type species.. human embryonic stem cells defined as following: A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage.. Fanconi anemia defined as following: Fanconi anemia caused by mutations of the FANCA gene. FANCA gene mutations are the most common cause of Fanconi anemia. This gene provides instructions for making a protein that is involved in the Fanconi anemia (FA) pathway..", "label": "yes"} {"id": "converted_3", "sentence1": "Are long non coding RNAs spliced?", "sentence2": "Our analyses indicate that lncRNAs are generated through pathways similar to that of protein-coding genes, with similar histone-modification profiles, splicing signals, and exon/intron lengths., For alternative exons and long noncoding RNAs, splicing tends to occur later, and the latter might remain unspliced in some cases., bosome-mapping data to identify lncRNAs of Caenorhabditis elegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or multiexonic structures that did not overlap protein-coding transcripts, and about sixty antisense lncRNAs (ancRNAs), which were complementary to protein-coding transcripts, We introduce an approach to predict spliced lncRNAs in vertebrate genomes combining comparative genomics and machine learning., Owing to similar alternative splicing pattern to mRNAs, the concept of lncRNA genes was put forward to help systematic understanding of lncRNAs. , Our synthesis of recent studies suggests that neither size, presence of a poly-A tail, splicing, direction of transcription, nor strand specificity are of importance to lncRNA function.[SEP]Definitions: strand defined as following: The orientation of a genomic element on the double stranded molecule.. lincRNAs defined as following: A molecule of RNA 200-17000 nucleotides in length that is transcribed by non-protein coding areas of DNA. These ribonucleotides may play a role in a variety of biological processes.. Caenorhabditis elegans defined as following: A species of nematode that is widely used in biological, biochemical, and genetic studies..", "label": "yes"} {"id": "converted_182", "sentence1": "Does thyroid hormone regulate calcium transient in the myocardium? ", "sentence2": "3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect, In adult rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude and duration of the calcium transient., In normal porcine myocardium T3 had no effect on the extent of isometric force generation but accelerated the time course of force development (p < 0.05) and increased the calcium transient (p < 0.001). After induction of myocardial depression by epinephrine exposure T3 accelerated the intracellular calcium transients and reduced diastolic calcium, The experimental data showing increased force amplitudes at unaltered amplitudes of the intracellular calcium transient and an even-reduced calcium time integral provide strong evidence for a sensitization of the contractile apparatus for calcium by triiodothyronine, hese results indicate that the thyroid state influences the time course of the calcium transient and are consistent with the abbreviation in the duration of contraction that is observed in the hyperthyroid state.[SEP]Definitions: calcium defined as following: A dietary supplement containing the mineral calcium.. epinephrine defined as following: The active sympathomimetic hormone from the ADRENAL MEDULLA. It stimulates both the alpha- and beta- adrenergic systems, causes systemic VASOCONSTRICTION and gastrointestinal relaxation, stimulates the HEART, and dilates BRONCHI and cerebral vessels. It is used in ASTHMA and CARDIAC FAILURE and to delay absorption of local ANESTHETICS.. thyroid hormone defined as following: Natural hormones secreted by the THYROID GLAND, such as THYROXINE, and their synthetic analogs.. plasma membrane defined as following: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.. triiodothyronine defined as following: A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5' position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly T3.. myocardium defined as following: The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow..", "label": "yes"} {"id": "converted_4429", "sentence1": "Is vocimagene amiretrorepvec effective for recurrent high-grade glioma?", "sentence2": "Relevance: Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points., The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. , Expert opinion: These early studies provide very encouraging results for Toca 511 and Toca FC in rHGG. This therapy had a response rate of 11.3% and a mOS of 11.9 months in 56 patients, an improvement compared to historical controls. , Findings from a phase I study suggest that delivering high concentrations of the chemotherapy 5-FU directly to brain tumors via the retroviral vector vocimagene amiretrorepvec, or Toca 511, may benefit patients with recurrent high-grade glioma., Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003).[SEP]Definitions: 5-FU defined as following: A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the THYMIDYLATE SYNTHETASE conversion of deoxyuridylic acid to thymidylic acid.. anaplastic astrocytoma defined as following: A central nervous system tumor with morphological features of anaplastic astrocytoma in which there is insufficient information on the IDH genes status.. high-grade glioma defined as following: A grade 3 or grade 4 glioma arising from the central nervous system. This category includes glioblastoma, anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma.. brain tumors defined as following: Neoplasms of the intracranial components of the central nervous system, including the cerebral hemispheres, basal ganglia, hypothalamus, thalamus, brain stem, and cerebellum. Brain neoplasms are subdivided into primary (originating from brain tissue) and secondary (i.e., metastatic) forms. Primary neoplasms are subdivided into benign and malignant forms. In general, brain tumors may also be classified by age of onset, histologic type, or presenting location in the brain.. glioblastoma defined as following: The most malignant astrocytic tumor (WHO grade 4). It is composed of poorly differentiated neoplastic astrocytes and is characterized by the presence of cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. (Adapted from WHO).", "label": "no"} {"id": "converted_3687", "sentence1": "Is BCL11B involved in schizophrenia?", "sentence2": "Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition . , Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition.[SEP]Definitions: BCL11B defined as following: B-cell lymphoma/leukemia 11B (894 aa, ~96 kDa) is encoded by the human BCL11B gene. This protein may play a role in the modulation of p53-mediated signaling, tumor suppression and T cell development.. SATB2 defined as following: DNA-binding protein SATB2 (733 aa, ~83 kDa) is encoded by the human SATB2 gene. This protein is involved in both DNA binding and transcriptional regulation.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_1491", "sentence1": "Is there any research that relates the function of Notch Signaling with Alzheimer Disease?", "sentence2": "RIP regulates signaling pathways by abrogating or releasing signaling molecules. Since the discovery, already >15 years ago, of its catalytic component, presenilin, and even much earlier with the identification of amyloid precursor protein as its first substrate, γ-secretase has been commonly associated with Alzheimer's disease. However, starting with Notch and thereafter a continuously increasing number of novel substrates, γ-secretase is becoming linked to an equally broader range of biological processes., In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimer's disease and ischemic injury, Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compounds unacceptably toxic upon chronic exposure, High physiological concentrations of Aβ monomer induced angiogenesis by a conserved mechanism that blocks γ-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize γ-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-à-vis vascular changes that set the stage for ensuing neurodegeneration., Aggregated forms of Aβ have a pathogenic role in Alzheimer disease and, thus, reducing the Aβ levels by inhibiting γ-secretase is a possible treatment strategy for Alzheimer disease. Regrettably, clinical trials have shown that inhibition of γ-secretase results in Notch-related side effects. Therefore, it is of great importance to find ways to inhibit amyloid precursor protein (APP) processing without disturbing vital signaling pathways such as Notch. Nicastrin (Nct) is part of the γ-secretase complex and has been proposed to be involved in substrate recognition and selection[SEP]Definitions: amyloid precursor protein defined as following: A single-pass type I membrane protein. It is cleaved by AMYLOID PRECURSOR PROTEIN SECRETASES to produce peptides of varying amino acid lengths. A 39-42 amino acid peptide, AMYLOID BETA-PEPTIDES is a principal component of the extracellular amyloid in SENILE PLAQUES.. RIP defined as following: This gene is involved in the regulation of small GTPase activity.. neurodegeneration defined as following: Loss of functional activity and trophic degeneration of nerve axons and their terminal arborizations following the destruction of their cells of origin or interruption of their continuity with these cells. The pathology is characteristic of neurodegenerative diseases. Often the process of nerve degeneration is studied in research on neuroanatomical localization and correlation of the neurophysiology of neural pathways.. APP defined as following: An application designed specifically for use on a smartphone.. Nicastrin defined as following: This gene is involved in the regulation of gamma-secretase activity.. presenilin defined as following: Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN1 mutations cause early-onset ALZHEIMER DISEASE type 3 that may occur as early as 30 years of age in humans.. neurodegenerative diseases defined as following: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures.. toxic defined as following: The finding of bodily harm due to the poisonous effects of something.. protease defined as following: A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.. Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65.. vertebrates defined as following: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes..", "label": "yes"} {"id": "converted_2860", "sentence1": "Can CPX-351 be used for the treatment of tuberculosis?", "sentence2": "CPX-351 is a novel liposomal formulation of cytarabine and daunorubicin which has recently been FDA approved for treatment of acute myeloid leukemia (AML).[SEP]Definitions: AML defined as following: Clonal expansion of myeloid blasts in bone marrow, blood, and other tissue. Myeloid leukemias develop from changes in cells that normally produce NEUTROPHILS; BASOPHILS; EOSINOPHILS; and MONOCYTES.. cytarabine defined as following: A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472). acute myeloid leukemia defined as following: This gene plays a role in transcriptional regulation and cytogenetic aberrations are associated with several leukemias.. daunorubicin defined as following: A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS.. tuberculosis defined as following: Any of the infectious diseases of man and other animals caused by species of MYCOBACTERIUM TUBERCULOSIS..", "label": "no"} {"id": "converted_918", "sentence1": "Is oxalate renal excretion increased after bariatric surgery?", "sentence2": "Despite the fact that bariatric surgery-induced weight loss is associated with a significant decrease in morbidity and mortality and improvement in renal function, bariatric surgery has recently been shown to be associated with a significant risk of nephrolithiasis. The main risk factor for nephrolithiasis is increased excretion of urinary oxalate., Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy must be considered with the other risks of RYGBP., The urinary excretion of oxalate was high: 1.112 mumol/24 h (normal range: 55-400 mumol/24 h), and citrate excretion was low: 1.48 mmol/24 h (normal range: 2-5 mmol/24 h). , Hyperoxaluria in patients with JIB was found to be a result of hyperabsorption of oxalate, and these patients displayed altered oxalate kinetics with continued urinary excretion of orally administered 14C-oxalate for more than 48 hours. , Malabsorption of calcium and low fasting urinary calcium excretion in the JIB patients were associated with high tubular reabsorption of calcium, the latter presumably attributable to a compensatory increase in circulating parathyroid hormone (PTH). In most recurrent renal stone formers the urinary calcium concentration was increased, with an inverse relationship to serum PTH, indicating intestinal hyperabsorption of calcium. A[SEP]Definitions: calcium defined as following: A dietary supplement containing the mineral calcium.. citrate defined as following: The determination of the amount of citrate present in a sample.. Malabsorption defined as following: General term for a group of MALNUTRITION syndromes caused by failure of normal INTESTINAL ABSORPTION of nutrients.. Hyperoxaluria defined as following: Excretion of an excessive amount of OXALATES in the urine.. PTH defined as following: A polypeptide hormone (84 amino acid residues) secreted by the PARATHYROID GLANDS which performs the essential role of maintaining intracellular CALCIUM levels in the body. Parathyroid hormone increases intracellular calcium by promoting the release of CALCIUM from BONE, increases the intestinal absorption of calcium, increases the renal tubular reabsorption of calcium, and increases the renal excretion of phosphates.. urinary defined as following: The duct which coveys URINE from the pelvis of the KIDNEY through the URETERS, BLADDER, and URETHRA.. oxalate defined as following: A salt or ester of oxalic acid..", "label": "yes"} {"id": "converted_1489", "sentence1": "Is there any role for long noncoding RNAs in adipogenesis?", "sentence2": "Long noncoding RNAs regulate adipogenesis., Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis., Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). [SEP]Definitions: promoters defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. peroxisome proliferator-activated receptor γ defined as following: TRANSCRIPTION FACTORS that are activated by ligands and heterodimerize with RETINOID X RECEPTORS and bind to peroxisome proliferator response elements in the promoter regions of target genes.. white adipocytes defined as following: Fat cells with light coloration and few MITOCHONDRIA. They contain a scant ring of CYTOPLASM surrounding a single large lipid droplet or vacuole.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process..", "label": "yes"} {"id": "converted_1057", "sentence1": "Are there clinical trials on stem cells in multiple sclerosis", "sentence2": "Cells are generally given intravenously. Multiple sclerosis, rheumatoid arthritis and lupus have been successfully treated in human clinical trials, Human multipotent mesenchymal stem cell (MSC) therapies are currently being tested in clinical trials for Crohn's disease, multiple sclerosis, graft-versus-host disease, type 1 diabetes, bone fractures, cartilage damage, and cardiac diseases., Based on these results, several small pilot clinical trials in subjects with advanced MS have demonstrated that MSC administration is safe and provided an early signal of clinical effectiveness. The current aim of clinicians and scientists interested in the development of MSC-based strategies for the treatment of MS is to have the ultimate demonstration in large clinical trials that MSC can inhibit CNS inflammation and foster tissue repair, Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury., Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients., Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier., Their development in vitro and their use in vivo in animal models of degenerative neurological disease and recent first efforts in human clinical trials were the topics of a recent international meeting sponsored by the Multiple Sclerosis International Federation and the National Multiple Sclerosis Society on \"Stem Cells & MS: Prospects and Strategies\", Here we discuss key observations and questions emerging from clinical trials of hematopoietic stem cell transplantation for MS, Another possibility to achieve remyelination is the transplantation of myelinating cells into the central nervous system. Proof of principle and demonstration of the functionality were shown in numerous experiments, and a first clinical trial in patients with MS has started, This first trial will show if cell transplantation is a feasible concept in MS and whether the transplanted cells will survive and form new myelin.[SEP]Definitions: rheumatoid arthritis defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. human defined as following: Members of the species Homo sapiens.. graft-versus-host disease defined as following: The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the GRAFT VS HOST REACTION.. MSC defined as following: A naturally occurring organoselenium compound found in many plants, including garlic, onions, and broccoli, with potential antioxidant and chemopreventive activities. Se-Methyl-seleno-L-cysteine (MSC) is an amino acid analogue of cysteine in which a methylselenium moiety replaces the sulphur atom of cysteine. This agent acts as an antioxidant when incorporated into glutathione peroxidase and has been shown to exhibit potent chemopreventive activity in animal models.. multiple sclerosis defined as following: An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903). Mesenchymal stem cells defined as following: An undifferentiated stromal cell with the ability to develop into the cells that form distinct mesenchymal tissues; such as bone, muscle, connective tissue, blood vessels, and lymphatic tissue.. Fingolimod defined as following: An orally available derivate of myriocin and sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) modulator, with potential anti-inflammatory and immunomodulating activities. Upon oral administration, fingolimod, as a structural analogue of sphingosine, selectively targets and binds to S1PR1 on lymphocytes and causes transient receptor activation followed by S1PR1 internalization and degradation. This results in the sequestration of lymphocytes in lymph nodes. By preventing egress of lymphocytes. fingolimod reduces both the amount of circulating peripheral lymphocytes and the infiltration of lymphocytes into target tissues. This prevents a lymphocyte-mediated immune response and may reduce inflammation. S1PR1, a G-protein coupled receptor, plays a key role in lymphocyte migration from lymphoid tissues. Fingolimod also shifts macrophages to an anti-inflammatory M2 phenotype, and modulates their proliferation, morphology, and cytokine release via inhibition of the transient receptor potential cation channel, subfamily M, member 7 (TRPM7).. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. stroke defined as following: A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810). myelin defined as following: The lipid-rich sheath surrounding AXONS in both the CENTRAL NERVOUS SYSTEMS and PERIPHERAL NERVOUS SYSTEM. The myelin sheath is an electrical insulator and allows faster and more energetically efficient conduction of impulses. The sheath is formed by the cell membranes of glial cells (SCHWANN CELLS in the peripheral and OLIGODENDROGLIA in the central nervous system). Deterioration of the sheath in DEMYELINATING DISEASES is a serious clinical problem.. CNS defined as following: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.. lupus defined as following: chronic form of cutaneous lupus erythematosus in which the skin lesions mimic those of the systemic form but in which systemic signs are rare; characterized by the presence of discoid skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy; lesions are surrounded by an elevated erythematous border; the condition typically involves the face and scalp, but widespread dissemination may occur.. cardiac diseases defined as following: Pathological conditions involving the HEART including its structural and functional abnormalities.. stem cells defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells..", "label": "yes"} {"id": "converted_1402", "sentence1": "Are there Conserved Noncoding Elements (CNEs) in plant genomes?", "sentence2": "Conservation and functional element discovery in 20 angiosperm plant genomes, The detailed view of conservation across angiosperms revealed not only high coding-sequence conservation but also a large set of previously uncharacterized intergenic conservation, Conserved noncoding sequences highlight shared components of regulatory networks in dicotyledonous plants, Using a comparative genomics approach with four dicotyledonous plant species (Arabidopsis thaliana, papaya [Carica papaya], poplar [Populus trichocarpa], and grape [Vitis vinifera]), we detected hundreds of CNSs upstream of Arabidopsis genes, Long identical multispecies elements in plant and animal genomes., Using an alignment-free information-retrieval approach, we have comprehensively identified all long identical multispecies elements (LIMEs), which include both syntenic and nonsyntenic regions, of at least 100 identical base pairs shared by at least two genomes, In contrast, among six plant genomes, we only found nonsyntenic LIMEs, Although complex LIMEs were found in both animal and plant genomes, they differed significantly in their composition and copy number, Ultraconserved elements between the genomes of the plants Arabidopsis thaliana and rice, We consequently compared the genomes of Arabidopsis thaliana and rice, which diverged about 200 million years ago, and identified 25 ultraconserved elements that are longer than 100 bp, ultraconserved elements in plants tend to occur in clusters and locate at noncoding regions, the functions of these plant ultraconserved elements and the reasons why they are practically frozen during the evolution of millions of years remain a mystery, Conserved noncoding sequences in the grasses, Using a local sequence alignment set to deliver only significant alignments, we found one or more CNSs in the noncoding regions of the majority of genes studied. Grass genes have dramatically fewer and much smaller CNSs than mammalian genes, Conserved noncoding sequences among cultivated cereal genomes identify candidate regulatory sequence elements and patterns of promoter evolution, Surveys for conserved noncoding sequences (CNS) among genes from monocot cereal species were conducted to assess the general properties of CNS in grass genomes and their correlation with known promoter regulatory elements, Comparisons of orthologous maize-rice and maize-sorghum gene pairs identified 20 bp as a minimal length criterion for a significant CNS among grass genes, with few such CNS found to be conserved across rice, maize, sorghum, and barley[SEP]Definitions: cereal defined as following: Seeds from grasses (POACEAE) which are important in the diet.. conservation defined as following: The maintenance of certain characteristics in an unchanged condition.. genomes defined as following: The genetic complement of an organism, including all of its GENES, as represented in its DNA, or in some cases, its RNA.. promoter defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. CNS defined as following: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.. plants defined as following: Multicellular, eukaryotic life forms of kingdom Plantae. Plants acquired chloroplasts by direct endosymbiosis of CYANOBACTERIA. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (MERISTEMS); cellulose within cells providing rigidity; the absence of organs of locomotion; absence of nervous and sensory systems; and an alternation of haploid and diploid generations. It is a non-taxonomical term most often referring to LAND PLANTS. In broad sense it includes RHODOPHYTA and GLAUCOPHYTA along with VIRIDIPLANTAE.. plant genomes defined as following: The genetic complement of a plant (PLANTS) as represented in its DNA.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_2207", "sentence1": "Is Prochlorococcus the most abundant photosynthetic organism?", "sentence2": "The marine cyanobacterium Prochlorococcus is the smallest and most abundant photosynthetic organism on Earth., The marine cyanobacterium Prochlorococcus is the numerically dominant photosynthetic organism in the oligotrophic oceans, and a model system in marine microbial ecology., The marine cyanobacterium Prochlorococcus is the most abundant photosynthetic organism in oligotrophic regions of the oceans., The oceanic picoplankton Prochlorococcus - probably the most abundant photosynthetic organism on our planet - can grow at great depths where light intensity is very low.[SEP]", "label": "yes"} {"id": "converted_2657", "sentence1": "Are AAV vectors considered for the treatment of retinal dystrophies?", "sentence2": " These novel gene vectors aim to more safely and efficiently transduce retinal cells, expand the gene packaging capacity of AAV, and utilize new strategies to correct the varying mechanisms of dysfunction found with inherited retinal dystrophies. [SEP]Definitions: retinal dystrophies defined as following: A group of disorders involving predominantly the posterior portion of the ocular fundus, due to degeneration in the sensory layer of the RETINA; RETINAL PIGMENT EPITHELIUM; BRUCH MEMBRANE; CHOROID; or a combination of these tissues..", "label": "yes"} {"id": "converted_191", "sentence1": "Are thyroid hormone receptor alpha1 mutations implicated in thyroid hormone resistance syndrome?", "sentence2": "This study reports the consequences of LT4 treatment over a prolonged period of time in 2 of the first patients with a heterozygous mutation in TRα1., Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TR alpha1 in TR betaPV mice, and severe impairment of postnatal growth was manifested in TR betaPV mice deficient in TR alpha1., Heterozygous 2- to 3-week- old mice exhibit a severe retardation of post-natal development and growth, but only a minor reduction in serum thyroxine levels. , The data demonstrate a novel array of effects mediated by a dominant negative TRalpha1, and may provide important clues for identification of a potentially unrecognized human disorder and its treatment., No mutations in DNA- and hormone-binding-domains of TRbeta1 and TRalpha1 genes were found in proband, suggesting that the defect could be due to an unknown mutation in either the TR gene or a post receptor abnormality, These results demonstrate that the lack of TR alpha1 exacerbates the manifestation of RTH in TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH. [SEP]Definitions: mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. LT4 defined as following: The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (MONOIODOTYROSINE) and the coupling of iodotyrosines (DIIODOTYROSINE) in the THYROGLOBULIN. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form TRIIODOTHYRONINE which exerts a broad spectrum of stimulatory effects on cell metabolism.. TR defined as following: Backflow of blood from the RIGHT VENTRICLE into the RIGHT ATRIUM due to imperfect closure of the TRICUSPID VALVE..", "label": "yes"} {"id": "converted_3503", "sentence1": "Are stretch enhancers transcribed more than super-enhancers?", "sentence2": "Super-enhancers are transcriptionally more active and cell type-specific than stretch enhancers., We found that stretch enhancers are more abundant, more distal to transcription start sites, cover twice as much the genome, and are significantly less conserved than super-enhancers. In contrast, super-enhancers are significantly more enriched for active chromatin marks and cohesin complex, and more transcriptionally active than stretch enhancers. Importantly, a vast majority of super-enhancers (85%) overlap with only a small subset of stretch enhancers (13%), which are enriched for cell type-specific biological functions, and control cell identity genes. These results suggest that super-enhancers are transcriptionally more active and cell type-specific than stretch enhancers, and importantly, most of the stretch enhancers that are distinct from super-enhancers do not show an association with cell identity genes, are less active, and more likely to be poised enhancers., These results suggest that super-enhancers are transcriptionally more active and cell type-specific than stretch enhancers, and importantly, most of the stretch enhancers that are distinct from super-enhancers do not show an association with cell identity genes, are less active, and more likely to be poised enhancers.[SEP]Definitions: cohesin complex defined as following: A protein complex that is required for sister chromatid cohesion in eukaryotes. The cohesin complex forms a molecular ring complex, and is composed of structural maintenance of chromosomes (SMC) and kleisin proteins. For example, in yeast, the complex is composed of the SMC proteins Smc1p and Smc3p, and the kleisin protein Scc1p. In vertebrates, the complex is composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their hinge domains to a kleisin (RAD21, REC8 or RAD21L) which links them, and one STAG protein (STAG1, STAG2 or STAG3). [GOC:jl, GOC:sp, GOC:vw, PMID:9887095]. genome defined as following: Anatomical set of genes in all the chromosomes..", "label": "no"} {"id": "converted_2577", "sentence1": "Is Citrobacter rodentium pathogenic?", "sentence2": "One day after colonization, mice were infected with the colonic pathogen, Citrobacter rodentium., The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases., EPEC-like mouse pathogen Citrobacter rodentium, Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). [SEP]Definitions: Escherichia coli defined as following: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.. Citrobacter rodentium defined as following: A species of gram-negative bacteria in the genus CITROBACTER, family ENTEROBACTERIACEAE. As an important pathogen of laboratory mice, it serves as a model for investigating epithelial hyperproliferation and tumor promotion. It was previously considered a strain of CITROBACTER FREUNDII.. EPEC defined as following: Strains of ESCHERICHIA COLI characterized by attaching-and-effacing histopathology. These strains of bacteria intimately adhere to the epithelial cell membrane and show effacement of microvilli. In developed countries they are associated with INFANTILE DIARRHEA and infantile GASTROENTERITIS and, in contrast to ETEC strains, do not produce ENDOTOXINS.. human defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_2843", "sentence1": "Is ADP-ribosylation a PTM?", "sentence2": "ADP-ribosylation is a PTM, in which ADP-ribosyltransferases use nicotinamide adenine dinucleotide (NAD+) to modify target proteins with ADP-ribose, Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses., ADP-ribosylation is a post-translational modification (PTM) implicated in several crucial cellular processes, ranging from regulation of DNA repair and chromatin structure to cell metabolism and stress responses.[SEP]Definitions: ADP-ribosyltransferases defined as following: This gene is involved in cellular repair and apoptosis.. nicotinamide adenine dinucleotide defined as following: A coenzyme composed of ribosylnicotinamide 5'-diphosphate coupled to adenosine 5'-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). (Dorland, 27th ed). ADP-ribose defined as following: An ester formed between the aldehydic carbon of RIBOSE and the terminal phosphate of ADENOSINE DIPHOSPHATE. It is produced by the hydrolysis of nicotinamide-adenine dinucleotide (NAD) by a variety of enzymes, some of which transfer an ADP-ribosyl group to target proteins.. protein posttranslational modification defined as following: Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.. Poly-ADP-ribosylation defined as following: The transfer of multiple ADP-ribose molecules to amino acids within target proteins.. ADP-ribosylation defined as following: The transfer of ADP-ribose to amino acids within proteins or to the amino group at N2 of a 2'-deoxyguanosine residue in double-stranded DNA..", "label": "yes"} {"id": "converted_888", "sentence1": "Does replication timing affect the rate of somatic mutations?", "sentence2": "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.[SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. genome defined as following: Anatomical set of genes in all the chromosomes.. chromosome arm defined as following: Under the microscope chromosomes appear as thin, thread-like structures. They all have a short arm and long arm separated by a primary constriction called the centromere. The short arm is designated as p and the long arm as q.. yeast defined as following: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as \"baker's\" or \"brewer's\" yeast. The dried form is used as a dietary supplement.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. RNA viruses defined as following: Viruses whose genetic material is RNA..", "label": "yes"} {"id": "converted_1532", "sentence1": "Is selumetinib effective in thyroid cancer?", "sentence2": "A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours., BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor)., Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of>6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma., CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition., MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro., Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC., The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). , BACKGROUND AND AIM: Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer., CONCLUSIONS: Compared with current chemotherapy, selumetinib has modest clinical activity as monotherapy in patients with advanced cancer, but combinations of selumetinib with cytotoxic agents in patients with BRAF or KRAS mutations hold great promise for cancer treatment., Selumetinib may be an effective redifferentiating agent and could be used within several years., Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer., METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. , Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations)., CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. , ECENT FINDINGS: For patients with advanced differentiated thyroid cancers, sorafenib, selumetinib, pazopanib and sunitinib have been investigated with promising results. , Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer., Selumetinib may be an effective redifferentiating agent and could be used within several years., Here, selumetinib targets the mitogen-activated protein kinase pathway in papillary thyroid carcinoma and shows limited single-agent activity in the patients with tumors that harbor the (V600E)BRAF mutation., CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. [SEP]Definitions: pazopanib defined as following: A small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. Pazopanib selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, c-kit and platelet derived growth factor receptor (PDGF-R), which may result in inhibition of angiogenesis in tumors in which these receptors are upregulated.. Selumetinib defined as following: An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK or MAPK/ERK kinase) 1 and 2. MEK 1 and 2 are dual specificity kinases that are essential mediators in the activation of the RAS/RAF/MEK/ERK pathway, are often upregulated in various cancer cells, and are drivers of diverse cellular responses, including proliferation. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.. iodine defined as following: homeopathic drug. thyroid cancer defined as following: A primary or metastatic malignant neoplasm affecting the thyroid gland.. interferon defined as following: Human interferons have been classified into 3 groups: alpha, beta, and gamma. Both alpha- and beta-IFNs, previously designated type I, are acid-stable, but they differ immunologically and in regard to some biologic and physiochemical properties. The IFNs produced by virus-stimulated leukocytes (leukocyte IFNs) are predominantly of the alpha type. Those produced by lymphoblastoid cells are about 90% alpha and 10% beta. Induced fibroblasts produce mainly or exclusively the beta type. The alpha- and beta-IFNs differ widely in amino acid sequence. The gamma or immune IFNs, which are produced by T lymphocytes in response to mitogens or to antigens to which they are sensitized, are acid-labile and serologically distinct from alpha- and beta-IFNs. (from OMIM 147570). MEK defined as following: A dual-specific protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES and are themselves phosphorylated by MAP KINASE KINASE KINASES. JNK kinases (also known as SAPK kinases) are a subfamily.. BRAF defined as following: Serine/threonine-protein kinase B-raf (766 aa, ~84 kDa) is encoded by the human BRAF gene. This protein plays a role in protein phosphorylation, mitogenesis and neuronal signal transduction.. RAI defined as following: Human PPP1R13L wild-type allele is located in the vicinity of 19q13.32 and is approximately 27 kb in length. This allele, which encodes RelA-associated inhibitor protein, plays a role in the modulation of both apoptosis and transcription.. papillary thyroid cancer defined as following: A differentiated adenocarcinoma arising from the follicular cells of the thyroid gland. Radiation exposure is a risk factor and it is the most common malignant thyroid lesion, comprising 75% to 80% of all thyroid cancers in iodine sufficient countries. Diagnostic procedures include thyroid ultrasound and fine needle biopsy. Microscopically, the diagnosis is based on the distinct characteristics of the malignant cells, which include enlargement, oval shape, elongation, and overlapping of the nuclei. The nuclei also display clearing or have a ground glass appearance.. toxicity defined as following: The finding of bodily harm due to the poisonous effects of something.. PTC defined as following: The evaluation of the liver and biliary tree using a contrast agent injected directly into the liver.. colorectal carcinoma defined as following: A malignant epithelial neoplasm that arises from the colon or rectum and invades through the muscularis mucosa into the submucosa. The vast majority are adenocarcinomas.. cixutumumab defined as following: A fully human IgG1 monoclonal antibody directed against the human insulin-like growth factor-1 receptor (IGF-1R) with potential antineoplastic activity. Cixutumumab selectively binds to membrane-bound IGF-1R, thereby preventing the binding of the natural ligand IGF-1 and the subsequent activation of PI3K/AKT signaling pathway. Downregulation of the PI3K/AKT survival pathway may result in the induction of cancer cell apoptosis and may decrease cancer cellular proliferation. IGF-1R, a receptor tyrosine kinase of the insulin receptor superfamily overexpressed by many cancer cell types, stimulates cell proliferation, enables oncogenic transformation, and suppresses apoptosis; IGF-1R signaling has been implicated in tumorigenesis and metastasis.. TC defined as following: Human CD55 wild-type allele is located in the vicinity of 1q32 and is approximately 40 kb in length. This allele, which encodes complement decay-accelerating factor protein, is involved in the modulation of complement activity.. MHC class I defined as following: Genetic loci in the vertebrate major histocompatibility complex which encode polymorphic characteristics not related to immune responsiveness or complement activity, e.g., B loci (chicken), DLA (dog), GPLA (guinea pig), H-2 (mouse), RT-1 (rat), HLA-A, -B, and -C class I genes of man.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. NRAS defined as following: Human Oncogene N-RAS is a mutated variant of NRAS Gene (RAS Family), which encodes p21 N-Ras Protein, a monomeric GTPase involved in transmembrane signal transduction that alternates between inactive GDP-bound and active GTP-bound forms. RAS is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase-activating protein. Mitogen-stimulated RAS stabilizes MYC protein and enhances MYC accumulation by the RAS/RAF/MAPK pathway, which appears to inhibit the proteasome-dependent degradation of MYC. Implicated in a variety of human tumors, specific amino acid mutations activate c-RAS and transform cells. Oncogene NRAS disrupts normal cell function.. sunitinib defined as following: An indolinone derivative and tyrosine kinase inhibitor with potential antineoplastic activity. Sunitinib blocks the tyrosine kinase activities of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor b (PDGFRb), and c-kit, thereby inhibiting angiogenesis and cell proliferation. This agent also inhibits the phosphorylation of Fms-related tyrosine kinase 3 (FLT3), another receptor tyrosine kinase expressed by some leukemic cells.. sorafenib defined as following: A synthetic compound targeting growth signaling and angiogenesis. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.. basal cell carcinoma defined as following: A malignant skin neoplasm that seldom metastasizes but has potentialities for local invasion and destruction. Clinically it is divided into types: nodular, cicatricial, morphaic, and erythematoid (pagetoid). They develop on hair-bearing skin, most commonly on sun-exposed areas. Approximately 85% are found on the head and neck area and the remaining 15% on the trunk and limbs. (From DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1471). tongue defined as following: A muscular organ in the mouth that is covered with pink tissue called mucosa, tiny bumps called papillae, and thousands of taste buds. The tongue is anchored to the mouth and is vital for chewing, swallowing, and for speech.. iodine-124 defined as following: A radioactive isotope of iodine, a nonmetallic element of the halogen group, with an atomic mass of 124 and a half-life of 4.18 days with radioisotopic activity. Selectively accumulating in thyroid tissue, iodine I 124 emits positrons that can be detected by positron emission tomography (PET), allowing localization of thyroid tissue. This radioisotope also emits gamma rays.. squamous cell carcinoma defined as following: A squamous cell carcinoma (SCC) arising from the anal canal or the anal margin (perianal skin). Human papillomavirus is detected in the majority of cases. Homosexual HIV-positive men have an increased risk of developing anal squamous cell carcinoma in comparison to the general male population. Symptoms include anal pruritus, discomfort when sitting, pain, change in bowel habit, and bleeding. The prognosis is generally better for anal margin SCC than for anal canal SCC.. selumetinib defined as following: An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK or MAPK/ERK kinase) 1 and 2. MEK 1 and 2 are dual specificity kinases that are essential mediators in the activation of the RAS/RAF/MEK/ERK pathway, are often upregulated in various cancer cells, and are drivers of diverse cellular responses, including proliferation. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers..", "label": "yes"} {"id": "converted_2661", "sentence1": "Has rituximab been considered as a treatment for chronic fatigues syndrome? (November 2017)", "sentence2": " The use of rintatolimod and rituximab as well as counselling, behavioural and rehabilitation therapy programs may be of benefit for CFS/ME, but the evidence of their effectiveness is still limited. [SEP]Definitions: rintatolimod defined as following: A synthetic derivative of inosinic acid with antiretroviral and immunomodulatory properties. Atvogen acts through a number of pathways to stimulate intracellular antiviral activity of the immune system: it stimulates interferon production; activates the oligoadenylate synthase-RNase L pathway; stimulates natural killer cell activity; and acts as a non-mitogenic stimulator of the immune system. This agent also inhibits replication of human immunodeficiency virus (HIV) in vitro. (NCI04). rituximab defined as following: A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS..", "label": "yes"} {"id": "converted_3479", "sentence1": "Is modified vaccinia Ankara effective for smallpox?", "sentence2": "BACKGROUND: Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. , The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). , INTRODUCTION: To guide the use of modified vaccinia Ankara (MVA) vaccine in response to a release of smallpox virus, the immunogenicity and safety of shorter vaccination intervals, and administration by jet injector (JI), were compared to the standard schedule of administration on Days 1 and 29 by syringe and needle (S&N)., Erratum: Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial., Modified vaccinia Ankara virus (MVA) is a smallpox vaccine candidate. , A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects., BACKGROUND: Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. , CONCLUSIONS: One or two doses of MVA were safe and immunogenic in a 56-80 years old vaccinia-experienced population. , The results suggest that a single dose of MVA in a 56-80 years old population was well tolerated and sufficient to rapidly boost the long-term B cell memory response induced by a prior vaccination with a traditional smallpox vaccine., Modified Vaccinia Ankara (MVA) poxvirus has been assessed for cardiac safety in a large placebo-controlled clinical trial., BACKGROUND: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. , IMVAMUNE, an attenuated modified vaccinia Ankara virus vaccine for smallpox infection., Bavarian Nordic is developing IMVAMUNE, which is based on a live attenuated modified vaccinia Ankara virus, for the potential prevention of smallpox infection, particularly in those patients contraindicated to traditional smallpox vaccines, such as the immunocompromised and those with eczema or dermatitis., IMVAMUNE: modified vaccinia Ankara strain as an attenuated smallpox vaccine., Modified vaccinia Ankara: potential as an alternative smallpox vaccine., Evaluation of modified vaccinia virus Ankara as an alternative vaccine against smallpox in chronically HIV type 1-infected individuals undergoing HAART., Modified vaccinia Ankara: potential as an alternative smallpox vaccine, Modified vaccinia Ankara ( MVA ) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile ( SNS ) as a liquid formulation for subcutaneous ( SC ) administration at a dose of 1×10 ( 8 ) TCID50 in a volume of 0.5mL, Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations, Bavarian Nordic is developing IMVAMUNE , which is based on a live attenuated modified vaccinia Ankara virus , for the potential prevention of smallpox infection , particularly in those patients contraindicated to traditional smallpox vaccines , such as the immunocompromised and those with eczema or dermatitis, One of the most advanced and most promising vectors is the attenuated , non-replicating poxvirus MVA ( modified vaccinia virus Ankara) , a safer derivative of the uniquely successful smallpox vaccine, Modified vaccinia virus Ankara ( MVA ) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax, Modified Vaccinia virus Ankara ( MVA ) is an attenuated derivative , also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer, While modified vaccinia virus Ankara ( MVA ) is currently in clinical development as a safe vaccine against smallpox and heterologous infectious diseases , its immunogenicity is likely limited due to the inability of the virus to replicate productively in mammalian hosts, Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations., Modified Vaccinia virus Ankara (MVA) is a replication-deficient and attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer., Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations.[SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. dermatitis defined as following: Any inflammation of the skin.. infectious diseases defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. vaccinia virus defined as following: The type species of ORTHOPOXVIRUS, related to COWPOX VIRUS, but whose true origin is unknown. It has been used as a live vaccine against SMALLPOX. It is also used as a vector for inserting foreign DNA into animals. Rabbitpox virus is a subspecies of VACCINIA VIRUS.. viral vector defined as following: A viral gene transduction agent used to transfer genes or genetic materials, such as retroviruses and adenoviruses.. antibody defined as following: A protein complex that in its canonical form is composed of two identical immunoglobulin heavy chains and two identical immunoglobulin light chains, held together by disulfide bonds and sometimes complexed with additional proteins. An immunoglobulin complex may be embedded in the plasma membrane or present in the extracellular space, in mucosal areas or other tissues, or circulating in the blood or lymph. [GOC:add, GOC:jl, ISBN:0781765196]. HAART defined as following: Drug regimens, for patients with HIV INFECTIONS, that aggressively suppress HIV replication. The regimens usually involve administration of three or more different drugs including a protease inhibitor.. virus defined as following: Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells.. mammalian defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. vaccines defined as following: Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases.. eczema defined as following: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents (Dorland, 27th ed).. HIV defined as following: Includes the spectrum of human immunodeficiency virus infections that range from asymptomatic seropositivity, thru AIDS-related complex (ARC), to acquired immunodeficiency syndrome (AIDS)..", "label": "yes"} {"id": "converted_3094", "sentence1": "Can cardiospheres be produced from skin fibroblasts?", "sentence2": "Therefore, there is an emerging interest in generating cardiosphere-like stem cells from somatic cells via somatic reprogramming. , Here we provide the detailed protocol for generating induced cardiospheres (iCS) for cardiac regeneration by somatic reprogramming of mouse fibroblasts using a panel of pluripotent transcription factors and cardiotrophic growth factors.[SEP]Definitions: somatic cells defined as following: Nucleated cell which has one or more diploid sets (46 pairs) of chromosomes..", "label": "yes"} {"id": "converted_4419", "sentence1": "Is Sotatercept effective for Pulmonary Arterial Hypertension?", "sentence2": "Sotatercept for the Treatment of Pulmonary Arterial Hypertension., CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension., Sotatercept for the Treatment of Pulmonary Arterial Hypertension, CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertensio, n hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest.CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background t[SEP]Definitions: sotatercept defined as following: A soluble fusion protein composed of the extracellular domain of the activin receptor type IIA (ActRIIA) linked to the Fc portion of human IgG1 with anabolic bone activity. Sotatercept selectively binds to activin, inhibiting its binding to ActRIIA and ActRIIA signaling, resulting in the stimulation of osteoblast activity and the inhibition of osteoclast activity and so normal bone formation and increased bone mineral density and strength. The Fc moiety of this fusion protein binds to the salvage receptor FcRN, preventing its lysosomal degradation and so extending its half-life in the circulatory system.. cardiac arrest defined as following: Cessation of heart beat or MYOCARDIAL CONTRACTION. If it is treated within a few minutes, heart arrest can be reversed in most cases to normal cardiac rhythm and effective circulation.. pulmonary arterial hypertension defined as following: Increased blood pressure in the arteries of the lungs; the etiology is unknown.. Pulmonary Arterial Hypertension defined as following: Increased blood pressure in the arteries of the lungs; the etiology is unknown.. Sotatercept defined as following: A soluble fusion protein composed of the extracellular domain of the activin receptor type IIA (ActRIIA) linked to the Fc portion of human IgG1 with anabolic bone activity. Sotatercept selectively binds to activin, inhibiting its binding to ActRIIA and ActRIIA signaling, resulting in the stimulation of osteoblast activity and the inhibition of osteoclast activity and so normal bone formation and increased bone mineral density and strength. The Fc moiety of this fusion protein binds to the salvage receptor FcRN, preventing its lysosomal degradation and so extending its half-life in the circulatory system..", "label": "yes"} {"id": "converted_1542", "sentence1": "Is thyroid hormone therapy indicated in patients with heart failure?", "sentence2": "Patients with chronic heart failure and subclinical hypothyroidism significantly improved their physical performance when normal TSH levels were reached., Early and sustained physiological restoration of circulating L-T3 levels after MI halves infarct scar size and prevents the progression towards heart failure. This beneficial effect is likely due to enhanced capillary formation and mitochondrial protection., These data indicate that T(3) replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression., In these patients, the administration of synthetic triiodothyronine (T(3)) was well tolerated and induced significant improvement in cardiac function without increased heart rate and metabolic demand., In DC patients, short-term synthetic L-T(3) replacement therapy significantly improved neuroendocrine profile and ventricular performance., Triiodothyronine was well tolerated without episodes of ischemia or clinical arrhythmia. There was no significant change in heart rate or metabolic rate and there was minimal increase in core temperature. Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect.[SEP]Definitions: Triiodothyronine defined as following: A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5' position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly T3.. ischemia defined as following: A surgical procedure during which the blood supply to an organ or tissue is interrupted and then later reestablished.. peripheral defined as following: On or near an edge or constituting an outer boundary; the outer area.. heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs.. infarct defined as following: Formation of an infarct, which is NECROSIS in tissue due to local ISCHEMIA resulting from obstruction of BLOOD CIRCULATION, most commonly by a THROMBUS or EMBOLUS.. DC defined as following: A predominantly X-linked recessive syndrome characterized by a triad of reticular skin pigmentation, nail dystrophy and leukoplakia of mucous membranes. Oral and dental abnormalities may also be present. Complications are a predisposition to malignancy and bone marrow involvement with pancytopenia. (from Int J Paediatr Dent 2000 Dec;10(4):328-34) The X-linked form is also known as Zinsser-Cole-Engman syndrome and involves the gene which encodes a highly conserved protein called dyskerin.. scar defined as following: Formation of new tissue formed in the healing of a wound..", "label": "no"} {"id": "converted_682", "sentence1": "Is sumoylation implicated in myogenesis?", "sentence2": "Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) has broad de-SUMOylation activities in vitro, which is essential for embryonic heart development., Silencing SENP2 can reduce myostatin expression and, therefore, promote myogenesis of skeletal muscle. These results reveal the important role of SENP2 in the regulation of myostatin expression and myogenesis., Overexpression of c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN function in myogenesis is largely unknown., Notably, loss of sumoylation in the Lys-50 site (via a Lys-to-Arg point mutation) potently activates muscle-specific gene expression and enhances myotube formation. Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation., Although this modification has little effect on SnoN repression of the plasminogen activator inhibitor-1 promoter and only modestly potentiates SnoN repression of the p21 promoter, SnoN sumoylation robustly augments the ability of SnoN to suppress transcription of the myogenesis master regulatory gene myogenin, Our study also points to a physiological role for SnoN sumoylation in the control of myogenin expression in differentiating muscle cells., Here, we biochemically characterize SnoN sumoylation in detail and report the physiological function of the modification. , An essential role of small ubiquitin-like modifier (SUMO)-specific Protease 2 in myostatin expression and myogenesis., These results reveal the important role of SENP2 in the regulation of myostatin expression and myogenesis., The E3 SUMO ligase Nse2 regulates sumoylation and nuclear-to-cytoplasmic translocation of skNAC-Smyd1 in myogenesis., Sumoylation of the basic helix-loop-helix transcription factor sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis., We show that the overall load of sumoylated proteins present in myoblasts diminishes progressively throughout myogenesis, These novel results suggest that protein sumoylation plays a pivotal role in myoblast differentiation and is required to regulate the activity of key targets downstream of MyoD and myogenin., a composite sequence motif has recently been identified that couples phosphorylation, sumoylation, and perhaps also deacetylation to control transcriptional repression in stress response, mitogen and nuclear hormone signaling, myogenesis, and neuronal differentiation., Mutation of these SUMO acceptor sites in Sharp-1 does not impact its subcellular localization but attenuates its ability to act as a transcriptional repressor and inhibit myogenic differentiation. Consistently, co-expression of the SUMO protease SENP1 with wild type Sharp-1 abrogates Sharp-1-dependent inhibition of myogenesis. , Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation., Ubiquitin Specific Protease 25 (USP25), a member of the deubiquitinase family, is involved in several disease-related signal pathways including myogenesis, immunity and protein degradation. , In addition, we show that the skNAC interaction partner Smyd1 contains a putative sumoylation motif and is sumoylated in muscle cells, with depletion of Mms21/Nse2 leading to reduced concentrations of sumoylated Smyd1. Taken together, our data suggest that the function, specifically the balance between the nuclear and cytosolic roles, of the skNAC-Smyd1 complex might be regulated by sumoylation.[SEP]Definitions: myostatin defined as following: A growth differentiation factor that is a potent inhibitor of SKELETAL MUSCLE growth. It may play a role in the regulation of MYOGENESIS and in muscle maintenance during adulthood.. muscle cells defined as following: Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal (MUSCLE FIBERS, SKELETAL), cardiac (MYOCYTES, CARDIAC), and smooth (MYOCYTES, SMOOTH MUSCLE). They are derived from embryonic (precursor) muscle cells called MYOBLASTS.. skNAC defined as following: Human NACA wild-type allele is located within 12q23-q24.1 and is approximately 25 kb in length. This allele, which encodes nascent polypeptide-associated complex subunit alpha protein, is involved in the regulation of protein sorting. A point mutation in the gene may be associated with ovarian serous carcinoma.. SnoN defined as following: Ski-like protein (684 aa, ~77 kDa) is encoded by the human SKIL gene. This protein plays a role in the regulation of both gene transcription and signal transduction.. histone methyltransferase defined as following: Enzymes that catalyze the transfer of methyl groups to LYSINE or ARGININE residues of HISTONES, especially histone H3 and histone H4 proteins. They play a critical role in EPIGENETIC PROCESSES.. transcriptional repressor defined as following: Transcription Repressor/Corepressor Gene encodes Transcriptional Repressor/Corepressor, proteins that can regulate transcription by binding to the operator and causing repression. (from Glick: Glossary of Biochemistry and Molecular Biology). MyoD defined as following: Human MYOD1 wild-type allele is located in the vicinity of 11p15.4 and is approximately 3 kb in length. This allele, which encodes myoblast determination protein 1, is involved in the regulation of transcription, the cell cycle and the mediation of muscle differentiation.. myogenin defined as following: Myogenin (224 aa, ~25 kDa) is encoded by the human MYOG gene. This protein is involved in both transcription and myogenesis.. SENP2 defined as following: Human SUMO1 wild-type allele is located in the vicinity of 2q33 and is approximately 32 kb in length. This allele, which encodes small ubiquitin-related modifier 1 protein, is involved in the post-translational modification of proteins.. myoblasts defined as following: Embryonic (precursor) cells of the myogenic lineage that develop from the MESODERM. They undergo proliferation, migrate to their various sites, and then differentiate into the appropriate form of myocytes (MYOCYTES, SKELETAL; MYOCYTES, CARDIAC; MYOCYTES, SMOOTH MUSCLE).. mitogen defined as following: Growth Factors are extracellular signaling molecules (ligands) involved in control of target cell proliferation, cell survival, and cell differentiation. (NCI). modification defined as following:Respond with exceptions, completions and modifications or revisions done before completion
. Mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. p21 defined as following: A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.. regulatory gene defined as following: Genes which regulate or circumscribe the activity of other genes; specifically, genes which code for PROTEINS or RNAs which have GENE EXPRESSION REGULATION functions..", "label": "yes"} {"id": "converted_353", "sentence1": "Are there any functional differences between Mfd and its human Cocaine syndrome protein B (CSB) homolog?", "sentence2": "In humans, the TCR coupling factor, CSB, plays a critical role in restoring transcription following both UV-induced and oxidative DNA damage. It also contributes indirectly to the global repair of some forms of oxidative DNA damage. The Escherichia coli homolog, Mfd, is similarly required for TCR of UV-induced lesions., Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage., CSB has an ATPase activity that is stimulated strongly by DNA; however, it neither acts as a helicase nor does it dissociate stalled RNA polymerase II, suggesting a coupling mechanism in humans different from that in prokaryotes. , In addition, these findings imply that Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage., In addition, these findings imply that Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage., In contrast, no difference was detected in the rate of transcription recovery in mfd, uvrA, fpg, nth, or polB dinB umuDC mutants relative to wild-type cells following oxidative damage[SEP]Definitions: ATPase defined as following: A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.. CSB defined as following: A form of syndromic craniosynostosis with characteristics of highly variable craniosynostosis with frontal bossing, turribrachycephaly and cloverleaf skull anomaly. Hypoplasia of the supraorbital ridges, cleft palate, extra teeth and limb anomalies has also been described. Associated problems include headache, poor vision, and seizures. Intelligence is normal.. TCR defined as following: The nucleotide-excision repair process that carries out preferential repair of DNA lesions on the actively transcribed strand of the DNA duplex. In addition, the transcription-coupled nucleotide-excision repair pathway is required for the recognition and repair of a small subset of lesions that are not recognized by the global genome nucleotide excision repair pathway. [PMID:10197977, PMID:11900249]. RNA polymerase II defined as following: A DNA-dependent RNA polymerase present in bacterial, plant, and animal cells. It functions in the nucleoplasmic structure and transcribes DNA into RNA. It has different requirements for cations and salt than RNA polymerase I and is strongly inhibited by alpha-amanitin. EC 2.7.7.6.. humans defined as following: Members of the species Homo sapiens.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. mutants defined as following: An altered form of an individual, organism, population, or genetic character that differs from the corresponding wild type due to one or more alterations (mutations)..", "label": "yes"} {"id": "converted_2669", "sentence1": "Is CXCL7 a chemokine?", "sentence2": "CXCL7, a chemokine highly expressed in platelets, , Chemokine CXCL7 Heterodimers[SEP]Definitions: platelets defined as following: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation.. CXCL7 defined as following: Human PPBP wild-type allele is located within 4q12-q13 and is approximately 1 kb in length. This allele, which encodes platelet basic protein, plays a role in chemotaxis, neutrophil activation and a variety of other cellular processes.. chemokine defined as following: Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: C; (CHEMOKINES, C); CC; (CHEMOKINES, CC); and CXC; (CHEMOKINES, CXC); according to variations in a shared cysteine motif..", "label": "yes"} {"id": "converted_1615", "sentence1": "Are high-flow nasal cannulae effective for treatment of preterm infants?", "sentence2": "The use of high-flow nasal cannulae is an increasingly popular alternative to nasal continuous positive airway pressure (CPAP) for noninvasive respiratory support of very preterm infants (gestational age, <32 weeks) after extubation., The use of high-flow nasal cannulae was noninferior to the use of nasal CPAP, with treatment failure occurring in 52 of 152 infants (34.2%) in the nasal-cannulae group and in 39 of 151 infants (25.8%) in the CPAP group (risk difference, 8.4 percentage points; 95% confidence interval, -1.9 to 18.7). , Although the result for the primary outcome was close to the margin of noninferiority, the efficacy of high-flow nasal cannulae was similar to that of CPAP as respiratory support for very preterm infants after extubation. , Recently high flow nasal cannula (HFNC) is emerging as an efficient, better tolerated form of NIV, allowing better access to the baby's face, which may improve nursing, feeding and bonding., In conclusion, there is a growing evidence of the feasibility of HFNC as an alternative mode of NIV. , HHHFNC and NCPAP produced similar rates of extubation failure., The use of HFNC as a respiratory support modality is increasing in the infant, pediatric, and adult populations as an alternative to non-invasive positive pressure ventilation., Current evidence suggests that HFNC is well tolerated and may be feasible in a subset of patients who require ventilatory support with non-invasive ventilation., Heated, humidified, high-flow nasal cannula oxygen therapy (HHHFNC) has been used to improve ventilation in preterm infants. , Increasing flow rates of HHHFNC therapy are associated with linear increases in NP pressures in bronchiolitis patients. , An alternative to the use of nasal continuous positive airway pressure (NCPAP) as a non-invasive modality to support respiratory distress in premature infants has been the recent introduction of high flow nasal cannula (HFNC) devices in many neonatal units. There has been increased use of HFNC presumably because of anecdotal reports and experience that it is easy to use, and well tolerated by the infants, while experiencing decreased nasal septumerosion., High-flow nasal cannulae (HFNC) are gaining in popularity as a form of non-invasive respiratory support for preterm infants in neonatal intensive care units around the world., HFNC may be as effective as NCPAP at improving respiratory parameters such as tidal volume and work of breathing in preterm infants, but probably only at flow rates >2 litres/min. , There is growing evidence of the feasibility of HFNC as an alternative to other forms of non-invasive ventilation in preterm infants. , When used as primary respiratory support after birth, one trial found similar rates of treatment failure in infants treated with HFNC and nasal CPAP. Following extubation, one trial found that infants treated with HFNC had a significantly higher rate of reintubation than those treated with nasal CPAP. Another trial found similar rates of reintubation for humidified and non-humidified HFNC, and the fourth trial found no difference between two different models of equipment used to deliver humidified HFNC. , When used following extubation, HFNC may be associated with a higher rate of reintubation than nasal CPAP. , Early weaning from CPAP to high flow nasal cannula in preterm infants is associated with prolonged oxygen requirement: a randomized controlled trial., After randomization, the no-NC group had fewer days on oxygen [median (interquartile range): 5 (1-8) vs 14 (7.5-19.25) days, p<0.001] and shorter duration of respiratory support [10.5 (4-21) vs 18 (11.5-29) days, p=0.03]. There were no differences between groups regarding success of weaning from NCPAP. , Weaning preterm infants from NCPAP to NC is associated with increased exposure to oxygen and longer duration of respiratory support., A number of centers use high-flow nasal cannula (HFNC) in the management of AOP without measuring the positive distending pressure (PDP) generated., HFNC is as effective as NCPAP in the management of AOP.[SEP]Definitions: NIV defined as following: A type of mechanical ventilation procedure that uses a non-invasive means, such as a face mask or nasal mask, to deliver oxygenated air into the lungs.. respiratory distress defined as following: A pathological increase in the effort and frequency of breathing movements.. NC defined as following: A rare developmental skin condition consisting of abnormal pilosebaceous follicle development. It is characterized by linear or band-like distributions of groups of comedones, usually on the face, neck, upper arm, chest, and abdomen, that appear at birth or in childhood.. bronchiolitis defined as following: Inflammation of the BRONCHIOLES..", "label": "yes"} {"id": "converted_1367", "sentence1": "Is HER2 active only when it dimerizes?", "sentence2": "HER activation is driven by the formation of various dimer complexes between members of this receptor family., rtuzumab is the first humanized monoclonal antibody in a new class of drugs, the HER dimerization inhibitors, approved by the Food and Drug, Pertuzumab is a novel anti-HER2 monoclonal antibody, which blocks HER2 dimerization with other ligand-activated HER family members. Here, we explored the complement-mediated anti-tumor effects of trastuzumab and pertuzumab on HER2-positive tumor cells of various histological origins., ays. In this study, we report that an anti-HER2 monoclonal antibody (HER2Mab), which blocks HER2 dimerization with HER3, induces HER3 dimerization with EGFR in both low and high HER2 expressing cancer cells., Recent evidence from both basic and clinical studies suggests that ERBB3 (HER3) serves as a key activator of downstream signaling through dimerization with other ERBB proteins and plays a critical role in the widespread clinical resistance to EGFR and HER2 targeting cancer therapies. , HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways., Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the partners., Our results show that quantification of HER dimerization provides information about receptor activation that cannot be obtained by quantification of single receptors. , Pertuzumab is a novel humanized monoclonal antibody that blocks human epidermal growth factor receptor 2 (HER2) dimerization. It was recently approved by the US FDA for use in combination with trastuzumab and docetaxel for patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. , he HER dimerization status may be more important than HER receptor expression per se in determining sensitivity or resistance to a given therapeutic agen, and HER2 dimerization inhibitors, One of the mechanisms by which tumor cell proliferation can be inhibited consists in hampering HER2 dimerization by targeting its extracellular domain with specific antibodies. , Pertuzumab, a humanized monoclonal antibody, is the first HER2 dimerization inhibitor. It binds to the dimerization site on the HER2 domain and prevents ligand-driven pairing of HER2 with other HER receptors, thus inhibiting tumor cell growth and survival, Pertuzumab, another monoclonal antibody, is a HER2 dimerization inhibitor that binds to a different epitope on HER2 than trastuzumab and inhibits HER2 dimer formation with other HER family members such as HER3 and HER1. [SEP]Definitions: HER defined as following: A Niger-Congo Bantu language spoken by the Herero and Mbanderu peoples in Namibia and Botswana.. ERBB3 defined as following: This gene is involved in signal transduction pathways that result in cellular proliferation or differentiation. The gene has also been associated with numerous cancers.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. HER2 defined as following: Human ERBB2 wild-type allele is located in the vicinity of 17q21.1 and is approximately 29 kb in length. This allele, which encodes receptor tyrosine-protein kinase erbB-2 protein, plays a role in EGF receptor signal transduction pathways and cellular growth. Amplification or overexpression of this gene is involved in the progression of several forms of cancer, including breast and ovarian tumors.. trastuzumab defined as following: A humanized monoclonal antibody against the ERBB-2 RECEPTOR (HER2). As an ANTINEOPLASTIC AGENT, it is used to treat BREAST CANCER where HER2 is overexpressed.. tumor cell defined as following: Cells of, or derived from, a tumor.. HER1 defined as following: This gene is involved in the epidermal growth factor signal transduction pathway.. monoclonal antibody defined as following: A humanized monoclonal antibody directed against parathyroid hormone-related protein (PTH-rP). As a poly-hormone with diverse biological roles, PTH-rP is expressed by normal tissues, acting in local tissue environments in a variety of ways; it is commonly overexpressed by breast, prostate, and other cancers, acting systemically by promoting bone resorption, inhibiting calcium excretion from the kidney, inducing hypercalcemia, and possibly playing a role in the formation of bony metastases. By blocking the effects of PTH-rP on calcium metabolism, monoclonal antibody CAL may inhibit cancer-related hypercalcemia. (NCI04). EGFR family defined as following: A family of structurally related cell-surface receptors that signal through an intrinsic PROTEIN-TYROSINE KINASE. The receptors are activated upon binding of specific ligands which include EPIDERMAL GROWTH FACTORS, and NEUREGULINS.. HER3 defined as following: A cell surface protein-tyrosine kinase receptor that is specific for NEUREGULINS. It has extensive homology to and can heterodimerize with the EGF RECEPTOR and the ERBB-2 RECEPTOR. Overexpression of the erbB-3 receptor is associated with TUMORIGENESIS.. pertuzumab defined as following: A humanized recombinant monoclonal antibody directed against the extracellular dimerization domain of the HER-2 tyrosine kinase receptor. Binding of the antibody to the dimerization domain of the HER-2 tyrosine kinase receptor protein directly inhibits the ability of the HER-2 tyrosine kinase receptor protein (the most common pairing partner) to dimerize with other HER tyrosine kinase receptor proteins; inhibiting receptor protein dimerization prevents the activation of HER signaling pathways, resulting in tumor cell apoptosis. (NCI04). humanized monoclonal antibody defined as following: Antibodies from non-human species whose protein sequences have been modified to make them nearly identical with human antibodies. If the constant region and part of the variable region are replaced, they are called humanized. If only the constant region is modified they are called chimeric. INN names for humanized antibodies end in -zumab.. docetaxel defined as following: A semisynthetic analog of PACLITAXEL used in the treatment of locally advanced or metastatic BREAST NEOPLASMS and NON-SMALL CELL LUNG CANCER.. extracellular domain defined as following: Any part of a transmembrane protein that projects into the environment surrounding a cell.. tyrosine kinase receptors defined as following: A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity.. epitope defined as following: Sites on an antigen that interact with specific antibodies..", "label": "yes"} {"id": "converted_1298", "sentence1": "Are there Conserved Noncoding Elements (CNEs) in invertebrate genomes?", "sentence2": "Here, we use genome-wide comparisons between C. intestinalis and C. savignyi to identify putative urochordate cis-regulatory sequences. Ciona conserved non-coding elements (ciCNEs) are associated with largely the same key regulatory genes as vertebrate CNEs, We have identified Conserved Non-coding Elements (CNEs) in the regulatory region of Caenorhabditis elegans and Caenorhabditis briggsae , Here we report that nematode genomes contain an alternative set of CNEs that share sequence characteristics, but not identity, with their vertebrate counterparts. CNEs thus represent a very unusual class of sequences that are extremely conserved within specific animal lineages yet are highly divergent between lineages, A core set of genes that regulate development is associated with CNEs across three animal groups (worms, flies and vertebrates), The genomes of vertebrates, flies, and nematodes contain highly conserved noncoding elements (CNEs)., The genomes of vertebrates, flies, and nematodes contain highly conserved noncoding elements (CNEs)[SEP]Definitions: regulatory genes defined as following: Genes which regulate or circumscribe the activity of other genes; specifically, genes which code for PROTEINS or RNAs which have GENE EXPRESSION REGULATION functions.. sequences defined as following: The sequence of nucleotide residues along a DNA chain.. regulatory region defined as following: Nucleic acid sequences involved in regulating the expression of genes.. genomes defined as following: The genetic complement of an organism, including all of its GENES, as represented in its DNA, or in some cases, its RNA.. vertebrates defined as following: Animals having a vertebral column, members of the phylum Chordata, subphylum Craniata comprising mammals, birds, reptiles, amphibians, and fishes.. nematodes defined as following: class of unsegmented helminths with fundamental bilateral symmetry and secondary triradiate symmetry of the oral and esophageal structures; many species are parasites.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. flies defined as following: An order of the class Insecta. Wings, when present, number two and distinguish Diptera from other so-called flies, while the halteres, or reduced hindwings, separate Diptera from other insects with one pair of wings. The order includes the families Calliphoridae, Oestridae, Phoridae, SARCOPHAGIDAE, Scatophagidae, Sciaridae, SIMULIIDAE, Tabanidae, Therevidae, Trypetidae, CERATOPOGONIDAE; CHIRONOMIDAE; CULICIDAE; DROSOPHILIDAE; GLOSSINIDAE; MUSCIDAE; TEPHRITIDAE; and PSYCHODIDAE. The larval form of Diptera species are called maggots (see LARVA)..", "label": "yes"} {"id": "converted_3344", "sentence1": "Is marimastat effective for small-cell lung cancer?", "sentence2": "The phase III trial in small cell lung cancer was discontinued when the results of study 140 were released in February 2001 showing that marimastat was not significantly more effective than placebo in prolonging the survival of small cell lung cancer patients., CONCLUSION: Treatment with marimastat after induction therapy for SCLC did not result in improved survival and had a negative impact on quality of life., There were no significant differences in survival in a non-small cell lung cancer prinomastat study, and in a small cell lung cancer marimastat trial., There were no significant differences in survival in a non-small cell lung cancer prinomastat study , and in a small cell lung cancer marimastat trial. , The phase III trial in small cell lung cancer was discontinued when the results of study 140 were released in February 2001 showing that marimastat was not significantly more effective than placebo in prolonging the survival of small cell lung cancer patients.[SEP]Definitions: SCLC defined as following: A form of highly malignant lung cancer that is composed of small ovoid cells (SMALL CELL CARCINOMA).. marimastat defined as following: An orally-active synthetic hydroxamate with potential antineoplastic activity. Marimastat covalently binds to the zinc(II) ion in the active site of matrix metalloproteinases (MMPs), thereby inhibiting the action of MMPs, inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis. This agent may also inhibit tumor necrosis factor-alpha converting enzyme (TACE), an enzyme involved in tumor necrosis factor alpha (TNF-alpha) production that may play a role in some malignancies as well as in the development of arthritis and sepsis. (NCI04).", "label": "no"} {"id": "converted_1651", "sentence1": "Does SCRIB deregulation promote cancer?", "sentence2": "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.[SEP]Definitions: Scribble defined as following: Protein scribble homolog (1630 aa, ~175 kDa) is encoded by the human SCRIB gene. This protein is involved in cell polarization.. cancer defined as following: A malignant tumor at the original site of growth.. prostate cancer defined as following: A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas.. tumor suppressor gene defined as following: Genes that inhibit expression of the tumorigenic phenotype. They are normally involved in holding cellular growth in check. When tumor suppressor genes are inactivated or lost, a barrier to normal proliferation is removed and unregulated growth is possible.. mammals defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. humans defined as following: Members of the species Homo sapiens.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. H-Ras defined as following: Human HRAS wild-type allele is located in the vicinity of 11p15.5 and is approximately 3 kb in length. This allele, which encodes GTPase HRas protein, is involved in cellular mitogenesis. Mutations of HRAS are implicated in Costello syndrome, bladder cancer and oral squamous cell carcinoma.. prostate hyperplasia defined as following: A disease caused by hyperplastic process of non-transformed prostatic cells.. MAPK defined as following: A superfamily of PROTEIN SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).. Scrib defined as following: This gene is involved in the establishment of cell polarity.. carcinoma defined as following: A malignant neoplasm made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. It is a histological type of neoplasm and not a synonym for \"cancer.\". breast cancer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. product defined as following:Participant material that is brought forth (produced) in the act (e.g., specimen in a specimen collection, access or drainage in a placement service, medication package in a dispense service). It does not matter whether the material produced had existence prior to the service, or whether it is created in the service (e.g., in supply services the product is taken from a stock).
. tumor cell defined as following: Cells of, or derived from, a tumor.. extracellular matrix defined as following: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere.. mammary defined as following: Glandular tissue in the BREAST of human that is under the influence of hormones such as ESTROGENS; PROGESTINS; and PROLACTIN. In WOMEN, after PARTURITION, the mammary glands secrete milk (MILK, HUMAN) for the nourishment of the young.. lgl defined as following: A form of ventricular pre-excitation characterized by a short PR interval and a normal QRS complex. In this syndrome, the atrial impulse conducts via the JAMES FIBERS which connect the atrium to BUNDLE OF HIS bypassing the upper ATRIOVENTRICULAR NODE. HEART VENTRICLES are depolarized normally through the His-Purkinje system.. hepatocellular carcinoma defined as following: A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested.. SCRIB defined as following: This gene is involved in the establishment of cell polarity..", "label": "yes"} {"id": "converted_1067", "sentence1": "Can RG7112 inhibit MDM2?", "sentence2": "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.[SEP]Definitions: stem cells defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. MDM2 defined as following: E3 ubiquitin-protein ligase Mdm2 (491 aa, ~55 kDa) is encoded by the human MDM2 gene. This protein is involved in the mediation of the ubiquitination and degradation of protein substrates, and the inhibition of apoptosis induction that is mediated by cellular tumor antigen p53.. liposarcoma defined as following: A malignant tumor derived from primitive or embryonal lipoblastic cells. It may be composed of well-differentiated fat cells or may be dedifferentiated: myxoid (LIPOSARCOMA, MYXOID), round-celled, or pleomorphic, usually in association with a rich network of capillaries. Recurrences are common and dedifferentiated liposarcomas metastasize to the lungs or serosal surfaces. (From Dorland, 27th ed; Stedman, 25th ed). MPN defined as following: Conditions which cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. They all involve dysregulation of multipotent MYELOID PROGENITOR CELLS, most often caused by a mutation in the JAK2 PROTEIN TYROSINE KINASE.. p53 defined as following: Human TP53 wild-type allele is located in the vicinity of 17p13.1 and is approximately 19 kb in length. This allele, which encodes cellular tumor antigen p53 protein, plays a role in cell cycle regulation during the G0/G1transition. Alterations of the TP53 gene occur as both somatic and germline mutations in human malignancies in select cancer-prone families with Li-Fraumeni syndrome.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. macrophage inhibitory cytokine-1 defined as following: Growth/differentiation factor 15 (308 aa, ~34 kDa) is encoded by the human GDF15 gene. This protein plays a role in both tissue differentiation and signal transduction.. MDM2 inhibitor defined as following: Any agent that binds to mouse double minute 2 (human double minute 2 homolog; MDM2; HDM2) and/or prevents the interaction with the tumor suppressor protein p53, with potential antineoplastic activity.. malignancies defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. Ki-67 defined as following: This gene is involved in cellular proliferation.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. P21 defined as following: A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.. human defined as following: Members of the species Homo sapiens.. hematopoietic progenitor cells defined as following: Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood.. MIC-1 defined as following: Human GDF15 wild-type allele is located within 19p13.1-13.2 and is approximately 3 kb in length. This allele, which encodes growth/differentiation factor 15 protein, plays a role in the regulation of tissue differentiation and maintenance..", "label": "yes"} {"id": "converted_1846", "sentence1": "Can Diabetes be caused by a defect in a potassium chanel?", "sentence2": "Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively., To date, all patients affected by neonatal diabetes due to a mutation in the pore-forming subunit of the channel (Kir6.2, KCNJ11) are heterozygous for the mutation. , e report the first clinical case of neonatal diabetes caused by a homozygous KCNJ11 mutation, Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel;, We report a case of a 6-week-old infant with diabetes mellitus based on a genetic defect in the sulfonylurea receptor 1 (SUR1), an ATP-sensitive potassium (KATP) channel protein., In diabetes, vascular KATP channel function is impaired.[SEP]Definitions: congenital hyperinsulinism defined as following: A familial, nontransient HYPOGLYCEMIA with defects in negative feedback of GLUCOSE-regulated INSULIN release. Clinical phenotypes include HYPOGLYCEMIA; HYPERINSULINEMIA; SEIZURES; COMA; and often large BIRTH WEIGHT. Several sub-types exist with the most common, type 1, associated with mutations on an ATP-BINDING CASSETTE TRANSPORTERS (subfamily C, member 8).. insulin defined as following: A synthetic or animal-derived form of insulin used in the treatment of diabetes mellitus. Therapeutic insulin is formulated to be short-, intermediate- and long-acting in order to individualize an insulin regimen according to individual differences in glucose and insulin metabolism. Therapeutic insulin may be derived from porcine, bovine or recombinant sources. Endogenous human insulin, a pancreatic hormone composed of two polypeptide chains, is important for the normal metabolism of carbohydrates, proteins and fats and has anabolic effects on many types of tissues.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. diabetes defined as following: A heterogeneous group of disorders characterized by HYPERGLYCEMIA and GLUCOSE INTOLERANCE.. sulfonylurea receptor 1 defined as following: ATP-BINDING CASSETTE PROTEINS that are highly conserved and widely expressed in nature. They form an integral part of the ATP-sensitive potassium channel complex which has two intracellular nucleotide folds that bind to sulfonylureas and their analogs.. KATP channel defined as following: Heteromultimers of Kir6 channels (the pore portion) and sulfonylurea receptor (the regulatory portion) which affect function of the HEART; PANCREATIC BETA CELLS; and KIDNEY COLLECTING DUCTS. KATP channel blockers include GLIBENCLAMIDE and mitiglinide whereas openers include CROMAKALIM and minoxidil sulfate.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. Diabetes defined as following: A heterogeneous group of disorders characterized by HYPERGLYCEMIA and GLUCOSE INTOLERANCE..", "label": "yes"} {"id": "converted_44", "sentence1": "Does BNP increase after intensive exercise in athletes?", "sentence2": "NT-pro-BNP was significantly elevated postexercise in both adults and adolescents and remained above baseline at 24 h in both groups., NT-pro-BNP concentrations increased significantly (28 +/- 17.1 vs 795 +/- 823 ng x L, P < 0.05), whereas postrace cTnT were elevated in just five athletes (20%)., [NT-pro-BNP] was observed immediately after the marathon (median [NT-pro-BNP] before: 39.6 pg ml(-1), after: 138.6 pg ml(-1), p=0.003) with a further increase on day one. [BNP] did not increase immediately after the marathon but increased on day one (median [BNP] before: 15 pg ml(-1), day one: 27.35 pg ml(-1), p=0.006)., Pro-BNP was significantly increased immediately post-race (27+/-21 vs 7+/-2 pmol/L pre-race, P < or = 0.007), which 12-24 h later, decreased to 19+/-14 pmol/L (P = 0.07 vs pre-race)., The relatively high NT-proBNP levels after active recovery when psychophysical stress is higher, because of cycling and cold water immersion, suggest that not only endurance exercise, but also strenuous, stressful short exercise can induce an increase in NT-proBNP concentrations., Running a marathon significantly increases NT-pro-BNP levels in healthy adults. This increase could be partially attributed to cardiac stress., Increases in NT-proBNP can be found in a major part of obviously healthy athletes after prolonged strenuous exercise. The release of BNP during and after exercise may not result from myocardial damage but may have cytoprotective and growth-regulating effects. The different nature of exercise-induced increases in BNP and cardiac troponins has to be elucidated in the future., In healthy cyclists, transient increases in NT-pro-BNP and cTnT are more likely to reflect cardiac fatigue than injury., The rise in BNP in older athletes may reflect a reversible, mainly diastolic left ventricular dysfunction. , Plasma BNP concentrations were higher in both the judo and marathon groups than in controls, and positively correlated with LV mass as well as with deceleration time., Such exercise significantly increased ANP and BNP levels in healthy men, and the increases could be partially attributed to myocardial damage during the race.[SEP]Definitions: cTnT defined as following: Troponin T, cardiac muscle (298 aa, ~36 kDa) is encoded by the human TNNT2 gene. This protein plays a role in cardiac muscle contraction.. NT-pro-BNP defined as following: N-terminal fragment brain natriuretic protein (76 aa, ~9 kDa) is encoded by the human NPPB gene. This protein is a marker for cardiac failure.. BNP defined as following: A recombinant version of the cardiac neurohormone, human B-type natriuretic peptide (hBNP) produced by the ventricular myocardium. Nesiritide binds to natriuretic peptide receptors on vascular smooth muscle and endothelial cells, through which it triggers guanylate cyclase dependent signal transduction resulting in increase of intracellular concentrations of cGMP. This leads to smooth muscle cell relaxation causing arterial and venous dilatation.. ANP defined as following: A potent natriuretic and vasodilatory peptide or mixture of different-sized low molecular weight PEPTIDES derived from a common precursor and secreted mainly by the HEART ATRIUM. All these peptides share a sequence of about 20 AMINO ACIDS..", "label": "yes"} {"id": "converted_1130", "sentence1": "Do DNA double-strand breaks play a causal role in carcinogenesis?", "sentence2": "The DNA non-homologous end-joining repair gene XRCC6/Ku70 plays an important role in the repair of DNA double-strand breaks (DSBs) induced by both exogenous and endogenous DNA-damaging agents. Defects in overall DSB repair capacity can lead to genomic instability and carcinogenesis., The tumor suppressor breast cancer susceptibility protein 1 (BRCA1) protects our cells from genomic instability in part by facilitating the efficient repair of DNA double-strand breaks (DSBs). BRCA1 promotes the error-free repair of DSBs through homologous recombination and is also implicated in the regulation of nonhomologous end joining (NHEJ) repair fidelity., The increased frequency of DSB mutagenesis and MMEJ repair in the absence of BRCA1 suggests a potential mechanism for carcinogenesis., Comet assay under neutral conditions allows detection of DNA double-strand breaks (DSBs), which has consequence to genome instability and carcinogenesis., Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks., Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells., Zinc chromate induces chromosome instability and DNA double strand breaks in human lung cells., Our study shows that zinc chromate induced concentration-dependent increases in cytotoxicity, chromosome damage and DNA double strand breaks in human lung cells., Foci formation of P53-binding protein 1 in thyroid tumors: activation of genomic instability during thyroid carcinogenesis., Nitric oxide and acid induce double-strand DNA breaks in Barrett's esophagus carcinogenesis via distinct mechanisms., DNA double-strand break repair capacity and risk of breast cancer., A tumorigenic role of the non-homologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks (DSBs) has been suggested by our finding of a significant association between increased breast cancer risk and a cooperative effect of single-nucleotide polymorphisms in NHEJ genes., Carcinogen-induced DNA double strand break repair in sporadic breast cancer., Induction of DNA double strand breaks and alterations in the repair of these breaks is implicated in breast carcinogenesis. Prior studies have demonstrated that peripheral blood mononuclear cells (PBMC) from breast cancer patients exhibit increased numbers of DNA strand breaks after exposure to ionizing radiation, but these studies did not specifically measure DNA double strand breaks and it is not known whether chemical carcinogens produce similar effects., Abnormal DNA end-joining activity in human head and neck cancer., In human cells, DNA double-strand breaks (DSBs) are repaired primarily by the DNA end-joining (EJ) process and thus, abnormal DNA EJ activities lead to an accumulation of mutations and/or aneuploidy, resulting in genetic instability of cells. Since genetic instability is the hallmark of cancer cells, we studied the DNA EJ activities of normal, non-malignant immortalized and malignant human epithelial cells to investigate the association between DNA EJ and carcinogenesis., Homologous recombination repair plays an important role in DSB repair and impairment of this repair mechanism may lead to loss of genomic integrity, which is one of the hallmarks of cancer. Recent research has shown that the tumor suppressor genes p53 and BRCA1 and -2 are involved in the proper control of homologous recombination, suggesting a role of this type of repair in human cancer., In order to study the role of DNA damage processing in the development of cutaneous squamous cell carcinoma (SCC), we assessed the ability of six keratinocyte cell lines from a multistage-tumor progression model to repair three types of DNA damage: pyrimidine dimers, oxidative DNA lesions and DNA double strand breaks (DSB)., However, an acquired deficiency in repairing DNA double strand breaks can be one mechanism promoting progression towards malignancy, possibly through impairing chromosomal stability., Recent findings demonstrate that accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks in cells, which escaped apoptosis due to proliferative stress., Although DNA double-strand breaks and apoptosis may relate to arsenite-induced damage and carcinogenesis, the mechanism of action remains obscure.[SEP]Definitions: peripheral blood mononuclear cells defined as following: A peripheral blood cell with a single nucleus. This category includes lymphocytes and monocytes.. DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. mutagenesis defined as following: Production of genetic alterations by any technique, including chemicals, radiation, recombination, or other molecular biology methods.. thyroid tumors defined as following: Tumors or cancer of the THYROID GLAND.. P53-binding protein 1 defined as following: Apoptosis-stimulating of p53 protein 2 (1128 aa, ~126 kDa) is encoded by the human TP53BP2 gene. This protein plays a role in cell cycle arrest and the regulation of cellular tumor antigen p53-dependent apoptosis.. Nitric oxide defined as following: A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. zinc chromate defined as following: A yellowish, crystalline, inorganic compound that emits toxic chromium fumes upon heating. Zinc chromate is highly corrosive and is a strong oxidizing agent. This substance is used as a corrosion inhibitor, metal conditioner and is used in paints, varnishes and oil colors. Zinc chromate primarily affects the lungs causing shortness of breath, bronchitis, pneumonia and asthma but can also affect the gastrointestinal tract, liver, kidneys and immune system. This substance is a known human carcinogen and is associated with an increased risk of developing lung cancer and cancer of the sinonasal cavity. (NCI05). BRCA1 defined as following: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.. acquired deficiency defined as following: An imbalanced nutritional status resulting from insufficient intake of nutrients to meet normal physiological requirement.. breast cancer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. malignancy defined as following: A malignant tumor at the original site of growth.. tumor suppressor genes p53 defined as following: Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. human defined as following: Members of the species Homo sapiens.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. NHEJ defined as following: The repair of a double-strand break in DNA in which the two broken ends are rejoined with little or no sequence complementarity. Information at the DNA ends may be lost due to the modification of broken DNA ends. This term covers instances of separate pathways, called classical (or canonical) and alternative nonhomologous end joining (C-NHEJ and A-NHEJ). These in turn may further branch into sub-pathways, but evidence is still unclear. [GOC:rph, PMID:10827453, PMID:24837021].", "label": "yes"} {"id": "converted_905", "sentence1": "Are viruses involved in the etiology of human subacute thyroiditis?", "sentence2": "he etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain, although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses., Subacute thyroiditis is an inflammatory disorder of the thyroid caused probably by viruses. I, We believe that the etiologic agent was the Epstein-Barr virus because heterophile and Epstein-Barr virus-specific antibodies were positive., ltogether, these results indicate that the mechanism of inhibition of Spumavirinae infection by interferon differs from that described for the other Retroviridae, and particularly for types B, C and D viruses. Our data is of therapeutic interest since Spumavirinae have been linked to pathological processes such as de Quervain thyroiditis.[SEP]Definitions: Quervain thyroiditis defined as following: Spontaneously remitting inflammatory condition of the THYROID GLAND, characterized by FEVER; MUSCLE WEAKNESS; SORE THROAT; severe thyroid PAIN; and an enlarged damaged gland containing GIANT CELLS. The disease frequently follows a viral infection.. viruses defined as following: Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells.. human defined as following: Members of the species Homo sapiens..", "label": "yes"} {"id": "converted_1365", "sentence1": "Is Mammaprint approved by the United States Food and Drug Administration?", "sentence2": "an FDA-cleared 70-gene signature of MammaPrint panel , on MammaPrint, the first and only assay for breast cancer management that has been cleared by the FDA., The MammaPrint assay has the advantages of a 510(k) clearance by the US Food and Drug Administration, a larger gene number which may enhance further utility, and the potentially wider patient eligibility including lymph node-positive, ER-negative, , The MammaPrint assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node-positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy). [SEP]Definitions: MammaPrint defined as following: An in vitro molecular diagnostic test that uses gene expression profiling to analyze gene activity within a breast cancer tumor sample. It looks at the activity of 70 genes and is useful in assessing the likelihood of metastasis and recurrence.. breast cancer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. Mammaprint defined as following: An in vitro molecular diagnostic test that uses gene expression profiling to analyze gene activity within a breast cancer tumor sample. It looks at the activity of 70 genes and is useful in assessing the likelihood of metastasis and recurrence..", "label": "yes"} {"id": "converted_3555", "sentence1": "Is AZD5153 active in prostate cancer?", "sentence2": "AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo., Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor.METHODS: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H3] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153's activity in vivo.RESULTS: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206.CONCLUSION: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells., AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells., CONCLUSION\n\nTogether, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells., AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells., RESULTS\n\nAZD5153 inhibited proliferation and survival of established and primary prostate cancer cells., RESULTS AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells., AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells., AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells., CONCLUSION Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells., AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo, AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells.[SEP]Definitions: Bcl-2 defined as following: The B-cell leukemia/lymphoma-2 genes, responsible for blocking apoptosis in normal cells, and associated with follicular lymphoma when overexpressed. Overexpression results from the t(14;18) translocation. The human c-bcl-2 gene is located at 18q24 on the long arm of chromosome 18.. Signaling defined as following: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.. CDK4 defined as following: Cyclin-dependent kinase 4 is a key regulator of G1 PHASE of the CELL CYCLE. It partners with CYCLIN D to phosphorylate RETINOBLASTOMA PROTEIN. CDK4 activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P16.. prostate cancer defined as following: A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas.. BRD4 defined as following: Bromodomain-containing protein 4 (1362 aa, ~152 kDa) is encoded by the human BRD4 gene. This protein plays a role in the mitotic process.. Myc defined as following: Myc proto-oncogene protein (439 aa, ~49 kDa) is encoded by the human MYC gene. This protein plays a role in the regulation of transcription and cell proliferation.. AKT defined as following: Expressed in diverse tissues, Protein Kinase B (AKT/RAC Family) is a group (Alpha, Beta and Gamma) of cytoplasmic serine/threonine enzymes that covalently transfer the terminal, gamma phosphate group from ATP to a variety of substrate proteins and regulate cell signaling responses to insulin, PDGF, and IGF1 (through PI3K) involved in cell survival, cell proliferation, differentiation, apoptosis, glycogen synthesis, and glucose uptake.. Annexin V defined as following: This gene is involved in anticoagulation processes and mediates lipid binding.. AZD5153 defined as following: An orally bioavailable bivalent inhibitor of bromodomain-containing protein 4 (BRD4), with potential antineoplastic activity. Upon oral administration, the BRD4 inhibitor AZD5153 selectively binds to the acetylated lysine recognition motifs in two bromodomains in the BRD4 protein, thereby preventing the binding of BRD4 to acetylated lysines on histones. This disrupts chromatin remodeling and dysregulates expression of target genes, which leads to the downregulation of the expression of certain growth-promoting genes, induces apoptosis and inhibits the proliferation of BRD4-overexpressing tumor cells. BRD4, a member of the human bromodomain and extra-terminal (BET) family of proteins, is a transcriptional regulator that is overexpressed in certain tumor cells and plays an important role in cellular proliferation.. PC-3 defined as following: An adenocarcinoma cell line established in 1979 from a bone metastasis from a 62 year old Caucasian male patient with stage IV prostate carcinoma.. cyclin D1 defined as following: Protein encoded by the bcl-1 gene which plays a critical role in regulating the cell cycle. Overexpression of cyclin D1 is the result of bcl-1 rearrangement, a t(11;14) translocation, and is implicated in various neoplasms.. FOSL1 defined as following: Human FOSL1 wild-type allele is located in the vicinity of 11q13 and is approximately 8 kb in length. This allele, which encodes FOSL1 protein, is involved in transcriptional regulation.. propidium iodide defined as following: A fluorescent nucleic acid dye which binds only to double-stranded nucleic acids. It has a molecular weight of 668.4, an absorbance maximum of 535nm, and an emission maximum of 617 nm. It is commonly used to determine the DNA content of a cell or to discriminate viable from non-viable cells.. Bromodomain-containing protein 4 defined as following: This gene plays a role in mitosis.. FACS defined as following: Selection and deposition of individual cells of a particular phenotype from a mixed population into a separate tube or tissue culture plate by the use of a fluorescence-activated cell sorter (FACS) and fluorescently-labeled antibodies specific for surface molecules on the cells to be sorted.. PI defined as following: Backflow of blood from the PULMONARY ARTERY into the RIGHT VENTRICLE due to imperfect closure of the PULMONARY VALVE..", "label": "yes"} {"id": "converted_274", "sentence1": "Is single-cell analysis (SCA) possible in proteomics?", "sentence2": "Toward Single Cell Analysis by Plume Collimation in Laser Ablation Electrospray Ionization Mass Spectrometry., he advent of proteomics and genomics at a single-cell level has set the basis for an outstanding improvement in analytical technology and data acquisition., The new-generation technology of single-cell analysis is able to better characterize a cell's population, identifying and differentiating outlier cells, in order to provide both a single-cell experiment and a corresponding bulk measurement, through the identification, quantification and characterization of all system biology aspects (genomics, transcriptomics, proteomics, metabolomics, degradomics and fluxomics). The movement of omics into single-cell analysis represents a significant and outstanding shift., Laser ablation electrospray ionization (LAESI) is a novel method for the direct imaging of biological tissues by mass spectrometry. By performing ionization in the ambient environment, this technique enables in vivo studies with potential for single-cell analysis., Other approaches for MS-based chemical imaging and profiling include those based on near-field laser ablation and inductively-coupled plasma MS analysis, which offer complementary capabilities for subcellular chemical imaging and profiling., Mass spectrometry imaging and profiling of single cells., his is rapidly changing with the recent examples of single cell genomics, transcriptomics, proteomics and metabolomics. The rate of change is expected to accelerate owing to emerging technologies that range from micro/nanofluidics to microfabricated interfaces for mass spectrometry to third- and fourth-generation automated DNA sequencers, Single-cell analysis (SCA) has been increasingly recognized as the key technology for the elucidation of cellular functions, which are not accessible from bulk measurements on the population level. Thus far, SCA has been achieved by miniaturization of established engineering concepts to match the dimensions of a single cell, Single-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells., The amount of single proteins in single cells can be as low as one copy per cell and is for most proteins in the attomole range or below; usually considered as insufficient for proteomic analysis., n Arabidopsis thaliana, we have successfully identified nine unique proteins in a single-cell sample and 56 proteins from a pool of 15 single-cell samples from glucosinolate-rich S-cells by nanoLC-MS/MS proteomic analysis, thus establishing the proof-of-concept for true single-cell proteomic analysis, A first step towards practical single cell proteomics: a microfluidic antibody capture chip with TIRF detection.[SEP]Definitions: proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. SCA defined as following: Cessation of heart beat or MYOCARDIAL CONTRACTION. If it is treated within a few minutes, heart arrest can be reversed in most cases to normal cardiac rhythm and effective circulation..", "label": "no"} {"id": "converted_4421", "sentence1": "Is the 22-item sino-nasal outcome test (SNOT-22) a widely used measure for Health-Related Quality-of-Life (HRQOL) associated with chronic rhinosinusitis (CRS)?", "sentence2": "The Sino-Nasal-Outcome-Test-22 (SNOT-22) represents the reference questionnaire to assess symptoms, health-related quality-of-life (HRQOL) and treatment-response in patients with chronic rhinosinusitis (CRS). , Assessment of health-related quality-of-life in patients with chronic Rhinosinusitis - Validation of the German Sino-Nasal Outcome Test-22 (German-SNOT-22)., Patients meeting diagnostic criteria for CRS were prospectively enrolled in a cross-sectional study. Responses from the Sinonasal Outcomes Test-22 (SNOT-22), a measure of patient HRQOL, as well as the Lund-Kennedy and Lund-Mackay scores were recorded at enrollment, Three groups of 12 participants each were examined: patients with CRS without polyposis (CRS group), patients with symptoms of CRS but radiologically normal sinuses (symptoms-only), and healthy controls. Measurements of nNO were carried out using aspiration method and humming maneuver. All participants completed the Sino-Nasal Outcome Test (SNOT-22)., PURPOSE: The Sino-Nasal-Outcome-Test-22 (SNOT-22) represents the reference questionnaire to assess symptoms, health-related quality-of-life (HRQOL) and treatment-response in patients with chronic rhinosinusitis (CRS)., tcomes included scores on the CRS disease severity visual analog scale (VAS), 22-item Sino-Nasal Outcome Test (SNOT-22), 5-dimension EuroQoL (EQ-5D) general health status VAS, and 36-item Short-Form Health Survey (SF-36) for HRQoL and nasal polyp-related healthcare resource use questionnaires.RE, BACKGROUND: The 22-item Sino-Nasal Outcome Test (SNOT-22) is a commonly utilized outcome measure for chronic rhinosinus, BACKGROUND: The 22-item sino-nasal outcome test (SNOT-22) is a widely used and powerful patient-reported outcomes measure for chronic rhinosinus, BACKGROUND: Prior study demonstrated that baseline 22-item Sino-Nasal Outcome Test (SNOT-22) aggregate scores accurately predict selection of surgical intervention in patients with chronic rhinosinus, OBJECTIVES/HYPOTHESIS: Sinonasal Outcomes Test-22 (SNOT-22) is used widely as a patient-reported sinonasal quality-of-life (QOL) instrument for endoscopic endonasa, Is sino-nasal outcome test-22 reliable for guiding chronic rhinosinusitis patients for endoscopic sinus surgery, The Sino-Nasal Outcome Test-22 as a tool to identify chronic rhinosinusitis in adults with cystic fibrosis, rden. Our objective was to investigate the utility of the 22-item Sino-Nasal Outcome Test (SNOT-22) as a tool to identify CRS in adults wit, OBJECTIVES/HYPOTHESIS: The 22-item Sinonasal Outcome Test (SNOT-22) is a validated chronic rhinosinusitis health-related quality-of-life outcome (HRQoL) measure; however, SNOT-22 domains have not been validated specifically for chronic rhinosinusitis with nas, OBJECTIVE: The SNOT-22 (22-item Sinonasal Outcome Test) is a high-quality outcome measure that assesses chronic rhinosinusitis-specific quality of lif, BACKGROUND: The 22-item sino-nasal outcome test (SNOT-22) is a widely used and powerful patient-reported outcomes measure for chronic rhinosinusitis (CRS, OBJECTIVES/HYPOTHESIS: The 22-item Sinonasal Outcome Test (SNOT-22) is a validated chronic rhinosinusitis health-related quality-of-life outcome (HRQoL) measure; however, SNOT-22 domains have not been validated specifically for chronic rhinosinusitis with nasal polyps (CRSwNP, BACKGROUND: The 22-item Sino-Nasal Outcome Test (SNOT-22) is a commonly utilized outcome measure for chronic rhinosinusitis (CRS, OBJECTIVES/HYPOTHESIS: The 22-item Sinonasal Outcome Test (SNOT-22) is a validated chronic rhinosinusitis health-related quality-of-life outcome (HRQoL) measure; however, SNOT-22 domains have not been validated specifically for chronic rhinosinusitis with nasal polyps (CRSwNP).STUDY DESIGN: Validation of SNOT-22 domain structure, using data from 3 randomized, placebo-controlled, double-blinded, multicenter clinical trials of dupilumab in adults with moderate-to-severe CRSwNP.METHODS: Preliminary dimensional structure was derived by exploratory factor analyses of SNOT-22 data from a phase 2 trial (NCT01920, OBJECTIVES: We set out to determine the psychometric validation of a disease-specific health related quality of life instrument for use in chronic rhinosinusitis, the 22 item Sinonasal Outcome Test (SNOT-22), a modification of a pre-existing instrument, the SNOT-20.DESIGN, SETTING AND PARTICIPANTS: The National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis was a prospective cohort study collecting data on 3128 adult patients undergoing sinonasal sur, OBJECTIVE: The SNOT-22 (22-item Sinonasal Outcome Test) is a high-quality outcome measure that assesses chronic rhinosinusitis-specific quali, act of CRS. We sought to determine if 22-item Sino-Nasal Outcome Test (SNOT-22) score is predictive of patient-perceived CRS symptom control.METHODS: Prospective cross-sectional study of 2, The Sinonasal Outcome Test (SNOT-22) Is a Poor Diagnostic Tool for Chronic Rhinosinusitis., The 22-item Sino-Nasal Outcome Test accurately reflects patient-reported control of chronic rhinosinusitis symptomatology., Development of Sinonasal Outcome Test (SNOT-22) Domains in Chronic Rhinosinusitis With Nasal Polyps., cture with strong Cronbach's alpha values (all >0.80). Moderate-to-high correlations were observed between change in SNOT-22 domain scores and other study patient-reported outcome measures, along with large effect-size estimates (≥0.7), demonstrating re[SEP]Definitions: Nasal Polyps defined as following: Focal accumulations of EDEMA fluid in the NASAL MUCOSA accompanied by HYPERPLASIA of the associated submucosal connective tissue. Polyps may be NEOPLASMS, foci of INFLAMMATION, degenerative lesions, or malformations.. chronic rhinosinusitis defined as following: Inflammation of the paranasal sinuses that typically lasts beyond eight weeks. It is caused by infections, allergies, and the presence of sinus polyps or deviated septum. Signs and symptoms include headache, nasal discharge, swelling in the face, dizziness, and breathing difficulties.. lif defined as following: An INTERLEUKIN-6 related cytokine that exhibits pleiotrophic effects on many physiological systems that involve cell proliferation, differentiation, and survival. Leukemia inhibitory factor binds to and acts through the lif receptor.. nas defined as following: The histopathological evaluation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) based on the NAFLD scoring system. (Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21.). CRS defined as following: Transplacental infection of the fetus with rubella usually in the first trimester of pregnancy, as a consequence of maternal infection, resulting in various developmental abnormalities in the newborn infant. They include cardiac and ocular lesions, deafness, microcephaly, mental retardation, and generalized growth retardation. (From Dorland, 27th ed). modification defined as following:Respond with exceptions, completions and modifications or revisions done before completion
. polyposis defined as following: A condition characterized by the presence of numerous polyps.. nNO defined as following: One of the two written standards of the Norwegian language.. dupilumab defined as following: A recombinant human monoclonal immunoglobulin G4 (IgG4) antibody directed against the alpha chain of the interleukin-4 receptor (IL-4R alpha) with potential immunomodulatory activities. Upon injection, dupilumab selectively binds to the IL-4R alpha chain. This disrupts IL-4/IL-13 signaling and prevents the activation of downstream pathways that mediate type 2 inflammation and may potentially inhibit tumor cell proliferation, survival, and metastasis. IL-4 and IL-13 receptors are present on the surface of numerous cells involved in the pathophysiology of type-2 helper T-cell (Th2) allergic responses, including B-lymphocytes, eosinophils, dendritic cells (DCs), monocytes, macrophages, basophils, keratinocytes, bronchial epithelial cells, endothelial cells, fibroblasts, and airway smooth muscle cells. Additionally, both IL-4 and IL-13 receptors are overexpressed in a variety of cancers and IL-4 and IL-13 and may serve as biomarkers for cancer aggressiveness. IL-4 and IL-13 are thought to be key regulatory cytokines in the tumor microenvironment (TME) and may play a role in the activation of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) that mediate tumor cell survival..", "label": "yes"} {"id": "converted_2959", "sentence1": "Is Adar3 involved in learning and memory?", "sentence2": "Adar3 Is Involved in Learning and Memory in Mice., The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown. Meta-analysis of published data indicates that mouse Adar3 expression is highest in the hippocampus, thalamus, amygdala, and olfactory region. Consistent with this, we show that mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. We also show that ADAR3 transiently translocates from the cytoplasm to the nucleus upon KCl-mediated activation in SH-SY5Y cells. These results indicate that ADAR3 contributes to cognitive processes in mammals., Adar3 Is Involved in Learning and Memory in Mice.-deficient mice. [SEP]Definitions: amygdala defined as following: Almond-shaped group of basal nuclei anterior to the INFERIOR HORN OF THE LATERAL VENTRICLE of the TEMPORAL LOBE. The amygdala is part of the limbic system.. nucleus defined as following: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed). mammals defined as following: Warm-blooded vertebrate animals belonging to the class Mammalia, including all that possess hair and suckle their young.. cytoplasm defined as following: The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990). double stranded RNA binding domains defined as following: An RNA-binding motif characterized by an alpha-beta-beta-beta-alpha fold that binds DOUBLE-STRANDED RNA. It occurs in many eukaryotic proteins as well as in bacterial and viral proteins.. anxiety defined as following: Persistent and disabling ANXIETY..", "label": "yes"} {"id": "converted_2370", "sentence1": "Can the yeast protein Abf1 act as insulator?", "sentence2": "Saccharomyces cerevisiae Rap1p and Abf1p proteins are endowed with a potent insulating capacity, Insulating domains in Rap1p coincide with previously described transcription activation domains, whereas four adjacent subdomains spanning the whole of the Abf1p C terminus (440-731) were found to display autonomous insulating capacity, That both Rap1p and Abf1p silencing domains either contain or largely overlap with an insulating domain suggests that insulation conveys some undefined chromosome organization capacity that also contributes a function in silencing. [SEP]", "label": "yes"} {"id": "converted_3572", "sentence1": "Does the Mcm2-Ctf4-Polα axis play a role in transfer of histones to leading strand DNA at the replication forks?", "sentence2": "The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands., Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)2 tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Polα axis facilitates the transfer of parental (H3-H4)2 tetramers to lagging-strand DNA at replication forks. Mutating the conserved histone-binding domain of the Mcm2 subunit of the CMG (Cdc45-MCM-GINS) DNA helicase, which translocates along the leading-strand template, results in a marked enrichment of parental (H3-H4)2 on leading strand, due to the impairment of the transfer of parental (H3-H4)2 to lagging strands. Similar effects are observed in Ctf4 and Polα primase mutants that disrupt the connection of the CMG helicase to Polα that resides on lagging-strand template. Our results support a model whereby parental (H3-H4)2 complexes displaced from nucleosomes by DNA unwinding at replication forks are transferred by the CMG-Ctf4-Polα complex to lagging-strand DNA for nucleosome assembly at the original location.[SEP]Definitions: DNA defined as following: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).. nucleosomes defined as following: The repeating structural units of chromatin, each consisting of approximately 200 base pairs of DNA wound around a protein core. This core is composed of the histones H2A, H2B, H3, and H4.. nucleosome assembly defined as following: The aggregation, arrangement and bonding together of a nucleosome, the beadlike structural units of eukaryotic chromatin composed of histones and DNA. [GOC:mah]. DNA helicase defined as following: Proteins that catalyze the unwinding of duplex DNA during replication by binding cooperatively to single-stranded regions of DNA or to short regions of duplex DNA that are undergoing transient opening. In addition, DNA helicases are DNA-dependent ATPases that harness the free energy of ATP hydrolysis to translocate DNA strands.. complexes defined as following: A molecular entity formed by loose association involving two or more component molecular entities. The bonding between the components is normally weaker than in a covalent bond.. histones defined as following: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each..", "label": "no"} {"id": "converted_616", "sentence1": "Is statin use associated with improved outcomes after aneurysmal subarachnoid hemorrhage?", "sentence2": "Statins have been shown in two recent small phase I/II trials to be associated with a marked reduction in clinical and transcranial Doppler (TCD) evidence of vasospasm after aneurysmal subarachnoid haemorrhage (SAH). , Statins did not result in reduced TCD velocities, clinical or angiographic vasospasm, or improvements in global outcome at the time of hospital discharge. , There remains significant uncertainty as to the role of statins in preventing vasospasm after SAH., Although the results of 2 randomized clinical trials demonstrated that statin decreases the incidence of symptomatic cerebral vasospasm after aSAH, retrospective studies have failed to confirm this., There were no differences in the incidence of symptomatic vasospasm (25.3 vs 30.5%; p = 0.277), in-hospital mortality rate (18 vs 15%; p = 0.468), length of hospitalization (21 +/- 15 vs 19 +/- 12 days; p = 0.281), or poor outcome at discharge (Glasgow Outcome Scale Scores 1-2: 21.7 vs 18.2%; p = 0.416) between the simvastatin and nonstatin cohorts. , The uniform introduction of simvastatin did not reduce the incidence of symptomatic cerebral vasospasm, death, or poor outcome in patients with aSAH. Simvastatin was well tolerated, but its benefit may be less than has been previously reported., Cholesterol-reducing agents might improve unfavourable outcomes., We cannot draw any conclusions about the effectiveness and safety of lowering cholesterol in aneurysmal SAH because of insufficient reliable evidence from only one small trial., Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid hemorrhage., There was an improvement in the functional outcome in the simvastatin group at 1, 3 or 6 months in the follow-up; however, this difference was not statistically significant., There was benefit of simvastatin in terms of reduction in clinical vasospasm, mortality or improved functional outcome, however, this was not statistically significant., Cerebral vasomotor reactivity, however, is significantly improved after long-term statin administration in most patients with severe small vessel disease, aneurysmal subarachnoid hemorrhage, or impaired baseline CA., Atorvastatin decreases computed tomography and S100-assessed brain ischemia after subarachnoid aneurysmal hemorrhage: a comparative study., In the overall population, cerebral vasospasm was significantly less common in the statin-treated group. Severity of vasospasm, as assessed on the most severe angiogram, was lowered with statin. Statins significantly reduced volume of ischemia in patients with vasospasm and an uncomplicated coiling procedure. S100B levels were significantly lower in statin-treated patients, and the decrease was greatest among high-grade patients (World Federation of Neurological Surgeons 3-5). No differences were found between statin-treated and untreated groups regarding rescue therapy intensity or 1-yr clinical outcomes., Atorvastatin reduces the incidence, the severity and the ischemic consequences of vasospasm as assessed on computed tomography. In high-grade World Federation of Neurological Surgeons patients, atorvastatin decreases serum levels of S100B, a biomarker of brain ischemia. Despite these positive effects on biomarkers, no improvement of outcome was seen in the overall population, although there was a tendency for a better clinical outcome in high-grade patients., 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved clinical outcomes after ischemic stroke and subarachnoid hemorrhage, but with an increased risk of incidental spontaneous intracerebral hemorrhage (ICH)., Statins are known to have pleiotropic vascular effects, some of which may interrupt the pathogenesis of DNDs. Based on promising preliminary reports, many clinicians routinely administer statins to prevent DNDs., However, observational studies have not revealed an association between statin-use and reduced DNDs or improved neurological outcomes. Results of RCTs have been inconsistent and limited by small sample size, but together suggest that statins may reduce DNDs, with no clear impact on mortality or neurological recovery., the role of statins in the management of patients with SAH remains unclear. Although promising, statins should not, at this time, be considered standard care., In patients with SAH, they may decrease the incidence of symptomatic vasospasm, although the effects on overall outcome are less clear., Statins treatment may have potential clinical impact in vascular disease beyond cholesterol lowering. Its benefits have been documented in cerebral ischaemia and in subarachnoid haemorrhage., A recent meta-analysis investigating the efficacy of statin treatment in patients with aneurysmal subarachnoid hemorrhage reported a reduced incidence of vasospasm, delayed cerebral ischemia, and mortality in statin-treated patients., The results of the present systematic review do not lend statistically significant support to the finding of a beneficial effect of statins in patients with aneurysmal subarachnoid hemorrhage as reported in a previous meta-analysis., Pre-treatment with cholesterol lowering drugs of the statin family may exert protective effects in patients with ischaemic stroke and subarachnoid haemorrhage but their effects are not clear in patients with intracerebral haemorrhage (ICH). , Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality., We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH., Novel uses of their anti-inflammatory properties in sepsis and vasomotor properties in subarachnoid haemorrhage are being further investigated by randomised trials., A trend towards a lower mortality within 14 days in patients receiving solely simvastatin and those receiving statin and magnesium as compared with the control group was found. , Initiation of statin therapy after aneurysmal SAH significantly reduces the incidence of vasospasm, delayed ischemic deficits, and mortality., The addition of statins to standard care was not associated with any reduction in the development of vasospasm or improvement in outcomes after aneurysmal subarachnoid hemorrhage. , We have previously demonstrated that acute pravastatin therapy after aneurysmal subarachnoid hemorrhage ameliorates vasospasm-related delayed ischemic deficits., This trial demonstrates that acute statin treatment reduces traditional rescue therapy for vasospasm after aneurysmal subarachnoid hemorrhage. Improvement in early outcome has proved robust at 6 months, particularly in relation to physical and psychosocial (Short Form 36) outcome., The authors previously have demonstrated that acute treatment with pravastatin after aneurysmal subarachnoid hemorrhage (SAH) can ameliorate vasospasm-related delayed ischemic neurological deficits (DINDs)., The neuroprotective effects of acute treatment with pravastatin following aneurysmal SAH are associated with enhancement of autoregulation, Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial., The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit., Acute treatment with pravastatin after aSAH is safe and ameliorates cerebral vasospasm, improves cerebral autoregulation, and reduces vasospasm-related DID., SAH statin users demonstrated significant improvement in 14-day functional outcome, a significantly lower incidence of DCI and cerebral infarctions of any type, as well as prevention of TCD highest mean velocity elevation. However, we did not find a significant statin impact on mortality or global outcome (Modified Rankin Scale) in this small sample. [SEP]Definitions: Statins defined as following: Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis.. ischemia defined as following: A surgical procedure during which the blood supply to an organ or tissue is interrupted and then later reestablished.. ischaemic stroke defined as following: An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of brain tissue.. SAH defined as following: A Turkic language spoken by the Yakut people in the Sakha Republic in the Russian Federation.. Simvastatin defined as following: A derivative of LOVASTATIN and potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL RECEPTORS, it increases breakdown of LDL CHOLESTEROL.. cholesterol defined as following: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.. brain injury defined as following: Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.. Atorvastatin defined as following: A synthetic lipid-lowering agent. Atorvastatin competitively inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. Atorvastatin also increases the number of LDL receptors on hepatic cell surfaces to enhance uptake and catabolism of LDL and reduces LDL production and the number of LDL particles. This agent lowers plasma cholesterol and lipoprotein levels and modulates immune responses by suppressing MHC II (major histocompatibility complex II) on interferon gamma-stimulated, antigen-presenting cells such as human vascular endothelial cells. (NCI04). subarachnoid haemorrhage defined as following: Bleeding into the intracranial or spinal SUBARACHNOID SPACE, most resulting from INTRACRANIAL ANEURYSM rupture. It can occur after traumatic injuries (SUBARACHNOID HEMORRHAGE, TRAUMATIC). Clinical features include HEADACHE; NAUSEA; VOMITING, nuchal rigidity, variable neurological deficits and reduced mental status.. cerebral ischaemia defined as following: Diminished or absent blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurologic damage.. vascular disease defined as following: Pathological processes involving any of the BLOOD VESSELS in the cardiac or peripheral circulation. They include diseases of ARTERIES; VEINS; and rest of the vasculature system in the body.. intracerebral haemorrhage defined as following: Bleeding into one or both CEREBRAL HEMISPHERES including the BASAL GANGLIA and the CEREBRAL CORTEX. It is often associated with HYPERTENSION and CRANIOCEREBRAL TRAUMA.. vasospasm defined as following: spasm of the blood vessels resulting in decrease in their caliber.. pravastatin defined as following: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES).. death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. S100B defined as following: This gene is involved in metal-ion binding.. DCI defined as following: A noninvasive (noninfiltrating) carcinoma of the breast characterized by a proliferation of malignant epithelial cells confined to the mammary ducts or lobules, without light-microscopy evidence of invasion through the basement membrane into the surrounding stroma.. cerebral infarctions defined as following: The formation of an area of NECROSIS in the CEREBRUM caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., INFARCTION, ANTERIOR CEREBRAL ARTERY), and etiology (e.g., embolic infarction).. aSAH defined as following: Human ASAH1 wild-type allele is located in the vicinity 8p22 of and is approximately 29 kb in length. This allele, which encodes acid ceramidase protein, is involved in ceramide metabolism. Mutation of the gene is associated with both Farber lipogranulomatosis and spinal muscular atrophy with progressive myoclonic epilepsy..", "label": "yes"} {"id": "converted_3217", "sentence1": "Is ustekinumab a polyclonal antibody?", "sentence2": "Ustekinumab, a human monoclonal IgG1 antibody targeting the p40-subunit shared by interleukin (IL)12 and IL-23, represents a potential treatment for atopic dermatitis (AD).[SEP]Definitions: atopic dermatitis defined as following: A chronic inflammatory genetically determined disease of the skin marked by increased ability to form reagin (IgE), with increased susceptibility to allergic rhinitis and asthma, and hereditary disposition to a lowered threshold for pruritus. It is manifested by lichenification, excoriation, and crusting, mainly on the flexural surfaces of the elbow and knee. In infants it is known as infantile eczema.. IL-23 defined as following: Binding to interleukin-23. [GOC:jl]. human defined as following: Members of the species Homo sapiens.. polyclonal antibody defined as following: A heterogeneous antibody derived from a host organism, typically produced by immunization of a suitable mammal with an antigen which induces B-lymphocytes to produce IgG immunoglobulins specific for the antigen. The resulting collection of antibodies have specificity for different epitopes of the antigen..", "label": "no"} {"id": "converted_4098", "sentence1": "Is Nanog repressed in pluripotent stem cells?", "sentence2": "Aggregation of embryonic stem cells induces Nanog repression and primitive endoderm differentiation, Interestingly, cell aggregation by itself induced Nanog repression at the outer layer, which was essential for aggregation-induced primitive endoderm formation, early embryonic development, when downregulation of Nanog plays a crucial role., The homeobox gene Nanog is a key intrinsic determinant of self renewal in embryonic stem (ES) cells, and its repression leads ES cells to selectively differentiate into primitive endoderm., These data indicate that the Grb2/Mek pathway primarily mediates Nanog gene repression upon ES cell differentiation into primitive endoderm., Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells, Nanog and Oct4 are essential transcription factors that regulate self-renewal and pluripotency of ES cells. , the mechanisms by which Nanog and Oct4 modulate ES cell fate remain unknown. , Nanog, Oct4 and repressor proteins co-occupy Nanog-target genes in mouse ES cells, suggesting that Nanog and Oct4 together may communicate with distinct repression complexes to control gene transcription., Nanog and Oct4 associate with unique repressor complexes on their target genes to control ES cell fate., he main finding of this study is that knockdown of Trp53 and Pten independently resulted in significantly higher expression levels of the pluripotency-associated gene Nanog, and we hypothesize that TRP53 and PTEN mediated repression is important for the insulation of male germ cells from pluripotency., The homeodomain transcription factor NANOG plays a central role in maintaining hESC pluripotency, The newly derived NANOG reporter hESC lines present novel tools to visualize NANOG expression in viable hESCs. , Loss of Pten causes tumor initiation following differentiation of murine pluripotent stem cells due to failed repression of Nanog., Furthermore, our data show that the mechanism by which Pten null ECCs emerge in vitro and cause tumors in vivo is through increased survival and self-renewal, due to failed repression of the transcription factor Nanog., We report here that Nanog and Oct4 are reexpressed in two mouse embryonic stem cell (mESC) lines following exposure to the differentiating agent DETA/NO., Furthermore, Nanog binding to the promoter of Brachyury leads to repression of this gene, thus disrupting mesendoderm transition., Maintaining pluripotency and indefinite self-renewal of embryonic stem cells requires a tight control of the expression of several key stemness factors, particularly Nanog and Oct4 transcription factors., Current evidence suggests that ES cells maintain their pluripotent state by expressing a battery of transcription factors including Oct4 and Nanog., Embryonic stem (ES) cell pluripotency is dependent upon sustained expression of the key transcriptional regulators Oct4, Nanog, and Sox2., The expression of Oct4 is activated by FoxD3 and Nanog but repressed by Oct4 itself, thus, exerting an important negative feedback loop to limit its own activity., Nanog, Oct4, and Sox2 form the core of a transcription factor network that maintains embryonic stem cells in the pluripotent state in both humans and mice., w that Bmi1 is enriched in the extraembryonic (endoderm [XEN] and trophectodermal stem [TS]) compartment and repressed by Nanog in pluripotent embryonic stem (ES) cells. In vivo, Bm, Nanog is a newly identified transcriptional factor bearing a homeodomain and expressed in pluripotential cells of preimplantation and early postimplantation embryos, and embryonic stem (ES) and embryonic germ (EG) cells., Knockout experiments indicate that Nanog functions as a key player in maintaining the pluripotency of stem cells., Thus, in germ cell development, NANOG is expressed in proliferating germ cells, in which nuclear reprogramming is progressing., Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkappaB and cooperating with Stat3., We performed a genome-wide screen that combined full-length mESC transcriptome genomic mapping data with chromatin immunoprecipitation genomic location maps of the key mESC transcription factors Oct4 and Nanog., Nanog safeguards pluripotency in mouse embryonic stem cells (mESCs)., Notably, the expression of Nanog, a key pluripotency regulator and repressor of extraembryonic endoderm specification in ES cells, was significantly reduced in Zic3 knockdown cells.[SEP]Definitions: Nanog gene defined as following: This gene plays a role in the underlying pluripotency of inner cell mass and embryonic stem cells.. FoxD3 defined as following: Forkhead box protein D3 (478 aa, ~48 kDa) is encoded by the human FOXD3 gene. This protein is involved in embryonic development.. endoderm defined as following: The inner of the three germ layers of an embryo.. TRP53 defined as following: Human TP53 wild-type allele is located in the vicinity of 17p13.1 and is approximately 19 kb in length. This allele, which encodes cellular tumor antigen p53 protein, plays a role in cell cycle regulation during the G0/G1transition. Alterations of the TP53 gene occur as both somatic and germline mutations in human malignancies in select cancer-prone families with Li-Fraumeni syndrome.. stem cells defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. Zic3 defined as following: Human ZIC3 wild-type allele is located in the vicinity of Xq26.2 and is approximately 11 kb in length. This allele, which encodes zinc finger protein ZIC 3, plays roles in transcription, cardiac and neural development and left-right specification. Mutations are associated with X-linked heterotaxy.. Sox2 defined as following: Transcription factor SOX-2 protein (317 aa, ~34 kDa) is encoded by the human SOX2 gene. This protein is involved in neural cell progenitor differentiation and neurogenesis.. mESC defined as following: PLURIPOTENT STEM CELLS derived from the BLASTOCYST INNER CELL MASS of day 3.5 mouse embryos.. homeodomain defined as following: The DNA-binding homeo domain was originally identified in transcription factor proteins encoded by homeobox genes (homeotic genes). The homeo domain is structurally similar to the helix-turn-helix DNA-binding domain of CRO and Lambda repressor.. Pten defined as following: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (403 aa, ~47 kDa) is encoded by the human PTEN gene. This protein plays a role in signaling and as both a dual-specificity phosphoprotein phosphatase and a lipid phosphatase.. Stat3 defined as following: Signal transducer and activator of transcription 3 (770 aa, ~88 kDa) is encoded by the human STAT3 gene. This protein plays a role in cytokine signaling and gene expression.. Bmi1 defined as following: Polycomb complex protein BMI-1 (326 aa, ~37 kDa) is encoded by the human BMI1 gene. This protein is involved in transcriptional repression during embryonic development.. complexes defined as following: A molecular entity formed by loose association involving two or more component molecular entities. The bonding between the components is normally weaker than in a covalent bond.. embryonic stem cells defined as following: Cells derived from the BLASTOCYST INNER CELL MASS which forms before implantation in the uterine wall. They retain the ability to divide, proliferate and provide progenitor cells that can differentiate into specialized cells.. Oct4 defined as following: This gene plays a role in early mammalian development.. promoter defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. NFkappaB defined as following: This gene is involved in the regulation of apoptosis, signal transduction and gene transcription.. germ cells defined as following: The reproductive cells in multicellular organisms at various stages during GAMETOGENESIS.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. hESCs defined as following: A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage.. humans defined as following: Members of the species Homo sapiens.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. Nanog defined as following: This gene plays a role in the underlying pluripotency of inner cell mass and embryonic stem cells.. pluripotent stem cells defined as following: Cells that can give rise to cells of the three different GERM LAYERS..", "label": "no"} {"id": "converted_828", "sentence1": "Is muscle lim protein (MLP) involved in cardiomyopathies?", "sentence2": "Muscle LIM protein (MLP) has been proposed to be a central player in the pathogenesis of heart muscle disease. In line with this notion, the homozygous loss of MLP results in cardiac hypertrophy and dilated cardiomyopathy. Moreover, MLP is induced in several models of cardiac hypertrophy such as aortic banding and myocardial infarction. , Muscle LIM protein (MLP) null mice are often used as a model for human dilated cardiomyopathy., A lack of MLP leads to an age-dependent impairment of excitation-contraction coupling with resulting contractile dysfunction and secondary fibrosis., Loss of murine MLP results in dilated cardiomyopathy, and mutations in human MLP lead to cardiac hypertrophy, indicating a critical role for MLP in maintaining normal cardiac function., Our data indicate that MLP contributes to muscle stiffness and is necessary for maximum work and power generation., Interestingly, MLP was also found to be down-regulated in humans with heart failure (Zolk et al. Circulation 101:2674-2677, 2000) and MLP mutations are able to cause hypertrophic and dilated forms of cardiomyopathy in humans (Bos et al. Mol Genet Metab 88:78-85, 2006; Geier et al. Circulation 107:1390-1395, 2003; Hershberger et al. Clin Transl Sci 1:21-26, 2008; Knöll et al. Cell 111:943-955, 2002; Knöll et al. Circ Res 106:695-704, 2010; Mohapatra et al. Mol Genet Metab 80:207-215, 2003)., MLP soon became an important model for experimental cardiology when it was first demonstrated that MLP deficiency leads to myocardial hypertrophy followed by a dilated cardiomyopathy and heart failure phenotype (Arber et al. Cell 88:393-403, 1997). , Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. , We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation., Muscle LIM protein (MLP) is a cytoskeletal protein located at the Z-disc of sarcomeres. Mutations in the human MLP gene are associated with hypertrophic and dilated cardiomyopathy., Our data demonstrate that Mlp84B is essential for normal cardiac function and establish the Drosophila model for the investigation of the mechanisms connecting defective cardiac Z-disc components to the development of cardiomyopathy., Muscle LIM protein (MLP) is a cytoskeletal LIM-only protein expressed in striated muscle. Mutations in human MLP are associated with cardiomyopathy;, TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte's stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). , Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations. MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation. The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation., MLP (muscle-LIM-protein) deficient mice develop DCM and changes in the mechanical coupling of cardiomyocytes result in alterations at the intercalated disks and enhanced accumulation of adherens junction proteins., Targeted deletion of cytoskeletal muscle LIM protein (MLP) in mice consistently leads to dilated cardiomyopathy (DCM) after one or more months. , In summary, young MLPKO mice revealed substantial alterations in passive myocardial properties and relaxation time, but not in most systolic characteristics. These results indicate that the progression to heart failure in the MLPKO model may be driven by diastolic myocardial dysfunction and abnormal passive properties rather than systolic dysfunction., Mice lacking the muscle LIM protein (MLP) develop morphological and clinical signs resembling human dilated cardiomyopathy and heart failure., Our results show that the absence of MLP causes a local loss of mitochondria. We hypothesize that this is caused by a disturbed interaction between cytoskeleton and mitochondria, which interferes with energy sensing and energy transfer. Recovery of energy depletion by stimulating mitochondrial biogenesis might be a useful therapeutic strategy for improving the energy imbalance in heart failure., Previous work has shown that mutations in muscle LIM protein (MLP) can cause hypertrophic cardiomyopathy (HCM). In order to gain an insight into the molecular basis of the disease phenotype, we analysed the binding characteristics of wild-type MLP and of the (C58G) mutant MLP that causes hypertrophic cardiomyopathy., The molecular basis for HCM-causing mutations in the MLP gene might therefore be an alteration in the equilibrium of interactions of the ternary complex MLP-N-RAP-alpha-actinin., Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and alpha-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure., We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). , MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans., Family studies revealed cosegregation of clinically affected individuals with the respective mutations in MLP. CONCLUSION: Here, we present evidence that mutations in the CRP3/MLP gene can cause HCM., The skeletal muscle LIM protein 1 (SLIM1) is highly expressed in skeletal and cardiac muscle, and its expression is downregulated significantly in dilated human cardiomyopathy. , Targeted disruption of muscle LIM protein (MLP) has previously been shown to result in dilated cardiomyopathy with many of the clinical signs of heart failure, although the effects of MLP disruption on passive ventricular mechanics and myocyte architecture are not known., These results suggest that the disruption of the cytoskeletal protein MLP results in less compliant passive tissue and concomitant structural alterations in the three-dimensional myocyte architecture that may in part explain the ventricular dysfunction in the dilated heart., Mutations in cysteine and glycine-rich protein 3 (CSRP3), the gene encoding MLP, have been directly associated with human cardiomyopathies, whereas aberrant expression patterns are reported in human cardiac and skeletal muscle diseases., Muscle LIM protein (MLP) has been proposed to be a central player in the pathogenesis of heart muscle disease., Previous work has shown that mutations in muscle LIM protein (MLP) can cause hypertrophic cardiomyopathy (HCM)[SEP]Definitions: cysteine defined as following: A thiol-containing non-essential amino acid that is oxidized to form CYSTINE.. mitochondria defined as following: Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed). cardiomyocytes defined as following: Striated muscle cells found in the heart. They are derived from cardiac myoblasts (MYOBLASTS, CARDIAC).. heart muscle disease defined as following: A group of diseases in which the dominant feature is the involvement of the CARDIAC MUSCLE itself. Cardiomyopathies are classified according to their predominant pathophysiological features (DILATED CARDIOMYOPATHY; HYPERTROPHIC CARDIOMYOPATHY; RESTRICTIVE CARDIOMYOPATHY) or their etiological/pathological factors (CARDIOMYOPATHY, ALCOHOLIC; ENDOCARDIAL FIBROELASTOSIS).. muscle defined as following: Contractile tissue that produces movement in animals.. EFE defined as following: A condition characterized by the thickening of ENDOCARDIUM due to proliferation of fibrous and elastic tissue, usually in the left ventricle leading to impaired cardiac function (CARDIOMYOPATHY, RESTRICTIVE). It is most commonly seen in young children and rarely in adults. It is often associated with congenital heart anomalies (HEART DEFECTS CONGENITAL;) INFECTION; or gene mutation. Defects in the tafazzin protein, encoded by TAZ gene, result in a form of autosomal dominant familial endocardial fibroelastosis.. heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs.. genetic defined as following: Having to do with information that is passed from parents to offspring through genes in sperm and egg cells.. zyxin defined as following: Zyxin (572 aa, ~61 kDa) is encoded by the human ZYX gene. This protein is involved in focal adhesion assembly and function.. Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. striated muscle defined as following: A subtype of striated muscle, attached by TENDONS to the SKELETON. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles.. cytosolic defined as following: Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.. DCM defined as following: A chlorinated methotrexate derivative. Dichloromethotrexate inhibits the enzyme dihydrofolate reductase, thereby preventing the synthesis of purine nucleotides and thymidylates and inhibiting DNA and RNA synthesis. This agent is metabolized and excreted by the liver. (NCI04). HCM defined as following: A form of CARDIAC MUSCLE disease, characterized by left and/or right ventricular hypertrophy (HYPERTROPHY, LEFT VENTRICULAR; HYPERTROPHY, RIGHT VENTRICULAR), frequent asymmetrical involvement of the HEART SEPTUM, and normal or reduced left ventricular volume. Risk factors include HYPERTENSION; AORTIC STENOSIS; and gene MUTATION; (FAMILIAL HYPERTROPHIC CARDIOMYOPATHY).. dilated cardiomyopathy defined as following: Cardiomyopathy which is characterized by dilation and contractile dysfunction of the left and right ventricles. It may be idiopathic, or it may result from a myocardial infarction, myocardial infection, or alcohol abuse. It is a cause of congestive heart failure.. mutant defined as following: An altered form of an individual, organism, population, or genetic character that differs from the corresponding wild type due to one or more alterations (mutations).. alpha-actinin defined as following: cytoskeletal protein present in Z lines of muscle fibrils and at sites of non-muscle cell contact with a substrate.. myocardial hypertrophy defined as following: Thickening of the myocardium often due to chronic pressure overload.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. myocyte defined as following: Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal (MUSCLE FIBERS, SKELETAL), cardiac (MYOCYTES, CARDIAC), and smooth (MYOCYTES, SMOOTH MUSCLE). They are derived from embryonic (precursor) muscle cells called MYOBLASTS.. Z-disc defined as following: Platelike region of a muscle sarcomere to which the plus ends of actin filaments are attached. [GOC:mtg_muscle, ISBN:0815316194]. arginine defined as following: An essential amino acid that is physiologically active in the L-form.. monoclonal antibody defined as following: A humanized monoclonal antibody directed against parathyroid hormone-related protein (PTH-rP). As a poly-hormone with diverse biological roles, PTH-rP is expressed by normal tissues, acting in local tissue environments in a variety of ways; it is commonly overexpressed by breast, prostate, and other cancers, acting systemically by promoting bone resorption, inhibiting calcium excretion from the kidney, inducing hypercalcemia, and possibly playing a role in the formation of bony metastases. By blocking the effects of PTH-rP on calcium metabolism, monoclonal antibody CAL may inhibit cancer-related hypercalcemia. (NCI04). genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. cytoskeletal defined as following: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm.. sarcomere defined as following: The repeating contractile units of the MYOFIBRIL, delimited by Z bands along its length.. cytoskeletal protein defined as following: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. cardiac hypertrophy defined as following: Enlargement of the HEART due to chamber HYPERTROPHY, an increase in wall thickness without an increase in the number of cells (MYOCYTES, CARDIAC). It is the result of increase in myocyte size, mitochondrial and myofibrillar mass, as well as changes in extracellular matrix.. humans defined as following: Members of the species Homo sapiens.. ventricular dysfunction defined as following: A condition in which HEART VENTRICLES exhibit impaired function.. muscle stiffness defined as following: A feeling of tension or tightness in one or more muscles.. cardiomyopathies defined as following: A group of diseases in which the dominant feature is the involvement of the CARDIAC MUSCLE itself. Cardiomyopathies are classified according to their predominant pathophysiological features (DILATED CARDIOMYOPATHY; HYPERTROPHIC CARDIOMYOPATHY; RESTRICTIVE CARDIOMYOPATHY) or their etiological/pathological factors (CARDIOMYOPATHY, ALCOHOLIC; ENDOCARDIAL FIBROELASTOSIS)..", "label": "yes"} {"id": "converted_1206", "sentence1": "Is the SDHAF2 gene encoding a protein necessary for flavination of SDHA?", "sentence2": "Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. , At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes., the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), SDHAF2, required for flavination of SDHA, At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes., Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA., In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function., At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes, Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA, CONTEXT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. , This gene is co-expressed with a number of genes encoding mitochondrial proteins, including SDH1-1, and has low partial sequence similarity to human SDHAF2, a protein required for flavin-adenine dinucleotide (FAD) insertion into SDH. , At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes., Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA.[SEP]Definitions: NF1 defined as following: An autosomal dominant inherited disorder (with a high frequency of spontaneous mutations) that features developmental changes in the nervous system, muscles, bones, and skin, most notably in tissue derived from the embryonic NEURAL CREST. Multiple hyperpigmented skin lesions and subcutaneous tumors are the hallmark of this disease. Peripheral and central nervous system neoplasms occur frequently, especially OPTIC NERVE GLIOMA and NEUROFIBROSARCOMA. NF1 is caused by mutations which inactivate the NF1 gene (GENES, NEUROFIBROMATOSIS 1) on chromosome 17q. The incidence of learning disabilities is also elevated in this condition. (From Adams et al., Principles of Neurology, 6th ed, pp1014-18) There is overlap of clinical features with NOONAN SYNDROME in a syndrome called neurofibromatosis-Noonan syndrome. Both the PTPN11 and NF1 gene products are involved in the SIGNAL TRANSDUCTION pathway of Ras (RAS PROTEINS).. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. SDH defined as following: A flavoprotein containing oxidoreductase that catalyzes the dehydrogenation of SUCCINATE to fumarate. In most eukaryotic organisms this enzyme is a component of mitochondrial electron transport complex II.. SDHB defined as following: Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (280 aa, ~32 kDa) is encoded by the human SDHB gene. This protein plays a role in the mediation of redox reactions in the mitochondrial electron transport chain.. SDHAF2 defined as following: Succinate dehydrogenase assembly factor 2, mitochondrial (166 aa, ~20 kDa) is encoded by the human SDHAF2 gene. This protein is involved in the regulation of electron transport between succinate and ubiquinone.. TMEM127 defined as following: This gene may play a role in signaling and protein trafficking.. succinate dehydrogenase defined as following: This gene is involved in the electron transport chain.. SDHD defined as following: Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (159 aa, ~17 kDa) is encoded by the human SDHD gene. This protein plays a role in the regulation of the electron transport chain.. SDHA defined as following: Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial (664 aa, ~73 kDa) is encoded by the human SDHA gene. This protein is involved in the mitochondrial electron transport chain.. FAD defined as following: A condensation product of riboflavin and adenosine diphosphate. The coenzyme of various aerobic dehydrogenases, e.g., D-amino acid oxidase and L-amino acid oxidase. (Lehninger, Principles of Biochemistry, 1982, p972). SDH1 defined as following: Human SDHB wild-type allele is located within 1p36.1-p35 and is approximately 35 kb in length. This allele, which encodes succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial protein, is involved in the electron transport chain. Mutation of the gene is associated with pheochromocytoma, hereditary paraganglioma type 4, Carney-Stratakis syndrome and Cowden-like syndrome.. insertion defined as following: Something inserted or to be inserted.. SDHC defined as following: Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (169 aa, ~19 kDa) is encoded by the human SDHC gene. This protein is involved in the localization of succinate dehydrogenase.. mitochondrial proteins defined as following: Proteins encoded by the mitochondrial genome or proteins encoded by the nuclear genome that are imported to and resident in the MITOCHONDRIA.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. RET proto-oncogene defined as following: This gene plays an essential role in neural crest development, cellular growth and differentiation. Mutations in the gene are associated with a variety of neoplasias and carcinomas.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. VHL defined as following: An autosomal dominant disorder caused by mutations in a tumor suppressor gene. This syndrome is characterized by abnormal growth of small blood vessels leading to a host of neoplasms. They include HEMANGIOBLASTOMA in the RETINA; CEREBELLUM; and SPINAL CORD; PHEOCHROMOCYTOMA; pancreatic tumors; and renal cell carcinoma (see CARCINOMA, RENAL CELL). Common clinical signs include HYPERTENSION and neurological dysfunctions.. SDHAF2 gene defined as following: This gene is involved in the electron transport chain..", "label": "yes"} {"id": "converted_856", "sentence1": "Is Dicer part of the RISC loading complex?", "sentence2": "Dicer is a component of the protein machinery (the RNA Induced Silencing Complex [RISC]) which is involved in catalyzing the formation of mature microRNAs from their precursors in the process of microRNA biogenesis., RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators., The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. , Although the major RNAi pathway proteins are found in most subcellular compartments, the miRNA- and siRNA-loaded Ago2 populations co-sediment almost exclusively with the rER membranes, together with the RISC loading complex (RLC) factors Dicer, TAR RNA binding protein (TRBP) and protein activator of the interferon-induced protein kinase (PACT)., RNA interference (RNAi) is mediated by small interfering RNAs (siRNAs), which are liberated from double-stranded (ds)RNA precursors by Dicer and guide the RNA-induced silencing complex (RISC) to targets., . Dicer, an RNase III enzyme, plays a central role in the RNAi pathway by cleaving precursors of both of these classes of RNAs to form mature siRNAs and miRNAs, which are then loaded into the RNA-induced silencing complex (RISC). , Canonical siRNAs are 21 nucleotides (nt) in length and are loaded to the RNA Induced Silencing Complex when introduced into the cells, while longer siRNA molecules are first processed by endogenous Dicer and thus termed Dicer-substrate siRNA (DsiRNA). [SEP]Definitions: RNAs defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). Dicer defined as following: Endoribonuclease Dicer (1922 aa, ~219 kDa) is encoded by the human DICER1 gene. This protein plays a role in both pri-miRNA processing and RNA interference.. RLC defined as following: Human ITGA9 wild-type allele is located in the vicinity of 3p22.2 and is approximately 371 kb in length. This allele, which encodes integrin alpha-9 protein, plays a role in cell adhesion-regulated signaling. Aberrant expression is associated with small cell lung cancers.. small interfering RNAs defined as following: Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.. miRNAs defined as following: Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing.. RISC defined as following: A RNA-protein complex that catalyzes facilitates the association of either a microRNA or a small interfering RNA with its complementary coding RNA and then degrades the targeted coding RNA molecule.. molecules defined as following: An aggregate of two or more atoms in a defined arrangement held together by chemical bonds.. nucleotides defined as following: The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed). cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. RNA binding protein defined as following: Proteins that bind to RNA molecules. Included here are RIBONUCLEOPROTEINS and other proteins whose function is to bind specifically to RNA.. TAR defined as following: A rare syndrome characterized by the presence of thrombocytopenia associated with bilateral absence of the radius bone.. Ago2 defined as following: Protein argonaute-2 (859 aa, ~97 kDa) is encoded by the human AGO2 gene. This protein plays a role in RNA catabolism..", "label": "yes"} {"id": "converted_3854", "sentence1": "Are super enhancers structurally insulated in chromatin loops?", "sentence2": "Dissecting super-enhancer hierarchy based on chromatin interactions, Genetic ablation of hub enhancers results in profound defects in gene activation and local chromatin landscape., We also demonstrate that the Wap super-enhancer, which is built on STAT5 and other common transcription factors, retains its exquisite mammary specificity when placed into globally permissive chromatin, suggesting a limited role of chromatin in controlling cell specificity. , Although there is evidence that chromatin neighbourhoods, formed by the zinc-finger protein CTCF, can sequester enhancers and their target genes, there is limited in vivo evidence for CTCF demarcating super-enhancers and preventing cross talk between distinct regulatory elements., CTCF sites are porous borders, allowing a super-enhancer to activate a secondary target., Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. [SEP]Definitions: embryonic stem cell defined as following: Cells derived from the BLASTOCYST INNER CELL MASS which forms before implantation in the uterine wall. They retain the ability to divide, proliferate and provide progenitor cells that can differentiate into specialized cells.. STAT5 defined as following: Two highly conserved members of the signal transducer and activator of transcription (STAT) protein family, STAT5A and STAT5B. Constitutive phosphorylation of STAT5 proteins, which leads to constitutive activation and aberrant expression of STAT5-dependent genes, has been observed in various neoplastic diseases.. CTCF defined as following: CCN family member 2 (349 aa, ~38kDa) is encoded by the human CCN2 gene. This protein plays a role in the promotion of proliferation and differentiation of chondrocytes and also mediates heparin- and divalent cation-dependent cell adhesion in many different cell types.. sites defined as following: A position in relation to its surroundings.. Transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. chromatin defined as following: The ordered and organized complex of DNA, protein, and sometimes RNA, that forms the chromosome. [GOC:elh, PMID:20404130]. mammary defined as following: Glandular tissue in the BREAST of human that is under the influence of hormones such as ESTROGENS; PROGESTINS; and PROLACTIN. In WOMEN, after PARTURITION, the mammary glands secrete milk (MILK, HUMAN) for the nourishment of the young.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "no"} {"id": "converted_3482", "sentence1": "Is PF-05190457 an inverse agonist of the ghrelin receptor?", "sentence2": "Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects., To evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults., PF-05190457 is a well-tolerated first-in-class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing.[SEP]Definitions: agonist defined as following: An agent that has affinity for a receptor and intrinsic activity at that receptor.. ghrelin receptor defined as following: Transmembrane proteins that recognize and bind GHRELIN, a potent stimulator of GROWTH HORMONE secretion and food intake in mammals. Ghrelin receptors are found in the pituitary and HYPOTHALAMUS. They belong to the family of G-PROTEIN-COUPLED RECEPTORS..", "label": "yes"} {"id": "converted_1505", "sentence1": "Is it possible to visualize subtahalamic nucleus by using transcranial ultrasound?", "sentence2": "After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus. TCS had no influence on lead temperature, electrical parameters of DBS device or clinical state of patients. TCS measures of lead coordinates agreed with MRI measures in anterior-posterior and medial-lateral axis. Lead dislocation requiring reinsertion was reliably detected., TCS may therefore become a first-choice modality to monitor lead location., Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts. , Peroperative transcranial sonography for electrode placement into the targeted subthalamic nucleus of patients with Parkinson disease: technical note, The correct anatomic position of the electrode tip could be indirectly assessed thanks to the topographic relationship of the STN with the hyperechogenic substantia nigra and the nucleus ruber., CONCLUSIONS: Transcranial sonography is easily feasible during stereotactic surgery. In combination with the clinical effects of electrostimulation on the symptoms of Parkinson's disease and with stereotactic x-ray images, it enables the assessment and the documentation of the correct position of implanted STN electrodes in real time., After measuring thermal effects of TCS and imaging artefact sizes of DBS lead using a skull phantom, we prospectively enrolled 34 patients with DBS of globus pallidus internus, ventro-intermediate thalamic or subthalamic nucleus, Two pilot studies have demonstrated that the intraoperative visualization with TCS and the TCS-assisted insertion of deep-brain stimulation (DBS) electrodes into the subthalamic nucleus and the globus pallidus interna are feasible and safe provided there is exact knowledge on the extent of electrode TCS imaging artifacts[SEP]Definitions: TCS defined as following: A hereditary disorder occurring in two forms: the complete form (Franceschetti's syndrome) is characterized by antimongoloid slant of the palpebral fissures, COLOBOMA of the lower lid, MICROGNATHIA and hypoplasia of the ZYGOMATIC ARCHES, and CONGENITAL MICROTIA. It is transmitted as an autosomal trait. The incomplete form (Treacher Collins syndrome) is characterized by the same anomalies in less pronounced degree. It occurs sporadically, but an autosomal dominant mode of transmission is suspected. (Dorland, 27th ed). STN defined as following: Human EEF1A2 wild-type allele is located in the vicinity of 20q13.3 and is approximately 11 kb in length. This allele, which encodes elongation factor 1-alpha 2 protein, is involved in the promotion of protein elongation. The gene is expressed aberrantly at elevated levels in many ovarian cancers.. position defined as following: A reference to the alignment of an object, a particular situation or view of a situation, or the location of an object.. insertion defined as following: Something inserted or to be inserted.. Parkinson's disease defined as following: A progressive, degenerative neurologic disease characterized by a TREMOR that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. LEWY BODIES are present in the substantia nigra and locus coeruleus but may also be found in a related condition (LEWY BODY DISEASE, DIFFUSE) characterized by dementia in combination with varying degrees of parkinsonism. (Adams et al., Principles of Neurology, 6th ed, p1059, pp1067-75). subthalamic nucleus defined as following: Lens-shaped structure on the inner aspect of the INTERNAL CAPSULE. The SUBTHALAMIC NUCLEUS and pathways traversing this region are concerned with the integration of somatic motor function.. globus defined as following: A feeling of a lump in the throat that occurs between meals in the absence of other gastrointestinal and motility disorders (e.g., DYSPHAGIA; GASTROESOPHAGEAL REFLUX)..", "label": "yes"} {"id": "converted_2618", "sentence1": "Can non ubiquitinated Tomm20 promote mitophagy?", "sentence2": " A total of 338 new targets were identified and from these we validated glycogen synthase kinase 3β (Gsk3β), which can phosphorylate α-synuclein, and translocase of outer mitochondrial membrane 20 (Tomm20), a mitochondrial translocase that, when ubiquitinated, promotes mitophagy, as SCFFbxo7substrates both in vitro and in vivo Ubiquitin chain restriction analyses revealed that Fbxo7 modified Gsk3β using K63 linkages. [SEP]Definitions: glycogen synthase kinase 3β defined as following: This gene plays a role in neuronal morphogenesis.. translocase defined as following: A class of enzymes that catalyze the movement of ions or molecules across or within membranes..", "label": "no"} {"id": "converted_844", "sentence1": "Is there a genome-wide technique for the detection of R-loop formation?", "sentence2": "Genome-wide analysis of fragile sites by chromatin immunoprecipitation (ChIP) and microarray (ChIP-chip) of phosphorylated H2A in these mutants supported a transcription-dependent mechanism of DNA damage characteristic of R loops, We have used a bisulfite-sensitivity assay to demonstrate genome-wide increase in the occurrence of RNA-DNA hybrids (R-loops), including from antisense and read-through transcripts, in a nusG missense mutant defective for Rho-dependent termination., The results demonstrate a key function of FACT in the resolution of R-loop-mediated transcription-replication conflicts, likely associated with a specific chromatin organization., Previous work revealed that GC skew and R-loop formation associate with a core set of unmethylated CpG island (CGI) promoters in the human genome[SEP]Definitions: H2A defined as following: Slightly lysine rich histone. One of four histones assembled into a nucleosomal core octamer. Various posttranslationally modified forms and variants exist. Combines with histone H2B in a heterodimer; two H2A/H2B dimers are incorporated in the nucleosomal octamer.. FACT defined as following: A non-profit corporation co-founded by the International Society for Cellular Therapy and the American Society of Blood and Marrow Transplantation for the purposes of voluntary inspection and accreditation in the field of cellular therapy. Founded in 1996, FACT establishes standards for high quality medical and laboratory practice in cellular therapies. FACT Standards are evidence-based requirements set by world-renowned experts vested in the improvement and progress of cellular therapy.. promoters defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. mutants defined as following: An altered form of an individual, organism, population, or genetic character that differs from the corresponding wild type due to one or more alterations (mutations).. R-loops defined as following: An RNA-DNA hybrid structure formed when newly transcribed RNA remains bound to its DNA template. Stability of R-loops may play a role in GENETIC INSTABILITY.. R-loop defined as following: An RNA-DNA hybrid structure formed when newly transcribed RNA remains bound to its DNA template. Stability of R-loops may play a role in GENETIC INSTABILITY..", "label": "yes"} {"id": "converted_4223", "sentence1": "Has the companion diagnostic HercepTest received FDA approval?", "sentence2": "The FDA-Approved Breast Cancer HER2 Evaluation Kit (HercepTest; Dako) May Miss Some HER2-Positive Breast Cancers., HER2 fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) tests were performed on 52 cases using a US Food and Drug Administration (FDA)-approved kit (HercepTest, FDA kit) and a laboratory-developed test (LDT) with the HercepTest antibody and a Leica Bond automated stainer.[SEP]", "label": "yes"} {"id": "converted_1548", "sentence1": "Is the gene SLC6A2 associated with orthostatic intolerance?", "sentence2": "Orthostatic intolerance is a debilitating syndrome characterized by tachycardia on assumption of upright posture. The norepinephrine (NE) transporter (NET) has been implicated in a genetic form of the disorder. , Thus attenuated baroreflex function and reduced sympathetic outflow may contribute to the orthostatic intolerance of severe NET deficiency., A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters., Recently, our laboratory reported a polymorphism in the human NET (hNET) gene A457P in an individual with the autonomic disorder orthostatic intolerance (OI). , Nonsynonymous single nucleotide polymorphisms (SNPs) in the human NET (hNET) gene that influence transporter function can contribute to disease, such as the nonfunctional transporter, A457P, identified in orthostatic intolerance. , Orthostatic intolerance is not necessarily related to a specific mutation (Ala457Pro) in the human norepinephrine transporter gene., We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS., The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS., In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications. We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS., A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS.[SEP]Definitions: SLC6A2 defined as following: Sodium-dependent noradrenaline transporter (617 aa, ~69 kDa) is encoded by the human SLC6A2 gene. This protein plays a role in the reuptake of norepinephrine by presynaptic cells.. OI defined as following: COLLAGEN DISEASES characterized by brittle, osteoporotic, and easily fractured bones. It may also present with blue sclerae, loose joints, and imperfect dentin formation. Most types are autosomal dominant and are associated with mutations in COLLAGEN TYPE I.. human defined as following: Members of the species Homo sapiens.. SLC6A2 gene defined as following: This gene plays a role in neurotransmitter recycling.. norepinephrine transporter gene defined as following: Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of noradrenergic neurons. They remove NOREPINEPHRINE from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS. The norepinephrine transporter regulates signal amplitude and duration at noradrenergic synapses and is the target of ADRENERGIC UPTAKE INHIBITORS.. mutant defined as following: An altered form of an individual, organism, population, or genetic character that differs from the corresponding wild type due to one or more alterations (mutations).. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. Orthostatic intolerance defined as following: Symptoms of cerebral hypoperfusion or autonomic overaction which develop while the subject is standing, but are relieved on recumbency. Types of this include NEUROCARDIOGENIC SYNCOPE; POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME; and neurogenic ORTHOSTATIC HYPOTENSION. (From Noseworthy, JH., Neurological Therapeutics Principles and Practice, 2007, p2575-2576). polymorphism defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.. orthostatic intolerance defined as following: Symptoms of cerebral hypoperfusion or autonomic overaction which develop while the subject is standing, but are relieved on recumbency. Types of this include NEUROCARDIOGENIC SYNCOPE; POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME; and neurogenic ORTHOSTATIC HYPOTENSION. (From Noseworthy, JH., Neurological Therapeutics Principles and Practice, 2007, p2575-2576). gene SLC6A2 defined as following: This gene plays a role in neurotransmitter recycling..", "label": "yes"} {"id": "converted_1242", "sentence1": "Is nimodipine recommended for prevention of vasospasm in aneurysmal subarachnoid hemorrhage patients?", "sentence2": "This article discusses some of these unresolved issues, including the use of medications such as nimodipine, antifibrinolytics, statins, and magnesium; coiling or clipping for aneurysm securement; and the prevention and treatment of potential complications., The results of this study were as follows: nimodipine demonstrated benefit following aneurysmal SAH; other calcium channel blockers, including nicardipine, do not provide unequivocal benefit; triple-H therapy, fasudil, transluminal balloon angioplasty, thrombolytics, endothelin receptor antagonists, magnesium, statins, and miscellaneous therapies such as free radical scavengers and antifibrinolytics require additional study., The present results suggest that fasudil is equally or more effective than nimodipine for the prevention of cerebral vasospasm and subsequent ischemic injury in patients undergoing surgery for SAH., Three studies (2 meta-analyses and 1 randomized controlled trial) demonstrated that nimodipine use confers benefits (reduced morbidity and mortality) for patients with aneurysmatic subarachnoid hemorrhage., Nimodipine is the only preventative treatment that can be recommended., Nimodipine (Nimotop), HMG Co-A reductase inhibitor (statins) and enoxaparin (Lovenox) were the only drugs with level-1 evidence available for the treatment of vasospasm from aneurysmal subarachnoid hemorrhage as defined by the US Preventative Services Task Force., The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH)., There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively)., Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging., The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH., the risk of delayed cerebral ischemia is reduced with nimodipine and avoiding hypovolemia, A recommendations (standard) for the prophylaxis and treatment of cerebral vasospasm with oral Nimodipine in good grade patients., Of the 75 patients initially considered for active treatment, 83% underwent surgery within 48 hours of rupture, all received nimodipine, 16% received tissue plasminogen activator to lyse subarachnoid or intraventricular clots, 40% underwent hypertensive treatment, and 7% underwent transluminal balloon angioplasty for vasospasm., All patients with aneurysmal SAH should be treated with the calcium antagonist nimodipine, and in certain circumstances patients should receive anticonvulsants., The following review gives an account of pathophysiological mechanisms; the importance of treatment with calcium antagonists, hypervolaemic haemodilution, and induced arterial hypertension is discussed in light of the current literature., Seven placebo-controlled clinical studies have shown that nimodipine improves the outcome of patients with severe neurological damage due to cerebral vasospasm., In a series of 100 individuals with a ruptured supratentorial aneurysm, who were subjected to aneurysm operation in the acute stage and who subsequently received intravenous treatment with the calcium channel blocker nimodipine, the occurrence of DID with FND was reduced to 5%., There are many possible successful treatment options for preventing vasospasm, delayed ischemic neurologic deficits, and poor neurologic outcome following aneurysmal subarachnoid hemorrhage; however, further multicenter RCTs need to be performed to determine if there is a significant benefit from their use. Nimodipine is the only treatment that provided a significant benefit across multiple studies., Absence of symptomatic vasospasm, occurrence of low density areas associated with vasospasm on CT, and occurrence of adverse events were similar between the two groups. The clinical outcomes were more favorable in the fasudil group than in the nimodipine group (p = 0.040). The proportion of patients with good clinical outcome was 74.5% (41/55) in the fasudil group and 61.7% (37/60) in the nimodipine group., Cerebral vasospasm is the classic cause of delayed neurological deterioration leading to cerebral ischemia and infarction, and thus, poor outcome and occasionally death, after aneurysmal subarachnoid hemorrhage (SAH). Advances in diagnosis and treatment, principally nimodipine, intensive care management, hemodynamic manipulations, and endovascular neuroradiology procedures, have improved the prospects for these patients, but outcomes remain disappointing., Cerebral vasospasm is the classic cause of delayed neurological deterioration after aneurysmal subarachnoid hemorrhage, leading to cerebral ischemia and infarction, and thus to poor outcome and occasionally death. Advances in diagnosis and treatment-principally the use of nimodipine, intensive care management, hemodynamic manipulations and endovascular neuroradiology procedures-have improved the prospects for these patients, but outcomes remain disappointing., Cerebral vasospasm and delayed cerebral ischemia remain common complications of aneurysmal subarachnoid hemorrhage (SAH), and yet therapies for cerebral vasospasm are limited. Despite a large number of clinical trials, only calcium antagonists have strong evidence supporting their effectiveness., The only proven therapy for vasospasm is nimodipine., nimodipine is indicated after SAH and tirilazad is not effective., Fasudil hydrochloride and nimodipine both showed inhibitory effects on cerebral vasospasm. The incidence of symptomatic vasospasm was five of 33 patients in the fasudil group and nine of 32 patients in the nimodipine group. Good recovery evaluated by the Glasgow Outcome Scale was achieved by 23 of 33 patients in the fasudil group and 19 of 34 patients in the nimodipine group. Both drugs significantly improved consciousness levels and neurological deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more than nimodipine.[SEP]Definitions: Lovenox defined as following: brand name of enoxaparin. hydrochloride defined as following: A salt that is comprised of a hydrogen and chloride ion that can be linked to a base form of a drug making it water-soluble. (NCI). hypovolemia defined as following: An abnormally low volume of blood circulating through the body. It may result in hypovolemic shock (see SHOCK).. Nimodipine defined as following: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure.. nicardipine defined as following: A potent calcium channel blockader with marked vasodilator action. It has antihypertensive properties and is effective in the treatment of angina and coronary spasms without showing cardiodepressant effects. It has also been used in the treatment of asthma and enhances the action of specific antineoplastic agents.. enoxaparin defined as following: Low-molecular-weight fragment of heparin, having a 4-enopyranosuronate sodium structure at the non-reducing end of the chain. It is prepared by depolymerization of the benzylic ester of porcine mucosal heparin. Therapeutically, it is used as an antithrombotic agent. (From Merck Index, 11th ed). endothelin receptor antagonists defined as following: Compounds and drugs that bind to and inhibit or block the activation of ENDOTHELIN B RECEPTORS.. aneurysm defined as following: Pathological outpouching or sac-like dilatation in the wall of any blood vessel (ARTERIES or VEINS) or the heart (HEART ANEURYSM). It indicates a thin and weakened area in the wall which may later rupture. Aneurysms are classified by location, etiology, or other characteristics.. SAH defined as following: A Turkic language spoken by the Yakut people in the Sakha Republic in the Russian Federation.. infarctions defined as following: Formation of an infarct, which is NECROSIS in tissue due to local ISCHEMIA resulting from obstruction of BLOOD CIRCULATION, most commonly by a THROMBUS or EMBOLUS.. statins defined as following: Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis.. vasospasm defined as following: spasm of the blood vessels resulting in decrease in their caliber.. cerebral ischemia defined as following: The formation of an area of NECROSIS in the CEREBRUM caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., INFARCTION, ANTERIOR CEREBRAL ARTERY), and etiology (e.g., embolic infarction).. neurological damage defined as following: Traumatic injuries to the brain, cranial nerves, spinal cord, autonomic nervous system, or neuromuscular system, including iatrogenic injuries induced by surgical procedures.. aphasia defined as following: A cognitive disorder marked by an impaired ability to comprehend or express language in its written or spoken form. This condition is caused by diseases which affect the language areas of the dominant hemisphere. Clinical features are used to classify the various subtypes of this condition. General categories include receptive, expressive, and mixed forms of aphasia.. neurological deficits defined as following: Loss of movement function.. rupture defined as following: Forcible or traumatic tear or break of an organ or other soft part of the body.. free radical scavengers defined as following: Substances that eliminate free radicals. Among other effects, they protect PANCREATIC ISLETS against damage by CYTOKINES and prevent myocardial and pulmonary REPERFUSION INJURY.. nimodipine defined as following: A calcium channel blockader with preferential cerebrovascular activity. It has marked cerebrovascular dilating effects and lowers blood pressure..", "label": "yes"} {"id": "converted_2282", "sentence1": "Is dasatinib effective for treatment of glioblastoma?", "sentence2": "RESULTS: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056)., CONCLUSIONS: Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. , Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents., Dasatinib in conjunction with bevacizumab does not appear to have activity in patients with recurrent, heavily pretreated GBM.[SEP]Definitions: Dasatinib defined as following: An orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes.. glioblastoma defined as following: The most malignant astrocytic tumor (WHO grade 4). It is composed of poorly differentiated neoplastic astrocytes and is characterized by the presence of cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. (Adapted from WHO). vandetanib defined as following: An orally bioavailable 4-anilinoquinazoline. Vandetanib selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGFR2), thereby blocking VEGF-stimulated endothelial cell proliferation and migration and reducing tumor vessel permeability. This agent also blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that mediates tumor cell proliferation and migration and angiogenesis.. bevacizumab defined as following: An anti-VEGF humanized murine monoclonal antibody. It inhibits VEGF RECEPTORS and helps to prevent PATHOLOGIC ANGIOGENESIS.. GBM defined as following: A sheet of amorphous extracellular material upon which the basal surfaces of epithelial cells rest and is the covering surface of a glomerular capillary, interposed between the cellular elements and the underlying connective tissue.. temsirolimus defined as following: An ester analog of rapamycin. Temsirolimus binds to and inhibits the mammalian target of rapamycin (mTOR), resulting in decreased expression of mRNAs necessary for cell cycle progression and arresting cells in the G1 phase of the cell cycle. mTOR is a serine/threonine kinase which plays a role in the PI3K/AKT pathway that is upregulated in some tumors.. cilengitide defined as following: A cyclic Arg-Gly-Asp peptide with potential antineoplastic activity. Cilengitide binds to and inhibits the activities of the alpha(v)beta(3) and alpha(v)beta(5) integrins, thereby inhibiting endothelial cell-cell interactions, endothelial cell-matrix interactions, and angiogenesis. (NCI04). toxicities defined as following: The finding of bodily harm due to the poisonous effects of something.. dasatinib defined as following: An orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes..", "label": "no"} {"id": "converted_3046", "sentence1": "Does Rhamnose have any effect on aging?", "sentence2": "The monosaccharide analysis showed that rhamnose (Rha) and glucose (Glu) may play vital roles in maintaining the antioxidant and anti-aging activities. , Some of these mechanisms will be reviewed as well as the capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP) to counteract several of the mechanisms involved in skin aging.[SEP]Definitions: glucose defined as following: The determination of the amount of glucose present in a sample.. rhamnose defined as following: A methylpentose whose L- isomer is found naturally in many plant glycosides and some gram-negative bacterial lipopolysaccharides.. monosaccharide defined as following: Single chain carbohydrates that are the most basic units of CARBOHYDRATES. They are typically colorless crystalline substances with a sweet taste and have the same general formula CnH2nOn..", "label": "yes"} {"id": "converted_2463", "sentence1": "Can Logic Alignment Free (LAF) be used for bacterial genomes classification?", "sentence2": "LAF: Logic Alignment Free and its application to bacterial genomes classification., In this paper, we present Logic Alignment Free (LAF), a method that combines alignment-free techniques and rule-based classification algorithms in order to assign biological samples to their taxa. This method searches for a minimal subset of k-mers whose relative frequencies are used to build classification models as disjunctive-normal-form logic formulas (if-then rules). We apply LAF successfully to the classification of bacterial genomes to their corresponding taxonomy. In particular, we succeed in obtaining reliable classification at different taxonomic levels by extracting a handful of rules, each one based on the frequency of just few k-mers. State of the art methods to adjust the frequency of k-mers to the character distribution of the underlying genomes have negligible impact on classification performance, suggesting that the signal of each class is strong and that LAF is effective in identifying it., In this paper, we present Logic Alignment Free (LAF), a method that combines alignment-free techniques and rule-based classification algorithms in order to assign biological samples to their taxa., LAF: Logic Alignment Free and its application to bacterial genomes classification.[SEP]Definitions: LAF defined as following: A soluble factor produced by MONOCYTES; MACROPHAGES, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, INTERLEUKIN-1ALPHA and INTERLEUKIN-1BETA. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation.. bacterial genomes defined as following: The genetic complement of a BACTERIA as represented in its DNA..", "label": "yes"} {"id": "converted_2205", "sentence1": "Does the Abelson-related gene (ARG) gene encode for a serine kinase?", "sentence2": "One isoform of Arg/Abl2 tyrosine kinase is nuclear and the other seven cytosolic isoforms differently modulate cell morphology, motility and the cytoskeleton., The non-receptor tyrosine kinase Abelson related gene (Arg/Abl2) regulates cell migration and morphogenesis by modulating the cytoskeleton. , The human Arg (Abl2) nonreceptor tyrosine kinase has a role in cytoskeletal rearrangements by its C-terminal F-actin- and microtubule-binding sequences. , The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts., The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARG involvement in a human malignancy., Ultraviolet-A and -B differentially modify the tyrosine-kinase profile of human keratinocytes and induce the expression of Arg+., Arg (Abelson-related gene, Abl2) was the PTK with the highest prevalence (30% of all PTKs) and UVA led to a further induction of Arg expression reaching nine-fold mRNA baseline expression at 17 h after irradiation., To investigate the expression profile of protein tyrosine kinases (PTKs) in normal human epidermal keratinocytes (NHEK) in response to UVA and UVB we employed a reversed transcriptase polymerase chain reaction (PCR) approach using degenerate primers derived from the conserved catalytic domain of PTKs. , By 3'rapid amplification of cDNA ends-polymerase chain reaction (3'RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG., The non-receptor tyrosine kinase Abelson related gene (Arg/Abl2) regulates cell migration and morphogenesis by modulating the cytoskeleton., Arg (Abelson-related gene, Abl2) was the PTK with the highest prevalence (30% of all PTKs) and UVA led to a further induction of Arg expression reaching nine-fold mRNA baseline expression at 17 h after irradiation., We studied the relationship of direct karyotypes, determined at diagnosis and remission, to Abelson-related tyrosine kinase activity and the cytogenetic features of erythroid and myeloid colonies derived from remission marrow of six children with acute lymphoblastic leukemia (ALL)., ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases, The non-receptor tyrosine kinase Abelson related gene (Arg/Abl2) regulates cell migration and morphogenesis by modulating the cytoskeleton, The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains., ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases., We report that the Abelson (Abl) and Abl-related gene (Arg) nonreceptor tyrosine kinases are required for maintenance of cortical dendrites in the mouse brain., The products of the human ARG gene and the human ABL gene characterize the Abelson family of non-receptor tyrosine protein kinases., The products of the human Arg gene and human, mouse, Drosophila, and nematode Abl genes characterize the Abelson family of nonreceptor tyrosine protein kinase., By 3'rapid amplification of cDNA ends-polymerase chain reaction (3'RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG., The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts.[SEP]Definitions: protein tyrosine kinases defined as following: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.. chimeric protein defined as following: A protein in which the coding region of two genes have become in-frame and co-continuous. Fusion proteins can be formed by chromosomal breakage and/or recombination and also can be experimentally created using recombinant DNA techniques.. ETV6 defined as following: Human ETV6 wild-type allele is located in the vicinity of 12p13 and is approximately 246 kb in length. This allele, which encodes transcription factor ETV6 protein, is involved in the repression of transcription by RNA polymerase II. Several malignancies, particularly leukemias, are linked to chromosomal translocations of this gene.. ARG defined as following: This gene plays a role in signal transduction.. erythroid defined as following: 1) Reddish in color. 2) relating to erythrocytes or their precursors.. Abelson tyrosine-protein kinase defined as following: Abelson tyrosine-protein kinase 2 (1182 aa, ~128 kDa) is encoded by the human ABL2 gene. This protein plays a role in cell motility, apoptosis, cell adhesion, receptor endocytosis, autophagy, tyrosine phosphorylation and signal transduction.. acute lymphoblastic leukemia defined as following: A type of ALL characterized by elevated levels of B-cell lymphoblasts in the bone marrow and the blood. [NCIT:C8644]. transcripts defined as following: The initial RNA molecule produced by transcription.. c-Abl defined as following: This gene is involved in cell adhesion, differentiation, division and stress response.. mRNA defined as following: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.. Abl defined as following: An autosomal recessive disorder of lipid metabolism. It is caused by mutation of the microsomal triglyceride transfer protein that catalyzes the transport of lipids (TRIGLYCERIDES; CHOLESTEROL ESTERS; PHOSPHOLIPIDS) and is required in the secretion of BETA-LIPOPROTEINS (low density lipoproteins or LDL). Features include defective intestinal lipid absorption, very low serum cholesterol level, and near absent LDL.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. nematode defined as following: class of unsegmented helminths with fundamental bilateral symmetry and secondary triradiate symmetry of the oral and esophageal structures; many species are parasites.. isoform defined as following: Refers to variants of the same protein which can be separated on special conducting media using electrophoresis. The differences may arise from genetically determined differences in primary structure or by modification of the same primary sequence.. ALL defined as following: Leukemia with an acute onset, characterized by the presence of lymphoblasts in the bone marrow and the peripheral blood. It includes the acute B lymphoblastic leukemia and acute T lymphoblastic leukemia.. tyrosine kinase defined as following: This gene is involved in both protein phosphorylation and interferon-mediated signaling.. human defined as following: Members of the species Homo sapiens.. HLH defined as following: A rare but potentially life-threatening disorder characterized by the proliferation of histiocytes and macrophages and phagocytosis of red blood cells, white blood cells, and platelets. It may be inherited or secondary, due to infections, autoimmune disorders, or underlying malignancies. Signs and symptoms include fever, lymphadenopathy, hepatomegaly, splenomegaly, and pancytopenia.. homology defined as following: A gene from one species which corresponds to a gene in another species and that is related via a common ancestral species. These genes retain a similar sequence and function.. Abelson-related gene defined as following: This gene plays a role in signal transduction.. serine kinase defined as following: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors..", "label": "no"} {"id": "converted_847", "sentence1": "Is transcription-associated mutagenesis (TAM) related to gene expression levels?", "sentence2": "These mutations were frequent in plasmid-borne lacS expressed at a high level but not in single-copy lacS in the chromosome or at lower levels of expression in a plasmid., The results suggest that important DNA repair or replication fidelity functions are impaired or overwhelmed in pJlacS, with results analogous to those of the \"transcription-associated mutagenesis\" seen in bacteria and eukaryotes., the rate of point mutation in a gene increases with the expression level of the gene. Transcription induces mutagenesis on both DNA strands, indicating simultaneous actions of several TAM mechanisms., High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM)., High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage. Here, we describe a pGAL-CAN1 forward mutation assay for studying transcription-associated mutagenesis (TAM) in yeast., The acquisition of mutations was directly correlated to the level of transcription, Our results demonstrate that the level of Leu(+) reversions increased significantly in parallel with the induced increase in transcription levels., Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression, spontaneous mutation rate is directly proportional to the transcription level, suggesting that movement of RNA polymerase through the target initiates a mutagenic process(es), High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM)., Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions., Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication., High levels of transcription in Saccharomyces cerevisiae are associated with increased genetic instability, which has been linked to DNA damage., Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions., Using comparative genomics of related species as well as mutation accumulation lines, we show in yeast that the rate of point mutation in a gene increases with the expression level of the gene, High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM), Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions, High-levels of transcription through a gene stimulate spontaneous mutation rate, a phenomenon termed transcription-associated mutation (TAM)[SEP]Definitions: chromosome defined as following: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification.. gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. point mutation defined as following: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.. yeast defined as following: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as \"baker's\" or \"brewer's\" yeast. The dried form is used as a dietary supplement.. eukaryotes defined as following: Organism or cells with a nucleus separated from the cytoplasm by a two membrance nuclear envelope and compartmentalization of function into distinct cytoplasmic organelles.. mutagenesis defined as following: Production of genetic alterations by any technique, including chemicals, radiation, recombination, or other molecular biology methods.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. plasmid defined as following: Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.. TAM defined as following: A rare congenital myopathy characterized ultrastructurally by the presence of tubular aggregates in the subsarcolemmal region of the muscle fiber. It most commonly presents with slowly progressive proximal muscle weakness predominantly of the lower limbs, periodic paralysis, post-exertion muscle cramps, and muscular pain. Ocular anomalies like ophthalmoplegia or pupillary abnormalities may be associated. The intensity of the symptoms is variable, cases with normal muscle strength but myalgia or fatigue, as well as clinically asymptomatic cases have been described.. RNA polymerase defined as following: Enzymes that catalyze DNA template-directed extension of the 3'-end of an RNA strand one nucleotide at a time. They can initiate a chain de novo. In eukaryotes, three forms of the enzyme have been distinguished on the basis of sensitivity to alpha-amanitin, and the type of RNA synthesized. (From Enzyme Nomenclature, 1992).. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. bacteria defined as following: One of the three domains of life (the others being Eukarya and ARCHAEA), also called Eubacteria. They are unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. Bacteria can be classified by their response to OXYGEN: aerobic, anaerobic, or facultatively anaerobic; by the mode by which they obtain their energy: chemotrophy (via chemical reaction) or PHOTOTROPHY (via light reaction); for chemotrophs by their source of chemical energy: CHEMOLITHOTROPHY (from inorganic compounds) or chemoorganotrophy (from organic compounds); and by their source for CARBON; NITROGEN; etc.; HETEROTROPHY (from organic sources) or AUTOTROPHY (from CARBON DIOXIDE). They can also be classified by whether or not they stain (based on the structure of their CELL WALLS) with CRYSTAL VIOLET dye: gram-negative or gram-positive..", "label": "yes"} {"id": "converted_488", "sentence1": "Can exosomes be detected in urine?", "sentence2": "Exosomes are nanovesicles secreted into the extracellular environment upon internal vesicle fusion with the plasma membrane. The molecular content of exosomes is a fingerprint of the releasing cell type and of its status. For this reason, and because they are released in easily accessible body fluids such as blood and urine, they represent a precious biomedical tool. , Exosomes are vesicles that are released from the kidney into urine., Quantification of human urinary exosomes by nanoparticle tracking analysis., Urinary extracellular vesicles (uEVs) are released by cells throughout the nephron and contain biomolecules from their cells of origin., Urinary exosomes have been proposed as potential diagnostic tools., Urinary exosomes as a source of kidney dysfunction biomarker in renal transplantation, . Here we sought to optimize the methodologies for the isolation and quantification of urinary exosomal microRNA as a prelude to biomarker discovery studies. , Exosomes are small (30-150 nm) vesicles containing unique RNA and protein cargo, secreted by all cell types in culture. They are also found in abundance in body fluids including blood, saliva, and urine. , Urinary exosome-like vesicles (ELVs) are a heterogenous mixture (diameter 40-200 nm) containing vesicles shed from all segments of the nephron including glomerular podocytes, Exosomes are cytoplasm containing vesicles released by many cells that can be found in several biological fluids including urine., Proteomic analysis of urinary exosomes in cardiovascular and associated kidney diseases by two-dimensional electrophoresis and LC-MS/MS[SEP]Definitions: vesicles defined as following: An abnormal fluid-filled cleft (e.g. as in the epidermis) or membrane-bound space.. molecular defined as following: Relating to or produced by or consisting of molecules.. RNA defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). plasma membrane defined as following: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.. human defined as following: Members of the species Homo sapiens.. cytoplasm defined as following: The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990). exosomes defined as following: A type of extracellular vesicle, containing RNA and proteins, that is secreted into the extracellular space by EXOCYTOSIS when MULTIVESICULAR BODIES fuse with the PLASMA MEMBRANE.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. kidney dysfunction defined as following: An abnormal functionality of the kidney. [HPO:probinson]. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. extracellular defined as following: The space external to the outermost structure of a cell. For cells without external protective or external encapsulating structures this refers to space outside of the plasma membrane. This term covers the host cell environment outside an intracellular parasite. [GOC:go_curators]. kidney diseases defined as following: Pathological processes of the KIDNEY or its component tissues..", "label": "yes"} {"id": "converted_3047", "sentence1": "Is there any approved treatment for NAFLD?", "sentence2": "Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited., Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, reflecting the epidemic of global obesity. Those with the progressive variant of NAFLD, non-alcoholic steatohepatitis (NASH), are at significantly increased risk of multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH., Although much progress has been made in enhancing our understanding of NAFLD pathogenesis, development of pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complexities in clinical trial design. , Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy., Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. [SEP]Definitions: non-alcoholic steatohepatitis defined as following: Fatty replacement and damage to the hepatocytes not related to alcohol use. It may lead to cirrhosis and liver failure.. Nonalcoholic fatty liver disease defined as following: A term referring to fatty replacement of the hepatic parenchyma which is not related to alcohol use.. variant defined as following: An alteration or difference from a norm or standard.. liver disease defined as following: A non-neoplastic or neoplastic disorder that affects the liver, bile ducts, and gallbladder. Representative examples of non-neoplastic disorders include hepatitis, cirrhosis, cholangitis, and cholecystitis. Representative examples of neoplastic disorders include hepatocellular adenoma, hepatocellular carcinoma, and cholangiocarcinoma.. NAFLD defined as following: A term referring to fatty replacement of the hepatic parenchyma which is not related to alcohol use..", "label": "no"} {"id": "converted_1486", "sentence1": "Does ventriculoperitoneal shunt improve normal pressure hydrocephalus?", "sentence2": "Clinical improvement depends not only on the capability to restore the cerebrospinal fluid dynamic, but also on the ability of cerebral parenchyma to recover the metabolic function., After shunting, the global CMRglu significantly increased (2.95 ± 0.44 vs 4.38 ± 0.68, p = 10(-7)) in all INPH patients with a mean percentage value of 48.7%. , Our preliminary data show that changes in the CMRglu are promptly reversible after surgery and that there is a relationship between the early metabolic changes and clinical symptoms, independently from the simultaneous changes in the ventricular size. The remarkable and prompt improvement in the global CMRglu and in symptoms may also have important implications for the current concept of \"neuronal plasticity\" and for the cells' reactivity in order to recover their metabolic function., Outcome of shunting in INPH is most often successful when patients are accurately diagnosed, suitably evaluated for surgical candidacy, and managed carefully throughout the preoperative, surgical, and postoperative periods., The decision to perform the only efficient procedure, i.e., a ventricular shunt operation, depends upon a number of established arguments in favor of that procedure. Clinical improvement, which is often spectacular, can then confirm the diagnosis. , During the 1st postoperative year, there was improvement in the condition of 22 patients (96%) who had received a ventricular shunt; 21 of these patients (91%) remained improved until death or for at least 5 years., Shunt treatment showed an effect on cognitive functions of distractibility of attention and motor speed, but not on intelligence of memory. Three patients deteriorated, eleven remained stable and sixteen showed significant improvement on psychological tests, mainly those for attention, motor speed and memory, but rarely did any improvement of intelligence occur.[SEP]Definitions: death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. cerebrospinal fluid defined as following: A watery fluid that is continuously produced in the CHOROID PLEXUS and circulates around the surface of the BRAIN; SPINAL CORD; and in the CEREBRAL VENTRICLES..", "label": "yes"} {"id": "converted_3701", "sentence1": "Have toll-like receptor 2 activators been found in food?", "sentence2": "Toll-like receptor 2 (TLR2) is a widely expressed pattern recognition receptor critical for innate immunity. TLR2 is also a key regulator of mucosal immunity implicated in the development of allergic disease. TLR2 activators are found in many common foods,, TLR2 activators are found in many common foods, but the role of TLR2 in oral tolerance and allergic sensitization to foods is not well understood., TLR2 activators are found in many common foods, but the role of TLR2 in oral tolerance and allergic sensitization to foods is not well understood.[SEP]Definitions: TLR2 defined as following: Human TLR2 wild-type allele is located within 4q32 and is approximately 18 kb in length. This allele, which encodes toll-like receptor 2 protein, is involved in pathogen recognition, cytokine mediation and innate immunity.. allergic sensitization defined as following: A process characterized by an initial humoral or cell-mediated immune response to a foreign antigen resulting in the production of specific antibodies and/or immune cells which may then lead to an allergic disposition.. Toll-like receptor 2 defined as following: This gene plays a role in pathogen recognition and mediates the host response to gram-positive bacteria and yeast.. foods defined as following: Substances taken in by the body to provide nourishment..", "label": "yes"} {"id": "converted_4316", "sentence1": "Is fusobacterium associated with Lemierre's syndrome?", "sentence2": "Invasive infections with Fusobacterium necrophorum including Lemierre's syndrome: an 8-year Swedish nationwide retrospective study., Lemierre's syndrome is defined as an oropharyngeal infection due to Fusobacterium necrophorum,, Lemierre's syndrome is a rare but life-threatening condition characterized by an oropharyngeal infection typically secondary to Fusobacterium necrophorum resulting in septic thrombophlebitis of the internal jugular vein. , Lemierre's syndrome is a rare condition that results from oropharyngeal infection with the gram-negative, anaerobic Fusobacterium necrophorum., INTRODUCTION: Like Fusobacterium necrophorum, Fusobacterium nucleatum is capable causing Lemierre's syndrome., [Lemierre syndrome variant: Hepatic abscesses and hepatic venous thrombosis due to Fusobacterium nucleatum septicemia]., Fusobacterium necrophorum-induced sepsis: an unusual case of Lemierre's syndrome., F necrophorum is most commonly associated with Lemierre's syndrome: a septic thrombophlebitis of the internal jugular vein., Fusobacterium necrophorum Septicemia Leading to Lemierre's Syndrome in an Immunocompetent Individual: A Case Report., We present a case of a patient with Lemierre's syndrome caused by Fusobacterium necrophorum who developed a right frontal lobe brain abscess., Lemierre's syndrome secondary to Fusobacterium necrophorum infection, a rare cause of hepatic abscess., Lemierre's syndrome is an uncommon complication of pharyngitis commonly associated with an anaerobic gram negative bacterium, Fusobacterium necrophorum., The following presentation is a case of Lemierre's syndrome in a 23-year-old healthy individual who is infected by a rare species: Fusobacterium nucleatum., However, Fusobacterium species causing Lemierre's variant gastrointestinal syndrome has only been reported in case reports., Fusobacterium species is known for being a causative agent for Lemierre's syndrome, which is characterized by thrombophlebitis of the jugular vein., The Fusobacterium species is known for its association with septic thrombophlebitis of the internal jugular vein (Lemierre's syndrome). Lemierre's syndrome is as, Lemierre's syndrome due to Fusobacterium necrophorum., Fusobacterium species are well described as the causative pathogen in Lemierre's syndrome, a suppurative thrombophlebitis of the jugular vein. However, they are less r, Introduction: Lemierre's syndrome is a rare but serious complication of an oral infection mostly related to Fusobacterium necrophorum. This condition combines j, Fusobacterium necrophorum is a gram-negative anaerobic bacterium that is the causative agent of the invasive disease Lemierre's syndrome., INTRODUCTION: Lemierre's syndrome is defined as an oropharyngeal infection due to Fusobacterium necrophorum, associated with septic thrombophlebitis of the internal , Fusobacterium nucleatum is a gram-negative bacillius commonly found in oropharynx and is traditionally associated with Lemierre syndrome, which is characterized by history of recent oropharyngeal infection, internal jugular vein thrombosis, and isolation of anaerobic pathogens, mainly Fuosobacterium necrophorum. Ho, Lemierre's syndrome is an uncommon complication of pharyngitis commonly associated with an anaerobic gram negative bacterium, Fusobacterium necrophorum. , Fusobacterium species is known for being a causative agent for Lemierre's syndrome, which is characterized by thrombophlebitis of the jugular vein. , Lemierre's syndrome is a systemic complication commonly caused by oropharyngeal infection by Fusobacterium species, which manifests itself as an internal jugular vein thrombosis formation. , Lemierre's syndrome is a rare but serious condition, characterized by disseminated infection with Fusobacterium necrophorum, most often originating from the oropharynx. T, Lemierre's syndrome is a rare clinical condition that generally develops secondary to oropharyngeal infection caused by Fusobacterium necrophorum, which is an anaerobic bacteria. , Lemierre's syndrome, a systemic anaerobic infection caused by Fusobacterium necrophorum, is characterized by an acute oropharyngeal infection, septic thrombophlebitis of the internal jugular veins, sepsis, and multiple metastatic infections. It c, Lemierre's syndrome, a systemic anaerobic infection caused by Fusobacterium necrophorum, is characterized by an acute oropharyngeal infection, septic thrombophlebitis of the internal jugular vein, sepsis, and multiple metastatic infections. It c, Fusobacterium necrophorum is a rare infection most notable for causing Lemierre's syndrome., We present a patient with an atypical presentation of Fusobacterium infection, the genus responsible for Lemierre's syndrome., INTRODUCTION: Like Fusobacterium necrophorum, Fusobacterium nucleatum is capable causing Lemier, Fusobacterium necrophorum, a well‐known cause of Lemierre's syndrome, was identified., We report an unusual case of Lemierre's syndrome due to a rare species of Fusobacterium, that is, Fusobacterium nucleatum preceded by Mycoplasma pneumoniae pharyngitis and followed later by Epstein-Barr virus infectious mononucleosis., We present a case of invasive Fusobacterium infection that meets all criteria for Lemierre syndrome except lacking internal jugular thrombosis., Fusobacterium necrophorum is ananaerobic Gram-negative bacillus and is the most common organism reported to cause Lemierre's syndrome which usually occurs one to three weeks post pharyngitis or oropharyngeal surgery., Lemierre's disease: postanginal bacteremia and pulmonary involvement caused by Fusobacterium necrophorum., Increased diagnosis of Lemierre syndrome and other Fusobacterium necrophorum infections at a Children's Hospital., The Fusobacterium species is known for its association with septic thrombophlebitis of the internal jugular vein (Lemierre's syndrome)., Fusobacterium species have rarely been implicated in cases of gastrointestinal variant of Lemierre's syndrome., Fusobacterium species are well described as the causative pathogen in Lemierre's syndrome, a suppurative thrombophlebitis of the jugular vein., F. necrophorum is unique among non-spore-forming anaerobes, first for its virulence and association with Lemierre's syndrome as a monomicrobial infection and second because it seems probable that it is an exogenously acquired infection., Fusobacteria are most often associated with the classic presentation of Lemierre's syndrome consisting of a sore throat, internal jugular vein thrombophlebitis, and septic emboli to the lungs., Fusobacterium necrophorum plays a causal role in a rare and life-threatening condition, Lemierre's syndrome., Lemierre's syndrome is a rare disorder of young adults caused by the anaerobic bacterium, Fusobacterium necrophorum and occasionally by other Fusobacterium species (F. nucleatum, F. mortiferum and F. varium etc)., Lemierre's syndrome is a severe complication of Fusobacterium necrophorum oropharyngeal infection associated with metastatic foci of infection, internal jugular vein thrombosis, and septicemia., Short blood culture time-to-positivity in Fusobacterium necrophorum bacteremia is associated with Lemierre's syndrome., The causative organisms are the anaerobic fusobacteria, most commonly Fusobacterium necrophorum., In a 3-year prospective study, all cases of disseminated Fusobacterium necrophorum infections found in Denmark from 1998 to 2001 were analysed, with the aim of describing the epidemiology and clinical features of the variants of Lemierre's syndrome and disseminated non-head-and-neck-associated F. necrophorum infections.[SEP]Definitions: variants defined as following: An alteration or difference from a norm or standard.. pharyngitis defined as following: Inflammation of the throat (PHARYNX).. Septicemia defined as following: Systemic disease associated with the presence of pathogenic microorganisms or their toxins in the blood.. Fusobacterium infection defined as following: Infections with bacteria of the genus FUSOBACTERIUM.. Lemierre's disease defined as following: A superinfection of the damaged oropharyngeal mucosa by FUSOBACTERIUM NECROPHORUM leading to the secondary septic THROMBOPHLEBITIS of the internal jugular vein.. Hepatic abscesses defined as following: Solitary or multiple collections of PUS within the liver as a result of infection by bacteria, protozoa, or other agents.. infection defined as following: An illness caused by an infectious agent or its toxins that occurs through the direct or indirect transmission of the infectious agent or its products from an infected individual or via an animal, vector or the inanimate environment to a susceptible animal or human host.. Fusobacteria defined as following: A phylum of anaerobic Gram-negative bacteria that are a normal component of the gut flora.. oropharynx defined as following: The middle portion of the pharynx that lies posterior to the mouth, inferior to the SOFT PALATE, and superior to the base of the tongue and EPIGLOTTIS. It has a digestive function as food passes from the mouth into the oropharynx before entering ESOPHAGUS.. Fusobacterium nucleatum defined as following: A species of gram-negative, anaerobic, rod-shaped bacteria isolated from the gingival margin and sulcus and from infections of the upper respiratory tract and pleural cavity.. Fusobacterium necrophorum defined as following: A species of gram-negative, non-spore-forming bacteria isolated from the natural cavities of man and other animals and from necrotic lesions, abscesses, and blood.. lungs defined as following: Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood.. thrombophlebitis defined as following: Inflammation of a vein associated with a blood clot (THROMBUS).. organism defined as following: A living entity.. fusobacterium defined as following: A genus of gram-negative, anaerobic, rod-shaped bacteria found in cavities of humans and other animals. No endospores are formed. Some species are pathogenic and occur in various purulent or gangrenous infections.. Lemierre's syndrome defined as following: A superinfection of the damaged oropharyngeal mucosa by FUSOBACTERIUM NECROPHORUM leading to the secondary septic THROMBOPHLEBITIS of the internal jugular vein..", "label": "yes"} {"id": "converted_211", "sentence1": "Is long QT syndrome a cause for sudden cardiac death in athletes?", "sentence2": "A diversity of cardiovascular disorders including hypertrophic cardiomyopathy, congenital coronary anomalies, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, aortic rupture due to Marfan syndrome, myocarditis, valvular disease and electrical disorders (Wolff-Parkinson-White syndrome, long QT syndrome, Brugada syndrome), as well as commotio cordis represent the common causes of SCD in young athletes., Sudden cardiac death is the leading cause of mortality among young athletes with an incidence of 1-2 per 100,000 athletes per annum., The majority of cases are caused by an underlying structural cardiac abnormality, most commonly hypertrophic cardiomyopathy. More recently, the understanding of non-structural causes such as long QT syndrome and Brugada syndrome has grown and diagnostic criteria have been developed. , This review considers in particular the causes of death affecting athletes below 35 years of age. In this age group the largest proportion of deaths are caused by diseases with autosomal dominant inheritance such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT-syndrome, and Marfan's syndrome. , Knowledge of sudden cardiac death in young athletes is imperative for all physicians and allied health professionals. , In this article, we review several etiologies of sudden cardiac death, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Wolff-Parkinson-White syndrome, long QT syndrome, Brugada syndrome, and commotio cordis. , Sudden cardiac death (SCD) in young athletes is generally caused by inherited cardiac disorders., The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia., The most common cause of sudden cardiac death in athletes is hypertrophic cardiomyopathy. Other reasons are congenital coronary artery anomalies, nivocarditis, dilatative cardiomyopathy, arrhythmogenic cardiomyopathy of the right ventricle, sarcoidosis, mitral valve prolapse, aortic valve stenosis, atherosclerosis, long QT syndrome, and blunt impact to the chest., The congenital long QT syndrome (LQTS) is caused by cardiac ion channel mutations, which predispose young individuals to sudden cardiac death often related to exercise. , A group of relatively uncommon but important genetic cardiovascular diseases (GCVDs) are associated with increased risk for sudden cardiac death during exercise, including hypertrophic cardiomyopathy, long-QT syndrome, Marfan syndrome, and arrhythmogenic right ventricular cardiomyopathy., Primary electrical disorders (such as the long QT syndrome) are rarely present in athletes but, so far, are a considerable reason for disqualification from sport activity. [SEP]Definitions: death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. commotio cordis defined as following: A sudden CARDIAC ARRHYTHMIA (e.g., VENTRICULAR FIBRILLATION) caused by a blunt, non-penetrating impact to the precordial region of chest wall. Commotio cordis often results in sudden death without prompt cardiopulmonary defibrillation.. long QT syndrome defined as following: A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME.. Marfan syndrome defined as following: An autosomal dominant disorder of CONNECTIVE TISSUE with abnormal features in the heart, the eye, and the skeleton. Cardiovascular manifestations include MITRAL VALVE PROLAPSE; AORTIC ANEURYSM; and AORTIC DISSECTION. Other features include lens displacement (ectopia lentis), disproportioned long limbs and enlarged DURA MATER (dural ectasia). Marfan syndrome (type 1) is associated with mutations in the gene encoding FIBRILLIN-1 (FBN1), a major element of extracellular microfibrils of connective tissue. Mutations in the gene encoding TYPE II TGF-BETA RECEPTOR (TGFBR2) are associated with Marfan syndrome type 2.. atherosclerosis defined as following: Thickening and loss of elasticity of the walls of ARTERIES of all sizes. There are many forms classified by the types of lesions and arteries involved, such as ATHEROSCLEROSIS with fatty lesions in the ARTERIAL INTIMA of medium and large muscular arteries.. SCD defined as following: Schnyder corneal dystrophy (SCD) is a rare form of stromal corneal dystrophy (see this term) characterized by corneal clouding or crystals within the corneal stroma, and a progressive decrease in visual acuity.. ventricular tachycardia defined as following: An electrocardiographic finding of three or more consecutive complexes of ventricular organ with a rate greater than a certain threshold (100 or 120 beats per minute are commonly used). The QRS complexes are wide and have an abnormal morphology. (CDISC). dilated cardiomyopathy defined as following: Cardiomyopathy which is characterized by dilation and contractile dysfunction of the left and right ventricles. It may be idiopathic, or it may result from a myocardial infarction, myocardial infection, or alcohol abuse. It is a cause of congestive heart failure.. Wolff-Parkinson-White syndrome defined as following: A form of ventricular pre-excitation characterized by a short PR interval and a long QRS interval with a delta wave. In this syndrome, atrial impulses are abnormally conducted to the HEART VENTRICLES via an ACCESSORY CONDUCTING PATHWAY that is located between the wall of the right or left atria and the ventricles, also known as a BUNDLE OF KENT. The inherited form can be caused by mutation of PRKAG2 gene encoding a gamma-2 regulatory subunit of AMP-activated protein kinase.. sudden cardiac death defined as following: Unexpected rapid natural death due to cardiovascular collapse within one hour of initial symptoms. It is usually caused by the worsening of existing heart diseases. The sudden onset of symptoms, such as CHEST PAIN and CARDIAC ARRHYTHMIAS, particularly VENTRICULAR TACHYCARDIA, can lead to the loss of consciousness and cardiac arrest followed by biological death. (from Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., 2005). autosomal dominant inheritance defined as following: A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele. [HPO:curators]. mitral valve prolapse defined as following: Abnormal protrusion or billowing of one or both of the leaflets of MITRAL VALVE into the LEFT ATRIUM during SYSTOLE. This allows the backflow of blood into left atrium leading to MITRAL VALVE INSUFFICIENCY; SYSTOLIC MURMURS; or CARDIAC ARRHYTHMIA.. Brugada syndrome defined as following: An autosomal dominant defect of cardiac conduction that is characterized by an abnormal ST-segment in leads V1-V3 on the ELECTROCARDIOGRAM resembling a right BUNDLE-BRANCH BLOCK; high risk of VENTRICULAR TACHYCARDIA; or VENTRICULAR FIBRILLATION; SYNCOPAL EPISODE; and possible sudden death. This syndrome is linked to mutations of gene encoding the cardiac SODIUM CHANNEL alpha subunit.. myocarditis defined as following: Inflammatory processes of the muscular walls of the heart (MYOCARDIUM) which result in injury to the cardiac muscle cells (MYOCYTES, CARDIAC). Manifestations range from subclinical to sudden death (DEATH, SUDDEN). Myocarditis in association with cardiac dysfunction is classified as inflammatory CARDIOMYOPATHY usually caused by INFECTION, autoimmune diseases, or responses to toxic substances. Myocarditis is also a common cause of DILATED CARDIOMYOPATHY and other cardiomyopathies.. aortic valve stenosis defined as following: A pathological constriction that can occur above (supravalvular stenosis), below (subvalvular stenosis), or at the AORTIC VALVE. It is characterized by restricted outflow from the LEFT VENTRICLE into the AORTA.. arrhythmogenic right ventricular cardiomyopathy defined as following: A congenital cardiomyopathy that is characterized by infiltration of adipose and fibrous tissue into the RIGHT VENTRICLE wall and loss of myocardial cells. Primary injuries usually are at the free wall of right ventricular and right atria resulting in ventricular and supraventricular arrhythmias.. cardiovascular disorders defined as following: Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.. LQTS defined as following: A rare group of genetic, cardiac rhythm diseases characterized by a prolongation of the QT interval at basal electrocardiography (ECG) and by a high risk of life-threatening arrhythmias.. aortic rupture defined as following: The tearing or bursting of the wall along any portion of the AORTA, such as thoracic or abdominal. It may result from the rupture of an aneurysm or it may be due to TRAUMA..", "label": "yes"} {"id": "converted_4701", "sentence1": "Is ASF1 phopshorylated by the Tousled-like kinases?", "sentence2": "Asf1, a key histone H3-H4 chaperone required for this process, is phosphorylated by Tousled-like kinases (TLKs). , The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone, The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 , TLKs interact specifically (and phosphorylate) with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, TLK1 substrates were identified as the histone H3 and Asf1 (a histone H3/H4 chaperone)[SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. chromatin assembly defined as following: The assembly of DNA, histone proteins, other associated proteins, and sometimes RNA, into chromatin structure, beginning with the formation of the basic unit, the nucleosome, followed by organization of the nucleosomes into higher order structures, ultimately giving rise to a complex organization of specific domains within the nucleus. [PMID:20404130]. humans defined as following: Members of the species Homo sapiens.. histone H3 defined as following: Histone H3 is a core subunit of the eukaryotic nucleosome complex. Histones are basic nuclear proteins responsible for the nucleosome structure of chromatin. Repeating nucleosome units contain two molecules each of Histones H2A, H2B, H3, and H4 that form an octamer complex around which approximately 146 base pairs of DNA is wrapped. Linker Histone H1 interacts with DNA between nucleosome units in mediating chromatin compaction into higher order structures. (NCI). chromatin assembly factor defined as following: A histone chaperone protein that plays a role in the deposition of NUCLEOSOMES on newly synthesized DNA. It is comprised of three different subunits of 48, 60, and 150 kDa molecular size. The 48 kDa subunit, RETINOBLASTOMA-BINDING PROTEIN 4, is also a component of several other protein complexes involved in chromatin remodeling.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "yes"} {"id": "converted_3080", "sentence1": "Is treatment with Bacillus Calmette Guerin used for bladder cancer?", "sentence2": "Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. , this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy., response of urothelial precancerous lesions to intravesical BCG treatment, bladder cancer (BC) is a major clinical issue.METHODS: We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette-Guerin (BCG)., To evaluate the efficacy and safety of a tailored endovesical immunotherapy protocol with biweekly BCG for elderly Patients with high risk non muscle invasive bladder cancer , Bacillus of Calmette-Guerin (BCG) therapy for high risk non muscle invasive bladder cancer treatment in older patients., BCG (Bacillus of Calmette Guerin) has been used for more than 20 years and is currently the most active agent for superficial bladder cancer therapy., BCG (Bacillus of Calmette Guerin) therapy of high-risk superficial bladder cancer., Production of IL-5, a classical T(H)2 cytokine, following bacillus Calmette guerin immunotherapy of bladder cancer., Intravesical Bacillus Calmette-Guerin is used to treat patients with superficial bladder cancer., There is some evidence that BCG therapy improves survival and progression rates of patients with high-risk superficial bladder cancer decreasing the proportion who require radical cystectomy., Local immunotherapy with bacillus Calmette-Guerin (BCG) is an effective and frequently used treatment for superficial bladder cancer., CONCLUSIONS\nIntravesical bacillus Calmette-Guerin is a viable therapeutic option in patients with high risk superficial bladder cancer and concomitant lymphoma or chronic lymphocytic leukemia, treatment with low dose oral steroids or treatment with inhaled steroids., PURPOSE\nBacillus Calmette-Guerin is the most effective therapy for nonmuscle invasive bladder cancer., INTRODUCTION\nBacillus Calmette-Guerin (BCG) is a live attenuated strain of Mycobacterium bovis that has been used to treat urothelial carcinoma since 1976, and has been reported to eradicate disease in more than 70% of patients with in situ and stage I disease., Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer., Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results., We describe a 53 year- old man with a disseminated bacillus Calmette-Guerin (BCG) infection after intravescical instillation for bladder carcinoma., We tested the hypothesis that tumor expression of natural cytotoxicity receptor ligands can serve as a predictive factor for the response to intravesical bacillus Calmette-Guerin in patients with nonmuscle invasive, high grade bladder cancer., Bacillus Calmette-Guerin immunotherapy has been found by a number of investigators to be effective in the treatment and prevention of superficial bladder cancer., Pancreatic and psoas abscesses as a late complication of intravesical administration of bacillus Calmette-Guerin for bladder cancer: a case report and review of the literature.This case illustrates the fact that although intravesical administration of bacillus Calmette-Guerin is generally considered to be safe, it is not exempt from complications and these could appear immediately after treatment or as a delayed complication many years later., Effects of local bacillus Calmette-Guerin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall.The antitumoral effects of intravesical bacillus Calmette-Guerin against recurrent superficial urothelial bladder cancer seem to be linked to immunological effector mechanisms. , Fatal sepsis following intravesical bacillus Calmette-Guerin administration for bladder cancer.Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer. , Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results.We treated 40 patients with superficial bladder cancer via intravesical bacillus Calmette-Guerin for 1) prophylaxis against tumor recurrence, 2) residual carcinoma or 3) flat carcinoma in situ. , Bacillus Calmette-Guerin immunotherapy for bladder cancer.Bacillus Calmette-Guerin immunotherapy has been found by a number of investigators to be effective in the treatment and prevention of superficial bladder cancer. , Safety and efficacy of intravesical bacillus Calmette-Guerin instillations in steroid treated and immunocompromised patients.Intravesical bacillus Calmette-Guerin is a viable therapeutic option in patients with high risk superficial bladder cancer and concomitant lymphoma or chronic lymphocytic leukemia, treatment with low dose oral steroids or treatment with inhaled steroids. , Our results suggest that intralesional bacillus Calmette-Guerin immunotherapy can afford long term protection from transplanted bladder cancer, and that live bacillus Calmette-Guerin is superior to levamisole and P3 + Re-glycolipid + bacillus Calmette-Guerin cell walls in the treatment of bladder cancer., A randomized controlled prospective evaluation of intravesical and percutaneous bacillus Calmette-Guerin immunotherapy was done in 57 patients with transitional cell carcinoma of the bladder., Up to 90% of patients with high grade superficial bladder tumors experience tumor recurrence and up to 50% have progression despite bacillus Calmette-Guerin treatment., We review how the bacillus Calmette-Guerin vaccine evolved to become standard therapy for superficial bladder cancer., We reviewed the historical literature describing the origin of the bacillus Calmette-Guerin vaccine as an anticancer agent and its singular success as the most effective immunotherapy used against a human neoplasm.[SEP]Definitions: MSH2 defined as following: DNA mismatch repair protein Msh2 (934 aa, ~105 kDa) is encoded by the human MSH2 gene. This protein is involved in DNA mismatch repair.. levamisole defined as following: An antihelminthic drug that has been tried experimentally in rheumatic disorders where it apparently restores the immune response by increasing macrophage chemotaxis and T-lymphocyte function. Paradoxically, this immune enhancement appears to be beneficial in rheumatoid arthritis where dermatitis, leukopenia, and thrombocytopenia, and nausea and vomiting have been reported as side effects. (From Smith and Reynard, Textbook of Pharmacology, 1991, p435-6). steroid defined as following: A group of polycyclic compounds closely related biochemically to TERPENES. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (STEROLS), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. (From Hawley's Condensed Chemical Dictionary, 11th ed). Bacillus Calmette-Guerin defined as following: An attenuated form of Mycobacterium bovis that is used to generate the Bacillus Calmette-Guerin vaccine.. lymphoma defined as following: A general term for various neoplastic diseases of the lymphoid tissue.. MSI defined as following: The occurrence of highly polymorphic mono- and dinucleotide MICROSATELLITE REPEATS in somatic cells. It is a form of genome instability associated with defects in DNA MISMATCH REPAIR.. urothelial carcinoma defined as following: A malignant neoplasm derived from the transitional epithelium of the urinary tract (urinary bladder, ureter, urethra, or renal pelvis). It is frequently papillary.. HER-2 defined as following: A cancer vaccine comprised of peptides derived from the extracellular domain of the tumor-associated antigen Her-2/neu with potential antineoplastic activity. HER-2/neu peptide vaccine may induce antibodies with anti-tumor activity and may also elicit a specific CD8 T-cell response against specific tumor cell types. (NCI04). IL-5 defined as following: Binding to interleukin-5. [GOC:jl]. T1 defined as following: This gene plays a role in energy metabolism and mitochondrial ADP/ATP flux.. psoas abscesses defined as following: Abscess of the PSOAS MUSCLES resulting usually from disease of the lumbar vertebrae, with the pus descending into the muscle sheath. The infection is most commonly tuberculous or staphylococcal.. predictive factor defined as following: Characteristics and conditions that have a bearing on the likelihood of a person developing a disease or disorder.. Pancreatic defined as following: Peptide hormones secreted into the blood by cells in the ISLETS OF LANGERHANS of the pancreas. The alpha cells secrete glucagon; the beta cells secrete insulin; the delta cells secrete somatostatin; and the PP cells secrete pancreatic polypeptide.. MLH1 defined as following: This gene plays a role in DNA mismatch repair.. TURBT defined as following: A surgical procedure used to treat bladder tumors, during which a resectoscope is passed through the urethra and into the bladder.. bladder defined as following: A musculomembranous sac along the URINARY TRACT. URINE flows from the KIDNEYS into the bladder via the ureters (URETER), and is held there until URINATION.. transitional cell carcinoma defined as following: A malignant neoplasm derived from TRANSITIONAL EPITHELIAL CELLS, occurring chiefly in the URINARY BLADDER; URETERS; or RENAL PELVIS.. chronic lymphocytic leukemia defined as following: A chronic leukemia characterized by abnormal B-lymphocytes and often generalized lymphadenopathy. In patients presenting predominately with blood and bone marrow involvement it is called chronic lymphocytic leukemia (CLL); in those predominately with enlarged lymph nodes it is called small lymphocytic lymphoma. These terms represent spectrums of the same disease.. superficial bladder cancer defined as following: An infiltrating carcinoma of the bladder that has not invaded into the bladder muscularis propria.. bladder tumor defined as following: Tumors or cancer of the URINARY BLADDER.. Mycobacterium bovis defined as following: The bovine variety of the tubercle bacillus. It is called also Mycobacterium tuberculosis var. bovis.. bladder carcinoma defined as following: A carcinoma arising from the bladder epithelium. Approximately 90% of the bladder carcinomas are transitional cell carcinomas. The remainder are squamous cell carcinomas, adenocarcinomas and small cell neuroendocrine carcinomas.. human defined as following: Members of the species Homo sapiens.. bladder cancer defined as following: A primary or metastatic malignant neoplasm involving the bladder.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary..", "label": "yes"} {"id": "converted_1613", "sentence1": "Do plant genomes contain CpG islands?", "sentence2": "This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants, In plant genomes, there exist discrete regions rich in CpG dinucleotides, namely CpG clusters. In rice, most of these CpG clusters are associated with genes. Rice genes are grouped into one of the five classes according to the position of an associated CpG cluster. Among them, class 1 genes, which harbor a CpG cluster at the 5'-terminus, share similarities with human genes having CpG islands, Segmental distribution of genes harboring a CpG island-like region on rice chromosomes, Highly-expressed Arabidopsis genes had overall a more marked GC-skew in the TSS compared to genes with low expression levels. We therefore propose that the GC-skew around the TSS in some plants and fungi is related to transcription. It might be caused by mutations during transcription initiation or the frequent use of transcription factor-biding sites having a strand preference. In addition, GC-skew is a good candidate index for TSS prediction in plant genomes, where there is a lack of correlation among CpG islands and genes, Preliminary analysis shows that promoter location based on the detection of potential CpG/CpNpG islands in the Arabidopsis genome is not straightforward. Nevertheless, because the landscape of CpG/CpNpG islands differs considerably between promoters and introns on the one side and exons (whether coding or not) on the other, more sophisticated approaches can probably be developed for the successful detection of \"putative\" CpG and CpNpG islands in plants, This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants., These plant CpG-rich clusters satisfied the criteria used for identifying human CpG islands, which suggests that these CpG clusters may be regarded as plant CpG islands., CONCLUSIONS: This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants., In plant genomes, there exist discrete regions rich in CpG dinucleotides, namely CpG clusters., These plant CpG-rich clusters satisfied the criteria used for identifying human CpG islands, which suggests that these CpG clusters may be regarded as plant CpG islands., Unmethylated CpG islands associated with genes in higher plant DNA., This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some of these genomic properties might be considered as specific to plants., These plant CpG-rich clusters satisfied the criteria used for identifying human CpG islands, which suggests that these CpG clusters may be regarded as plant CpG islands, We screened plant genome sequences, primarily from rice and Arabidopsis thaliana, for CpG islands, and identified DNA segments rich in CpG dinucleotides within these sequences[SEP]Definitions: TSS defined as following: A rare acute life-threatening systemic bacterial noncontagious illness caused by any of several related staphylococcal exotoxins. It is characterized by high fever, hypotension, rash, multi-organ dysfunction, and cutaneous desquamation during the early convalescent period. The toxins affect the host immune system, causing an exuberant and pathological host inflammatory response. Laboratory findings include leukocytosis, elevated prothrombin time, hypoalbuminemia, hypocalcemia, and pyuria.. strand defined as following: The orientation of a genomic element on the double stranded molecule.. sequences defined as following: The sequence of nucleotide residues along a DNA chain.. exons defined as following: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.. promoters defined as following: A DNA sequence at which RNA polymerase binds and initiates transcription.. chromosomes defined as following: A specific pair of human chromosomes in group A (CHROMOSOMES, HUMAN, 1-3) of the human chromosome classification.. position defined as following: A reference to the alignment of an object, a particular situation or view of a situation, or the location of an object.. coding defined as following: The activity of implementing rules that are used to map the elements of one set onto the elements of another set, usually on a one-to-one basis.. introns defined as following: Sequences of DNA in the genes that are located between the EXONS. They are transcribed along with the exons but are removed from the primary gene transcript by RNA SPLICING to leave mature RNA. Some introns code for separate genes.. plants defined as following: Multicellular, eukaryotic life forms of kingdom Plantae. Plants acquired chloroplasts by direct endosymbiosis of CYANOBACTERIA. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (MERISTEMS); cellulose within cells providing rigidity; the absence of organs of locomotion; absence of nervous and sensory systems; and an alternation of haploid and diploid generations. It is a non-taxonomical term most often referring to LAND PLANTS. In broad sense it includes RHODOPHYTA and GLAUCOPHYTA along with VIRIDIPLANTAE.. plant DNA defined as following: Deoxyribonucleic acid that makes up the genetic material of plants.. plant genomes defined as following: The genetic complement of a plant (PLANTS) as represented in its DNA.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA..", "label": "yes"} {"id": "converted_524", "sentence1": "Is the protein β1-integrin recycled?", "sentence2": "Pathways selectively regulating β1-integrin recycling are implicated in cancer invasion and metastasis,, integrin-positive early and recycling endosomes , LPA-induced recycling of β1 integrin,, RCP-mediated recycling of α5β1 integrin , CycD1 overexpression increased β1 integrin recycling , inhibition of autophagy slowed down the lysosomal degradation of internalized β1 integrins and promoted its membrane recycling, recycling pathway for β1-integrin, β1 integrin recycling, β1 integrin recycling, controlling β1 integrin recycling to the plasma membrane , integrin recycling pathway, Distinct recycling of active and inactive β1 integrins., Integrin functions are controlled by regulating their affinity for ligand, and by the efficient recycling of intact integrins through endosomes., β1 integrins, resulting in their recycling to the cell surface where they can be reused.[SEP]Definitions: β1 integrin defined as following: A family of transmembrane glycoproteins (MEMBRANE GLYCOPROTEINS) consisting of noncovalent heterodimers. They interact with a wide variety of ligands including EXTRACELLULAR MATRIX PROTEINS; COMPLEMENT, and other cells, while their intracellular domains interact with the CYTOSKELETON. The integrins consist of at least three identified families: the cytoadhesin receptors (RECEPTORS, CYTOADHESIN), the leukocyte adhesion receptors (RECEPTORS, LEUKOCYTE ADHESION), and the VERY LATE ANTIGEN RECEPTORS. Each family contains a common beta-subunit (INTEGRIN BETA CHAINS) combined with one or more distinct alpha-subunits (INTEGRIN ALPHA CHAINS). These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development; HEMOSTASIS; THROMBOSIS; WOUND HEALING; immune and nonimmune defense mechanisms; and oncogenic transformation.. plasma membrane defined as following: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.. cell surface defined as following: The external part of the cell wall and/or plasma membrane. [GOC:jl, GOC:mtg_sensu, GOC:sm]. endosomes defined as following: Cytoplasmic vesicles formed when COATED VESICLES shed their CLATHRIN coat. Endosomes internalize macromolecules bound by receptors on the cell surface..", "label": "yes"} {"id": "converted_1360", "sentence1": "Is triadin involved in cardiac function?", "sentence2": "Junctin (JCN), a 26-kd sarcoplasmic reticulum (SR) transmembrane protein, forms a quaternary protein complex with the ryanodine receptor, calsequestrin, and triadin in the SR lumen of cardiac muscle. Within this complex, calsequestrin, triadin, and JCN appear to be critical for normal regulation of ryanodine receptor-mediated calcium (Ca) release., Recent studies have uncovered functional roles of both JCN and triadin in the mouse heart, using transgenic overexpression strategies, which exhibit varying phenotypes including mild SR structural alterations, prolongation of Ca transient decay, impaired relaxation, and cardiac hypertrophy and/or heart failure., Triadin is involved in the regulation of cardiac excitation-contraction coupling. , Thus the maintenance of triadin expression is essential for normal SR Ca cycling and contractile function., Ca2+ release from the cardiac junctional sarcoplasmic reticulum (SR) is regulated by a complex of proteins, including the ryanodine receptor (RyR), calsequestrin (CSQ), junctin (JCN), and triadin 1 (TRD)., Impaired sarcoplasmic reticulum (SR) Ca release has been suggested to contribute to the depressed cardiac function in heart failure. The release of Ca from the SR may be regulated by the ryanodine receptor, triadin, junctin, calsequestrin, and a histidine-rich, Ca-binding protein (HRC).[SEP]Definitions: junctin defined as following: Junctin-2 (210 aa, ~24 kDa) is encoded by the human ASPH gene. This protein is involved in calcium homeostasis in striated muscle.. Junctin defined as following: This gene is involved in calcium ion channel regulation and amino acid hydroxylation.. ryanodine receptor defined as following: A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.. sarcoplasmic reticulum defined as following: A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.. SR defined as following: Human SNCG wild-type allele is located within10q23.2-q23.3 and is approximately 13 kb in length. This allele, which encodes gamma-synuclein protein, plays a role in the modulation of axonal architecture and neurofilament integrity. This gene is highly expessed in advanced breast carcinomas, suggesting a correlation between SNCG overexpression and breast tumor development.. RyR defined as following: A voltage-gated calcium-release channel complex of the sarcoplasmic or endoplasmic reticulum. It plays an important role in the excitation-contraction (E-C) coupling of muscle cells. RyR comprises a family of ryanodine receptors, widely expressed throughout the animal kingdom. [GOC:ame, PMID:22822064]. TRD defined as following: One component of the gamma-delta T-cell receptor. Encoded by a locus on chromosome 14. Somatic recombination results in formation of the active gene.. heart failure defined as following: Heart failure accompanied by EDEMA, such as swelling of the legs and ankles and congestion in the lungs.. cardiac hypertrophy defined as following: Enlargement of the HEART due to chamber HYPERTROPHY, an increase in wall thickness without an increase in the number of cells (MYOCYTES, CARDIAC). It is the result of increase in myocyte size, mitochondrial and myofibrillar mass, as well as changes in extracellular matrix..", "label": "yes"} {"id": "converted_2021", "sentence1": "Is siltuximab effective for Castleman disease?", "sentence2": "Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease., The recent approvals in North America, Europe and Brazil of siltuximab, a monoclonal antibody against IL-6, for iMCD now provide a safe and effective therapy that targets a key aspect of pathogenesis. In the first ever randomized, placebo-controlled trial in iMCD, siltuximab significantly reduced disease burden and symptoms in a large portion (34%) of patients., Despite recent significant advances in our understanding of this disease and the increasing therapeutic experience with rituximab, tocilizumab and siltuximab, there are still difficult questions concerning its aetiology, prognosis and optimal treatment., Emerging treatments in Castleman disease - a critical appraisal of siltuximab., Siltuximab, a chimeric monoclonal antibody to IL-6, has thus emerged as a promising treatment option in a disease lacking efficacious therapy. Here, we review the findings of recent studies evaluating single-agent siltuximab treatment in CD, including the first-ever randomized clinical trial in this disease. Although much more work is needed to establish a standardized treatment approach, siltuximab appears to be a safe and effective treatment for patients with newly diagnosed and previously treated CD., FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease., On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. , Currently, there are more effective therapeutic alternatives in multicentric Castleman disease: treatment with monotherapy of rituximab or in combination therapy with immunomodulatory drugs (thalidomide or lenalidomide, treatment with anti-IL-6 (siltuximab) or against its receptor (tocilizumab). , Currently, there are more effective therapeutic alternatives in multicentric Castleman disease: treatment with monotherapy of rituximab or in combination therapy with immunomodulatory drugs (thalidomide or lenalidomide, treatment with anti-IL-6 (siltuximab) or against its receptor (tocilizumab)., Siltuximab for multicentric Castleman disease., Siltuximab: A Review in Idiopathic (Human Herpesvirus-8-Negative) Multicentric Castleman Disease., Siltuximab (IL6 antibody) is approved for the treatment of multicentric Castleman disease (MCD)., A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease., A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease., Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease., Siltuximab (Sylvant). Castleman's disease: good symptomatic efficacy in some patients., Siltuximab: a new option for the management of Castleman's disease., Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease., PURPOSE: To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease.EXPERIMENTAL DESIGN: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks., Dose selection of siltuximab for multicentric Castleman's disease., Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD).METHODS: PK/PD modeling was applied to explore the relationship between siltuximab PK and CRP suppression following intravenous siltuximab infusion in 47 patients with B cell non-Hodgkin's lymphoma (n = 17), multiple myeloma (n = 13), or CD (n = 17)., Currently, there are more effective therapeutic alternatives in multicentric Castleman disease: treatment with monotherapy of rituximab or in combination therapy with immunomodulatory drugs (thalidomide or lenalidomide, treatment with anti-IL-6 (siltuximab) or against its receptor (tocilizumab), Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis).Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castlemans disease and well tolerated with prolonged exposure, Siltuximab, an anti-IL-6 monoclonal antibody, has demonstrated durable tumor and symptomatic responses in a multinational, randomized, placebo-controlled study of MCD.This preplanned safety analysis was conducted to evaluate the long-term safety of siltuximab treatment among 19 patients with MCD who had stable disease or better and were enrolled in a phase-1 study and subsequent ongoing, open-label, phase-2 extension study, Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease, Siltuximab (IL6 antibody) is approved for the treatment of multicentric Castleman disease (MCD), Siltuximab for multicentric Castleman disease, FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease, On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative, Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial., EXPERIMENTAL DESIGN: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. , Currently, there are more effective therapeutic alternatives in multicentric Castleman disease: treatment with monotherapy of rituximab or in combination therapy with immunomodulatory drugs (thalidomide or lenalidomide, treatment with anti-IL-6 (siltuximab) or against its receptor (tocilizumab)., To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease.In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks., On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative., Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease.Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer., The recent approvals in North America, Europe and Brazil of siltuximab, a monoclonal antibody against IL-6, for iMCD now provide a safe and effective therapy that targets a key aspect of pathogenesis., Although much more work is needed to establish a standardized treatment approach, siltuximab appears to be a safe and effective treatment for patients with newly diagnosed and previously treated CD., No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days).These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD., Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD.METHODS: We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals., Siltuximab for multicentric Castleman disease., Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease., Emerging treatments in Castleman disease - a critical appraisal of siltuximab., Siltuximab (Sylvant). Castleman's disease: good symptomatic efficacy in some patients., Siltuximab: a new option for the management of Castleman's disease., Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial., Siltuximab: A Review in Idiopathic (Human Herpesvirus-8-Negative) Multicentric Castleman Disease.[SEP]Definitions: NHL defined as following: Malignant lymphoma in which the majority of neoplastic cells within the follicles are large cleaved or noncleaved cells. The degree to which the follicular center cells retain their ability to form follicles varies with the state of B-cell transformation.. lenalidomide defined as following: A thalidomide analog with potential antineoplastic activity. Lenalidomide inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells.. IL-6 defined as following: A recombinant therapeutic agent which is chemically identical to or similar to the endogenous cytokine interleukin-6 (IL-6) with antiapoptotic, proinflammatory, antiinflammatory, proproliferative and proangiogenic activities. IL-6 binds to its receptor (IL-6R), activating a receptor-CD130 receptor complex; the CD130 portion of the complex is a signal transduction protein that activates JAK kinases and Ras-mediated signaling pathways, which in turn activate downstream signaling pathways, resulting in the activation of various transcription factors (STAT, ELK-1, NF-IL-6, etc.) and gene transcription. The physiological effects of IL-6 are complex and varied and include hematopoietic, pyrogenic and thermogenic, proinflammatory, antiinflammatory, proproliferative (anti-apoptotic), and angiogenic effects.. multicentric Castlemans disease defined as following: A form of angiofollicular lymphoid hyperplasia characterized by fever, generalized lymphadenopathy, hypergammaglobulinemia, and dysfunction of multiple organs. Other signs and symptoms include anemia, thrombocytopenia, hepatomegaly, peripheral neuropathy and pleural effusions. Morphologically, in the majority of cases the lymph nodes show features of angiofollicular lymphoid hyperplasia of the plasma cell type. In a minority of cases, changes of angiofollicular lymphoid hyperplasia of the hyaline-vascular type are seen. In contrast to patients with localized disease who are usually cured following resection of the lesion, patients with the multicentric form of the disease may follow a progressive clinical course, complicated by infection, Kaposi sarcoma, or lymphoma.. Castleman disease defined as following: Large benign, hyperplastic lymph nodes. The more common hyaline vascular subtype is characterized by small hyaline vascular follicles and interfollicular capillary proliferations. Plasma cells are often present and represent another subtype with the plasma cells containing IgM and IMMUNOGLOBULIN A.. CRP defined as following: A plasma protein that circulates in increased amounts during inflammation and after tissue damage. C-Reactive Protein measured by more sensitive methods often for coronary heart disease risk assessment is referred to as High Sensitivity C-Reactive Protein (hs-CRP).. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. tocilizumab defined as following: A recombinant, humanized IgG1 monoclonal antibody directed against the interleukin-6 receptor (IL-6R) with immunosuppressant activity. Tocilizumab targets and binds to both the soluble form of IL-6R (sIL-6R) and the membrane-bound form (mIL-6R), thereby blocking the binding of IL-6 to its receptor. This prevents IL-6-mediated signaling. IL-6, a pro-inflammatory cytokine that plays an important role in the regulation of the immune response, is overproduced in autoimmune disorders, certain types of cancers and possibly various other inflammatory conditions.. lower respiratory tract infection defined as following: An acute or chronic, viral or bacterial infectious process that affects the lower respiratory tract.. Siltuximab defined as following: A chimeric, human-murine, monoclonal antibody targeting the pro-inflammatory cytokine interleukin 6 (IL-6), with antitumor and anti-inflammatory activities. Upon intravenous administration of siltuximab, this agent targets and binds to IL-6. This inhibits the binding of IL-6 to the IL-6 receptor (IL-6R), which results in the blockade of the IL-6/IL-6R-mediated signal transduction pathway. This inhibits cancer cell growth in tumors overexpressing IL-6.. B-cell non-Hodgkin lymphoma defined as following: A group of heterogeneous lymphoid tumors generally expressing one or more B-cell antigens or representing malignant transformations of B-lymphocytes.. anaphylactic reaction defined as following: An acute hypersensitivity reaction due to exposure to a previously encountered ANTIGEN. The reaction may include rapidly progressing URTICARIA, respiratory distress, vascular collapse, systemic SHOCK, and death.. rituximab defined as following: A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS.. toxicity defined as following: The finding of bodily harm due to the poisonous effects of something.. PK defined as following: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40.. fatigue defined as following: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.. IL6 defined as following: A cytokine that stimulates the growth and differentiation of B-LYMPHOCYTES and is also a growth factor for HYBRIDOMAS and plasmacytomas. It is produced by many different cells including T-LYMPHOCYTES; MONOCYTES; and FIBROBLASTS.. monoclonal antibody defined as following: A humanized monoclonal antibody directed against parathyroid hormone-related protein (PTH-rP). As a poly-hormone with diverse biological roles, PTH-rP is expressed by normal tissues, acting in local tissue environments in a variety of ways; it is commonly overexpressed by breast, prostate, and other cancers, acting systemically by promoting bone resorption, inhibiting calcium excretion from the kidney, inducing hypercalcemia, and possibly playing a role in the formation of bony metastases. By blocking the effects of PTH-rP on calcium metabolism, monoclonal antibody CAL may inhibit cancer-related hypercalcemia. (NCI04). thalidomide defined as following: A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of TUMOR NECROSIS FACTOR-ALPHA from monocytes, and modulates other cytokine action.. hemoglobin defined as following: A tetrameric complex of 2 molecules of hemoglobin subunit alpha (encoded by either the HBA1 or HBA2 gene) and 2 molecules of hemoglobin subunit beta (encoded by the HBB gene).. PD defined as following: A score of 4 or 5 on a 5-point PET scale with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end of treatment assessment.. multiple myeloma defined as following: A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY.. anti-IL-6 monoclonal antibody defined as following: Any monoclonal antibody targeting the cytokine interleukin-6 (IL-6).. siltuximab defined as following: A chimeric, human-murine, monoclonal antibody targeting the pro-inflammatory cytokine interleukin 6 (IL-6), with antitumor and anti-inflammatory activities. Upon intravenous administration of siltuximab, this agent targets and binds to IL-6. This inhibits the binding of IL-6 to the IL-6 receptor (IL-6R), which results in the blockade of the IL-6/IL-6R-mediated signal transduction pathway. This inhibits cancer cell growth in tumors overexpressing IL-6..", "label": "yes"} {"id": "converted_1510", "sentence1": "Is gastro esophageal reflux related to burning mouth syndrome?", "sentence2": "Our results suggest that there is no causal connection between LPR episodes and the occurrence of intraoral burning sensations in the examined patients., As reported below, although this symptom may well be diagnostically misleading, careful diagnosis based on clinical signs may distinguish patients with BMS from those with reflux disease, and successful management of burning mouth is often enables.[SEP]Definitions: LPR defined as following: Microscopic examination of tissue specimen(s) by a pathologist in the local institution where a patient had a procedure performed, using local standardized methods and criteria..", "label": "no"} {"id": "converted_1574", "sentence1": "Does the concentration of protein HIF-1α increase after the administration of the cytoprotective prodrug\"amifostine\" (ethyol) ?", "sentence2": "We demonstrated that the treatment of several human cancer cell lines with therapeutical doses of WR-1065 led to a strong induction of different VEGF-A mRNA isoforms independently of HIF-1alpha, e investigated the involvement of hypoxia-regulated proteins (Hypoxia inducible factors HIF1alpha, HIF2alpha and carbonic anhydrase CA9) in HNC resistance to accelerated and hypofractionated radiotherapy, In accord with previously reported studies, high levels of the hypoxia regulated proteins HIF1alpha and CA9 in HNC predict resistance to platinum based radio-chemotherapy. Whether HIF2alpha expressing tumors are more sensitive to larger radiotherapy fractions, compared to standard radiotherapy fractionation, is an issue that deserves further investigation., HIF1alpha and HIF2alpha were expressed in the nuclei and cytoplasm of cancer cells, while CA9 had a membrane reactivity. A high expression of HIF1alpha, HIF2alpha and CA9 was noted in 21/39 (53.8%), 20/39 (51.3%) and 23/39 (58.9%) cases, respectively. Complete response was obtained in 85.2% of patients and HIF1alpha was marginally related with persistent disease after RT (p = 0.05). HIF1alpha was significantly associated with poor local relapse free survival (LRFS) (p = 0.006) and overall survival (p = 0.008), whilst HIF2alpha was no, The glucose and oxygen levels in the peripheral blood of patients receiving 1000 mg amifostine were determined at various time-points in order to investigate the metabolic changes induced by amifostine. MDA468 breast tumor cell lines were incubated with a high amifostine concentration (10 m M) to overcome the natural resistance of cancer cells to influx of the non-hydrolyzed WR-2721, and the HIF1 alpha protein levels were determined by Western blot analysis, Since it is doubtful whether dephosphorylation of amifostine to the active metabolite WR-1065 occurs within tumoral tissues (an acidic environment that lacks vascular alkaline phosphatase activity), intracellular hypoxia and upregulation of HIF1 alpha represents an additional, normal tissue-specific, amifostine cytoprotective pathway., . Incubation of cell lines with amifostine resulted in HIF1 alpha induction[SEP]Definitions: glucose defined as following: The determination of the amount of glucose present in a sample.. Hypoxia defined as following: A disorder characterized by a decrease in the level of oxygen in the body.. amifostine defined as following: A phosphorothioate proposed as a radiation-protective agent. It causes splenic vasodilation and may block autonomic ganglia.. intracellular defined as following: The organized colloidal complex of organic and inorganic substances (as proteins and water) that constitutes the living nucleus, cytoplasm, plastids, and mitochondria of the cell. It is composed mainly of nucleic acids, proteins, lipids, carbohydrates, and inorganic salts.. cancer cells defined as following: Cells of, or derived from, a malignant tumor.. HIF-1alpha defined as following: Hypoxia-inducible factor 1-alpha (826 aa, ~93 kDa) is encoded by the human HIF1A gene. This protein plays a role in transcriptional regulation in response to hypoxia.. cytoplasm defined as following: The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990). HNC defined as following: Human MMP8 wild-type allele is located in the vicinity of 11q22.3 and is approximately 12 kb in length. This allele, which encodes neutrophil collagenase protein, is involved in the regulation of matrix remodeling via the degradation of fibrillar collagens (types I, II and III).. VEGF-A defined as following: The original member of the family of endothelial cell growth factors referred to as VASCULAR ENDOTHELIAL GROWTH FACTORS. Vascular endothelial growth factor-A was originally isolated from tumor cells and referred to as \"tumor angiogenesis factor\" and \"vascular permeability factor\". Although expressed at high levels in certain tumor-derived cells it is produced by a wide variety of cell types. In addition to stimulating vascular growth and vascular permeability it may play a role in stimulating VASODILATION via NITRIC OXIDE-dependent pathways. Alternative splicing of the mRNA for vascular endothelial growth factor A results in several isoforms of the protein being produced.. cell lines defined as following: Established cell cultures that have the potential to propagate indefinitely.. CA9 defined as following: Human CA9 wild-type allele is located in the vicinity of 9p13.3 and is approximately 7 kb in length. This allele, which encodes carbonic anhydrase 9 protein, plays a role in intracellular pH balance.. tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. human defined as following: Members of the species Homo sapiens.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species..", "label": "yes"} {"id": "converted_1354", "sentence1": "Has the presence of delayed enhancement been documented in athletes performing strenuous exercise?", "sentence2": "Atypical findings such as marked cardiac dilation, reduced deformation, or small patches of delayed gadolinium enhancement may be commonly encountered in well-trained athletes, but, at present, the prognostic significance of such findings is unknown. , On CMR, DGE localized to the interventricular septum was identified in 5 of 39 athletes who had greater cumulative exercise exposure and lower RVEF (47.1 ± 5.9 vs. 51.1 ± 3.7%, P = 0.042) than those with normal CMR., Post-event cardiac MRI demonstrated the interval appearance of delayed enhancement of gadolinium at the inferior insertion of the right ventricle and in the interventricular septum-a novel finding that may represent subtle inflammation secondary to a combined exercise and altitude effect., No evidence of delayed enhancement of the left ventricular myocardium was found on CMR imaging, suggesting that the increase in cardiac biomarkers after the marathon may not have be due to myocardial necrosis., Of the 102 runners, five had a CAD pattern of LGE, and seven had a non-CAD pattern of LGE. The CAD pattern of LGE was located in the territory of the left anterior descending coronary artery more frequently than was the non-CAD pattern (P = .0027, Fisher exact test). The prevalence of LGE in runners was higher than that in age-matched control subjects (12% vs 4%; P = .077, McNemar exact test).[SEP]Definitions: interventricular septum defined as following: The muscular structure separating the right and the left lower chambers (HEART VENTRICLES) of the heart. The ventricular septum consists of a very small membranous portion just beneath the AORTIC VALVE, and a large thick muscular portion consisting of three sections including the inlet septum, the trabecular septum, and the outlet septum.. myocardial necrosis defined as following: NECROSIS of the MYOCARDIUM caused by an obstruction of the blood supply to the heart (CORONARY CIRCULATION).. gadolinium defined as following: An element of the rare earth family of metals. It has the atomic symbol Gd, atomic number 64, and atomic weight 157.25. Its oxide is used in the control rods of some nuclear reactors.. territory defined as following: A constituent administrative district of a nation.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. strenuous exercise defined as following: 20-60 minutes of exercise which elevates your heart rate to 80-90% of your maximum heart rate performed at least 3-4 times per week..", "label": "yes"} {"id": "converted_4708", "sentence1": "Can whole genome sequencing be used for diagnosis of mitochondrial disease?", "sentence2": "Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.[SEP]Definitions: mitochondrial disorders defined as following: Diseases caused by abnormal function of the MITOCHONDRIA. They may be caused by mutations, acquired or inherited, in mitochondrial DNA or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondria dysfunction due to adverse effects of drugs, infections, or other environmental causes.. cardiomyopathies defined as following: A group of diseases in which the dominant feature is the involvement of the CARDIAC MUSCLE itself. Cardiomyopathies are classified according to their predominant pathophysiological features (DILATED CARDIOMYOPATHY; HYPERTROPHIC CARDIOMYOPATHY; RESTRICTIVE CARDIOMYOPATHY) or their etiological/pathological factors (CARDIOMYOPATHY, ALCOHOLIC; ENDOCARDIAL FIBROELASTOSIS).. intellectual disability defined as following: Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28). metabolic disorders defined as following: Generic term for diseases caused by an abnormal metabolic process. It can be congenital due to inherited enzyme abnormality (METABOLISM, INBORN ERRORS) or acquired due to disease of an endocrine organ or failure of a metabolically important organ such as the liver. (Stedman, 26th ed). mitochondrial disease defined as following: Diseases caused by abnormal function of the MITOCHONDRIA. They may be caused by mutations, acquired or inherited, in mitochondrial DNA or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondria dysfunction due to adverse effects of drugs, infections, or other environmental causes..", "label": "yes"} {"id": "converted_545", "sentence1": "Have hESC been tested for the treatment of age-related macular degeneration?", "sentence2": "Development of human embryonic stem cell therapies for age-related macular degeneration, In this review, we describe recent approaches to develop cell-based therapies for the treatment of AMD. Recent research has focused on replacing the retinal pigment epithelium (RPE), a monolayer of cells vital to photoreceptor cell health. We discuss the various methods used to differentiate and purify RPE from human embryonic stem cells (HESC), and describe the surgical approaches being used to transplant these cells in existing and forthcoming clinical trials., Age-related macular degeneration (AMD) is characterized by the loss or dysfunction of retinal pigment epithelium (RPE) and is the most common cause of vision loss among the elderly. Stem-cell-based strategies, using human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs), may provide an abundant donor source for generating RPE cells in cell replacement therapies., This study contributes to our understanding of the utility of hESC/hiPSC-derived RPE in AMD therapy., Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness., Human embryonic stem cells (hESCs) are a promising source of retinal pigment epithelium (RPE) cells: cells that can be used for the treatment of common and incurable forms of blindness, such as age-related macular degeneration., A potential application of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is the generation of retinal pigmented epithelium (RPE) to treat age-related macular degeneration (AMD), a common but incurable retinal disease., Human embryonic stem cells (hESCs) are a promising source of retinal pigment epithelium (RPE) cells: cells that can be used for the treatment of common and incurable forms of blindness, such as age-related macular degeneration, A potential application of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is the generation of retinal pigmented epithelium (RPE) to treat age-related macular degeneration (AMD), a common but incurable retinal disease, Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness., A potential application of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is the generation of retinal pigmented epithelium (RPE) to treat age-related macular degeneration (AMD), a common but incurable retinal disease. RPE cells derived from hESCs (hESC-RPEs) and iPSCs (iPSC-RPEs) express essential RPE markers and can rescue visual function in animal models., Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively.[SEP]Definitions: retinal degeneration defined as following: A retrogressive pathological change in the retina, focal or generalized, caused by genetic defects, inflammation, trauma, vascular disease, or aging. Degeneration affecting predominantly the macula lutea of the retina is MACULAR DEGENERATION. (Newell, Ophthalmology: Principles and Concepts, 7th ed, p304). Stargardt defined as following: An autosomal recessive and rarely autosomal dominant inherited disorder caused by mutations in the ABCA4 or ELOVL4 genes respectively. It is characterized by macular degeneration that begins in late childhood resulting in progressive loss of vision.. retinal pigment epithelium defined as following: The single layer of pigment-containing epithelial cells in the RETINA, situated closely to the tips (outer segments) of the RETINAL PHOTORECEPTOR CELLS. These epithelial cells are macroglia that perform essential functions for the photoreceptor cells, such as in nutrient transport, phagocytosis of the shed photoreceptor membranes, and ensuring retinal attachment.. rat defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. human defined as following: Members of the species Homo sapiens.. Human embryonic stem cells defined as following: A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage.. cells defined as following: The fundamental, structural, and functional units or subunits of living organisms. They are composed of CYTOPLASM containing various ORGANELLES and a CELL MEMBRANE boundary.. retinal defined as following: A diterpene derived from the carotenoid VITAMIN A which functions as the active component of the visual cycle. It is the prosthetic group of RHODOPSIN (i.e., covalently bonded to ROD OPSIN as 11-cis-retinal). When stimulated by visible light, rhodopsin transforms this cis-isomer of retinal to the trans-isomer (11-trans-retinal). This transformation straightens-out the bend of the retinal molecule and causes a change in the shape of rhodopsin triggering the visual process. A series of energy-requiring enzyme-catalyzed reactions convert the 11-trans-retinal back to the cis-isomer.. retinal disease defined as following: Diseases involving the RETINA.. blindness defined as following: The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of EYE DISEASES; OPTIC NERVE DISEASES; OPTIC CHIASM diseases; or BRAIN DISEASES affecting the VISUAL PATHWAYS or OCCIPITAL LOBE.. AMD defined as following: Age-related loss of vision in the central portion of the retina (macula), secondary to retinal degeneration.. vision loss defined as following: A condition in which the ability to see is impaired..", "label": "yes"} {"id": "converted_2662", "sentence1": "Does oncogene-induced DNA replication stress inhibit genomic instability?", "sentence2": "Oncogene-induced DNA replication stress is thought to drive genomic instability in cancer., We propose that single-stranded DNA generated in response to oncogene-induced replication stress compromises the repair of deaminated cytosines and other damaged bases, leading to the observed SNS mutator phenotype.[SEP]Definitions: cancer defined as following: A malignant tumor at the original site of growth.. SNS defined as following: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system..", "label": "no"} {"id": "converted_3174", "sentence1": "Was stelara developed by Amgen?", "sentence2": "NICE does not specifically recommend switching from one biologic to another, and only ustekinumab (UST; STELARA®, Janssen Pharmaceuticals, Inc., Horsham, PA, USA) is recommended after anti-tumour necrosis factor failure.[SEP]Definitions: Janssen Pharmaceuticals defined as following: A pharmaceutical company providing medicines for an array of health concerns in several therapeutic areas. The company conducts research and development into oncology, mental illness, neurological disorders, gastrointestinal disorders, fungal infection, and allergies.. NICE defined as following: An antimicrobial lock solution (ALS) containing the nitrate nitroglycerin, sodium citrate and ethanol, with potential antimicrobial and anticoagulant activities. Upon application to the catheter as an ALS, the nitroglycerin is converted into nitric oxide (NO), which exerts antimicrobial activity. The citrate exerts anticoagulant activity, thereby preventing blood clotting and occlusion and maintaining the fluidity of the administered solution. In addition, both citrate and ethanol exert antimicrobial activity. This may prevent bacterial colonization on the surface of the catheter, biofilm formation and prevents catheter-associated infections.. PA defined as following: A SI derived unit of pressure equivalent to one newton per square meter or 10 bars or to 1.45x10E-4 pounds per square inch.. UST defined as following: Any examination of software/hardware functionality that takes place outside of the developer's controlled environment..", "label": "no"} {"id": "converted_167", "sentence1": "Is CD84 genetically associated with arthritis?", "sentence2": "The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients), Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity, Three members of this gene family, Ly108, Ly9, and CD84, exhibit polymorphisms that strongly influence susceptibility to systemic autoimmunity, notably in mice, but also in some human populations[SEP]Definitions: peripheral blood mononuclear cells defined as following: A peripheral blood cell with a single nucleus. This category includes lymphocytes and monocytes.. Ly108 defined as following: Human SLAMF6 wild-type allele is located in the vicinity of 1q23.2 and is approximately 38 kb in length. This allele, which encodes SLAM family member 6 protein, plays a role as a coreceptor in natural killer cell activation.. Ly9 defined as following: T-lymphocyte surface antigen Ly-9 (655 aa, ~72 kDa) is encoded by the human LY9 gene. This protein is involved in the positive regulation of helper T-cell Th17 differentiation.. allele defined as following: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.. human defined as following: Members of the species Homo sapiens.. RA defined as following: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.. 3' UTR defined as following: The sequence at the 3' end of messenger RNA that does not code for product. This region contains transcription and translation regulating sequences.. polymorphisms defined as following: The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.. SNP defined as following: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.. etanercept defined as following: A recombinant version of soluble human TNF receptor fused to an IgG FC fragment that binds specifically to TUMOR NECROSIS FACTOR and inhibits its binding with endogenous TNF receptors. It prevents the inflammatory effect of TNF and is used to treat RHEUMATOID ARTHRITIS; PSORIATIC ARTHRITIS and ANKYLOSING SPONDYLITIS.. arthritis defined as following: Acute or chronic inflammation of JOINTS..", "label": "yes"} {"id": "converted_2190", "sentence1": "Is there an association between Histone H3.3 mutations and glioma?", "sentence2": "PURPOSE: Histone H3.3 (H3F3A) mutation in the codon for lysine 27 (K27M) has been found as driver mutations in pediatric glioblastoma and has been suggested to play critical roles in the pathogenesis of thalamic gliomas and diffuse intrinsic pontine gliomas. We report a case of thalamic glioma with H3F3A K27M mutation, which was detected in both the primary tumor diagnosed as diffuse astrocytoma obtained during the first surgery and also in the tumor diagnosed as anaplastic astrocytoma obtained at the second surgery., CONCLUSION: This report demonstrates minute neuroradiological and pathological features of malignant transformation from thalamic low grade glioma with H3F3A K27M mutation., Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78 % of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36 % of non-brainstem gliomas carrying either K27M or G34R/V mutations., The pathological diagnosis was anaplastic oligodendroglioma, and we identified a mutation in histone H3.3 in the tumor specimen., CONCLUSIONS: Pediatric brainstem oligodendroglial tumors can include histone H3.3-mutated tumors and have a tendency to disseminate throughout the neuroaxis at the time of relapse., We highlight the genetic aberrations recently discovered in isocitrate dehydrogenase, alpha thalassemia/mental retardation syndrome X-linked, death-domain-associated protein, histone H3.3, and telomerase reverse transcriptase and discuss how these mutations lead to unexpected changes in the epigenetic landscape in gliomas., Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood, Exon sequencing has identified a mutation in K27M of the histone H3.3 gene (H3F3A K27M and G34R/V) in about 20% of pediatric glioblastomas, but it remains to be seen whether these mutations can be considered specific for pediatric diffuse high-grade astrocytomas or also occur in other pediatric brain tumors, The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression, A lesson learned from the H3.3K27M mutation found in pediatric glioma: a new approach to the study of the function of histone modifications in vivo, Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature., Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3., Mutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma., Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults., K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas., Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs)., Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation., Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1)., Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.[SEP]Definitions: H3.1 defined as following: This gene is involved in the regulation of chromosome dynamics.. isocitrate dehydrogenase defined as following: An enzyme of the oxidoreductase class that catalyzes the conversion of isocitrate and NAD+ to yield 2-ketoglutarate, carbon dioxide, and NADH. It occurs in cell mitochondria. The enzyme requires Mg2+, Mn2+; it is activated by ADP, citrate, and Ca2+, and inhibited by NADH, NADPH, and ATP. The reaction is the key rate-limiting step of the citric acid (tricarboxylic) cycle. (From Dorland, 27th ed) (The NADP+ enzyme is EC 1.1.1.42.) EC 1.1.1.41.. histone modifications defined as following: The covalent alteration of one or more amino acid residues within a histone protein. [GOC:krc]. anaplastic oligodendroglioma defined as following: A central nervous system tumor with morphological features of anaplastic oligodendroglioma in which there is insufficient information on the IDH genes and 1p/19q codeletion status.. glioblastoma multiforme defined as following: The most malignant astrocytic tumor (WHO grade 4). It is composed of poorly differentiated neoplastic astrocytes and is characterized by the presence of cellular polymorphism, nuclear atypia, brisk mitotic activity, vascular thrombosis, microvascular proliferation, and necrosis. It typically affects adults and is preferentially located in the cerebral hemispheres. (Adapted from WHO). genetic defined as following: Having to do with information that is passed from parents to offspring through genes in sperm and egg cells.. gliomas defined as following: Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21). Mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. spinal cord defined as following: A cylindrical column of tissue that lies within the vertebral canal. It is composed of WHITE MATTER and GRAY MATTER.. astrocytoma defined as following: Neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors. Fibrillary astrocytomas are the most common type and may be classified in order of increasing malignancy (grades I through IV). In the first two decades of life, astrocytomas tend to originate in the cerebellar hemispheres; in adults, they most frequently arise in the cerebrum and frequently undergo malignant transformation. (From Devita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2013-7; Holland et al., Cancer Medicine, 3d ed, p1082). histone H3 defined as following: Histone H3 is a core subunit of the eukaryotic nucleosome complex. Histones are basic nuclear proteins responsible for the nucleosome structure of chromatin. Repeating nucleosome units contain two molecules each of Histones H2A, H2B, H3, and H4 that form an octamer complex around which approximately 146 base pairs of DNA is wrapped. Linker Histone H1 interacts with DNA between nucleosome units in mediating chromatin compaction into higher order structures. (NCI). HIST1H3B defined as following: Human H3C2 wild-type allele is located in the vicinity of 6p22.1 and is approximately 1 kb in length. This allele, which encodes histone H3.1 protein, plays a role in the modulation of chromatin structure.. pons defined as following: The front part of the hindbrain (RHOMBENCEPHALON) that lies between the MEDULLA and the midbrain (MESENCEPHALON) ventral to the cerebellum. It is composed of two parts, the dorsal and the ventral. The pons serves as a relay station for neural pathways between the CEREBELLUM to the CEREBRUM.. codon defined as following: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (CODON, TERMINATOR). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, TRANSFER) complementary to all codons. These codons are referred to as unassigned codons (CODONS, NONSENSE).. anaplastic astrocytoma defined as following: A central nervous system tumor with morphological features of anaplastic astrocytoma in which there is insufficient information on the IDH genes status.. methionine defined as following: A preparation of METHIONINE that includes a mixture of D-methionine and L-methionine isomers.. thalamus defined as following: Paired bodies containing mostly GRAY MATTER and forming part of the lateral wall of the THIRD VENTRICLE of the brain.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. histone H3.3 gene defined as following: This gene plays a role in nucleosome assembly.. GBM defined as following: A sheet of amorphous extracellular material upon which the basal surfaces of epithelial cells rest and is the covering surface of a glomerular capillary, interposed between the cellular elements and the underlying connective tissue.. H3F3A defined as following: Human H3-3A wild-type allele is located in the vicinity of 1q42.12 and is approximately 10 kb in length. This allele, which encodes histone H3.3 protein, plays a role in both nucleosome assembly and transcriptional regulation.. tumor cells defined as following: Cells of, or derived from, a tumor.. mutation defined as following: Any transmissible change in the genetic material of an organism, which can result from radiation, viral infection, transposition, treatment with mutagenic chemicals and errors during DNA replication or meiosis. The effects of mutation range from single base changes to loss or gain of complete chromosomes. As many of the simpler alterations to DNA may be repaired, such changes are only heritable once the change is fixed in the DNA by the process of replication. Mutations may be associated with genetic diversity or with pathologies including cancer.. telomerase reverse transcriptase defined as following: This gene is involved in cell cycle regulation and telomere maintenance.. variants defined as following: An alteration or difference from a norm or standard.. H3K27 defined as following: The lysine residue found at amino acid position 28 in the histone H3 protein. Methylation of this residue may be a marker for transcriptionally repressed genes.. human embryonic stem cells defined as following: A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage.. glioma defined as following: Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21).", "label": "yes"} {"id": "converted_213", "sentence1": "Is protein M3/6 a dual specificity phosphatase?", "sentence2": "Involvement of the dual-specificity phosphatase M3/6 in c-Jun N-terminal kinase inactivation following cerebral ischemia in the rat hippocampus., The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat hippocampi. , This study examines the molecular mechanism underlying JNK dephosphorylation and inactivation evoked by dual-specificity phosphates following cerebral ischemia., Phosphatases play a particularly important role in this respect, by tightly controlling MAPK phosphorylation and activation. M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK and, to a lesser extent, p38 MAPKs and is found in a complex with these kinases, along with other pathway components, held together by scaffold proteins. , Dual-specificity phosphatases (DUSPs) play a very important role in these events by modulating the extent of JNK phosphorylation and activation and thus regulating cellular responses to stress. M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK., M3/6 is a dual-specificity phosphatase selective for JNK [7, 8]. , Here we describe two new dual specificity phosphatases of the CL100/MKP-1 family that are selective for inactivating ERK or JNK/SAPK and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase of this family to display highly specific inactivation of JNK/SAPK and p38 MAP kinases. , We previously demonstrated that the dual specificity phosphatases (DSPs) MKP7 and M3/6 bind the scaffold JNK-interacting protein-1 (JIP-1) and inactivate the bound subset of JNK (1)., the dual-specificity phosphatase M3/6, dual-specificity phosphatase M3/6 (DUSP8), M3/6 (DUSP8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of JNK , the M3/6 dual-specificity phosphatase, M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK, M3/6 is a dual-specificity phosphatase selective for JNK, The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases., Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation of JNK by arsenite., Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6., Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters., M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK., M3/6 is a dual-specificity phosphatase selective for JNK [7, 8], M3/6 (DUSP8) is one of the dual-specificity protein phosphatases with distinct specificity towards JNK, Here we describe how diverse cellular stresses affect differently the stability and activity of a JNK-inactivating dual-specificity threonine-tyrosine phosphatase M3/6, M3/6 is a dual-specificity phosphatase selective for JNK [7, 8], Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters. Analysis of a delta-like domain., The results revealed upregulation of dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat hippocampi, Indeed, expanded polyglutamine impaired the solubility of the dual-specificity JNK phosphatase M3/6, Here we report that JIP-1 also binds the dual-specificity phosphatases MKP7 and M3/6 via a region independent of its JNK binding domain., Differential regulation of M3/6 (DUSP8) signaling[SEP]Definitions: MAPK defined as following: A superfamily of PROTEIN SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).. Phosphatases defined as following: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate.. JNK defined as following: Human MAPK8 wild-type allele is located in the vicinity of 10q11.22 and is approximately 133 kb in length. This allele, which encodes mitogen-activated protein kinase 8 protein, plays a role in the induction of programmed cell death mediated by both tumor necrosis factor-alpha and ultraviolet radiation.. rat defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. MKP-3 defined as following: Dual specificity protein phosphatase 6 (381 aa, ~42 kDa) is encoded by the human DUSP6 gene. This protein plays a role in both dephosphorylation and inactivation of mitogen-activated protein kinases.. region defined as following: The continents and countries situated on those continents; the UNITED STATES and each of the constituent states arranged by region; CANADA and each of its provinces; AUSTRALIA and each of its states; the major bodies of water and major islands on both hemispheres; and selected major cities.. Dual-specificity phosphatases defined as following: A sub-class of protein tyrosine phosphatases that contain an additional phosphatase activity which cleaves phosphate ester bonds on SERINE or THREONINE residues that are located on the same protein.. cerebral ischemia defined as following: The formation of an area of NECROSIS in the CEREBRUM caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., INFARCTION, ANTERIOR CEREBRAL ARTERY), and etiology (e.g., embolic infarction).. phorbol esters defined as following: Tumor-promoting compounds obtained from CROTON OIL (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C..", "label": "yes"} {"id": "converted_3856", "sentence1": "Does an antiphlogistic promotes inflammation?", "sentence2": "The therapeutic effect of olipiphate was demonstrated for chronic inflammation of advanced arthritis and concanavalin A-related acute edema. The best systemic effect was obtained with 50 mg/kg, symptomatic--100 mg/kg. Skin wounds treated with 5% olipiphate (26 + 2) healed faster than those treated with 2% solcoseryl (30 + 0.8) or in control (33 + 0.6). It was shown histologically that the proliferative and antiphlogistic effect of olipiphate involved no scars., Moreover, we observed an in vitro-inhibition of human neutrophil elastase, a protease involved in the inflammatory process, by extracts and fractions from yarrow, which suggests additional mechanisms of antiphlogistic action., Blood 5-HT in adrenalectomized rats with inflammationadrenalectomized rats 42 days and 3 months old with inflammation after injection of phenylbutazone an increase of 5-HT was observed, but in 18-month-old animals in which antiphlogistic action is highest a decrease of 5-HT was observed., These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites., The antiphlogistic Ibuprofen incorporated in liposomes caused a decrease of the inflammatory edema induced by Carrageenan in the distal part of the rat's hind leg after both the intramuscular and percutaneous administration., Enhancement of the immunoreactivity inhibition caused by the drugs was not proportional to the increase in their antiphlogistic effects determined by the Selye model of inflammation., Antiinflammatory agents: new series of N-substituted amino acids with complex pyrimidine structures endowed with antiphlogistic activity., investigate whether the antiphlogistic ingredient may suppress the inflammatory response to ultraviolet (UV) irradiation, the SPF was determined in vivo. F, Antiphlogistics were found to enhance the membrane viscosity both in control and under inflammation., e in vivo determination of the SPF. Evidence of anti-inflammatory activity of the sunscreen antiphlogistics bisabolol and panthenol was also not apparent in the UV model over a time course of 48 h. Conlusion: The antiphlogistic ingredients panthenol and bisabolol incorporated in the tested sunscreen formula do not interfere with erythema reddening and thus , nts was analyzed in vitro. To investigate whether the antiphlogistic ingredient may suppress the inflammatory response to ultraviolet (UV) irradiation, the , The aim of this study was to analyze the formation of the most relevant inflammation mediators including proteins and lipids in human fibroblasts upon inflammatory stimulation and subsequent treatment with dexamethasone, a powerful antiphlogistic drug.[SEP]Definitions: fractions defined as following: A part, a fragment of a whole.. lipids defined as following: A generic term for fats and lipoids, the alcohol-ether-soluble constituents of protoplasm, which are insoluble in water. They comprise the fats, fatty oils, essential oils, waxes, phospholipids, glycolipids, sulfolipids, aminolipids, chromolipids (lipochromes), and fatty acids. (Grant & Hackh's Chemical Dictionary, 5th ed). methotrexate defined as following: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. dexamethasone defined as following: An anti-inflammatory 9-fluoro-glucocorticoid.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. rats defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. membrane defined as following: A device that is made from or resembles a thin flexible sheet of material.. liposomes defined as following: Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins.. erythema defined as following: Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes.. adenosine defined as following: A nucleoside that is composed of ADENINE and D-RIBOSE. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter.. protease defined as following: A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.. 5-HT defined as following: A biochemical messenger and regulator, synthesized from the essential amino acid L-TRYPTOPHAN. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Multiple receptor families (RECEPTORS, SEROTONIN) explain the broad physiological actions and distribution of this biochemical mediator.. Ibuprofen defined as following: A non-steroidal anti-inflammatory agent with analgesic, antipyretic, and anti-inflammatory properties. phenylbutazone defined as following: A butyl-diphenyl-pyrazolidinedione that has anti-inflammatory, antipyretic, and analgesic activities. It has been used in ANKYLOSING SPONDYLITIS; RHEUMATOID ARTHRITIS; and REACTIVE ARTHRITIS.. Skin wounds defined as following: A cutaneous wound is a defined as a disruption of normal anatomic structure and function of the skin that occured owing to an injury of the skin. Wound healing is a dynamic, interactive processinvolving soluble mediators, blood cells, extracellularmatrix, and parenchymal cells. Wound healing has three phases: inflammation, tissue formation, and tissue remodeling, that overlap in time. [PMID:10471461]. Carrageenan defined as following: A water-soluble extractive mixture of sulfated polysaccharides from RED ALGAE. Chief sources are the Irish moss CHONDRUS CRISPUS (Carrageen), and Gigartina stellata. It is used as a stabilizer, for suspending COCOA in chocolate manufacture, and to clarify BEVERAGES.. intramuscular defined as following: Intramuscular injection is a route of drug administration via injection into muscle tissue. Aqueous or oleaginous solutions and emulsions or suspensions may be administered. Absorption rates, delay in availability of the drug to the systemic circulation, and duration of effect are perfusion-limited, depend on molecular size of the agent, volume, and osmolarity of the drug solution, fat content of the injection site, and patient physical activity..", "label": "no"} {"id": "converted_4433", "sentence1": "Should perampanel be used for amyotrophic lateral sclerosis?", "sentence2": "RESULTS: Six participants were enrolled. All had adverse events, mostly behavioral. Two completed the trial and the other four withdrew due to adverse events. All participants reported resolution of these events after discontinuation of the drug. The trial was halted due to the large number of adverse events.DISCUSSION: The use of perampanel in this study of ALS was limited by its poor tolerability, CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group., DISCUSSION: The use of perampanel in this study of ALS was limited by its poor tolerabilit[SEP]Definitions: Perampanel defined as following: An orally active, non-competitive, and selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, with anti-epileptic activity. Although the mechanism of action through which perampanel exerts its antiepileptic effect has not been fully elucidated, this agent antagonizes the AMPA subtype of the excitatory glutamate receptor found on postsynaptic neurons in the central nervous system (CNS). This antagonistic action prevents AMPA receptor activation by glutamate and results in the inhibition of neuronal excitation, repetitive neuronal firing, and the stabilization of hyper-excited neural membranes. Glutamate, the primary excitatory neurotransmitter in the CNS, plays an important role in various neurological disorders caused by neuronal hyperexcitation.. ALS defined as following: A degenerative disorder affecting upper MOTOR NEURONS in the brain and lower motor neurons in the brain stem and SPINAL CORD. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous ASTROCYTES and atrophy of anterior SPINAL NERVE ROOTS and corticospinal tracts. (From Adams et al., Principles of Neurology, 6th ed, pp1089-94). perampanel defined as following: An orally active, non-competitive, and selective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, with anti-epileptic activity. Although the mechanism of action through which perampanel exerts its antiepileptic effect has not been fully elucidated, this agent antagonizes the AMPA subtype of the excitatory glutamate receptor found on postsynaptic neurons in the central nervous system (CNS). This antagonistic action prevents AMPA receptor activation by glutamate and results in the inhibition of neuronal excitation, repetitive neuronal firing, and the stabilization of hyper-excited neural membranes. Glutamate, the primary excitatory neurotransmitter in the CNS, plays an important role in various neurological disorders caused by neuronal hyperexcitation.. amyotrophic lateral sclerosis defined as following: An inherited form of amyotrophic lateral sclerosis, usually inherited in an autosomal dominant pattern, caused by mutation(s) in the SOD1 gene, encoding superoxide dismutase..", "label": "no"} {"id": "converted_1030", "sentence1": "Are DNA helicases involved in progeroid syndromes?", "sentence2": "Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases,, Progeroid syndromes (PSs) constitute a group of disorders characterized by clinical features mimicking physiological aging at an early age., However, all the characterized PSs enter in the field of rare monogenic disorders and several causative genes have been identified. These can be separated in subcategories corresponding to (i) genes encoding DNA repair factors, in particular, DNA helicases, and (ii) genes affecting the structure or post-translational maturation of lamin A, a major nuclear component., None of the known progerias represents true precocious ageing. Some of them, including Werner (WS), Bloom (BS), and Rothmund-Thomson syndromes (RTS) as well as combined xeroderma pigmentosa-Cockayne syndrome (XP-CS) are characterised by features resembling precocious ageing and the increased risk of malignant disease. Such phenotypes result from the mutations of the genes encoding proteins involved in the maintenance of genomic integrity, in most cases DNA helicases., Single-gene mutations can produce human progeroid syndromes--phenotypes that mimic usual or \"normative\" aging., The prototypic example of the former is the Werner syndrome, a condition caused by mutations of the RecQ family of DNA helicases., Progeria and progeroid syndromes are characterized by the earlier onset of complex senescent phenotypes. WRN was originally identified as a gene responsible for Werner syndrome (WS; \"Progeria of Adults\"). The WRN gene product has RecQ-type helicase domains in the central region of the protein.[SEP]Definitions: gene defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. lamin A defined as following: A subclass of developmentally regulated lamins having a neutral isoelectric point. They are found to disassociate from nuclear membranes during mitosis.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. WRN defined as following: An autosomal recessive disorder that causes premature aging in adults, characterized by sclerodermal skin changes, cataracts, subcutaneous calcification, muscular atrophy, a tendency to diabetes mellitus, aged appearance of the face, baldness, and a high incidence of neoplastic disease.. RTS defined as following: An autosomal recessive inherited syndrome usually caused by mutations in the RECQL4 gene. It is characterized by poikilodermatous skin changes, sparse hair, cataracts, small stature, skeletal abnormalities, and an increased predisposition to cancer, particularly osteosarcoma.. PSs defined as following: A very rare genetic syndrome caused by deletions on the proximal short arm of chromosome 11. It is characterized by the presence of multiple exostoses and enlarged parietal foramina.. DNA helicases defined as following: Proteins that catalyze the unwinding of duplex DNA during replication by binding cooperatively to single-stranded regions of DNA or to short regions of duplex DNA that are undergoing transient opening. In addition, DNA helicases are DNA-dependent ATPases that harness the free energy of ATP hydrolysis to translocate DNA strands.. human defined as following: Members of the species Homo sapiens.. Progeria defined as following: An abnormal congenital condition, associated with defects in the LAMIN TYPE A gene, which is characterized by premature aging in children, where all the changes of cell senescence occur. It is manifested by premature graying; hair loss; hearing loss (DEAFNESS); cataracts (CATARACT); ARTHRITIS; OSTEOPOROSIS; DIABETES MELLITUS; atrophy of subcutaneous fat; skeletal hypoplasia; elevated urinary HYALURONIC ACID; and accelerated ATHEROSCLEROSIS. Many affected individuals develop malignant tumors, especially SARCOMA.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA..", "label": "yes"} {"id": "converted_2232", "sentence1": "Is there any role of TBR1 in autism?", "sentence2": "TBR1 regulates autism risk genes in the developing neocortex, Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development., T-Brain-1--A Potential Master Regulator in Autism Spectrum Disorders., T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs., Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism., The activity-regulated gene expression of transcription factors is required for neural plasticity and function in response to neuronal stimulation. T-brain-1 (TBR1), a critical neuron-specific transcription factor for forebrain development, has been recognized as a high-confidence risk gene for autism spectrum disorders. , Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). , Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism., T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1 (-∕-) mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs). Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs., TBR1 regulates autism risk genes in the developing neocortex., De novo TBR1 mutations in sporadic autism disrupt protein functions., In humans, PAX6, EOMES, and TBR1 have been linked to intellectual disability and autism., It is therefore possible that TBR1 controls the expression of other autism risk factors., Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain., T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor., Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs)., Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism., Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis., Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs)., T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor, Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis, Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs), Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis., It is therefore possible that TBR1 controls the expression of other autism risk factors., TBR1 regulates autism risk genes in the developing neocortex., De novo TBR1 mutations in sporadic autism disrupt protein functions., Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.[SEP]Definitions: Gpc6 defined as following: This gene plays a role in protein binding.. TBR1 gene defined as following: This gene is involved in both brain development and transcriptional regulation.. EOMES defined as following: This gene plays a role in both transcriptional activation and embryonic development.. PAX6 defined as following: This gene plays a role in transcriptional regulation.. T-Brain-1 defined as following: T-box brain protein 1 (682 aa, ~74 kDa) is encoded by the human TBR1 gene. This protein is involved in both transcriptional regulation and brain development.. olfactory bulb defined as following: Ovoid body resting on the CRIBRIFORM PLATE of the ethmoid bone where the OLFACTORY NERVE terminates. The olfactory bulb contains several types of nerve cells including the mitral cells, on whose DENDRITES the olfactory nerve synapses, forming the olfactory glomeruli. The accessory olfactory bulb, which receives the projection from the VOMERONASAL ORGAN via the vomeronasal nerve, is also included here.. Gad1 defined as following: Glutamate decarboxylase 1 (594 aa, ~67 kDa) is encoded by the human GAD1 gene. This protein is involved in the conversion of glutamate to gamma-aminobutyric acid.. cerebral cortex defined as following: The thin layer of GRAY MATTER on the surface of the CEREBRAL HEMISPHERES that develops from the TELENCEPHALON and folds into gyri and sulci. It reaches its highest development in humans and is responsible for intellectual faculties and higher mental functions.. Grin2b defined as following: This gene plays a role in both neurotransmitter binding and ion transport.. intellectual disability defined as following: Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28). autism defined as following: A disorder beginning in childhood. It is marked by the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interest. Manifestations of the disorder vary greatly depending on the developmental level and chronological age of the individual. (DSM-V). autism spectrum disorders defined as following: A spectrum of developmental disorders that includes autism, Asperger syndrome, and Rett syndrome. Signs and symptoms include poor communication skills, defective social interactions, and repetitive behaviors.. Cd44 defined as following: Acidic sulfated integral membrane glycoproteins expressed in several alternatively spliced and variable glycosylated forms on a wide variety of cell types including mature T-cells, B-cells, medullary THYMOCYTES; GRANULOCYTES; MACROPHAGES; erythrocytes, and fibroblasts. Their interaction with HYALURONIC ACID mediates binding of lymphocytes to high endothelial VENULES.. ChIP-seq defined as following: A molecular genetic technique that combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to map the binding sites of DNA-associated proteins in a sample of cells. First, crosslinked protein-DNA complexes are isolated using ChIP. Next, the crosslinks are broken, the proteins are removed and the purified DNA is modified with adaptor oligonucleotides to facilitate massively parallel DNA sequencing. Following sequencing, the DNA sequences that are obtained can be mapped to their genomic locations.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. amygdala defined as following: Almond-shaped group of basal nuclei anterior to the INFERIOR HORN OF THE LATERAL VENTRICLE of the TEMPORAL LOBE. The amygdala is part of the limbic system.. Nfia defined as following: Nuclear factor 1 A-type (509 aa, ~56 kDa) is encoded by the human NFIA gene. This protein plays a role in the regulation of both gene replication and transcription.. mutations defined as following: The result of any gain, loss or alteration of the sequences comprising a gene, including all sequences transcribed into RNA.. variants defined as following: An alteration or difference from a norm or standard.. humans defined as following: Members of the species Homo sapiens.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. ASD defined as following: Developmental abnormalities in any portion of the ATRIAL SEPTUM resulting in abnormal communications between the two upper chambers of the heart. Classification of atrial septal defects is based on location of the communication and types of incomplete fusion of atrial septa with the ENDOCARDIAL CUSHIONS in the fetal heart. They include ostium primum, ostium secundum, sinus venosus, and coronary sinus defects.. TBR1 defined as following: This gene is involved in both brain development and transcriptional regulation..", "label": "yes"} {"id": "converted_2227", "sentence1": "Is Downs syndrome associated with decreased risk of leukemia?", "sentence2": "The association of Down's syndrome and leukemia has been documented for over 50 years. Multiple studies have established the incidence of leukemia in Down's syndrome patients to be 10- to 20-fold higher than that in the general population., We present a case of congenital acute myeloid leukemia manifesting from the very first day of birth. Diagnosis of acute myeloid leukemia was suspected by the presence of blasts in the peripheral blood smear and was confirmed on bone marrow by flowcytometry. Karyotyping revealed Trisomy 21., Juvenile myelomonocytic leukemia (JMML) and a solitary cases of acute myeloid leukemia (AML) in Downs syndrome. , This was thus confirmed to be a case with transient leukemia with Downs syndrome.[SEP]Definitions: JMML defined as following: A leukemia affecting young children characterized by SPLENOMEGALY, enlarged lymph nodes, rashes, and hemorrhages. Traditionally classed as a myeloproliferative disease, it is now considered a mixed myeloproliferative-mylelodysplastic disorder.. acute myeloid leukemia defined as following: Clonal expansion of myeloid blasts in bone marrow, blood, and other tissue. Myeloid leukemias develop from changes in cells that normally produce NEUTROPHILS; BASOPHILS; EOSINOPHILS; and MONOCYTES.. leukemia defined as following: A progressive, malignant disease of the blood-forming organs, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias were originally termed acute or chronic based on life expectancy but now are classified according to cellular maturity. Acute leukemias consist of predominately immature cells; chronic leukemias are composed of more mature cells. (From The Merck Manual, 2006). Downs syndrome defined as following: A chromosome disorder associated either with an extra CHROMOSOME 21 or an effective TRISOMY for chromosome 21. Clinical manifestations include HYPOTONIA, short stature, BRACHYCEPHALY, upslanting palpebral fissures, epicanthus, Brushfield spots on the iris, protruding tongue, small ears, short, broad hands, fifth finger clinodactyly, single transverse palmar crease, and moderate to severe INTELLECTUAL DISABILITY. Cardiac and gastrointestinal malformations, a marked increase in the incidence of LEUKEMIA, and the early onset of ALZHEIMER DISEASE are also associated with this condition. Pathologic features include the development of NEUROFIBRILLARY TANGLES in neurons and the deposition of AMYLOID BETA-PROTEIN, similar to the pathology of ALZHEIMER DISEASE. (Menkes, Textbook of Child Neurology, 5th ed, p213).", "label": "no"} {"id": "converted_248", "sentence1": "Is low T3 syndrome a prognostic marker in patients with renal insufficiency?", "sentence2": "Low T3 was particularly common (44.3 %), and clearly associated with increased 6- and 12-month mortality and decreased overall survival (log rank test, P=0.007). , Increased rT3 may be more common in ESRD patients than previously described, and together with decreased T3 it may serve as an indicator of poor prognosis in subsequent months., The presence of TFT alterations seems to not be associated with clinical and prognostic implications in AKI patients., Multivariate analysis, according to receiver operating characteristic (ROC) curves, showed that mortality was best predicted by total triiodothyronine (T3)., Finally, low T3 but not low free triiodothyronine was associated with worse all-cause (Likelihood ratio = 45.4; P < 0.0001) and cardiovascular mortality (Likelihood ratio = 47.8; P < 0.0001) after adjustment for confounding factors., In Cox analyses, fT3 was a significant predictor of mortality independent of the main traditional as well as non-traditional risk factors., All-cause and CV mortality rates were significantly higher in patients with 'lower' T3 levels than in the 'higher' T3 group (113.4 vs 18.2 events per 1000 patient-years, P<0.001, and 49.8 vs 9.1 events per 1000 patient-years, P=0.001, respectively). The Kaplan-Meier analysis also showed significantly worse cumulative survival rates in the 'lower' T3 group (P<0.001). In the Cox regression analysis, low T3 was an independent predictor of all-cause mortality even after adjusting for traditional risk factors (hazard ratio=3.76, P=0.021). , In CKD patients with proteinuria, low T3 concentration predicted all-cause mortality and cardiovascular event independently of the severity of proteinuria., Low-T3 syndrome is a frequent finding among HD patients, but it does not predict outcome. However, serum fT3 level is a strong and inverse mortality predictor, in part explained by its underlying association with nutritional state and inflammation., These data suggest that low FT3 levels are not predictive for mortality in a subgroup of stable HD patients who could survive more than 12 months., Low fT3 is an independent predictor of death in hemodialysis patients. These data lend support to the hypothesis that thyroid dysfunction is implicated in the high risk of the ESRD population.[SEP]Definitions: death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. FT3 defined as following: A traditional unit of volume equal to 1728 cubic inches, or 1/27 cubic yard, or 0.028 316 85 cubic meter (28.316 85 liters). The cubic foot holds about 7.4805 US gallons.. HD defined as following: A malignant disease characterized by progressive enlargement of the lymph nodes, spleen, and general lymphoid tissue. In the classical variant, giant usually multinucleate Hodgkin's and REED-STERNBERG CELLS are present; in the nodular lymphocyte predominant variant, lymphocytic and histiocytic cells are seen.. inflammation defined as following: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function.. T3 defined as following: This gene plays a regulatory role in the production and utilization of ATP.. proteinuria defined as following: The presence of proteins in the urine, an indicator of KIDNEY DISEASES.. ESRD defined as following: The end-stage of CHRONIC RENAL INSUFFICIENCY. It is characterized by the severe irreversible kidney damage (as measured by the level of PROTEINURIA) and the reduction in GLOMERULAR FILTRATION RATE to less than 15 ml per min (Kidney Foundation: Kidney Disease Outcome Quality Initiative, 2002). These patients generally require HEMODIALYSIS or KIDNEY TRANSPLANTATION.. cardiovascular defined as following: The HEART and the BLOOD VESSELS by which BLOOD is pumped and circulated through the body.. CKD defined as following: Impairment of the renal function secondary to chronic kidney damage persisting for three or more months.. TFT defined as following: Blood tests used to evaluate the functioning of the thyroid gland.. renal insufficiency defined as following: A severe irreversible decline in the ability of kidneys to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism..", "label": "yes"} {"id": "converted_5", "sentence1": "Does metformin interfere thyroxine absorption?", "sentence2": "LT4 absorption is unchanged by concomitant metformin ingestion., It has been hypothesized that metformin may suppress serum thyrotropin (TSH) concentrations by enhancing LT4 absorption or by directly affecting the hypothalamic-pituitary axis.[SEP]Definitions: metformin defined as following: A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289).", "label": "no"} {"id": "converted_4238", "sentence1": "Does daily atemoya juice intake change the pharmacokinetics of CYP1A2 substrates?", "sentence2": "Atemoya juice significantly inhibited CYP1A2 activity in human liver microsomes, but not the activities of CYP2C9 and CYP3A. In spite of this inhibition, preadministration of atemoya had no effect on the pharmacokinetics of phenacetin, a CYP1A2 substrate, in rats. , The results indicate that a daily intake of atemoya would not change the pharmacokinetics of CYP1A2 substrates such as phenacetin as well as CYP2C9- and CYP3A-substrate drugs.[SEP]Definitions: CYP2C9 defined as following: A cytochrome P-450 subtype that has specificity for acidic XENOBIOTICS. It oxidizes a broad range of important clinical drugs that fall under the categories of NONSTEROIDAL ANTI-INFLAMMATORY AGENTS; HYPOGLYCEMIC AGENTS; ANTCOAGULANTS; and DIURETICS.. phenacetin defined as following: A phenylacetamide that was formerly used in ANALGESICS but nephropathy and METHEMOGLOBINEMIA led to its withdrawal from the market. (From Smith and Reynard, Textbook of Pharmacology,1991, p431). rats defined as following: The common rat, Rattus norvegicus, often used as an experimental organism.. CYP3A defined as following: A cytochrome P-450 suptype that has specificity for a broad variety of lipophilic compounds, including STEROIDS; FATTY ACIDS; and XENOBIOTICS. This enzyme has clinical significance due to its ability to metabolize a diverse array of clinically important drugs such as CYCLOSPORINE; VERAPAMIL; and MIDAZOLAM. This enzyme also catalyzes the N-demethylation of ERYTHROMYCIN.. human defined as following: Members of the species Homo sapiens.. CYP1A2 substrates defined as following: Any substance acted upon by cytochrome P450 1A2..", "label": "no"} {"id": "converted_3736", "sentence1": "Is αCGRP a member of the CGRP family?", "sentence2": "αCGRP, another amyloidogenic member of the CGRP family., Therefore, in this work, we investigated the amyloidogenic profile of αCGRP, a 37-residue-long peptide hormone, utilizing both biophysical experimental techniques and Molecular Dynamics simulations. These efforts unravel a novel amyloidogenic member of the CGRP family and provide insights into the mechanism underlying the αCGRP polymerization., These efforts unravel a novel amyloidogenic member of the CGRP family and provide insights into the mechanism underlying the αCGRP polymerization., These efforts unravel a novel amyloidogenic member of the CGRP family and provide insights into the mechanism underlying the αCGRP polymerization.[SEP]Definitions: CGRP defined as following: A 37-amino acid peptide derived from the calcitonin gene. It occurs as a result of alternative processing of mRNA from the calcitonin gene. The neuropeptide is widely distributed in the brain, gut, perivascular nerves, and other tissue. The peptide produces multiple biological effects and has both circulatory and neurotransmitter modes of action. In particular, it is a potent endogenous vasodilator.. peptide hormone defined as following: OBSOLETE. (Was not defined before being made obsolete). [GOC:ai].", "label": "yes"} {"id": "converted_508", "sentence1": "Does cortical spreading depression appear in ischemic penumbra following ischemic stroke?", "sentence2": "During the subacute phase, the irreversible damage expands into the penumbra: multiple electrical and biological signals are triggered by periinfarct, spreading depression-like depolarizations leading to hypoxia and stepwise increase in lactate., Experimental and clinical studies indicate that waves of cortical spreading depolarization (CSD) appearing in the ischemic penumbra contribute to secondary lesion growth., Analysis of MCA occlusions (MCAOs) revealed a first CSD wave starting off during ischemic decline at the emerging core region, propagating concentrically over large portions of left cortex., Subsequent recurrent waves of CSD did not propagate concentrically but preferentially circled around the ischemic core., In the vicinity of the core region, CSDs were coupled to waves of predominantly vasoconstrictive CBF(LSF) responses, resulting in further decline of CBF in the entire inner penumbra and in expansion of the ischemic core., We conclude that CSDs and corresponding CBF responses follow a defined spatiotemporal order, and contribute to early evolution of ischemic territories., Astrocytes in the metabolically compromised ischemic penumbra-like area showed a long lasting swelling response to spontaneous spreading depolarizations despite rapid dendritic recovery in a photothrombotic occlusion model of focal stroke., Spontaneous spreading depolarizations (SDs) occur in the penumbra surrounding ischemic core., These SDs, often referred to as peri-infarct depolarizations, cause vasoconstriction and recruitment of the penumbra into the ischemic core in the critical first hours after focal ischemic stroke; however, the real-time spatiotemporal dynamics of SD-induced injury to synaptic circuitry in the penumbra remain unknown., We propose that metabolic stress resulting from recurring SDs facilitates acute injury at the level of dendrites and dendritic spines in metabolically compromised tissue, expediting penumbral recruitment into the ischemic core., Although the mechanism remains unknown, SDs show delayed electrophysiological recovery within the ischemic penumbra., Spreading depression-like peri-infarct depolarizations not only characterize but also worsen penumbra conditions in cortical border zones of experimental focal ischemia., We conclude that in focal ischemia, transient peri-infarct depolarizations emerge not only in cortical but also in striatal gray matter, thereby demonstrating the existence of subcortical zones of ischemic penumbra., Spreading depression (SD) has been demonstrated following focal ischemia, and the additional workload imposed by SD on a tissue already compromised by a marked reduction in blood flow may contribute to the evolution of irreversible damage in the ischemic penumbra., While the changes in the glucose-related metabolites persisted during recovery even in anterior portions of the cortex in both groups in the aftermath of the SD, the magnitude of the changes was greater in the penumbra than in the normal cortex., SD appears to impose an equivalent increase in energy demands in control and ischemic brain, but the ability of the penumbra to recover from the insult is compromised., Thus, increasing the energy imbalance in the penumbra after multiple SDs may hasten the deterioration of the energy status of the tissue and eventually contribute to terminal depolarization and cell death, particularly in the penumbra., It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply., Transient decreases of the apparent diffusion coefficient (ADC) of water as measured by fast diffusion-weighted imaging (DWI) in the ischemic border zone are thought to reflect cellular swelling associated with spreading depression., Severely delayed recovery time after spreading depression is thought to represent the ischemic penumbra., One current but controversial hypothesis is that this penumbra tissue often eventually dies because of the metabolic stress imposed by multiple cortical spreading depression (CSD) waves, that is, by ischemic depolarizations., After simulated infarction, the model displays the linear relation between final infarct size and the number of CSD waves traversing the penumbra that has been reported experimentally, although damage with each individual wave progresses nonlinearly with time., These findings support the hypothesis that CSD waves play an important causal role in the death of ischemic penumbra tissue., MCAO also triggers periodic periinfarction depolarizing waves (PIDs) in the ischemic penumbra, the territory of salvage., Here, the effects of SD at reduced flow conditions as encountered in the ischemic penumbra are examined., The experiments illustrate how peri-infarct depolarizations may detrimentally affect the penumbra., In the second series of experiments, periinfarct depolarizations (PIDs) were recorded with an extracellular DC electrode at two locations in the ischemic penumbra for the initial 3 h following MCAO., In vivo two-photon microscopy of green fluorescent protein-expressing neurons in this penumbra-like area at risk revealed that SDs were temporally correlated with rapid (<6 s) dendritic beading.[SEP]Definitions: death defined as following: Irreversible cessation of all bodily functions, manifested by absence of spontaneous breathing and total loss of cardiovascular and cerebral functions.. extracellular defined as following: The space external to the outermost structure of a cell. For cells without external protective or external encapsulating structures this refers to space outside of the plasma membrane. This term covers the host cell environment outside an intracellular parasite. [GOC:go_curators]. lactate defined as following: The determination of the amount of lactic acid present in a sample.. dendrites defined as following: Extensions of the nerve cell body. They are short and branched and receive stimuli from other NEURONS.. territory defined as following: A constituent administrative district of a nation.. SDs defined as following: A patient reported questionnaire composed of rating scales developed to measure the degree of distress experienced by the patient for specific symptoms.. CBF defined as following: CBF is an alpha/beta heterodimeric transcription factor involved in the transcriptional regulation of several genes important in hematopoiesis. The CBFalpha subunit binds directly to the enhancer core DNA sequence on target genes, whereas the beta subunit does not bind the DNA directly but increases the affinity and stabilizes the binding of the alpha subunit to the DNA.. dendritic spines defined as following: A small, membranous protrusion from a dendrite that forms a postsynaptic compartment, typically receiving input from a single presynapse. They function as partially isolated biochemical and an electrical compartments. Spine morphology is variable:they can be thin, stubby, mushroom, or branched, with a continuum of intermediate morphologies. They typically terminate in a bulb shape, linked to the dendritic shaft by a restriction. Spine remodeling is though to be involved in synaptic plasticity. [GOC:nln]. Astrocytes defined as following: A class of large neuroglial (macroglial) cells in the central nervous system - the largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from \"star\" cells) are irregularly shaped with many long processes, including those with \"end feet\" which form the glial (limiting) membrane and directly and indirectly contribute to the BLOOD-BRAIN BARRIER. They regulate the extracellular ionic and chemical environment, and \"reactive astrocytes\" (along with MICROGLIA) respond to injury.. terminal defined as following: Being or situated at an end; occurring at or forming an end.. hypoxia defined as following: A disorder characterized by a decrease in the level of oxygen in the body.. cortex defined as following: Pathological processes of the ADRENAL CORTEX.. MCA defined as following: The largest of the cerebral arteries. It trifurcates into temporal, frontal, and parietal branches supplying blood to most of the parenchyma of these lobes in the CEREBRAL CORTEX. These are the areas involved in motor, sensory, and speech activities.. cortical defined as following: The outer layer of the adrenal gland. It is derived from MESODERM and comprised of three zones (outer ZONA GLOMERULOSA, middle ZONA FASCICULATA, and inner ZONA RETICULARIS) with each producing various steroids preferentially, such as ALDOSTERONE; HYDROCORTISONE; DEHYDROEPIANDROSTERONE; and ANDROSTENEDIONE. Adrenal cortex function is regulated by pituitary ADRENOCORTICOTROPIN.. DC defined as following: A predominantly X-linked recessive syndrome characterized by a triad of reticular skin pigmentation, nail dystrophy and leukoplakia of mucous membranes. Oral and dental abnormalities may also be present. Complications are a predisposition to malignancy and bone marrow involvement with pancytopenia. (from Int J Paediatr Dent 2000 Dec;10(4):328-34) The X-linked form is also known as Zinsser-Cole-Engman syndrome and involves the gene which encodes a highly conserved protein called dyskerin.. ischemic stroke defined as following: An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of brain tissue..", "label": "yes"} {"id": "converted_4040", "sentence1": "Is there an upper limit on the functional fraction of the human genome?", "sentence2": "Mutational load considerations lead to the conclusion that the functional fraction within the human genome cannot exceed 25%, and is probably considerably lower.[SEP]", "label": "yes"} {"id": "converted_4145", "sentence1": "Is atenolol metabolized by CYP2D6?", "sentence2": "The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole).[SEP]Definitions: propoxyphene defined as following: The d-isomer of synthetic diphenyl propionate derivative propoxyphene, with narcotic analgesic effect. This agent mimics the effects of the endogenous opiate dextropropoxyphene, by binding to mu receptors located throughout the central nervous system. The binding results in GTP to GDP exchanges on the mu-G-protein complex, by which effector adenylate cyclase is inactivated thereby decreasing intracellular cAMP. This, in turn, inhibits the release of various nociceptive neurotransmitters, such as substance P, gamma-aminobutyric acid (GABA), dopamine, acetylcholine, noradrenaline, vasopressin, and somatostatin. In addition, dextropropoxyphene closes N-type voltage-gated calcium channels and opens calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization, thereby reducing neuronal excitability, which further decreases the perception of pain.. SSRIs defined as following: Any agent that increases the extracellular level of the neurotransmitter serotonin (5-HT) by inhibiting its reuptake into the presynaptic cell. Increased level in the synaptic cleft prolongs the action of 5-HT on the postsynaptic receptor. This type of agent is typically used as an antidepressant and in the treatment of anxiety disorders and some personality disorders. They are also typically effective and used in treating some cases of insomnia.. donepezil defined as following: The hydrochloride salt of a piperidine derivative with neurocognitive-enhancing activity. Donepezil reversibly inhibits acetylcholinesterase, thereby blocking the hydrolysis of the neurotransmitter acetylcholine and, consequently, increasing its activity. This agent may improve neurocognitive function in Alzheimer's disease, reduce sedation associated with opioid treatment of cancer pain, and improve neurocognitive function in patients who have received radiation therapy for primary brain tumors or brain metastases.. galantamine defined as following: A benzazepine derived from norbelladine. It is found in GALANTHUS and other AMARYLLIDACEAE. It is a cholinesterase inhibitor that has been used to reverse the muscular effects of GALLAMINE TRIETHIODIDE and TUBOCURARINE and has been studied as a treatment for ALZHEIMER DISEASE and other central nervous system disorders.. codeine defined as following: An opioid analgesic related to MORPHINE but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough.. tamoxifen defined as following: One of the SELECTIVE ESTROGEN RECEPTOR MODULATORS with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the ENDOMETRIUM.. rivastigmine defined as following: A carbamate-derived reversible CHOLINESTERASE INHIBITOR that is selective for the CENTRAL NERVOUS SYSTEM and is used for the treatment of DEMENTIA in ALZHEIMER DISEASE and PARKINSON DISEASE.. metoprolol defined as following: A selective adrenergic beta-1 blocking agent that is commonly used to treat ANGINA PECTORIS; HYPERTENSION; and CARDIAC ARRHYTHMIAS.. atenolol defined as following: A cardioselective beta-1 adrenergic blocker possessing properties and potency similar to PROPRANOLOL, but without a negative inotropic effect.. CYP2D6 defined as following: Cytochrome P450 2D6 (497 aa, ~56 kDa) is encoded by the human CYP2D6 gene. This protein plays a role in flavoprotein metabolism..", "label": "no"} {"id": "converted_1691", "sentence1": "Is STAT3 transcription factor regulated by mTORC1?", "sentence2": "Mechanistically, mTORC1 mediated IL-6-induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity., we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription, Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3)., Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process, Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas HIF-1α degradation remains unaffected, Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process. , TSC1/TSC2 inactivation inhibits AKT through mTORC1-dependent up-regulation of STAT3-PTEN cascade., Mechanistically, mTORC1 signaling was activated by excess amino acids, which then positively regulated Notch1 expression through the activation of the signal transducer and activator of transcription 3 (STAT3). , Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids., Here, we review the connections between mTORC1 and gene transcription by focusing on its impact in regulating the activation of specific transcription factors including including STAT3, SREBPs, PPARγ, PPARα, HIF1α, YY1–PGC1α and TFEB. We also discuss the importance of these transcription factors in mediating the effects of mTORC1 on various cellular processes in physiological and pathological contexts.[SEP]Definitions: TFEB defined as following: Transcription factor EB (476 aa, ~53 kDa) is encoded by the human TFEB gene. This protein plays a role in transcriptional regulation.. S6K1 defined as following: Human RPS6KB1 wild-type allele is located in the vicinity of 17q23.1 and is approximately 57 kb in length. This allele, which encodes ribosomal protein S6 kinase beta-1 protein, plays a role in the regulation of protein phosphorylation.. epithelial cells defined as following: Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells.. 4E-BP1 defined as following: Eukaryotic translation initiation factor 4E-binding protein 1 (118 aa, ~13 kDa) is encoded by the human EIF4EBP1 gene. This protein is involved in the modulation of translation and the sequestration of eukaryotic translation initiation factor 4E.. STAT3 defined as following: Signal transducer and activator of transcription 3 (770 aa, ~88 kDa) is encoded by the human STAT3 gene. This protein plays a role in cytokine signaling and gene expression.. AKT defined as following: Expressed in diverse tissues, Protein Kinase B (AKT/RAC Family) is a group (Alpha, Beta and Gamma) of cytoplasmic serine/threonine enzymes that covalently transfer the terminal, gamma phosphate group from ATP to a variety of substrate proteins and regulate cell signaling responses to insulin, PDGF, and IGF1 (through PI3K) involved in cell survival, cell proliferation, differentiation, apoptosis, glycogen synthesis, and glucose uptake.. mTORC1 defined as following: A protein complex that is involved in the both serine/threonine phosphorylation and the regulation of protein synthesis in response to cellular stress.. AMPK defined as following: Intracellular signaling protein kinases that play a signaling role in the regulation of cellular energy metabolism. Their activity largely depends upon the concentration of cellular AMP which is increased under conditions of low energy or metabolic stress. AMP-activated protein kinases modify enzymes involved in LIPID METABOLISM, which in turn provide substrates needed to convert AMP into ATP.. hypoxia defined as following: A disorder characterized by a decrease in the level of oxygen in the body.. transcription factors defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process..", "label": "yes"} {"id": "converted_362", "sentence1": "Is there a package in R/bioconductor for classification of alternative splicing?", "sentence2": "spliceR: an R package for classification of alternative splicing and prediction of coding potential from RNA-seq data., Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential., spliceR uses the full-length transcript output from RNA-seq assemblers to detect single or multiple exon skipping, alternative donor and acceptor sites, intron retention, alternative first or last exon usage, and mutually exclusive exon events. For each of these events spliceR also annotates the genomic coordinates of the differentially spliced elements, facilitating downstream sequence analysis. For each transcript isoform fraction values are calculated to identify transcript switching between conditions. Lastly, spliceR predicts the coding potential, as well as the potential nonsense mediated decay (NMD) sensitivity of each transcript., Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential., Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential. , Recent software improvements in full-length transcript deconvolution prompted us to develop spliceR, an R package for classification of alternative splicing and prediction of coding potential.[SEP]Definitions: spliceR defined as following: A device designed to join pieces of a material into a continuous length.. transcript defined as following: The initial RNA molecule produced by transcription.. RNA-seq defined as following: A procedure that can determine the nucleotide sequence for all of the RNA transcripts in an individual.. alternative splicing defined as following: A process whereby multiple RNA transcripts are generated from a single gene. Alternative splicing involves the splicing together of other possible sets of EXONS during the processing of some, but not all, transcripts of the gene. Thus a particular exon may be connected to any one of several alternative exons to form a mature RNA. The alternative forms of mature MESSENGER RNA produce PROTEIN ISOFORMS in which one part of the isoforms is common while the other parts are different..", "label": "yes"} {"id": "converted_3536", "sentence1": "Is there an increased risk of meningiomas in atomic bomb survivors?", "sentence2": "RESULTS: Meningioma was the most common tumor among clinically diagnosed tumors, followed by neuroepithelial tumor, schwannoma, and pituitary tumor. , The predominance of meningiomas over neuroepithelial tumors in the Japanese population was noteworthy and warrants further investigation. , Risk increases, although not statistically significant, were seen for meningiomas (ERR(Sv) = 0.6, 95% CI = -0.01 to 1.8), gliomas (ERR(Sv) = 0.6, 95% CI = -0.2 to 2.0), other nervous system tumors (ERR(Sv) = 0.5, 95% CI = <-0.2 to 2.2), and pituitary tumors (ERR(Sv) = 1.0, 95% CI = <-0.2 to 3.5)., High incidence of meningioma among Hiroshima atomic bomb survivors., The incidence of meningioma among Hiroshima atomic bomb survivors has increased since 1975. There was a significant correlation between the incidence and the dose of radiation to the brain. The present findings strongly suggest that meningioma is one of the tumors induced by atomic bombing in Hiroshima., Incidence of intracranial meningiomas in Nagasaki atomic-bomb survivors., The analysis showed a high correlation between incidence of meningiomas and distance from the hypocenter. The incidence among Nagasaki atomic-bomb survivors over 40 years of age, especially in those proximally exposed, appears to be increasing, in inverse proportion to the exposure distance, since 1981, 36 years after the explosion of the atomic bomb., The incidence of meningioma among Hiroshima atomic bomb survivors has increased since 1975., The present findings strongly suggest that meningioma is one of the tumors induced by atomic bombing in Hiroshima., The incidences of meningioma among the survivors of Hiroshima in 5-year intervals since 1975 were 5.3, 7.4, 10.1, and 14.9, respectively., The analysis showed a high correlation between incidence of meningiomas and distance from the hypocenter.[SEP]Definitions: intracranial meningiomas defined as following: A meningioma that arises within the cranial cavity.. meningiomas defined as following: A relatively common neoplasm of the CENTRAL NERVOUS SYSTEM that arises from arachnoidal cells. The majority are well differentiated vascular tumors which grow slowly and have a low potential to be invasive, although malignant subtypes occur. Meningiomas have a predilection to arise from the parasagittal region, cerebral convexity, sphenoidal ridge, olfactory groove, and SPINAL CANAL. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2056-7). Meningioma defined as following: A grade I, slowly growing meningioma. Only a minority of tumors recur following complete resection.. neuroepithelial tumors defined as following: Neoplasms composed of neuroepithelial cells, which have the capacity to differentiate into NEURONS, oligodendrocytes, and ASTROCYTES. The majority of craniospinal tumors are of neuroepithelial origin. (From Dev Biol 1998 Aug 1;200(1):1-5). tumors defined as following: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.. pituitary tumors defined as following: Neoplasms which arise from or metastasize to the PITUITARY GLAND. The majority of pituitary neoplasms are adenomas, which are divided into non-secreting and secreting forms. Hormone producing forms are further classified by the type of hormone they secrete. Pituitary adenomas may also be characterized by their staining properties (see ADENOMA, BASOPHIL; ADENOMA, ACIDOPHIL; and ADENOMA, CHROMOPHOBE). Pituitary tumors may compress adjacent structures, including the HYPOTHALAMUS, several CRANIAL NERVES, and the OPTIC CHIASM. Chiasmal compression may result in bitemporal HEMIANOPSIA.. gliomas defined as following: Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21). schwannoma defined as following: A neoplasm that arises from SCHWANN CELLS of the cranial, peripheral, and autonomic nerves. Clinically, these tumors may present as a cranial neuropathy, abdominal or soft tissue mass, intracranial lesion, or with spinal cord compression. Histologically, these tumors are encapsulated, highly vascular, and composed of a homogenous pattern of biphasic fusiform-shaped cells that may have a palisaded appearance. (From DeVita Jr et al., Cancer: Principles and Practice of Oncology, 5th ed, pp964-5). nervous system tumors defined as following: Benign and malignant neoplastic processes arising from or involving components of the central, peripheral, and autonomic nervous systems, cranial nerves, and meninges. Included in this category are primary and metastatic nervous system neoplasms..", "label": "yes"} {"id": "converted_4696", "sentence1": "Do Afamin bind Vitamin E?", "sentence2": "The plasma glycoprotein afamin has been previously identified as an alternative carrier protein for vitamin E in extravascular fluids such as plasma and cerebrospinal, ovarian follicular, and seminal fluids., afamin, a vitamin E-binding protein in human plasma, the human vitamin E-binding protein afamin, Afamin is a plasma vitamin E-binding glycoprotein, The human vitamin E-binding glycoprotein afamin is primarily expressed in the liver and has been associated with prevalent and incident metabolic syndrome[SEP]Definitions: human defined as following: Members of the species Homo sapiens.. metabolic syndrome defined as following: A combination of medical conditions that when present, increase the risk of heart attack, stroke, and diabetes mellitus. It includes the following medical conditions: increased blood pressure, central obesity, dyslipidemia, impaired glucose tolerance, and insulin resistance..", "label": "yes"} {"id": "converted_3144", "sentence1": "Is the protein Asporin related to disease?", "sentence2": "Accumulating evidence demonstrates the involvement of asporin in OA pathogenesis., Asporin has been reported as a tumor suppressor in breast cancer, while asporin-activated invasion has been described in gastric cancer., Asporin has been implicated as an oncogene in various types of human cancers; , These results suggested that asporin promoted the tumor growth and metastasis of CRC, and it could be a potential therapeutic target for CRC patients in future., Our results suggest that ASPN is a stromally expressed biomarker that correlates with disease progression, and is observed in reactive stroma. [SEP]Definitions: oncogene defined as following: Genes whose gain-of-function alterations lead to NEOPLASTIC CELL TRANSFORMATION. They include, for example, genes for activators or stimulators of CELL PROLIFERATION such as growth factors, growth factor receptors, protein kinases, signal transducers, nuclear phosphoproteins, and transcription factors. A prefix of \"v-\" before oncogene symbols indicates oncogenes captured and transmitted by RETROVIRUSES; the prefix \"c-\" before the gene symbol of an oncogene indicates it is the cellular homolog (PROTO-ONCOGENES) of a v-oncogene.. breast cancer defined as following: A primary or metastatic malignant neoplasm involving the breast. The vast majority of cases are carcinomas arising from the breast parenchyma or the nipple. Malignant breast neoplasms occur more frequently in females than in males.. human defined as following: Members of the species Homo sapiens.. CRC defined as following: The disappearance of all signs of cancer, including the absence of a detectable disease-related genetic abnormality, as determined by techniques such as karyotyping or FISH, in response to treatment.. cancers defined as following: A tumor composed of atypical neoplastic, often pleomorphic cells that invade other tissues. Malignant neoplasms often metastasize to distant anatomic sites and may recur after excision. The most common malignant neoplasms are carcinomas, Hodgkin and non-Hodgkin lymphomas, leukemias, melanomas, and sarcomas.. gastric cancer defined as following: A primary or metastatic malignant neoplasm involving the stomach.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown..", "label": "yes"} {"id": "converted_543", "sentence1": "Is the gene DUX4 epigenetically regulated in somatic cells?", "sentence2": "There are several genes on chromosome 4q35 region including DUX4 within D4Z4 repeats. Transcription of these genes is usually repressed by epigenetic modifications of this chromosomal region and also accumulation of transcriptional repressors to the repeat array., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. , The human double-homeodomain retrogene DUX4 is expressed in the testis and epigenetically repressed in somatic tissues., Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by decreased epigenetic repression of the D4Z4 macrosatellite repeats and ectopic expression of DUX4, a retrogene encoding a germline transcription factor encoded in each repeat., These mice recapitulate important epigenetic and DUX4 expression attributes seen in patients and controls, respectively, including high DUX4 expression levels in the germline, (incomplete) epigenetic repression in somatic tissue, and FSHD-specific variegated DUX4 expression in sporadic muscle nuclei associated with D4Z4 chromatin relaxation., DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells., In contrast to control skeletal muscle and most other somatic tissues, full-length DUX4 transcript and protein is expressed at relatively abundant levels in human testis, most likely in the germ-line cells. Induced pluripotent (iPS) cells also express full-length DUX4 and differentiation of control iPS cells to embryoid bodies suppresses expression of full-length DUX4, whereas expression of full-length DUX4 persists in differentiated FSHD iPS cells. Together, these findings indicate that full-length DUX4 is normally expressed at specific developmental stages and is suppressed in most somatic tissues., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues., DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells. , DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues., Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD., Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues, The human double-homeodomain retrogene DUX4 is expressed in the testis and epigenetically repressed in somatic tissues, Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD, DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells, Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues, The identification of the gene(s) and the exact epigenetic pathway underlining this disease will be mandatory to increase the rate of diagnosis for FSHD2 patients and to confirm the hypothesis of a common FSHD1 and FSHD2 pathophysiological pathway involving DUX4 gene, This deletion induces epigenetic modifications that affect the expression of several genes located in the vicinity. In each D4Z4 element, we identified the double homeobox 4 (DUX4) gene. DUX4 expresses a transcription factor that plays a major role in the development of FSHD through the initiation of a large gene dysregulation cascade that causes myogenic differentiation defects, atrophy and reduced response to oxidative stress. , decreased epigenetic repression and variegated expression of DUX4 in skeletal muscle, (incomplete) epigenetic repression in somatic tissue,, Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle., derepression of the DUX4 retrogene, The aim of our study was to identify relationships between epigenetic parameters correlating with a relaxed chromatin state of the DUX4 promoter region and clinical severity as measured by a clinical severity score or muscle pathologic changes in D4Z4 contraction-dependent (FSHD1) and -independent (FSHD2) facioscapulohumeral muscular dystrophy patients. , Specifically, abundance of RNA transcripts encoded by the DUX4 locus correlated to differential DNA methylation and H3K36me3 enrichment., Together, these findings indicate that full-length DUX4 is normally expressed at specific developmental stages and is suppressed in most somatic tissue[SEP]Definitions: DUX4 defined as following: Human DUX4L1 gene is located in the vicinity of 4q35 and is approximately 2 kb in length. The product is a processed pseudogene that produces an RNA transcript, but does not encode a protein product. This gene is within a D4Z4 repeat array; contraction of this macrosatellite repeat is associated with facioscapulohumeral muscular dystrophy (FSHD).. FSHD defined as following: An autosomal dominant degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. (Neuromuscul Disord 1997;7(1):55-62; Adams et al., Principles of Neurology, 6th ed, p1420). chromosome 4 defined as following: A specific pair of GROUP B CHROMOSOMES of the human chromosome classification.. stem cell defined as following: Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown.. transcription factor defined as following: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.. protein defined as following: Protein; provides access to the encoding gene via its GenBank Accession, the taxon in which this instance of the protein occurs, and references to homologous proteins in other species.. muscular dystrophy defined as following: A heterogeneous group of inherited MYOPATHIES, characterized by wasting and weakness of the SKELETAL MUSCLE. They are categorized by the sites of MUSCLE WEAKNESS; AGE OF ONSET; and INHERITANCE PATTERNS.. DUX4 gene defined as following: This gene plays a role in transcriptional regulation.. genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.. germ-line cells defined as following: The reproductive cells in multicellular organisms at various stages during GAMETOGENESIS.. FSHD1 defined as following: An autosomal dominant form of facioscapulohumeral muscular dystrophy associated with contraction of the D4Z4 macrosatellite repeat.. chromosomal region defined as following: Any subdivision of a chromosome along its length. [GOC:dos]. H3K36me3 defined as following: A post-translationally modified form of histone H3 where the lysine residue at position 36 is trimethylated. This modification may be involved in defining exon boundaries; it also may be a marker for genes targeted for transcriptional repression.. testis defined as following: The male gonad containing two functional parts: the SEMINIFEROUS TUBULES for the production and transport of male germ cells (SPERMATOGENESIS) and the interstitial compartment containing LEYDIG CELLS that produce ANDROGENS.. atrophy defined as following: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes.. repeat defined as following: Something occurring more than once.. human defined as following: Members of the species Homo sapiens.. iPS cells defined as following: Cells from adult organisms that have been reprogrammed into a pluripotential state similar to that of EMBRYONIC STEM CELLS.. somatic cells defined as following: Nucleated cell which has one or more diploid sets (46 pairs) of chromosomes.. repeats defined as following: Make or do or perform again..", "label": "yes"} {"id": "converted_4001", "sentence1": "Should nerinetide be used for treatment of ischaemic stroke?", "sentence2": "337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups., INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo.[SEP]Definitions: ischaemic stroke defined as following: An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of brain tissue..", "label": "no"} {"id": "converted_3173", "sentence1": "Can prevnar 13 be used in children?", "sentence2": "PCV13 is approved for routine vaccination of all infants as a 4-dose series at age 2, 4, 6, and 12-15 months for children who previously received 1 or more doses of the 7-valent pneumococcal conjugate vaccine (PCV7), and for children with underlying medical conditions that increase their risk for pneumococcal disease or its complications. , Based on published immunogenicity and safety data, as well as the recent recommendations by the ACIP for routine use in infants and indications for high-risk pediatric patients, PCV13 is a revised formulation of pneumococcal vaccine that should be included on pharmacy formularies., To review the immunogenicity, efficacy, and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in pediatric patients.[SEP]", "label": "yes"} {"id": "converted_367", "sentence1": "Is bapineuzumab effective for treatment of patients with Alzheimer's disease?", "sentence2": " Thus far, results from two large phase 3 trial programs with bapineuzumab and solaneuzumab, respectively, have brought rather disappointing results., More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. , Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function., The marginal effects observed in recent clinical studies of solanezumab, targeting monomeric Aβ, and bapineuzumab, targeting amyloid plaques, prompted expert comments that drug discovery efforts in Alzheimer's disease should focus on soluble forms of Aβ rather than fibrillar Aβ deposits found in amyloid plaques., Phase III trials showed that bapineuzumab failed to improve cognitive and functional performances in AD patients, and was associated with a high incidence of amyloid-related imaging abnormalities (ARIA)., Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab, have been carried out; however, all trials have failed to demonstrate apparent clinical benefits. , Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline., Despite negative topline phase 3 clinical trial results for bapineuzumab and solanezumab in mild to moderate AD, findings from these trials and recent advances suggest renewed optimism for anti-amyloid therapies. , The lack of progress in the development of disease-modifying therapy in Alzheimer's disease (AD) was highlighted recently by the cessation of a phase 3 clinical trial studying the effects of bapineuzumab on mild to moderate disease. No treatment benefit was apparent, whereas several serious side effects occurred more commonly in the treatment group compared to placebo. , Clinical studies using the N-terminal-directed anti-Aβ antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of Aβ plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of Aβ plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models., The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. , The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Aβ burden in the brain of AD patients. However, the preliminary cognitive efficacy of bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg)., However, the preliminary cognitive efficacy of bapineuzumab, a humanized anti-Aβ monoclonal antibody, appears uncertain. Moreover, the occurrence of vasogenic edema and, more rarely, brain microhemorrhages, especially in apolipoprotein E ϵ4 carriers, have led to abandoning of the highest dose of the drug. , However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD. , The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of Aβ due to immunotherapy., These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment., Bapineuzumab has been shown to reduce Aβ burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE ε4 carriers, and vasogenic edema may limit its clinical use. , Bapineuzumab appears capable of reducing the cerebral beta-amyloid peptide burden in patients with Alzheimer's disease. However, particularly in APOE 4 carriers, its ability to slow disease progression remains uncertain, and vasogenic edema - a dose-limiting and potentially severe adverse reaction - may limit its clinical applicability., The first is a phase 2 study of passive immunotherapy with bapineuzumab, a humanized anti-Abeta monoclonal antibody directed against the N-terminus of Abeta. This trial showed no differences within dose cohorts on the primary efficacy analysis. Exploratory analyses showed potential treatment differences on cognitive and functional endpoints in study completers and apolipoprotein E epsilon4 noncarriers. A safety concern was the occurrence of reversible vasogenic edema. , The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers.[SEP]Definitions: apolipoprotein E 4 defined as following: A class of protein components which can be found in several lipoproteins including HIGH-DENSITY LIPOPROTEINS; VERY-LOW-DENSITY LIPOPROTEINS; and CHYLOMICRONS. Synthesized in most organs, Apo E is important in the global transport of lipids and cholesterol throughout the body. Apo E is also a ligand for LDL receptors (RECEPTORS, LDL) that mediates the binding, internalization, and catabolism of lipoprotein particles in cells. There are several allelic isoforms (such as E2, E3, and E4). Deficiency or defects in Apo E are causes of HYPERLIPOPROTEINEMIA TYPE III.. lacunar infarcts defined as following: Brain infarction that affects small subcortical vessels due to occlusion of a penetrating artery deep in the brain. It may lead to lacunar stroke.. Solanezumab defined as following: A humanized monoclonal antibody (IgG1) raised against amyloid beta peptides with Alzheimer disease treatment application. Solanezumab recognizes and binds the middle amino acid residues 16-24 of the amyloid beta peptide and may be used in a passive immunotherapy treatment.. drug defined as following: Any natural, endogenously-derived, synthetic or semi-synthetic compound with pharmacologic activity. A pharmacologic substance has one or more specific mechanism of action(s) through which it exerts one or more effect(s) on the human or animal body. They can be used to potentially prevent, diagnose, treat or relieve symptoms of a disease. Formulation specific agents and some combination agents are also classified as pharmacologic substances.. Abeta defined as following: Human APP wild-type allele is located in the vicinity of 22q13.2 and is approximately 290 kb in length. This allele, which encodes amyloid beta A4 protein, is involved in transcriptional activation and peptide regulation. APP defects can cause Alzheimer's disease and cerebroarterial amyloidosis.. Bapineuzumab defined as following: A humanized monoclonal antibody (IgG1) raised against amyloid beta peptides with Alzheimer disease treatment application. Bapineuzumab recognizes and binds the N-terminal amino acids 1-5 of the amyloid beta peptide, and may be used in a passive immunotherapy treatment.. Alzheimer's disease defined as following: Alzheimer's disease caused by mutation(s) in the APP gene, encoding amyloid-beta A4 protein. The onset of this condition typically occurs before age 65.. monoclonal antibodies defined as following: Antibodies produced by a single clone of cells.. vasogenic edema defined as following: Edema that is characterized by increased permeability of capillary endothelial cells.. CSF defined as following: A watery fluid that is continuously produced in the CHOROID PLEXUS and circulates around the surface of the BRAIN; SPINAL CORD; and in the CEREBRAL VENTRICLES.. ARIA defined as following: Human NRG1 wild-type allele is located within 8p21-p12 and is approximately 1,124 kb in length. This allele, which encodes pro-neuregulin-1, membrane-bound isoform protein, is involved in the compositional regulation of neurotransmitter receptors in maturing synapses in the brain, proliferation and differentiation.. humanized monoclonal antibody defined as following: Antibodies from non-human species whose protein sequences have been modified to make them nearly identical with human antibodies. If the constant region and part of the variable region are replaced, they are called humanized. If only the constant region is modified they are called chimeric. INN names for humanized antibodies end in -zumab.. bapineuzumab defined as following: A humanized monoclonal antibody (IgG1) raised against amyloid beta peptides with Alzheimer disease treatment application. Bapineuzumab recognizes and binds the N-terminal amino acids 1-5 of the amyloid beta peptide, and may be used in a passive immunotherapy treatment..", "label": "no"} {"id": "converted_2936", "sentence1": "Can midostaurin inhibit angiogenesis?", "sentence2": "Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor.[SEP]Definitions: vascular endothelial growth factor receptor defined as following: A 180-kDa VEGF receptor found primarily in endothelial cells that is essential for vasculogenesis and vascular maintenance. It is also known as Flt-1 (fms-like tyrosine kinase receptor-1). A soluble, alternatively spliced isoform of the receptor may serve as a binding protein that regulates the availability of various ligands for VEGF receptor binding and signal transduction.. protein kinase C defined as following: An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters.. Midostaurin defined as following: A synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors.. midostaurin defined as following: A synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors..", "label": "yes"} {"id": "converted_2795", "sentence1": "Is chlorotoxin a peptide?", "sentence2": "chlorotoxin peptide , Chlorotoxin (CTX) is a 36-amino-acid disulfide-containing peptide derived from the venom of the scorpion Leiurus quinquestriatus., The mature Odontobuthus doriae chlorotoxin peptide has a 35-amino-acid residue and four disulfide bounds. , Chlorotoxin (CTX), a disulfide-rich peptide from the scorpion Leiurus quinquestriatus,[SEP]Definitions: Chlorotoxin defined as following: A neurotoxin with potential anticancer property. Chlorotoxin (CTX) is a 36-amino acid peptide found in the venom of the deathstalker scorpion, and a chloride channel blocker. This toxin binds preferentially to glioma cells via the transmembrane endopeptidase matrix metalloproteinase-2 (MMP-2), and thereby prevents the spread of tumor cells. MMP-2 is specifically up-regulated in gliomas and related cancers, but is not normally expressed in brain.. venom defined as following: A toxin used by animals and injected into their victims by a bite or sting. CTX defined as following: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.. chlorotoxin a defined as following: A neurotoxin with potential anticancer property. Chlorotoxin (CTX) is a 36-amino acid peptide found in the venom of the deathstalker scorpion, and a chloride channel blocker. This toxin binds preferentially to glioma cells via the transmembrane endopeptidase matrix metalloproteinase-2 (MMP-2), and thereby prevents the spread of tumor cells. MMP-2 is specifically up-regulated in gliomas and related cancers, but is not normally expressed in brain.. peptide defined as following: Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are considered to be larger versions of peptides that can form into complex structures such as ENZYMES and RECEPTORS..", "label": "yes"} {"id": "converted_3996", "sentence1": "Are mucin overexpression associated with disease?", "sentence2": "The pathological mechanism underlying hepatolithiasis is closely related to bacterial infections of the intrahepatic bile duct, followed by chronic inflammation and the overexpression of mucin 5AC (MUC5AC)., MUC1 is a membrane glycoprotein, which in adenocarninomas is overexpressed and exhibits truncated O-glycosylation. , Mucin 13 (MUC13) is reportedly overexpressed in human malignancies., Inflammation causes MUC1 overexpression and hypoglycosylation. [SEP]Definitions: MUC1 defined as following: Human MUC1 wild-type allele is located within 1q21 and is approximately 121 kb in length. This allele, which encodes mucin-like protein 1, plays a role in both cellular defense by binding pathogens and in cell signaling.. mucin defined as following: Mucin-1 (1255 aa, ~122 kDa) is encoded by the human MUC1 gene. This protein plays a role in both signaling and cell adhesion.. human defined as following: Members of the species Homo sapiens.. membrane glycoprotein defined as following: Glycoproteins found on the membrane or surface of cells.. MUC5AC defined as following: Mucin-5AC (5030 aa, ~527 kDa) is encoded by the human MUC5AC gene. This protein plays a role in the defense of the gastrointestinal and respiratory tracts from microorganism infection.. intrahepatic bile duct defined as following: Passages within the liver for the conveyance of bile. Includes right and left hepatic ducts even though these may join outside the liver to form the common hepatic duct.. hepatolithiasis defined as following: The presence of solitary or multiple stones in the intrahepatic bile ducts.. disease defined as following: A definite pathologic process with a characteristic set of signs and symptoms. It may affect the whole body or any of its parts, and its etiology, pathology, and prognosis may be known or unknown..", "label": "yes"} {"id": "converted_4065", "sentence1": "Is ofatumumab effective for multiple sclerosis?", "sentence2": "Anti-CD20 Agents for Multiple Sclerosis: Spotlight on Ocrelizumab and Ofatumumab., Ofatumumab, a fully human anti-CD20 monoclonal antibody, that binds a distinct epitope, has been further investigated in phase 3 trials for relapsing forms of MS. , Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk., Currently, new therapies are emerging that promise more convenience and an improved safety profile (ofatumumab) or remyelinating potential with clinical improvement (opicinumab)., The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit., AREAS COVERED: In this manuscript, we review mechanisms of action, efficacy, safety, and tolerance of anti-CD20 therapies for MS, including rituximab, ocrelizumab, and ofatumumab., Another CD20 directed mAb, ofatumumab, is in phase 3. , Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk., CONCLUSION: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data., CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. [SEP]Definitions: ocrelizumab defined as following: A Fc-modified, humanized monoclonal antibody directed against the B-cell CD20 cell surface antigen, with immunosuppressive activity. Ocrelizumab binds to CD20 on the surfaces of B-cells, triggering complement-dependent cell lysis (CDCL) and antibody-dependent cell-mediated cytotoxicity (ADCC) of B-cells overexpressing CD20. The CD20 antigen, a non-glycosylated cell surface phosphoprotein that acts as a calcium ion channel, is found on over 90% of B-cells, B-cell lymphomas, and other lymphoid tumor cells of B-cell origin; it plays an important role in B-cell functioning.. ofatumumab defined as following: A fully human, high-affinity IgG1 monoclonal antibody directed against the B cell CD20 cell surface antigen with potential antineoplastic activity. Ofatumumab binds specifically to CD20 on the surfaces of B cells, triggering complement-dependent cell lysis (CDCL) and antibody-dependent cell-mediated cytotoxicity (ADCC) of B cells overexpressing CD20. The CD20 antigen, found on over 90% of B cells, B cell lymphomas, and other B cells of lymphoid tumors of B cell origin, is a non-glycosylated cell surface phosphoprotein that acts as a calcium ion channel; it is exclusively expressed on B cells during most stages of B cell development.. CD20 defined as following: Human MS4A1 wild-type allele is located within 11q12 and is approximately 13 kb in length. This allele, which encodes B-lymphocyte antigen CD20 protein, plays a role in the development and differentiation of B-cells into plasma cells.. human defined as following: Members of the species Homo sapiens.. rituximab defined as following: A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS.. multiple sclerosis defined as following: An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903). RMS defined as following: A statistical measure of the magnitude of a set of variable values. The root mean square is the square root of the mean value for the squares of the original values..", "label": "yes"} {"id": "converted_1216", "sentence1": "Can desvenlafaxine be used at a dose of 50mg/day?", "sentence2": "Long-term use of desvenlafaxine was safe and well tolerated, with a clinical benefit/risk profile similar to that in other populations., e objective of this study was to evaluate the long-term safety of desvenlafaxine for continuation treatment of major depressive disorder (MDD) in Japanese patients. This was a phase 3, multicenter, 10-month, open-label study with flexible dosing of desvenlafaxine (25, 50, 100 mg/day), n an effort to establish the lowest effective dose of desvenlafaxine (administered as desvenlafaxine succinate), we assessed the efficacy, safety, and tolerability of 10- and 50-mg/day desvenlafaxine vs placebo for the treatment of major depressive disorder, Change from baseline to final evaluation in adjusted HAM-D(17) total scores was not significantly different comparing desvenlafaxine 10 mg/day (-9.28) and desvenlafaxine 50 mg/day (-8.92) with placebo (-8.42), Overall rates of treatment-emergent adverse events with both doses were similar to placebo, However, in a companion study reported separately, desvenlafaxine 50 mg, but not 25 mg, separated from placebo. Taken together, these studies suggest that 50 mg is the minimum effective dose of desvenlafaxine for the treatment of major depressive disorder. , Desvenlafaxine XR was dosed at 50 mg/day for 10 days., Desvenlafaxine therapy is initiated at the therapeutic dose (50 mg/day) without a need for dose titration., Clinical studies have investigated the efficacy of DVS in doses ranging from 50 to 400 mg/day for the treatment of MDD in adult outpatients. The effects of DVS 50 mg/day have been clearly distinguished from placebo in the reduction of MDD symptoms in such clinical trials. No additional therapeutic benefits were found at doses > 50 mg/day. The recommended dose of DVS ranges from 50 to 100 mg., Adult outpatients with major depressive disorder received desvenlafaxine doses ranging from 50-400 mg/day or placebo for 8 weeks, At the recommended therapeutic dose of 50 mg/day, discontinuation due to adverse events was similar to placebo, atients received fixed (50, 100, 200, or 400 mg/day; n=1,342) or flexible doses (100-400 mg/day; n=463) of desvenlafaxine or placebo (n=1,108), Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed., To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD), Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) scores > or =20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks., Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D(17) (-11.5) compared with placebo (-9.5, p=0.018), These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. , CONCLUSIONS: Desvenlafaxine at the recommended dose of 50 mg/d was effective in relapse prevention of depression during a 6-month period in patients who demonstrated stable response after 20 weeks of open-label desvenlafaxine treatment.[SEP]Definitions: Desvenlafaxine defined as following: A synthetic phenethylamine bicyclic derivative with antidepressant activity. Desvenlafaxine is a selective reuptake inhibitor of serotonin and norepinephrine due to its high binding affinities to the pre-synaptic serotonin and norepinephrine transporters. By blocking both transporters, this agent prolongs neurotransmitter activities of both serotonin and norepinephrine, thereby alleviating depressive state.. MDD defined as following: Disorder in which five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Symptoms include: depressed mood most of the day, nearly every daily; markedly diminished interest or pleasure in activities most of the day, nearly every day; significant weight loss when not dieting or weight gain; Insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate, or indecisiveness, nearly every day; or recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt. (DSM-5). mg/day defined as following: A unit of mass flow rate equivalent to the rate at which one thousandth of a gram of matter crosses a given surface or is delivered to a given object or space over a period of time equal to twenty four hours. Milligram per twenty four hours is also a dose administration rate unit equal to the rate at which one thousandth of a gram of a product is administered per unit of time equal to twenty four hours.. desvenlafaxine defined as following: A synthetic phenethylamine bicyclic derivative with antidepressant activity. Desvenlafaxine is a selective reuptake inhibitor of serotonin and norepinephrine due to its high binding affinities to the pre-synaptic serotonin and norepinephrine transporters. By blocking both transporters, this agent prolongs neurotransmitter activities of both serotonin and norepinephrine, thereby alleviating depressive state..", "label": "yes"} {"id": "converted_724", "sentence1": "Are there any clinical trials of the effect of evening primrose oil on postmenopausal symptoms ?", "sentence2": "To analyze whether the time (morning/evening) of administration of a compound containing 60 mg of dry soy seed extract (glycine max) with 40% of total isoflavones, primrose oil and α-tocopherol modifies the effect on the climacteric syndrome., The object of this study was to evaluate the effect of different doses of a compound containing isoflavones 60 mg, primrose oil 440 mg and vitamin E 10 mg. (IOVE) on menopausal complaints. This was an open, multicentre, randomised, group comparative, efficacy and safety trial., Emphasis was placed on randomized, double-blind, placebo-controlled clinical trials, as these provide the best efficacy and safety data, Nonprescription therapies reviewed include black cohosh, dong quai, evening primrose oil, physical activity, phytoestrogens, and red clover, The effect of oral evening primrose oil on menopausal hot flashes: a randomized clinical trial., The aim of this study was to compare the efficacy of evening primrose with placebo in improvement of menopausal hot flashes. , The application of oral evening primrose oil compared with placebo for controlling hot flashes may decrease more the intensity of attacks , Our search identified 58 randomised controlled trials of which 11 involved the use of clonidine, six for SSRIs, four for gabapentin, seven for black cohosh, seven for red clover, 18 for phytoestrogens, two for ginseng, one for evening primrose,, Single clinical trials have found no benefit for dong quai, evening primrose oil,, Single clinical trials have found that dong quai, evening primrose oil,, To evaluate the efficacy of gamolenic acid provided by evening primrose oil in treating hot flushes and sweating associated with the menopause. DESIGN: Randomised, double blind, placebo controlled study.[SEP]Definitions: SSRIs defined as following: Any agent that increases the extracellular level of the neurotransmitter serotonin (5-HT) by inhibiting its reuptake into the presynaptic cell. Increased level in the synaptic cleft prolongs the action of 5-HT on the postsynaptic receptor. This type of agent is typically used as an antidepressant and in the treatment of anxiety disorders and some personality disorders. They are also typically effective and used in treating some cases of insomnia.. gamolenic acid defined as following: An omega-6 fatty acid produced in the body as the delta 6-desaturase metabolite of linoleic acid. It is converted to dihomo-gamma-linolenic acid, a biosynthetic precursor of monoenoic prostaglandins such as PGE1. (From Merck Index, 11th ed). gabapentin defined as following: A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of PARTIAL SEIZURES; NEURALGIA; and RESTLESS LEGS SYNDROME.. isoflavones defined as following: 3-Phenylchromones. Isomeric form of FLAVONOIDS in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position.. climacteric syndrome defined as following: A grouping of variable physical, vasomotor and psychological symptoms in climacteric females. Physical symptoms include: cessation of menses, headaches, fatigue, weight gain and vaginal dryness. Vasomotor symptoms typically include: palpitations, hot flashes and night sweats. Psychological symptoms may include: decrease in libido, emotional lability, difficulty concentrating and insomnia.. clonidine defined as following: An imidazoline sympatholytic agent that stimulates ALPHA-2 ADRENERGIC RECEPTORS and central IMIDAZOLINE RECEPTORS. It is commonly used in the management of HYPERTENSION.. dong quai defined as following: An herbal extract derived from the root of the plant Angelica sinensis with possible antiinflammatory, antispasmodic, vasodilatory, estrogenic, and antitumor activities. Angelica sinensis contains volatile oils, including safrole, isosafrole, and n-butylphthalide; coumarin derivatives, including psoralens, bergapten, osthol, imperatorin, and oxypeucedanin; and ferulic acid. The coumarin derivatives in this agent may vasodilate and relax smooth muscle and may exhibit additive anticoagulant effects. Ferulic acid, a phenolic phytochemical present in plant cell walls, may neutralize free radicals such as reactive oxygen species. In addition, Angelica sinensis extract has been shown to inhibit the growth and induce apoptosis of glioblastoma mutltiforme brain tumor cells through p53-dependent and p53-independent pathways..", "label": "yes"} {"id": "converted_3406", "sentence1": "Does xaliproden improve prognosis of amyotrophic lateral sclerosis?", "sentence2": "Treatment for crampsThere is evidence (13 RCTs, N = 4012) that for the treatment of cramps in MND, compared to placebo:- memantine and tetrahydrocannabinol (THC) are probably ineffective (moderate-quality evidence);- vitamin E may have little or no effect (low-quality evidence); and- the effects of L-threonine, gabapentin, xaliproden, riluzole, and baclofen are uncertain as the evidence is either very low quality or the trial specified the outcome but did not report numerical data., The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion., . The six months intent-to-treat analysis showed no statistically significant effect but a trend in favour of 2 mg xaliproden compared to placebo for reduction in the rate of deterioration of FVC, limbs functional score, and manual muscle testing score (MMT)., These results support the use of a staging process to select suitable patients for phase II studies, and suggest that xaliproden may have potential effects in ALS and deserve further study., An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS., The six months intent-to-treat analysis showed no statistically significant effect but a trend in favour of 2 mg xaliproden compared to placebo for reduction in the rate of deterioration of FVC, limbs functional score, and manual muscle testing score (MMT)., An effect of xaliproden on functional parameters, especially VC, was noted., These results support the use of a staging process to select suitable patients for phase II studies, and suggest that xaliproden may have potential effects in ALS and deserve further study., The six months intent-to-treat analysis showed no statistically significant effect but a trend in favour of 2 mg xaliproden compared to placebo for reduction in the rate of deterioration of FVC, limbs functional score, and manual muscle testing score (MMT)., Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.[SEP]Definitions: THC defined as following: An X-linked recessive bleeding disorder caused by mutation(s) in the WAS gene, encoding Wiskott-Aldrich syndrome protein, resulting in thrombocytopenia.. memantine defined as following: AMANTADINE derivative that has some dopaminergic effects. It has been proposed as an antiparkinson agent.. tetrahydrocannabinol defined as following: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound.. baclofen defined as following: A GAMMA-AMINOBUTYRIC ACID derivative that is a specific agonist of GABA-B RECEPTORS. It is used in the treatment of MUSCLE SPASTICITY, especially that due to SPINAL CORD INJURIES. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission.. MMT defined as following: A rare autosomal dominant syndrome caused by mutations in the MYCN oncogene. It is characterized by microcephaly, limb abnormalities, esophageal and/or duodenal atresia.. ALS defined as following: A degenerative disorder affecting upper MOTOR NEURONS in the brain and lower motor neurons in the brain stem and SPINAL CORD. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous ASTROCYTES and atrophy of anterior SPINAL NERVE ROOTS and corticospinal tracts. (From Adams et al., Principles of Neurology, 6th ed, pp1089-94). dextromethorphan defined as following: Methyl analog of DEXTRORPHAN that shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is an NMDA receptor antagonist (RECEPTORS, N-METHYL-D-ASPARTATE) and acts as a non-competitive channel blocker. It is one of the widely used ANTITUSSIVES, and is also used to study the involvement of glutamate receptors in neurotoxicity.. quinidine defined as following: An optical isomer of quinine, extracted from the bark of the CHINCHONA tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular ACTION POTENTIALS, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.. L-threonine defined as following: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.. cramps defined as following: A sustained and usually painful contraction of muscle fibers. This may occur as an isolated phenomenon or as a manifestation of an underlying disease process (e.g., UREMIA; HYPOTHYROIDISM; MOTOR NEURON DISEASE; etc.). (From Adams et al., Principles of Neurology, 6th ed, p1398). gabapentin defined as following: A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of PARTIAL SEIZURES; NEURALGIA; and RESTLESS LEGS SYNDROME.. riluzole defined as following: A glutamate antagonist (RECEPTORS, GLUTAMATE) used as an anticonvulsant (ANTICONVULSANTS) and to prolong the survival of patients with AMYOTROPHIC LATERAL SCLEROSIS.. indinavir defined as following: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability.. limbs defined as following: The farthest or outermost projections of the body, such as the HAND and FOOT.. amyotrophic lateral sclerosis defined as following: An inherited form of amyotrophic lateral sclerosis, usually inherited in an autosomal dominant pattern, caused by mutation(s) in the SOD1 gene, encoding superoxide dismutase..", "label": "no"} {"id": "converted_980", "sentence1": "Is there a relationship between junctin and ryanodine receptors?", "sentence2": "Junctin, a 26 kDa intra-sarcoplasmic reticulum (SR) protein, forms a quaternary complex with triadin, calsequestrin and the ryanodine receptor (RyR) at the junctional SR membrane. , Junctin ablation appears to affect how RyRs 'sense' SR Ca(2+) load, resulting in decreased diastolic SR Ca(2+) leak despite an elevated [Ca(2+)](SR). , Single channel recordings of RyRs from WT and JCN-KO cardiac SR indicate that the absence of junctin produces a dual effect on the normally linear response of RyRs to luminal [Ca(2+)]: at low luminal [Ca(2+)] (<1 mmol l(-1)), junctin-devoid RyR channels are less responsive to luminal [Ca(2+)]; conversely, high luminal [Ca(2+)] turns them hypersensitive to this form of channel modulation. Thus, junctin produces complex effects on Ca(2+) sparks, transients, and leak, but the luminal [Ca(2+)]-dependent dual response of junctin-devoid RyRs demonstrates that junctin normally acts as an activator of RyR channels at low luminal [Ca(2+)], and as an inhibitor at high luminal [Ca(2+)]., Normal Ca(2+) signalling in skeletal muscle depends on the membrane associated proteins triadin and junctin and their ability to mediate functional interactions between the Ca(2+) binding protein calsequestrin and the type 1 ryanodine receptor in the lumen of the sarcoplasmic reticulum., We show here that purified skeletal ryanodine receptors are similarly activated by purified triadin or purified junctin added to their luminal side, although a lack of competition indicated that the proteins act at independent sites. Surprisingly, triadin and junctin differed markedly in their ability to transmit information between skeletal calsequestrin and ryanodine receptors. Purified calsequestrin inhibited junctin/triadin-associated, or junctin-associated, ryanodine receptors and the calsequestrin re-associated channel complexes were further inhibited when luminal Ca(2+) fell from 1mM to, By fusing GCaMP6f to the N-terminus of triadin 1 or junctin, GCaMP6f-T/J was targeted to dyadic junctions, where it colocalized with t-tubules and RyRs after adenovirus-mediated gene transfer. , The junctional face of the jSR, facing the transverse tubules, is occupied by a molecular complex composed of the transmembrane Ca2+ release channels (ryanodine receptors); the luminal protein calsequestrin (CSQ); the 2 membrane proteins, junctin (Jct), and triadin (Tr), which mediate CSQ-ryanodine receptor interactions; and several other components., Calsequestrin, the main calcium buffer in the sarcoplasmic reticulum, provides a pool of calcium for release through the ryanodine receptor and acts as a luminal calcium sensor for the channel via its interactions with triadin and junctin. We examined the influence of phosphorylation of calsequestrin on its ability to store calcium, to polymerise and to regulate ryanodine receptors by binding to triadin and junctin. , Junctin is a 26 kDa membrane protein that binds to calsequestrin, triadin, and ryanodine receptors (RyRs) within the junctional sarcoplasmic reticulum of calcium release units. [SEP]Definitions: junctin defined as following: This gene is involved in calcium ion channel regulation and amino acid hydroxylation.. calcium defined as following: A dietary supplement containing the mineral calcium.. Junctin defined as following: This gene is involved in calcium ion channel regulation and amino acid hydroxylation.. RyR defined as following: A voltage-gated calcium-release channel complex of the sarcoplasmic or endoplasmic reticulum. It plays an important role in the excitation-contraction (E-C) coupling of muscle cells. RyR comprises a family of ryanodine receptors, widely expressed throughout the animal kingdom. [GOC:ame, PMID:22822064]. type 1 ryanodine receptor defined as following: Ryanodine receptor 1 (5038 aa, ~565 kDa) is encoded by the human RYR1 gene. This protein is involved in the transport of calcium ions from the sarcoplasmic reticulum and neurons.. membrane proteins defined as following: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.. luminal defined as following: Relating to the lumen of a blood vessel or other tubular structure.. proteins defined as following: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.. lumen defined as following: A SI derived unit of luminous flux. It is the amount of light that falls on a unit area at unit distance from a source of one candela.. sarcoplasmic reticulum defined as following: A network of tubules and sacs in the cytoplasm of SKELETAL MUSCLE FIBERS that assist with muscle contraction and relaxation by releasing and storing calcium ions.. ryanodine receptor defined as following: A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.. WT defined as following: A designation used to describe a wild-type zebrafish line that is of unknown stock.. membrane defined as following: A device that is made from or resembles a thin flexible sheet of material..", "label": "yes"} {"id": "converted_2797", "sentence1": "Is selenocysteine an aminoacid?", "sentence2": "Selenocysteine (Sec), a rare genetically encoded amino acid with unusual chemical properties, is of great interest for protein engineering., Selenocysteine (SeC) is a naturally available Se-containing amino acid that displays splendid anticancer activities against several human tumors. [SEP]Definitions: Selenocysteine defined as following: A naturally occurring amino acid in both eukaryotic and prokaryotic organisms. It is found in tRNAs and in the catalytic site of some enzymes. The genes for glutathione peroxidase and formate dehydrogenase contain the TGA codon, which codes for this amino acid.. amino acid defined as following: Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins.. Sec defined as following: A unit of time, one of the seven base units of the International System of Units (Systeme International d'Unites, SI). The second is the duration of 919 263 177 0 periods of the specified light radiation corresponding to the transition between the two hyperfine levels of the caesium 133 atom in its ground state at 0 K. According to the convention, 60 seconds constitute one minute; 3,600 seconds constitute one hour.. human defined as following: Members of the species Homo sapiens.. selenocysteine defined as following: A naturally occurring amino acid in both eukaryotic and prokaryotic organisms. It is found in tRNAs and in the catalytic site of some enzymes. The genes for glutathione peroxidase and formate dehydrogenase contain the TGA codon, which codes for this amino acid..", "label": "yes"} {"id": "converted_3552", "sentence1": "Is the BAGEL algorithm used for arrayed CRISPR screens?", "sentence2": "BAGEL: a computational framework for identifying essential genes from pooled library screens., The adaptation of the CRISPR-Cas9 system to pooled library gene knockout screens in mammalian cells represents a major technological leap over RNA interference, the prior state of the art. New methods for analyzing the data and evaluating results are needed.RESULTS: We offer BAGEL (Bayesian Analysis of Gene EssentiaLity), a supervised learning method for analyzing gene knockout screens. Coupled with gold-standard reference sets of essential and nonessential genes, BAGEL offers significantly greater sensitivity than current methods, while computational optimizations reduce runtime by an order of magnitude.CONCLUSIONS: Using BAGEL, we identify ~2000 fitness genes in pooled library knockout screens in human cell lines at 5 % FDR, a major advance over competing platforms. BAGEL shows high sensitivity and specificity even across screens performed by different labs using different libraries and reagents., CONCLUSIONS\n\nUsing BAGEL, we identify ~2000 fitness genes in pooled library knockout screens in human cell lines at 5 % FDR, a major advance over competing platforms., BAGEL: a computational framework for identifying essential genes from pooled library screens, CONCLUSIONS\nUsing BAGEL, we identify ~2000 fitness genes in pooled library knockout screens in human cell lines at 5 % FDR, a major advance over competing platforms., CONCLUSIONS: Using BAGEL, we identify ~2000 fitness genes in pooled library knockout screens in human cell lines at 5 % FDR, a major advance over competing platforms., Conclusions Using BAGEL, we identify ~2000 fitness genes in pooled library knockout screens in human cell lines at 5 % FDR, a major advance over competing platforms.[SEP]Definitions: reagents defined as following: Any natural or synthetic substance used in a chemical or biological reaction in order to produce, identify, or measure another substance.. RNA defined as following: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed). genes defined as following: A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms..", "label": "no"} {"id": "converted_3744", "sentence1": "Has tocilizumab been assessed against Covid-19?", "sentence2": "Preliminary clinical results have indicated that antagonism of the IL-6 receptor (IL-6R), including with the FDA-approved humanized monoclonal antibody tocilizumab, can improve the outcomes of patients with severe or critical COVID-19 while maintaining a good safety profile.[SEP]Definitions: IL-6 receptor defined as following: Cell surface receptors that are specific for INTERLEUKIN-6. They are present on T-LYMPHOCYTES, mitogen-activated B-LYMPHOCYTES, and peripheral MONOCYTES. The receptors are heterodimers of the INTERLEUKIN-6 RECEPTOR ALPHA SUBUNIT and the CYTOKINE RECEPTOR GP130.. IL-6R defined as following: Combining with interleukin-6 and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity. [GOC:jl, GOC:signaling]. tocilizumab defined as following: A recombinant, humanized IgG1 monoclonal antibody directed against the interleukin-6 receptor (IL-6R) with immunosuppressant activity. Tocilizumab targets and binds to both the soluble form of IL-6R (sIL-6R) and the membrane-bound form (mIL-6R), thereby blocking the binding of IL-6 to its receptor. This prevents IL-6-mediated signaling. IL-6, a pro-inflammatory cytokine that plays an important role in the regulation of the immune response, is overproduced in autoimmune disorders, certain types of cancers and possibly various other inflammatory conditions..", "label": "yes"} {"id": "converted_2394", "sentence1": "Does erythromycin increase risk of hypertrophic pyloric stenosis?", "sentence2": "Post-natal erythromycin exposure and risk of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis., PURPOSE: Macrolide antibiotics, erythromycin, in particular, have been linked to the development of infantile hypertrophic pyloric stenosis (IHPS)., Overall, erythromycin exposure was significantly associated with development of IHPS [OR 2.45 (1.12-5.35), p = 0.02]. , Data on erythromycin exposure in the first 14 days of life was extracted from 4/9 studies and identified a strong association between erythromycin exposure and subsequent development IHPS [OR 12.89 (7.67-2167), p < 0.00001].CONCLUSION: This study demonstrates a significant association between post-natal erythromycin exposure and development of IHPS, which seems stronger when exposure occurs in the first 2 weeks of life., BACKGROUND AND OBJECTIVE: Use of oral erythromycin in infants is associated with infantile hypertrophic pyloric stenosis (IHPS)., CONCLUSIONS: Ingestion of oral azithromycin and erythromycin places young infants at increased risk of developing IHPS., An association between erythromycin and IHPS was also confirmed. Exposure to erythromycin in the first 14 days of life had an aOR of 13.3 (95% CI, 6.80-25.9), and 15 to 42 days of life, aOR 4.10 (95% CI, 1.69-9.91). , Early exposure to oral erythromycin in young infants, particularly in the first 2 weeks of life, has previously been associated with the development of hypertrophic pyloric stenosis. We report a case of an infant who received an abbreviated 4-day course of oral erythromycin for suspected Chlamydia conjunctivitis at 5 days of life then underwent pyloromyotomy for pyloric stenosis less than 2 weeks later., Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis., A case report has suggested that exposure to erythromycin through breast milk might cause infantile hypertrophic pyloric stenosis., Macrolide antibiotics, erythromycin, in particular, have been linked to the development of infantile hypertrophic pyloric stenosis (IHPS)., Infants prescribed systemic erythromycin had increased risk of IHPS, with the highest risk in the first 2 weeks of age (relative risk = 10.51 for erythromycin in first 2 weeks, 95% CI 4.48, 24.66)., There was an association between maternal prescriptions for nonerythromycin macrolides and infantile hypertrophic pyloric stenosis (adjusted odds ratio 2.77, 95% confidence interval 1.22, 6.30, P =.01).