tbuckley/cabot-search huggingface dataset:
The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance
Authors: A. M. Valdes, E. Evangelou, H. J. M. Kerkhof, A. Tamm, S. A. Doherty, K. Kisand, A. Tamm, I. Kerna, A. Uitterlinden, A. Hofman, F. Rivadeneira, C. Cooper, E. M. Dennison, W. Zhang, K. R. Muir, J. P. A. Ioannidis, M. Wheeler, R. A. Maciewicz, J. B. van Meurs, N. K. Arden, T. D. Spector, M. Doherty
Journal: Annals of the Rheumatic Diseases (2010)

Osteoarthritis of the knee is a major cause of pain, disability and the use of healthcare resources among middle-aged and older people.1 Although osteoarthritis is multifactorial, it is known to have a significant genetic contribution and a number of studies have attempted to dissect such a contribution (see Valdes and Spector2 for review).

The GDF5 gene encodes the growth differentiation factor 5, a bone morphogenetic protein involved in joint formation, expressed in different joint structures, which has been shown to ameliorate tendon, ligament and bone healing after trauma in mice.3 4

A promoter polymorphism (rs143383) in GDF5 has been found to be strongly associated with both hip and knee osteoarthritis in Asian individuals,4 and is the most widely replicated genetic association with knee osteoarthritis, although much less so for hip and hand osteoarthritis.5 This variant is functional, with the lower gene expression variant having increased genetic risk.4

A large-scale meta-analysis reported the association of the major (T) allele with knee osteoarthritis achieved OR 1.15 p=9.7×10−7 and achieved p=9×10−5 (OR 1.13, 95% CI 1.06 to 1.20) when Asian subjects were excluded.5

The genome-wide statistical significance level of p<5×10−8 is increasingly …
Definition of Disease-Risk Stratification Groups in Childhood Medulloblastoma Using Combined Clinical, Pathologic, and Molecular Variables
Authors: David W. Ellison, Mehmet Kocak, James Dalton, Hisham Megahed, Meryl E. Lusher, Sarra L. Ryan, Wei Zhao, Sarah Leigh Nicholson, Roger E. Taylor, Simon Bailey, Steven C. Clifford
Journal: Journal of Clinical Oncology (2010)

Medulloblastomas are heterogeneous and include relatively good-prognosis tumors characterized by Wnt pathway activation, as well as those that cannot be successfully treated with conventional therapy. Developing a practical therapeutic stratification that allows accurate identification of disease risk offers the potential to individualize adjuvant therapy and to minimize long-term adverse effects in a subgroup of survivors.Using formalin-fixed paraffin-embedded (FFPE) tissue for immunohistochemistry, fluorescent in situ hybridization, and direct sequencing to identify tumors with a Wnt pathway signature and those harboring copy number abnormalities (CNAs) of potential prognostic significance (MYC/MYCN amplification, CNAs of chromosome 6 and 17), we evaluated clinical, pathologic, and molecular outcome indicators and stratification models in a cohort (n = 207) of patients with medulloblastoma 3 to 16 years of age from the International Society of Pediatric Oncology CNS9102 (PNET3) trial.Metastatic disease and large-cell/anaplastic (LC/A) phenotype were the clinicopathologic variables associated with poor progression-free survival (PFS). Nuclear immunoreactivity for β-catenin, CTNNB1 mutation, and monosomy 6 all identified a group of good-prognosis patients. MYC amplification was associated with poor outcome, but other CNAs were not. Low-risk medulloblastomas were defined as β-catenin nucleopositive tumors without metastasis at presentation, LC/A phenotype, or MYC amplification. High-risk medulloblastomas were defined as tumors with metastatic disease, LC/A phenotype, or MYC amplification. Low-risk, standard-risk, and high-risk categories of medulloblastoma had significantly (P < .0001) different outcomes.Integrating assays of molecular biomarkers undertaken on routinely collected diagnostic FFPE tissue into stratification schemes for medulloblastoma alongside clinical and pathologic outcome indicators can refine current definition of disease risk and guide adjuvant therapy.
Ontogeny of the Hematopoietic System
Authors: Ana Cumano, Isabelle Godin
Journal: Annual Review of Immunology (2007)

Blood cells are constantly produced in the bone marrow (BM) of adult mammals. This constant turnover ultimately depends on a rare population of progenitors that displays self-renewal and multilineage differentiation potential, the hematopoietic stem cells (HSCs). It is generally accepted that HSCs are generated during embryonic development and sequentially colonize the fetal liver, the spleen, and finally the BM. Here we discuss the experimental evidence that argues for the extrinsic origin of HSCs and the potential locations where HSC generation might occur. The identification of the cellular components playing a role in the generation process, in these precise locations, will be important in understanding the molecular mechanisms involved in HSC production from undifferentiated mesoderm.
Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin's lymphoma: correlation of complete response, time-to-event and overall survival end points
Authors: L Lee, L Wang, M Crump
Journal: Annals of Oncology (2011)

The correlation between efficacy end points in randomized controlled trials (RCTs) of systemic therapy for non-Hodgkin's lymphoma (NHL) was investigated to identify an appropriate surrogate end point for overall survival (OS).RCTs of previously untreated NHL published from 1990 to 2009 were identified. Associations between absolute differences in efficacy end points were determined using nonparametric Spearman's rank correlation coefficients (r(s)).Thirty-eight RCTs representing 85 treatment arms for aggressive NHL and 20 RCTs representing 42 arms for indolent NHL were included. For aggressive NHL, differences in 3-year progression-free survival (PFS)/event-free survival (EFS) were high correlated with differences in 5-year OS {r(s) of 0.90 [95% confidence interval (CI) 0.73-0.96]} and linear regression determined that a 10% improvement in 3-year EFS or PFS would predict for a 7% ± 1% improvement in 5-year OS. For indolent histology disease, differences in complete response were strongly correlated with differences in 3-year EFS [r(s) 0.86 (95% CI 0.35-0.97)], but there was no correlation between 3-year time-to-event end points and 5-year OS.Improvements in 3-year EFS/PFS are highly correlated with improvements in 5-year OS in aggressive NHL and should be explored as a candidate surrogate end point. Definition of these relationships may inform future clinical trial design and interpretation of interim trial data.
Catecholaminergic Polymorphic Ventricular Tachycardia Is Caused by Mutation-Linked Defective Conformational Regulation of the Ryanodine Receptor
Authors: Hitoshi Uchinoumi, Masafumi Yano, Takeshi Suetomi, Makoto Ono, Xiaojuan Xu, Hiroki Tateishi, Tetsuro Oda, Shinichi Okuda, Masahiro Doi, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Tomoko Ohkusa, Noriaki Ikemoto, Masunori Matsuzaki
Journal: Circulation Research (2010)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in a well-defined region of the cardiac type 2 ryanodine receptor (RyR)2. However, the underlying mechanism by which a single mutation in such a large molecule produces drastic effects on channel function remains unresolved.Using a knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we investigated the molecular mechanism by which CPVT is induced by a single point mutation within the RyR2.The R2474S/+ KI mice showed no apparent structural or histological abnormalities in the heart, but they showed clear indications of other abnormalities. Bidirectional or polymorphic ventricular tachycardia was induced after exercise on a treadmill. The interaction between the N-terminal (amino acids 1 to 600) and central (amino acids 2000 to 2500) domains of the RyR2 (an intrinsic mechanism to close Ca(2+) channels) was weakened (domain unzipping). On protein kinase A-mediated phosphorylation of the RyR2, this domain unzipping further increased, resulting in a significant increase in the frequency of spontaneous Ca(2+) transients. cAMP-induced aberrant Ca(2+) release events (Ca(2+) sparks/waves) occurred at much lower sarcoplasmic reticulum Ca(2+) content as compared to the wild type. Addition of a domain-unzipping peptide, DPc10 (amino acids 2460 to 2495), to the wild type reproduced the aforementioned abnormalities that are characteristic of the R2474S/+ KI mice. Addition of DPc10 to the (cAMP-treated) KI cardiomyocytes produced no further effect.A single point mutation within the RyR2 sensitizes the channel to agonists and reduces the threshold of luminal [Ca(2+)] for activation, primarily mediated by defective interdomain interaction within the RyR2.
Proteus syndrome: diagnosis in adulthood
Authors: None Child, None Werring, None DU Vivier
Journal: British Journal of Dermatology (1998)

We describe a 24-year-old woman with many of the classical features of the Proteus syndrome. In childhood she had undergone bilateral forefoot amputations because of massive bilateral cerebriform hypertrophy of the feet. Other features include abnormally large fingers on one hand, a lymphangioma circumscriptum, an epidermal naevus, prominent venous varicosities and scattered lipomas. The disorder occurs sporadically and is thought to be secondary to a postzygotic mutation that survives by mosaicism.
Estrogen-Induced Activation of Mammalian Target of Rapamycin Is Mediated via Tuberin and the Small GTPase Ras Homologue Enriched in Brain
Authors: Jane Yu, Elizabeth Petri Henske
Journal: Cancer Research (2006)

Abstract Inhibitors of the mammalian target of rapamycin (mTOR) are currently in clinical trials for the treatment of breast cancer. The mechanisms through which mTOR are activated in breast cancer and the relationship of mTOR activation to steroid hormones, such as estrogen, that are known to influence breast cancer pathogenesis, are not yet understood. Using MCF-7 cells as a model, we found that 17-β estradiol (E2) rapidly increased the phosphorylation of downstream targets of mTOR: p70 ribosomal protein S6 kinase, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 1. The phosphoinositide-3-kinase inhibitor, wortmannin, and the mTOR inhibitor, rapamycin, blocked E2-induced activation of p70 ribosomal protein S6 kinase. We hypothesized that tuberin and the small GTPase Ras homologue enriched in brain (Rheb), regulators of the mTOR pathway, mediate E2-induced activation of mTOR. Consistent with this hypothesis, E2 rapidly (within 5 minutes) stimulated tuberin phosphorylation at T1462, a site at which Akt phosphorylates and inactivates tuberin. E2 also rapidly decreased the inactive, GDP-bound form of Rheb. Finally, we found that small interfering RNA down-regulation of endogenous Rheb blocked the E2-stimulated proliferation of MCF-7 cells, demonstrating that Rheb is a key determinant of E2-dependent cell growth. Taken together, these data reveal that the TSC/Rheb/mTOR pathway plays a critical role in the regulation of E2-induced proliferation, and highlight Rheb as a novel molecular target for breast cancer therapy. (Cancer Res 2006; 66(19): 9461-6)
Optimising the treatment of upper gastrointestinal fistulae
Authors: I Gonzalez-Pinto, E M. Gonzalez
Journal: Gut (2001)

A three stage strategy is generally employed in the management of gastrointestinal fistulae which can form due to surgery, disease, or trauma. The condition is investigated leading to diagnosis, conservative treatment is initiated to stabilise the patient, followed by specific surgical treatment measures in complicated cases, or in the absence of spontaneous closure. Conservative management of fistulae is based on parenteral nutrition and bowel rest, as well as on control of infection, electrolytic disturbances, and local care of the fistula tract. Surgical treatment may be required although generally only in particularly serious cases. Somatostatin-14 has been used in addition to parenteral nutrition to further reduce the volume and enzymatic activity of the fluid output through the fistula tract, generally with good results. The majority of reports have shown a beneficial effect, and randomised studies have demonstrated a reduction in closure time and morbidity. However, due to a combination of the seriousness and rarity of the condition and the difficulties inherent in trial design, data from large scale, double blind, randomised, controlled studies investigating the use of pharmacotherapy in the treatment of established gastrointestinal fistulae are lacking. Nevertheless, preliminary data from initial trials suggest that somatostatin-14 and its analogue octreotide considerably improve the conservative treatment of gastrointestinal fistulae in the absence of distal obstruction. In addition, reduction of the concentration of caustic enzymes in the discharge will benefit both wound healing and nutritional losses. With reduced closure time, the period of hospitalisation will be shortened with potentially considerable economic reductions and improvements in quality of life for the patient.
Low gluten diet in the treatment of adult coeliac disease: effect on jejunal morphology and serum anti-gluten antibodies.
Authors: A M Montgomery, A K Goka, P J Kumar, M J Farthing, M L Clark
Journal: Gut (1988)

Treatment of patients with coeliac disease with a low gluten containing diet (LGD) remains controversial. We have studied jejunal morphology and antigluten (AG) antibody titres by ELISA in patients on a LGD of 2.5-5 g/day for three to 14 months (median six months) and compared results with patients on a strict gluten free diet (GFD) for six to 27 months (median 13 months). We found no significant difference in villous height or crypt depth (eight LGD v 10 GFD patients) or serum AG-IgA, -IgG, and IgM titres (13 LGD v 12 GFD patients). there was however, a significant increase (p less than 0.05) in intra-epithelial lymphocytes in those patients on a LGD. We conclude that adult coeliac patients can tolerate a LGD without gross morphological change and without initiating significant AG antibody responses.
Predictors of Postoperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery
Authors: Milton Hollenberg
Journal: JAMA (1992)

<h3>Objective.</h3> —To identify predictors of postoperative myocardial ischemia in patients scheduled to undergo major noncardiac surgery. <h3>Design.</h3> —Historical, clinical, laboratory, and physiological data were obtained prospectively before and during surgery to identify potential univariate predictors of postoperative myocardial ischemia, which then were entered into multivariate logistic models. Continuous two-lead electrocardiograms before, during, and after surgery were used to identify episodes of myocardial ischemia. <h3>Setting.</h3> —Department of Veterans Affairs tertiary care hospital. <h3>Patients.</h3> —A consecutive sample of 474 men at high risk for or with coronary artery disease who were scheduled to undergo major noncardiac surgery (95% compliance rate). <h3>Main Outcome Measure.</h3> —Significant variables identified by multivariate logistic models that are associated with postoperative myocardial ischemia. <h3>Results.</h3> —Five major preoperative predictors of postoperative myocardial ischemia were identified: (1) left ventricular hypertrophy by electrocardiogram; (2) history of hypertension; (3) diabetes mellitus; (4) definite coronary artery disease; and (5) use of digoxin. The risk of postoperative myocardial ischemia increased progressively with the number of predictors present: in 22% of patients with no predictors, in 31% with one predictor, in 46% with two predictors, in 70% with three predictors, and in 77% with four predictors. <h3>Conclusion.</h3> —Patient subgroups who are at high risk for developing postoperative myocardial ischemia and who might benefit the most from intensive Holter monitoring in the postoperative period now can be identified preoperatively. (<i>JAMA</i>. 1992;268:205-209)
Inhibition by CaINH of Hageman Factor Fragment Activation of Coagulation, Fibrinolysis, and Kinin Generation
Authors: Alan D. Schreiber, Allen P. Kaplan, K. Frank Austen
Journal: Journal of Clinical Investigation (1973)

Highly purified inhibitor of the first component of complement (CāINH) was shown to inhibit the capacity of active Hageman factor fragments to initiate kinin generation, fibrinolysis, and coagulation. The inhibition of prealbumin Hageman factor fragments observed was dependent upon the time of interaction of the fragments with CāINH and not to an effect upon kallikrein or plasmin generated. The inhibition of the coagulant activity of the intermediate sized Hageman factor fragment by CāINH was not due to an effect on PTA or other clotting factors. The inhibition by CāINH of both the prealbumin and intermediate sized Hageman factor fragments occurred in a dose response fashion. The CāINH did not appear to be consumed when the activity of the Hageman factor fragments was blocked, although the fragments themselves could no longer be recovered functionally or as a protein on alkaline disc gel electrophoretic analysis. These results suggest that the CāINH may have an enzymatic effect on the fragments or that an additional site on CāINH is involved in Cā inactivation.
Strong BCL10 nuclear expression identifies gastric MALT lymphomas that do not respond to H pylori eradication
Authors: H. Ye, L. Gong, H. Liu, A. Ruskone-Fourmestraux, D. De Jong, S. Pileri, C. Thiede, A. Lavergne, H. Boot, G. Caletti, T. Wündisch, T. Molina, B. G. Taal, S. Elena, A. Neubauer, K. A. MacLennan, R. Siebert, E. D. Remstein, A. Dogan, M. Q. Du
Journal: Gut (2005)

appropriate DNA change has been identified.
Neither necessary nor sufficient for addiction
Authors: Valerie Gray Hardcastle
Journal: Behavioral and Brain Sciences (2008)

Abstract Although Redish et al. have pulled together a large number of approaches to understanding decision-making and common errors in cognition, they have outlined neither the necessary nor the sufficient attributes of addiction. They are correct in claiming that addiction is multifaceted and probably more akin to a syndrome than a genuine disease. But grasping what that multifaceted syndrome is still eludes us.
Amyloid A gene family expression in different mouse tissues.
Authors: R L Meek, E P Benditt
Journal: The Journal of Experimental Medicine (1986)

Serum amyloid A (SAA) is a major acute-phase reactant and apoprotein of high density lipoprotein (HDL). SAA is encoded by a family of three active genes. We examined hepatic expression and searched for extrahepatic expression of the three SAA mRNAs after injection with casein or LPS. Studies using an SAA cDNA, which detects all three SAA mRNAs, revealed that after casein injection liver SAA mRNA was elevated approximately 1,000-fold. Adrenal gland expressed SAA mRNA at a low level (0.5% of hepatic level), and was the only extrahepatic tissue with elevated SAA mRNA after casein injection. The small intestine, primarily the ileum, and the large intestine of unstimulated control animals contained 5- and 15-fold higher SAA mRNA levels than control liver. LPS also elevated liver SAA mRNA approximately 1,000-fold. However, in contrast to casein injection, every extrahepatic tissue examined expressed SAA mRNA. Lung and kidney contained 2-5% and large intestine contained nearly 10% of SAA mRNA levels found in liver RNA. SAA mRNA levels were lower in the remaining tissues and ranged from 0.1% in the brain and pancreas to 1.0% in the small intestine, with the ileum containing 50-fold more than the duodenum. Analysis of liver with SAA1, SAA2, and SAA3 mRNA-specific oligonucleotide probes revealed that SAA1 and SAA2 mRNA were elevated approximately 50-fold higher than SAA3 mRNA after casein administration. LPS, however, induced all three SAA mRNAs equally. In extrahepatic tissues, SAA1, SAA2, and SAA3 mRNAs were expressed differentially and can be grouped into three general classes: tissues expressing all three genes, tissues expressing SAA1 and SAA3, and tissues expressing predominantly or only SAA3.
Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells.
Authors: B M Hall, M E Jelbart, K E Gurley, S E Dorsch
Journal: The Journal of Experimental Medicine (1985)

DA rats grafted with major histocompatibility complex-incompatible PVG heart grafts and treated with cyclosporine (CY) for 10 d do not reject their grafts, and develop a state of specific unresponsiveness toward PVG allografts. Cells from these animals tested in an adoptive transfer assay were incapable of restoring PVG graft rejection, and capable of specifically inhibiting the capacity of adoptively transferred normal lymph node cells (LNC) to do so. They effected third party Wistar/Furth (W/F) graft rejection, however. Adoptive transfer assays with purified subpopulations of the lymphocytes that mediated this effect showed that W3/25+ T cells of the helper/inducer subclass, when injected alone, failed to restore rejection, and were also able, when injected with normal LNC or the W/25+ cells separated from them, to prevent these cells from effecting rejection. MRC OX8+ T cells of the cytotoxic/suppressor subclass, B cells, and serum from rats with long-surviving grafts all failed to inhibit the allograft responsiveness of normal LNC, and thus were not identified as mediators of the state of specific unresponsiveness. These results show that the specific unresponsiveness that develops in rats with long-surviving grafts, and which, in part at least, is responsible for prolonged graft survival, is due to an alteration in the alloreactivity of the helper/inducer subclass of T cells. These cells not only lack the capacity to initiate a rejection response against the alloantigens of the graft, but also have the ability to inhibit the capacity of normal W3/25+ cells to do so.
Epinastine (WAL 801CL) modulates the noncholinergic contraction in guinea-pig airways &lt;I&gt;in vitro&lt;/I&gt; by a prejunctional 5-HT&lt;SUB&gt;1&lt;/SUB&gt;-like receptor
Authors: L.J. Dupont, C.J. Meade, M.G. Demedts, G.M. Verleden
Journal: European Respiratory Journal (1996)

Electrical field stimulation (EFS) of guinea-pig airways, in vitro, evokes an excitatory nonadrenergic noncholinergic (eNANC) contraction mediated by release of tachykinins from sensory nerve endings. Epinastine (WAL 801CL) is an antihistaminic drug with binding affinity at certain other receptors, including alpha-adrenergic receptors and various serotonin (5-HT) receptor subtypes. It is used in asthma treatment; however, its mechanism of action remains to be fully defined. We have investigated whether epinastine could modulate the eNANC contraction in guinea-pig airways in vitro, and have tried to elucidate its receptor mechanism. Epinastine (0.1-100 microM) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 91 +/- 7% at 100 microM. Pretreatment of the tissues with combined 5-HT1/5-HT2 antagonists, methysergide (1 microM) or methiothepin (0.1 microM), significantly attenuated the inhibitory effect of epinastine on the noncholinergic contraction. Pretreatment with tropisetron (1 microM), a 5-HT3 antagonist, ketanserin (10 microM), a 5-HT2 antagonist, thioperamide (10 microM), a histamine H3 antagonist, or phentolamine (10 microM), an alpha-adrenergic antagonist, however, had no effect. Chlorpheniramine (10 microM), another histamine H1 receptor antagonist without significant 5-HT receptor binding affinity, did not produce any inhibition of the eNANC contraction. Epinastine (100 microM) did not displace the dose-response curve to exogenously applied substance P (0.01-10 microM). These results suggest that epinastine, although identified as a 5-HT antagonist, acts as a 5-HT1 agonist and that it inhibits the noncholinergic contraction in guinea-pig airways through stimulation of a prejunctional 5-HT1-like receptor, located to sensory nerves.