tbuckley/cabot-search huggingface dataset:
<i>PLS3</i> Mutations in X-Linked Osteoporosis with Fractures
Authors: Fleur S. van Dijk, M. Carola Zillikens, Dimitra Micha, Markus Riessland, Carlo L.M. Marcelis, Christine E. de Die-Smulders, Janine Milbradt, Anton A. Franken, Arjan J. Harsevoort, Klaske D. Lichtenbelt, Hans E. Pruijs, M. Estela Rubio-Gozalbo, Rolf Zwertbroek, Youssef Moutaouakil, Jaqueline Egthuijsen, Matthias Hammerschmidt, Renate Bijman, Cor M. Semeins, Astrid D. Bakker, Vincent Everts, Jenneke Klein-Nulend, Natalia Campos-Obando, Albert Hofman, Gerard J. te Meerman, Annemieke J.M.H. Verkerk, André G. Uitterlinden, Alessandra Maugeri, Erik A. Sistermans, Quinten Waisfisz, Hanne Meijers-Heijboer, Brunhilde Wirth, Marleen E.H. Simon, Gerard Pals
Journal: New England Journal of Medicine (2013)

Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.
Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells
Authors: Shafiq U. Ahmed, Ross Carruthers, Lesley Gilmour, Salih Yildirim, Colin Watts, Anthony J. Chalmers
Journal: Cancer Research (2015)

Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G2-M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G2-M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC.
Sorafenib Inhibits Cell Migration and Stroma-Mediated Bortezomib Resistance by Interfering B-cell Receptor Signaling and Protein Translation in Mantle Cell Lymphoma
Authors: Sílvia Xargay-Torrent, Mónica López-Guerra, Arnau Montraveta, Ifigènia Saborit-Villarroya, Laia Rosich, Alba Navarro, Patricia Pérez-Galán, Gaël Roué, Elias Campo, Dolors Colomer
Journal: Clinical Cancer Research (2012)

We evaluated the antitumoral properties of the multikinase inhibitor sorafenib in mantle cell lymphoma (MCL), an aggressive B lymphoma for which current therapies have shown limited efficacy.Sensitivity to sorafenib was analyzed in MCL cell lines and primary samples in the context of BCR and microenvironment simulation. Sorafenib signaling was characterized by quantitative PCR, Western blotting, immunofluorescence, and protein immunoprecipitation. Migration analysis included flow cytometric counting, actin polymerization assays, and siRNA-mediated knockdown of focal adhesion kinase (FAK). In vivo antitumor effect of sorafenib and bortezomib was analyzed in an MCL xenograft mouse model.Sorafenib rapidly dephosphorylates the BCR-associated kinases, Syk and Lyn, as well as FAK, an Src target involved in focal adhesion. In this line, sorafenib displays strong synergy with the Syk inhibitor, R406. Sorafenib also blocks Mcl-1 and cyclin D1 translation, which promotes an imbalance between pro- and antiapoptotic proteins and facilitates Bax release from cyclin D1, leading to the induction of mitochondrial apoptosis and caspase-dependent and -independent mechanisms. Moreover, sorafenib inhibits MCL cell migration and CXCL12-induced actin polymerization. FAK knockdown partially prevents this inhibitory effect, indicating that FAK is a relevant target of sorafenib. Furthermore, sorafenib enhances the antitumoral activity of bortezomib in an MCL xenograft mouse model as well as overcomes stroma-mediated bortezomib resistance in MCL cells.We show for the first time that sorafenib interferes with BCR signaling, protein translation and modulates the microenvironment prosurvival signals in MCL, suggesting that sorafenib, alone or in combination with bortezomib, may represent a promising approach to treat patients with MCL.
Clinical trials update from the American Heart Association 2007: CORONA, RethinQ, MASCOT, AF‐CHF, HART, MASTER, POISE and stem cell therapy
Authors: John G.F. Cleland, Alison P. Coletta, Ahmed Tageldien Abdellah, Damien Cullington, Andrew L. Clark, Alan S. Rigby
Journal: European Journal of Heart Failure (2008)
VENEREAL DISEASE PROPHYLAXIS
Authors: W. de Broke, B. Donkin, Wm. A. Lane, J. Crichton-Browne, E. Askwith, J. L. Hawthorne, R. A. Lyster, F. Mott, E. Pritchard, G. A. Reid, C. W. Saleeby, J. H. Sequeira, H. W. Bayly
Journal: BMJ (1920)
Increased Risk of Systemic Relapses Associated With Bone Marrow Micrometastasis and Circulating Tumor Cells in Localized Ewing Tumor
Authors: Gudrun Schleiermacher, Martine Peter, Odile Oberlin, Thierry Philip, Hervé Rubie, Françoise Mechinaud, Danièle Sommelet-Olive, Judith Landman-Parker, Danièle Bours, Jean Michon, Olivier Delattre
Journal: Journal of Clinical Oncology (2002)

The presence of metastasis is a major prognostic factor in Ewing tumor (ET). The relapse pattern of patients with localized tumors has long indicated that cases with disseminated ET cells escape detection at diagnosis. ET cells are characterized by specific gene fusions that can be detected with high sensitivity and specificity by reverse transcriptase polymerase chain reaction (RT-PCR).RT-PCR targeting EWS-FLI-1 or EWS-ERG transcripts was used to search for occult tumor cells in peripheral blood (PB) and bone marrow (BM) at diagnosis in 172 patients with ET, and the prognostic significance of this parameter was assessed.As we suggested previously in a smaller series of patients, RT-PCR positivity of the BM was correlated with a high risk of adverse outcome in the overall study population (P =.007). More interestingly, among patients with otherwise localized tumors, BM micrometastasis also predicted significantly poorer disease-free survival rates (P =.043). The presence of circulating tumor cells (CTC) was more frequently observed in patients with large tumors (P =.006). CTC were associated with a poor outcome among patients with clinically localized disease (P =.045). Patients with clinically localized disease and peripheral occult tumor cells as evidenced by BM and/or PB RT-PCR positivity had axial or proximal tumors and experienced relapses at a systemic rather than at a local level.Patients with localized ET and BM micrometastasis or CTC are comparable to patients with metastases in terms of the localization of the primary tumor, outcome, and relapse pattern.
Medical Costs of CKD in the Medicare Population
Authors: Amanda A. Honeycutt, Joel E. Segel, Xiaohui Zhuo, Thomas J. Hoerger, Kumiko Imai, Desmond Williams
Journal: Journal of the American Society of Nephrology (2013)

Estimates of the medical costs associated with different stages of CKD are needed to assess the economic benefits of interventions that slow the progression of kidney disease. We combined laboratory data from the National Health and Nutrition Examination Survey with expenditure data from Medicare claims to estimate the Medicare program's annual costs that were attributable to CKD stage 1-4. The Medicare costs for persons who have stage 1 kidney disease were not significantly different from zero. Per person annual Medicare expenses attributable to CKD were $1700 for stage 2, $3500 for stage 3, and $12,700 for stage 4, adjusted to 2010 dollars. Our findings suggest that the medical costs attributable to CKD are substantial among Medicare beneficiaries, even during the early stages; moreover, costs increase as disease severity worsens. These cost estimates may facilitate the assessment of the net economic benefits of interventions that prevent or slow the progression of CKD.
The Duration of Zidovudine Benefit in Persons With Asymptomatic HIV Infection
Authors: P A Volberding, S W Lagakos, J M Grimes, D S Stein, H H Balfour, R C Reichman, J A Bartlett, M S Hirsch, J P Phair, R T Mitsuyasu
Journal: JAMA (1994)

<h3>Objective.</h3> —To determine the durability of zidovudine-induced delay in clinical progression of asymptomatic human immunodeficiency virus (HIV) disease and to assess the relationship between this effect and the entry CD4<sup>+</sup>cell count. <h3>Design and Interventions.</h3> —Extended follow-up data from subjects participating in protocol 019 of the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group were examined. Subjects were offered a total daily dose of 500 mg of open-label zidovudine after the unblinding of the original randomized trial in 1989. Original treatment groups included placebo, 500 mg of zidovudine, or 1500 mg of zidovudine daily in divided doses. Three distinct analyses were conducted to assess the duration of zidovudine's effect on progression to AIDS or death: (1) analysis of all follow-up information from all subjects, (2) analysis of all subjects but with follow-up of original placebo-assigned subjects censored at the time open-label zidovudine was initiated, and (3) analysis of the effect of initiating zidovudine in subjects initially assigned to receive placebo. <h3>Setting.</h3> —University-based and university-affiliated AIDS research clinics participating in AIDS Clinical Trials Group protocol 019. <h3>Patients.</h3> —A total of 1565 asymptomatic HIV-infected subjects with entry CD4<sup>+</sup>cell counts less than 0.50×10<sup>9</sup>/L (500/μL). <h3>Main Outcome Measure.</h3> —Time to progression to AIDS or death. <h3>Results.</h3> —During follow-up of up to 4.5 years (mean, 2.6 years), 232 subjects progressed to AIDS or died. In each of the three analyses described herein, zidovudine was associated with a significant (<i>P</i>=.008,.004,.007) decrease in the risk of such progression. However, each of these analyses also indicated a decreasing placebo:zidovudine relative risk with duration of use (<i>P</i>=.002,.08,.04), suggesting a nonpermanent effect. The duration of benefit appeared to be related to entry CD4<sup>+</sup>cell count, with greater benefit in those with higher counts at entry. No significant differences in survival were found between those originally randomized to zidovudine or placebo. <h3>Conclusions.</h3> —Zidovudine at 500 mg/d caused a significant delay in progression to AIDS or death, but its earlier use in asymptomatic disease was not associated with an additional prolongation of survival compared with delayed initiation. The delay in progression diminished over time especially in subjects with entry CD4<sup>+</sup>cell counts less than 0.30×10<sup>9</sup>/L (300/μL). Treatment strategies that alter drug regimens before the loss of zidovudine benefit should be explored. (<i>JAMA</i>. 1994;272:437-442)
Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis
Authors: Daniel H Solomon, Thorvardur Jon Love, Claire Canning, Sebastian Schneeweiss
Journal: Annals of the Rheumatic Diseases (2010)

To examine the risk of diabetes mellitus (DM) among subjects with rheumatoid arthritis (RA), psoriatic arthritis or psoriasis (PsA/PsO), compared with non-rheumatic controls.Study cohorts were assembled using linked healthcare utilisation data from British Columbia. All people with at least two diagnoses of RA or PsA/PsO were included and compared with a cohort of people without any known rheumatic disease. The outcome of interest was a diagnosis of new-onset DM, as defined by initiation of an antidiabetic drug. Incidence rates (IRs) per 1000 person-years and IR ratios were calculated and Cox regression models were constructed to determine the hazard ratio (HR) for diabetes by age, gender, systemic immunosuppressive drug and glucocorticoid use.The study cohort comprised 48 718 subjects with RA, 40 346 with PsA/PsO and 442 033 without any rheumatic disease. The IR for DM among subjects with RA was 8.6 per 1000 person-years (95% CI 8.5 to 8.7), PsA/PsO 8.2 (95% CI 8.1 to 8.3) and for non-rheumatic controls 5.8 (95% CI 5.8 to 5.8). The adjusted HR for RA compared with non-rheumatic controls was 1.5 (95% CI 1.4 to 1.5) and 1.4 (95% CI 1.3 to 1.5) for PsA/PsO.RA and PsA/PsO appear to be associated with an increased risk of DM. The ability of potent antirheumatic treatments to reverse this trend warrants study.
Use of Multiple Metabolic and Genetic Markers to Improve the Prediction of Type 2 Diabetes: the EPIC-Potsdam Study
Authors: Matthias B. Schulze, Cornelia Weikert, Tobias Pischon, Manuela M. Bergmann, Hadi Al-Hasani, Erwin Schleicher, Andreas Fritsche, Hans-Ulrich Häring, Heiner Boeing, Hans-Georg Joost
Journal: Diabetes Care (2009)

OBJECTIVE We investigated whether metabolic biomarkers and single nucleotide polymorphisms (SNPs) improve diabetes prediction beyond age, anthropometry, and lifestyle risk factors. RESEARCH DESIGN AND METHODS A case-cohort study within a prospective study was designed. We randomly selected a subcohort (n = 2,500) from 26,444 participants, of whom 1,962 were diabetes free at baseline. Of the 801 incident type 2 diabetes cases identified in the cohort during 7 years of follow-up, 579 remained for analyses after exclusions. Prediction models were compared by receiver operatoring characteristic (ROC) curve and integrated discrimination improvement. RESULTS Case-control discrimination by the lifestyle characteristics (ROC-AUC: 0.8465) improved with plasma glucose (ROC-AUC: 0.8672, P &amp;lt; 0.001) and A1C (ROC-AUC: 0.8859, P &amp;lt; 0.001). ROC-AUC further improved with HDL cholesterol, triglycerides, γ-glutamyltransferase, and alanine aminotransferase (0.9000, P = 0.002). Twenty SNPs did not improve discrimination beyond these characteristics (P = 0.69). CONCLUSIONS Metabolic markers, but not genotyping for 20 diabetogenic SNPs, improve discrimination of incident type 2 diabetes beyond lifestyle risk factors.
Common Cholesteryl Ester Transfer Protein Mutations, Decreased HDL Cholesterol, and Possible Decreased Risk of Ischemic Heart Disease
Authors: Birgit Agerholm-Larsen, Anne Tybjærg-Hansen, Peter Schnohr, Rolf Steffensen, Børge G. Nordestgaard
Journal: Circulation (2000)

Background —Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from HDL in exchange for triglycerides in apolipoprotein B–containing lipoproteins. Methods and Results —We studied 2 common mutations in CETP , A373P and R451Q, in 8467 healthy women and men from the Danish general population and in 1636 Danish women and men with ischemic heart disease. The prevalence of 373P and 451Q was 0.10 and 0.07, respectively, for heterozygous carriers and 0.003 and 0.002, respectively, for homozygous carriers. All carriers of the 451Q allele also carried the 373P allele. HDL cholesterol in female noncarriers, heterozygotes, and homozygotes of 373P was 1.74±0.01 (mean±SE), 1.62±0.02, and 1.38±0.09 mmol/L, respectively (ANOVA, P &lt;0.001). In men, equivalent values were 1.40±0.01, 1.26±0.02, and 1.19±0.09 mmol/L, respectively (ANOVA, P &lt;0.001). HDL cholesterol decreased similarly as a function of 451Q genotypes and all 373P/451Q genotype combinations. Furthermore, apolipoprotein AI and the HDL cholesterol/apolipoprotein AI ratio was also lower in carriers of either of these mutations for both sexes. Finally, the CETP genotype was not associated with risk of ischemic heart disease unless we adjusted for HDL cholesterol: female heterozygous and homozygous carriers versus noncarriers had 36% lower risk of ischemic heart disease (95% CI 4% to 57%); in male carriers, we observed a similar trend. Conclusions —The A373P/R451Q polymorphism in CETP is associated with decreases in HDL cholesterol of 0.12 to 0.36 mmol/L in women and 0.14 to 0.21 mmol/L in men and possibly with a paradoxical 36% decrease in the risk of ischemic heart disease in women.
Intracranial Carotid Artery Atherosclerosis and the Risk of Stroke in Whites
Authors: Daniel Bos, Marileen L. P. Portegies, Aad van der Lugt, Michiel J. Bos, Peter J. Koudstaal, Albert Hofman, Gabriel P. Krestin, Oscar H. Franco, Meike W. Vernooij, M. Arfan Ikram
Journal: JAMA Neurology (2014)

Intracranial atherosclerosis represents a relatively unexplored, but potentially important, cause of stroke in a white population.To investigate the relationship between intracranial carotid artery calcification (ICAC) as a marker of intracranial atherosclerosis and the risk of stroke in whites.A population-based cohort study in the general community with 6 years of follow-up was conducted (the Rotterdam Study). Between 2003 and 2006, a random sample of 2323 stroke-free persons (mean age, 69.5 years) underwent computed tomography scanning to quantify ICAC volume. All participants were continuously monitored for the occurrence of stroke until January 1, 2012.Atherosclerotic calcification in the intracranial internal carotid arteries.Incident stroke.During 14,055 person-years of follow-up, 91 participants had a stroke, of which 74 were ischemic. Larger ICAC volume was related to a higher risk of stroke, independent of cardiovascular risk factors, ultrasound carotid plaque score, and calcification in other vessels (fully adjusted hazard ratio per an increase of 1 SD in ICAC volume, 1.43 [95% CI, 1.04-1.96]). Intracranial carotid artery calcification contributed to 75% of all strokes; for aortic arch and extracranial carotid artery calcification this incidence was only 45% and 25%, respectively.Our findings establish intracranial atherosclerosis as a major risk factor for stroke in the general white population and suggest that its contribution to the proportion of all strokes may be greater than that of large-artery atherosclerosis in more proximally located vessel beds.
C-Reactive Protein in Diabetic and Nondiabetic Patients With Acute Myocardial Infarction
Authors: Wolfgang Otter, Michael Winter, Wittich Doering, Eberhard Standl, Oliver Schnell
Journal: Diabetes Care (2007)

Atherosclerosis has been reported to be associated with chronic low-grade inflammation of the vasculary structure and the endothelial cells (1–4). C-reactive-protein (CRP) is a marker for inflammation and is enhanced in both atherosclerosis and coronary artery disease (5–7). CRP plasma levels above the cutoff of 3 mg/l, as assessed with high-sensitivity immunoassays, have been shown to indicate an increase in cardiovascular risk (8). Diabetes is an independent risk factor of atherosclerosis (9,10). It is considered a state of low-grade inflammation (11–13). CRP levels have been reported to be augmented in diabetic patients (11–13). The Munich Myocardial Infarction Registry analyzes the outcome of hospital mortality in both diabetic and nondiabetic subjects (13,14). The present study aimed at determining the role of CRP in patients with myocardial infarction and comparing the results between diabetic and nondiabetic patients.

All patients of the Munich Myocardial Infarction Registry (2001–2004, n = 1,237) were included in the analysis. Myocardial infarction was defined and treated according to the recommendations of the European Society of Cardiology and the American College of Cardiology (15,16–18).

The presence of diabetes was defined if the patient had been informed of this diagnosis or was on prescribed antidiabetes treatment. Patients without diagnosis but with blood glucose ≥200 mg/dl (3) were also classified as having diabetes (14). CRP was measured on admission and analyzed by a highly sensitive CRP-Assay, (Roche Diagnostics, Basel, Switzerland).

### Statistics

Group comparisons were performed by Mann-Whitney U …
Evidence for involvement of dual-function T cells in rejection of MHC class I disparate skin grafts. Assessment of MHC class I alloantigens as in vivo helper determinants.
Authors: A S Rosenberg, T Mizuochi, A Singer
Journal: The Journal of Experimental Medicine (1988)

The present study further characterizes the cellular mechanisms involved in the in vivo rejection of MHC class I-disparate skin allografts. Previously, we demonstrated that class I-specific rejection responses could result from collaborations between distinct populations of lymphokine-secreting T helper (Th) and lymphokine-responsive T effector (Teff) cells. In the present study, we have assessed the possibility that class I-specific rejection responses could also result from a second cellular mechanism involving a single population of dual-function Th/Teff cells that would not have any further requirement for cell-cell collaboration. Our experimental strategy was to determine the ability of MHC class I-allospecific T cells, in response to class I allodeterminants expressed on skin grafts, to provide help in vivo for activation of helper-dependent Teff cells. We found that class I anti-Kbm1-allospecific T cells would reject bm1 skin allografts, but would not generate help for the activation of helper-dependent effector cells that were specific for third-party skin allografts (e.g., grafts expressing Kbm6, Qa1a, or H-Y allodeterminants). This failure of anti-Kbm1 T cells to provide help in response to bm1 skin allografts was not due to an inability of lymphokine-secreting anti-Kbm1 Th cells to recognize and respond in vivo to Kbm1 allodeterminants expressed on skin, since lymphokine-secreting anti-Kbm1 Th cells were specifically primed in animals engrafted with bm1 skin allografts. Nor was any evidence found that this failure was due to active suppression of anti-Kbm1 helper activity. Rather, we found that anti-Kbm1 T cells consumed nearly all of the helper factors they secreted. Taken together, these results are most consistent with the in vivo activity of dual-function Th/Teff cells that consume the lymphokines they secrete. Thus, this study demonstrates that MHC class I-disparate skin allografts can be rejected by two mechanisms, depending on the ability of the allospecific Teff cell to secrete helper lymphokines. MHC class I-disparate grafts can be rejected by (a) class I-allospecific Teff cells that are unable to produce lymphokine but are responsive to exogenous T cell help; and (b) class I-allospecific dual-function Th/Teff cells that are able to both produce and consume soluble lymphokine.