tbuckley/cabot-search huggingface dataset:
Sequence Variant Discovery in DNA Repair Genes from Radiosensitive and Radiotolerant Prostate Brachytherapy Patients
Authors: Trevor J. Pugh, Mira Keyes, Lorena Barclay, Allen Delaney, Martin Krzywinski, Dallas Thomas, Karen Novik, Cindy Yang, Alexander Agranovich, Michael McKenzie, W. Jim Morris, Peggy L. Olive, Marco A. Marra, Richard A. Moore
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The presence of intrinsic radiosensitivity within prostate cancer patients may be an important factor contributing to development of radiation toxicity. We investigated whether variants in genes responsible for detecting and repairing DNA damage independently contribute to toxicity following prostate brachytherapy. Experimental Design: Genomic DNA was extracted from blood samples of 41 prostate brachytherapy patients, 21 with high and 20 with low late toxicity scores. For each patient, 242 PCR amplicons were generated containing 173 exons of eight candidate genes: ATM, BRCA1, ERCC2, H2AFX, LIG4, MDC1, MRE11A, and RAD50. These amplicons were sequenced and all sequence variants were subjected to statistical analysis to identify those associated with late radiation toxicity. Results: Across 41 patients, 239 sites differed from the human genome reference sequence; 170 of these corresponded to known polymorphisms. Sixty variants, 14 of them novel, affected protein coding regions and 43 of these were missense mutations. In our patient population, the high toxicity group was enriched for individuals with at least one LIG4 coding variant (P = 0.028). One synonymous variant in MDC1, rs28986317, was associated with increased radiosensitivity (P = 0.048). A missense variant in ATM, rs1800057, associated with increased prostate cancer risk, was found exclusively in two high toxicity patients but did not reach statistical significance for association with radiosensitivity (P = 0.488). Conclusions: Our data revealed new germ-line sequence variants, indicating that existing sequence databases do not fully represent the full extent of sequence variation. Variants in three DNA repair genes were linked to increased radiosensitivity but require validation in larger populations.
New hope for functional dyspepsia?
Authors: Peter Bytzer
Journal: Gut (2012)

> “Hope is a good breakfast but a bad supper” 
> 
> Francis Bacon (1561–1626)

Functional dyspepsia (FD) has been defined as persistent or recurrent symptoms of unknown cause thought to originate in the proximal gastrointestinal tract. Symptom patterns may vary but usually include epigastric pain or burning. Non-painful dyspeptic symptoms such as early satiation, nausea, postprandial fullness and vomiting suggest an underlying abnormality in gastroduodenal motility. The Rome III consensus committee suggests that FD is subdivided into an epigastric pain syndrome and a postprandial distress syndrome based on symptom patterns.1 These terms have replaced the previous categories of ‘ulcer-like’ and ‘dysmotility-like’ dyspepsia. Dyspeptic symptoms are very common in the general population with prevalence rates of 20–40%, and although FD is not associated with increased mortality or morbidity the symptoms have a major impact on health-related quality of life, utilisation of healthcare resources and work productivity.2

FD is probably a multifactorial disorder. Acid, Helicobacter pylori infection, visceral hypersensitivity, disturbances in gastric motility or accommodation and various psychosocial factors have all been implicated. Empiric antisecretory therapy, H pylori eradication or prokinetics remain the mainstay of treatment for FD, even though meta-analyses have shown limited or no symptomatic effects,3 4 and to date, …
Changes in the Incidence of Lower Extremity Amputations in Individuals With and Without Diabetes in England Between 2004 and 2008
Authors: Eszter P. Vamos, Alex Bottle, Michael E. Edmonds, Jonathan Valabhji, Azeem Majeed, Christopher Millett
Journal: Diabetes Care (2010)

OBJECTIVE To describe recent trends in the incidence of nontraumatic amputations among individuals with and without diabetes and estimate the relative risk of amputations among individuals with diabetes in England. RESEARCH DESIGN AND METHODS We identified all patients aged &amp;gt;16 years who underwent any nontraumatic amputation in England between 2004 and 2008 using national hospital activity data from all National Health Service hospitals. Age- and sex-specific incidence rates were calculated using the total diabetes population in England every year. To test for time trend, we fitted Poisson regression models. RESULTS The absolute number of diabetes-related amputations increased by 14.7%, and the incidence decreased by 9.1%, from 27.5 to 25.0 per 10,000 people with diabetes, during the study period (P &amp;gt; 0.2 for both). The incidence of minor and major amputations did not significantly change (15.7–14.9 and 11.8–10.2 per 10,000 people with diabetes; P = 0.66 and P = 0.29, respectively). Poisson regression analysis showed no statistically significant change in diabetes-related amputation incidence over time (0.98 decrease per year [95% CI 0.93–1.02]; P = 0.12). Nondiabetes-related amputation incidence decreased from 13.6 to 11.9 per 100,000 people without diabetes (0.97 decrease by year [0.93–1.00]; P = 0.059). The relative risk of an individual with diabetes undergoing a lower extremity amputation was 20.3 in 2004 and 21.2 in 2008, compared with that of individuals without diabetes. CONCLUSIONS This national study suggests that the overall population burden of amputations increased in people with diabetes at a time when the number and incidence of amputations decreased in the aging nondiabetic population.
Resting Memory CD8+ T Cells are Hyperreactive to Antigenic Challenge In Vitro
Authors: Maria Pihlgren, Patrice M. Dubois, Martine Tomkowiak, Tove Sjögren, Jacqueline Marvel
Journal: The Journal of Experimental Medicine (1996)

The characteristics of CD8+ T cells responsible for memory responses are still largely unknown. Particularly, it has not been determined whether different activation thresholds distinguish naive from memory CD8+ T cell populations. In most experimental systems, heterogeneous populations of primed CD8+ T cells can be identified in vivo after immunization. These cells differ in terms of cell cycle status, surface phenotype, and/or effector function. This heterogeneity has made it difficult to assess the activation threshold and the relative role of these subpopulations in memory responses. In this study we have used F5 T cell receptor transgenic mice to generate a homogeneous population of primed CD8+ T cells. In the F5 transgenic mice, peptide injection in vivo leads to activation of most peripheral CD8+ T cells. In vivo BrdU labeling has been used to follow primed T cells over time periods spanning several weeks after peptide immunization. Our results show that the majority of primed CD8+ T cells generated in this system are not cycling and express increased levels of CD44 and Ly6C. These cells remain responsive to secondary peptide challenge in vivo as evidenced by short term upregulation of activation markers such as CD69 and CD44. The activation thresholds of naive and primed CD8+ T cells were compared in vitro. We found that CD8+ T cells from primed mice are activated by peptide concentrations 10-50-fold lower than naive mice. In addition, the kinetics of interleukin 2R alpha chain upregulation by primed CD8+ T cells differ from naive CD8+ T cells. These primed hyperresponsive CD8+ T cells might play an important role in the memory response.
Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting.
Authors: E K Rowinsky, V Chaudhry, A A Forastiere, S E Sartorius, D S Ettinger, L B Grochow, B G Lubejko, D R Cornblath, R C Donehower
Journal: Journal of Clinical Oncology (1993)

PURPOSE To determine the maximum-tolerated doses (MTD), the principal toxicities, and the pharmacologic behavior of high doses of Taxol (paclitaxel; Bristol-Myers Squibb, New York, NY) combined with cisplatin and granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS Untreated and minimally pretreated solid-tumor patients received 24-hour infusions of Taxol on day 1 followed by cisplatin on day 2 and G-CSF, 5 micrograms/kg/d subcutaneously (SC), beginning on day 3. Treatment was repeated every 3 weeks. Starting doses of Taxol and cisplatin were 135 and 75 mg/m2, respectively. RESULTS The development of a severe peripheral neuropathy and/or severe myalgias precluded the chronic administration of Taxol and cisplatin with G-CSF at doses greater than 250 mg/m2 and 75 mg/m2, respectively. At this dose, the mean Taxol steady-state plasma concentration (Css) exceeds concentrations capable of inducing pertinent antimicrotubule effects in vitro. The severity of the neuropathy was related to the cumulative dose of Taxol, the magnitude of the dose administered during each treatment, and the presence of a pre-existing medical disorder associated with peripheral neuropathy. A proximal myopathy of modest severity also was documented. Although severe neutropenia occurred frequently, especially at the MTD, it was rarely associated with fever (8% of courses), and absolute neutrophil counts (ANCs) less than 500/microL never persisted for more than 5 days. Responses were noted in non-small-cell lung cancer (NSCLC) and head and neck, breast, and esophageal cancers. CONCLUSION Taxol and cisplatin doses of 250 mg/m2 and 75 mg/m2, respectively, can be administered repetitively with G-CSF to untreated and minimally pretreated patients. However, these doses are not recommended for patients with pre-existing neuropathies until additional experience in high-risk patients is obtained. Although this Taxol dose is nearly 85% higher than the dose that can be combined with cisplatin in the absence of G-CSF, this high-dose regimen should not be used outside the investigational setting until a dose-response relationship has been demonstrated for Taxol in randomized clinical trials.
Distribution of a Persistent Sodium Current Across the Ventricular Wall in Guinea Pigs
Authors: Bernhard F. A. S. Sakmann, Anthony J. Spindler, Simon M. Bryant, Klaus W. Linz, Denis Noble
Journal: Circulation Research (2000)

Abstract —A tetrodotoxin-sensitive persistent sodium current, I pNa , was found in guinea pig ventricular myocytes by whole-cell patch clamping. This current was characterized in cells derived from the basal left ventricular subendocardium, midmyocardium, and subepicardium. Midmyocardial cells show a statistically significant ( P &lt;0.05) smaller I pNa than subendocardial and subepicardial myocytes. There was no significant difference in I pNa current density between subepicardial and subendocardial cells. Computer modeling studies support a role of this current in the dispersion of action potential duration across the ventricular wall.
Combination and Monotherapy with Zidovudine and Zalcitabine in Patients with Advanced HIV Disease
Authors: Margaret A. Fischl, Kenneth Stanley, Ann C. Collier, Jean Marie Arduino, Daniel S. Stein, Judith E. Feinberg, J. Davis Allan, Jonathan C. Goldsmith, William G. Powderly
Journal: Annals of Internal Medicine (1995)

Objective: To compare the safety and efficacy of continuing zidovudine therapy with that of zalcitabine alone or zalcitabine and zidovudine used together. Design: A randomized, double-blind, controlled trial. Setting: AIDS Clinical Trials units and National Hemophilia Foundation sites. Patients: 1001 patients with symptomatic human immunodeficiency (HIV) disease and 300 or fewer CD4 cells/mm3 or asymptomatic HIV disease and 200 or fewer CD4 cells/mm3 who had tolerated zidovudine therapy for 6 months or more. Intervention: Patients were randomly assigned to receive zidovudine, 600 mg/d; zalcitabine, 2.25 mg/d; or zidovudine, 600 mg/d, and zalcitabine, 2.25 mg/d. Measurements: The primary end point was time to disease progression or death. Results: The median follow-up time was 17.7 months. The estimated 12-month event-free rates were 70%, 67%, and 73%, respectively, for the zidovudine, zalcitabine, and combination groups (P =0.26). A trend analysis showed significantly lower progression rates for combination therapy compared with zidovudine therapy as the pretreatment CD4 cell count increased (P = 0.027). For patients with 150 or more CD4 cells/mm3, those receiving combination therapy were less likely to have disease progression or to die than were those receiving zidovudine (relative risk, 0.51; 95% CI, 0.28 to 0.93; P = 0.029). We observed no difference between the zalcitabine and zidovudine groups (relative risk, 0.74; CI, 0.40 to 1.36; P = 0.33). For patients with 50 to 150 CD4 cells/mm3 or fewer than 50 CD4 cells/mm3, we found no differences among the treatment groups (P = 0.69 and P = 0.57, respectively). Severe toxic effects occurred less frequently among patients with 150 or more CD4 cells/mm3. Conclusions: We found no overall benefits of zalcitabine used alone or with zidovudine. However, a trend analysis suggested a better outcome for combination therapy compared with zidovudine as the pretreatment CD4 cell count increased. *Other members of the AIDS Clinical Trials Group who participated in this study are listed in the Appendix.
Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide
Authors: Carsten J. Kirschning, Holger Wesche, T. Merrill Ayres, Mike Rothe
Journal: The Journal of Experimental Medicine (1998)

Bacterial lipopolysaccharide (LPS) induces activation of the transcription factor nuclear factor κB (NF-κB) in host cells upon infection. LPS binds to the glycosylphosphatidylinositol (GPI)- anchored membrane protein CD14, which lacks an intracellular signaling domain. Here we investigated the role of mammalian Toll-like receptors (TLRs) as signal transducers for LPS. Overexpression of TLR2, but not TLR1, TLR4, or CD14 conferred LPS inducibility of NF-κB activation in mammalian 293 cells. Mutational analysis demonstrated that this LPS response requires the intracellular domain of TLR2. LPS signaling through TLR2 was dependent on serum which contains soluble CD14 (sCD14). Coexpression of CD14 synergistically enhanced LPS signal transmission through TLR2. In addition, purified recombinant sCD14 could substitute for serum to support LPS-induced TLR2 activation. LPS stimulation of TLR2 initiated an interleukin 1 receptor–like NF-κB signaling cascade. These findings suggest that TLR2 may be a signaling component of a cellular receptor for LPS.
Leptin–STAT3–G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression
Authors: Chao-Ching Chang, Meng-Ju Wu, Jer-Yen Yang, Ignacio G. Camarillo, Chun-Ju Chang
Journal: Cancer Research (2015)

Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBR(hi)). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBR(hi) population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy.
Role of MUTYH and MSH2 in the Control of Oxidative DNA Damage, Genetic Instability, and Tumorigenesis
Authors: Maria Teresa Russo, Gabriele De Luca, Ida Casorelli, Paolo Degan, Sara Molatore, Flavia Barone, Filomena Mazzei, Tania Pannellini, Piero Musiani, Margherita Bignami
Journal: Cancer Research (2009)

Abstract Mismatch repair is the major pathway controlling genetic stability by removing mispairs caused by faulty replication and/or mismatches containing oxidized bases. Thus, inactivation of the Msh2 mismatch repair gene is associated with a mutator phenotype and increased cancer susceptibility. The base excision repair gene Mutyh is also involved in the maintenance of genomic integrity by repairing premutagenic lesions induced by oxidative DNA damage. Because evidence in bacteria suggested that Msh2 and Mutyh repair factors might have some overlapping functions, we investigated the biological consequences of their single and double inactivation in vitro and in vivo. Msh2−/− mouse embryo fibroblasts (MEF) showed a strong mutator phenotype at the hprt gene, whereas Mutyh inactivation was associated with a milder phenotype (2.9 × 10−6 and 3.3 × 10−7 mutation/cell/generation, respectively). The value of 2.7 × 10−6 mutation/cell/generation in Msh2−/−Mutyh−/− MEFs did not differ significantly from Msh2−/− cells. When steady-state levels of DNA 8-oxo-7,8-dihydroguanine (8-oxoG) were measured in MEFs of different genotypes, single gene inactivation resulted in increases similar to those observed in doubly defective cells. In contrast, a synergistic accumulation of 8-oxoG was observed in several organs of Msh2−/−Mutyh−/− animals, suggesting that in vivo Msh2 and Mutyh provide separate repair functions and contribute independently to the control of oxidative DNA damage. Finally, a strong delay in lymphomagenesis was observed in Msh2−/−Mutyh−/− when compared with Msh2−/− animals. The immunophenotype of these tumors indicate that both genotypes develop B-cell lymphoblastic lymphomas displaying microsatellite instability. This suggests that a large fraction of the cancer-prone phenotype of Msh2−/− mice depends on Mutyh activity. [Cancer Res 2009;69(10):4372–9]
Titration of intrahepatic (−) HCV RNA by strand-specific RT-PCR in chronic hepatitis C: morphological and clinical correlations
Authors: F. Negro, K. Krawczynski, R. Quadri, M. Mondelli, L. Rubbia-Brandt, M. Baud, J.-P. Zarski, A. Hadengue
Journal: Journal of Hepatology (1998)
Counselling increases physical activity behaviour nine weeks after rehabilitation
Authors: H P van der Ploeg, K R M Streppel, A J van der Beek, L H V van der Woude, M M R Vollenbroek-Hutten, W H van Harten, W van Mechelen
Journal: British Journal of Sports Medicine (2006)

Background: For people with disabilities, a physically active lifestyle can reduce the risk of secondary health problems and improve overall functioning. Objectives: To determine the effects of the sport stimulation programme “rehabilitation and sports” (R&amp;S) and R&amp;S combined with the daily physical activity promotion programme “active after rehabilitation” (AaR) on sport participation and daily physical activity behaviour nine weeks after inpatient or outpatient rehabilitation. Methods: Subjects in four intervention rehabilitation centres were randomised to a group receiving R&amp;S only (n = 315) or a group receiving R&amp;S and AaR (n = 284). Subjects in six control rehabilitation centres (n = 603) received the usual care. Most common diagnoses were stroke, neurological disorders, and back disorders. Two sport and two daily physical activity outcomes were assessed with questionnaires seven weeks before and nine weeks after the end of rehabilitation. Data were analysed by intention to treat and on treatment multilevel analyses, comparing both intervention groups with the control group. Results: The R&amp;S group showed no significant change. Intention to treat analyses of the R&amp;S+AaR group showed significant improvements in one sport (p = 0.02) and one physical activity outcome (p = 0.03). On treatment analyses in the R&amp;S+AaR group showed significant improvements in both sport outcomes (p&lt;0.01 and p = 0.02) and one physical activity outcome (p&lt;0.01). Conclusions: Only the combination of R&amp;S and AaR had increased sports participation and daily physical activity behaviour nine weeks after the end of inpatient or outpatient rehabilitation.
Physiological and anthropometric determinants of sport climbing performance
Authors: Christine M Mermier, Jeffrey M Janot, Daryl L Parker, Jacob G Swan
Journal: British Journal of Sports Medicine (2000)

To identify the physiological and anthropometric determinants of sport climbing performance.Forty four climbers (24 men, 20 women) of various skill levels (self reported rating 5.6-5.13c on the Yosemite decimal scale) and years of experience (0.10-44 years) served as subjects. They climbed two routes on separate days to assess climbing performance. The routes (11 and 30 m in distance) were set on two artificial climbing walls and were designed to become progressively more difficult from start to finish. Performance was scored according to the system used in sport climbing competitions where each successive handhold increases by one in point value. Results from each route were combined for a total climbing performance score. Measured variables for each subject included anthropometric (height, weight, leg length, arm span, % body fat), demographic (self reported climbing rating, years of climbing experience, weekly hours of training), and physiological (knee and shoulder extension, knee flexion, grip, and finger pincer strength, bent arm hang, grip endurance, hip and shoulder flexibility, and upper and lower body anaerobic power). These variables were combined into components using a principal components analysis procedure. These components were then used in a simultaneous multiple regression procedure to determine which components best explain the variance in sport rock climbing performance.The principal components analysis procedure extracted three components. These were labelled training, anthropometric, and flexibility on the basis of the measured variables that were the most influential in forming each component. The results of the multiple regression procedure indicated that the training component uniquely explained 58.9% of the total variance in climbing performance. The anthropometric and flexibility components explained 0.3% and 1.8% of the total variance in climbing performance respectively.The variance in climbing performance can be explained by a component consisting of trainable variables. More importantly, the findings do not support the belief that a climber must necessarily possess specific anthropometric characteristics to excel in sport rock climbing.