tbuckley/cabot-search huggingface dataset:
Genetic targeting of B-RafV600E affects survival and proliferation and identifies selective agents against BRAF-mutant colorectal cancer cells
Authors: Benjamin Hirschi, Eike Gallmeier, Andreas Ziesch, Maximilian Marschall, Frank T Kolligs
Journal: Molecular Cancer (2014)

Abstract Background Colorectal cancers carrying the B-Raf V600E-mutation are associated with a poor prognosis. The purpose of this study was to identify B-Raf V600E -mediated traits of cancer cells in a genetic in vitro model and to assess the selective sensitization of B-Raf V600E -mutant cancer cells towards therapeutic agents. Methods Somatic cell gene targeting was used to generate subclones of the colorectal cancer cell line RKO containing either wild-type or V600E-mutant B-Raf kinase. Cell-biologic analyses were performed in order to link cancer cell traits to the BRAF -mutant genotype. Subsequently, the corresponding tumor cell clones were characterized pharmacogenetically to identify therapeutic agents exhibiting selective sensitivity in B-Raf V600E -mutant cells. Results Genetic targeting of mutant BRAF resulted in restoration of sensitivity to serum starvation-induced apoptosis and efficiently inhibited cell proliferation in the absence of growth factors. Among tested agents, the B-Raf inhibitor dabrafenib was found to induce a strong V600E-dependent shift in cell viability. In contrast, no differential sensitizing effect was observed for conventional chemotherapeutic agents (mitomycin C, oxaliplatin, paclitaxel, etoposide, 5-fluorouracil), nor for the targeted agents cetuximab, sorafenib, vemurafenib, RAF265, or for inhibition of PI3 kinase. Treatment with dabrafenib efficiently inhibited phosphorylation of the B-Raf downstream targets Mek 1/2 and Erk 1/2. Conclusion Mutant BRAF alleles mediate self-sufficiency of growth signals and serum starvation-induced resistance to apoptosis. Targeting of the BRAF mutation leads to a loss of these hallmarks of cancer. Dabrafenib selectively inhibits cell viability in B-Raf V600E mutant cancer cells.
Community Diabetes Care: A 10-year Perspective
Authors: Roland G Hiss, Robert M Anderson, George E Hess, Cathie J Stepien, Wayne K Davis
Journal: Diabetes Care (1994)

OBJECTIVE To compare diabetes care and education at the community level in 1981 and 1991 in order to record progress achieved in the decade of the 1980s, determine if there is a gap that must be closed to reach diabetes-related objectives for 2000, and establish a baseline to which changes stimulated by the Diabetes Control and Complications Trial can be compared. RESEARCH DESIGN AND METHODS In eight Michigan communities, representative primary-care physicians (61 in 1981; 68 in 1991) and their diabetic patients (428 and 440) were identified. Communities, physicians, and patients were randomly selected. Participating patients were interviewed and examined in their community or home to assess the kind and extent of diabetes care they had been receiving; their metabolic, nutritional, educational, and psychosocial status; their diabetic history and current status; and other related factors. The diabetic status, care, and education of the 1981 community patients were compared with those of patients studied in 1991. RESULTS Positive changes in diabetes care and education at the community level from 1981 to 1991 were seen in the areas of patient glucose monitoring, insulin administration practices, hypertension control, exercise recommendations in diabetic management; and smoking rates. Negative changes occurred in the percentage of non-insulin-dependent diabetes mellitus (NIDDM) patients receiving diabetes education and frequency of office visits to the patient's primary-care physician. Changes of indeterminate value included a sharp decline in primary diabetes admissions to the hospital and a decrease in the proportion of NIDDM patients managed with insulin. Many other hoped-for changes from 1981 status, such as screening for retinopathy, foot-care practices, and overall metabolic control of diabetes, did not occur. CONCLUSIONS The decade of the 1980s produced modest, but not impressive, improvements in diabetes care and education at the community level. Progress must be accelerated if the diabetes-related objectives included in the national targets for health promotion and disease prevention for 2000 are to be met.
ME-15 * INTERACTION BETWEEN CANCER STEM CELLS AND MYELOID DERIVED SUPPRESSOR CELLS DRIVES IMMUNOSUPPRESSION AND GLIOBLASTOMA GROWTH
Authors: B. Otvos, A. Alvarado, J. Hale, K. Stoltz, M. Sinyuk, P. Rayman, W. Flavahan, Q. Wu, A. Jarrar, J. Rich, R. Ransohoff, J. Finke, M. Vogelbaum, J. Lathia
Journal: Neuro-Oncology (2014)

Cellular and molecular regulation of the immune system is exquisitely controlled in the brain and disrupted in neoplasia. Glioblastoma (GBM) has an immunosuppressive phenotype, and despite the accumulation of immune cells in the tumor microenvironment, tumor growth persists. Myeloid derived suppressor cells (MDSCs) are a class of immature immune cells that mitigate cytotoxic T cell responses and promote immunosuppression in a variety of cancers. MDSCs are increased in the peripheral blood of GBM patients, but their role in the GBM microenvironment is undefined. We observed co-localization between arginase (Arg1) producing immunosuppressive MDSCs and cancer stem cells (CSCs) in GBM patient specimens and xenografts, leading to the hypothesis that CSCs stimulate MDSCs to promote immunosuppression. Intracranial injections of CSCs into mice led to GBM formation, expansion of the Arg1-producing MDSCs within the marrow of GBM-bearing mice, and increased levels of MDSCs within the GBM microenvironment. CSC conditioned media increased Arg1 production of murine marrow MDSCs which were then able to modulate cytotoxic T cell responses in co-culture models. Screening of conditioned media revealed cytokines secreted selectively by CSCs that activated MDSCs suppression. Removal of CSC-secreted factors decreased MDSCs in the GBM microenvironment, increased cytotoxic T cell infiltration, and had a pronounced survival benefit. Peripheral targeting of MDSCs through a sub-therapeutic dose of 5-fluorouracil (5-FU) in an immunocompetent syngeneic mouse model led to a similar phenotype to CSC-secreted factor removal in the GBM microenvironment, and an even greater survival benefit. Taken together, our results suggest a critical role of MDSC-mediated immunosuppression in GBM, a novel paradigm of immunomodulation by CSCs, and demonstrate that peripheral removal of MDSCs leads to increased T cell infiltration into GBM, and consequently suggest a novel chemotherapeutic strategy that is not generally toxic to bone marrow and that is not dependent on agents crossing the blood brain barrier.
Carcinogenic Activity of Alkylating Agents2
Authors: B. L. Van Duuren, B. M. Goldschmidt, C. Katz, I. Seidman, J. S. Paul
Journal: JNCI Journal of the National Cancer Institute (1974)

Administered by 1 or more routes into female ICR/Ha Swiss mice, 17 direct-acting alkylating agents and related compounds were tested for carcinogenic activity. The routes of administration were skin, 2-stage tumorigenesis on skin, subcutaneous (sc) injection, and intraperitoneal (ip) injection. Dimethylcarbamyl chloride, a potent carcinogen to skin, induced a high incidence of sarcom3S at the injection site after sc or ip injection. Four of the other 15 compounds (ethyl bromoacetate, 2,3- dichloro-p-dioxane, glycol sulfate, and diethy-β,γ-epoxypropylphosphonate) tested through sc injection induced significant incidences (P< 0.01) of sarcomas at the injection site. Whereas sarcomas were induced by most compounds tested by sc injection, only 2 of these, dimethylcarbamyl chloride and 1,2,4,5,9,10-triepoxydecane, also induced carcinomas upon application to skin.
Load-Reducing Therapy Prevents Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Plakoglobin-Deficient Mice
Authors: Larissa Fabritz, Mark G. Hoogendijk, Brendon P. Scicluna, Shirley C.M. van Amersfoorth, Lisa Fortmueller, Susanne Wolf, Sandra Laakmann, Nina Kreienkamp, Ilaria Piccini, Günter Breithardt, Patricia Ruiz Noppinger, Henning Witt, Klaus Ebnet, Thomas Wichter, Bodo Levkau, Werner W. Franke, Sebastian Pieperhoff, Jacques M.T. de Bakker, Ruben Coronel, Paulus Kirchhof
Journal: Journal of the American College of Cardiology (2011)
Pathogenesis of the impaired gall bladder contraction of coeliac disease.
Authors: A M Brown, M J Bradshaw, R Richardson, J G Wheeler, R F Harvey
Journal: Gut (1987)

We have investigated the possibility that the abnormally decreased gall bladder contraction after meals in patients with coeliac disease might result in part from an abnormality in the gall bladder response to endogenous cholecystokinetic hormones--for example, cholecystokinin and motilin--rather than solely from decreased secretion of such hormones. Eight patients with untreated coeliac disease and nine controls received intravenous infusions of the pure synthetic cholecystokinin analogue caerulein, 2-16 ng/kg/hour. Gall bladder emptying was measured on a minute-by-minute basis using 99mTc-HIDA scans. In the patients with coeliac disease, gall bladder emptying was greatly decreased (34.6 +/- 9.9 v 61.5 +/- 7.5% at 60 minutes, p less than 0.02), and a much greater dose of caerulein was needed to initiate gall bladder contraction (3.80 +/- 1.08 v 1.49 +/- 0.56 ng/kg, p less than 0.02). These results suggest that the abnormal gall bladder contraction in coeliac disease is not simply because of impaired release of cholecystokinin. Although mechanical factors secondary to the increased gall bladder size in patients with coeliac disease might to some extent account for the findings, the alternative explanation is that the gall bladder muscle is for some reason resistant to the action of cholecystokinetic agents. A similar phenomenon affecting the pancreas might contribute to the abnormally decreased pancreatic secretion found in coeliac disease.
Unrelated cord blood transplantation for adult patients with acute myeloid leukemia: higher incidence of acute graft-versus-host disease and lower survival in male patients transplanted with female unrelated cord blood—a report from Eurocord, the Acute Leukemia Working Party, and the Cord Blood Committee of the Cellular Therapy and Immunobiology Working Party of the European Group for Blood and Marrow Transplantation
Authors: Frédéric Baron, Myriam Labopin, Annalisa Ruggeri, Mohamad Mohty, Guillermo Sanz, Noel Milpied, Andrea Bacigalupo, Alessandro Rambaldi, Francesca Bonifazi, Alberto Bosi, Jorge Sierra, Ibrahim Yakoub-Agha, Josep Maria Ribera Santasusana, Eliane Gluckman, Arnon Nagler
Journal: Journal of Hematology & Oncology (2015)

In the setting of allogeneic human leukocyte antigen (HLA)-matched bone marrow transplantation, transplanting male patients with grafts from female donors has been associated with a higher incidence of graft-versus-host disease (GVHD) and of nonrelapse mortality (NRM). The aim of the current analysis was to compare transplantation outcomes in male patients given female unrelated cord blood (UCB) versus other gender combinations. Data from 552 consecutive patients with acute myeloid leukemia (AML) given a single UCB transplantation between 2000 and 2014 were included. In comparison with other gender combination, male patients given female UCB (n = 131) had a trend for a higher incidence of grades II–IV acute GVHD (33 versus 25 %, P = 0.08), a trend for a higher incidence of NRM (41 versus 33 %, P = 0.06), and a lower leukemia-free (LFS, 30 versus 41 %, P = 0.01) and overall survival (OS, 33 versus 45 %, P = 0.008). In multivariate analyses, taking into consideration all patients for which data on HLA-matching and cell dose transplanted were fully available (n = 363), male patients transplanted with a female UCB had a trend for a higher incidence of grade III–IV acute GVHD (hazard ratio (HR) = 2.0, P = 0.06), a trend for a higher NRM (HR = 1.5, P = 0.06), and a worse LFS (HR = 1.4, P = 0.04) and OS (HR = 1.3, P = 0.06). Our data suggest that male patients transplanted with female UCB might have higher risk of acute GVHD and of NRM leading to worse LFS and OS. These results should be confirmed in other large cohorts of patients before used for determining the choice of an UCB unit.
Burden of disease caused by Haemophilus influenzae type b in children younger than 5 years: global estimates
Authors: James P Watt, Lara J Wolfson, Katherine L O'Brien, Emily Henkle, Maria Deloria-Knoll, Natalie McCall, Ellen Lee, Orin S Levine, Rana Hajjeh, Kim Mulholland, Thomas Cherian
Journal: The Lancet (2009)
Acute pseudoaneurysm of the femoral artery after repeated trauma in full-contact karate practice: Figure 1
Authors: E Doiz, F Garrido, R Conejero, P García, E Fernández
Journal: British Journal of Sports Medicine (2008)

Traumatic pseudoaneurysms of the deep femoral artery are only encountered infrequently in sports medical literature. We present the case of a male who, after practising full-contact karate, experienced pain and oedema in the right thigh. The ultrasound results and the arteriography showed the presence of a pseudoaneurysm in a branch of the deep femoral artery. Traumatic pseudoaneurysms of the deep femoral artery are normally secondary to endovascular interventions or to mycotic infections in injecting drug users. The majority appear asymptomatically as a pulsatile mass, although on occasions clinical signs of compression (pain, neurological or venous symptoms) may occur or, if the aneurysm bursts, hypovolemic shock.
Actinomycin D Decreases Mcl-1 Expression and Acts Synergistically with ABT-737 against Small Cell Lung Cancer Cell Lines
Authors: Haishan Xu, Geoffrey W. Krystal
Journal: Clinical Cancer Research (2010)

Abstract Purpose: ABT-737, which blocks the function of Bcl-2 and Bcl-XL but not Mcl-1, has shown single-agent activity in preclinical models of small cell lung cancer (SCLC). Elevated expression of Mcl-1 induces resistance to ABT-737 in SCLC. Based on the short half-life of Mcl-1 mRNA and protein, we hypothesized that the actinomycin D could reverse Mcl-1–induced resistance to ABT-737. Experimental Design: The dose-response of multiple SCLC cell lines to actinomycin D in the absence and presence of ABT-737 was followed by the assessment of Bcl-2 family expression and poly ADP ribose polymerase cleavage by Western blot, viability by tetrazolium dye reduction and clonogenic assay, and cell cycle kinetics by flow cytometry. Results: Actinomycin D decreased Mcl-1 expression and resulted in a cell line–dependent increase in Noxa expression. Clinically relevant concentrations of actinomycin D from 0.4 to 4 ng/mL showed single-agent activity across a panel of SCLC cell lines. When combined with low micromolar doses of ABT-737, near complete loss of viability was seen with synergistic combination indices of 0.5 to 0.7. Exposure to 4 ng/mL actinomycin was only required for the first 24 hours of the combined incubation, mimicking a clinically achievable area under the curve, but the presence of ABT-737 was required for an additional 48 hours to obtain maximal effect. Conclusions: Clinically relevant concentrations of actinomycin D act synergistically with ABT-737 to induce SCLC apoptosis, which can be at least partially attributed to the actinomycin D–induced decrease in Mcl-1 and increase in Noxa expression. Taken together, these data suggest the feasibility of combining actinomycin D with BH3-mimetic drugs in the clinical setting. Clin Cancer Res; 16(17); 4392–400. ©2010 AACR.
Potentially Avoidable 30-Day Hospital Readmissions in Medical Patients
Authors: Jacques Donzé, Drahomir Aujesky, Deborah Williams, Jeffrey L. Schnipper
Journal: JAMA Internal Medicine (2013)

Because effective interventions to reduce hospital readmissions are often expensive to implement, a score to predict potentially avoidable readmissions may help target the patients most likely to benefit.To derive and internally validate a prediction model for potentially avoidable 30-day hospital readmissions in medical patients using administrative and clinical data readily available prior to discharge.Retrospective cohort study.Academic medical center in Boston, Massachusetts.All patient discharges from any medical services between July 1, 2009, and June 30, 2010.Potentially avoidable 30-day readmissions to 3 hospitals of the Partners HealthCare network were identified using a validated computerized algorithm based on administrative data (SQLape). A simple score was developed using multivariable logistic regression, with two-thirds of the sample randomly selected as the derivation cohort and one-third as the validation cohort.Among 10 731 eligible discharges, 2398 discharges (22.3%) were followed by a 30-day readmission, of which 879 (8.5% of all discharges) were identified as potentially avoidable. The prediction score identified 7 independent factors, referred to as the HOSPITAL score: h emoglobin at discharge, discharge from an o ncology service, s odium level at discharge, p rocedure during the index admission, i ndex t ype of admission, number of a dmissions during the last 12 months, and l ength of stay. In the validation set, 26.7% of the patients were classified as high risk, with an estimated potentially avoidable readmission risk of 18.0% (observed, 18.2%). The HOSPITAL score had fair discriminatory power (C statistic, 0.71) and had good calibration.This simple prediction model identifies before discharge the risk of potentially avoidable 30-day readmission in medical patients. This score has potential to easily identify patients who may need more intensive transitional care interventions.
Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial
Authors: Michael Brundage, Matthew R. Sydes, Wendy R. Parulekar, Padraig Warde, Richard Cowan, Andrea Bezjak, Peter Kirkbride, Matthew Parliament, Clare Moynihan, Jean-Paul Bahary, Mahesh K.B. Parmar, Karen Sanders, Bingshu E. Chen, Malcolm D. Mason
Journal: Journal of Clinical Oncology (2015)

Purpose The NCIC CTG PR3/MRC PR07 randomized phase III trial compared androgen-deprivation therapy (ADT) alone versus ADT with radiotherapy (RT) for patients with locally advanced prostate cancer. This article reports the health-related quality-of-life (HRQOL) outcomes of this trial. Patients and Methods A total of 1,205 patients were randomly allocated to either ADT alone or ADT with RT. HRQOL was assessed at baseline and every 6 months thereafter using the European Organisation for Research and Treatment of Cancer Core Questionnaire and a prostate cancer–specific checklist or the Functional Assessment of Cancer Therapy–Prostate questionnaire. Mean changes from baseline scores for five function domains and nine symptom domains were analyzed as those most relevant to ADT and RT. The proportions of patients with improved, stable, or worsened HRQOL scores according to instrument-specific minimal important differences were calculated. Results Baseline questionnaires were completed by 1,028 patients (88%). At 6 months, RT had a statistically significant impact on mean score for bowel symptoms (P = .02), diarrhea (P &lt; .001), urinary function (P = .003), and erectile dysfunction (P = .008); by 3 years, however, there were no significant between-group differences in any domain. Generalized linear mixed modeling revealed no significant between-arm differences in any of the function scales but showed significant deterioration in both arms over time for Functional Assessment of Cancer Therapy–Prostate total score, treatment outcome index, and physical and functional well-being. Conclusion The addition of RT to ADT for patients with locally advanced prostate cancer significantly improved overall survival and had only modest and transient negative impact on relevant domains of HRQOL.
A Major Role for Mitotic cdc2 Kinase Inactivation in the Establishment of the Mitotic DNA Damage Checkpoint
Authors: Emilie Bayart, Olga Grigorieva, Serge Leibovitch, Rosine Onclercq-Delic, Mounira Amor-Guéret
Journal: Cancer Research (2004)

Abstract Cdc2 kinase is inactivated when DNA damage occurs during the spindle assembly checkpoint. Here, we show that the level of mitotic Bloom syndrome protein phosphorylation reflects the level of cdc2 activity. A complete inactivation of cdc2 by either introduction of DNA double-strand breaks or roscovitine treatment prevents exit from mitosis. Thus, mitotic cdc2 inactivation plays a major role in the establishment of the mitotic DNA damage checkpoint. In response to mitotic cdc2 inactivation, the M/G1 transition is delayed after releasing the drug block in nonmalignant cells, whereas tumor cells exit mitosis without dividing and rereplicate their DNA, which results in mitotic catastrophe. This opens the way for new chemotherapeutic strategies.
Effect of Abrupt Change From Standard to Low Serum Levels of Lithium: A Reanalysis of Double-Blind Lithium Maintenance Data
Authors: Roy H. Perlis, Gary S. Sachs, Beny Lafer, Michael W. Otto, Stephen V. Faraone, John M. Kane, Jerrold F. Rosenbaum
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Growing evidence suggests that abrupt lithium discontinuation increases the risk of recurrence for patients with bipolar disorder. To assess the effect of abrupt change in lithium dose, the authors reanalyzed data from a previously reported, randomized, double-blind trial of standard- versus low-dose lithium for maintenance therapy in bipolar disorder. METHOD: In the original study, serum lithium levels were obtained during a 2-month open stabilization period for 94 patients with bipolar disorder who were then randomly assigned to be maintained on a low (serum level=0.4–0.6 meq/liter) or a standard (0.8–1.0 meq/liter) level of lithium therapy. Patients were then followed for up to 182 weeks. This reanalysis examined the potential confounding influence of prerandomization lithium level and change in lithium level on the outcome of subjects assigned to a standard or low maintenance dose of lithium. RESULTS: In a Cox proportional hazards model incorporating pre- and postrandomization lithium levels and the interaction of these factors, only the interaction term remained significantly associated with time to recurrence. CONCLUSIONS: The findings indicate that change in serum lithium level may be a more powerful predictor of recurrence of bipolar disorder than the absolute assignment to a low or a standard dose of lithium and suggest that an abrupt decrease in lithium level should be avoided. This reanalysis did not directly address optimal maintenance lithium levels but raises questions about the original study’s finding of superiority for lithium levels ≥0.8 meq/liter. The results underscore the importance of accounting for the possible confounding effects of changes in the intensity of pharmacotherapy in studies of maintenance therapies for bipolar disorder.