tbuckley/cabot-search huggingface dataset:
Assessment of <i>BCR-ABL1</i> Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors
Authors: David Marin, Amr R. Ibrahim, Claire Lucas, Gareth Gerrard, Lihui Wang, Richard M. Szydlo, Richard E. Clark, Jane F. Apperley, Dragana Milojkovic, Marco Bua, Jiri Pavlu, Christos Paliompeis, Alistair Reid, Katayoun Rezvani, John M. Goldman, Letizia Foroni
Journal: Journal of Clinical Oncology (2011)

We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics.We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere.Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively).A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
Phenylarsine Oxide Induces Apoptosis in Bax- and Bak-Deficient Cells through Upregulation of Bim
Authors: Biyun Ni, Qi Ma, Baowei Li, Lixia Zhao, Yong Liu, Yushan Zhu, Quan Chen
Journal: Clinical Cancer Research (2011)

Bax and Bak are regarded as key mediators for cytochrome c (Cyt c) release and apoptosis. Loss of Bax or Bak is often reported in human cancers and renders resistance of these cancerous cells to chemotherapy. Here, we investigated that phenylarsine oxide (PAO) could induce Bax/Bak-independent apoptosis.Annexin V/propidium iodide (PI) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and caspase activation assays were conducted to detect apoptosis in Bax/Bak-deficient mouse embryonic fibroblasts (MEF) and HCT116 bax(-/-) colorectal cancer cells. Cyt c release and Bim expression were assessed by Western blotting and immunostaining. Bim was stably knocked down by short hairpin RNA. Immunoprecipitation was applied to detect the interaction between Bim and Bcl-2. Both subcutaneous and colorectal orthotopic tumor implantation models were used in nude mice to investigate the effect of PAO in vivo.PAO triggered Cyt c release and apoptosis in a Bax/Bak-independent manner. Bim and Bcl-2 were both involved in this process. PAO augmented the expression of Bim and strengthened the interaction between Bim and Bcl-2. Furthermore, PAO attenuated the growth of Bax-deficient cancer cells in vivo.Our results showed that PAO induced apoptosis in chemotherapy-resistant cancer cells, which suggests that PAO has the potential to serve as a chemotherapeutic agent for Bax- and Bak-deficient cancers.
Naturally occurring anti-inflammatory factors in the synovial fluids of patients with rheumatic disease and their possible mode of action.
Authors: R B Capstick, D A Lewis, J A Cosh
Journal: Annals of the Rheumatic Diseases (1975)

Evidence has been shown that pathological synovial fluid contained a substance capable of stabilizing rat liver lysosomes which was partly inactivated by treatment with trypsin and by storage. Such synovial fluid also appeared to contain a substance which labilized lysosomes and which was more stable than the stabilizing substance. (2) The lysosomal stabilizing substance described above was nondialysable and migrated electrophoretically with the alpha and beta globulins to which class it has been tentatively ascribed. (3) Pathological synovial fluid contained proteases which were active at acid pH and at neutral pH. It also appeared to contain a substance capable of inhibiting these proteases. (4) Alpha2-Macroglobulin has been detected in pathogenic synovial fluid.
Sustained Ventricular Tachycardia and Ventricular Fibrillation Complicating Non–ST-Segment–Elevation Acute Coronary Syndromes
Authors: Jonathan P. Piccini, Jennifer A. White, Rajendra H. Mehta, Yuliya Lokhnygina, Sana M. Al-Khatib, Pierluigi Tricoci, Charles V. Pollack, Gilles Montalescot, Frans Van de Werf, C. Michael Gibson, Robert P. Giugliano, Robert M. Califf, Robert A. Harrington, L. Kristin Newby
Journal: Circulation (2012)

Ventricular arrhythmias remain a lethal complication of acute coronary syndromes (ACS). However, the incidence and prognosis of sustained ventricular tachycardia/ventricular fibrillation (VT/VF) in contemporary non-ST-segment-elevation (NSTE) ACS populations are not well described.We examined the incidence of VT/VF and subsequent survival among 9211 patients enrolled in the Early Glycoprotein IIb/IIIa Inhibition in NSTE ACS (EARLY ACS) trial. The cumulative incidence of VT/VF was 1.5% (n=141); 0.6% (n=55) had VT/VF ≤48 hours after enrollment, and 0.9% (n=86) had VT/VF >48 hours after enrollment. Patients with VT/VF more frequently had prior heart failure, an ejection fraction <30%, and triple-vessel coronary artery disease. Predictors of sustained VT/VF were similar regardless of the timing of VT/VF (≤48 versus >48 hours). Patients with VT/VF ≤48 hours after enrollment had higher 30-day mortality than those who did not have VT/VF ≤48 hours (13.0% versus 2.2%; adjusted odds ratio, 6.73; 95% confidence interval, 2.68-16.9). The increased risk of death associated with VT/VF ≤48 hours persisted at 1 year. The risk of mortality, relative to patients without VT/VF, was greater for patients with VT/VF >48 hours (hazard ratio, 20.70; 95% confidence interval, 15.39-27.85) than for those with earlier VT/VF (hazard ratio, 7.45; 95% confidence interval, 4.60-12.08; P=0.0003). The frequency of arrhythmic death was higher in patients with VT/VF than in those without VT/VF (26.4% versus 6.9%).Sustained VT/VF is infrequent after NSTE ACS but is as likely to occur after 48 hours as within the first 48 hours. The marked increase in all-cause death among NSTE ACS patients with both early and late sustained VT/VF raises important considerations for aggressive monitoring beyond 48 hours and interventions to prevent arrhythmic death in these patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.
Ventilation heterogeneity in children with well controlled asthma with normal spirometry indicates residual airways disease
Authors: K A Macleod, A R Horsley, N J Bell, A P Greening, J A Innes, S Cunningham
Journal: Thorax (2008)

In adults with asthma, ventilation heterogeneity, independent of inflammation, has been hypothesised to be associated with airway remodelling. Bronchial biopsy in preschool children with wheeze demonstrates early structural changes. Ventilation heterogeneity is sensitive to airway disease in other paediatric respiratory conditions such as cystic fibrosis, so may be sensitive to early airway disease in asthma. An observational study was performed in which it was hypothesised that ventilation heterogeneity (lung clearance index (LCI) and phase III slope indices (S(cond) and S(acin))) were more sensitive than conventional measurements (forced expiratory volume in 1 s (FEV(1)) and exhaled nitric oxide (Feno)) for detecting residual airways disease in children with well controlled asthma.In 31 children with asthma of mean age 10.6 years (range 5-15), FEV(1), LCI, S(cond) and S(acin) were measured at two separate visits, before and after blinded salbutamol or placebo, with Feno measured once. 29 healthy volunteers of mean age 11.2 years (range 5-16) completed measurements at one visit only.Baseline mean (SD) LCI was significantly higher in children with asthma than in controls (6.69 (0.91) vs 6.24 (0.47), p = 0.02). There were no significant differences in FEV(1) or median Feno. Following salbutamol there was a small significant change in mean (SD) FEV(1) (from -1.26 (1.25) to -0.93 (0.23), p = 0.03) but not in LCI, S(cond) or S(acin). Importantly, LCI remained significantly higher after bronchodilator in children with asthma than in controls (6.64 (0.69), p = 0.01).This study identifies the presence of residual ventilation heterogeneity in children with well controlled asthma and normal FEV(1). The role of LCI in measuring early airway disease in children with asthma requires further exploration, possibly as a surrogate of structural remodelling.
Cancer Pharmacogenomics and Pharmacoepidemiology: Setting a Research Agenda to Accelerate Translation
Authors: Andrew N. Freedman, Leah B. Sansbury, William D. Figg, Arnold L. Potosky, Sheila R. Weiss Smith, Muin J. Khoury, Stefanie A. Nelson, Richard M. Weinshilboum, Mark J. Ratain, Howard L. McLeod, Robert S. Epstein, Geoffrey S. Ginsburg, Richard L. Schilsky, Geoffrey Liu, David A. Flockhart, Cornelia M. Ulrich, Robert L. Davis, Lawrence J. Lesko, Issam Zineh, Gurvaneet Randhawa, Christine B. Ambrosone, Mary V. Relling, Nat Rothman, Heng Xie, Margaret R. Spitz, Rachel Ballard-Barbash, James H. Doroshow, Lori M. Minasian
Journal: JNCI Journal of the National Cancer Institute (2010)

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.
Pharmacologically Regulated Regeneration of Functional Human Pancreatic Islets
Authors: Gary P. Kobinger, Shaoping Deng, Jean-Pierre Louboutin, Marko Vatamaniuk, Victor M. Rivera, Moh-Moh Lian, James F. Markmann, Tim Clackson, Steven E. Raper, Franz Matschinsky, James M. Wilson
Journal: Molecular Therapy (2004)

Transplantation of allogeneic islets can correct the metabolic abnormalities of Type I diabetes. Limited availability of donor pancreas tissues restricts the application of this therapeutic modality to a subset of eligible recipients. In an attempt to expand the utility of available donor human pancreas tissue, we developed a method to stimulate the proliferation of insulin-secreting beta-cells within human islets. A lentiviral vector was used to introduce into human islets chimeric signaling receptors that are activated to stimulate cell proliferation through interactions with a small-molecule drug called a chemical inducer of dimerization (CID). In vitro exposure of vector-transduced human islets to the CID expanded the number of cells and increased regulated insulin secretion. Transplantation of the regenerated islets into diabetic immunodeficient mice, followed by in vivo administration of the CID, corrected hyperglycemia. This strategy has the potential to reduce the quantity of human islets required for treatment of patients with Type I diabetes.
Probable Zoonotic Leprosy in the Southern United States
Authors: Richard W. Truman, Pushpendra Singh, Rahul Sharma, Philippe Busso, Jacques Rougemont, Alberto Paniz-Mondolfi, Adamandia Kapopoulou, Sylvain Brisse, David M. Scollard, Thomas P. Gillis, Stewart T. Cole
Journal: New England Journal of Medicine (2011)

In the southern region of the United States, such as in Louisiana and Texas, there are autochthonous cases of leprosy among native-born Americans with no history of foreign exposure. In the same region, as well as in Mexico, wild armadillos are infected with Mycobacterium leprae.
Low dose aspirin and cognitive function in middle aged to elderly adults: randomised controlled trial
Authors: Jackie F Price, Marlene C Stewart, Ian J Deary, Gordon D Murray, Peter Sandercock, Isabella Butcher, F Gerald R Fowkes
Journal: BMJ (2008)

<b>Objective</b> To determine the effects of low dose aspirin on cognitive function in middle aged to elderly men and women at moderately increased cardiovascular risk. <b>Design</b> Randomised double blind placebo controlled trial. <b>Setting</b> Central Scotland. <b>Participants</b> 3350 men and women aged over 50 participating in the aspirin for asymptomatic atherosclerosis trial. <b>Intervention</b> Low dose aspirin (100 mg daily) or placebo for five years. <b>Main outcome measures</b> Tests of memory, executive function, non-verbal reasoning, mental flexibility, and information processing five years after randomisation, with scores used to create a summary cognitive score (general factor). <b>Results</b> At baseline, mean vocabulary scores (an indicator of previous cognitive ability) were similar in the aspirin (30.9, SD 4.7) and placebo (31.1, SD 4.7) groups. In the primary intention to treat analysis, there was no significant difference at follow-up between the groups in the proportion achieving over the median general factor cognitive score (32.7% and 34.8% respectively, odds ratio 0.91, 95% confidence interval 0.79 to 1.05, P=0.20) or in mean scores on the individual cognitive tests. There were also no significant differences in change in cognitive ability over the five years in a subset of 504 who underwent detailed cognitive testing at baseline. <b>Conclusion</b> Low dose aspirin does not affect cognitive function in middle aged to elderly people at increased cardiovascular risk. <b>Trial registration</b> ISRCTN 66587262.
Osteopontin But Not Osteonectin Messenger RNA Expression Is a Prognostic Marker in Curatively Resected Non-Small Cell Lung Cancer
Authors: Sylke Schneider, JiMin Yochim, Jan Brabender, Kazumi Uchida, Kathleen D. Danenberg, Ralf Metzger, Paul M. Schneider, Dennis Salonga, Arnulf H. Hölscher, Peter V. Danenberg
Journal: Clinical Cancer Research (2004)

The purpose of this study was to better define the role of osteopontin (OPN) and osteonectin [also known as secreted protein acidic and rich in cysteine (SPARC)] in lung tumorigenesis by comparing the expressions of these genes in lung tumor tissue and matched normal tissue and by determining the prognostic significance of the gene expressions.Quantitative real-time reverse transcription-PCR was used to analyze OPN and SPARC mRNA expression in normal lung tissue and matching tumor samples from 82 patients with non-small cell lung cancer. Gene expression data for each patient were matched to survival data.The overall median mRNA expression level of OPN was about 20-fold higher in tumor tissues than in matching normal lung tissues (P < 0.001), whereas SPARC gene expression was not significantly different in both tissue types. Forty of 82 patients had high (>or=4.1) intratumoral OPN expression, and 15 of 82 patients had high (>or15.5) SPARC expression. High OPN expression in the tumor tissue was associated with inferior survival (P = 0.014), whereas high SPARC expression showed a trend toward longer survival (P = 0.095). The impact of high OPN and low SPARC expression on patient survival was additive (P = 0.001).The large increase in OPN expression in tumors compared with normal tissue and its association with survival suggest a role for OPN in lung tumorigenesis.
Identification of Sokotrasterol Sulfate As a Novel Proangiogenic Steroid
Authors: Siun Murphy, Bruno Larrivée, Ingrid Pollet, Kyle S. Craig, David E. Williams, Xin-Hui Huang, Megan Abbott, Fred Wong, Cameron Curtis, Thomas P. Conrads, Timothy Veenstra, Mira Puri, York Hsiang, Michel Roberge, Raymond J. Andersen, Aly Karsan
Journal: Circulation Research (2006)

The potential to promote neovascularization in ischemic tissues using exogenous agents has become an exciting area of therapeutics. In an attempt to identify novel small molecules with angiogenesis promoting activity, we screened a library of natural products and identified a sulfated steroid, sokotrasterol sulfate, that induces angiogenesis in vitro and in vivo. We show that sokotrasterol sulfate promotes endothelial sprouting in vitro, new blood vessel formation on the chick chorioallantoic membrane, and accelerates angiogenesis and reperfusion in a mouse hindlimb ischemia model. We demonstrate that sulfation of the steroid is critical for promoting angiogenesis, as the desulfated steroid exhibited no endothelial sprouting activity. We thus developed a chemically synthesized sokotrasterol sulfate analog, 2β,3α,6α-cholestanetrisulfate, that demonstrated equivalent activity in the hindlimb ischemia model and resulted in the generation of stable vessels that persisted following cessation of therapy. The function of sokotrasterol sulfate was dependent on cyclooxygenase-2 activity and vascular endothelial growth factor induction, as inhibition of either cyclooxygenase-2 or vascular endothelial growth factor blocked angiogenesis. Surface expression of α v β 3 integrin was also necessary for function, as neutralization of α v β 3 integrin, but not β 1 integrin, binding abrogated endothelial sprouting and antiapoptotic activity in response to sokotrasterol sulfate. Our findings indicate that sokotrasterol sulfate and its analogs can promote angiogenesis in vitro and in vivo and could potentially be used for promoting neovascularization to relieve the sequelae of vasoocclusive diseases.
Female gender as a determinant of cough threshold to inhaled capsaicin
Authors: M Fujimura, K Kasahara, Y Kamio, M Naruse, T Hashimoto, T Matsuda
Journal: European Respiratory Journal (1996)

Chronic, nonproductive cough and cough associated with the use of angiotensin converting enzyme inhibitors, are more frequently observed in females as compared to males. To examine the influence of sex, age, height, weight and pulmonary function on airway cough sensitivity, cough threshold to inhaled capsaicin, an index of the airway cough sensitivity, was measured in 160 nonsmoking, nonatopic healthy subjects. Forty young males (aged 24 +/- 2 yrs) 40 young females (aged 22 +/- 2 yrs) 40 middle-aged males (aged 48 +/- 5 yrs) and 40 middle-aged females (aged 50 +/- 7 yrs) were studied. The cough threshold was defined as the lowest concentration of inhaled capsaicin causing five or more coughs. The cough threshold was 3-5 fold lower in females than in males both in young (p&lt;0.001) and middle-aged (p&lt;0.005) subjects. Cough threshold was weakly but significantly correlated to height, weight, forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) when all subjects were considered together but not when each group was considered separately. Multiple regression analysis revealed that sex difference was the significant predictive factor for the cough threshold in either age group. These results confirm that cough sensitivity is heightened in females and suggest that influence of height and pulmonary function on the cough threshold may have resulted from sex difference.
Adequacy of reporting monitoring regimens of risk factors for cardiovascular disease in clinical guidelines: systematic review
Authors: I. Moschetti, D. Brandt, R. Perera, M. Clarke, C. Heneghan
Journal: BMJ (2011)

<b>Objective</b> To assess the reporting of monitoring recommendations in guidelines on the prevention and treatment of cardiovascular disease. <b>Data sources</b> Medline, Trip database, National Guideline Clearinghouse, and databases containing guidelines published from January 2002 to February 2010. <b>Data selection</b> Three major risk factors for cardiovascular disease: cholesterol level, smoking, and hypertension. The primary outcome was the frequency with which the guidelines dealt with monitoring of risk factors. Secondary outcomes were completeness of monitoring recommendations, defined by the presence of what to monitor, when to monitor, what to do if the targets or variables were not met, and the reported level or strength of the evidence. <b>Results</b> 117 guidelines were identified, 84 (72%) of which contained a section on lipids. Of those guidelines with a section on lipids, 53% (n=44) provided no information or specific recommendations on what to monitor, 51% (n=43) provided no information on when to monitor, and 64% (n=54) provided no guidance on what to do if the target was out of range. Guidelines for hypertension (n=79) and smoking (n=65) were little better, with 63% (n=50) and 54% (n=35), respectively, providing no recommendation for what to monitor. The number of guidelines that explicitly referenced the level of evidence for monitoring was low, with most of the recommendations based on weak levels of evidence. <b>Conclusion</b> Many guidelines for cardiovascular disease do not report clearly what to monitor and what to do if a change is detected. If no evidence is available to support a specific monitoring schedule, this should be explicit in the guideline, with a description of the new research that would fill the gap.
MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression
Authors: Jennifer H Mansfield, Brian D Harfe, Robert Nissen, John Obenauer, Jalagani Srineel, Aadel Chaudhuri, Raphael Farzan-Kashani, Michael Zuker, Amy E Pasquinelli, Gary Ruvkun, Phillip A Sharp, Clifford J Tabin, Michael T McManus
Journal: Nature Genetics (2004)
Potential New Therapies for the Treatment of HIV-1 Infection
Authors: Jon H. Condra, Michael D. Miller, Daria J. Hazuda, Emilio A. Emini
Journal: Annual Review of Medicine (2002)

▪ Abstract The development and clinical use of chemotherapeutic agents for the treatment of persistent HIV-1 infection over the past decade has profoundly and favorably affected the course of HIV-1 disease for many infected individuals. Unfortunately, the long-term use of these therapies is complicated by unwanted metabolic side effects, by issues of adherence, and by the selection of viral variants with reduced susceptibility. These complications have spurred the search for new anti-HIV-1 agents having improved pharmacological properties and expressing activity against viral variants resistant to the currently available agents. This brief review describes the current state of this search as well as potentially novel viral targets for chemotherapeutic intervention.