tbuckley/cabot-search huggingface dataset:
Novel Effect of Oxidized Low-Density Lipoprotein
Authors: Sergiy Sukhanov, Yusuke Higashi, Shaw-Yung Shai, Hiroyuki Itabe, Koichi Ono, Sampath Parthasarathy, Patrick Delafontaine
Journal: Circulation Research (2006)

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classical glycolytic enzyme that is involved in cellular energy production and has important housekeeping functions. We used the natural prooxidant and proatherogenic molecule oxidized low-density lipoprotein (OxLDL) to determine a potential link between OxLDL-promoted oxidative stress, GAPDH expression, and smooth muscle cell energy metabolism. OxLDL but not native LDL (nLDL) produced a 60% to 100% dose- and time-dependent reduction of GAPDH protein. OxLDL increased reactive oxygen species (ROS) formation, including rapid elevation of H 2 O 2 levels. OxLDL decreased intracellular catalase expression, likely contributing to the increase in H 2 O 2 . Antioxidants, anti-CD36 receptor antibody, NADPH oxidase, or lipoxygenase blockers decreased OxLDL-specific ROS and prevented GAPDH downregulation. 12/15-Lipoxygenase or p47phox deficiency resulted in attenuation of GAPDH downregulation, but 5-lipoxygenase suppression had no effect. OxLDL or exogenous H 2 O 2 oxidized GAPDH thiols, decreasing GAPDH protein half-life and increasing GAPDH sensitivity to proteasome-mediated protein degradation in vitro. OxLDL- or small interfering RNA–specific downregulation of GAPDH resulted in 65% reduction in glycolysis rate and 82% decrease in ATP levels. In conclusion, our data demonstrate that OxLDL downregulated GAPDH via a H 2 O 2 -dependent decrease in protein stability. GAPDH protein damage resulted in marked depletion of cellular ATP levels. Our data have important implications for understanding the metabolic effect of OxLDL on the vessel wall and mechanism of atherogenesis.
The epidemiology of injuries at the London 2012 Paralympic Games
Authors: Stuart E Willick, Nick Webborn, Carolyn Emery, Cheri A Blauwet, Pia Pit-Grosheide, Jaap Stomphorst, Peter Van de Vliet, Norma Angelica Patino Marques, J Oriol Martinez-Ferrer, Esmè Jordaan, Wayne Derman, Martin Schwellnus
Journal: British Journal of Sports Medicine (2013)

Background The characteristics and incidence of injuries at the Summer Paralympic Games have not previously been reported. A better understanding of injuries improves the medical care of athletes and informs future injury prevention strategies. Objective The objective of this prospective cohort study was to characterise the incidence and nature of injuries during the London 2012 Summer Paralympic Games. Methods Injury information was obtained from two databases. One database was populated from medical encounter forms completed by providers at the time of assessment in one of the medical stations operated by the Organising Committee. The second database was populated daily with information provided by team medical personnel who completed a comprehensive, web-based injury survey. Results The overall injury incidence rate was 12.7 injuries/1000 athlete-days. Injury rates were similar in male and female athletes. The precompetition injury rates in women were higher than those in the competition period. Higher injury rates were found in older athletes and certain sports such as football 5-a-side (22.4 injuries/1000 athlete-days). Overall, 51.5% of injuries were new onset acute traumatic injuries. The most commonly injured region (percentage of all injuries) was the shoulder (17.7%), followed by the wrist/hand (11.4%), elbow (8.8%) and knee (7.9%). Conclusions This is the largest and most comprehensive epidemiological report examining injuries in Paralympic athletes. Injury rates differ according to age and sport. Upper limb injuries are common. The knowledge gained from this study will inform future injury surveillance studies and the development of prevention strategies in Paralympic sport. The Epidemiology of Injuries at the London 2012 Paralympic Games.
Alterations of the colonic flora and their effect on the hydrogen breath test.
Authors: T Gilat, H Ben Hur, E Gelman-Malachi, R Terdiman, Y Peled
Journal: Gut (1978)

The hydrogen breath test was performed by ingestion of 20 g lactulose and analysis of end-expiratory air. Eighteen patients undergoing colonoscopy, 17 receiving antibiotics, 12 prepared for colon surgery, and 15 controls were examined. The test was repeated under control conditions in the treated patients. Eleven of 55 subjects failed to produce significant amounts of hydrogen under control conditions. This 20% proportion of non-hydrogen producers is much higher than that reported by other investigators. The hydrogen production was very markedly depressed after preparation for colonscopy and antibiotic therapy. The effect of neomycin and enemata as used in preparation for colon surgery was less marked. Hydrogen production by the colonic flora is thus subject to individual variations and may be affected by various therapeutic regimens. All these may cause false negative results when using the hydrogen breath test to evaluate carbohydrate absorption. The test should therefore not be performed for a considerable time after therapeutic manipulation of the colonic flora.
A Phase II Randomized Study of HIV-Specific T-Cell Gene Therapy in Subjects with Undetectable Plasma Viremia on Combination Antiretroviral Therapy
Authors: Steven G. Deeks, Bridget Wagner, Peter A. Anton, Ronald T. Mitsuyasu, David T. Scadden, Christine Huang, Catherine Macken, Douglas D. Richman, Cindy Christopherson, Carl H. June, Richard Lazar, David F. Broad, Sayeh Jalali, Kristen M. Hege
Journal: Molecular Therapy (2002)

Highly active antiretroviral therapy (HAART) can suppress HIV replication to undetectable levels in plasma, but it is unlikely to eradicate cellular reservoirs of virus. Immunotherapies that are cytolytic may be useful adjuncts to drug therapies that target HIV replication. We have generated HIV-specific CD4+ and CD8+ T cells bearing a chimeric T-cell receptor (CD4ζ) composed of the extracellular and transmembrane domain of human CD4 (which binds HIVgp120) linked to the intracellular-ζ signaling chain of the CD3 T-cell receptor. CD4ζ-modified T cells can inhibit viral replication, kill HIV-infected cells in vitro, and survive for prolonged periods in vivo. We report the results of a phase II randomized trial of CD4ζ gene–modified versus unmodified T cells in 40 HIV-infected subjects on HAART with plasma viral loads <50 copies/ml. Serial analyses of residual blood and tissue HIV reservoirs were done for 6 months postinfusion. No significant between-group differences were noted in viral reservoirs following therapy. However, infusion of gene-modified, but not unmodified, T cells was associated with a decrease from baseline in HIV burden in two of four reservoir assays and a trend toward fewer patients with recurrent viremia. Both groups experienced a treatment-related increase in CD4+ T-cell counts.
Supra-additive Growth Inhibition by a Celecoxib Analogue and Carboxyamido-triazole Is Primarily Mediated through Apoptosis
Authors: Mary E. Winters, Arpita I. Mehta, Emanuel F. Petricoin, Elise C. Kohn, Lance A. Liotta
Journal: Cancer Research (2005)

Abstract Combination studies of celecoxib and chemotherapeutic agents suggest that combining cyclooxygenase-2 inhibitors with other agents may have supra-additive or synergistic effects on tumor growth inhibition. Carboxyamido-triazole (CAI), a voltage-independent calcium channel inhibitor, has been shown to induce growth inhibition and apoptosis in cancer cells. We found that continuous exposure to cytostatic doses of CAI and LM-1685, a celecoxib analogue, reduced the proliferation and survival of seven human cancer cell lines by at least one log (P ≤ 0.001) over either agent alone. To explore the mechanism of action of this combination, we further studied the effects of LM-1685/CAI on CCL-250 colorectal carcinoma cells. We found that the supra-additive antiproliferative effects occurred throughout a range of LM-1685 doses (5-25 μmol/L) and paralleled a decrease in COX-2 activity as measured by prostaglandin E2 production. In these cells, treatment with LM-1685/CAI suppressed the extracellular signal-regulated kinase pathway within the first hour but ultimately results in high, sustained activation of ERK over a 9-day period (P = 0.0005). Suppression of cyclin D1 and phospho-AKT, and cleavage of caspase-3 and PARP were concomitant with persistent ERK activation. Addition of PD98059, a MEK-1 inhibitor, suppressed ERK activation and significantly but incompletely reversed these signaling events and apoptosis. Flow cytometry experiments revealed that the CAI/LM-1685 combination induced a 3-fold increase in apoptosis over control (P = 0.005) in 3 days. We show that the combination of CAI and LM-1685 produces a cytotoxic effect by suppressing proliferation and triggering apoptosis.
Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years
Authors: A. de Gramont, C. Boni, M. Navarro, J. Tabernero, T. Hickish, C. Topham, A. Bonetti, P. Clingan, C. Lorenzato, T. André
Journal: Journal of Clinical Oncology (2007)

4007 Background: The MOSAIC study was designed to evaluate the effects of the FOLFOX4 regimen (5-FU/LV + oxaliplatin) on 3- year disease free survival (DFS) probability in patients with stage II and III colon cancer. Methods: Patients (n=2246) with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive 5-FU/LV (LV5FU2) or FOLFOX4 every 2 weeks for 12 cycles. Results: Results for the primary endpoint of the study (for the overall population, with a median follow-up [FU] of 3 years), showed a significant benefit in DFS for the FOLFOX4-treated patients (78.2% vs 72.9%; HR: 0.77, p=0.002) (André et al, NEJM, 2004). Patients were followed beyond the 3-year cut-off for DFS and overall survival (OS) updates. Final DFS, at 5 years FU, are consistent with earlier results (HR: 0.80, p = 0.003). In addition, at a median FU of 6 years, the study demonstrates a significant benefit in OS for the stage III patients. Summary of OS results (median FU 6 years) Long-term safety update shows no increase in the rate of secondary cancer (5.0% in both treatment arms). Conclusions: These results confirm the benefit of the FOLFOX4 regimen in adjuvant colon cancer patients. [Table: see text] No significant financial relationships to disclose.
Fortnightly review: Ductal carcinoma in situ of the breast
Authors: M. J Silverstein
Journal: BMJ (1998)

Ductal carcinoma in situ is a proliferation of malignant epithelial cells within the ductolobular system of the breast that show no light microscopic evidence of invasion through the basement membrane into the surrounding stroma (fig 1). Several forms of histological architecture are recognised, the most common of which are comedo, cribriform, solid, micropapillary, and papillary. Until recently, ductal carcinoma in situ was a relatively uncommon disease, representing only about 1% of all newly diagnosed cases of breast cancer.1 It was usually regarded as a single disease with a single treatment, namely, mastectomy. Most patients presenting with ductal carcinoma in situ had symptoms—a palpable mass or discharge from the nipple. During the past decade, as mammography has become more widely used and technically better, the number of new cases has increased dramatically. Most patients now present with lesions that are not palpable and are clinically occult. Furthermore, the notion of ductal carcinoma in situ as a single disease has evaporated. It is now well recognised as a heterogeneous group of lesions with a diverse malignant potential. As our understanding of the disease has evolved and the range of treatment options has widened, the process of making decisions about management has become more complex and controversial. Ductal carcinoma in situ has become so common and so confusing that the first textbook devoted solely to the disorder was not published until 1997.2 #### Summary points
Reduced Myocardial Nerve Growth Factor Expression in Human and Experimental Heart Failure
Authors: David M. Kaye, Gautam Vaddadi, Sara L. Gruskin, Xiao-Jun Du, Murray D. Esler
Journal: Circulation Research (2000)

Abstract —Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained. Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (n=11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (n=11, P &lt;0.05). In a rat model of CHF, a 40% reduction ( P &lt;0.05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content ( P &lt;0.05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 μmol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. The full text of this article is available at http://www.circresaha.org.
Berger in retrospect: effect of varied weight training programmes on strength
Authors: R N Carpinelli
Journal: British Journal of Sports Medicine (2002)

The evidence that multiple sets of exercise are superior to a single set for maximal strength gains, as suggested by Berger in 1962, is reviewed. The validity and practical significance of Berger's strength training study are questioned. Well controlled, methodologically sound studies that minimise confounding variables are required to support the hypothesis that multiple sets of exercise elicit superior gains in strength.
Costs of asthma are correlated with severity: a 1-yr prospective study
Authors: P. Godard, P. Chanez, L. Siraudin, N. Nicoloyannis, G. Duru
Journal: European Respiratory Journal (2001)

Asthma prevalence is increasing and asthma-related costs are likely to increase, but few studies have analysed the relationship of asthma costs and severity. The impact of severity on costs was quantified in a cohort of 318 asthmatic patients followed up prospectively for 1 yr. Patients presenting with a broad range of severity of the disease (intermittent, mild persistent, moderate persistent, severe persistent) were recruited by chest physicians throughout France and treated for 1 yr according to customary clinical practice and following international guidelines. Severity, direct and indirect costs, and quality of life (QoL) were assessed. A multivariate analysis was conducted to relate factors contributing to the costs measured. Mean direct costs for goods and services excluding hospitalization, numbers of consultations, supplementary examinations, and the use and cost of bronchodilators and corticosteroids, indirect costs of days lost from work, and adverse QoL parameters all increased significantly with increasing severity. This also applied to mean age, body weight, asthma duration, depression of forced expiratory volume in one second, and inhaled corticosteroid posology in the 234 patients completing the study. There was a significant relationship (r=0.614, p&lt;0.001) between direct costs (hospitalization and cures were excluded) and three domains of the QoL questionnaire (mobility, pain and energy). Overall costs of asthma (including individual direct costs, indirect costs, and intangible quality of life costs) are clearly related to severity. This is the first study in asthma to combine rigorous independent classification of grades of severity in statistically valid numbers of patients of grades receiving “real-world” treatment and followed-up prospectively for 1 yr. It allowed severity to be accurately related to direct, indirect and intangible costs of asthma. Quality of life explained a significant part of these costs.
Anoxia-induced release of prostaglandins in rabbit isolated hearts.
Authors: A J Block, H Feinberg, K Herbaczynska-Cedro, J R Vane
Journal: Circulation Research (1975)

We investigated the relationship between prostaglandin release and the coronary vasodilation evoked by anoxia. Isolated rabbit hearts were perfused via the aorta with Krebs-Ringer's solution. The coronary effluent was bioassayed continuously in terms of prostaglandin E2 for prostaglandinlike substance which was present (at less than 1 ng/ml) in 60 of 66 hearts. This basal release was abolished by the prostaglandin synthetase inhibitor, indomethacin (1-2 mug/ml), a result which adds further to the identity of the prostaglandinlike substance as a prostaglandin. Anoxia increased coronary flow sometimes by 100% and evoked prostaglandin release shortly thereafter. Ablolition of prostaglandin synthesis by indomethacin pretreatment did not affect nor did infusion of exogenous prostaglandin mimic the anoxia-induced flow increment; thus, we conclude that prostaglandin release cannot account for the anoxia-induced vasodilator response. Furthermore, the failure of indomethacin to alter resting coronary blood flow suggests that a local prostaglandin release is not responsible for either the maintenance or the modulation of coronary flow in this preparation.
Anti-TNF antibody treatment of Crohn's disease
Authors: S J H van Deventer
Journal: Annals of the Rheumatic Diseases (1999)

Crohn's disease and ulcerative colitis are the two idiopathic chronic inflammatory bowel diseases. Although these diseases may show substantial phenotypic overlap, it is widely accepted that these represent distinct pathogenic entities. The cause of neither ulcerative colitis nor Crohn's disease is known, and genetic as well as environmental factors have been implicated. Previous reports implicating single microbial pathogens ( Mycobacterium paratuberculosis, measles ) in Crohn's disease are controversial and have not been confirmed.1-11 On the other hand, evidence that antigen driven ill controlled activation of mucosal T lymphocytes is a major disease mechanism has accumulated in recent years, and this has led to novel therapeutic strategies. I here review the clinical results of anti-TNF antibody treatment against the background of current knowledge of the regulation of mucosal immune activation.

The incidence of Crohn's disease is increasing in Western Europe and the USA, and is now 6–10/100 000 inhabitants.12 13Because Crohn's disease is a lifetime disorder, the prevalence is at least 20-fold higher. The clinical symptoms and signs of Crohn's disease can be rather non-specific, including abdominal pain, weight loss, fatigue and (bloody) diarrhoea, but most patients with active disease have an increased erythrocyte sedimentation rate (ESR) or raised circulating C reactive protein concentrations. Although commonly known as “terminal ileitis”, only about 30% of patients have disease restricted to the terminal ileum, and most patients have isolated large bowel, or combined small and large bowel involvement. The disease may also involve the oral cavity, oesophagus and stomach, and can occur outside the intestinal tract, in particular in the perineal area (histologically characterised by granulomatous lymphangitis) or located in surgical wounds. About 20% of patients have perianal fistulas, and the presence of such lesions is a substantial risk factor for eventual complete loss of the large bowel and construction of a permanent …
Peroxisome Proliferator–Activated Receptor α Protects against Glomerulonephritis Induced by Long-Term Exposure to the Plasticizer Di-(2-Ethylhexyl)Phthalate
Authors: Yuji Kamijo, Kazuhiko Hora, Tamie Nakajima, Keiichi Kono, Kyoko Takahashi, Yuki Ito, Makoto Higuchi, Kendo Kiyosawa, Hidekazu Shigematsu, Frank J Gonzalez, Toshifumi Aoyama
Journal: Journal of the American Society of Nephrology (2006)

Safety concerns about di-(2-ethylhexyl)phthalate (DEHP), a plasticizer and a probable endocrine disruptor, have attracted considerable public attention, but there are few studies about long-term exposure to DEHP. DEHP toxicity is thought to involve peroxisome proliferator–activated receptor α (PPARα), but this contention remains controversial. For investigation of the long-term toxicity of DEHP and determination of whether PPARα mediates toxicity, wild-type and PPARα-null mice were fed a diet that contained 0.05 or 0.01% DEHP for 22 mo. PPARα-null mice that were exposed to DEHP exhibited prominent immune complex glomerulonephritis, most likely related to elevated glomerular oxidative stress. Elevated NADPH oxidase, low antioxidant enzymes, and absence of the PPARα-dependent anti-inflammatory effects that normally antagonize the NFκB signaling pathway accompanied the glomerulonephritis in PPARα-null mice. The results reported here indicate that PPARα protects against the nephrotoxic effects of long-term exposure to DEHP.
Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features
Authors: D. S. Kim, J. H. Park, B. K. Park, J. S. Lee, A. G. Nicholson, T. Colby
Journal: European Respiratory Journal (2005)

Although acute exacerbations of idiopathic pulmonary fibrosis are well recognised, there are no studies documenting their prevalence or identifying pre-existing risk factors. This study analysed the clinical, radiological and pathological data of 11 patients who satisfied the criteria for acute exacerbation among 147 patients with biopsy-proven idiopathic pulmonary fibrosis. There were five additional patients who had similar demographics, radiology and surgical lung biopsy pathology, but had clinically less severe disease, and so were not included. The 2-yr frequency of acute exacerbation was 9.6% after the diagnosis. Most exacerbations were idiopathic, although two cases presented after surgical lung biopsy and one after bronchoalveolar lavage. No significant risk factor was found by univariate proportional hazard analysis. Imaging revealed diffuse bilateral ground-glass opacification superimposed on subpleural reticular and honeycombing densities. The biopsies of four patients taken during acute exacerbation exhibited diffuse alveolar damage superimposed upon usual interstitial pneumonia. The findings of this study demonstrate that acute exacerbation of idiopathic pulmonary fibrosis is rather common and this exacerbation is likely to have a spectrum of severity.
Lineage-Specific Biomarkers Predict Response to FGFR Inhibition
Authors: David C. Loch, Pamela M. Pollock
Journal: Cancer Discovery (2012)

Abstract Summary: In this issue of Cancer Discovery, Guagnano and colleagues use a large and diverse annotated collection of cancer cell lines, the Cancer Cell Line Encyclopedia, to correlate whole-genome expression and genomic alteration datasets with cell line sensitivity data to the novel pan-fibroblast growth factor receptor (FGFR) inhibitor NVP-BGJ398. Their findings underscore not only the preclinical use of such cell line panels in identifying predictive biomarkers, but also the emergence of the FGFRs as valid therapeutic targets, across an increasingly broad range of malignancies. Cancer Discov; 2(12); 1081–3. ©2012 AACR. Commentary on Guagnano et al., p. 1118