tbuckley/cabot-search huggingface dataset:
Hepatitis C: new clues to better vaccines?
Authors: Marian E Major
Journal: Gut (2015)

HCV is a major public health problem in the USA and worldwide with the majority of acute infections progressing to chronicity in the absence of therapy. HCV infection is recognised as one of the major causes of liver disease, and is associated with the majority of liver transplantations in most countries. There have been tremendous advances in antiviral drug treatment for HCV over recent years, and current therapies can clear infections in the vast majority of people treated.1 However, treatment success can be limited by a range of factors, not least of which include the cost of therapy, which makes access to treatment challenging for many both within the USA and elsewhere. For these reasons, safe, effective and affordable prophylactic vaccines against HCV remain the best long-term hope for bringing the global epidemic under control. Such vaccines will also help to circumvent issues such as drug resistance, drug–drug interaction in patients with HIV coinfection, susceptibility of treated individuals to reinfection and drug side effects.

There is strong evidence that an effective HCV vaccine to prevent chronic infection is attainable. A form of protective immunity has been demonstrated in studies of both chimpanzees and humans that have been exposed to the virus after recovering from primary infections.2 ,3 Although HCV RNA can be detected in these secondary infections, the kinetics are different due to rapid control of viral …
Adeno-Associated Virus–Mediated Antiangiogenic Gene Therapy with Thrombospondin-1 Type 1 Repeats and Endostatin
Authors: Xuefeng Zhang, Jianfeng Xu, Jack Lawler, Ernest Terwilliger, Sareh Parangi
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Recombinant adeno-associated virus (rAAV)-mediated antiangiogenic gene therapy offers a powerful strategy for cancer treatment, maintaining sustained levels of antiangiogenic factors with coincident enhanced therapeutic efficacy. We aimed to develop rAAV-mediated antiangiogenic gene therapy delivering endostatin and 3TSR, the antiangiogenic domain of thrombospondin-1. Experimental Design: rAAV vectors were constructed to express endostatin (rAAV-endostatin) or 3TSR (rAAV-3TSR). The antiangiogenic efficacy of the vectors was characterized using a vascular endothelial growth factor (VEGF)-induced mouse ear angiogenesis model. To evaluate the antitumor effects of the vectors, immunodeficient mice were pretreated with rAAV-3TSR or rAAV-endostatin and received orthotopic implantation of cancer cells into the pancreas. To mimic clinical situations, mice bearing pancreatic tumors were treated with intratumoral injection of rAAV-3TSR or rAAV-endostatin. Results: rAAV-mediated i.m. gene delivery resulted in expression of the transgene in skeletal muscle with inhibition of VEGF-induced angiogenesis at a distant site (the ear). Local delivery of the vectors into the mouse ear also inhibited VEGF-induced ear angiogenesis. Pretreatment of mice with i.m. or intrasplenic injection of rAAV-endostatin or rAAV-3TSR significantly inhibited tumor growth. A single intratumoral injection of each vector also significantly decreased the volume of large established pancreatic tumors. Tumor microvessel density was significantly decreased in each treatment group and was well correlated with tumor volume reduction. Greater antiangiogenic and antitumor effects were achieved when rAAV-3TSR and rAAV-endostatin were combined. Conclusions: rAAV-mediated 3TSR and endostatin gene therapy showed both localized and systemic therapeutic effects against angiogenesis and tumor growth and may provide promise for patients with pancreatic cancer.
Measurements of Carotid Intima-Media Thickness and of Interadventitia Common Carotid Diameter Improve Prediction of Cardiovascular Events
Authors: Damiano Baldassarre, Anders Hamsten, Fabrizio Veglia, Ulf de Faire, Steve E. Humphries, Andries J. Smit, Philippe Giral, Sudhir Kurl, Rainer Rauramaa, Elmo Mannarino, Enzo Grossi, Rodolfo Paoletti, Elena Tremoli
Journal: Journal of the American College of Cardiology (2012)
Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD
Authors: Kenji Mizumura, Suzanne M. Cloonan, Kiichi Nakahira, Abhiram R. Bhashyam, Morgan Cervo, Tohru Kitada, Kimberly Glass, Caroline A. Owen, Ashfaq Mahmood, George R. Washko, Shu Hashimoto, Stefan W. Ryter, Augustine M.K. Choi
Journal: Journal of Clinical Investigation (2014)

The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, Pink1(-/-) mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.
Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition
Authors: Javier Milara, Adela Serrano, Teresa Peiró, Enrique Artigues, Amadeu Gavaldà, Montse Miralpeix, Esteban J. Morcillo, Julio Cortijo
Journal: European Respiratory Journal (2012)

Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of this remodelling, peribronchiolar fibrosis is observed in the small airways of COPD patients and contributes to airway obstruction. Fibroblast-to-myofibroblast transition is a key step in peribronchiolar fibrosis formation. This <i>in vitro</i> study examined the effect of cigarette smoke on bronchial fibroblast-to-myofibroblast transition, and whether aclidinium bromide inhibits this process. Human bronchial fibroblasts were incubated with aclidinium bromide (10<sup>−9</sup>–10<sup>−7</sup> M) and exposed to cigarette smoke extract. Collagen type I and α-smooth muscle actin (α-SMA) expression were measured by real-time PCR and Western blotting, as myofibroblast markers. Intracellular reactive oxygen species, cyclic AMP (cAMP), extracellular signal-regulated kinase (ERK)1/2 and choline acetyltransferase were measured as intracellular signalling mediators. Cigarette smoke-induced collagen type I and α-SMA was mediated by the production of reactive oxygen species, the depletion of intracellular cAMP and the increase of ERK1/2 phosphorylation and choline acetyltransferase. These effects could be reversed by treatment with the anticholinergic aclidinium bromide, by silencing the mRNA of muscarinic receptors M1, M2 or M3, or by the depletion of extracellular acetylcholine by treatment with acetylcholinesterase. A non-neuronal cholinergic system is implicated in cigarette smoke-induced bronchial fibroblast-to-myofibroblast transition, which is inhibited by aclidinium bromide.
A Bayesian cost-effectiveness analysis of a telemedicine-based strategy for the management of sleep apnoea: a multicentre randomised controlled trial
Authors: Valentina Isetta, Miguel A Negrín, Carmen Monasterio, Juan F Masa, Nuria Feu, Ainhoa Álvarez, Francisco Campos-Rodriguez, Concepción Ruiz, Jorge Abad, Francisco J Vázquez-Polo, Ramon Farré, Marina Galdeano, Patricia Lloberes, Cristina Embid, Mónica de la Peña, Javier Puertas, Mireia Dalmases, Neus Salord, Jaime Corral, Bernabé Jurado, Carmen León, Carlos Egea, Aida Muñoz, Olga Parra, Roser Cambrodi, María Martel-Escobar, Meritxell Arqué, Josep M Montserrat
Journal: Thorax (2015)

<h3>Background</h3> Compliance with continuous positive airway pressure (CPAP) therapy is essential in patients with obstructive sleep apnoea (OSA), but adequate control is not always possible. This is clinically important because CPAP can reverse the morbidity and mortality associated with OSA. Telemedicine, with support provided via a web platform and video conferences, could represent a cost-effective alternative to standard care management. <h3>Aim</h3> To assess the telemedicine impact on treatment compliance, cost-effectiveness and improvement in quality of life (QoL) when compared with traditional face-to-face follow-up. <h3>Methods</h3> A randomised controlled trial was performed to compare a telemedicine-based CPAP follow-up strategy with standard face-to-face management. Consecutive OSA patients requiring CPAP treatment, with sufficient internet skills and who agreed to participate, were enrolled. They were followed-up at 1, 3 and 6 months and answered surveys about sleep, CPAP side effects and lifestyle. We compared CPAP compliance, cost-effectiveness and QoL between the beginning and the end of the study. A Bayesian cost-effectiveness analysis with non-informative priors was performed. <h3>Results</h3> We randomised 139 patients. At 6 months, we found similar levels of CPAP compliance, and improved daytime sleepiness, QoL, side effects and degree of satisfaction in both groups. Despite requiring more visits, the telemedicine group was more cost-effective: costs were lower and differences in effectiveness were not relevant. <h3>Conclusions</h3> A telemedicine-based strategy for the follow-up of CPAP treatment in patients with OSA was as effective as standard hospital-based care in terms of CPAP compliance and symptom improvement, with comparable side effects and satisfaction rates. The telemedicine-based strategy had lower total costs due to savings on transport and less lost productivity (indirect costs). <h3>Trial register number</h3> NCT01716676.
Glucocorticoid Receptor Antagonism as a Novel Therapy for Triple-Negative Breast Cancer
Authors: Maxwell N. Skor, Erin L. Wonder, Masha Kocherginsky, Anju Goyal, Ben A. Hall, Yi Cai, Suzanne D. Conzen
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Triple-negative breast cancer (TNBC) accounts for 10% to 20% of newly diagnosed invasive breast cancer. Finding effective targets for chemotherapy-resistant TNBC has proven difficult in part because of TNBC's molecular heterogeneity. We have previously reported that likely because of the antiapoptotic activity of glucocorticoid receptor (GR) in estrogen receptor (ER)-negative breast epithelial and cancer cells, high GR expression/activity in early-stage TNBC significantly correlates with chemotherapy resistance and increased recurrence. We hypothesized that pretreatment with mifepristone, a GR antagonist, would potentiate the efficacy of chemotherapy in GR+ TNBCs by inhibiting the antiapoptotic signaling pathways of GR and increasing the cytotoxic efficiency of chemotherapy. Experimental Design: TNBC cell apoptosis was examined in the context of physiologic glucocorticoid concentrations, chemotherapy, and/or pharmacologic concentrations of mifepristone. We used high-throughput live microscopy with continuous recording to measure apoptotic cells stained with a fluorescent dye and Western blot analysis to detect caspase-3 and PARP cleavage. The effect of mifepristone on GR-mediated gene expression was also measured. TNBC xenograft studies were performed in female severe combined immunodeficient (SCID) mice and tumors were measured following treatment with vehicle, paclitaxel, or mifepristone/paclitaxel. Results: We found that although mifepristone treatment alone had no significant effect on TNBC cell viability or clonogenicity in the absence of chemotherapy, the addition of mifepristone to dexamethasone/paclitaxel treatment significantly increased cytotoxicity and caspase-3/PARP cleavage. Mifepristone also antagonized GR-induced SGK1 and MKP1/DUSP1 gene expression while significantly augmenting paclitaxel-induced GR+ MDA-MB-231 xenograft tumor shrinkage in vivo. Conclusions: These results suggest that mifepristone pretreatment could be a useful strategy for increasing tumor cell apoptosis in chemotherapy-resistant GR+ TNBC. Clin Cancer Res; 19(22); 6163–72. ©2013 AACR.
A Conversation with Susan Band Horwitz
Authors: Susan Band Horwitz, I. David Goldman
Journal: The Annual Review of Pharmacology and Toxicology (2015)

Susan Band Horwitz is a Distinguished Professor and holds the Falkenstein Chair in Cancer Research at Albert Einstein College of Medicine in New York. She is co-chair of the Department of Molecular Pharmacology and associate director for therapeutics at the Albert Einstein Cancer Center. After graduating from Bryn Mawr College, Dr. Horwitz received her PhD in biochemistry from Brandeis University. She has had a continuing interest in natural products as a source of new drugs for the treatment of cancer. Her most seminal research contribution has been in the development of Taxol ® . Dr. Horwitz and her colleagues made the discovery that Taxol had a unique mechanism of action and suggested that it was a prototype for a new class of antitumor drugs. Although Taxol was an antimitotic agent blocking cells in the metaphase stage of the cell cycle, Dr. Horwitz recognized that Taxol was blocking mitosis in a way different from that of other known agents. Her group demonstrated that the binding site for Taxol was on the β-tubulin subunit. The interaction of Taxol with the β-tubulin subunit resulted in stabilized microtubules, essentially paralyzing the cytoskeleton, thereby preventing cell division. Dr. Horwitz served as president (2002–2003) of the American Association for Cancer Research (AACR). She is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. She has received numerous honors and awards, including the C. Chester Stock Award from Memorial Sloan Kettering Cancer Center, the Warren Alpert Foundation Prize from Harvard Medical School, the Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research, the American Cancer Society's Medal of Honor, and the AACR Award for Lifetime Achievement in Cancer Research. The following interview was conducted on January 23, 2014.
Racial and Ethnic Differences in Microalbuminuria Prevalence in a Diabetes Population
Authors: Bessie A. Young, Wayne J. Katon, Michael Von Korff, Greg E. Simon, Elizabeth H. B. Lin, Paul S. Ciechanowski, Terry Bush, Malia Oliver, Evette J. Ludman, Edward J. Boyko
Journal: Journal of the American Society of Nephrology (2004)

The objective of this study was to determine whether racial or ethnic differences in prevalence of diabetic microalbuminuria were observed in a large primary care population in which comparable access to health care exists. A cross-sectional analysis of survey and automated laboratory data 2969 primary care diabetic patients of a large regional health maintenance organization was conducted. Study data were analyzed for racial/ethnic differences in microalbuminuria (30 to 300 mg albumin/g creatinine) and macroalbuminuria (&gt;300 mg albumin/g creatinine) prevalence among diabetes registry–identified patients who completed a survey that assessed demographics, diabetes care, and depression. Computerized pharmacy, hospital, and laboratory data were linked to survey data for analysis. Racial/ethnic differences in the odds of microalbuminuria and macroalbuminuria were assessed by unconditional logistic regression, stratified by the presence of hypertension. Among those tested, the unadjusted prevalence of micro- or macroalbuminuria was 30.9%, which was similar among the various racial/ethnic groups. Among those without hypertension, microalbuminuria was twofold greater (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.14 to 3.53) and macroalbuminuria was threefold greater (OR 3.17; 95% CI 1.09 to 9.26) for Asians as compared with whites. Among those with hypertension, adjusted odds of microalbuminuria were greater for Hispanics (OR 3.82; 95% CI 1.16 to 12.57) than whites, whereas adjusted odds of macroalbuminuria were threefold greater for blacks (OR 3.32; 95% CI 1.26 to 8.76) than for whites. For most racial/ethnic minorities, hypertriglyceridemia was significantly associated with greater odds of micro- and macroalbuminuria. Among a large primary care population, racial/ethnic differences exist in the adjusted prevalence of microalbuminuria and macroalbuminuria depending on hypertension status. In this setting, racial/ethnic differences in early diabetic nephropathy were observed despite comparable access to diabetes care.
Distinguishing Colonization From Infection With <i>Staphylococcus aureus</i> in Diabetic Foot Ulcers With Miniaturized Oligonucleotide Arrays
Authors: Albert Sotto, Jean-Louis Richard, Nourredine Messad, Nicolas Molinari, Nathalie Jourdan, Sophie Schuldiner, Ariane Sultan, Christian Carrière, Bertrand Canivet, Luce Landraud, Gérard Lina, Jean-Philippe Lavigne
Journal: Diabetes Care (2012)

To extend our previous work on evaluating the use of oligonucleotide arrays to discriminate colonization from infection owing to Staphylococcus aureus in diabetic foot ulcers (DFUs).Patients admitted to 14 French diabetic foot departments for a DFU were screened for entry into the study. At admission, ulcers were classified based on clinical examination according to the Infectious Diseases Society of America system. Only patients with monomicrobial culture for S. aureus were included. In persons with an uninfected ulcer, a second wound bacterial specimen was obtained 1 month later. Using oligonucleotide arrays, S. aureus resistance and virulence genes were determined, and each isolate was affiliated to a clonal complex (CC).S. aureus was initially isolated from 75 uninfected and 120 infected ulcers; 35 were methicillin resistant. A total of 44 (59%) strains from uninfected DFUs belonged to CC5/CC8 clones vs. 6 (5%) from infected DFUs (P < 0.001). During follow-up, 57 (76%) of uninfected DFUs healed or had a favorable outcome; the strain in 49 (86%) of them belonged to CC5/CC8. Conversely, 18 (24%) had a poor outcome but not a single strain belonged to CC5/CC8 clone. Moreover, lukDE was significantly associated with a favorable outcome of the wound.As suggested by our previous study, the use of DNA arrays appears to be a promising technique that might help distinguishing uninfected from infected wounds, predicting ulcer outcome and then contributing to a more adequate use of antibiotics.
Coenzyme Q10 Improves Endothelial Dysfunction in Statin-Treated Type 2 Diabetic Patients
Authors: Sandra J. Hamilton, Gerard T. Chew, Gerald F. Watts
Journal: Diabetes Care (2009)

OBJECTIVE The vascular benefits of statins might be attenuated by inhibition of coenzyme Q10 (CoQ10) synthesis. We investigated whether oral CoQ10 supplementation improves endothelial dysfunction in statin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS In a double-blind crossover study, 23 statin-treated type 2 diabetic patients with LDL cholesterol &amp;lt;2.5mmol/l and endothelial dysfunction (brachial artery flow-mediated dilatation [FMD] &amp;lt;5.5%) were randomized to oral CoQ10 (200 mg/day) or placebo for 12 weeks. We measured brachial artery FMD and nitrate-mediated dilatation (NMD) by ultrasonography. Plasma F2-isoprostane and 24-h urinary 20-hydroxyeicosatetraenoic acid (HETE) levels were measured as systemic oxidative stress markers. RESULTS Compared with placebo, CoQ10 supplementation increased brachial artery FMD by 1.0 ± 0.5% (P = 0.04), but did not alter NMD (P = 0.66). CoQ10 supplementation also did not alter plasma F2-isoprostane (P = 0.58) or urinary 20-HETE levels (P = 0.28). CONCLUSIONS CoQ10 supplementation improved endothelial dysfunction in statin-treated type 2 diabetic patients, possibly by altering local vascular oxidative stress.
NCCN Task Force Report: Specialty Pharmacy
Authors: Rowena N. Schwartz, Kirby J. Eng, Deborah A. Frieze, Tracy K. Gosselin, Niesha Griffith, Amy Hatfield Seung, Jennifer M. Hinkel, Philip E. Johnson, Shirley A. Johnson, Edward C. Li, Audrea Hotsko Szabatura, Michael K. Wong
Journal: Journal of the National Comprehensive Cancer Network (2010)

The use of specialty pharmacies is expanding in oncology pharmacy practice. Specialty pharmacies provide a channel for distributing drugs that, from the payor perspective, creates economies of scale and streamlines the delivery of expensive drugs. Proposed goals of specialty pharmacy include optimization of pharmaceutical care outcomes through ensuring appropriate medication use and maximizing adherence, and optimization of economic outcomes through avoiding unwarranted drug expenditure. In oncology practice, specialty pharmacies have become a distribution channel for various agents. The use of a specialty pharmacy, and the addition of the pharmacist from the specialty pharmacy to the health care team, may not only provide benefits for care but also present challenges in oncology practice. The NCCN Specialty Pharmacy Task Force met to identify and examine the impact of specialty pharmacy practice on the care of people with cancer, and to provide recommendations regarding issues discussed. This report provides recommendations within the following categories: education and training of specialty pharmacy practitioners who care for individuals with cancer, coordination of care, and patient safety. Areas for further evaluation are also identified.