tbuckley/cabot-search huggingface dataset:
Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial
Authors: Eric Lawitz, Edward Gane, Brian Pearlman, Edward Tam, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-Pierre Bronowicki, Laura Lester, William Sievert, Reem Ghalib, Luis Balart, Fredrik Sund, Martin Lagging, Frank Dutko, Melissa Shaughnessy, Peggy Hwang, Anita Y M Howe, Janice Wahl, Michael Robertson, Eliav Barr, Barbara Haber
Journal: The Lancet (2014)
Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells
Authors: None Anggakusuma, Che C Colpitts, Luis M Schang, Heni Rachmawati, Anne Frentzen, Stephanie Pfaender, Patrick Behrendt, Richard J P Brown, Dorothea Bankwitz, Joerg Steinmann, Michael Ott, Philip Meuleman, Charles M Rice, Alexander Ploss, Thomas Pietschmann, Eike Steinmann
Journal: Gut (2013)

<h3>Objective</h3> Hepatitis C virus (HCV) infection causes severe liver disease and affects more than 160 million individuals worldwide. People undergoing liver organ transplantation face universal re-infection of the graft. Therefore, affordable antiviral strategies targeting the early stages of infection are urgently needed to prevent the recurrence of HCV infection. The aim of the study was to determine the potency of turmeric curcumin as an HCV entry inhibitor. <h3>Design</h3> The antiviral activity of curcumin and its derivatives was evaluated using HCV pseudo-particles (HCVpp) and cell-culture-derived HCV (HCVcc) in hepatoma cell lines and primary human hepatocytes. The mechanism of action was dissected using R18-labelled virions and a membrane fluidity assay. <h3>Results</h3> Curcumin treatment had no effect on HCV RNA replication or viral assembly/release. However, co-incubation of HCV with curcumin potently inhibited entry of all major HCV genotypes. Similar antiviral activities were also exerted by other curcumin derivatives but not by tetrahydrocurcumin, suggesting the importance of α,β-unsaturated ketone groups for the antiviral activity. Expression levels of known HCV receptors were unaltered, while pretreating the virus with the compound reduced viral infectivity without viral lysis. Membrane fluidity experiments indicated that curcumin affected the fluidity of the HCV envelope resulting in impairment of viral binding and fusion. Curcumin has also been found to inhibit cell-to-cell transmission and to be effective in combination with other antiviral agents. <h3>Conclusions</h3> Turmeric curcumin inhibits HCV entry independently of the genotype and in primary human hepatocytes by affecting membrane fluidity thereby impairing virus binding and fusion.
Authors’ reply to Lee and colleagues
Authors: Teppo Järvinen, Karl Michaëlsson, Jarkko Jokihaara, Gary S Collins, Thomas L Perry, Barbara Mintzes, Vijaya Musini, Juan Erviti, Javier Gorricho, James M Wright, Harri Sievänen
Journal: BMJ (2015)

Lee and colleagues of the National Bone Health Alliance (NBHA) call for expanded fracture liaison services (FLS), because secondary prevention represents the most productive opportunity for pharmacotherapy. Intuitively this seems logical, but supporting arguments do not stand up to scrutiny.1 2

The effectiveness of FLS should be tested in randomised controlled trials (RCTs) to see whether this approach can achieve the “quality outcomes” referred to1—prevention of second fractures—as opposed to the proportion of patients evaluated or prescribed drugs. Presently, evidence on FLS is limited to observational studies or …
A Classification of Unstable Angina Revisited
Authors: Christian W. Hamm, Eugene Braunwald
Journal: Circulation (2000)

Abstract —Unstable angina is a critical phase of coronary heart disease with widely variable symptoms and prognosis. A decade ago, a classification of unstable angina based on clinical symptoms was introduced. This system was then validated by prospective clinical studies to correlate with the prognosis and was linked to angiographic and histological findings. It has been used to categorize patients in many large clinical trials. In recent years, the pathophysiological roles of platelet activation and inflammation in unstable angina have been elucidated. Subsequently, improved markers of myocardial injury, acute-phase proteins, and hemostatic markers that may be associated with clinical outcomes have been identified. Particularly, cardiac-specific troponin T and troponin I have been shown to represent the best predictors of early risk in patients with angina at rest. Accordingly, it is suggested that the original classification be extended by subclassifying one large group of unstable angina patients, ie, those with angina at rest within the past 48 hours (class IIIB), into troponin-positive (T pos ) and troponin-negative (T neg ) patients. The 30-days risk for death and myocardial infarction is considered to be up to 20% in class IIIB-T pos but &lt;2% in class IIIB-T neg patients. Initial results suggest that troponins may function as surrogate markers for thrombus formation and can effectively guide therapy with glycoprotein IIb/IIIa antagonists or low-molecular-weight heparins. These observations provide additional impetus for adding the measurement of these markers to the clinical classification and represent a novel concept of treating these high-risk patients.
Heterosexual transmission of HIV
Authors: V. F. Guinee
Journal: JAMA (1992)

<h3>To the Editor.</h3> —Heterosexual transmission of HIV is decidedly in one direction, according to recent data published and distributed by the AIDS Surveillance Unit of the New York City Department of Health. Among 26985 men with AIDS reported through March 1991, a history of acquiring the infection because of intercourse with women at risk was elicited in only 11 instances.<sup>1</sup>This is in contrast to 1148 (25%) of 4640 women with AIDS who reported having sex with men at risk (the report notes that data are not tabulated on intravenous drug users who also report high-risk heterosexual contact). It is probable that the pool of high-risk men exceeds the infected female population. For example, there are 9420 reported intravenous drug-user cases among men and 2623 among women. Thus, there would be a greater chance of a woman contracting HIV from any given sexual contact with a man than vice
Cancer in Asbestos-Mining and Other Areas of Quebec 2
Authors: Saxon Graham, Madeleine Blanchet, Thomas Rohrer
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Cancer in Asbestos-Mining and Other Areas of Quebec Get access Saxon Graham, Ph.D., Saxon Graham, Ph.D. 3Research Program in Social Epidemiology and Control of Cancer, Departments of Sociology and Social and Preventive Medicine, State University of New York at Buffalo, 4224 Ridge Lea, Amherst, N.Y. 14226. Search for other works by this author on: Oxford Academic PubMed Google Scholar Madeleine Blanchet, M.D., Madeleine Blanchet, M.D. 4Director of Epidemiological Studies, Ministère des Affaires Sociales, Gouvernment du Québec, Quebec, Canada. Search for other works by this author on: Oxford Academic PubMed Google Scholar Thomas Rohrer, M.A. Thomas Rohrer, M.A. 5Research Program in Social Epidemiology and Control of Cancer, State University of New York at Buffalo. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 59, Issue 4, October 1977, Pages 1139–1145, https://doi.org/10.1093/jnci/59.4.1139 Published: 01 October 1977 Article history Received: 24 January 1977 Accepted: 06 April 1977 Published: 01 October 1977
The Chemokine Receptor D6 Has Opposing Effects on Allergic Inflammation and Airway Reactivity
Authors: Gregory S. Whitehead, Tie Wang, Laura M. DeGraff, Jeffrey W. Card, Sergio A. Lira, Gerard J. Graham, Donald N. Cook
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2 (Th2)-associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its pulmonary function is unknown.This study tested whether D6 regulates pulmonary chemokine levels, inflammation, or airway responsiveness during allergen-induced airway disease.D6-deficient and genetically matched C57BL/6 mice were sensitized and challenged with ovalbumin. ELISA and flow cytometry were used to measure levels of cytokines and leukocytes, respectively. Mechanical ventilation was used to measure airway reactivity.The ability of D6 to diminish chemokine levels in the lung was chemokine concentration dependent. CCL17 and CCL22 were abundant in the airway, and their levels were attenuated by D6 when they were within a defined concentration range. By contrast, airway concentrations of CCL3, CCL5, and CCL11 were low and unaffected by D6. Allergen-challenged D6-deficient mice had more dendritic cells, T cells, and eosinophils in the lung parenchyma and more eosinophils in the airway than similarly challenged C57BL/6 mice. By contrast, D6-deficient mice had reduced airway responses to methacholine compared with C57BL/6 mice. Thus, D6 has opposing effects on inflammation and airway reactivity.The ability of D6 to scavenge chemokines in the lung is dependent on chemokine concentration. The absence of D6 increases inflammation, but reduces airway reactivity. These findings suggest that inhibiting D6 function might be a novel means to attenuate airway responses in individuals with allergic asthma.
The clinical Significance of serum CD8 antigen levels in adult patients with Hodgkin's disease
Authors: A. Gause, K. Verpoort, V. Roschansky, A. Tschiersch, D. Hasenclever, R. Schmits, V. Diehl, O. Brosteanu, M. Pfreundschuh
Journal: Annals of Oncology (1991)
Anabolic agents: recent strategies for their detection and protection from inadvertent doping
Authors: Hans Geyer, Wilhelm Schänzer, Mario Thevis
Journal: British Journal of Sports Medicine (2014)

According to the World Anti-Doping Agency (WADA) Prohibited List, anabolic agents consist of exogenous anabolic androgenic steroids (AAS), endogenous AAS and other anabolic agents such as clenbuterol and selective androgen receptor modulators (SARMs). Currently employed strategies for their improved detection include the prolongation of the detection windows for exogenous AAS, non-targeted and indirect analytical approaches for the detection of modified steroids (designer steroids), the athlete’s biological passport and isotope ratio mass spectrometry for the detection of the misuse of endogenous AAS, as well as preventive doping research for the detection of SARMs. The recent use of these strategies led to 4–80-fold increases of adverse analytical findings for exogenous AAS, to the detection of the misuse of new designer steroids, to adverse analytical findings of different endogenous AAS and to the first adverse analytical findings of SARMs. The strategies of the antidoping research are not only focused on the development of methods to catch the cheating athlete but also to protect the clean athlete from inadvertent doping. Within the past few years several sources of inadvertent doping with anabolic agents have been identified. Among these are nutritional supplements adulterated with AAS, meat products contaminated with clenbuterol, mycotoxin (zearalenone) contamination leading to zeranol findings, and natural products containing endogenous AAS. The protection strategy consists of further investigations in case of reasonable suspicion of inadvertent doping, publication of the results, education of athletes and development of methods to differentiate between intentional and unintentional doping.
Wait-and-See Policy for Clinical Complete Responders After Chemoradiation for Rectal Cancer
Authors: Monique Maas, Regina G.H. Beets-Tan, Doenja M.J. Lambregts, Guido Lammering, Patty J. Nelemans, Sanne M.E. Engelen, Ronald M. van Dam, Rob L.H. Jansen, Meindert Sosef, Jeroen W.A. Leijtens, Karel W.E. Hulsewé, Jeroen Buijsen, Geerard L. Beets
Journal: Journal of Clinical Oncology (2011)

Purpose Neoadjuvant chemoradiotherapy for rectal cancer can result in complete disappearance of tumor and involved nodes. In patients without residual tumor on imaging and endoscopy (clinical complete response [cCR]) a wait-and-see-policy (omission of surgery with follow-up) might be considered instead of surgery. The purpose of this prospective cohort study was to evaluate feasibility and safety of a wait-and-see policy with strict selection criteria and follow-up. Patients and Methods Patients with a cCR after chemoradiotherapy were prospectively selected for the wait-and-see policy with magnetic resonance imaging (MRI) and endoscopy plus biopsies. Follow-up was performed 3 to 6 monthly and consisted of MRI, endoscopy, and computed tomography scans. A control group of patients with a pathologic complete response (pCR) after surgery was identified from a prospective cohort study. Functional outcome was measured with the Memorial Sloan-Kettering Cancer Center (MSKCC) bowel function questionnaire and Wexner incontinence score. Long-term outcome was estimated by using Kaplan-Meier curves. Results Twenty-one patients with cCR were included in the wait-and-see policy group. Mean follow-up was 25 ± 19 months. One patient developed a local recurrence and had surgery as salvage treatment. The other 20 patients are alive without disease. The control group consisted of 20 patients with a pCR after surgery who had a mean follow-up of 35 ± 23 months. For these patients with a pCR, cumulative probabilities of 2-year disease-free survival and overall survival were 93% and 91%, respectively. Conclusion A wait-and-see policy with strict selection criteria, up-to-date imaging techniques, and follow-up is feasible and results in promising outcome at least as good as that of patients with a pCR after surgery. The proposed selection criteria and follow-up could form the basis for future randomized studies.
Surfactant treatment before reperfusion improves the immediate function of lung transplants in rats.
Authors: M E Erasmus, A H Petersen, G Hofstede, H P Haagsman, S Bambang Oetomo, J Prop
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

An impaired function of alveolar surfactant can cause lung transplant dysfunction early after reperfusion. In this study it was investigated whether treatment with surfactant before reperfusion improves the immediate function of lung transplants and whether an improved transplant function was associated with an increase in alveolar surfactant components. Left lungs with 6-h (n = 8) or prolonged 20-h ischemia (n = 10) were transplanted syngeneically in rats. In both ischemia groups half of the lung transplants were treated with surfactant just before reperfusion. Lung function was measured during reperfusion for 1 h. Thereafter, the rats were killed and bronchoalveolar lavage was performed to measure alveolar surfactant components. We found that surfactant treatment improved the immediate function of lung transplants in parallel with a higher amount of total surfactant phospholipids, a higher percentage of the heavy subtype of surfactant, a normalized percentage of phosphatidylcholine, and a higher amount of endogenous surfactant protein A (SP-A). We conclude that surfactant treatment before reperfusion does improve the immediate lung transplant function in rats in association with an increase in alveolar surfactant components. More particularly, the amount of (endogenous) SP-A is thought to be crucial for the efficacy of surfactant treatment after lung transplantation.
Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver
Authors: Dirk Grimm, Lora Wang, Joyce S. Lee, Nina Schürmann, Shuo Gu, Kathleen Börner, Theresa A. Storm, Mark A. Kay
Journal: Journal of Clinical Investigation (2010)

shRNA overexpression from viral gene therapy vectors can trigger cytotoxicity leading to organ failure and lethality in mice and rats. This process likely involves saturation of endogenous cellular RNAi factors including exportin-5 (Xpo-5). Here, we have shown that Xpo-5 overexpression enhanced shRNA efficiency in the liver of adult mice but increased hepatotoxicity. We identified the 4 members of the human Argonaute (Ago) protein family as downstream factors involved in saturation of endogenous cellular RNAi, all of which were able to interact with shRNAs in cells and mice. In Ago/shRNA coexpression studies, Ago-2 (Slicer) was the primary rate-limiting determinant of both in vitro and in vivo RNAi efficacy, toxicity, and persistence. In adult mice, vector-based Ago-2/Xpo-5 coexpression enhanced U6-driven shRNA silencing of exogenous and endogenous hepatic targets, reduced hepatotoxicity, and extended RNAi stability by more than 3 months. Use of weaker RNA polymerase III promoters to minimize shRNA expression likewise alleviated in vivo toxicity and permitted greater than 95% persistent knockdown of hepatitis B virus and other transgenes in mouse liver for more than 1 year. Our studies substantiate that abundant small RNAs can overload the endogenous RNAi pathway and reveal possible strategies for reducing hepatotoxicity of short- and long-term clinical gene silencing in humans.
Activation of RhoA and Inhibition of Myosin Phosphatase as Important Components in Hypertension in Vascular Smooth Muscle
Authors: Tetsuya Seko, Masaaki Ito, Yasuko Kureishi, Ryuji Okamoto, Nobuyuki Moriki, Katsuya Onishi, Naoki Isaka, David J. Hartshorne, Takeshi Nakano
Journal: Circulation Research (2003)

Two mechanisms are proposed to account for the inhibition of myosin phosphatase (MP) involved in Ca 2+ sensitization of vascular muscle, ie, phosphorylation of either MYPT1, a target subunit of MP or CPI-17, an inhibitory phosphoprotein. In cultured vascular aorta smooth muscle cells (VSMCs), stimulation with angiotensin II activated RhoA, and this was blocked by pretreatment with 8-bromo-cGMP. VSMCs stimulated by angiotensin II, endothelin-1, or U-46619 significantly increased the phosphorylation levels of both MYPT1 (at Thr696) and CPI-17 (at Thr38). The angiotensin II-induced phosphorylation of MYPT1 was completely blocked by 8-bromo-cGMP or Y-27632 (a Rho-kinase inhibitor), but not by GF109203X (a PKC inhibitor). In contrast, phosphorylation of CPI-17 was inhibited only by GF109203X. Y-27632 dramatically corrected the hypertension in N ω -nitro- l -arginine methyl ester (L-NAME)-treated rats, and this hypertension also was sensitive to isosorbide mononitrate. The level of the active form of RhoA was significantly higher in aortas from L-NAME-treated rats. Expression of RhoA, Rho-kinase, MYPT1, CPI-17, and myosin light chain kinase were not significantly different in aortas from L-NAME-treated and control rats. Activation of RhoA without changes in levels of other signaling molecules were observed in three other rat models of hypertension, ie, stroke-prone spontaneously hypertensive rats, renal hypertensive rats, and DOCA-salt rats. These results suggest that independent of the cause of hypertension, a common point in downstream signaling and a critical component of hypertension is activation of RhoA and subsequent activation of Rho-kinase.
Structure-Function Relationship Between Corneal Nerves and Conventional Small-Fiber Tests in Type 1 Diabetes
Authors: Gavasker A. Sivaskandarajah, Elise M. Halpern, Leif E. Lovblom, Alanna Weisman, Steven Orlov, Vera Bril, Bruce A. Perkins
Journal: Diabetes Care (2013)

OBJECTIVE In vivo corneal confocal microscopy (IVCCM) has been proposed as a noninvasive technique to assess small nerve fiber structural morphology. We investigated the structure-function relationship of small fibers in diabetic sensorimotor polyneuropathy (DSP). RESEARCH DESIGN AND METHODS Ninety-six type 1 diabetic subjects with a spectrum of clinical DSP and 64 healthy volunteers underwent IVCCM examinations to determine corneal nerve structure, including corneal nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and fiber tortuosity (CNFT). Small nerve fiber function was assessed by cooling detection thresholds (CDTs), axon reflex–mediated neurogenic vasodilatation in response to cutaneous heating by laser Doppler imaging flare technique (LDIFLARE), and heart rate variability (HRV). Linear associations between structural and functional measures in type 1 diabetic subjects were determined using Spearman correlation coefficients and linear regression analysis. RESULTS Of the type 1 diabetic subjects, with a mean age of 38.2 ± 15.5 years and a mean HbA1c of 7.9 ± 1.4%, 33 (34%) had DSP according to the consensus definition. Modest correlations were observed between CNFL, CNFD, and CNBD and all functional small-fiber tests (rs = 0.25 to 0.41; P ≤ 0.01 for all comparisons). For example, quantitatively every 1 mm/mm2 lower CNFL was associated with a 0.61°C lower CDT, a 0.07 cm2 lower LDIFLARE area, and a 1.78% lower HRV. No significant associations were observed for CNFT and the functional small-fiber measures. CONCLUSIONS Small nerve fiber structural morphology assessed by IVCCM correlated well with functional measures of small nerve fiber injury. In particular, CNFL, CNFD, and CNBD demonstrated clear structure-function relationships.
Diagnostic and Prognostic Performances Over 9 Years of a Selective Screening Strategy for Gestational Diabetes Mellitus in a Cohort of 18,775 Subjects
Authors: Emmanuel Cosson, Amélie Benbara, Isabelle Pharisien, Minh Tuan Nguyen, Aurélie Revaux, Boris Lormeau, Dorian Sandre-Banon, Nabil Assad, Camille Pillegand, Paul Valensi, Lionel Carbillon
Journal: Diabetes Care (2012)

We aimed to evaluate a selective screening strategy for gestational diabetes mellitus (GDM) based on the presence of risk factors: BMI ≥25 kg/m(2), age ≥35 years, family history of diabetes, personal history of GDM, or birth of a child with macrosomia.Of 20,630 deliveries between 2002 and 2010, we selected 18,775 deliveries in women with no known diabetes and for whom all risk factors were known. GDM was universally screened and defined as fasting plasma glucose level ≥5.3 mmol/L and/or 2-h postload (75 g) glucose level ≥7.8 mmol/L.The prevalence of at least one risk factor has increased since 2002 (P < 0.001) from 51.7 to 61.5%, with no change in the GDM prevalence (mean 14.4%, intention to screen). At least one risk factor was present in 58.5% of women who represented 65.3% of all those with GDM. The presence of risk factors was significantly associated with GDM (odds ratio 1.4 [95% CI 1.3-1.5], P < 0.001) and with GDM-related events (preeclampsia/large for gestational age/dystocia) (P < 0.001) with the following incidences: no GDM/no risk factor 8.8%, no GDM/risk factor 11.1%, GDM/no risk factor 16.7%, and GDM/risk factor 18.2%.The presence of risk factors increased during the last decade. This condition is predictive of GDM and GDM-related events. However, a selective screening would lead to missing one-third of the women with GDM who, even without risk factors, had more events than women without GDM. Therefore, these data stand against the present selective screening currently proposed in the French guidelines.