tbuckley/cabot-search huggingface dataset:
Reply
Authors: Brian L. Pearlman, Carole M. Ehleben
Journal: Hepatology (2013)

We appreciate Dahari and Cotler's interest in our findings. We agree that viral kinetics during the lead-in phase with peg-interferon-α/ribavirin (PEG/RBV) may enable individualization and prediction of a minimum therapy duration to effect a sustained virological response (SVR); we likewise agree that further studies would be necessary to confirm this approach. We believe that Wang, Pfeiffer, and Morgan missed the point of our analysis regarding the interleukin (IL)−28B genotype. We do not dispute that relative to the non-CC subtype, CC conferred an advantage in terms of higher SVR rates (CC 97% and 97% versus non-CC 78% and 76% in double and triple therapy arms, respectively); however, in genotype 1-infected patients with low viral load at baseline who achieve aviremia at week 4 with PEG/RBV, there was no benefit in adding boceprevir, regardless of a patient's IL28B subtype. Although patients with the unfavorable subtype respond less well to therapy, for those patients with low viral load and RVR after lead-in with PEG/RBV there is still no advantage of adding a protease inhibitor. Brian L. Pearlman, M.D.1Carole M. Ehleben, Ph.D.2 1Center for Hepatitis C, Atlanta Medical Center Medical College of Georgia Emory School of Medicine Atlanta, GA 2Department of Graduate Medical Education Atlanta Medical Center Atlanta, GA
Abstract 18280: Induced Hypothermia After Out-of-Hospital Cardiac Arrest: Body Habitus and Survival
Authors: Pierre Charbel Atallah, Ovidiu Niculescu, Barry Franklin
Journal: Circulation (2014)

Introduction:  Recent studies have demonstrated an obesity paradox suggesting that overweight and mildly obese patients with cardiovascular disease may have better outcomes when compared with their underweight or normal weight counterparts.   Hypothesis:  The present study sought to test the hypothesis that body habitus is associated with survival in the setting of induced hypothermia after out-of-hospital cardiac arrest.   Methods:  We evaluated 90 patients (51 men, 39 women, mean age 60) with out-of-hospital cardiac arrest who underwent induced hypothermia using a target esophageal temperature of 33.5 °C with specific reference to the association between body mass index (BMI) and survival to hospital discharge for shockable and non-shockable electrocardiographic (ECG) rhythms. Pearson’s chi-square tests and Mantel-Haenszel statistics were used to control for associated variables and to test outcomes.   Results:  44 patients presented with shockable ECG rhythms (ventricular fibrillation and pulseless ventricular tachycardia) and 29 survived to hospital discharge (OR, 10.77; 95% CI: 3.55, 34.7; P    Conclusions:  These data are the first to show that rates of survival to hospital discharge differ across BMI categories for patients who undergo induced hypothermia after experiencing out-of-hospital cardiac arrest. Among patients presenting with shockable ECG rhythms, overweight and moderately obese patients had the highest rates of survival. Further studies are needed to confirm the relationship between body habitus and survival in this cohort of patients.
Abstract 19292: The Efficacy of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients with Coronary Artery Disease and No Heart Failure in the Modern Statin Era: a Meta-Analysis of Randomized-Controlled Trials
Authors: Vu Hoang, Daniel Addison, Mahboob Alam, Salim Virani, Yochai Birnbaum
Journal: Circulation (2014)

Background: Data from randomized-controlled trials regarding the efficacy of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) in patients with coronary artery disease (CAD) but no evidence of heart failure are inconclusive. Current ACC/AHA guidelines support their use in this population. The variation in efficacy of ACEi and ARBs in improving cardiovascular (CV) outcomes may be related to the rising use of statin therapy in the past two decades. Methods: We conducted literature review of randomized-controlled trials with ACEi or ARBs as the single intervention, focusing on studies involving patients with CAD including patients with left ventricular dysfunction but no clinical symptoms of heart failure. The MEDLINE database was searched for publications between 1/1/1980 and 12/31/2012 with searched terms including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, coronary artery disease, cardiovascular events, and myocardial infarction. Of the 1553 potentially relevant publications, 19 (14 ACEi and 5 ARB) met the inclusion criteria for a total of 99,631 randomized patients followed for a mean of 38 months. We evaluated the endpoints of CV mortality, all-cause mortality, non-fatal MI, and stroke. The relationship between endpoints across the 19 trials and the percentage of patients on statins in each trial (with available data) were evaluated using meta-regression analysis, expressed as highest standardized regression coefficient, Beta. Results: ACEi and ARB therapy across the 19 trials was associated with decreased CV mortality (OR 0.85; 95% CI 0.78-0.93) and all-cause mortality (OR 0.92; 95% CI 0.86-0.98). When adjusted for the percentage of statin, 46% of patients in the cohort, there was a significant linear decrease in the odds of CV mortality reduction with ACEi and ARB therapy (Beta = 0.01; p = 0.034). Conclusion: In patients with CAD and no evidence of heart failure, the additive benefits of ACEi and ARBs in decreasing CV mortality are blunted by statin therapy. The exact mechanism(s) for this result is unclear and further investigation is warranted. The modification of current ACC/AHA practice guidelines should be considered.
Cord blood transplants may restore defective immune systems
Authors: Roger Dobson
Journal: BMJ (2001)

Doctors have successfully transplanted umbilical cord blood from unrelated donors to treat three children with defective immune systems. Banked, unrelated umbilical cord blood was used to reconstitute the defective immune systems of two brothers with X-linked lymphoproliferative syndrome (XLP) aged 8 months and 4 years and another 11 year old boy with X-linked hyper-IgM immunodeficiency (XHIM).

Two years after the transplants the boys seem to …
Multiresistant Salmonella enterica serovar 4,[5],12:i:- in Europe: a new pandemic strain?
Authors: K L Hopkins, M Kirchner, B Guerra, S A Granier, C Lucarelli, M C Porrero, A Jakubczak, E  J Threlfall, D. J Mevius
Journal: Eurosurveillance (2010)

A marked increase in the prevalence of S. enterica serovar 4,[5],12:i:- with resistance to ampicillin, streptomycin, sulphonamides and tetracyclines (R-type ASSuT) has been noted in food-borne infections and in pigs/pig meat in several European countries in the last ten years. One hundred and sixteen strains of S. enterica serovar 4,[5],12:i:- from humans, pigs and pig meat isolated in England and Wales, France, Germany, Italy, Poland, Spain and the Netherlands were further subtyped by phage typing, pulsed-field gel electrophoresis and multilocus variable number tandem repeat analysis to investigate the genetic relationship among strains. PCR was performed to identify the fljB flagellar gene and the genes encoding resistance to ampicillin, streptomycin, sulphonamides and tetracyclines. Class 1 and 2 integrase genes were also sought. Results indicate that genetically related serovar 4,[5],12:i:- strains of definitive phage types DT193 and DT120 with ampicillin, streptomycin, sulphonamide and tetracycline resistance encoded by blaTEM, strA-strB, sul2 and tet(B) have emerged in several European countries, with pigs the likely reservoir of infection. Control measures are urgently needed to reduce spread of infection to humans via the food chain and thereby prevent the possible pandemic spread of serovar 4,[5],12:i:- of R-type ASSuT as occurred with S. Typhimurium DT104 during the 1990s.
Abstract 18093: Bleeding Events in Clopidogrel-Treated Patients with STEMI is Associated with a Genetic Risk Score Based on High-Risk Genetic Polymorphisms
Authors: Jia-Hui Zhang, Jin-Qing Yuan, Xian-Min Meng, Xiao-Fang Tang, Jing Wang, Yi Yao
Journal: Circulation (2014)

Introduction: Gene polymorphisms of ABCB1, CYP2C19, PON1 and P2Y12 may influence pharmacodynamics and clinical events of clopidogrel treatment. Hypothesis: We assessed the hypothesis that a genetic risk score based on identified high-risk single nucleotide polymorphisms (SNPs) would be associated with bleedings in clopidogrel-treated Chinese STEMI patients after percutaneous coronary intervention (PCI). Methods: A total of 503 consecutive patients with STEMI who received an uneventful PCI and were exposed to clopidogrel treatment for 12 months, were enrolled in the single-center registry. There were 38 tag SNPs selected from ABCB1, CYP2C19, PON1 and P2Y12 genes, which were detected by the ligase detection reaction. The primary clinical safety endpoint was the incidence of major bleeding events. Major bleeding was quantified according to bleeding academic research consortium definition (BARC) criteria, including type 3 and 5 in the analysis. The follow-up period was 12 months. Results: Overall, 46 BARC≥3 bleeding events (9.1%) occurred, which included 11 (2.1%) cases of BARC 3b bleedings and 35 (7.0%) cases of BARC 3a bleedings. After adjustment for traditional clinical risk factors, multivariate logistic regression analysis identified SNPs significantly associated with bleedings were ABCB1 (rs1045642, rs2235047, rs7779562), P2Y12 (rs6809699) and CYP2C19*17. A genetic risk score was constructed by summing the number of risk alleles. Bleedings were significantly associated with increased genetic risk score tertile. Patients in the top tertile of the genetic score were estimated to have a 3.268-fold (95%CI=1.198-8.929, p=0.021) increased risk of bleedings compared with those in the bottom tertile. As a continuous variable, the risk score resulted in an OR of 1.326 per unit increase in score (95%CI=1.098-1.601, p=0.003). Conclusions: This genetic score was significantly associated with bleedings after PCI in our study population.
Mass spectrometry methods for biomarker research for chronic lung allograft dysfunction (CLAD) in systems prediction of CLAD (SysCLAD)
Authors: Johanna Claustre, Sébastien Quétant, Candice Trocmé, Sandrine Bourgoin-Voillard, Hélène Flamant-Waret, Izabel Bérard, Bertrand Toussaint, Karine Botturi-Cavaillès, Antoine Magnan, Laurent Nicod, Christophe Pison, Michel Sève
Journal: European Respiratory Journal (2014)

Background : CLAD is an irreversible and heterogeneous condition, associating Bronchiolitis Obliterans Syndrome (BOS), and Restrictive Allograft Syndrome (RAS). RAS and early onset of BOS are correlated with a poor prognosis and a significant morbidity in lung transplant recipients. As a part of SysCLAD, a FP-7 funded project aimed to predict CLAD, this study was designed to find biomarkers of CLAD in lung transplant recipients from the French cohort of lung transplant COLT and the Swiss cohort STCS, by using 2 mass spectrometry (MS) techniques.   Methods : BALF and plasma in the 200 first patients of COLT cohort who reached 3 years post-transplantation or developed an early form of CLAD were selected for analysis from systematic visits at months 6 and 12. First, SELDI-TOF MS analysis, a high-throughput method, allowed obtaining individual proteomic profiles using 3 complementary arrays: CM10 (cation array), Q10 (anion array) and IMAC-Cu (copper array). Furthermore, after pooling samples according to patients9 phenotype (BOS, RAS, stable), iTRAQ-MALDI-TOF MS and MS/MS analysis, a sensitive and quantitative method, allowed biomarker identification after peptide separation by off-gel fractionation and nano-reversed phase chromatography.   Results : In a pilot study, 45 proteins were differentially expressed in BALF with SELDI-TOF MS analysis. Identification and quantification of these potential biomarkers is currently performed with iTRAQ analysis.   Conclusion : Identification and validation of early biomarkers of CLAD with these two complementary methods may help to understand involved mechanisms and to earlier diagnose CLAD onset at a reversible stage.
Lichen planus with lesions on the palms and/or soles: prevalence and clinicopathological study of 36 patients
Authors: J. Sánchez-Pérez, L. Rios Buceta, J. Fraga, A. García-Díez
Journal: British Journal of Dermatology (2000)

According to the literature, palmoplantar lesions in lichen planus (LP) are uncommon, and do not usually have the classically described clinical morphology. The aim of this study was to evaluate the prevalence of palmoplantar lesions in LP and to describe the characteristic clinicopathological appearances of LP affecting palms and soles. Palmoplantar LP with accompanying skin involvement accounted for 26% of our cases. The presence of very pruriginous erythematous scaly and/or hyperkeratotic plaques, with well-defined edges, located on the internal plantar arch, without involvement of the fingertips, and which usually disappear in a few months, is characteristic of palmoplantar LP. Histopathological examination shows the characteristic features of LP.
Oral administration of the PARP-1 inhibitor GPI 15427 increases the anti-tumor activity of irinotecan against colon carcinomas
Authors: Lucio Tentori, Carlo Leonetti, Marco Scarsella, Matteo Vergati, Allessia Muzi, Weizhing Xu, Rena G. Lapidus, Jie Zhang, Grazia Graziani
Journal: Cancer Research (2005)

2567   Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been investigated as enhancer of anticancer therapy. We recently demonstrated that the novel PARP-1 inhibitor GPI 15427 increases the anti-tumor efficacy of temozolomide (TMZ) against a variety of tumor types such as melanoma, lymphoma, glioblastoma multiforme, even when the tumors are located at the CNS site. Among the PARP-1 inhibitors tested so far as chemosensitizers in xenograft models, GPI 15427 is the first agent that achieved oral efficacy against tumors grown intracranially as well as subcutaneously in mice, while all the other PARP-1 inhibitors were administered intraperitoneally against subcutaneous tumors. In addition, oral administration of the GPI 15427 is well tolerated with an LD50 > 1000 mg/kg/day x 5 days po. Furthermore, at 40 mg/kg/day x 5 day po, GPI 15427 does not exacerbate reduction of white blood cells by the maximal tolerated dose of TMZ in mice. To broaden the utility of GPI 15427 as a sensitizer for other chemotherapy, in this study we tested whether it can enhance the anti-tumor efficacy of topoisomerase I inhibitor irinotecan, a water-soluble analogue of the natural alkaloid camptothecin, with considerable therapeutic activity in advanced colorectal carcinoma. Irinotecan triggers tumor cell apoptosis by stabilizing the linkage between topoisomerase I and DNA, eventually resulting in lethal DNA breaks when the replication fork encounters the complex. In in vitro testing, HT-29, HCT-116, HCT-15 and LoVo human colon carcinoma cells were exposed to graded concentrations of GPI 15427 to determine concentrations for maximal PARP inhibition without growth inhibitory effect. GPI 15427 was then tested for its ability to enhance tumor growth inhibition induced by 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. The results of colony formation assay identified HT-29 as the most resistant colon carcinoma cell lines to SN-38. GPI 15427 increased the growth inhibitory effect of the topoisomerase I inhibitor on HT-29 by 2-3-fold. We then tested GPI 15427 in HT-29 tumor bearing mice. GPI 15427 (40 mg/kg,  po ) was administered for five consecutive days 1 h before irinotecan (10 mg/kg/ip) for two cycles. Efficacy of treatments was evaluated by comparing tumor growth in untreated mice, mice treated with irinotecan, or mice treated with irinotecan + GPI 15427. The results indicated that GPI 15427 significantly increased antitumor efficacy of irinotecan (P
Synchronicity of LV Contraction as a Determinant of LV Twist Mechanics
Authors: Myung-Ki Seo, Sung-A. Chang, Hyung-Kwan Kim, Dong-Ho Shin, Eue-Keun Choi, Yong-Jin Kim, Seil Oh, Goo-Yeong Cho, Dae-Won Sohn, Byung-Hee Oh, Young-Bae Park
Journal: JACC. Cardiovascular imaging (2011)
Abstract O-2: The Role of Post-translational Modifications in SERCA2a-related Cardiac Dysfunction
Authors: Changwon Kho, Dongtak Jeong, Ahyoung Lee, Shinichi Mitsuyama, Jae Gyun Oh, Roger Hajjar
Journal: Circulation Research (2014)

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) has become a validated target for the treatment of heart failure (HF). The relationship between reduced SERCA2a activity and decreases in protein expression in the setting of HF has been found to be non-linear and the toxic intracellular milieu in HF contributes to SERCA2a’s dysfunction. Post-translational modification (PTM) of SERCA2a has been recently described to as an important mechanism that can explain a reduction in SERCA2a activity in HF. Based on a comprehensive proteomic analysis, we found that the levels and activity of SERCA2a in cardiomyocytes are modulated in parallel with the levels of small ubiquitin-like modifier type 1 (SUMO-1). Moreover, our work has shown that SUMO-1 plays a critical role in protecting SERCA2a from pathological conditions (Kho et al, Nature, 2011). More recently, we demonstrated that SUMO-1 gene transfer and its combination with SERCA2a led to a reversal of HF in a porcine model of ischemic induced HF (Tilemann et al, Sci Transl Med, 2013). In our analysis of SERCA2a PTM in animal models of HF, we observed that SERCA2a is acetylated, and that this acetylation is more prominent in failing hearts. The acetylation of SERCA2a was validated by acetylation assays with acetyltransferase and HDAC inhibitors. We identified several lysine residues on SERCA2a for susceptible to acetylation. In addition, we found that Sirt1 enzyme deacetylates SERCA2a. Sirt1 down-regulation in HL-1 cells using small interfering RNA increased SERCA2a acetylation and thereby decreased its activity. Moreover, SERCA2a acetylation was increased when Sirt1 was depleted by recombinant adeno-associated virus carrying short hairpin RNA for Sirt1 in mice model, which reflected a decrease in intensity of interaction between Sirt1 and SERCA2a. Reduced acetylation was accompanied by an increase in SERCA2a SUMOylation in the heart. Decreased acetylation, combined with increased SUMOylation, of SERCA2a may contribute to the cardioprotective effects of Sirt1. Our results show that SERCA2a acetylation increases during HF and negatively impacts SERCA2a’s function, suggesting that the down-regulation of SERCA2a acetylation may afford a novel intervention in the setting of heart failure.
Toxic Chemicals, Health, and the Environment.
Authors: Lester B. Lave, Arthur C. Upton
Journal: Annals of Internal Medicine (1987)

This book contains nine selections. Some of the titles are: Controlling Toxic Chemicals in the Environment; Measuring Toxic Chemicals in the Environment: A Materials Balance Approach; The Food Chain as a Source of Toxic Chemical Exposure; Biological Monitoring of Environmental Toxic Chemicals; and Biomedical Aspects of Environmental Toxicology.
Radiation Oncologist Concerns About Increased Electronic Brachytherapy Use for Skin Cancer
Authors: Bruce G. Haffty, David C. Beyer, Brian D. Kavanagh
Journal: JAMA Dermatology (2015)

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Abstract B87: Cell lines generated from PDAC transgenic mice reveal integrin αvβ6 modifies the invasive phenotype of pancreatic cancer
Authors: Claire S. Reader, Sabari Vallath, Jennifer Morton, Colin Steele, Hemant M. Kocher, Stephen M. Keyse, Owen Sansom, John F. Marshall
Journal: Cancer Research (2015)

Abstract Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the UK. Five-year survival rates are less than 3% and haven’t improved over the last 40 years. Thus novel approaches are required urgently. We have found that high expression of the integrin β6 subunit gene (ITGB6) correlates with a significant reduction (Hazard Ratio 1.74; Logrank p=6x10-4) in overall survival from PDAC. Thus we have begun to examine the biological functions mediated by αvβ6 in a transgenic model of PDAC. A panel of cell lines were generated from PDAC tumors of a novel transgenic mouse and characterized for markers of tissue identity, integrin expression and ability to invade using 3D-organotypic assays. Cell populations appeared to contain both epithelial (E-cadherin positive) and mesenchymal (vimentin positive) characteristics, highlighting their polyclonality. In addition, two cell populations, KVC1 and KPCD3, expressed low levels of αvβ6 and were studied further. KVC1 and KPCD3 cells were labeled with 10D5 (anti-αvβ6) and sorted by FACS to obtain high-αvβ6 expressing monoclonal cell lines. The resulting cell lines after four rounds of sorting (S4) demonstrated mean MFI values of approximately 4.5-fold (KVC1 vs. KVC1 S4 A+) and approximately 3-fold (KPCD3 vs. KPCD3 S4 E+) higher than their parental counterparts. To compare the invasion profile of the parental populations and S4 monoclonal cell lines, cells were placed in 3D organotypic assays with mouse embryonic fibroblasts (MEFs) for 14 days before gels were fixed and processed to paraffin. H&amp;E stained sections revealed that parental populations KVC1 and KPCD3 formed invasive, single-cell walled ductal structures that had penetrated into the matrigel-collagen mix, but only in the presence of MEFs. In contrast, αvβ6-positive S4 populations, KVC1 S4 A+ and KPCD3 S4 E+, also demonstrated strong invasion but the invasive ductal phenotype was lost, the cells invading as small cohesive groups and individual cells. These data suggest that the pattern of PDAC tumour invasion may be modulated by expression of the integrin αvβ6. Current studies explore the mechanisms by which these phenotypic changes are generated. Citation Format: Claire S. Reader, Sabari Vallath, Jennifer Morton, Colin Steele, Hemant M. Kocher, Stephen M. Keyse, Owen Sansom, John F. Marshall. Cell lines generated from PDAC transgenic mice reveal integrin αvβ6 modifies the invasive phenotype of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B87.