tbuckley/cabot-search huggingface dataset:
BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory
Authors: Timothy E. O’Sullivan, Lexus R. Johnson, Helen H. Kang, Joseph C. Sun
Journal: Immunity (2015)

Highlights•MCMV infection induces dynamic changes in NK cell mitochondrial quality•Autophagy is essential for the generation of NK cell memory•Pharmacologic induction of autophagy enhances NK cell memory formation•Mitophagy is required for anti-viral NK cell survival through removal of ROSSummaryNatural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived "memory" cells, processes poorly understood at the molecular level. Here, we found that as proliferating NK cells accumulated dysfunctional mitochondria during viral infection, a protective mitophagy pathway was induced during the contraction phase to promote their survival in a reactive oxygen species (ROS)-dependent manner. Inhibition of mechanistic target of rapamycin (mTOR) or activation of AMP-activated protein kinase (AMPK) during the contraction-to-memory phase transition of the antiviral response increased autophagic activity and enhanced memory NK cell numbers through an Atg3-dependent mechanism. Furthermore, we demonstrated a temporally regulated role for mitophagy-inducing proteins BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L) in the generation of robust NK cell memory. Thus, our study reveals the functional importance of mitophagy during the dynamic response of these cytolytic innate lymphocytes.Graphical abstract
Abstract 2812: The clinical effects of dendritic cell and cytokine-induced killer cell therapy for lung cancer after surgery
Authors: Daiqing Gao, Changyou Li, Peng Zhao, Xiaofang Wei, Xihe Xie, Weihong Sun, Qingming Guo, Danni Zhu, Tianyi Gao, Aris T. Alexandrou, Jian Jian Li
Journal: Cancer Research (2014)

Abstract Objective:The aim of the study was to evaluate the safety and therapeutic efficacy of autologous dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) for the treatment of lung cancer patients. Methods:In the present study, we recruited a group of 40 lung cancer patients after surgery registered in the Biotherapy Center during 2005-2011 and randomly divided patients into two groups: Twenty patients treated with DC-CIK therapy as the treatment group and the other twenty patients served as controls.Subjects were administrated with 1×106 units of IL-2 daily for 5 days before mononuclear cell isolation from peripheral blood. For the treatment group, after primary tumors were removed by surgery, 1-3 doses of DCs and CIKs were perfused via peripheral veins. The immunologic function,short-term therapeutic effects, 5-years overall survival rate (OS), and disease free survival rate (DFS) were compared between the two groups.In addition, the peripheral blood samples were extracted from all patients before and after DC-CIK therapy,analyzed for T cell subsets by flow cytometry,and the intracellular cytokines of T cells were detected simultaneously. Results:OS for 1, 3, and 5 years of DC-CIK therapy group were 100%, 88%, and 88% respectively which contrasted with 78%,66%, and 25% in the control group. DFS 1, 3, and 5 years of DC-CIK therapy groups were 100%, 85%,65% respectively compared to 73%,58%, 23% in the control groups. Although there were no changes in the subsets of T cells in peripheral blood before and after DC-CIK therapy, the intrace1lular cytokines IFN-γ,IL-2,IL-4, and IL-6 of the immune cells were noticeably improved in the treatment group. Conclusion:DC-CIK therapy is a potential effective therapeutic modality to improve OS and DFS in post-surgical lung cancer patients. Citation Format: Daiqing Gao, Changyou Li, Peng Zhao, Xiaofang Wei, Xihe Xie, Weihong Sun, Qingming Guo, Danni Zhu, Tianyi Gao, Aris T. Alexandrou, Jian Jian Li. The clinical effects of dendritic cell and cytokine-induced killer cell therapy for lung cancer after surgery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2812. doi:10.1158/1538-7445.AM2014-2812
Targeted Therapy for Patients with BRAF-Mutant Lung Cancer Results from the European EURAF Cohort
Authors: Oliver Gautschi, Julie Milia, Bastien Cabarrou, Marie-Virginia Bluthgen, Benjamin Besse, Egbert F Smit, Juergen Wolf, Solange Peters, Martin Früh, Dieter Koeberle, Youssouf Oulkhouir, Martin Schuler, Alessandra Curioni-Fontecedro, Benjamin Huret, Mallorie Kerjouan, Sebastian Michels, Georg Pall, Sacha Rothschild, Gerald Schmid-Bindert, Matthias Scheffler, Rémi Veillon, Luciano Wannesson, Joachim Diebold, Gérard Zalcman, Thomas Filleron, Julien Mazières
Journal: Journal of Thoracic Oncology (2015)
Oral Contraceptives and Breast Cancer
Authors: K H Johnson, P S Millard
Journal: JAMA (1989)

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Abstract 16078: Left Ventricular Scarring is a Common Substrate of Electrical Instability in Young Subjects Dying Suddenly With Mitral Valve Prolapse
Authors: Cristina Basso, Stefania Rizzo, Arianna Peralta, Martina Perazzolo Marra, Domenico Corrado, Gaetano Thiene
Journal: Circulation (2011)

BACKGROUND - Mitral valve prolapse (MVP) occurs in up to 5% of the general population. Since it may be associated with sudden death (SD), the we evaluated the prevalence of MVP in young SD victims and the pathological substrate accounting for electrical instability.   METHODS - The study has been carried by selecting young SD victims with MVP as the sole cardiac abnormality found at autopsy and 15 age-matched controls who died due to extracardiac causes (mean age 28 years, range 15-43). Gross and histology were carried out according to the SD protocol with sampling from the mitral valve leaflets and ventricular myocardium. In selected cases, primary antibodies against the phosphorilated form of Smad 2 were used.   RESULTS - MVP was the cause of SD in 27 (17 F, mean age 29,7 years, range 14-40) out of 481 cases of cardiovascular SD (6%). Two had Marfan stigmata. Twelve (44%) had an in vivo diagnosis of MVP with mild incompetence and 5 (18.5%) were on beta-blockers due to non sustained ventricular arrhythmias. SD occurred mostly at rest (70%); two women died during pregnancy. MVP leaflets had a four-fold increase in thickness compared to the normal valves (p   CONCLUSION - MVP represent a no-so rare cause (6%) of arrhythmic SD in the young. Scarring of the left ventricular myocardium, due to increased activation of the intracellular TGF-beta pathway similar to that observed in the valve leaflets, might explain the electrical instability. These myocardial abnormalities, likely induced by stretching of papillary muscles, suggest a role of contrast-enhancement cardiac magnetic resonance in risk stratification of MVP patients.
Mycobacterium tuberculosis, how long did you walk?
Authors: Vanda Areias, Inês Neves, Raquel Melo, Aurora Carvalho, Raquel Duarte
Journal: European Respiratory Journal (2013)

Aim:  Determine the time elapsed between the onset of symptoms until the first observation by a health professional and the time from the first observation to diagnosis.   Methods: We conducted a questionnaire-based survey to pts with active TB followed in the CDC treatment of VNG in May and June 2012.   Results: 54 pts, 68% males, mean age of 48 years.The first healthcare place that the patient went after the onset of symptoms was to emergency department 20 pts (37%), a general practitioner 17 pts (31%), a hospital consultation 9 pts (17%), a private clinic 3 pts (5%), Chest Diagnosis Centre 3 pts (5%), a pharmacy 2 pts (4%). The median time from onset of symptoms and the observation by a health professional was 37 days. Patients with symptoms of anorexia and weight loss took longer to access to health care (53 vs 18 days, p = 0.01 and 52 vs 12 days, respectively).  The pt was observed on average 3 times before the diagnosis was made. Pts who took less than 15 days to access to the health care system went mainly to the emergency department (48%), while pts who took more than 15 days were observed mainly by a general practitioner (52%, p = 0.03),  The median time from the first consultation and diagnosis was 56 days. Pts with respiratory symptoms had on average a diagnosis faster than the others (38 vs 127 days, p = 0.01). The majority of pts in whom the diagnosis was made in less than 15 days, were first observed in the emergence department (57%), while pts whose diagnosis took longer than 15 days were observed by a general practitioner (39%, p=0.03).  The median time from onset of symptoms and diagnosis was 92 days.   Conclusion: These results suggest the need to implement strategies for earlier diagnosis of tuberculosis.
MRI detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease
Authors: Mark O. Wielpütz, Michael Puderbach, Annette Kopp-Schneider, Mirjam Stahl, Eva Fritzsching, Olaf Sommerburg, Sebastian Ley, Migle Sumkauskaite, Jürgen Biederer, Hans-Ulrich Kauczor, Monika Eichinger, Marcus Mall
Journal: European Respiratory Journal (2014)

Rationale: Recent studies demonstrating early structural lung damage in infants and preschool children with cystic fibrosis (CF) suggest that non-invasive monitoring will be important to identify patients who may benefit from early therapeutic intervention. Previous studies demonstrated that magnetic resonance imaging (MRI) detects structural and functional abnormalities in lungs from older CF patients without radiation exposure. We evaluated the potential of MRI to detect abnormal lung structure and perfusion in infants and preschool children with CF, and to monitor response to therapy for pulmonary exacerbation.  Methods: MRI studies were performed in 50 children with CF (age 3.1±2.1years, range 0-6years) in stable clinical condition (n=40) or pulmonary exacerbation before and after antibiotic treatment (n=10), and in 26 non-CF controls (2.9±1.9years). T1- and T2-weighted sequences before and after contrast and first-pass perfusion imaging were acquired, and assessed using a morpho-functional score.  Results: MRI demonstrated bronchial wall thickening/bronchiectasis, mucus plugging and perfusion deficits from the first year of life in most stable patients with CF (global score 10.0±4.0), but not in non-CF controls (score 0.0±0.0; p  Conclusions: MRI detected abnormalities in lung structure and perfusion, and response to therapy for exacerbations in infants and preschool children with CF. These results support the development of MRI for non-invasive monitoring and as an endpoint for early CF lung disease.
Lesson of the Week: Myxoedema revealed by simvastatin induced myopathy
Authors: M A Al-Jubouri, P G Briston, D Sinclair, R H Chinn, R M Young
Journal: BMJ (1994)

With the increasing use of hypolipidaemic agents, more cases of toxic myopathy and rhabdomyolysis related to these drugs are becoming apparent.1 This effect is not specific to one class of compounds: almost all hypolipidaemic agents have been implicated, including statins, fibrates, and nicotinic acid.*RF 2-4* Renal impairment, hypoalbuminaemia, and the use of drug combinations, such as statins with fibrates or cyclosporin, predispose to and potentiate muscle toxicity.1

* Secondary causes of hypercholesterolaemia should be considered before starting hypolipdaemic treatment

Hypercholesterolaemia is a common feature of myxoedema and may be the sole presentation of the disease. Indeed, as a result of the widespread use of cholesterol screening, increasing numbers of hypothyroid patients may present with hypercholesterolaemia rather than the classic features of hypothyroidism.5 Likewise myopathy, which may be clinical or subclinical and is associated with raised plasma activities of the skeletal muscle enzymes creatine …
Development Of Novel Alkylating Chemotherapeutics, Phenyl-Chloroethyl Urea Family, Targeting Mitochondrial Prohibitin For Selective Killing Of Leukemic Cells
Authors: Hye-Ran Kim, Hwan-Young Kim, Trang Nguyen Thi Dai, Il-Kwon Lee, Hyeoung-Joon Kim, Jong-Hee Shin, Soon-Pal Suh, Dong-Wook Ryang, Myung-Geun Shin
Journal: Blood (2013)
A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial
Authors: L. Marsay, C. Dold, C.A. Green, C.S. Rollier, G. Norheim, M. Sadarangani, M. Shanyinde, C. Brehony, A.J. Thompson, H. Sanders, H. Chan, K. Haworth, J.P. Derrick, I.M. Feavers, M.C. Maiden, A.J. Pollard
Journal: Journal of Infection (2015)

ObjectivesOuter membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines.MethodsThe OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 μg or 50 μg of MenPF-1 were delivered intra-muscularly to 52 healthy adults.ResultsMenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetAonPorAoff compared to 51% in the strain 44/76 FetAoffPorAoff, demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies.ConclusionThis study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.
Abstract P128: Inhomogeneous Upregulation of Sodium Channel Nav1.5 and Its Role in Discordant T Wave and Mechanical Alternans in Left Ventricular Hypertrophy
Authors: Xiao-Qing Quan, Tengxian Liu, Donglin Guo, Ying Wu, Samantha J. Fromme, Robert H. Cox, Peter R. Kowey, Gan-Xin Yan
Journal: Circulation (2009)

Objectives: Left ventricular hypertrophy (LVH) is associated with T wave alternans (TWA) that often heralds the development of malignant ventricular arrhythmias. Previous studies have shown that LV...
Abstract 2686: Early Mortality Despite Prophylactic ICD Implantation in Patients With Ischemic Cardiomyopathy
Authors: Sunil Mirchandani, Kenneth M Stein, Steven M Markowitz, Sei Iwai, Bindi K Shah, Jim W Cheung, Vivian R Tan, Sandhya Dhruvakumar, David P Dobesh, Dmitry Nemirovsky, Bruce B Lerman, Suneet Mittal
Journal: Circulation (2006)

Introduction : Multiple randomized clinical trials have shown that an ICD improves survival in patients (pts) with an ischemic cardiomyopathy. Although a life expectancy ≤ 1 year is considered a contraindication to ICD implantation, the incidence and predictors of early mortality remain undefined.   Methods : We evaluated consecutive pts with ischemic heart disease and depressed left ventricular ejection fraction (LVEF ≤ 35%) who underwent prophylactic ICD implantation between February 2002 and December 2004. No pt underwent pre-implant electrophysiologic testing. Predictors of mortality within one year of ICD implantation were determined using Cox-regression analysis.   Results : The study population consisted of 123 pts (103 male, age 70 ± 11 years) with a mean EF of 25 ± 6 %. The mean QRS duration was 149 ± 29 msec and 75 (61%) pts had class III CHF. Sixty-two (50%) pts received a LV lead. During a follow-up of 2.1 ± 1.1 years, 34 (28%) pts died. Overall, 22 (65%) of these 34 pts died ≤ 1 year post-ICD implantation. Pts who died within a year were less likely to be taking a β-blocker (73 vs 93%, p=0.005) and more likely to have unrevascularized coronary artery disease (32 vs 15%, p=0.06). No other predictor of early mortality was identified. In multivariate analysis, lack of β-blocker use was the only predictor of early mortality (RR 3.6, 95% CI: 1.4–9.3, p=0.007). The 1-year mortality in pts not taking a β-blocker was 43%.   Conclusions : In a real world population of pts with an ischemic cardiomyopathy, overall mortality is high in the first year after ICD implantation. Lack of β-blocker use significantly increases the likelihood of early mortality in these pts.
Depression: New Evidence in Support of Biological Differentiation
Authors: Paul E. Garfinkel, Jerry J. Warsh, Harvey C. Stancer
Journal: American Journal of Psychiatry (1979)

The authors studied monoamine metabolism in patients with bipolar (manic-depressive) and unipolar depressive illness and in normal control subjects under strict dietary conditions before and during administration of carbidopa, a peripheral decarboxylase inhibitor. They found that unipolar depressed patients excreted higher amounts of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in the drug-free period and while receiving carbidopa and significantly less tryptamine only after carbidopa administration. Plasma tryptophan levels differed in the three groups. The authors state that their research design reveals changes in serotonin and norepinephrine metabolism in unipolar depressed subjects that distinguish this group from normal and bipolar depressed subjects, suggesting a reduced CNS uptake of tryptophan in unipolar depression.
Diseases of Occupations
Journal: Thorax (1995)

agement of malignant pleural effusion.Thoracoscopic inspection of the pleural space provides optimal conditions for effective pleurodesis by facilitating a dry pleural cavity and may be more important, with regard to success, than the choice of sclerosant.Nevertheless his experience with talc is most in- teresting, and we agree that further data in the form of a prospective randomised trial are required to clarify management which remains largely a matter of personal experience and reflects local expertise.
Abstract 3099: Reasons for Failure of Percutaneous Epicardial Catheter Ablation after Unsuccessful Endocardial Approach
Authors: Robert A Schweikert, Walid I Saliba, J. David Burkhardt, Jennifer E Cummings, Mauricio Arruda, Mandeep Bhargava, David O Martin, Oussama M Wazni, Mohamed Kanj, Kenneth Civello, Michael McWilliams, Mohammed Khan, Shane Bailey, Andrea Natale
Journal: Circulation (2006)
Abstract B11: Understanding how the Hedgehog pathway mediates stromal desmoplasia in Pancreatic Ductal Adencarcinoma
Authors: Dafydd H. Thomas, Albert K. Lee, Stephen A. Sastra, Carmine F. Palermo, Raul Rabadan, P Olive Kenneth
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers partly due to its profound primary chemoresistance. Previous work from this laboratory found that the prominent desmoplastic stroma observed in PDA is a significant factor in the tumor chemoresistance. We reported that, in established tumors, inhibition of the Hedgehog (Hh) pathway in tumor fibroblasts caused a loss of tumor stroma including α-smooth muscle actin positive (α-SMA) cells. This resulted in an increase in drug delivery to the tumor and subsequent reduction in tumor volume, leading to prolonged survival in a clinically relevant mouse model of PDA. However, the mechanisms by which Hh signaling contributes to the desmoplastic stroma in PDA remain unknown. In this study we have attempted to identify the target genes of the Hh pathway in the stroma of pancreatic tumors. Using a novel tumor biopsy procedure coupled with RNA-SEQ analysis we have identified genes acutely sensitive to Hh pathway inhibition in the KPC mouse model of PDA. Following 2 days of post biopsy treatment with the Smoothened inhibitor IPI926 the Hh pathway genes Gli1 and Ptch2 were significantly down-regulated. In addition, the Hh target gene, wnt inhibitory factor 1 (Wif1) and other novel genes which may be promoting stromal desmoplasia were significantly down-regulated due to Hh pathway inhibition. In addition to studying the target genes of the Hh-pathway in the stroma we have utilized a Gli1-GFP reporter mouse to study the Hh target cells in the stroma. Previous work has suggested that Hh target cells in pancreatic tumors are myofibroblasts and thus α-SMA positive. However, we observed that while some Gli1 positive stromal cells are α-SMA positive a significant proportion are α-SMA negative. In addition, costaining KPC-Gli1-GFP tumors for other stromal markers, including Fibroblast specific protein-1 (FSP-1), Glial Fibrillic Acidic Protein (GFAP), zinc finger E-box binding homeobox 1 (Zeb1) and Neuron-Glial Antigen 2 (NG-2) reveals subsets of Hh target cells in the tumor stroma. These data suggest a complex mechanism of Hh-regulated development of the desmoplastic stroma. To date the mechanisms of Hh-mediated stromal desmoplasia remain refractory. Taken together, these studies attempt to uncover the Hh target genes and cell types in the stroma of pancreatic tumors and provide an explanation for Hh-mediated stromal desmoplasia in PDA. Citation Format: Dafydd H. Thomas, Albert K. Lee, Stephen A. Sastra, Carmine F. Palermo, Raul Rabadan, P Olive Kenneth. Understanding how the Hedgehog pathway mediates stromal desmoplasia in Pancreatic Ductal Adencarcinoma. [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 B11.