tbuckley/cabot-search huggingface dataset:
The Presence and Consequence of Nonalbuminuric Chronic Kidney Disease in Patients With Type 1 Diabetes
Authors: Lena M. Thorn, Daniel Gordin, Valma Harjutsalo, Stefanie Hägg, Robert Masar, Markku Saraheimo, Nina Tolonen, Johan Wadén, Per-Henrik Groop, Carol M. Forsblom
Journal: Diabetes Care (2015)

OBJECTIVE This study investigated the prevalence of nonalbuminuric chronic kidney disease in type 1 diabetes to assess whether it increases the risk of cardiovascular and renal outcomes as well as all-cause mortality. RESEARCH DESIGN AND METHODS This was an observational follow-up of 3,809 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. All patients were Caucasians and thoroughly examined at baseline. Their mean age was 37.6 ± 11.8 years and duration of diabetes 21.2 ± 12.1 years. Follow-up data on cardiovascular and renal outcomes and mortality were retrieved from registers. During 13 years of median follow-up, 378 developed end-stage renal disease, 415 suffered an incident cardiovascular event, and 406 died. RESULTS At baseline, 78 (2.0%) had nonalbuminuric chronic kidney disease. This was associated with older age, female sex, history of retinal laser treatment, cardiovascular events, and the number of antihypertensive drugs in use, but not with blood pressure levels or specific antihypertensive agents. Nonalbuminuric chronic kidney disease did not increase the risk of albuminuria (hazard ratio [HR] 2.0 [95% CI 0.9–4.4]) or end-stage renal disease (HR 6.4 [0.8–53.0]) but did increase the risk of cardiovascular events (HR 2.0 [1.4–3.5]) and all-cause mortality (HR 2.4 [1.4–3.9]). The highest risk of cardiovascular and renal end points was observed in the patients with albuminuria. CONCLUSIONS Nonalbuminuric chronic kidney disease is not a frequent finding in patients with type 1 diabetes, but when present, it is associated with an increased risk of cardiovascular morbidity and all-cause mortality but not with renal outcomes.
MxA inhibits hepatitis B virus replication by interaction with hepatitis B core antigen
Authors: Ning Li, Lei Zhang, Liangwei Chen, Wenfeng Feng, Yinfeng Xu, Feng Chen, Xiaohong Liu, Zhi Chen, Wei Liu
Journal: Hepatology (2012)

Human MxA, an interferon-inducible cytoplasmic dynamin-like GTPase, possesses antiviral activity against multiple RNA viruses. Recently, MxA has also been demonstrated to have activity against the hepatitis B virus (HBV), a well-known DNA virus responsible for acute and chronic liver disease in humans. We investigated the molecular mechanism for the anti-HBV activity of MxA. Our results demonstrated that in HepG2.2.15 cells, MxA GTPase independently suppressed the production of hepatitis B surface antigen and HBV DNA without changing the level of hepatitis B core antigen (HBcAg) and the distribution of HBV mRNA. MxA significantly reduced the level of the encapsidated pregenomic RNA. Through its central interactive domain, MxA interacted with HBcAg, causing accumulation of the proteins in perinuclear compartments. MxA-HBcAg interaction significantly affected the dynamics of HBcAg by immobilizing HBcAg in the perinuclear structures. Conclusion : MxA displays antiviral activity against HBV involving a mechanism of MxA-HBcAg interaction that may interfere with core particle formation.
Recognition and Killing of Autologous, Primary Glioblastoma Tumor Cells by Human Cytomegalovirus pp65-Specific Cytotoxic T Cells
Authors: Smita K. Nair, Gabriel De Leon, David Boczkowski, Robert Schmittling, Weihua Xie, Janet Staats, Rebecca Liu, Laura A. Johnson, Kent Weinhold, Gary E. Archer, John H. Sampson, Duane A. Mitchell
Journal: Clinical Cancer Research (2014)

Despite aggressive conventional therapy, glioblastoma (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique opportunity to target these viral proteins for tumor immunotherapy. Although the presence of CMV within malignant gliomas has been confirmed by several laboratories, its relevance as an immunologic target in GBM has yet to be established. The objective of this study was to explore whether T cells stimulated by CMV pp65 RNA-transfected dendritic cells (DC) target and eliminate autologous GBM tumor cells in an antigen-specific manner.T cells from patients with GBM were stimulated with autologous DCs pulsed with CMV pp65 RNA, and the function of the effector CMV pp65-specific T cells was measured.In this study, we demonstrate the ability to elicit CMV pp65-specific immune responses in vitro using RNA-pulsed autologous DCs generated from patients with newly diagnosed GBM. Importantly, CMV pp65-specific T cells lyse autologous, primary GBM tumor cells in an antigen-specific manner. Moreover, T cells expanded in vitro using DCs pulsed with total tumor RNA demonstrated a 10- to 20-fold expansion of CMV pp65-specific T cells as assessed by tetramer analysis and recognition and killing of CMV pp65-expressing target cells.These data collectively demonstrate that CMV-specific T cells can effectively target glioblastoma tumor cells for immunologic killing and support the rationale for the development of CMV-directed immunotherapy in patients with GBM.
The Research on Adverse Drug Events and Reports (RADAR) Project
Authors: Charles L. Bennett, Jonathan R. Nebeker, E. Allison Lyons, Matthew H. Samore, Marc D. Feldman, June M. McKoy, Kenneth R. Carson, Steven M. Belknap, Steven M. Trifilio, Glen T. Schumock, Paul R. Yarnold, Charles J. Davidson, Andrew M. Evens, Timothy M. Kuzel, Jorge P. Parada, Denis Cournoyer, Dennis P. West, Oliver Sartor, Martin S. Tallman, Dennis W. Raisch
Journal: JAMA (2005)

In 1998, a multidisciplinary team of investigators initiated RADAR (Research on Adverse Drug events And Reports), a clinically based postmarketing surveillance program that systematically investigates and disseminates information describing serious and previously unrecognized adverse drug and device reactions (ADRs).To describe the structure, operations, and preliminary findings from the RADAR project and related dissemination efforts by pharmaceutical suppliers and the US Food and Drug Administration (FDA).After identifying a serious and unexpected clinical event suitable for further investigation, RADAR collaborators postulated clinical hypotheses and derived case series and incidence estimates from physician queries, published and unpublished clinical trials, published case reports, FDA databases, and manufacturer sales figures.RADAR investigators identified 16 types of serious ADRs among 1699 patients, of whom 169 (10%) died as a result of the reaction. Initial cases were identified by 7 RADAR investigators, 4 collaborating physicians, 2 attorneys, and by reviewing 3 published reports. Additional sources included queries of occupational health programs and medical directors of interventional cardiology laboratories (3 types of ADRs), published manuscripts and clinical trials (11 types of ADRs), review of medical records at a RADAR site (2 types of ADRs), unpublished clinical trial reports (3 types of ADRs), and reports from attorneys, family members, or patients (4 types of ADRs). Incidence estimates, ranging from 0.4% to 33%, were derived from 5 clinical trial reports, 2 physician queries, and 2 observational databases. Laboratory support for hypotheses included identification of 3 neutralizing antibodies and 3 histopathological findings. ADR reports were disseminated as 8 revised package inserts, 7 "dear doctor" letters, and 9 peer-reviewed articles.A new, clinically based, hypothesis-driven approach to postmarketing surveillance may supplement existing regulatory surveillance systems and improve patient safety.
Loss of asymmetric distribution of sarcolemmal phosphatidylethanolamine during simulated ischemia in the isolated neonatal rat cardiomyocyte.
Authors: R J Musters, E Otten, E Biegelmann, J Bijvelt, J J Keijzer, J A Post, J A Op den Kamp, A J Verkleij
Journal: Circulation Research (1993)

In the present study we have investigated the reorganization of the sarcolemmal phospholipids during the first 60 minutes of simulated ischemia ("ischemia") as induced by anoxia, volume restriction, and nutrient deprivation. Experiments were carried out on [3H]acetate-labeled neonatal rat cardiomyocytes and isolated (nonradiolabeled) sarcolemmal membranes obtained from the same culture system. After 60 minutes of "ischemia," cellular high-energy phosphate (ATP) levels had decreased to approximately 40% of the control values, but no significant phospholipid hydrolysis was detected. Labeling experiments using the nonpermeant (primary amine-containing phospholipid) probe trinitrobenzenesulfonic acid and nonlytic treatment with (different) exogenous phospholipases A2 were both indicative of a shifted transbilayer distribution of the hexagonalII phase-preferring and fusion-promoting sarcolemmal phosphatidylethanolamine in favor of the outer membrane leaflet. This specific change in sarcolemmal phospholipid asymmetry preceded the loss of integrity of the sarcolemma, monitored by the release of lactate dehydrogenase as well as by scanning electron microscopy. It is proposed that, in addition to the previously reported lateral phospholipid reorganization, uncontrolled transbilayer movement of the non-bilayer-preferring phosphatidylethanolamine from the inner to the outer leaflet of the sarcolemma is an additional factor in destabilizing the lipid bilayer, eventually leading to the irreversible membrane damage seen after a prolonged period of ischemia.
Hemodynamic Disturbed Flow Induces Differential DNA Methylation of Endothelial Kruppel-Like Factor 4 Promoter In Vitro and In Vivo
Authors: Yi-Zhou Jiang, Juan M. Jiménez, Kristy Ou, Margaret E. McCormick, Ling-Di Zhang, Peter F. Davies
Journal: Circulation Research (2014)

Hemodynamic disturbed flow (DF) is associated with susceptibility to atherosclerosis. Endothelial Kruppel-Like Factor 4 (KLF4) is an important anti-inflammatory atheroprotective transcription factor that is suppressed in regions of DF.The plasticity of epigenomic KLF4 transcriptional regulation by flow-mediated DNA methylation was investigated in vitro and in arterial tissue.To recapitulate dominant flow characteristics of atheroprotected and atherosusceptible arteries, human aortic endothelial cells were subjected to pulsatile undisturbed flow or oscillatory DF containing a flow-reversing phase. Differential CpG site methylation was measured by methylation-specific polymerase chain reaction, bisulfite pyrosequencing, and restriction enzyme-polymerase chain reaction. The methylation profiles of endothelium from disturbed and undisturbed flow sites of adult swine aortas were also investigated. In vitro, DF increased DNA methylation of CpG islands within the KLF4 promoter that significantly contributed to suppression of KLF4 transcription; the effects were mitigated by DNA methyltransferase (DNMT) inhibitors and knockdown of DNMT3A. Contributory mechanisms included DF-induced increase of DNMT3A protein (1.7-fold), DNMT3A enrichment (11-fold) on the KLF4 promoter, and competitive blocking of a myocyte enhancer factor-2 binding site in the KLF4 promoter near the transcription start site. DF also induced DNMT-sensitive propathological expression of downstream KLF4 transcription targets nitric oxide synthase 3, thrombomodulin, and monocyte chemoattractant protein-1. In support of the in vitro findings, swine aortic endothelium isolated from DF regions expressed significantly lower KLF4 and nitric oxide synthase 3, and bisulfite sequencing of KLF4 promoter identified a hypermethylated myocyte enhancer factor-2 binding site.Hemodynamics influence endothelial KLF4 expression through DNMT enrichment/myocyte enhancer factor-2 inhibition mechanisms of KLF4 promoter CpG methylation with regional consequences for atherosusceptibility.
Need to test impact of DNA-based risk scores
Authors: Chris Griffiths, Deesha Patel, Ajiri Akporobaro, Nyasha Chinyanganya, Allan Hackshaw, Clive Seale, Robert Walton, Stephen Spiro
Journal: Thorax (2012)

Young and Hopkins highlight the emerging data suggesting that smokers who perceive themselves at a lower risk of lung cancer may be less likely to take part in, and less likely to adhere to, lung cancer screening programmes.1–4 Their work suggesting that a risk score that …
Occupational asthma due to isocyanates
Authors: CE Mapp, P Boschetto, L Dal Vecchio, P Maestrelli, LM Fabbri
Journal: European Respiratory Journal (1988)

162 subjects who had been exposed to isocyanates, who had developed symptoms during the exposure period, or in the evening or night and, therefore, had a history compatible with isocyanate-induced asthma, were studied with inhalation challenge testing to isocyanates (toluene diisocyanate and methylene diphenyl diisocyanate) and methacholine, because they were suspected of having occupational asthma. None of these subjects had symptomatic asthma before employment. The diagnosis of occupational asthma was delayed (duration of symptoms before diagnosis: 3.9 +/- 0.4 yrs). Isocyanate-asthma documented by a positive inhalation challenge to isocyanates was present in 57.4% of the subjects. A higher degree of airway responsiveness to methacholine was present in subjects with a positive isocyanate inhalation challenge compared to subjects with a negative challenge (Gmean and GESM: 0.407 (1.14) vs 0.942 (1.14) mg). The majority of the subjects complained of shortness of breath and cough. The low proportion of atopic subjects (21.5%) and of smokers (7.5%), and the high proportion of subjects with the late component in the asthmatic reaction (71%) appear to be common features in this disease.
3,4-Dihydroxybenzylamine: A Dopamine Analog With Enhanced Antitumor Activity Against B16 Melanoma
Authors: M M Wick
Journal: JNCI Journal of the National Cancer Institute (1979)

3,4-Dihydroxybenzylamine (DHBA), a dopamine analog, was much less toxic than dopamine when tested against the B16 melanoma in vivo and in vitro. Daily doses of 1,000 mg DHBA/kg were better tolerated than doses of 400 mg dopamine/kg. When tested against the B16 melanoma in (C57BL/6 x DBA/2)F1 mice, DHBA had a significantly improved therapeutic effect as shown by a life-span increased 70% as compared to 48% with dopamine. DHBA shared the catecholamine property of selectively inhibiting thymidine incorporation as compared to leucine or uridine incorporation. Because the inhibitory effects of DHBA on the B16 melanoma cells in vitro were similar to those of dopamine, much of the improved efficacy in vivo might be attributed to decreased toxicity.
STUDIES ON STARLING'S LAW OF THE HEART. III. OBSERVATIONS IN PATIENTS WITH MITRAL STENOSIS AND ATRIAL FIBRILLATION ON THE RELATIONSHIPS BETWEEN LEFT VENTRICULAR END-DIASTOLIC SEGMENT LENGTH, FILLING PRESSURE, AND THE CHARACTERISTICS OF VENTRICULAR CONTRACTION *
Authors: Eugene Braunwald, Robert L. Frye, Maurice M. Aygen, Joseph W. Gilbert
Journal: Journal of Clinical Investigation (1960)
Late-breaking abstract: Cough aerosol: Significant basis to design innovative control strategies in tuberculosis transmission in smokers
Authors: Jose Gustavo Zayas, Ming Chiao Chiang, Eric Wong, Fred MacDonald, Malcolm King
Journal: European Respiratory Journal (2011)

Introduction:  Smoking progressively alters the properties of airway mucus. Altered mucus responds differently to airflow interaction when coughing and may modify bioaerosol production.   Objective:  Characterize the cough bioaerosol in smokers to understand its relation to the transmission of tuberculosis (TB).   Method:  Cough aerosol was assessed in seven long-term smokers and compared with the aerosol of 44 non-smokers. Measurement of the size and number of cough droplets was accomplished using a laser diffraction system.   Results:  Long-term smokers emitted up to two orders of magnitude more droplets of all sizes than non-smokers when coughing.   Conclusions:  The number of droplets emitted by smokers when coughing could help to better understand the etiological association between smoking and TB. Optimal control of bioaerosol in smokers with TB, especially those with multiple and extreme drug resistance TB, might strengthen existing core TB control strategy. Acquired knowledge would lead to the development of informed public health policies, more effective practices and/or products to optimize TB control.
Transforming Growth Factor in Cancer: Janus, the Two-Faced God
Authors: D. Salomon
Journal: JNCI Journal of the National Cancer Institute (2014)

Growth factors and cytokines perform an important role in the etiology and progression of a number of different types of cancer (1,2). These peptides can function either as cis/autocrine or as trans/paracrine effectors for tumor cells and/or for different types of surrounding host cells that can influence tumor initiation, progression, and metastasis. The transforming growth factor β (TGF-β) superfamily, which is found in all metazoans, consists of 30 distinct ligands that include TGF-βs, activins, Nodal, bone morphogenetic proteins, and growth and differentiation factors (3). In mammals there are three different, highly homologous TGF-β isoforms, TGF-β1, TGF-β2, and TGF-β3, that are initially synthesized from a large inactive/latent precursor bound to other proteins and that need to be proteolytically processed by proprotein convertases to produce biologically active dimeric ligands. Activation of canonical (Smad-dependent) and noncanonical (Smad-independent) pathways by all members of this superfamily requires ligand binding to one of five distinct members of the type 2 serine/threonine kinase receptors and subsequent heterodimerization and serine/threonine transphosphorylation of one of seven different type 1 serine/threonine kinase receptors (3,4). For some ligands, additional coreceptors (eg, Cripto-1/Cryptic, endoglin, betaglycan, and Dragon) are needed for optimal ligand binding to and activation of the type 2–-type 1 receptor heterodimeric receptor complex. Reciprocally, there are inhibitory proteins (eg, Lefty, CD-109, BAMBI, COCO, Chordin, and Cerberus) that can bind to either ligands and/or the receptors and effectively antagonize signaling through this pathway (5,6).
Type 1 Diabetes Environmental Factors and Correspondence Analysis of HLA Class II Genes in the Yemenite Jewish Community in Israel
Authors: Naomi Weintrob, Elliot Sprecher, Shoshana Israel, Orit Pinhas-Hamiel, Oh Joong Kwon, Konstantin Bloch, Natali Abramov, Aviva Arbel, Zeev Josefsberg, Chaim Brautbar, Pnina Vardi
Journal: Diabetes Care (2001)

OBJECTIVE—The Israeli Yemenite Jewish community has displayed an exceptionally rapid increase in the frequency of type 1 diabetes, having the highest rate of all Israeli ethnic groups. We studied the role of the environment, in relation to the nature and frequency of HLA class II genes, to evaluate its possible involvement in the development of diabetes. RESEARCH DESIGN AND METHODS—We interviewed 196 elderly Yemenite women, who had immigrated to Israel as adults, in programmed encounters about signs and symptoms of type 1 diabetes, infant feeding customs, and infectious diseases in Yemen. We also performed HLA oligotyping of DRB1, DQA1, and DQB1 genes in 120 unrelated Yemenite Jews, including 44 type 1 diabetic patients and 76 healthy control subjects, and used these data in correspondence analysis comparing Yemenites with different Israeli ethnic groups. RESULTS—Interviews indicated that early exposure to cow’s milk was very common in Yemen. However, none of the women could recall classical presentations of diabetes. HLA oligotyping showed that gene frequencies of non-Asp-57 (of the HLA-DQB chain) in the patients (0.94) and control subjects (0.6) were similar to those of other populations with a known high incidence of type 1 diabetes. Correspondence analysis revealed that Yemenite Jews are genetically distinct from other ethnic groups in Israel. CONCLUSIONS—The genetic distinctiveness of Yemenite Jews may explain their unusually high incidence of type 1 diabetes in Israel. Despite the presence of highly susceptible diabetogenic HLA class II genes in this community, early exposure to cow’s milk did not cause phenotypic expression of diabetes in Yemen. This finding suggests that in this population, either cow’s milk does not play a crucial role in triggering diabetes, or environmentally conferred protection, such as frequent infectious disease in Yemen, was dominant.
Treatment of patients with dual hepatitis C and B by peginterferon α and ribavirin reduced risk of hepatocellular carcinoma and mortality
Authors: Chun-Jen Liu, Yu-Tseng Chu, Wen-Yi Shau, Raymond N Kuo, Pei-Jer Chen, Mei-Shu Lai
Journal: Gut (2013)

<h3>Objective</h3> Whether peginterferon α and ribavirin combination therapy reduces risk of hepatocellular carcinoma (HCC) or improves survival in patients dual-infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) is unknown. Since it is ethically impossible to conduct a randomised trial to learn the long-term efficacy, we rely upon the large database to explore the effectiveness of combination therapy among dual-infected patients. <h3>Design</h3> Data for this population-based retrospective cohort study were obtained from the treatment programme, Cancer Registry, National Health Insurance and death certification. We examined the risk of HCC, mortality and adverse events in 1096 treated and 18 988 untreated HCV–HBV dually-infected patients. Outcomes were analysed using the bias corrected inverse probability weighting (IPW) by propensity scores. Outcomes of HCV–HBV dually-infected and HCV mono-infected patients receiving the same treatment were compared using new user design with IPW estimators to adjust for confounding. <h3>Results</h3> After adjustment, combination therapy significantly reduced the risk of HCC (HR 0.76, 95% CI 0.59 to 0.97), liver-related mortality (HR 0.47, 95% CI 0.37 to 0.6) and all-cause mortality (HR 0.42, 95% CI 0.34 to 0.52). Nevertheless, the underlying HBV infection was still a risk factor for HCC and mortality after treatment. Treatment was associated with an increase in the incidence of thyroid dysfunction (HR 1.9, p&lt;0.001) and mood disorders (HR 1.81, p=0.005). <h3>Conclusions</h3> This is the first evidence showing that combination therapy decreased the risk of HCC and improved survival in HCV–HBV dually-infected patients despite a slight increase in the incidence of thyroid and mood disorders.
In Vivo Magnetic Resonance Spectroscopy in Cancer
Authors: Robert J. Gillies, David L. Morse
Journal: Annual Review of Biomedical Engineering (2005)

▪ Abstract Magnetic resonance spectroscopy (MRS) has been used for more than two decades to interrogate metabolite distributions in living cells and tissues. Techniques have been developed that allow multiple spectra to be obtained simultaneously with individual volume elements as small as 1 uL of tissue (i.e., 1 × 1 × 1 mm 3 ). The most common modern applications of in vivo MRS use endogenous signals from 1 H, 31 P, or 23 Na. Important contributions have also been made using exogenous compounds containing 19 F, 13 C, or 17 O. MRS has been used to investigate cardiac and skeletal muscle energetics, neurobiology, and cancer. This review focuses on the latter applications, with specific reference to the measurement of tissue choline, which has proven to be a tumor biomarker that is significantly affected by anticancer therapies.