tbuckley/cabot-search huggingface dataset:
Cardiovascular diseases and HCV infection: a simple association or more?
Authors: Salvatore Petta, Fabio Salvatore Macaluso, Antonio Craxì
Journal: Gut (2013)

HCV infection, metabolic disorders and cardiovascular alterations, considered alone or in combination, are common conditions in a large proportion of the general population. Consequently, determining whether the association of HCV infection with cardiometabolic disorders is simply coincidental or, conversely, caused by pathogenetic mechanisms (in)directly linking chronic HCV infection to these disorders, would be of extreme relevance.

Several clinical studies have shown that metabolic disorders—namely, type 2 diabetes,1 insulin resistance (IR)2 and hepatic steatosis3—are highly prevalent in patients with chronic hepatitis C (CHC) compared with non-infected patients. Experimental and clinical studies have shown that HCV is able to directly influence glucose and lipid metabolism and thus can perturb the metabolic homeostasis of the host, leading to extrahepatic consequences.4 ,5 However, unlike the classic forms of metabolic disturbances, CHC is associated with a favourable lipoprotein profile—that is, reduced levels of apolipoprotein B containing lipoproteins, such as low density lipoprotein and very low density lipoprotein cholesterol.6

The discordance between the increased prevalence of IR, steatosis and diabetes, and the favourable lipoprotein profile in CHC compared with non-infected individuals, may account for the similar prevalence of metabolic syndrome (ie, the presence of at least three of the following: visceral obesity, hyperglycaemia, arterial hypertension, low levels of high density lipoprotein cholesterol and high triglycerides levels)7 reported in data from the database of the third National Health and Nutrition Examination Survey (NHANES-III).8

These data raise the question of whether HCV infection per se and/or via induction of metabolic/inflammatory dysfunctions is associated with an increased cardiovascular risk.

With this in mind, cross sectional and prospective studies have evaluated the presence and occurrence of both cardiovascular alterations and cardiovascular mortality in HCV infected patients compared with non-infected patients, with contrasting results.6 ,9–34

This review was prompted by …
Intratumoral Heterogeneity of <i>ALK</i>-Rearranged and <i>ALK</i>/<i>EGFR</i> Coaltered Lung Adenocarcinoma
Authors: Weijing Cai, Dongmei Lin, Chunyan Wu, Xuefei Li, Chao Zhao, Limou Zheng, Shannon Chuai, Ke Fei, Caicun Zhou, Fred R. Hirsch
Journal: Journal of Clinical Oncology (2015)

Purpose Genetic intratumoral heterogeneity has a profound influence on the selection of clinical treatment strategies and on addressing resistance to targeted therapy. The purpose of this study was to explore the potential effect of intratumoral heterogeneity on both genetic and pathologic characteristics of ALK-rearranged lung adenocarcinoma (LADC). Methods We tested ALK fusions and EGFR mutations in 629 patients with LADC by using laser-capture microdissection to capture spatially separated tumor cell subpopulations in various adenocarcinoma subtypes and to test for ALK fusions and EGFR mutations in ALK-rearranged, EGFR-mutated, and ALK/EGFR coaltered LADCs to compare the oncogenic driver status between different tumor cell subpopulations in the same primary tumor. Results Among the 629 patients, 30 (4.8%) had ALK fusions, 364 (57.9%) had EGFR mutations, and two had ALK fusions that coexisted with EGFR mutations. Intratumoral heterogeneity of ALK fusions were identified in nine patients by reverse-transcriptase polymerase chain reaction. In the two patients with an ALK/EGFR coaltered status, genetic intratumoral heterogeneity was observed both between different growth patterns and within the same growth pattern. The relative abundance of ALK and EGFR alterations was different in the same captured area. ALK fusions were positively associated with a micropapillary pattern (P = .002) and were negatively associated with a lepidic pattern (P = .008) in an expanded statistical analysis of 900 individual adenocarcinoma components, although they appeared to be more common in acinar-predominant LADCs in the analysis of 629 patients. Conclusion Intratumoral genetic heterogeneity was demonstrated to coexist with histologic heterogeneity in both single-driver and ALK/EGFR coaltered LADCs. Altered oncogenic drivers in spatially separated subclones of the same tumor may be different.
Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X)
Authors: D THOMAS, B HAMMERLING, A WIMMER, K WU, E FICKER, Y KURYSHEV, D SCHERER, J KIEHN, H KATUS, W SCHOELS
Journal: Cardiovascular Research (2004)

Objective: The human ether-a-go-go-related gene (hERG) encodes the rapid component of the cardiac repolarizing delayed rectifier potassium current, IKr. The direct interaction of the commonly used protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM I) with hERG, KvLQT1/minK, and IKr currents was investigated in this study. Methods: hERG and KvLQT1/minK channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. In addition, hERG currents in stably transfected human embryonic kidney (HEK 293) cells, native IKr currents and action potentials in isolated guinea pig ventricular cardiomyocytes were recorded using whole-cell patch clamp electrophysiology. Results: Bisindolylmaleimide I blocked hERG currents in HEK 293 cells and Xenopus oocytes in a concentration-dependent manner with IC50 values of 1.0 and 13.2 μM, respectively. hERG channels were primarily blocked in the open state in a frequency-independent manner. Analysis of the voltage-dependence of block revealed a reduction of inhibition at positive membrane potentials. BIM I caused a shift of −20.3 mV in the voltage-dependence of inactivation. The point mutations tyrosine 652 alanine (Y652A) and phenylalanine 656 alanine (F656A) attenuated hERG current blockade, indicating that BIM I binds to a common drug receptor within the pore region. KvLQT1/minK currents were not significantly altered by BIM I. Finally, 1 μM BIM I reduced native IKr currents by 69.2% and lead to action potential prolongation. Conclusion: In summary, PKC-independent effects have to be carefully considered when using BIM I as PKC inhibitor in experimental models involving hERG channels and IKr currents.
Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis
Authors: A.E. Nieuwenhuis-Ruifrok, W.K.H. Kuchenbecker, A. Hoek, P. Middleton, R.J. Norman
Journal: Human Reproduction Update (2008)

Women of reproductive age, who are overweight or obese, are prone to infertility. Weight loss in these women leads to increased fecundity, higher chances of conception after infertility treatment and improved pregnancy outcome. In spite of the advantages, most patients have difficulty in losing weight and often regain lost weight over time. This review assesses whether treatment with insulin sensitizing drugs contributes to weight loss, compared with diet or a lifestyle modification programme.After a systematic search of the literature, only randomized controlled trials (RCTs), investigating the effect of insulin sensitizing drugs on weight loss compared with placebo and diet and/or a lifestyle modification programme, were included. Subjects were restricted to women of reproductive age. The main outcome measure was change in body mass index (BMI).Only 14 trials, unintentionally all but two on women with polycystic ovary syndrome (PCOS) only, were included in the analysis. Treatment with metformin showed a statistically significant decrease in BMI compared with placebo (weighted mean difference, -0.68; 95% CI -1.13 to -0.24). There was some indication of greater effect with high-dose metformin (>1500 mg/day) and longer duration of therapy (>8 weeks). Limitations were power, low use of intention-to-treat analysis and heterogeneity of the studies.A structured lifestyle modification programme to achieve weight loss should still be the first line treatment in obese women with or without PCOS. Adequately powered RCTs are required to confirm the findings of this review and to assess whether the addition of high-dose metformin therapy to a structured lifestyle modification programme might contribute to more weight loss.
Loss of TGF-β Adaptor β2SP Activates Notch Signaling and SOX9 Expression in Esophageal Adenocarcinoma
Authors: Shumei Song, Dipen M. Maru, Jaffer A. Ajani, Chia-Hsin Chan, Soichiro Honjo, Hui-Kuan Lin, Arlene Correa, Wayne L. Hofstetter, Marta Davila, John Stroehlein, Lopa Mishra
Journal: Cancer Research (2013)

TGF-β and Notch signaling pathways play important roles in regulating self-renewal of stem cells and gastrointestinal carcinogenesis. Loss of TGF-β signaling components activates Notch signaling in esophageal adenocarcinoma, but the basis for this effect has been unclear. Here we report that loss of TGF-β adapter β2SP (SPNB2) activates Notch signaling and its target SOX9 in primary fibroblasts or esophageal adenocarcinoma cells. Expression of the stem cell marker SOX9 was markedly higher in esophageal adenocarcinoma tumor tissues than normal tissues, and its higher nuclear staining in tumors correlated with poorer survival and lymph node invasion in esophageal adenocarcinoma patients. Downregulation of β2SP by lentivirus short hairpin RNA increased SOX9 transcription and expression, enhancing nuclear localization for both active Notch1 (intracellular Notch1, ICN1) and SOX9. In contrast, reintroduction into esophageal adenocarcinoma cells of β2SP and a dominant-negative mutant of the Notch coactivator mastermind-like (dnMAN) decreased SOX9 promoter activity. Tumor sphere formation and invasive capacity in vitro and tumor growth in vivo were increased in β2SP-silenced esophageal adenocarcinoma cells. Conversely, SOX9 silencing rescued the phenotype of esophageal adenocarcinoma cells with loss of β2SP. Interaction between Smad3 and ICN1 via Smad3 MH1 domain was also observed, with loss of β2SP increasing the binding between these proteins, inducing expression of Notch targets SOX9 and C-MYC, and decreasing expression of TGF-β targets p21(CDKN1A), p27 (CDKN1B), and E-cadherin. Taken together, our findings suggest that loss of β2SP switches TGF-β signaling from tumor suppression to tumor promotion by engaging Notch signaling and activating SOX9.
Simkania negevensis infection among Brazilian children hospitalized with community-acquired pneumonia
Authors: Cristiana M. Nascimento-Carvalho, Maria-Regina A. Cardoso, Mika Paldanius, Aldina Barral, César A. Araújo-Neto, Annika Saukkoriipi, Raija Vainionpää, Maija Leinonen, Olli Ruuskanen
Journal: Journal of Infection (2009)
Acidosis Inhibits Endothelial Cell Apoptosis and Function and Induces Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor Expression
Authors: Daniela D’Arcangelo, Francesco Facchiano, Laura Maria Barlucchi, Guido Melillo, Barbara Illi, Lucia Testolin, Carlo Gaetano, Maurizio C. Capogrossi
Journal: Circulation Research (2000)

Abstract —Endothelial cells are exposed to an acidotic environment in a variety of pathological and physiological conditions. However, the effect of acidosis on endothelial cell function is still largely unknown, and it was evaluated in the present study. Bovine aortic endothelial cells (BAECs) were grown in bicarbonate buffer equilibrated either with 20% CO 2 (pH 7.0, acidosis) or 5% CO 2 (pH 7.4, control). Acidosis inhibited BAEC proliferation in 10% FCS, whereas by day 7 in serum-free medium, cell number was 3-fold higher in acidotic cells than in control cells. Serum deprivation enhanced BAEC apoptosis, and apoptotic cell death was markedly inhibited by acidosis. Additionally, acidosis inhibited FCS-stimulated migration in a modified Boyden chamber assay and FCS-stimulated differentiation into capillary-like structures on reconstituted basement membrane proteins. Conditioned media from BAECs cultured for 48 hours either at pH 7.0 or pH 7.4 enhanced BAEC proliferation and migration at pH 7.4, and both effects were more marked with conditioned medium from BAECs grown in acidotic than in control conditions. Acidosis enhanced vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) mRNA expression as well as bFGF secretion, and a blocking bFGF antibody inhibited enhanced BAEC migration in response to conditioned medium from acidotic cells. These results show that acidosis protects endothelial cells from apoptosis and inhibits their proangiogenic behavior despite enhanced VEGF and bFGF mRNA expression and bFGF secretion.
A Comparison of Self-Reported Energy Intake With Total Energy Expenditure Estimated by Accelerometer and Basal Metabolic Rate in African-American Women With Type 2 Diabetes
Authors: Carmen D. Samuel-Hodge, Louise M. Fernandez, Carlos F. Henríquez-Roldán, Larry F. Johnston, Thomas C. Keyserling
Journal: Diabetes Care (2004)

OBJECTIVE—This study assesses the validity of dietary data from African-American women with type 2 diabetes by comparing reported energy intake (EI) with total energy expenditure (TEE) estimated by an accelerometer and basal metabolic rate (BMR). RESEARCH DESIGN AND METHODS—EI of 200 African-American women was assessed by three telephone-administered 24-h diet recalls using a multiple-pass approach. Physical activity was measured over a 7-day period by accelerometer, which also provided an estimate of TEE. Underreporting of EI was determined by using cutoffs for EI-to-TEE and EI-to-BMR ratios. RESULTS—Participants, on average, were 59 years of age, with a BMI of 35.7, 10.5 years of diagnosed diabetes, and 10.7 years of education. Mean EI was 1,299 kcal/day; mean EI-to-TEE and EI-to-BMR ratios were 0.65 and 0.88, respectively. Among the 185 subjects with complete dietary data, 81% (n = 150) were classified as energy underreporters using the EI-to-TEE ratio cutoff; 58% (n = 107) were classified as energy underreporters using the EI-to-BMR ratio. Energy underreporters had significantly lower reported fat, higher protein, but similar carbohydrate intakes compared with non-underreporters. The EI-to-TEE ratio was not significantly associated with any demographic variables or following a diet for diabetes, but it was inversely associated with BMI (r = −0.37, P &amp;lt; 0.0001). In a multivariate model, demographic variables, BMI, and following a diet for diabetes explained 16% of the variance in the EI-to-TEE ratio, with the latter two variables being the only significant predictors (inversely associated). CONCLUSIONS—Widespread energy underreporting among this group of overweight African-American women with type 2 diabetes severely compromised the validity of self-reported dietary data.
Constitutive Expression and Costimulatory Function of LIGHT/TNFSF14 on Human Melanoma Cells and Melanoma-Derived Microvesicles
Authors: Roberta Mortarini, Alessia Scarito, Daisuke Nonaka, Marina Zanon, Ilaria Bersani, Elisabetta Montaldi, Elisabetta Pennacchioli, Roberto Patuzzo, Mario Santinami, Andrea Anichini
Journal: Cancer Research (2005)

Abstract Neoplastic cells are thought to have defective expression of costimulatory molecules. However, in this study, we show that human melanoma cells express LIGHT/TNFSF14, a ligand of herpesvirus entry mediator on T cells and of lymphotoxin β receptor on stromal cells. In vitro, melanoma cells stained for LIGHT in the intracellular compartment, with weak or negative cell surface expression. However, LIGHT was expressed on tumor-derived microvesicles released from melanoma cells. In vivo, LIGHT was found in metastatic lesions, and the extent of lymphotoxin β receptor expression on the stromal cells was significantly associated with a “brisk” T-cell infiltrate in the neoplastic tissue. In the lesions with a brisk T-cell infiltrate, stromal cells surrounding the tumor also stained for the T-cell attractant chemokine CCL21. The intratumoral T lymphocytes frequently expressed herpesvirus entry mediator and were characterized by a differentiated phenotype. Coculture of lymphocytes with LIGHT+ melanoma-derived microvesicles or even with LIGHT+ melanoma cells in the presence of interleukin-2 costimulated LIGHT-dependent CD3+CD8+ T-cell proliferation. However, lymphocyte coculture with LIGHT+ microvesicles in the presence of interleukin-2 was also associated with an apoptotic response as documented by increased binding of Annexin V by CD3+CD8+ T cells. These data suggest that LIGHT constitutively expressed in human melanoma cells and microvesicles may contribute to regulate T-cell responses to tumor cells.
Disentangling the discordance between epidemiological associations and physiological mechanisms
Authors: Sanja Stanojevic, Tim J Cole, Janet Stocks, Philip H Quanjer
Journal: Thorax (2014)

Burney et al 1 recently presented an ecological analysis of Burden of Obstructive Lung Disease (BOLD) study data to investigate the association between chronic obstructive pulmonary disease (COPD) prevalence and mortality with smoking and poverty. It is striking that no association was observed between the national prevalence rates of COPD and airflow limitation. This raises serious questions about the accuracy of COPD diagnosis, and suggests that COPD was considerably overdiagnosed. Despite this, the authors’ main conclusion is that the high COPD mortality in low-income countries is associated with spirometric restriction, but the case for this is unconvincing.

There are several methodological reasons why the findings need …
Inference of Gorilla Demographic and Selective History from Whole-Genome Sequence Data
Authors: Kimberly F. McManus, Joanna L. Kelley, Shiya Song, Krishna R. Veeramah, August E. Woerner, Laurie S. Stevison, Oliver A. Ryder, Great Ape Genome Project, Jeffrey M. Kidd, Jeffrey D. Wall, Carlos D. Bustamante, Michael F. Hammer
Journal: Molecular Biology and Evolution (2014)

Although population-level genomic sequence data have been gathered extensively for humans, similar data from our closest living relatives are just beginning to emerge. Examination of genomic variation within great apes offers many opportunities to increase our understanding of the forces that have differentially shaped the evolutionary history of hominid taxa. Here, we expand upon the work of the Great Ape Genome Project by analyzing medium to high coverage whole-genome sequences from 14 western lowland gorillas (Gorilla gorilla gorilla), 2 eastern lowland gorillas (G. beringei graueri), and a single Cross River individual (G. gorilla diehli). We infer that the ancestors of western and eastern lowland gorillas diverged from a common ancestor approximately 261 ka, and that the ancestors of the Cross River population diverged from the western lowland gorilla lineage approximately 68 ka. Using a diffusion approximation approach to model the genome-wide site frequency spectrum, we infer a history of western lowland gorillas that includes an ancestral population expansion of 1.4-fold around 970 ka and a recent 5.6-fold contraction in population size 23 ka. The latter may correspond to a major reduction in African equatorial forests around the Last Glacial Maximum. We also analyze patterns of variation among western lowland gorillas to identify several genomic regions with strong signatures of recent selective sweeps. We find that processes related to taste, pancreatic and saliva secretion, sodium ion transmembrane transport, and cardiac muscle function are overrepresented in genomic regions predicted to have experienced recent positive selection.
Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides
Authors: Christopher S. Wilcox, Adam Pearlman
Journal: Pharmacological Reviews (2008)

Nitroxides can undergo one- or two-electron reduction reactions to hydroxylamines or oxammonium cations, respectively, which themselves are interconvertible, thereby providing redox metabolic actions. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-<i>N</i>-oxyl (tempol) is the most extensively studied nitroxide. It is a cell membrane-permeable amphilite that dismutates superoxide catalytically, facilitates hydrogen peroxide metabolism by catalase-like actions, and limits formation of toxic hydroxyl radicals produced by Fenton reactions. It is broadly effective in detoxifying these reactive oxygen species in cell and animal studies. When administered intravenously to hypertensive rodent models, tempol caused rapid and reversible dose-dependent reductions in blood pressure in 22 of 26 studies. This was accompanied by vasodilation, increased nitric oxide activity, reduced sympathetic nervous system activity at central and peripheral sites, and enhanced potassium channel conductance in blood vessels and neurons. When administered orally or by infusion over days or weeks to hypertensive rodent models, it reduced blood pressure in 59 of 68 studies. This was accompanied by correction of salt sensitivity and endothelial dysfunction and reduced agonist-evoked oxidative stress and contractility of blood vessels, reduced renal vascular resistance, and increased renal tissue oxygen tension. Thus, tempol is broadly effective in reducing blood pressure, whether given by acute intravenous injection or by prolonged administration, in a wide range of rodent models of hypertension.
Critical Evaluation of the Prostate from Cystoprostatectomies for Bladder Cancer: Insights from a Complete Sampling with the Whole Mount Technique
Authors: Rodolfo Montironi, Liang Cheng, Roberta Mazzucchelli, Marina Scarpelli, Ziya Kirkali, Francesco Montorsi, Antonio Lopez-Beltran
Journal: European Urology (2008)
Health System Reform
Authors: P. John Seward
Journal: JAMA (1995)

As early as 1990, the American Medical Association recognized the imperative for health system reform and advanced its own program called Health Access America.<sup>1</sup>Yet it was not until the campaign slogan of Harris Wofford and the promises of President Clinton that the great health system reform debate of the 1990s began. Many felt the need to extend insurance coverage, flatten the rise of health care expenditures, and to find new and innovative ways of providing cost-effective health care with an emphasis on preventive medicine. Public polls overwhelmingly indicate that the public believes the current system requires change, albeit without a clear indication of how. The medical profession as much as anyone sees the defects in the current system along with the intrusion of entrepreneurial giants and continues to declare the status quo unacceptable. Anticipation regarding possible reforms was high, activity frenetic, and expectations rampant, but the whole reform