tbuckley/cabot-search huggingface dataset:
Big-Benefit Mutations in a Bacteriophage Inhibited with Heat
Authors: J. J. Bull, M. R. Badgett, H. A. Wichman
Journal: Molecular Biology and Evolution (2000)

High temperature inhibits the growth of the wild-type bacteriophage ϕX174. Three different point mutations were identified that each recovered growth at high temperature. Two affected the major capsid protein (residues F188 and F242), and one affected the internal scaffolding protein (B114). One of the major capsid mutations (F242) is located in a β strand that contacts B114 in the procapsid during viral maturation, whereas the other capsid mutation (F188) is involved in subunit interactions at the threefold axis of symmetry. Selective coefficients of these mutations ranged from 13.9 to 3.8 in the inhibitory, hot environment, but all mutations reduced fitness at normal temperature. The selective effect of one of the mutations (F242) was evaluated at high temperature in four different genetic backgrounds and exhibited epistasis of diminishing returns: as log fitness of the background genotype increased from −0.1 to 4.1, the fitness boost provided by the F242 mutation decreased from 3.9 to 0.8. These results support a model in which viral fitness is bounded by an upper limit and the benefit of a mutation is scaled according to the remaining opportunity for fitness improvement in the genome.
Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Yuqing Huo, Lei Zhao, Matthew Craig Hyman, Pavel Shashkin, Brian L. Harry, Tracy Burcin, S. Bradley Forlow, Matthew A. Stark, David F. Smith, Sean Clarke, Suseela Srinivasan, Catherine C. Hedrick, Domenico Praticò, Joseph L. Witztum, Jerry L. Nadler, Colin D. Funk, Klaus Ley
Journal: Circulation (2004)

Mice lacking leukocyte type 12/15-lipoxygenase (12/15-LO) show reduced atherosclerosis in several models. 12/15-LO is expressed in a variety of cells, including vascular cells, adipocytes, macrophages, and cardiomyocytes. The purpose of this study was to determine which cellular source of 12/15-LO is important for atherosclerosis.Bone marrow from 12/15-LO-/-/apoE-/- mice was transplanted into apoE-/- mice and vice versa. Deficiency of 12/15-LO in bone marrow cells protected apoE-/- mice fed a Western diet from atherosclerosis to the same extent as complete absence of 12/15-LO, although plasma 8,12-iso-iPF2alpha-IV, a measure of lipid peroxidation, remained elevated. 12/15-LO-/-/apoE-/- mice regained the severity of atherosclerotic lesion typical of apoE-/- mice after replacement of their bone marrow cells with bone marrow from apoE-/- mice. Peritoneal macrophages obtained from wild-type but not 12/15-LO-/- mice caused endothelial activation in the presence of native LDL. Absence of 12/15-LO decreased the ability of macrophages to form foam cells when exposed to LDL.We conclude that macrophage 12/15-LO plays a dominant role in the development of atherosclerosis by promoting endothelial inflammation and foam cell formation.
TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome–positive leukemia cells
Authors: Kanako Uno, Takeshi Inukai, Nobuhiko Kayagaki, Kumiko Goi, Hiroki Sato, Atsushi Nemoto, Kazuya Takahashi, Keiko Kagami, Noriko Yamaguchi, Hideo Yagita, Ko Okumura, Toshiko Koyama-Okazaki, Toshio Suzuki, Kanji Sugita, Shinpei Nakazawa
Journal: Blood (2003)
Epidemiology of HPV 16 and Cervical Cancer in Finland and the Potential Impact of Vaccination: Mathematical Modelling Analyses
Authors: Ruanne V Barnabas, Päivi Laukkanen, Pentti Koskela, Osmo Kontula, Matti Lehtinen, Geoff P Garnett
Journal: PLoS Medicine (2006)

Background Candidate human papillomavirus (HPV) vaccines have demonstrated almost 90%-100% efficacy in preventing persistent, type-specific HPV infection over 18 mo in clinical trials. If these vaccines go on to demonstrate prevention of precancerous lesions in phase III clinical trials, they will be licensed for public use in the near future. How these vaccines will be used in countries with national cervical cancer screening programmes is an important question. Methods and Findings We developed a transmission model of HPV 16 infection and progression to cervical cancer and calibrated it to Finnish HPV 16 seroprevalence over time. The model was used to estimate the transmission probability of the virus, to look at the effect of changes in patterns of sexual behaviour and smoking on age-specific trends in cancer incidence, and to explore the impact of HPV 16 vaccination. We estimated a high per-partnership transmission probability of HPV 16, of 0.6. The modelling analyses showed that changes in sexual behaviour and smoking accounted, in part, for the increase seen in cervical cancer incidence in 35- to 39-y-old women from 1990 to 1999. At both low (10% in opportunistic immunisation) and high (90% in a national immunisation programme) coverage of the adolescent population, vaccinating women and men had little benefit over vaccinating women alone. We estimate that vaccinating 90% of young women before sexual debut has the potential to decrease HPV type-specific (e.g., type 16) cervical cancer incidence by 91%. If older women are more likely to have persistent infections and progress to cancer, then vaccination with a duration of protection of less than 15 y could result in an older susceptible cohort and no decrease in cancer incidence. While vaccination has the potential to significantly reduce type-specific cancer incidence, its combination with screening further improves cancer prevention. Conclusions HPV vaccination has the potential to significantly decrease HPV type-specific cervical cancer incidence. High vaccine coverage of women alone, sustained over many decades, with a long duration of vaccine-conferred protection, would have the greatest impact on type-specific cancer incidence. This level of coverage could be achieved through national coordinated programmes, with surveillance to detect cancers caused by nonvaccine oncogenic HPV types.
Hypnotherapy for non-cardiac chest pain: long-term follow-up
Authors: V Miller, H Jones, P J Whorwell
Journal: Gut (2007)

dysfunction was responsible for the poor outcome in our cirrhotic patients is attractive but not sufficiently supported by our data.Indeed, the statistical analysis excluded the possibility that a drop in the ejection fraction (EF) or any other echocardiographic variable, except E/A ratio, was associated with death.Moreover, none of the patients had cardiac symptoms and no death was caused by evident cardiac failure.Nevertheless, we hope that this subject will be investigated further in a larger group of patients.We agree with Abeles and colleagues that the most important message of our study is that cardiac function should be carefully assessed in critically ill patients with cirrhosis.This concept has recently been corroborated by other investigations, which showed that a relatively insufficient cardiac output was associated with the development of renal failure in cirrhotic patients with spontaneous bacterial peritonitis. 5The prevalence of diastolic dys- function in cirrhosis should be re-evaluated with more accurate methods such as colour Mmode echocardiography and Doppler tissue imaging, which are independent of the load conditions.
Arteriovenous haemangioma in chronic liver disease: clinical and histopathological features of four cases
Authors: M. Akiyama, N. Inamoto
Journal: British Journal of Dermatology (2001)

Journal Article Arteriovenous haemangioma in chronic liver disease: clinical and histopathological features of four cases Get access M. Akiyama, M. Akiyama Department of Dermatology, Teikyo University School of Medicine, Ichihara Hospital, Chiba 299‐0111, JapanDivision of Dermatology, Kitasato Institute Hospital, Tokyo, 108‐8642, Japan Masashi Akiyama, MD PhD. E‐mail: akiyama@med.teikyo‐u.ac.jp Search for other works by this author on: Oxford Academic Google Scholar N. Inamoto N. Inamoto Division of Dermatology, Kitasato Institute Hospital, Tokyo, 108‐8642, Japan Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 144, Issue 3, 1 March 2001, Pages 604–609, https://doi.org/10.1046/j.1365-2133.2001.04094.x Published: 01 March 2001
Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis
Authors: Fan Liu, Guoyan Cheng, Pierre-Jacques Hamard, Sarah Greenblatt, Lan Wang, Na Man, Fabiana Perna, Haiming Xu, Madhavi Tadi, Luisa Luciani, Stephen D. Nimer
Journal: Journal of Clinical Investigation (2015)

Epigenetic regulators play critical roles in normal hematopoiesis, and the activity of these enzymes is frequently altered in hematopoietic cancers. The major type II protein arginine methyltransferase PRMT5 catalyzes the formation of symmetric dimethyl arginine and has been implicated in various cellular processes, including pluripotency and tumorigenesis. Here, we generated Prmt5 conditional KO mice to evaluate the contribution of PRMT5 to adult hematopoiesis. Loss of PRMT5 triggered an initial but transient expansion of hematopoietic stem cells (HSCs); however, Prmt5 deletion resulted in a concurrent loss of hematopoietic progenitor cells (HPCs), leading to fatal BM aplasia. PRMT5-specific effects on hematopoiesis were cell intrinsic and depended on PRMT5 methyltransferase activity. We found that PRMT5-deficient hematopoietic stem and progenitor cells exhibited severely impaired cytokine signaling as well as upregulation of p53 and expression of its downstream targets. Together, our results demonstrate that PRMT5 plays distinct roles in the behavior of HSCs compared with HPCs and is essential for the maintenance of adult hematopoietic cells.
‘Treatment of the Sportsman's groin’: British Hernia Society's 2014 position statement based on the Manchester Consensus Conference
Authors: Aali J Sheen, B M Stephenson, D M Lloyd, P Robinson, D Fevre, H Paajanen, A de Beaux, A Kingsnorth, O J Gilmore, D Bennett, I Maclennan, P O'Dwyer, D Sanders, M Kurzer
Journal: British Journal of Sports Medicine (2013)

<h3>Introduction</h3> The aim was to produce a multidisciplinary consensus to determine the current position on the nomenclature, definition, diagnosis, imaging modalities and management of Sportsman9s groin (SG). <h3>Methods</h3> Experts in the diagnosis and management of SG were invited to participate in a consensus conference held by the British Hernia Society in Manchester, UK on 11–12 October 2012. Experts included a physiotherapist, a musculoskeletal radiologist and surgeons with a proven track record of expertise in this field. Presentations detailing scientific as well as outcome data from their own experiences were given. Records were made of the presentations with specific areas debated openly. <h3>Results</h3> The term ‘inguinal disruption’ (ID) was agreed as the preferred nomenclature with the term ‘Sportsman9s hernia’ or ‘groin’ rejected, as no true hernia exists. There was an overwhelming agreement of opinion that there was abnormal tension in the groin, particularly around the inguinal ligament attachment. Other common findings included the possibility of external oblique disruption with consequent small tears noted as well as some oedema of the tissues. A multidisciplinary approach with tailored physiotherapy as the initial treatment was recommended with any surgery involving releasing the tension in the inguinal canal by various techniques and reinforcing it with a mesh or suture repair. A national registry should be developed for all athletes undergoing surgery. <h3>Conclusions</h3> ID is a common condition where no true hernia exists. It should be managed through a multidisciplinary approach to ensure consistent standards and outcomes are achieved.
Pattern of declining blood pressure across replicate population surveys of the WHO MONICA project, mid-1980s to mid-1990s, and the role of medication
Authors: Hugh Tunstall-Pedoe, John Connaghan, Mark Woodward, Hanna Tolonen, Kari Kuulasmaa
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> Declining mean systolic and diastolic blood pressures were observed in most populations of the World Health Organization MONICA (monitoring trends and determinants in cardiovascular disease) project from the mid-1980s to mid-1990s. We tested whether pooled results would show mean change associated with decline in high readings only, resulting from better antihypertensive medication, or with similar falls in low, middle, and high readings, implying other causes. <b>Design</b> Independent, random sample, cross sectional population surveys, each end of the MONICA decade. <b>Setting</b> 38 populations in 21 countries across four continents. <b>Participants</b> Design target in each survey of 200 participants in each 10 year age and sex group from age 35 to 64 <b>Main outcome measures</b> Changes in the population in mean systolic and diastolic blood pressure, and in low, middle, and high readings—the 20th, 50th, and 80th centiles—and the differences between these changes. <b>Results</b> Individual populations differed considerably, but pooling the 38 population results gave mean changes in systolic blood pressure of −2.2 mm Hg in men, −3.3 mm Hg in women, and in diastolic blood pressure of −1.4 mm Hg in men and −2.2 mm Hg in women (overall average −2.26 mm Hg, population median −1.55 mm Hg). Antihypertensive medication, associated with high readings, rose by 0.5% to 11.4%. However, average falls in low and middle blood pressure readings were so similar to those in high readings and in the mean that no effect from improving treatment of hypertension was detected. Results in contrasted subgroups were consistent. <b>Conclusions</b> Blood pressure fell across 38 MONICA populations at all levels of readings, with no differential fall in high readings attributable to better control of hypertension. Despite the importance of medication to individuals, in that decade other determinants of blood pressure lowering must have been more pervasive and powerful in whole populations.
A Seven-transmembrane, G Protein–coupled Receptor, FPRL1, Mediates the Chemotactic Activity of Serum Amyloid A for Human Phagocytic Cells
Authors: Shao Bo Su, Wanghua Gong, Ji-Liang Gao, Weiping Shen, Philip M. Murphy, Joost J. Oppenheim, Ji Ming Wang
Journal: The Journal of Experimental Medicine (1999)

We have previously reported (Badolato, R., J.M. Wang, W.J. Murphy, A.R. Lloyd, D.F. Michiel, L.L. Bausserman, D.J. Kelvin, and J.J. Oppenheim. 1994. J. Exp. Med. 180:203; Xu, L., R. Badolato, W.J. Murphy, D.L. Longo, M. Anver, S. Hale, J.J. Oppenheim, and J.M. Wang. 1995. J. Immunol. 155:1184.) that the acute phase protein serum amyloid A (SAA) is a potent chemoattractant for human leukocytes in vitro and mouse phagocytes in vivo. To identify the signaling mechanisms, we evaluated patterns of cross-desensitization between SAA and other leukocyte chemoattrctants. We found that the chemotactic bacterial peptide, N-formyl- methionyl-leucyl-phenylalanine (fMLP), was able to specifically attenuate Ca2+ mobilization in human phagocytes induced by SAA, but only at very high concentrations, suggesting that SAA uses a low affinity fMLP receptor. Here we demonstrate that SAA selectively induced Ca2+ mobilization and migration of HEK cells expressing FPRL1, a human seven-transmembrane domain phagocyte receptor with low affinity for fMLP, and high affinity for lipoxin A4. Furthermore, radiolabeled SAA specifically bound to human phagocytes and FPRL1-transfected 293 cells. In contrast, SAA was not a ligand or agonist for FPR, the high affinity fMLP receptor. Thus, SAA is the first chemotactic ligand identified for FPRL1. Our results suggest that FPRL1 mediates phagocyte migration in response to SAA.
The Expression of Phospho-AKT, Phospho-mTOR, and PTEN in Extrahepatic Cholangiocarcinoma
Authors: Joon-Yong Chung, Seung-Mo Hong, Byeong Yeob Choi, HyungJun Cho, Eunsil Yu, Stephen M. Hewitt
Journal: Clinical Cancer Research (2009)

The protein kinase B (AKT) pathway plays a key role in the regulation of cellular survival, apoptosis, and protein translation, and has been shown to have prognostic significance in a number of cancers. We sought to define its role in extrahepatic cholangiocarcinoma.Two hundred twenty-one extrahepatic cholangiocarcinoma patients with clinicopathologic data, including survival, were arrayed into tissue microarrays. Phosphorylated AKT (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein expressions were studied with multiplex tissue immunoblotting assay.Expressions of p-AKT and p-mTOR were significantly increased in extrahepatic cholangiocarcinoma cases compared with normal and dysplastic bile duct epithelium (P < 0.05 both). Decreased PTEN expression was observed in patients with increasing depth of invasion (P < 0.05), T classification (P < 0.05), and stage grouping (P < 0.05), and the presence of invasion of the pancreas (P < 0.05) and duodenum (P < 0.05). Decreased PTEN expression (P = 0.004) as well as decreased PTEN/p-AKT (P = 0.003) and PTEN/p-mTOR (P = 0.009) expression showed shorter survival by univariate but not by multivariate analysis.The AKT pathway is activated in a subset of extrahepatic cholangiocarcinoma. Elevated PTEN expression correlates with longer survival. Quantitative data obtained by multiplex tissue immunoblotting may provide additional information than assessment of immunohistochemistry alone. Quantitative analysis of PTEN, PTEN/p-AKT and PTEN/p-mTOR shows differences in survival by univariate analysis.
PKCδ signalling regulates SR-A and CD36 expression and foam cell formation
Authors: Chin-Sheng Lin, Feng-Yen Lin, Ling-Jun Ho, Chien-Sung Tsai, Shu-Mung Cheng, Wan-Lin Wu, Chuan-Yueh Huang, Chen-Hao Lian, Shih-Ping Yang, Jenn-Haung Lai
Journal: Cardiovascular Research (2012)

AimsThe formation of foam cells is crucial in the initiation and progression of atherosclerosis. One of the critical steps in foam cell formation is the uptake of low-density lipoprotein (LDL) by macrophages via scavenger receptors (SRs). This study examined the role of protein kinase C (PKC) isoforms on foam cell formation.
Population Pharmacokinetics of Romidepsin in Patients with Cutaneous T-Cell Lymphoma and Relapsed Peripheral T-Cell Lymphoma
Authors: Sukyung Woo, Erin R. Gardner, Xiaohong Chen, Sandra B. Ockers, Caitlin E. Baum, Tristan M. Sissung, Douglas K. Price, Robin Frye, Richard L. Piekarz, Susan E. Bates, William D. Figg
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients with T-cell lymphoma. Experimental Design: Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition. Results: A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G&amp;gt;T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure. Conclusion: The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.
High Doses of Vitamin C Reverse <i>Escherichia coli</i> Endotoxin–Induced Hyporeactivity to Acetylcholine in the Human Forearm
Authors: Johannes Pleiner, Friedrich Mittermayer, Georg Schaller, Raymond J. MacAllister, Michael Wolzt
Journal: Circulation (2002)

Acute inflammation causes endothelial vasodilator dysfunction that may be mediated by oxidative stress.In this randomized, double-blind, crossover study, forearm blood flow responses to acetylcholine (ACh) (endothelium-dependent dilator) and glyceryl-trinitrate (GTN) (endothelium-independent dilator) were assessed before and after induction of acute systemic inflammation by low doses of Escherichia coli endotoxin (LPS) (20 IU/kg IV) in 8 healthy volunteers. The acute effect of intra-arterial vitamin C (24 mg/min) or placebo was studied 4 hours after LPS, respectively. Vitamin C alone was administered in control experiments. LPS administration caused systemic vasodilation, increased white blood count, elevated body temperature, and reduced vitamin C plasma concentrations. LPS decreased the responses of forearm blood flow to ACh by 30% (P<0.05) but not to GTN. Vitamin C completely restored the response to ACh, which was comparable with that observed under baseline conditions. Vitamin C had no effect on basal blood flow or ACh- or GTN-induced vasodilation in control subjects.Our data demonstrate that impaired endothelial vasodilation caused by E coli endotoxemia can be counteracted by high doses of antioxidants in vivo. Oxidative stress may play an important role in the pathogenesis of endothelial dysfunction during inflammation.
Thyroid Transcription Factor 1 Is an Independent Prognostic Factor for Patients With Stage I Lung Adenocarcinoma
Authors: Valsamo K. Anagnostou, Konstantinos N. Syrigos, Gerold Bepler, Robert J. Homer, David L. Rimm
Journal: Journal of Clinical Oncology (2008)

Thyroid transcription factor 1 (TTF1) is a transcription factor that regulates the expression of multiple genes involved in lung development. It is preferentially expressed in adenocarcinomas of the lung and has been investigated as a potential prognostic parameter in patients with lung cancer, with conflicting results. We quantitatively assessed TTF1 protein expression in two large and independent data sets to investigate the impact of TTF1 nuclear expression on patient survival.Automated quantitative analysis, a fluorescent-based method for analysis of in situ protein expression, was used to assess a series of cell lines to find the threshold of detection of TTF1 expression. Then two independent cohorts (176 and 237 cases, respectively) were measured by the same technique, and TTF1 expression was correlated with survival.Tumors expressed TTF1 in 45% and 58% of the cases in each cohort. TTF1 was consistently expressed in adenocarcinomas (n = 61 and 73; Spearman rho = 0.313 and 0.4 for the first and second set, respectively; P < .0001) independent of their differentiation and stage. Survival analysis showed that patients with stage I adenocarcinoma with TTF1 expression had a longer median overall survival than those without expression (n = 43, 44.3 v 26.2 months, P = .05 for the first cohort; n = 87; 49.7 v 38.5 months, P = .03 for the second cohort) Multivariate analysis revealed an independent lower risk of death for patients with stage I adenocarcinoma with TTF1-expressing tumors (hazard ratio = 0.479, 95% CI, 0.235 to 0.977; P = .043).TTF1 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of patients with stage I lung adenocarcinoma.