tbuckley/cabot-search huggingface dataset:
Arsenite and arsenate activate extracellular signal-regulated kinases 1/2 by an epidermal growth factor receptor-mediated pathway in normal human keratinocytes
Authors: T. Tanaka-Kagawa, N. Hanioka, H. Yoshida, H. Jinno, M. Ando
Journal: British Journal of Dermatology (2003)

Inorganic arsenic is an environmental contaminant and is associated with the increased risk of human skin cancer. Arsenic has been reported to activate or inhibit a variety of cellular signalling pathways which has effects on cell growth, differentiation and apoptosis. However, the molecular mechanisms of these arsenic-induced biological effects are not completely understood.To understand the molecular basis for the mode of action of arsenicals, we examined the effect of arsenite and arsenate on the activation of mitogen-activated protein kinases (MAPK) and the upstream signalling cascade in normal human epidermal keratinocytes (NHEK).NHEK were exposed to arsenite or arsenate. Western blot analysis was performed to determine the activation of extracellular signal-regulated kinases (ERK) 1/2, c-jun N-terminal kinases (JNK), p38, and MAPK or ERK kinases (MEK) 1/2. Epidermal growth factor receptor (EGFR) tyrosine phosphorylation and recruitment of its adaptor proteins, Shc and Grb2, to EGFR were detected by immunoprecipitation and Western blot analysis.Both arsenicals activated ERK1/2, which are most highly activated in response to mitogenic stimulation, in addition to JNK and p38, which show greater activation in response to cellular stresses. The kinetics of ERK1/2 activation differed from those of JNK and p38 activation. Both arsenicals transiently activated ERK1/2 prior to JNK and p38 activation. MEK1/2, upstream kinases of ERK1/2, were also activated by arsenicals with similar time kinetics to that of ERK1/2 activation. To investigate a signalling pathway leading to activation of MEK1/2-ERK1/2, we examined the tyrosine phosphorylation of EGFR and Shc adapter protein. Both arsenicals stimulated tyrosine phosphorylation of EGFR and Shc. After arsenical treatment, Shc immunoprecipitates contained coprecipitated EGFR and Grb2, suggesting that both arsenicals induce the assembly of EGFR-Shc-Grb2 complexes. Both the EGFR inhibitor tyrphostin AG1478 and anti-EGFR blocking antibody markedly attenuated ERK1/2 activation induced by arsenicals, but did not affect JNK and p38 activation.Our data indicate that both arsenite and arsenate activate the EGFR-Shc-Grb2-MEK1/2-ERK1/2 signalling cascade in NHEK.
An immunoglobulin light chain from a lupus-prone mouse induces autoantibodies in normal mice.
Authors: A Puccetti, T Koizumi, P Migliorini, J André-Schwartz, K J Barrett, R S Schwartz
Journal: The Journal of Experimental Medicine (1990)

Autoantibodies against the 70-kD U1 RNP nucleoprotein autoantigen and DNA were elicited in normal BALB/c mice with a purified Ig light chain. This light chain, derived from a lupus-prone MRL-lpr/lpr mouse, has two distinctive properties: it contains an idiotypic marker recognized by a monoclonal MRL-lpr/lpr anti-snRNP autoantibody, and the amino acid sequence of its third hypervariable region (CDR3) is homologous to a sequence in an antigenic region of the 70-kD U1 RNP polypeptide. The results demonstrate that an Ig idiotype that mimics an autoantigen can induce autoimmunization.
Retreatment With Omalizumab Results in Rapid Remission in Chronic Spontaneous and Inducible Urticaria
Authors: Martin Metz, Tatevik Ohanyan, Martin K. Church, Marcus Maurer
Journal: JAMA Dermatology (2014)

IMPORTANCEOmalizumab has emerged as a novel and effective treatment option for patients with antihistamine-resistant chronic urticaria.It is unclear whether patients with recurrent urticaria symptoms after discontinuation of omalizumab treatment can benefit from retreatment.OBJECTIVE To assess the response of patients with chronic urticaria who receive omalizumab retreatment.DESIGN, SETTING, AND PARTICIPANTS Retrospective analyses were conducted of outpatients treated at an urticaria specialist center of a university hospital.Participants included 25 consecutive patients (aged 18-74 years; 18 women) with chronic spontaneous urticaria, chronic inducible urticaria, or both who showed complete response to omalizumab treatment, experienced relapse after discontinuation of treatment, and received retreatment with omalizumab.INTERVENTIONS Subcutaneous treatment with omalizumab (150-600 mg/mo). MAIN OUTCOMES AND MEASURESResponse after retreatment was assessed by the urticaria activity score in patients with chronic spontaneous urticaria and by trigger threshold testing (in patients with cold urticaria or symptomatic dermographism) and/or a carefully determined history (in patients with cholinergic urticaria, solar urticaria, or pressure urticaria).Adverse events were documented. RESULTSAll patients experienced complete response after retreatment.None of the patients reported relevant adverse events during omalizumab treatment and retreatment.CONCLUSIONS AND RELEVANCE Omalizumab retreatment is effective and safe in patients with chronic urticaria who have benefited from initial omalizumab treatment.
Cervical cancer is not just a young woman's disease
Authors: S. M. Sherman, A. Castanon, E. Moss, C. W. E. Redman
Journal: BMJ (2015)

Susan Sherman and colleagues argue that the upper age limit for cervical screening needs revisiting and call for awareness campaigns to target older as well as younger women

Cervical screening programmes in many countries stop at around the age of 65 and much of the focus is often on younger women. For example, recent media campaigns in England and Wales have centred on lowering the age at first screening. Comparatively little attention has been given to older women despite the fact that they account for about a fifth of cases each year and half of deaths.1 2 Of the 3121 women diagnosed on average each year between 2009 and 2011 in the UK, only 64 were younger than 25 compared with 616 who were older than 65.1 As the population ages, this number of older women affected is set to increase. We argue that screening programmes should reflect this. 

The raw statistics conceal the full impact of cervical cancer on older women. Although the absolute figures decrease with increasing age, when the rate of new cases per 100 000 women is considered, a second peak in diagnoses after the age of 65 becomes apparent (table⇓). The case rate gradually decreases from 19.7 new diagnoses per 100 000 women aged 30-34 to a low of 8.6/100 000 women aged 65-69, but then rises again, reaching 12.5/100 000 in women aged 80-84. Furthermore, mortality data for the UK from 2010-12 show only seven deaths a year from cervical cancer in women younger than 25 but 449 deaths in women older than 65—nearly half of the total average deaths from cervical cancer in any year.2

View this table:

New cases (2009-11) of cervical cancer and deaths (2010-12) in UK by age 



Although recent research by Castanon and colleagues suggests that women aged 65 who have had …
Endoscopic injection therapy to prevent rebleeding from peptic ulcers with a protruding vessel: a controlled comparative trial.
Authors: P Rutgeerts, A M Gevers, M Hiele, L Broeckaert, G Vantrappen
Journal: Gut (1993)

Seventy five patients with severely bleeding peptic ulcer were included in a controlled comparative trial to assess the efficacy and safety of endoscopic injection therapy in preventing rebleeding from peptic ulcers that presented at endoscopy with a protruding vessel. Twenty five patients were treated with injection of epinephrine followed by polidocanol, 25 were treated with injection of absolute alcohol, and 25 with sham injection. Rebleeding occurred in 44% of patients in the sham group, 40% of those treated with epinephrine and polidocanol, and in 20% of those treated with absolute ethanol. The difference in the haemostasis rate between the control and ethanol treated subjects nearly reached significance (p = 0.07). A second therapy session resulted in haemostasis rates of 68% in the epinephrine-polidocanol group and of 88% in the absolute ethanol group. These rates after two treatments as well as the emergency surgery rates (32% in the epinephrine-polidocanol group and 8% in the absolute ethanol group; p = 0.07) were not significantly different. In eight of the 11 patients with rebleeding in the sham treatment group, definitive haemostasis was achieved by elective injection therapy. Overall transfusion requirements were mean (SD) 6.0 (0.7) units in the sham group, 6.0 (0.9) in the epinephrine-polidocanol group, and 3.9 (0.5) in the absolute ethanol group. Only the difference between ethanol and sham was significant (p = 0.02). This study shows that injection with absolute ethanol reduces rebleeding in these patients and significantly lowers transfusion requirements. Absolute ethanol was superior to epinephrine-polidocanol, which was not significantly better than sham therapy.
Applications of NMR Spectroscopy to Study Muscle Glycogen Metabolism in Man
Authors: M. Roden, MD, G. I. Shulman, MD, PhD
Journal: Annual Review of Medicine (1999)

Prior to the advent of nuclear magnetic resonance (NMR) spectroscopy, human glucose metabolism was studied through tracer and tissue biopsy methodology. NMR spectroscopy now provides a noninvasive means to monitor metabolic flux and intracellular metabolite concentrations continuously. 13 C NMR spectroscopy has shown that muscle glycogen synthesis accounts for the majority of insulin-stimulated muscle glucose uptake in normal volunteers and that defects in this process are chiefly responsible for insulin resistance in type 1 and type 2 diabetes mellitus, as well as in other insulin resistant states (obesity, insulin-resistant offspring of type 2 diabetic parents, elevation of plasma FFA concentrations). Furthermore, using 31 P NMR spectroscopy to measure intracellular glucose-6-phosphate, it has been shown that defects in insulin-stimulated glucose transport/phosphorylation activity are primarily responsible for the insulin resistance in these states.
Infarct scar: a dynamic tissue
Authors: Y Sun
Journal: Cardiovascular Research (2000)

Infarct scar, a requisite to the rebuilding of necrotic myocardium following myocardial infarction (MI), has long been considered inert. Earlier morphologic studies suggested healing at the infarct site was complete within 6–8 weeks following MI and resultant scar tissue, albeit necessary, was acellular and simply fibrillar collagen. Utilizing molecular and cellular biologic technologies, recent studies indicate otherwise. Infarct scar is composed of phenotypically transformed fibroblast-like cells, termed myofibroblasts (myoFb) because they express alpha-smooth muscle actin (α-SMA) and these microfilaments confer contractile behavior in response to various peptides and amines. These cells are nourished by a neovasculature and are persistent at the MI site, where they are metabolically active expressing components requisite to angiotensin (Ang) peptide generation, including converting enzyme, receptors for AngII and transforming growth factor (TGF)-β1. They continue to elaborate fibrillar type I collagen. Their generation of these peptides contribute to ongoing scar tissue collagen turnover and to fibrous tissue formation of noninfarcted myocardium. Infarct scar contraction accounts for its thinning and its tonus may contribute to abnormal ventricular chamber stiffness with diastolic dysfunction. Infarct scar is a dynamic tissue: cellular, vascularized, metabolically active and contractile. Pharmacologic interventions with angiotensin converting enzyme inhibitor or AT1 receptor antagonist has proven effective in attenuating scar tissue metabolic activity and minimizing adverse accumulation of fibrous tissue in noninfarcted myocardium.
Colorectal Cancer Mortality: Effectiveness of Biennial Screening for Fecal Occult Blood
Authors: J. S. Mandel, T. R. Church, F. Ederer, J. H. Bond
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: In 1993, a randomized controlled trial in Minnesota showed, after 13 years of follow-up, that annual fecal occult blood testing was effective in reducing colorectal cancer mortality by at least 33%. Biennial screening (i.e., every 2 years) resulted in only a 6% mortality reduction. Two European trials (in England andin Denmark) subsequently showed statistically significant 15% and 18% mortality reductions with biennial screening. Herein, we provide updated results —through 18 years of follow-up— from the Minnesota trial that address the apparent inconsistent findings among the trials regarding biennial screening. METHODS: From 1976 through 1977, a total of 46 551 study subjects, aged 50-80 years, were recruited and randomly assigned to an annual screen, a biennial screen, or a control group. A screen consisted of six guaiac-impregnated fecal occult blood tests (Hemoccult®) prepared in pairs from each of three consecutive fecal samples. Participants with at least one of the six tests that were positive were invited for a diagnostic examination that included colonoscopy. All participants were followed annually to ascertain incident colorectal cancers and deaths. RESULTS: The numbers of deaths from all causes were similar among the three study groups. Cumulative 18-year colorectal cancer mortality was 33% lower in the annual group than in the control group (rate ratio, 0.67; 95% confidence interval [CI] =0.51-0.83). The biennial group had a 21% lower colorectal cancer mortality rate than the control group (rate ratio, 0.79; 95% CI =0.62-0.97). A marked reduction was also noted in the incidence of Dukes' stage D cancers in both screened groups in comparison with the control group. CONCLUSION: The results from this study, together with the other two published randomized trials of fecal occult blood screening, are consistent in demonstrating a substantial, statistically significant reduction in colorectal cancer mortality from biennial screening.
An extracorporeal blood-cleansing device for sepsis therapy
Authors: Joo H Kang, Michael Super, Chong Wing Yung, Ryan M Cooper, Karel Domansky, Amanda R Graveline, Tadanori Mammoto, Julia B Berthet, Heather Tobin, Mark J Cartwright, Alexander L Watters, Martin Rottman, Anna Waterhouse, Akiko Mammoto, Nazita Gamini, Melissa J Rodas, Anxhela Kole, Amanda Jiang, Thomas M Valentin, Alexander Diaz, Kazue Takahashi, Donald E Ingber
Journal: Nature Medicine (2014)
Deficiency in ClC-3 Chloride Channels Prevents Rat Aortic Smooth Muscle Cell Proliferation
Authors: Guan-Lei Wang, Xue-Rong Wang, Mo-Jun Lin, Hua He, Xiu-Jian Lan, Yong-Yuan Guan
Journal: Circulation Research (2002)

Recent growing evidence suggests that chloride (Cl − ) channels are critical to the cell cycle. In cultured rat aortic vascular smooth muscle cells (VSMCs), we have previously found that Cl − channel blockers inhibit endothelin-1 (ET-1)–induced cell proliferation. The present study was designed to further identify the specific Cl − channels responsible for VSMC proliferation. Due to the lack of a specific blocker or opener of any known Cl − channels, we used the antisense strategy to investigate the potential role of ClC-3, a member of the voltage-gated Cl − channel gene family, in cell proliferation of cultured rat aortic VSMCs. With [ 3 H]-thymidine incorporation and immunoblots, we found that ET-1–induced cell proliferation was parallel to a significant increase in the endogenous expression of ClC-3 protein. Transient transfection of rat aortic VSMCs with antisense oligonucleotide specific to ClC-3 caused an inhibition in ET-1–induced expression of ClC-3 protein and cell proliferation of VSMCs in the same concentration- and time-dependent pattern, whereas sense and missense oligonucleotides resulted in no effects on ClC-3 protein expression and cell proliferation. These results strongly suggest that ClC-3 may be the Cl − channel involved in VSMC proliferation and thus provide compelling molecular evidence linking a specific Cl − channel to cell proliferation. The full text of this article is available at http://www.circresaha.org.
Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites
Authors: MM Mannan, DR Springall, C Enard, A Moradoghli-Haftvani, S Eddahibi, S Adnot, JM Polak
Journal: European Respiratory Journal (1995)

Levels of calcitonin gene-related peptide (CGRP), a vasodilator peptide present in nerves and airway endocrine cells of the rat respiratory tract, are increased in hypoxic lung and decreased in plasma, suggesting impaired CGRP release. We wanted to determine whether there was an adaptive functional response to reduced CGRP levels in hypoxia. Density of binding sites for CGRP were compared with its vascular actions following hypoxia, and with binding following administration of the sensory neurotoxin capsaicin to deplete neural CGRP. Autoradiography of lung sections incubated with 125I-labelled CGRP and other vasoactive peptides was used to quantify their binding sites, in male Wistar rats exposed to periods of hypoxia (inspiratory oxygen fraction (FI,O2) = 0.1) ranging 0-10 days (n = 5 each), in controls, and in rats treated neonatally with capsaicin. Relaxation to CGRP was compared in pulmonary artery of control and hypoxic rats. CGRP binding was seen in the vascular endothelium and was significantly elevated after 5 days of hypoxia (mean +/- SEM: control 4.6 +/- 0.4 versus hypoxic 16.6 +/- 2.4 amol.mm-2). CGRP-induced (5 x 10(-7)M) relaxation of pulmonary artery was reduced, compared with controls, following 8 and 21 days of hypoxia (mean +/- SEM) percentage of relaxation to phenylephrine: 78 +/- 3, 36 +/- 5 and 32 +/- 3, respectively) and was abolished by removal of endothelium. Capsaicin treatment also significantly elevated vascular CGRP binding. Atrial natriuretic peptide (ANP) binding levels were decreased in smooth muscle of all blood vessels after 7 days of hypoxia, but endothelin-1 (ET-1) and vasoactive intestinal peptide (VIP) binding was unchanged. We conclude that the vasodilator effects of CGRP are endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not due to reduction in receptors, thereby implicating alterations in the nitric oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.
The influence of viral load, ALT and genotypes on the viral genetic heterogeneity (quasispecies) in Turkish patients with chronic hepatitis C virus(HCV) infection
Authors: A.M. Bozdayi, Ö. Uzunalimog̈lu, N. Asian, H. Bozkaya, A.R. Türkylilmaz, B. Kayhan, T. Sahin, A. Alper, H. Cetinkaya, S. Karayalcin, C. Yurdaydin
Journal: Journal of Hepatology (1998)
Development and Validation of the Comprehensive Indoor Tanning Expectations Scale
Authors: Seth M. Noar, Jessica Gall Myrick, Brenda Morales-Pico, Nancy E. Thomas
Journal: JAMA Dermatology (2014)

Strong links between indoor tanning behavior and skin cancer have been demonstrated across several studies. Understanding the complex belief systems that underlie indoor tanning in young women is a crucial first step in developing interventions to deter this behavior.To develop and validate a comprehensive, multidimensional, theory-based outcome expectations measure to advance an understanding of the sets of beliefs that underlie indoor tanning behavior among young women.Cross-sectional study comprising a web-based survey of 11 sororities at a large university in the southeastern United States. Study participants (n = 706) were aged 18 to 25 years; 45.3% had tanned indoors in their lifetime and 30.3% in the past year.Intention to tan indoors, frequency of indoor tanning behavior in the past year, and indoor tanner type (nontanner, former tanner, or current tanner).A comprehensive scale assessing indoor tanning outcome expectations was developed. In total, 6 positive outcome expectations factors and 5 negative outcome expectations factors were identified. These subscales were reliable (coefficient α range, 0.86-0.95) and were significantly (mostly at P < .001) correlated with a set of established measures, including appearance motivation, indoor tanning attitudes and norms, and intention to tan indoors. Examination of subscales across the 3 indoor tanning groups also revealed significant (P < .001) differences on all 11 subscales. Current tanners had the most positive and least negative perceptions about indoor tanning, while nontanners had the most negative and least positive perceptions. Former tanners tended to fall in between these 2 groups. The 2 subscales with the largest differences across the groups were mood enhancement (positive outcome expectation) and psychological/physical discomfort (negative outcome expectation). Multiple linear regression analyses demonstrated several outcome expectations subscales to be significantly associated with intention to tan indoors and frequency of indoor tanning behavior.Results suggest that the Comprehensive Indoor Tanning Expectations (CITE) Scale provides a reliable and valid assessment of the complex sets of beliefs that underlie indoor tanning, including positive (motivational) and negative (deterrent) beliefs. This new scale may further advance research on indoor tanning beliefs and can guide health communications to prevent and deter indoor tanning behavior.
Peroxiredoxin-2 Represses Melanoma Metastasis by Increasing E-Cadherin/β-Catenin Complexes in Adherens Junctions
Authors: Doo Jae Lee, Dong Hoon Kang, Mina Choi, Yang Ji Choi, Joo Young Lee, Joo Hyun Park, Yoon Jung Park, Kyung Wha Lee, Sang Won Kang
Journal: Cancer Research (2013)

In melanoma, transition to the vertical growth phase is the critical step in conversion to a deadly malignant disease. Here, we offer the first evidence that an antioxidant enzyme has a key role in this transition. We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells. Silencing Prx2 expression stimulated proliferation and migration, whereas ectopic expression of Prx2 produced the opposite effect. Mechanistic investigations indicated that Prx2 negatively regulated Src/ERK activation status, which in turn fortified adherens junctions function by increasing E-cadherin expression and phospho-Y654-dependent retention of β-catenin in the plasma membrane. In murine melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, the natural compound gliotoxin, which is known to exert a Prx-like activity, inhibited proliferation and migration as well as lung metastasis of Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key regulator of invasion and metastasis in melanoma, and also suggest a pharmacologic strategy to effectively decrease deadly malignant forms of this disease.