tbuckley/cabot-search huggingface dataset:
Mechanisms of benzarone and benzbromarone-induced hepatic toxicity
Authors: Priska Kaufmann, Michael Török, Anya Hänni, Paul Roberts, Rodolfo Gasser, Stephan Krähenbühl
Journal: Hepatology (2005)

Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 micromol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 micromol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [micromol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial beta-oxidation was decreased by 71%, 87%, and 58% with 100 micromol/L amiodarone or benzarone and 50 micromol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and beta-oxidation only at 100 micromol/L. In the presence of 100 micromol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.
BCR-Tyrosine 177 Plays an Essential Role in Ras and Akt Activation and in Human Hematopoietic Progenitor Transformation in Chronic Myelogenous Leukemia
Authors: Su Chu, Liang Li, Harjeet Singh, Ravi Bhatia
Journal: Cancer Research (2007)

Abstract Chronic myelogenous leukemia (CML) results from the transformation of a primitive hematopoietic cell by the BCR/ABL gene. BCR/ABL signaling has been studied in cell lines and murine models, but the transforming effects of BCR/ABL are highly dependent on cellular context, and mechanisms responsible for the transformation of primitive human hematopoietic cells remain poorly understood. Current targeted therapies fail to eliminate malignant CML progenitors, and improved understanding of crucial molecular mechanisms of progenitor transformation may facilitate the development of improved therapeutic approaches. We investigated the role of BCR/ABL tyrosine 177 (BCR/ABL-Y177) in CML progenitor transformation by comparing the effects of expression of Y177-mutated BCR/ABL, wild-type BCR/ABL, or green fluorescent protein alone on normal CD34+ cells. We show that BCR/ABL-Y177 plays a critical role in CML progenitor expansion, proliferation, and survival. BCR/ABL expression results in enhanced Ras and Akt activity but reduced mitogen-activated protein kinase activity in human hematopoietic cells, which is reversed by BCR/ABL-Y177 mutation. Blocking BCR/ABL-Y177–mediated signaling enhances targeting of CML progenitors by imatinib mesylate. Our studies indicate that BCR/ABL-Y177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in CML. [Cancer Res 2007;67(14):7045–53]
Ectopic plantar nail: a report of two cases
Authors: P. Ena, V. Mazzarello, L.A. Dessy
Journal: British Journal of Dermatology (2003)

Journal Article Ectopic plantar nail: a report of two cases Get access P. Ena, P. Ena Departments of Dermatology, Biomedical Sciences–Section of Human Anatomy Pasquale Ena MD, Via F. Porcellana 56b, 07100 Sassari, Italy. E‐mail: dottena@uniss.it Search for other works by this author on: Oxford Academic Google Scholar V. Mazzarello, V. Mazzarello Departments of Dermatology, Biomedical Sciences–Section of Human Anatomy Search for other works by this author on: Oxford Academic Google Scholar L.A. Dessy L.A. Dessy Plastic Surgery, University of Sassari, Sassari, Italy Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 149, Issue 5, 1 November 2003, Pages 1071–1074, https://doi.org/10.1111/j.1365-2133.2003.05679.x Published: 01 November 2003 Article history Accepted: 15 June 2003 Published: 01 November 2003
Regulatory functions of hapten-reactive helper and suppressor T lymphocytes. I. Detection and characterization of hapten-reactive suppressor T-cell activity in mice immunized with hapten-isologous protein conjugate
Authors: H Yamamoto, T Hamaoka, M Yoshizawa, M Kuroki, M Kitagawa
Journal: The Journal of Experimental Medicine (1977)

Helper and suppressor T-cell activities were detected simultaneously in the spleen cells of mice immunized with para-azobenzoate (PAB)-mouse gammaglobulin (MGG). Dinitrophenyl (DNP)-specific B cells were raised by immunization with DNP-keyhole limpet hemocyanin (KLH) and used as the indicator B-cell population. The helper and suppressor T-cell activities were determined after adoptively transferring spleen cells from PAB-MGG- primed donors and DNP-KLH-primed donors into X-irradiated recipients. Stimulation of these recipients with DNP-MGG-PAB detected helper T-cell activity, which was measured in terms of increased anti-DNP antibody responses of DNP-KLH-primed cells over these responses in the presence of unprimed cells. On the other hand, when DNP-KLH-primed cells were stimulated with DNP-KLH-PAB in the presence of PAB-MGG-primed cells, anti-DNP antibody responses were substantially lower than in unprimed normal cells. This suppressor cell population was (a) hapten-reactive, (b) present in B-cell-depleted spleen cells, (c) Thy-1 positive, (d) detectable earlier than the helper T-cell activities after priming (e) more radiosensitive than helper cells, and (f) found in the spleen but not the lymph nodes in contrast to helper T cells. These data indicate that these suppressor T cells are distinct from the helper T cells. PAB-reactive T cells clearly suppressed the antibody response by inhibiting KLH-reactive helper T-cell functions. The hapten-reactive T-lymphocyte system described here should be useful for analyzing and manipulating the immune response and for studying regulatory interactions of helper and suppressor T cells in the induction of antibody responses.
Histochemical demonstration of histamine in primary cutaneous inflammation of the rat
Authors: C. PROTTEY, T. RUTHERFORD, T.F.M. FERGUSON
Journal: British Journal of Dermatology (1978)

A primary (non‐allergic) inflammatory response was elicited in the skin of albino rats by exaggerated application of sodium laurate solution, and the liberation of histamine, a known mediator of cutaneous inflammation in many species, was studied by a histofluorimetric stain specific for this amine which forms a complex with orthophthalaldehyde. Within the first 2 h after irritation both the epidermis and the upper dermis exhibited widespread diffuse, extracellular yellow fluorescence of the histamineorthophthalaldehyde complex; dilated blood vessels and many fibroblasts were also fluorescent. The extracellular and vascular staining increased in intensity up to about 6 h and then gradually faded. By about 12 h after irritation, yellow histamine fluorescence was located only as a narrow band in the upper dermis close to the dermo‐epidermal junction. The fluorescence was probably contained within cells, tentatively identified as leukocytes. Other than occasional mast cells in deeper regions of the dermis, no other histamine‐fluorescent cells were seen throughout the response. None of these features was observed in normal, control rat skin treated only with distilled water, and routinely we failed to observe more than just an occasional fluorescent mast cell in irritated or control skin alike. The morphological features of the inflammation closely resembled those described by others for chemical irritation of skin. This study indicates the presence of histamine in the early stages of cutaneous inflammation of the rat, and suggests routes of its dispersal at later stages, when other inflammatory mediators are known to be involved.
Overexpression of Methyl-CpG Binding Protein 2 Impairs T <sub>H</sub> 1 Responses
Authors: Tianshu Yang, Melissa B. Ramocki, Jeffrey L. Neul, Wen Lu, Luz Roberts, John Knight, Christopher S. Ward, Huda Y. Zoghbi, Farrah Kheradmand, David B. Corry
Journal: Science Translational Medicine (2012)

Duplication of the MECP2 gene in humans and mice results in immune dysregulation due in part to the suppression of IFN-γ production from T helper cells.
Insecticide treated bed nets to prevent malaria
Authors: U. D'Alessandro
Journal: BMJ (2001)

Papers p 270 

Evidence of the impact of insecticide treated materials, either bed nets or curtains, on morbidity from malaria and mortality from all causes in children has been growing over the past 10-20 years. 1 2 The studies have been carried out mainly, although not exclusively, in Africa (11 clinical trials out of 18 in the Cochrane review), the continent where 80% of all clinical cases and over 90% of all malaria deaths are estimated to occur. These data provide strong evidence that insecticide treated materials can substantially reduce childhood mortality, at least in places where malaria is a major contributor to death. However, all these trials were carried out in a way impossible to reproduce on a large scale and they measured efficacy—the potential impact of insecticide treated materials when implemented in almost ideal conditions. Problems can arise when bed nets are promoted outside the context of a clinical trial—though a paper in this week's BMJ (p 270) also suggests an approach that might circumvent some of them.3

The impact of insecticide treated materials on mortality was determined by intervention studies carried out in four African countries.4–7 All reported …
Home Monitoring of Foot Skin Temperatures to Prevent Ulceration
Authors: Lawrence A. Lavery, Kevin R. Higgins, Dan R. Lanctot, George P. Constantinides, Ruben G. Zamorano, David G. Armstrong, Kyriacos A. Athanasiou, C. Mauli Agrawal
Journal: Diabetes Care (2004)

OBJECTIVE—To evaluate the effectiveness of at-home infrared temperature monitoring as a preventative tool in individuals at high risk for diabetes-related lower-extremity ulceration and amputation. RESEARCH DESIGN AND METHODS—Eighty-five patients who fit diabetic foot risk category 2 or 3 (neuropathy and foot deformity or previous history of ulceration or partial foot amputation) were randomized into a standard therapy group (n = 41) or an enhanced therapy group (n = 44). Standard therapy consisted of therapeutic footwear, diabetic foot education, and regular foot evaluation by a podiatrist. Enhanced therapy included the addition of a handheld infrared skin thermometer to measure temperatures on the sole of the foot in the morning and evening. Elevated temperatures (&amp;gt;4°F compared with the opposite foot) were considered to be “at risk” of ulceration due to inflammation at the site of measurement. When foot temperatures were elevated, subjects were instructed to reduce their activity and contact the study nurse. Study subjects were followed for 6 months. RESULTS—The enhanced therapy group had significantly fewer diabetic foot complications (enhanced therapy group 2% vs. standard therapy group 20%, P = 0.01, odds ratio 10.3, 95% CI 1.2–85.3). There were seven ulcers and two Charcot fractures among standard therapy patients and one ulcer in the enhanced therapy group. CONCLUSIONS—These results suggest that at-home patient self-monitoring with daily foot temperatures may be an effective adjunctive tool to prevent foot complications in individuals at high risk for lower-extremity ulceration and amputation.
Expression of nicotinic receptors in the skin of patients with palmoplantar pustulosis
Authors: E. Hagforsen, M. Edvinsson, K. Nordlind, G. Michaelsson
Journal: British Journal of Dermatology (2002)

Summary Background A suggested role for nicotine in the pathogenesis of palmoplantar pustulosis (PPP) has been discussed. The target for the inflammation in PPP is the acrosyringium. Nicotine acts as an agonist on nicotinic acetylcholine receptors (nAChRs) and can influence a variety of cellular functions. Objectives To study the α3- and α7-nAChR expression in palmar skin of patients with PPP in comparison with that in healthy smoking and non-smoking controls. Methods Biopsies from 20 patients with PPP, seven healthy smokers and eight healthy non-smokers were studied by immunohistochemistry with a monoclonal anti-α3 and a polyclonal anti-α7 antibody. Results In healthy controls both nAChR subtypes showed stronger immunoreactivity in the eccrine glands and ducts than in the epidermis. The papillary endothelium was positive for both subtypes. Epidermal α3 staining was stronger and that of the coil and dermal ducts weaker in healthy smokers than in healthy non-smokers. In involved PPP skin, granulocytes displayed strong α3 immunoreactivity. The normal epidermal α7 staining pattern was abolished in PPP skin and was replaced by strong mesh-like surface staining, most markedly adjacent to the acrosyringium, which in controls was intensely α7 positive at this level. Endothelial α7 staining was stronger in PPP skin than in the controls. Conclusions Smoking can influence nAChR expression. The altered nAChR staining pattern in PPP skin may indicate a possible role for nicotine in the pathogenesis of PPP. We hypothesize that there is an abnormal response to nicotine in patients with PPP, resulting in inflammation.
Effects of maternal geohelminth infections on allergy in early childhood
Authors: Philip J. Cooper, Martha E. Chico, Leila D. Amorim, Carlos Sandoval, Maritza Vaca, Agostino Strina, Ana Clara Campos, Laura C. Rodrigues, Mauricio L. Barreto, David P. Strachan
Journal: Journal of Allergy and Clinical Immunology (2015)

Maternal geohelminth infections during pregnancy may protect against allergy development in childhood.We sought to investigate the effect of maternal geohelminths on the development of eczema, wheeze, and atopy during the first 3 years of life.A cohort of 2404 neonates was followed to 3 years of age in a rural district in coastal Ecuador. Data on wheeze and eczema were collected by means of questionnaire and physical examination at 13, 24, and 36 months of age. Atopy was measured based on skin prick test (SPT) reactivity to 9 allergens at 36 months. Maternal stool samples were examined for geohelminths by microscopy. Data on potential confounders was collected after birth by questionnaire.Geohelminths were observed in 45.9% of mothers. Eczema and wheeze were reported for 17.7% and 25.9%, respectively, of 2069 (86.1%) children with complete follow-up to 3 years, and allergen SPT reactivity to any allergen was present in 17.2% and to house dust mite in 8.7%. Maternal geohelminth infections were not significantly associated with eczema (adjusted odds ratio [OR], 1.26; 95% CI, 0.98-1.61), wheeze (adjusted OR, 1.02; 95% CI, 0.82-1.27), and SPT reactivity to any allergen (adjusted OR, 0.79; 95% CI, 0.61-1.01). In subgroup analyses maternal geohelminths were associated with a significantly reduced risk of SPT reactivity to mite and other perennial allergens, and maternal ascariasis was associated with an increased risk of eczema and reduced risk of SPT reactivity to all allergens.Our data do not support a protective effect of maternal infections with geohelminth parasites during pregnancy against the development of eczema and wheeze in early childhood, although there was evidence in subgroup analyses for a reduction in SPT reactivity to house dust mites and perennial allergens.
Increased Ventricular Preload Is Compensated by Myocyte Proliferation in Normal and Hypoplastic Fetal Chick Left Ventricle
Authors: Angela deAlmeida, Tim McQuinn, David Sedmera
Journal: Circulation Research (2007)

Hemodynamics influence cardiac development, and alterations in blood flow may lead to impaired cardiac growth and malformations. The developing myocardium adapts to augmented workload by increasing cell number (hyperplasia). The aim of this study was to determine the influence of alterations in ventricular preload on fetal myocyte proliferation by manipulation of intracardiac shunting at the atrial level. We hypothesized that partial clipping of the right atrial appendage would increase the blood flow to the left ventricle and, in turn, lead to an increase in chamber volume and myocardial mass based on myocyte proliferation. Using an ex ovo culture setup, we performed partial right atrial clipping on embryonic day 8 chick embryos. Ultrasound imaging was performed before and after the surgery to assess the changes in left ventricular volume. Sampling after 24 hours was preceded by 2 hour of pulse-labeling with 5-bromodeoxyuridine. Ultrasound imaging showed that partial right atrial clipping led to a significant increase in left ventricular end-diastolic volume, demonstrating increased blood flow and preload. Anti–5-bromodeoxyuridine immunolabeling revealed a significant increase in myocyte proliferation in the left ventricle and atrium. No significant changes were found in the right heart structures. Increased left ventricular myocyte proliferation and myocardial mass after right atrial clipping was also observed in embryos with experimental left ventricular hypoplasia. These results demonstrate the ability of fetal myocardium to respond to increased preload by myocyte hyperplasia and support the rationale for prenatal surgical interventions in certain cases of congenital heart disease such as hypoplastic left heart syndrome.
Modulation of p53, ErbB1, ErbB2, and Raf-1 Expression in Lung Cancer Cells by Depsipeptide FR901228
Authors: X. Yu
Journal: JNCI Journal of the National Cancer Institute (2002)

Histone deacetylases (HDACs) modulate chromatin structure by regulating acetylation of core histone proteins. HDAC inhibitors, such as depsipeptide FR901228 (FK228), induce growth arrest and apoptosis in a variety of human cancer cells by mechanisms that cannot be attributed solely to histone acetylation. This study evaluated the mechanisms by which FK228 mediates apoptosis in non-small-cell lung cancer (NSCLC) cells.Proliferation and apoptosis were assessed in a panel of NSCLC cell lines that vary in the expression of the growth-regulating proteins p53, pRb, and K-Ras treated with a clinically relevant dose of FK228 (25 ng/mL). Western blot and immunoprecipitation techniques were used to analyze expression of cell-cycle proteins (cyclin A, cyclin E, p53, and p21), signaling-related proteins (ErbB1, ErbB2, and Raf-1), activity of extracellular signal-regulated kinase 1 and 2 (ERK1/2), binding of mutant p53 and Raf-1 to heat shock protein (Hsp)90, and acetylation of Hsp90.FK228 treatment inhibited growth and induced apoptosis in NSCLC cells expressing wild-type or mutant p53. FK228 treatment led to altered expression of cyclin A, cyclin E, and p21, and to reduced expression of mutant, but not wild-type, p53. FK228-treated cells also were depleted of ErbB1, ErbB2, and Raf-1 proteins, and exhibited lower ERK1/2 activity. FK228 treatment also inhibited the binding of mutant p53 and Raf-1 to Hsp90; this inhibition was associated with acetylation of Hsp90.FK228 depletes the levels of several oncoproteins that are normally stabilized by binding to Hsp90 in cancer cells. The resulting ability of FK228 to diminish signal transduction via pathways involving Raf-1 and ERK may contribute to the potency and specificity of this novel antitumor agent.
FK506 can activate transforming growth factor- signalling in vascular smooth muscle cells and promote proliferation
Authors: A. Giordano, S. Romano, M. Mallardo, A. D'Angelillo, G. Cali, N. Corcione, P. Ferraro, M. F. Romano
Journal: Cardiovascular Research (2008)

FK506-binding protein (FKBP) 12 is an inhibitor of transforming growth factor (TGF)-beta type I receptors. Several lines of evidence support the view that TGF-beta stimulates vascular smooth muscle cell (VSMC) proliferation and matrix accumulation. We investigated the effect of FK506, also known as tacrolimus, on cellular proliferation and on matrix protein production in human VSMCs.We measured cell proliferation with flow cytometry using BrdU incorporation and fluorimetrically by measuring DNA concentration with Hoechst 33258. Western blot assay of whole-cell lysates was used to measure the levels of signalling proteins involved in proliferative pathways, in particular beta-catenin, pErk, pAkt, pmTOR, and cyclin D1. Collagen synthesis was also investigated by Western blotting. The TGF-beta signal was studied by both Western blotting and confocal microscopy. We used the SiRNA technique for FKBP12 gene silencing. Our results show that FK506 stimulates VSMC proliferation and collagen type I production. FK506 enhanced beta-catenin levels and activated the extracellular signal-regulated kinase, Akt, and mammalian target of rapamycin kinase, which are important effectors of proliferation. Accordingly, cyclin D1 expression was increased. We also demonstrate that FK506 activates the TGF-beta signal in VSMCs and that, through this mechanism, it stimulates cell proliferation.FK506 can act as a growth factor for VSMCs.
Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain
Authors: Udo Hoffmann, Quynh A. Truong, David A. Schoenfeld, Eric T. Chou, Pamela K. Woodard, John T. Nagurney, J. Hector Pope, Thomas H. Hauser, Charles S. White, Scott G. Weiner, Shant Kalanjian, Michael E. Mullins, Issam Mikati, W. Frank Peacock, Pearl Zakroysky, Douglas Hayden, Alexander Goehler, Hang Lee, G. Scott Gazelle, Stephen D. Wiviott, Jerome L. Fleg, James E. Udelson
Journal: New England Journal of Medicine (2012)

It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes.In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes.The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65).In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.).