tbuckley/cabot-search huggingface dataset:
Beneficial Effects of Trimetazidine in Ex Vivo Working Ischemic Hearts Are Due to a Stimulation of Glucose Oxidation Secondary to Inhibition of Long-Chain 3-Ketoacyl Coenzyme A Thiolase
Authors: Gary D. Lopaschuk, Rick Barr, Panakkezhum D. Thomas, Jason R.B. Dyck
Journal: Circulation Research (2003)

High rates of fatty acid oxidation in the heart and subsequent inhibition of glucose oxidation contributes to the severity of myocardial ischemia. These adverse effects of fatty acids can be overcome by stimulating glucose oxidation, either directly or secondary to an inhibition of fatty acid oxidation. We recently demonstrated that trimetazidine stimulates glucose oxidation in the heart secondary to inhibition of fatty acid oxidation. This inhibition of fatty acid oxidation was attributed to an inhibition of mitochondrial long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), an enzyme of fatty acid β-oxidation. However, the accompanying Research Commentary of MacInnes et al suggests that trimetazidine does not inhibit cardiac LC 3-KAT. This discrepancy with our data can be attributed to the reversible competitive nature of trimetazidine inhibition of LC 3-KAT. In the presence of 2.5 μmol/L 3-keto-hexadecanoyl CoA (KHCoA), trimetazidine resulted in a 50% inhibition of LC-3-KAT activity. However, the inhibition of LC 3-KAT could be completely reversed by increasing substrate (3-keto-hexadecanoyl CoA, KHCoA) concentrations to 15 μmol/L even at high concentrations of trimetazidine (100 μmol/L). The study of MacInnes et al was performed using concentrations of 3K-HCoA in excess of 16 μmol/L, a concentration that would completely overcome 100 μmol/L trimetazidine inhibition of LC 3-KAT. Therefore, the lack of inhibition of LC 3-KAT by trimetazidine in the MacInnes et al study can easily be explained by the high concentration of KHCoA substrate used in their experiments. In isolated working hearts perfused with high levels of fatty acids, we found that trimetazidine (100 μmol/L) significantly improves functional recovery of hearts subjected to a 30-minute period of global no-flow ischemia. This occurred in the absence of changes in oxygen consumption resulting in an improved increase in cardiac efficiency. Combined with our previous studies, we conclude that trimetazidine inhibition of LC 3-KAT decreases fatty acid oxidation and stimulates glucose oxidation, resulting in an improvement in cardiac function and efficiency after ischemia. The full text of this article is available online at http://www.circresaha.org.
Calcium signaling in neurodegeneration
Authors: Philippe Marambaud, Ute Dreses-Werringloer, Valérie Vingtdeux
Journal: Molecular Neurodegeneration (2009)

Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular level of the versatility of this ion has made overwhelming progress in the past several years and has been extensively reviewed. In the brain, calcium is fundamental in the control of synaptic activity and memory formation, a process that leads to the activation of specific calcium-dependent signal transduction pathways and implicates key protein effectors, such as CaMKs, MAPK/ERKs, and CREB. Properly controlled homeostasis of calcium signaling not only supports normal brain physiology but also maintains neuronal integrity and long-term cell survival. Emerging knowledge indicates that calcium homeostasis is not only critical for cell physiology and health, but also, when deregulated, can lead to neurodegeneration via complex and diverse mechanisms involved in selective neuronal impairments and death. The identification of several modulators of calcium homeostasis, such as presenilins and CALHM1, as potential factors involved in the pathogenesis of Alzheimer's disease, provides strong support for a role of calcium in neurodegeneration. These observations represent an important step towards understanding the molecular mechanisms of calcium signaling disturbances observed in different brain diseases such as Alzheimer's, Parkinson's, and Huntington's diseases.
Cholelithiasis: A clinical and dietary survey
Authors: M. Wheeler, L. L. Hills, B. Laby
Journal: Gut (1970)

Cholelithiasis among male and female patients at the Royal Melbourne Hospital was studied, and the incidence of the disease in relation to various clinical and dietary factors is discussed. The patients are distinguished by sex and country of origin, a distinction being made between patients born in Australia and those born in southern Europe and now living in Australia. Appropriate control groups were also studied.It was shown that the incidence of cholelithiasis is higher in women than in men (3.0% as opposed to 0.7% in the Melbourne Hospital group), and higher among patients born in southern Europe than in Australia. A correlation was also established between marriage and the disease, and, in women, between having had children and the disease. The dietary investigations showed that in Australia those patients with cholelithiasis were fatter than the control patients. Equally well there seemed to be a strong family tendency to develop gallstones. No association was found between cholelithiasis and blood grouping. In the comparison of the southern European group and the Australian-born group it was shown that the former group had a higher incidence of the disease (9.3% as opposed to 2.3%), and that the overall incidence of cholelithiasis increased with age in men and was constant in women. However, when taken separately, the incidence in Australian female patients did increase with age, the higher proportion of women from southern Europe with the disease where the incidence was, in fact, evenly distributed in all age groups, accounting for this apparent constancy. It was also shown that a woman born in southern Europe increased the risk to herself of developing gallstones within two to five years of moving to Australia, and the contributory factors are discussed.
Increased Pressure Induces Sustained Protein Kinase C–Independent Herbimycin A–Sensitive Activation of Extracellular Signal–Related Kinase 1/2 in the Rabbit Aorta in Organ Culture
Authors: Konstantin G. Birukov, Stéphanie Lehoux, Anna A. Birukova, Régine Merval, Vsevolod A. Tkachuk, Alain Tedgui
Journal: Circulation Research (1997)

The 42- and 44-kD mitogen-activated protein kinases, also referred to as extracellular signal-related kinase (ERK) 2 and 1, respectively, may be transiently activated by stretching vascular smooth muscle cells (VSMCs). Using an organ culture model of rabbit aorta, we studied short- and long-term ERK1/2 activation by intraluminal pressure (150 mm Hg). Activation of ERK1/2 was biphasic: it reached a maximum (217.5 +/- 8.4% of control) 5 minutes after pressurizing and decreased to 120.7 +/- 5.1% of control after 2 hours. Furthermore, after 24 hours of pressurizing, ERK1/2 activity was as high (241.8 +/- 14.7% of control) as in the acute phase. Long-term pressure-induced ERK1/2 activation correlated with stimulation of tyrosine phosphorylation of proteins in the 125- to 140-kD range. Neither protein kinase C inhibitors (1 mumol/L staurosporine or 50 mumol/L bisindolylmaleimide-I) nor tyrosine kinase inhibitors (50 mumol/L tyrphostin A48 or 50 mumol/L genistein) affected pressure-induced ERK1/2 activation. However, the Src-family tyrosine kinase inhibitor herbimycin A (500 nmol/L) did reduce both 5-minute (by 92 +/- 8%) and 24-hour (by 63 +/- 7%) pressure-induced ERK1/2 activation. Thus, our results demonstrate a sustained activation of ERK1/2 and tyrosine kinases by intraluminal pressure in the arterial wall. Pressure-induced ERK1/2 activation is PKC independent and Src-family tyrosine kinase dependent and possibly includes activation of extracellular matrix-associated tyrosine kinases.
Red Wine Polyphenols Inhibit Proliferation of Vascular Smooth Muscle Cells and Downregulate Expression of Cyclin A Gene
Authors: Katsuya Iijima, Masao Yoshizumi, Masayoshi Hashimoto, Seungbum Kim, Masato Eto, Junya Ako, Yi-Qiang Liang, Noriko Sudoh, Kazuaki Hosoda, Koichi Nakahara, Kenji Toba, Yasuyoshi Ouchi
Journal: Circulation (2000)

Background —Red wine polyphenols have been shown to contribute to the “French paradox” phenomenon, which consists of lower morbidity and mortality from coronary heart disease in the French population. Although vascular smooth muscle cell (VSMC) proliferation plays an important role in the progression of atherosclerotic lesions, the effects of red wine polyphenols on VSMC proliferation have not been elucidated. Methods and Results —We extracted the total polyphenolic fraction from red wine (RW-PF) by column chromatography. Treatment with RW-PF showed a potent inhibitory effect on the proliferation and DNA synthesis of cultured rat aortic smooth muscle cells (RASMCs). In contrast, the inhibitory effect of RW-PF on the proliferation of bovine carotid endothelial cells was observed only at much higher concentrations. To elucidate the molecular mechanisms of this antiproliferative effect of RW-PF on RASMCs, we investigated the effects of RW-PF on cell cycle regulation. RW-PF downregulated the expression of cyclin A mRNA and cyclin A promoter activity. In addition, RW-PF decreased the binding of nuclear proteins to the activating transcription factor (ATF) site in the cyclin A promoter and downregulated the mRNA levels of transcription factors, cAMP-responsive element–binding protein (CREB), and ATF-1. Conclusions —These results suggest that the downregulation of cyclin A gene expression may contribute to the antiproliferative effect of red wine polyphenols on RASMCs through the inhibition of transcription factor expression.
Psoriasis and Hydroxyurea
Authors: R. Touraine, J. Revuz, M. Tulliez
Journal: British Journal of Dermatology (1972)

Journal Article Psoriasis and Hydroxyurea Get access R. Touraine, R. Touraine Department of Dermatology Henri Mondor Hospital (Paris XII University) 94‐Creteil‐France Search for other works by this author on: Oxford Academic Google Scholar J. Revuz, J. Revuz Department of Dermatology Henri Mondor Hospital (Paris XII University) 94‐Creteil‐France Search for other works by this author on: Oxford Academic Google Scholar M. Tulliez M. Tulliez Department of Dermatology Henri Mondor Hospital (Paris XII University) 94‐Creteil‐France Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 86, Issue 1, 1 January 1972, Page 102, https://doi.org/10.1111/j.1365-2133.1972.tb01904.x Published: 01 January 1972
Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer
Authors: Hannelore V. Heemers, Lucy J. Schmidt, Zhifu Sun, Kevin M. Regan, S. Keith Anderson, Kelly Duncan, Dan Wang, Song Liu, Karla V. Ballman, Donald J. Tindall
Journal: Cancer Research (2011)

Abstract The androgen receptor (AR) is the principal target for treatment of non–organ-confined prostate cancer (PCa). Androgen deprivation therapies (ADT) directed against the AR ligand–binding domain do not fully inhibit androgen-dependent signaling critical for PCa progression. Thus, information that could direct the development of more effective ADTs is desired. Systems and bioinformatics approaches suggest that considerable variation exists in the mechanisms by which AR regulates expression of effector genes, pointing to a role for secondary transcription factors. A combination of microarray and in silico analyses led us to identify a 158-gene signature that relies on AR along with the transcription factor SRF (serum response factor), representing less than 6% of androgen-dependent genes. This AR-SRF signature is sufficient to distinguish microdissected benign and malignant prostate samples, and it correlates with the presence of aggressive disease and poor outcome. The AR-SRF signature described here associates more strongly with biochemical failure than other AR target gene signatures of similar size. Furthermore, it is enriched in malignant versus benign prostate tissues, compared with other signatures. To our knowledge, this profile represents the first demonstration of a distinct mechanism of androgen action with clinical relevance in PCa, offering a possible rationale to develop novel and more effective forms of ADT. Cancer Res; 71(5); 1978–88. ©2011 AACR.
David Oliver: What should senior doctors be paid?
Authors: David Oliver
Journal: BMJ (2015)

BerkshireThe English health secretary, Jeremy Hunt, claimed in his "25 year vision" that the average wage for a hospital consultant was £118 000 (€167 000; $184 000) a year, putting us in "the top 2% income bracket." 1 This made for a good soundbite, but Hunt's speech
NEW INSIGHTS INTO DOPAMINERGIC RECEPTOR FUNCTION USING ANTISENSE AND GENETICALLY ALTERED ANIMALS
Authors: David R. Sibley
Journal: The Annual Review of Pharmacology and Toxicology (1999)

▪ Abstract Dopaminergic receptors are widespread throughout the central and peripheral nervous systems, where they regulate a variety of physiological, behavioral, and endocrine functions. These receptors are also clinically important drug targets for the treatment of a number of disorders, such as Parkinson's disease, schizophrenia, and hyperprolactinemia. To date, five different dopamine receptor subtypes have been cloned and characterized. Many of these subtypes are pharmacologically similar, making it difficult to selectively stimulate or block a specific receptor subtype in vivo. Thus, the assignment of various physiological or behavioral functions to specific dopamine receptor subtypes using pharmacological tools is difficult. In view of this, a number of investigators have—in order to elucidate functional roles—begun to use highly selective genetic approaches to alter the expression of individual dopamine receptor subtypes in vivo. This review discusses recent studies involving the use of genetic approaches for the study of dopaminergic receptor function.
Expansion of myelin autoreactive CD8+ T lymphocytes in patients with neuropsychiatric systemic lupus erythematosus
Authors: C. Contin-Bordes, E. Lazaro, C. Richez, C. Jacquemin, O. Caubet, I. Douchet, J.-F. Viallard, J.-F. Moreau, J.-L. Pellegrin, P. Blanco
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> Delineation of mechanisms underlying neuropsychiatric systemic lupus erythematosus (NPSLE) and determination of biological markers could guide treatment choice. A study was undertaken to analyse the potential role of activated CD8+ T cells in NPSLE as previously reported in SLE nephritis. <h3>Methods</h3> Flow cytometric immunophenotyping of blood lymphocytes was performed in 30 patients with NPSLE and 36 healthy individuals. The antigenic specificity of CD8+ T cells was studied using HLA-A0201 tetramers loaded with several myelin-derived peptides. The intracellular level of interferon γ (IFNγ) produced by activated CD8+ T cells was determined by flow cytometry. <h3>Results</h3> A large increase in circulating activated CD8+ T lymphocytes expressing surface HLA-DR was found in patients with NPSLE without antiphospholipid syndrome (APS) (n=18) compared with patients with APS (n=12) or healthy controls (n=36). IFNγ-secreting myelin-specific CD8+ T cells were detected exclusively in the blood of patients with NPSLE without APS but with white matter lesions. <h3>Conclusions</h3> These data strongly support the existence of a new immune effector mechanism responsible for CNS involvement in patients with NPSLE and suggest that analysing HLA-DR expression combined with myelin-specific tetramer staining on CD8+ T lymphocytes may be a valuable additional tool for the monitoring of these patients.
Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4
Authors: Jason K. Kim, Ariel Zisman, Jonathan J. Fillmore, Odile D. Peroni, Ko Kotani, Pascale Perret, Haihong Zong, Jianying Dong, C. Ronald Kahn, Barbara B. Kahn, Gerald I. Shulman
Journal: Journal of Clinical Investigation (2001)

Using cre/loxP gene targeting, transgenic mice with muscle-specific inactivation of the GLUT4 gene (muscle GLUT4 KO) were generated and shown to develop a diabetes phenotype. To determine the mechanism, we examined insulin-stimulated glucose uptake and metabolism during hyperinsulinemic-euglycemic clamp in control and muscle GLUT4 KO mice before and after development of diabetes. Insulin-stimulated whole body glucose uptake was decreased by 55% in muscle GLUT4 KO mice, an effect that could be attributed to a 92% decrease in insulin-stimulated muscle glucose uptake. Surprisingly, insulin’s ability to stimulate adipose tissue glucose uptake and suppress hepatic glucose production was significantly impaired in muscle GLUT4 KO mice. To address whether these latter changes were caused by glucose toxicity, we treated muscle GLUT4 KO mice with phloridzin to prevent hyperglycemia and found that insulin-stimulated whole body and skeletal muscle glucose uptake were decreased substantially, whereas insulin-stimulated glucose uptake in adipose tissue and suppression of hepatic glucose production were normal after phloridzin treatment. In conclusion, these findings demonstrate that a primary defect in muscle glucose transport can lead to secondary defects in insulin action in adipose tissue and liver due to glucose toxicity. These secondary defects contribute to insulin resistance and to the development of diabetes.
Molecular mechanism implicated in Pemetrexed-induced apoptosis in human melanoma cells
Authors: Aitziber Buqué, Jangi Sh Muhialdin, Alberto Muñoz, Begoña Calvo, Sergio Carrera, Unai Aresti, Aintzane Sancho, Itziar Rubio, Guillermo López-Vivanco
Journal: Molecular Cancer (2012)

Metastatic melanoma is a lethal skin cancer and its incidence is rising every year. It represents a challenge for oncologist, as the current treatment options are non-curative in the majority of cases; therefore, the effort to find and/or develop novel compounds is mandatory. Pemetrexed (Alimta®, MTA) is a multitarget antifolate that inhibits folate-dependent enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, required for de novo synthesis of nucleotides for DNA replication. It is currently used in the treatment of mesothelioma and non-small cell lung cancer (NSCLC), and has shown clinical activity in other tumors such as breast, colorectal, bladder, cervical, gastric and pancreatic cancer. However, its effect in human melanoma has not been studied yet.In the current work we studied the effect of MTA on four human melanoma cell lines A375, Hs294T, HT144 and MeWo and in two NSCLC cell lines H1299 and Calu-3. We have found that MTA induces DNA damage, S-phase cell cycle arrest, and caspase- dependent and -independent apoptosis. We show that an increment of the intracellular reactive oxygen species (ROS) and p53 is required for MTA-induced cytotoxicity by utilizing N-Acetyl-L-Cysteine (NAC) to blockage of ROS and p53-defective H1299 NSCLC cell line. Pretreatment of melanoma cells with NAC significantly decreased the DNA damage, p53 up-regulation and cytotoxic effect of MTA. MTA was able to induce p53 expression leading to up-regulation of p53-dependent genes Mcl-1 and PIDD, followed by a postranscriptional regulation of Mcl-1 improving apoptosis.We found that MTA induced DNA damage and mitochondrial-mediated apoptosis in human melanoma cells in vitro and that the associated apoptosis was both caspase-dependent and -independent and p53-mediated. Our data suggest that MTA may be of therapeutic relevance for the future treatment of human malignant melanoma.
Long-term surveillance of invasive group A streptococcal disease in The Netherlands, 1994–2003
Authors: B.J.M. Vlaminckx, W. van Pelt, L.M. Schouls, A. van Silfhout, E.M. Mascini, C.P. Elzenaar, T. Fernandes, A. Bosman, J.F.P. Schellekens
Journal: Clinical Microbiology and Infection (2005)
Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C
Authors: J Nattermann
Journal: Gut (2005)

Impaired activity of natural killer (NK) cells has been proposed as a mechanism contributing to viral persistence in hepatitis C virus (HCV) infection. As the function of NK cells is primarily regulated by NK cell receptors (NKR), we analysed whether decreased NK cell function in hepatitis C may be related to dysregulated NKR expression.Expression of NK cell was analysed by flow cytometry on lymphocytes from HCV(+) subjects (n = 30), patients who became HCV(-) after antiviral therapy (n = 10), healthy individuals (n = 10), and hepatitis B virus (HBV) infected patients (n = 9). Cytolytic function of lymphocytes was studied in a redirected lysis assay and in a standard 51chromium release cytotoxicity assay, respectively.In patients with chronic hepatitis C, we found a significantly reduced proportion of NKp46 and NKp30 expressing NK cells compared with healthy and HBV infected subjects. Low expression of natural cytotoxicity receptor (NCR) was also confirmed in in vitro activated NK cell populations derived from HCV patients compared with uninfected donors. In contrast, patients who cleared HCV under antiviral therapy showed normal expression of NKp44, NKp30, and NKp46. Reduced NCR expression in chronic hepatitis C was associated with a parallel decrease in NCR mediated target cell killing. Furthermore, we found a significantly increased proportion of NKG2A expressing NK cells and CD8+ T cells in HCV positive patients, resulting in a reduced cytolytic activity against cells incubated with the HLA-E stabilising peptide HCV core35-44.The present study indicates that defective expression of NKR represents a novel mechanism contributing to impaired function of NK cells and CD8+ T cells in chronic hepatitis C.
Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer
Authors: Joo Mi Yi, Angela A. Guzzetta, Vasudev J. Bailey, Stephanie R. Downing, Leander Van Neste, Katherine B. Chiappinelli, Brian P. Keeley, Alejandro Stark, Alexander Herrera, Christopher Wolfgang, Emmanouil P. Pappou, Christine A. Iacobuzio-Donahue, Michael G. Goggins, James G. Herman, Tza-Huei Wang, Stephen B. Baylin, Nita Ahuja
Journal: Clinical Cancer Research (2013)

Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer.We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of eight promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis, including methylation and expression. We used a nanoparticle-enabled methylation on beads (MOB) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum.We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreatic cancers (n = 143), up to 100% in PanIN-3 and 97% in stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n = 42) from patients with pancreatic cancer, with a sensitivity for BNC1 of 79% [95% confidence interval (CI), 66%-91%] and for ADAMTS1 of 48% (95% CI, 33%-63%), whereas specificity was 89% for BNC1 (95% CI, 76%-100%) and 92% for ADAMTS1 (95% CI, 82%-100%). Overall sensitivity using both markers is 81% (95% CI, 69%-93%) and specificity is 85% (95% CI, 71%-99%).Promoter DNA methylation of BNC1 and ADAMTS1 is a potential biomarker to detect early-stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.