tbuckley/cabot-search huggingface dataset:
Abstract 5086: Pemetrexed induces a strong activation of AMPK in human carcinoma cells, even in the absence of LKB1
Authors: Scott B. Rothbart, Alexandra C. Racanelli, Richard G. Moran
Journal: Cancer Research (2010)

Abstract AMP-activated protein kinase (AMPK) is a major cellular energy sensor, functioning as a regulator of signaling cascades controlling protein, lipid, and carbohydrate metabolism. Because of the dependence of many tumors on the deregulation of the PI3K-AKT-mTOR signaling cascade, the discovery of AMPK activators is an attractive approach for cancer therapeutics, aimed at reinstating control over cellular metabolic functions altered during carcinogenesis rather than inhibiting cellular targets. The antifolate pemetrexed is FDA approved for first line treatment of mesothelioma and non-small cell lung cancer (NSCLC). While pemetrexed acts primarily as a thymidylate synthase inhibitor, we discovered that the drug is also an inhibitor of aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART), the second folate-dependent enzyme of de novo purine synthesis. The inhibition of AICART by pemetrexed resulted in a marked accumulation of the reaction substrate, ZMP, a known allosteric activator of AMPK in several human carcinoma cell lines. The mammalian target of rapamycin complex 1 (mTORC1) was inhibited following pemetrexed treatment, as determined by hypophosphorylation of S6K1 and 4EBP1, and this effect was dependent on AMPK activation. Co-administration of GSK690693, a pan AKT inhibitor prolonged mTORC1 inhibition following pemetrexed treatment and offset the consequences of negative feedback activation of mTORC1 through PI3-kinase and mTORC2 activity. Interestingly, cells insensitive to mTORC1 inhibition following AMPK activation retained sensitivity to the secondary effect of pemetrexed, apparently due to inhibition of lipid synthesis through phosphorylation of acetyl-CoA carboxylase by AMPK. We concluded that the growth inhibitory effect of pemetrexed following AMPK activation in human carcinoma cells was due to a combined effect of inhibition of mTORC1 signaling and lipogenesis, both of which were mediated by activation of AMPK. Somewhat surprisingly, several cell lines null for LKB1, the major upstream kinase of AMPK, retained sensitivity to the secondary effects of pemetrexed mediated through AMPK activation. This suggests that the effect of pemetrexed on AMPK activity will be preserved in tumors lacking LKB1, a common genotype of human NSCLC. Hence, pemetrexed exerts its effects on carcinoma cells by both inhibition of traditional antifolate targets and by a novel mechanism, activation of AMPK. (Supported in part by NIH Grant CA-27605) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5086.
US considers ban on British blood
Authors: S. Gottlieb
Journal: BMJ (1999)

A United States federal advisory panel to the US Food and Drug Administration has recommended barring people who visited Britain frequently or for long stays between 1980 and 1996 from donating blood because of the possible risk of transmitting the human form of bovine spongiform encephalopathy, known as new variant Creutzfeldt-Jakob disease.

The administration is not bound by the advisory panel's recommendations but generally follows them. New variant Creutzfeldt-Jakob disease has never been transmitted …
Abstract 2511: Comprehensive metabolic profiling of hepatocellular carcinoma and pancreatic tumors by capillary electrophoresis-mass spectrometry.
Authors: Motohisa Tada, Akiyoshi Hirayama, Fumihiko Kanai, Hideyuki Yoshitomi, Masayuki Ohtsuka, Masaru Miyazaki, Tomoyoshi Soga, Osamu Yokosuka
Journal: Cancer Research (2013)

Abstract (Background) Most cancer types have been widely known to generate energy primarily by glycolysis rather than oxidative phosphorylation even under normoxia (Warburg effect). However, inadequate blood supply resulting from defective angiogenesis is often observed in different kinds of cancer tissues, and their microenvironment is considered nutritionally unfavorable. How these cancer cells generate ATP is therefore still unclear. We previously reported enhanced glycolysis and significant accumulation of all amino acids except glutamine in both colon and stomach cancer tissues (Hirayama A, et al Cancer Res 2009). (Methods) Here, we investigated the metabolic microenvironment of hepatocelluar carcinoma (HCC)(n=28, HBV-positive (B) 7, HCV-positive (C) 6, NonBnonC (NBNC) 15), and pancreatic tumors (n=40, Invasive ductal adenocarcinoma (PDAC) 21, Intraductal papillary mucinous adenoma (IPMA) 5, Intraductal papillary mucinous carcinoma (IPMC) 14), using capillary electrophoresis-mass spectrometry (CE-MS). (Results) The amount of glucose were more than ten times higher in liver tissues, which indicates that liver tissue exist in nutritionally favorable microenvironment even in tumor tissue compared with pancreas tissue. Significant lactate accumulation was found in all cancer tissues (HCC, IPMC, and PDAC), which imply enhanced glycolysis. However, significant organ-specific differences were found in the levels of amino acids. Organ and etiology-specific difference were found in intermediates of TCA cycle. For example, citrate was increased in B-HCC, malate was decreased in NBNC-HCC, fumarate was decreased in B-HCC, NBNC-HCC, and PDAC, citrate was decreased in IPMC, iso-citrate was decreased in PDAC, compared to normal tissue, significantly. The concentration of most amino acids were not changed between normal and tumor tissues in HCC and pancreatic tumors, which suggests that these type of cancers do not depend on autophagy for their amino acid source. (Conclusions)Overall, these results provide metabolic phenotypes of different cancer tissues that reflect the tumor microenvironment. Citation Format: Motohisa Tada, Akiyoshi Hirayama, Fumihiko Kanai, Hideyuki Yoshitomi, Masayuki Ohtsuka, Masaru Miyazaki, Tomoyoshi Soga, Osamu Yokosuka. Comprehensive metabolic profiling of hepatocellular carcinoma and pancreatic tumors by capillary electrophoresis-mass spectrometry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2511. doi:10.1158/1538-7445.AM2013-2511
The College Drug Scene
Authors: Donald W. Goodwin
Journal: JAMA (1969)

Negro demonstrators at a midwestern university recently demanded, among other things, an end to "degrading research." What they wanted ended was not research itself but themselves as<i>subjects</i>of research. If the subjects of this book share the same sentiment, it will be understandable. Members of a "colony" of drug users living near the University of California at Berkeley, they and their comrades in the "psychedelic revolution" are being analyzed, dissected, and descended upon, notebook in hand, by a growing army of psychiatrists, sociologists, and other inquisitive types. The results, to date, have been disappointing. Clearly, a substantial number of individuals in their teens and 20s are experimenting with marihuana, LSD, and other "mindexpanders"; some use these drugs regularly. But the nature and dimensions of the problem remain obscure. This book to some extent illustrates why. The author, an assistant professor of criminology at the University of California, together with
Abciximab Facilitates the Rate and Extent of Thrombolysis
Authors: Elliott M. Antman, Robert P. Giugliano, C. Michael Gibson, Carolyn H. McCabe, Patrick Coussement, Neal S. Kleiman, Alec Vahanian, A. A. Jennifer Adgey, Ian Menown, Hans-Jürgen Rupprecht, R. Van der Wieken, John Ducas, Joel Scherer, Keaven Anderson, Frans Van de Werf, Eugene Braunwald
Journal: Circulation (1999)

Background —The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI. Methods and Results —Patients (n=888) with ST-elevation MI presenting &lt;12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 μg · kg −1 · min −1 ) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U · kg −1 · h −1 ), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U · kg −1 · h −1 ). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion ( P &lt;0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U · kg −1 · h −1 ) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%; P =0.0009) and 90 minutes (77% versus 62%; P =0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70). Conclusions —Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.
A Case of Isotretinoin-Induced Purpura Annularis Telangiectodes of Majocchi and Review of Substance-Induced Pigmented Purpuric Dermatosis
Authors: Rachel Kaplan, Shane A. Meehan, Marie Leger
Journal: JAMA Dermatology (2013)

IMPORTANCE Medications as well as chemical and food exposures have been causally linked to the development of pigmented purpuric dermatosis (PPD). We describe herein what is to our knowledge the first reported case of isotretinoin-induced PPD. OBSERVATIONS A woman in her 30s presented with purpura annularis telangiectodes of Majocchi on the lower extremities 2 months after initiating isotretinoin for the treatment of refractory nodulocystic acne. CONCLUSIONS AND RELEVANCE We believe isotretinoin was the most likely causative agent in this case because the lesions began after initiation of isotretinoin treatment and resolved shortly after its termination, and the pathologic findings were consistent with other described cases of drug-induced PPD. The lesions have continued to fade, and no new lesions have developed in a 3-month follow-up period. Drug-induced PPD is distinct from idiopathic PPD, and it is important to consider isotretinoin as a potential inciting agent.
Estimating the Number of Low-Income Americans Exposed to Household Air Pollution from Burning Solid Fuels
Authors: Derek K. Rogalsky, Pauline Mendola, Tricia A. Metts, William J. Martin
Journal: Environmental Health Perspectives (2014)

Exposure to household air pollution (HAP) from inefficient biomass and coal stoves kills nearly 4 million people every year worldwide. HAP is an environmental risk associated with poverty that affects an estimated 3 billion people mostly in low- and middle-income countries.Our goal was to estimate the number of low-income Americans exposed to potentially health-damaging concentrations of HAP.We mapped county-level data for the percentage of households using wood, coal, and/or coke as their primary heating fuel along with percent of the population below the federal poverty level. Using U.S. Census data and the likelihood of fugitive emissions as reported in the literature, we estimated the number of low-income Americans potentially exposed to HAP.Solid fuel is the primary heating source for > 2.5 million U.S. households, or 6.5 million people. The mapping exercise showed several rural areas, primarily in the northern and western regions, that have high levels of solid-fuel use and poverty. We then identified 117 counties with high co-incident poverty and solid-fuel use as high-priority counties for research into potential health risks from HAP. We estimate that between 500,000 and 600,000 low-income people in the United States are likely exposed to HAP from burning solid fuels within their homes.HAP occurs within the United States and should be further investigated for adverse health risks, especially among those living in areas with rural poverty.
Endangered Lives: Public Health in Victorian Britain
Authors: Lester S. King
Journal: JAMA (1984)

ABSTRACT To understand disease we must go beyond the individual doctor-patient relationship, go beyond science and technology, and enter into sociology, economics, and political science. All these factors come together in the concept of public health. This concept, that illness involves not merely the individual but society as a whole, did not find ready acceptance in the 19th century. The history of public health tells us how the attempts to change the milieu met, and sometimes overcame, obstacles. Improvement came about only through much trial and error, confusion and dispute, and conflict of interests. It was enormously difficult to identify the responsible factors and equally difficult to convince the public to do anything in the way of change.Endangered Lives gives us a rich cross-section of such public health problems as they affected Great Britain in the last two thirds of the 19th century—the period associated with Queen Victoria. Professor Wohl
Boerhaave's Men at Leyden and After
Authors: Lester S. King
Journal: JAMA (1977)

Hermann Boerhaave, probably the greatest teacher of medicine in modern times, exerted a vast influence that we can measure by studying the careers of his students. Boerhaave's specific influence on British medicine and, through the Scottish connection, on early American medicine, has received the attention of several scholars. Dr Underwood, with unsurpassed background and critical acumen, has gone back to original sources and published what will certainly be the definitive work on this subject. Through painstaking search he has traced the men from Great Britain who had studied in Leyden during Boerhaave's lifetime. They had studied there for various lengths of time. Some took degrees; others did not. Some became famous indeed; others remained obscure. Underwood has traced what happened to them and described the way they affected British medical life in England, Scotland, and Ireland. The analysis really covered the entire 18th century—for of all the British students who
Taxing soft drinks could reduce obesity and diabetes in India, finds study
Authors: D. Sachan
Journal: BMJ (2014)

New research has found that applying excise tax to sugar sweetened beverages such as soft drinks could reduce obesity and diabetes in India.

Led by Stanford University researcher Sanjay Basu, a team of scientists from the United Kingdom, United States, and India found that a 20% excise duty on sugar sweetened drinks would prevent 11.2 million new cases of obesity and overweight (a 3% decline) and 400 000 cases of type 2 diabetes (a 1.6% decline) between 2014 and 2023. The study was published in PLOS Medicine.1

The team looked at data …
CXCL12/CXCR4 Blockade Induces Multimodal Antitumor Effects That Prolong Survival in an Immunocompetent Mouse Model of Ovarian Cancer
Authors: Elda Righi, Satoshi Kashiwagi, Jianping Yuan, Michael Santosuosso, Pierre Leblanc, Rachel Ingraham, Benjamin Forbes, Beth Edelblute, Brian Collette, Deyin Xing, Magdalena Kowalski, Maria Cristina Mingari, Fabrizio Vianello, Michael Birrer, Sandra Orsulic, Glenn Dranoff, Mark C. Poznansky
Journal: Cancer Research (2011)

The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3(+) regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease.
600 SHORTENED COURSE OF THERAPY FOR CHRONIC HEPATITIS C GENOTYPE 1 (G1) PATIENTS DEVELOPING RAPID VIROLOGICAL RESPONSE (RVR): META- ANALYSIS OF RANDOMIZED CONTROLLED TRIALS (RCTS)
Authors: J.-P. Cervoni, C. Richou, T. Thévenot, V. Di Martino
Journal: Journal of Hepatology (2009)
CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells
Authors: Natalia Nieto, Scott L. Friedman, Patricia Greenwel, Arthur I. Cederbaum
Journal: Hepatology (1999)

Hepatic stellate cells (HSCs) are a major source of extracellular matrix, which, during fibrogenesis, undergo a process of “activation” characterized by increased proliferation and collagen synthesis. Oxidative stress can stimulate HSC proliferation and collagen synthesis in vitro . Cytochrome P4502E1 (CYP2E1) is an effective producer of reactive oxygen species. To study how intracellular oxidative stress modulates alpha 2 collagen type I (COL1A2) gene induction, a rat HSC line (HSC-T6) was transfected with human CYP2E1 complementary DNA in the sense and antisense orientation and with empty vector, and stable cell lines were generated. The cells expressing CYP2E1 displayed elevated production of reactive oxygen species and showed a 4-fold increase in COL1A2 messenger RNA (mRNA) levels; expression of this mRNA among different clones appeared to correlate with the level of CYP2E1. COL1A2 expression was decreased by vitamin E treatment or transfection with manganese superoxide dismutase, and was further increased after treatment with l -buthionine sulfoximine (BSO) to lower GSH levels. Thus, CYP2E1-dependent oxidative stress plays a major role in the elevation of COL1A2 mRNA levels in this system. Nuclear run-on assay showed a 3-and-a-half-fold increase in COL1A2 transcription in the cells expressing CYP2E1; stabilization of COL1A2 mRNA was also observed. These results indicate that under oxidative stress conditions, COL1A2 mRNA expression is regulated both transcriptionally and through mRNA stabilization. The CYP2E1-expressing HSC appear to be a valuable model for the sustained generation of reactive oxygen species and may allow the elucidation of signaling pathways responsible for oxidant stress-mediated collagen gene induction.
Methanogen prevalence throughout the gastrointestinal tract of pre-weaned dairy calves
Authors: Mi Zhou, Yanhong Chen, Philip J Griebel, Le Luo Guan
Journal: Gut Microbes (2014)

The methanogenic community throughout the gastrointestinal tract (GIT) of pre-weaned calves has not been well studied. The current study firstly investigated the distribution and composition of the methanogenic community in the rumen, ileum, and colon of 3-4 week-old milk-fed dairy calves (n = 4) using 16S rRNA gene clone library analysis. The occurrence of methanogens in the GIT of pre-weaned calves was further validated by using PCR-denaturing gradient gel electrophoresis (PCR-DGGE), and quantitative real-time PCR (qPCR) was applied to quantify the methanogenic community in the rumen, jejunum, ileum, cecum, colon and rectum of 8 3-4 week old animals. Both cloning libraries and PCR-DGGE revealed that phylotypes close to Methanobrevibacter were the main taxon along the GIT in pre-weaned sucking calves. The composition and abundance of methanogens varied significantly among individual animals, suggesting that host conditions may influence the composition of the symbiotic microbiota. Segregation of methanogenic communities throughout the GIT was also observed within individual animals, suggesting possible functional differences among methanogens residing in different GIT regions. This is the first study to analyze methanogenic communities throughout the GIT of milk-fed newborn dairy calves and reveal both their diversity and abundance. The identification of methanogens in the lower GIT of pre-weaned dairy calves warrants further investigation to better define methanogen roles in GIT function and their impact on host metabolism and health.
Non-communicating multiseptate gall bladder and choledochal cyst: a case report and review of publications.
Authors: C E Tan, E R Howard, M Driver, I M Murray-Lyon
Journal: Gut (1993)

A 14 year old girl with multiseptate gall bladder and cystic dilatation of the biliary tree is presented. This is the 20th published case report of patients with multiseptate gall bladder and only the second to be associated with a choledochal cyst. The cystic spaces of the gall bladder did not communicate with the neck of the gall bladder or the rest of the biliary tree, and this unusual feature has not been previously described. A multiseptate gall bladder with a normal biliary tree commonly causes symptoms suggestive of cholecystitis, although gall stones are seldom present. Diagnosis is confirmed by an oral cholecystogram or ultrasound scan that may show the fine intraluminal septae, and these features should be looked for in patients with biliary symptoms without biliary calculi. Cholecystectomy is curative for the isolated gall bladder anomaly but hepaticojejunostomy may be necessary for an associated choledochal cyst.