tbuckley/cabot-search huggingface dataset:
Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.
Authors: B D Lowes, W Minobe, W T Abraham, M N Rizeq, T J Bohlmeyer, R A Quaife, R L Roden, D L Dutcher, A D Robertson, N F Voelkel, D B Badesch, B M Groves, E M Gilbert, M R Bristow
Journal: Journal of Clinical Investigation (1997)

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.
Re: New Guidelines to Evaluate the Response to Treatment in Solid Tumors (Ovarian Cancer)
Authors: Gordon J. S. Rustin, Michael Quinn, Tate Thigpen, Andreas du Bois, Eric Pujade-Lauraine, Anders Jakobsen, Elizabeth Eisenhauer, Satoru Sagae, Kathryn Greven, Ignace Vergote, Andres Cervantes, Jan Vermorken
Journal: JNCI Journal of the National Cancer Institute (2004)
Lactic acidosis complicating treatment of ketosis of labour.
Authors: A C Ames, S Cobbold, J Maddock
Journal: BMJ (1975)

Hypertonic glucose, fructose, and sorbitol solutions were given intravenously to women in the first stage of labour who had ketonuria and ketonaemia as evidenced by a raised blood acetoacetate and 3-hydrosybutyrate. There was no difference in the antiketogenic action of these, which was rapid and effective, but when compared with a control group who were given normal saline they had a high incidence of hyperlactataemia, and nine out of 28 patients developed lactic acidosis after the infusions. The "lactatogenic" effect was shared by all three substrates, and when they are used in the treatment of ketosis of labour, and the mother develops lactic acidosis, they might exacerbate pre-existing lactic acidosis and precipitate fetal distress.
Bifidobacterium breve UCC2003 surface exopolysaccharide production is a beneficial trait mediating commensal-host interaction through immune modulation and pathogen protection
Authors: Saranna Fanning, Lindsay J. Hall, Douwe van Sinderen
Journal: Gut Microbes (2012)

Bifidobacteria constitute a substantial proportion of the human gut microbiota. There are currently many bifidobacterial strains with claimed probiotic attributes. The mechanism through which these strains reside within their host and exert benefits to the host is far from fully understood. We have shown in the case of Bifidobacterium breve UCC2003 that a cell surface exopolysaccharide (EPS) plays a role in in vivo persistence. Biosynthesis of two possible EPSs is controlled by a bidirectional gene cluster which guides alternate EPS synthesis by means of a reorienting promoter. The presence of EPS impacts on host immune response: the wild type, EPS-positive B. breve UCC2003 efficiently evades the adaptive B-cell host response, while its isogenic, EPS-deficient equivalent elicits a strong adaptive immune response. Functionally, EPS positive strains were more resilient to presence of acid and bile and were responsible for reduced colonization levels of Citrobacter rodentium, a gut pathogen. In conclusion, we have found that EPS is important in host interactions and pathogen protection, the latter indicative of a probiotic ability for the EPS of B. breve UCC2003.
Integrative Continuum: Accelerating Therapeutic Advances in Rare Autoimmune Diseases
Authors: Katja Van Herle, Jacinta M. Behne, Andre Van Herle, Terrence F. Blaschke, Terry J. Smith, Michael R. Yeaman
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Autoimmune diseases are chronic, life threatening, and of burgeoning public health concern. They rank among the 10 most common causes of death in women, and some have incidence rates surpassing those of heart disease and cancer. Emerging information regarding molecular and cellular mechanisms affords opportunities for the discovery of novel therapeutic strategies or the repurposing of FDA-approved pharmacologic agents. Yet, obstacles to drug development amplify as an inverse function of the incidence of rare autoimmune disease; challenges include heterogeneous clinical presentation, paucity of definitive biomarkers, and poorly validated measures of therapeutic response. An integrative continuum model to address these challenges is being applied to neuromyelitis optica (NMO)-a potentially devastating neurodegenerative process that has had limited therapeutic options. This model links target discovery with pharmacologic application to accelerate improved clinical efficacy. The application of such innovative strategies may help researchers overcome barriers to therapeutic advances in NMO and other rare autoimmune diseases.
Variation in the <i>CDKAL1</i> Gene Is Associated With the Titer of Antibodies to GAD
Authors: Axel Haupt, Martina Guthoff, Baptist Gallwitz, Hans-Ulrich Haring, Andreas Fritsche
Journal: Diabetes Care (2008)

Genome-wide association studies have described new diabetes susceptibility genes including TCF7L2 , CDKAL1 , HHEX , SLC30A8 , CDKN2A/B , and IGF2BP2 (1). Most of these novel risk loci are associated with impaired β-cell function (2). Impaired β-cell function due to autoimmune processes plays a role in the pathogenesis of type 1A diabetes and latent autoimmune diabetes in adults. Therefore, it is conceivable that some of the susceptibility genes may be related to autoimmunity and inflammation leading to β-cell dysfunction. This hypothesis was recently excluded for the variation in the TCF7L2 gene, which was not found to be associated with type 1 diabetes.

We investigated whether …
Intermittent ischemia produces a cumulative depletion of mitochondrial adenine nucleotides in the isolated perfused rat heart.
Authors: G K Asimakis, G S Sandhu, V R Conti, L A Sordahl, J B Zwischenberger
Journal: Circulation Research (1990)

The purpose of the present study was to determine if repetitive myocardial ischemia would result in the cumulative loss of mitochondrial adenine nucleotides. Isolated perfused rat hearts were subjected to continuous or intermittent ischemia. A single 5-minute period of continuous ischemia did not result in a significant decrease in the mitochondrial adenine nucleotide pool; a single 10-minute period of ischemia resulted in a decrease of approximately 17%. Next, the adenine nucleotide content of mitochondria from preischemic and 30-minute continuous ischemic hearts was compared with two groups of hearts undergoing intermittent ischemia (both groups receiving a total of 30 minutes of ischemia). One group received three 10-minute episodes of ischemia interrupted by 5-minute periods of reperfusion (3 x 10-minute intermittent ischemia); the other intermittent ischemic group received six 5-minute episodes of ischemia interrupted by 5-minute periods of perfusion (6 x 5-minute intermittent ischemia). The mitochondrial adenine nucleotide content (expressed as nanomoles per nanomole cytochrome a) for the preischemic and 30-minute continuous ischemic hearts was 14.7 +/- 0.6 and 8.0 +/- 0.4, respectively. The mitochondrial adenine nucleotide content of the 3 x 10-minute intermittent ischemia group (8.5 +/- 0.5) was not significantly different from the 30-minute continuous ischemic group. The mitochondrial adenine nucleotide content of the 6 x 5-minute intermittent ischemia group (11.0 +/- 0.6) was significantly larger than that of the 30-minute continuous and the 3 x 10-minute intermittent ischemia groups (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Consumption of anabolic steroids in sport, physical activity and as a drug of abuse: an analysis of the scientific literature and areas of research
Authors: V Agulló-Calatayud, G González-Alcaide, J C Valderrama-Zurián, R Aleixandre-Benavent
Journal: British Journal of Sports Medicine (2007)

Objective: The consumption of anabolic steroids (AS) has been growing continuously in recent years. It has gone beyond the sports world; AS are now widely used as drugs of abuse in connection with bodybuilding. This study sets out to assess the state of scientific research in the area. Design: Bibliometrics were employed to evaluate the literature retrieved from the principal relevant bibliographic databases: MEDLINE, SportDiscus, the Science Citation Index Expanded and the Social Sciences Citation Index. The core journals were identified along with the leading authors and research groups and their institutional affiliations. Techniques based on social network analysis were applied in order to build up a concept map of research. Results: 1325 documents were retrieved. They were produced by 3131 different researchers giving a Collaboration Index of 3.32. The institutions with the most productive authors were Ball State University (Muncie, IN, USA), the École Nationale Vétérinaire de Nantes (ENVN), the Institut Municipal dInvestigació Mèdica (IMIM) (Barcelona, Spain), the Institute of Biochemistry of the German Sport University Cologne (DSHS), Iowa State University, Maastricht University and the University of Iowa. Conclusions: It was concluded that there has been an upward trend in the number of research projects. The sources used complemented one another, as 78.04% of the documents retrieved were unique to one source. The productivity ranking was headed by sports medicine journals, followed by journals of chemistry, physiology, endocrinology and substance abuse. Besides sporting activities, the most important research clusters were those connected with bodybuilding and with youth groups.
Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells
Authors: Bahar Salimian Rizi, Christine Caneba, Aleksandra Nowicka, Ahmad W. Nabiyar, Xinran Liu, Kevin Chen, Ann Klopp, Deepak Nagrath
Journal: Cancer Research (2014)

Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of l-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using l-arginase and NOS inhibition in cancer cells using N(G)-nitro-l-arginine methyl ester (l-NAME), we demonstrate that patient-derived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASC-secreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASC-mediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through l-arginase, along with targeting microenvironment-secreted factors using l-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers.
Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase
Authors: Naomi Oi, Chul-Ho Jeong, Janos Nadas, Yong-Yeon Cho, Angelo Pugliese, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2010)

Abstract The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy-trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A4 hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. Cancer Res; 70(23); 9755–64. ©2010 AACR.
The descriptive epidemiology of warts in British schoolchildren
Authors: H.C. WILLIAMS, A. POTTIER, D. STRACHAN
Journal: British Journal of Dermatology (1993)

Journal Article The descriptive epidemiology of warts in British schoolchildren Get access H.C. WILLIAMS, H.C. WILLIAMS St John's Institute of Dermatology, St Thomas' Hospital, Lambeth Palace Road, London SEI 7EH, U.K. Dr Hywel C. Williams, St John's Dermatology Centre, St Thomas' Hospital, Lambeth Palace Road, London SEI 7EH. Search for other works by this author on: Oxford Academic Google Scholar A. POTTIER, A. POTTIER Department of Public Health Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K. Search for other works by this author on: Oxford Academic Google Scholar D. STRACHAN D. STRACHAN Department of Public Health Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 128, Issue 5, 1 May 1993, Pages 504–511, https://doi.org/10.1111/j.1365-2133.1993.tb00226.x Published: 01 May 1993 Article history Accepted: 03 December 1992 Published: 01 May 1993
Breast Cancer Cell Uptake of the Inflammatory Mediator Neutrophil Elastase Triggers an Anticancer Adaptive Immune Response
Authors: Elizabeth A. Mittendorf, Gheath Alatrash, Na Qiao, Yun Wu, Pariya Sukhumalchandra, Lisa S. St. John, Anne V. Philips, Haile Xiao, Mao Zhang, Kathryn Ruisaard, Karen Clise-Dwyer, Sijie Lu, Jeffrey J. Molldrem
Journal: Cancer Research (2012)

There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiologic basis for the prognostic significance of neutrophil elastase, a serine protease found in neutrophil granules, in a model of cyclin E (CCNE)-overexpressing breast cancer. We established that neutrophil elastase was expressed by TAN within breast cancer tissues but not by breast cancer cells. Neutrophil elastase modulated killing of breast cancer cells by CTLs specific for CCNE-derived HLA-A2-restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of neutrophil elastase from the microenvironment that was independent of neutrophil elastase enzymatic activity. Furthermore, neutrophil elastase uptake increased expression of low molecular weight forms of CCNE and enhanced susceptibility to peptide-specific CTL lysis, suggesting that CCNE peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an inflammatory mediator to an effective cytolytic response against an important breast cancer antigen.
IRE1α activation protects mice against acetaminophen-induced hepatotoxicity
Authors: Kyu Yeon Hur, Jae-Seon So, Vera Ruda, Maria Frank-Kamenetsky, Kevin Fitzgerald, Victor Koteliansky, Takao Iwawaki, Laurie H. Glimcher, Ann-Hwee Lee
Journal: The Journal of Experimental Medicine (2012)

The mammalian stress sensor IRE1α plays a central role in the unfolded protein, or endoplasmic reticulum (ER), stress response by activating its downstream transcription factor XBP1 via an unconventional splicing mechanism. IRE1α can also induce the degradation of a subset of mRNAs in a process termed regulated IRE1-dependent decay (RIDD). Although diverse mRNA species can be degraded by IRE1α in vitro, the pathophysiological functions of RIDD are only beginning to be explored. Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in young adults in the United States and is primarily caused by CYP1A2-, CYP2E1-, and CYP3A4-driven conversion of APAP into hepatotoxic metabolites. We demonstrate here that genetic ablation of XBP1 results in constitutive IRE1α activation in the liver, leading to RIDD of Cyp1a2 and Cyp2e1 mRNAs, reduced JNK activation, and protection of mice from APAP-induced hepatotoxicity. A pharmacological ER stress inducer that activated IRE1α suppressed the expression of Cyp1a2 and Cyp2e1 in WT, but not IRE1α-deficient mouse liver, indicating the essential role of IRE1α in the down-regulation of these mRNAs upon ER stress. Our study reveals an unexpected function of RIDD in drug metabolism.
Orphans in the Human Cytochrome P450 Superfamily: Approaches to Discovering Functions and Relevance in Pharmacology
Authors: F. Peter Guengerich, Qian Cheng
Journal: Pharmacological Reviews (2011)

As a result of technical advances in recombinant DNA technology and nucleotide sequencing, entire genome sequences have become available in the past decade and offer potential in understanding diseases. However, a central problem in the biochemical sciences is that the functions of only a fraction of the genes/proteins are known, and this is also an issue in pharmacology. This review is focused on issues related to the functions of cytochrome P450 (P450) enzymes. P450 functions can be categorized in several groups: 1) Some P450s have critical roles in the metabolism of endogenous substrates (e.g., sterols and fat-soluble vitamins). 2) Some P450s are not generally critical to normal physiology but function in relatively nonselective protection from the many xenobiotic chemicals to which mammals (including humans) are exposed in their diets [as well as more anthropomorphic chemicals (e.g., drugs, pesticides)]. 3) Some P450s have not been extensively studied and are termed "orphans" here. With regard to elucidation of any physiological functions of the orphan P450s, the major subject of this review, it is clear that simple trial-and-error approaches with individual substrate candidates will not be very productive in addressing questions about function. A series of liquid chromatography/mass spectrometry/informatics approaches are discussed, along with some successes with both human and bacterial P450s. Current information on what are still considered "orphan" P450s is presented. The potential for application of some of these approaches to other enzyme systems is also discussed.
Pulmonary Mycobacterium kansasii infection successfully treated with a regimen containing erythromycin.
Authors: P J Guest, M G Britton, H C Grundy, M D Yates
Journal: Thorax (1988)

Abstract We report a case in which erythromycin was used in place of rifampicin after a severe reaction to the latter in the treatment of pulmonary Mycobacterium kansasii infection.
Urinary bladder neoplasms induced by feeding bracken fern (Pteris aquilina) to cows.
Authors: A. M. Pamukcu, S. K. Göksoy, J. M. Price
Journal: Cancer Research (1967)

Summary  The chronic toxicity of bracken fern (Pteris aquilina) harvested near Bolu, Turkey, where bovine bladder tumors occur in a high incidence, was tested by feeding the plant to 18 cows of native stock ranging from 1.5 to 4 years of age. The cows weighed from 100 to 150 kg and were fed from 300 to 600 gm of dried or 400 to 1000 gm of fresh plant daily in an attempt to simulate natural exposure in the field. Of 18 animals fed bracken fern, 10 developed neoplasms of the urinary bladder and 3 of these lesions were carcinomas. The 2 carcinomas which invaded the muscular wall of the urinary bladder were found 2.6 and 3.3 years after the initiation of feeding. The 8 animals which died of toxicity without evidence of bladder neoplasms after a mean feeding time of 163 days included 5 of the 7 animals fed the highest dosage of bracken. Most of the animals which developed bladder lesions were fed bracken at a lower dietary level for a mean period of 550 days (range, 276 to 1192 days). Ten control animals not exposed to bracken fern did not manifest any clinical symptoms during the experiment. The histologic appearance of the neoplasms and other parameters of the study suggest that this experiment has resulted in the production of lesions that are indistinguishable from the naturally occurring bovine bladder tumors which are a common feature of bovine enzootic hematuria. These results provide further evidence for the presence of a carcinogenic substance in bracken fern.