tbuckley/cabot-search huggingface dataset:
Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients
Authors: Sebastien Viatte, Darren Plant, John Bowes, Mark Lunt, Stephen Eyre, Anne Barton, Jane Worthington
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Introduction</h3> There are now over 30 confirmed loci predisposing to rheumatoid arthritis (RA). Studies have been largely undertaken in patients with anticyclic citrullinated peptide (anti-CCP) positive RA, and some genetic associations appear stronger in this subgroup than in anti-CCP negative disease, although few studies have had adequate power to address the question. The authors therefore investigated confirmed RA susceptibility loci in a large cohort of anti-CCP negative RA subjects. <h3>Methods</h3> RA patients and controls, with serological and genetic data, were available from UK Caucasian patients (n=4068 anti-CCP positive, 2040 anti-CCP negative RA) and 13,009 healthy controls. HLA-DRB1 genotypes and 36 single nucleotide polymorphisms were tested for association between controls and anti-CCP positive or negative RA. <h3>Results</h3> The shared epitope (SE) showed a strong association with anti-CCP positive and negative RA, although the effect size was significantly lower in the latter (effect size ratio=3.18, p&lt;1.0E-96). A non-intronic marker at TNFAIP3, GIN1/C5orf30, STAT4, ANKRD55/IL6ST, BLK and PTPN22 showed association with RA susceptibility, irrespective of the serological status, the latter three markers remaining significantly associated with anti-CCP negative RA, after correction for multiple testing. No significant association with anti-CCP negative RA was detected for other markers (eg, AFF3, CD28, intronic marker at TNFAIP3), though the study power for those markers was over 80%. <h3>Discussion</h3> In the largest sample size studied to date, the authors have shown that the strength of association, the effect size and the number of known RA susceptibility loci associated with disease is different in the two disease serotypes, confirming the hypothesis that they might be two genetically different subsets.
Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure
Authors: Dimitra S Zagoura, Maria G Roubelakis, Vasiliki Bitsika, Ourania Trohatou, Kalliopi I Pappa, Alkistis Kapelouzou, Aristidis Antsaklis, Nicholas P Anagnou
Journal: Gut (2011)

<h3>Background</h3> There is increasing interest in the therapeutic potential of human mesenchymal stem cells (hMSCs), especially in diseases such as acute hepatic failure (AHF) that are predominantly caused by a variety of drugs and viruses. In previous studies, a distinct population termed human spindle-shaped MSCs were isolated and expanded from second trimester amniotic fluid (AF-MSCs) and characterised based on their phenotype, pluripotency and differentiation potential. <h3>Methods</h3> AF-MSCs, hepatic progenitor-like (HPL) cells and hepatocyte-like (HL) cells derived from AF-MSCs were transplanted into CCl<sub>4</sub>-injured NOD/SCID mice with the AHF phenotype in order to evaluate their therapeutic potential. Conditioned medium (CM) derived from AF-MSCs or HPL cells was then delivered intrahepatically in order to determine whether the engraftment of the cells or their secreted molecules are the most important agents for liver repair. <h3>Results</h3> Both HPL cells and AF-MSCs were incorporated into CCl<sub>4</sub>-injured livers; HPL cell transplantation had a greater therapeutic effect. In contrast, HL cells failed to engraft and contribute to recovery. In addition, HPL-CM was found to be more efficient than CM derived from AF-MSCs in treatment of the liver. Proteome profile analysis of HPL-CM indicated the presence of anti-inflammatory factors such as interleukins IL-10, IL-1ra, IL-13 and IL-27 which may induce liver recovery. Blocking studies of IL-10 secretion from HPL cells confirmed the therapeutic significance of this cytokine in the AHF mouse model. <h3>Conclusions</h3> Human spindle-shaped AF-MSCs or HPL cells might be valuable tools to induce liver repair and support liver function by cell transplantation. More importantly, the factors they release may also play an important role in cell treatment in diseases of the liver.
Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors
Authors: G C Minetti, C Colussi, R Adami, C Serra, C Mozzetta, V Parente, S Fortuni, S Straino, M Sampaolesi, M Di Padova, B Illi, P Gallinari, C Steinkühler, M C Capogrossi, V Sartorelli, R Bottinelli, C Gaetano, P L Puri
Journal: Nature Medicine (2006)
Multiple types of Ca2+ currents in single canine Purkinje cells.
Authors: G N Tseng, P A Boyden
Journal: Circulation Research (1989)

Whole-cell Ca2+ channel currents were recorded from isolated single canine Purkinje and ventricular cells to determine whether there were multiple types of Ca2+ channels in these two cell types, as in many other excitable tissues. The experimental conditions were such that currents other than Ca2+ channel currents were largely suppressed. The charge carrier was either Ca2+ or Ba2+ (5mM). In every canine Purkinje cell studied (n = 36), we saw T and L Ca2+ channel currents that are similar to their counterparts in other tissues. Neither current was affected by tetrodotoxin (30 microM), but both were reduced by Mn2+ (5mM). Ni2+ (50 microM) blocked T more than L current. Nisoldipine (1 microM) apparently abolished the L current but also decreased the T current by 50%. Substitution of Ba2+ for Ca2+ augmented and prolonged L current but did not affect T current significantly. At 36 degrees C and with 5 mM [Ca2+]o, T current inactivated over a voltage range from -70 to -30 mV whereas L current inactivated between -30 and +20 mV. T current was detectable in only some of the ventricular cells studied (8 out of 12). In these cells the ratio of maximal T current to maximal L current (0.2 +/- 0.1, n = 8) was lower than the T/L ratio in Purkinje cells (0.6 +/- 0.2, n = 6). The density of peak L current in ventricular cells (7.5 +/- 1.7 pA/pF, n = 8) was higher than that in Purkinje cells (4.4 +/- 3.4 pA/pF, n = 6). Therefore, in ventricular cells the L current is the main Ca2+ current whereas in Purkinje cells, the T current also contributes significantly to membrane electrical activity. In Purkinje cells, beta-adrenoceptor stimulation by isoproterenol (1 microM) increased L current but did not affect T current. On the other hand, in 70% (7 out of 10) of the Purkinje cells, alpha-adrenoceptor stimulation by 10 microM norepinephrine (in the presence of 2 microM propranolol) increased the T current. Our observations show that the distribution of the two types of Ca2+ channels in canine ventricle is heterogeneous and that the two types of Ca2+ channels are modulated by catecholamines by different receptors.
Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha.
Authors: M Korc, B Chandrasekar, Y Yamanaka, H Friess, M Buchier, H G Beger
Journal: Journal of Clinical Investigation (1992)

The epidermal growth factor (EGF) receptor is activated by both EGF and transforming growth factor-alpha (TGF-alpha). Using immunohistochemical and immunoblotting techniques we now report that the EGF receptor, EGF, and TGF-alpha are found in both pancreatic acini and ducts in the normal human pancreas, and that all three proteins are expressed at higher levels in human pancreatic cancer tissues. Using in situ hybridization techniques, we also report that the mRNA encoding the EGF receptor, EGF, and TGF-alpha colocalize with their respective proteins. Northern blot analysis of total RNA indicates that, by comparison with the normal pancreas, the pancreatic tumors exhibit a 3-, 15-, and 10-fold increase in the mRNA levels encoding the EGF receptor, EGF, and TGF-alpha, respectively. Furthermore, by in situ hybridization, there is a marked increase in these mRNA moieties within the tumor mass. These findings suggest that EGF and TGF-alpha may participate in the regulation of normal pancreatic exocrine function, and that overexpression of the EGF receptor and its two principal ligands may contribute to the pathophysiological processes that occur in human pancreatic cancer.
QT dispersion correlates to myocardial viability assessed by dobutamine stress echocardiography in patients with severely depressed left ventricular function due to coronary artery disease
Authors: Manolis Bountioukos, Arend F.L. Schinkel, Don Poldermans, Vittoria Rizzello, Eleni C. Vourvouri, Boudewijn J. Krenning, Elena Biagini, Jos R.T.C. Roelandt, Jeroen J. Bax
Journal: European Journal of Heart Failure (2004)
The Helicobacter pylori breath test: a surrogate marker for peptic ulcer disease in dyspeptic patients.
Authors: K E McColl, A el-Nujumi, L Murray, E el-Omar, D Gillen, A Dickson, A Kelman, T E Hilditch
Journal: Gut (1997)

BACKGROUND: There is interest in noninvasive H pylori testing as a means of predicting diagnosis and determining management in dyspeptic patients. AIMS: To assess the value of the 14C urea breath test as a predictor of peptic ulcer disease in patients presenting with dyspepsia. PATIENTS AND METHODS: 327 consecutive patients referred for investigation of dyspepsia had a 14C urea breath test performed before endoscopy. Patients were not included if they had previously confirmed ulcer disease, previous gastric surgery, or were taking non-steroidal anti-inflammatory drugs. RESULTS: Of the 182 patients with a positive 14C urea breath test, duodenal and/or gastric ulcers were present in 45% and erosive duodenitis in a further 2%. Oesophagitis was present in 12% of the breath test positive patients with two thirds of the oesophagitis patients having co-existent ulcer disease. The prevalence of ulcer disease in the H pylori positive dyspeptic patients was independently related to smoking and previous investigation status. If previously uninvestigated, the prevalence of ulcers was 67% in smokers and 46% in non-smokers. If previous upper gastrointestinal investigations were negative, the prevalence of ulcers was 53% in smokers and 28% in non-smokers. Of the 136 patients with a negative breath test, only 5% had peptic ulcers. The most frequent endoscopic finding in these H pylori negative subjects was oesophagitis, being present in 17%. CONCLUSIONS: This study demonstrates that a positive H pylori test is a powerful predictor of the presence of underlying ulcer disease in dyspeptic patients, especially if smokers, and that a negative H pylori test is a powerful predictor of the absence of ulcer disease. It also indicates that a negative upper gastrointestinal investigation does not preclude subsequent presentation with ulcer disease.
Dynamin inhibitors induce caspase-mediated apoptosis following cytokinesis failure in human cancer cells and this is blocked by Bcl-2 overexpression
Authors: Sanket Joshi, Antony W Braithwaite, Phillip J Robinson, Megan Chircop
Journal: Molecular Cancer (2011)

Abstract Background The aim of both classical (e.g. taxol) and targeted anti-mitotic agents (e.g. Aurora kinase inhibitors) is to disrupt the mitotic spindle. Such compounds are currently used in the clinic and/or are being tested in clinical trials for cancer treatment. We recently reported a new class of targeted anti-mitotic compounds that do not disrupt the mitotic spindle, but exclusively block completion of cytokinesis. This new class includes MiTMAB and OcTMAB (MiTMABs), which are potent inhibitors of the endocytic protein, dynamin. Like other anti-mitotics, MiTMABs are highly cytotoxic and possess anti-proliferative properties, which appear to be selective for cancer cells. The cellular response following cytokinesis failure and the mechanistic pathway involved is unknown. Results We show that MiTMABs induce cell death specifically following cytokinesis failure via the intrinsic apoptotic pathway. This involves cleavage of caspase-8, -9, -3 and PARP, DNA fragmentation and membrane blebbing. Apoptosis was blocked by the pan-caspase inhibitor, ZVAD, and in HeLa cells stably expressing the anti-apoptotic protein, Bcl-2. This resulted in an accumulation of polyploid cells. Caspases were not cleaved in MiTMAB-treated cells that did not enter mitosis. This is consistent with the model that apoptosis induced by MiTMABs occurs exclusively following cytokinesis failure. Cytokinesis failure induced by cytochalasin B also resulted in apoptosis, suggesting that disruption of this process is generally toxic to cells. Conclusion Collectively, these data indicate that MiTMAB-induced apoptosis is dependent on both polyploidization and specific intracellular signalling components. This suggests that dynamin and potentially other cytokinesis factors are novel targets for development of cancer therapeutics.
Salivary testosterone and cortisol in rugby players: correlation with psychological overtraining items
Authors: F Maso, G Lac, E Filaire, O Michaux, A Robert
Journal: British Journal of Sports Medicine (2004)

A psychocomportemental questionnaire has been devised by the consensus group of the Société Française de Médecine du Sport to characterise and quantify, using a list of functional and psychocomportemental signs, a state of "staleness", for which no biological indicator is unanimously recognised.To determine the relation between this diagnostic method and two hormones (cortisol and testosterone) often used as indicators of a state of fitness or staleness.The subjects were young rugby players. They were asked to complete the overtraining questionnaire and gave three saliva samples (at 8 am, 11 am, and 5 pm) during a rest day. Concentrations of cortisol and testosterone in the saliva were determined by radioimmunoassay.A preferential relation was found between the questionnaire score and testosterone concentration but not between the questionnaire score and cortisol concentration.The questionnaire may be a useful tool for screening subjects at risk of overtraining. Testosterone concentration is influenced by tiredness, and is therefore a valid marker of tiredness.
Failure to Respond
Authors: Michael E. Ezzie, William J. Janssen, James M. O'Brien, Charity C. Fox, Marvin I. Schwarz
Journal: New England Journal of Medicine (2008)

A 52-year-old man presented to his primary care physician with dyspnea and cough. For the past 15 years, he had had recurrent episodes of cough that were relieved only by intermittent courses of oral corticosteroids. In the past 3 weeks, his cough had increased in frequency, and severe dyspnea had developed. This time, 2 weeks of prednisone had not provided relief. He had occasional chills but no fever.
Genetic Discoveries Propagate New Epigenetic Drugs
Authors: K. Garber
Journal: JNCI Journal of the National Cancer Institute (2012)

O ne reason progress in epigenetic therapy for cancer has been so slow and painstaking is that the available drugs are old and imperfect. For example, the heavily-used azacitidine was first synthesized in the 1960s. But a new generation of epigenetic drugs appears to be on the way. They ’ re badly needed, because epigenetic therapy to date has shown little effect on solid tumors. (A recent lung cancer trial is the only exception.) There is even doubt that these drugs work by an epigenetic mechanism — that is, by altering chromatin (the packaged form of DNA) to change gene expression. “There is still a major issue about lack of really true epigenome targeting,” said Robert Brown, Ph.D., chair of translational oncology at Imperial College London, at the November 2011 Molecular Targets and Cancer Therapeutics meeting in San Francisco. Researchers have also had diffi culty identifying the subset of patients who could benefi t from treatment. For all these reasons, the fi eld of epigenetic therapy, while continuing to refi ne the use of the older drugs, is eager to try new ones. Current epigenetic drugs, said Brown, “we hope are just the tip of the iceberg.” Fortunately, completely novel classes of epigenetic drugs should soon become available for testing in patients. In the last few years, researchers have reported genetic alterations in tumors for several enzymes that have epigenetic functions. These enzymes — histone methyltransferases and histone demethylases — place and remove methyl groups from histones, proteins around which DNA is coiled. At least three biotech companies and several major pharmaceutical companies are now targeting these enzymes in cancer. Unlike histone deacetylase (HDACs), these drug targets have the imprimatur of genetics to show their importance in cancer, and drugs now in development have the potential to target individuals with specifi c genetic defects in their tumors.
Urinary leukotriene E4 in bronchial asthma
Authors: CM Smith, RJ Hawksworth, FC Thien, PE Christie, TH Lee
Journal: European Respiratory Journal (1992)

Leukotriene E4 (LTE4) is excreted into the urine in a relatively constant proportion of 4-7% when either leukotriene C4 (LTC4) or LTE4 is intravenously infused, regardless of the magnitude of the infused dose. Measurement of LTE4 in urine is, therefore, a convenient and non-invasive method for assessing changes in the rate of total body sulphidopeptide leukotriene production. We assayed urinary LTE4 in 17 normal subjects, 31 subjects with asthma without aspirin sensitivity, and 10 aspirin-sensitive subjects. The relationship between urinary LTE4 and nonspecific bronchial hyperresponsiveness, as assessed by the provocative dose producing a 20% fall in forced expiratory volume in one second (PD20) to inhaled histamine, was examined in 19 non-aspirin-sensitive asthmatic subjects. The urinary LTE4 values were log-normally distributed. Urinary LTE4 was detected in 28 of the 31 non-aspirin-sensitive asthmatic subjects, and the geometric mean (95% confidence interval (CI) of 43 (32-57) pg.mg-1 creatinine was no different to that of 34 (25-48) pg.mg-1 creatinine measured in the normal subjects. The geometric mean of 101 (55-186) pg.mg-1 creatinine measured in the aspirin-sensitive asthmatics was significantly higher than that measured in the normal subjects (p less than 0.005) and in the asthmatic subjects who were non-aspirin-sensitive (p less than 0.002), but there was considerable overlap between the three groups. There was no relationship between urinary LTE4 and PD20, or between urinary LTE4 and baseline forced expiratory volume in one second (FEV1) (% predicted). Thus, measurement of LTE4 in a single sample of urine will not predict the extent of bronchial hyperresponsiveness or degree of airflow obstruction.
Genetic and Environmental Determinants of Dimethylarginines and Association With Cardiovascular Disease in Patients With Type 2 Diabetes
Authors: Maike Anderssohn, Stela McLachlan, Nicole Lüneburg, Christine Robertson, Edzard Schwedhelm, Rachel M. Williamson, Mark W.J. Strachan, Ramzi Ajjan, Peter J. Grant, Rainer H. Böger, Jackie F. Price
Journal: Diabetes Care (2013)

To investigate determinants of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), including single nucleotide polymorphisms (SNPs), in the DDAH1, DDAH2, and AGXT2 genes and their associations with prevalent and incident cardiovascular disease (CVD) in older adults with type 2 diabetes mellitus.Prevalent CVD was assessed in men and women aged 60-75 years with type 2 diabetes as part of the Edinburgh Type 2 Diabetes Study (ET2DS), and the participants were prospectively followed up for 4 years for incident CVD. Dimethylarginines were measured in 783 of these subjects, and genotyping for tag SNPs in the DDAH1, DDAH2, and AGXT2 genes was performed in 935 subjects.Plasma ADMA levels were significantly associated with SNPs in DDAH1 (top SNP rs1554597; P = 9.0E-09), while SDMA levels were associated with SNPs in AGXT2 (top SNP rs28305; P = 1.3E-04). Significant, independent determinants of plasma ADMA were sex, L-arginine, creatinine, fasting glucose, and rs1554597 (all P < 0.05; combined R(2) = 0.213). Determinants of SDMA were age, sex, creatinine, L-arginine, diabetes duration, prevalent CVD, and rs28305 (all P < 0.05; combined R(2) = 0.425). Neither dimethylarginine was associated with incident CVD. None of the investigated SNPs were associated with overall CVD, although subgroup analysis revealed a significant association of AGXT2 rs28305 with intermittent claudication.Our study in a well-characterized population with type 2 diabetes does not support reported associations or causal relationship between ADMA and features of diabetes or CVD.
Consumption of Olive Oil and Specific Food Groups in Relation to Breast Cancer Risk in Greece
Authors: A. Trichopoulou, K. Katsouyanni, S. Stuver, L. Tzala, C. Gnardellis, E. Rimm, D. Trichopoulos
Journal: JNCI Journal of the National Cancer Institute (1995)

Background: Experimental animal studies suggest that olive oil consumption, as contrasted to consumption of other fat types, does not enhance the occurrence of chemically induced mammary tumors, but human data are sparse. Furthermore, evidence is inconclusive concerning the role of food groups, as distinct from that of major nutrients, in the etiology of breast cancer in women. Purpose: This analysis was conducted to evaluate and quantify the effect of consumption of olive oil, margarine, and a range of food groups on the risk of breast cancer. Methods: Data from a comprehensive, semiquantitative food-frequency questionnaire administered to 820 women with breast cancer and 1548 control women from the study base were used to calculate odds ratios (ORs) and X statistics of linear trend for the consumption of olive oil, margarine, and a series of food groups classified in quintiles. Adjustment for the effects of reproductive risk factors, energy intake, and mutual confounding influences was implemented through unconditional logistic regression modeling. Results: Vegetable consumption and fruit consumption were independently associated with statistically significant reductions of breast cancer risk by 12% and 8%, respectively, per quintile increase; no significant associations were evident for the other food groups examined. Increased olive oil consumption was associated with significantly reduced breast cancer risk (OR = 0.75 [95% confidence interval = 0.57–0.98] for more than once a day versus once a day), whereas increased margarine consumption was associated with significantly increased risk (OR = 1.05 [95% confidence interval = 1.00–1.10] for an increment of four times a month). The olive oil association was apparently concentrated among postmenopausal women, but the relevant interaction term was not statistically significant; there was no suggestion of interaction with menopausal status for consumption of either vegetables, fruits, or margarine. Conclusions: Although major categories of macronutrients do not show significant associations with breast cancer risk in most studies, including the present one, vegetables and fruits are inversely, significantly, and strongly associated with this risk. There also is evidence that olive oil consumption may reduce the risk of breast cancer, whereas margarine intake appears to be associated with an elevated risk for the disease. [J Natl Cancer Inst 87:110-116, 1995]