tbuckley/cabot-search huggingface dataset:
Establishment of β-Adrenergic Modulation of L-Type Ca <sup>2+</sup> Current in the Early Stages of Cardiomyocyte Development
Authors: Victor A. Maltsev, G. J. Ji, Anna M. Wobus, Bernd K. Fleischmann, Jürgen Hescheler
Journal: Circulation Research (1999)

beta-Adrenergic modulation of the L-type Ca2+ current (ICaL) was characterized for different developmental stages in murine embryonic stem cell-derived cardiomyocytes using the whole-cell patch-clamp technique at 37 degreesC. Cardiomyocytes first appeared in embryonic stem cell-derived embryoid bodies grown for 7 days (7d). ICaL was insensitive to isoproterenol, forskolin, and 8-bromo-cAMP in very early developmental stage (VEDS) cardiomyocytes (from 7+1d to 7+2d) but highly stimulated by these substances in late developmental stage (LDS) cardiomyocytes (from 7+9d to 7+12d), indicating that all signaling cascade components became functionally coupled during development. In early developmental stage (EDS) cells (from 7+3d to 7+5d), the stimulatory response to forskolin and 8-bromo-cAMP was relatively weak. The forskolin effect was strongly augmented by ATP-gamma-S. At this stage, basal ICaL was stimulated by the nonselective phosphodiesterase (PDE) inhibitor isobutylmethylxanthine, by PDE inhibitors selective for the PDE II, III, and IV isoforms, as well as by the phosphatase inhibitor okadaic acid. Stimulation of ICaL by the catalytic subunit of the cAMP-dependent protein kinase A (PKA) was found to be similar (about 3 times) throughout development and in adult mouse ventricular cardiomyocytes, indicating that no structural changes of the Ca2+ channel related to phosphorylation occurred during development. ICaL was stimulated by isoproterenol in the presence of a PKA inhibitor and GTP-gamma-S in LDS but not VEDS cardiomyocytes, suggesting the development of a membrane-delimited stimulatory pathway mediated through the stimulatory GTP binding protein, Gs. We conclude that uncoupling and/or low expression of Gs protein accounted for the ICaL insensitivity to beta-adrenergic stimulation in VEDS cardiomyocytes. Furthermore, in EDS cells at the 7+4d stage, the reduced beta-adrenergic response is due, at least in part, to high intrinsic PDE and phosphatase activities.
Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting
Authors: Sarah Tischer, Robert J. Fontana
Journal: Journal of Hepatology (2013)

Studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C genotype 1 infection have demonstrated dramatic increases in tacrolimus, cyclosporine, and mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldaprevir will likely have improved efficacy and safety profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based antiviral therapy are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.
Pulmonary artery pressure limits exercise capacity at high altitude
Authors: R. Naeije, S. Huez, M. Lamotte, K. Retailleau, S. Neupane, D. Abramowicz, V. Faoro
Journal: European Respiratory Journal (2010)

Altitude exposure is associated with decreased exercise capacity and increased pulmonary vascular resistance (PVR). Echocardiographic measurements of pulmonary haemodynamics and a cardiopulmonary exercise test were performed in 13 healthy subjects at sea level, in normoxia and during acute hypoxic breathing (1 h, 12% oxygen in nitrogen), and in 22 healthy subjects after acclimatisation to an altitude of 5,050 m. The measurements were obtained after randomisation, double-blinded to the intake of placebo or the endothelin A receptor blocker sitaxsentan (100 mg·day −1 for 7 days). Blood and urine were sampled for renal function measurements. Normobaric as well as hypobaric hypoxia increased PVR and decreased maximum workload and oxygen uptake ( V ′ O 2 ,max ). Sitaxsentan decreased PVR in acute and chronic hypoxia (both p&lt;0.001), and partly restored V ′ O 2 ,max , by 30 % in acute hypoxia (p&lt;0.001) and 10% in chronic hypoxia (p&lt;0.05). Sitaxsentan-induced changes in PVR and V ′ O 2 ,max were correlated (p = 0.01). Hypoxia decreased glomerular filtration rate and free water clearance, and increased fractional sodium excretion. These indices of renal function were unaffected by sitaxsentan intake. Selective endothelin A receptor blockade with sitaxsentan improves mild pulmonary hypertension and restores exercise capacity without adverse effects on renal function in hypoxic normal subjects.
Relationship of Sex to Diabetes Risk in Statin Trials
Authors: Mark O. Goodarzi, Xiaohui Li, Ronald M. Krauss, Jerome I. Rotter, Yii-Der I. Chen
Journal: Diabetes Care (2013)

Statins appear to modestly increase the risk of incident diabetes. While an early trial (the West of Scotland Coronary Prevention Study [WOSCOPS]) suggested possible protection against diabetes (1), the JUPITER study (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) documented a 25% increase in diabetes risk with statin treatment (3 vs. 2.4%, P = 0.01) (2). A meta-analysis of 13 statin trials (>91,000 subjects) documented a statistically significant 9% increased risk for incident diabetes (3). Women may be more susceptible than men to develop diabetes while taking statins. While the overall increase in diabetes incidence was 25% in JUPITER, sex stratification revealed that the risk was increased by 49% in women and by only 14% in men (4). A retrospective analysis of the Women’s Health Initiative (WHI) found that statin use was associated with a 71% increased risk of diabetes (95% CI, 1.61–1.83); after adjustment for potential confounders, the hazard ratio (HR) remained significant at 1.48 (1.38–1.59) (5). The effect of sex on incident diabetes has not been evaluated in …
Regional Myocardial Blood Flow in Awake Dogs
Authors: Frederick R. Cobb, Robert J. Bache, Joseph C. Greenfield
Journal: Journal of Clinical Investigation (1974)

The objectives of this study were to test the hypothesis in awake dogs that during control conditions endocardial vessels are maximally dilated and to determine whether variables introduced by general anesthesia and thoracotomy modify distribution of myocardial blood flow or impair capacity for augmentation of flow in response to a coronary vasodilator stimulus. Myocardial blood flow was measured in relatively small, 2-3 g, left ventricular epicardial and endocardial samples by using 7-10-μm radioisotope-labeled microspheres during control conditions and during infusion of adenosine in dosages which produced maximum increases in coronary blood flow. Measurements were made initially in awake resting animals and were repeated after pentobarbital anesthesia, thoracotomy, and pericardiotomy.
Targeting the Lymphotoxin-β Receptor with Agonist Antibodies as a Potential Cancer Therapy
Authors: Matvey Lukashev, Doreen LePage, Cheryl Wilson, Véronique Bailly, Ellen Garber, Alex Lukashin, Apinya Ngam-ek, Weike Zeng, Norman Allaire, Steve Perrin, Xianghong Xu, Kendall Szeliga, Kathleen Wortham, Rebecca Kelly, Cindy Bottiglio, Jane Ding, Linda Griffith, Glenna Heaney, Erika Silverio, William Yang, Matt Jarpe, Stephen Fawell, Mitchell Reff, Amie Carmillo, Konrad Miatkowski, Joseph Amatucci, Thomas Crowell, Holly Prentice, Werner Meier, Shelia M. Violette, Fabienne Mackay, Dajun Yang, Robert Hoffman, Jeffrey L. Browning
Journal: Cancer Research (2006)

The lymphotoxin-beta receptor (LT beta R) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LT beta R monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LT beta R caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LT beta R activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LT beta R with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers.
S144a Endogenous inhibition of experimentally induced cough in healthy subjects
Authors: E. C. Young, L. A. Houghton, K. J. Holt, A. A. Woodcock, J. A. Smith
Journal: Thorax (2011)

<h3>Background</h3> The pathophysiology of chronic cough may include peripheral/central sensitisation of afferent pathways and/or a failure of inhibitory pathways. Cough can be voluntarily suppressed in healthy subjects, but the role of endogenous inhibition is unknown. Endogenous inhibitory pain pathways can be activated by applying a painful conditioning stimulus to one body part, to inhibit pain elsewhere, described as “Diffuse Noxious Inhibitory Controls”. <h3>Aim</h3> To investigate if a painful conditioning stimulus applied to the hand would inhibit cough in healthy subjects. <h3>Methods</h3> This was a randomised, 4-way, cross-over study. The EC50 dose of capsaicin was pre-determined (inducing at least 50% maximal cough frequency) at screening, and subsequently administered at each of the 4 visits (&gt;48 h apart) in 2 blocks (1 h apart) of 4 inhalations (15 s apart), simultaneous with a randomised intervention: <b>B:</b> Basal-no intervention (both blocks) <b>W:</b> Warm-hand placed in non-painful 32°C water (both blocks) <b>C:</b> Cold-hand placed in painful 10°C or non-painful 32°C water (randomised order) <b>S:</b> Suppression-instructed to “try not to cough” or “cough freely” (randomised order) while placing hand in 32°C warm water. Coughs were counted and verified using sound recordings. Urge-to-cough was rated using a Modfied Borg Scale (0–10). <h3>Analysis</h3> The between-block change in cough frequency and urge-to-cough intensity was compared by intervention using paired t-tests after adjusting for an order-effect. Primary outcome was W versus C. Secondary outcomes were B versus W, and W versus S. <h3>Results</h3> 20 non-smoking healthy subjects [10 male; mean (SD) age 55.05 (14.2) yrs] with normal lung function and median (IQR) EC50 of 15.6 (23.50) μM capsaicin completed the study. Compared to B, W had no significant effect on cough (p=0.623) or urge-to-cough (p=0.285). Compared to W, C significantly reduced cough (p=0.048) (Abstract S144a figure 1A) and showed a trend towards a reduction in urge-to-cough (p=0.104) (Abstract S144a figure 1B). Compared to W, S significantly reduced cough (p=0.016) (see Abstract S144a figure 1C) but urge-to-cough did not change (p=0.631) (Abstract S144a figure 1D). <h3>Conclusion</h3> Applying a painful stimulus to the hand inhibits cough in healthy subjects, and may be a useful model for measuring endogenous inhibition of coughing. Further studies to investigate whether chronic cough patients demonstrate impaired inhibition using this experimental paradigm are underway.
Essentials of Geriatric Psychiatryedited by Dan G. Blazer, M.D., Ph.D., David C. Steffens, M.D., M.H.S., and Ewald W. Busse, M.D. Arlington, Va., American Psychiatric Publishing, 2007, 499 pp., $75.00.
Authors: DEBBY TSUANG
Journal: American Journal of Psychiatry (2007)
Fibrin Degradation Products in Pre-eclamptic Toxaemia and Eclampsia
Authors: A. H. Henderson, D. J. Pugsley, D. P. Thomas
Journal: BMJ (1970)

Serum levels of fibrinogen/fibrin degradation products, measured in African women, were significantly higher in pre-eclamptic toxaemia than in normal pregnancy, and were significantly higher with eclampsia than with toxaemia. These findings are in accord with the hypothesis that eclampsia and toxaemia are associated with disseminated intravascular coagulation, which may be responsible for certain clinical manifestations of these conditions.
Viral RNA Patterns and High Viral Load Reliably Define Oropharynx Carcinomas with Active HPV16 Involvement
Authors: Dana Holzinger, Markus Schmitt, Gerhard Dyckhoff, Axel Benner, Michael Pawlita, Franz X. Bosch
Journal: Cancer Research (2012)

Oropharyngeal squamous cell carcinomas (OPSCC) that are associated with human papilloma virus (HPV) infection carry a more favorable prognosis than those that are HPV-negative. However, it remains unclear which biomarker(s) can reliably determine which OPSCC specimens are truly driven by HPV infection. In this study, we analyzed 199 fresh-frozen OPSCC specimens for HPV DNA, viral load, RNA expression patterns typical for cervical carcinomas (CxCaRNA(+)), and the HPV-targeted tumor suppressor protein p16(INK4a) as markers for HPV infection. In this set of specimens, there was a 49% prevalence of DNA for the cancer-associated HPV type 16 (HPV(+)). However, there was only a 16% prevalence of high viral load and only a 20% prevalence of CxCaRNA(+), a marker of HPV16 carcinogenic activity. Among the CxCaRNA(+) tumors, 78% of the specimens exhibited overexpression of p16(INK4a), which also occurred in 14% of the HPV-negative tumors. Using a multivariate survival analysis with HPV negativity as the reference group, CxCaRNA(+) as a single marker conferred the lowest risk of death [HR = 0.28, 95% confidence interval (CI), 0.13-0.61] from oropharyngeal cancer, closely followed by high viral load (HR = 0.32, 95% CI, 0.14-0.73). In contrast, a weaker inverse association was found for OPSCC that were HPV(+) and p16(INK4a) high (HR = 0.55, 95% CI, 0.29-1.08). In summary, our findings argued that viral load or RNA pattern analysis is better suited than p16(INK4a) expression to identify HPV16-driven tumors in OPSCC patient populations.
Race and Colorectal Cancer Disparities: Health-Care Utilization vs Different Cancer Susceptibilities
Authors: A. O. Laiyemo, C. Doubeni, P. F. Pinsky, V. P. Doria-Rose, R. Bresalier, L. E. Lamerato, E. D. Crawford, P. Kvale, M. Fouad, T. Hickey, T. Riley, J. Weissfeld, R. E. Schoen, P. M. Marcus, P. C. Prorok, C. D. Berg
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundIt is unclear whether the disproportionately higher incidence and mortality from colorectal cancer among blacks compared with whites reflect differences in health-care utilization or colorectal cancer susceptibility.
A multigene predictor of outcome in glioblastoma
Authors: H. Colman, L. Zhang, E. P. Sulman, J. M. McDonald, N. L. Shooshtari, A. Rivera, S. Popoff, C. L. Nutt, D. N. Louis, J. G. Cairncross, M. R. Gilbert, H. S. Phillips, M. P. Mehta, A. Chakravarti, C. E. Pelloski, K. Bhat, B. G. Feuerstein, R. B. Jenkins, K. Aldape
Journal: Neuro-Oncology (2009)

Only a subset of patients with newly diagnosed glioblastoma (GBM) exhibit a response to standard therapy. To date, a biomarker panel with predictive power to distinguish treatment sensitive from treatment refractory GBM tumors does not exist. An analysis was performed using GBM microarray data from 4 independent data sets. An examination of the genes consistently associated with patient outcome, revealed a consensus 38-gene survival set. Worse outcome was associated with increased expression of genes associated with mesenchymal differentiation and angiogenesis. Application to formalin fixed-paraffin embedded (FFPE) samples using real-time reverse-transcriptase polymerase chain reaction assays resulted in a 9-gene subset which appeared robust in these samples. This 9-gene set was then validated in an additional independent sample set. Multivariate analysis confirmed that the 9-gene set was an independent predictor of outcome after adjusting for clinical factors and methylation of the methyl-guanine methyltransferase promoter. The 9-gene profile was also positively associated with markers of glioma stem-like cells, including CD133 and nestin. In sum, a multigene predictor of outcome in glioblastoma was identified which appears applicable to routinely processed FFPE samples. The profile has potential clinical application both for optimization of therapy in GBM and for the identification of novel therapies targeting tumors refractory to standard therapy.
Nuclear Factor-κB Activation Correlates with Better Prognosis and Akt Activation in Human Gastric Cancer
Authors: Byung Lan Lee, Hye Seung Lee, Jieun Jung, Sung Jin Cho, Hee-Yong Chung, Woo Ho Kim, Young-Woo Jin, Chong Soon Kim, Seon Young Nam
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Because the biological significance of constitutive nuclear factor-κB (NF-κB) activation in human gastric cancer is unclear, we undertook this study to clarify the regulatory mechanism of NF-κB activation and its clinical significance. Experimental Design: Immunohistochemistry for NF-κB/RelA was done on 290 human gastric carcinoma specimens placed on tissue array slides. The correlations between NF-κB activation and clinicopathologic features, prognosis, Akt activation, tumor suppressor gene expression, or Bcl-2 expression were analyzed. We also did luciferase reporter assay, Western blot analysis, and reverse transcription-PCR using the SNU-216 human gastric cancer cell line transduced with retroviral vectors containing constitutively active Akt or the NF-κB repressor mutant of IκBα. Results: Nuclear expression of RelA was found in 18% of the gastric carcinomas and was higher in early-stage pathologic tumor-node-metastasis (P = 0.019). A negative correlation was observed between NF-κB activation and lymphatic invasion (P = 0.034) and a positive correlation between NF-κB activation and overall survival rate of gastric cancer patients (P = 0.0228). In addition, NF-κB activation was positively correlated with pAkt (P = 0.047), p16 (P = 0.004), adenomatous polyposis coli (P &amp;lt; 0.001), Smad4 (P = 0.002), and kangai 1 (P &amp;lt; 0.001) expression. An in vitro study showed that NF-κB activity in gastric cancer cells is controlled by and controls Akt. Conclusions: NF-κB activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis and Akt activation. These findings suggest that NF-κB activation is a valuable prognostic variable in gastric carcinoma.
Detection of Verocytotoxin Bound to Circulating Polymorphonuclear Leukocytes of Patients with Hemolytic Uremic Syndrome
Authors: D. MAROESKA W. M. TE LOO, VICTOR W. M. VAN HINSBERGH, LAMBERTUS P. W. J. VAN DEN HEUVEL, LEO A. H. MONNENS
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The epidemic form of hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children and is characterized by a prodromal phase of sometimes bloody diarrhea. The role of verocytotoxin (VT)-producing Escherichia coli has been strongly implicated. Although antibodies against VT have been detected in the serum of patients with HUS, VT itself has never been detected in circulating blood. In this study, VT-2 was detected in the systemic circulation in 9 of 10 patients with the epidemic form of HUS. In those cases, VT-2 was bound exclusively to polymorphonuclear leukocytes (PMN). The detection of VT-2 bound to PMN was associated with the presence of diarrhea at the time the blood samples were obtained. The one patient for whom VT was not detected presented with atypical HUS. For 5 of the 10 patients with HUS who were studied, the time course of VT binding was analyzed; binding decreased in four patients. The finding of VT bound to PMN in the systemic circulation of patients with HUS is important for a clearer understanding of the pathogenesis of HUS and suggests new approaches for treatment in the future.
Data-Driven Prediction of Drug Effects and Interactions
Authors: Nicholas P. Tatonetti, Patrick P. Ye, Roxana Daneshjou, Russ B. Altman
Journal: Science Translational Medicine (2012)

Adverse drug events remain a leading cause of morbidity and mortality around the world. Many adverse events are not detected during clinical trials before a drug receives approval for use in the clinic. Fortunately, as part of postmarketing surveillance, regulatory agencies and other institutions maintain large collections of adverse event reports, and these databases present an opportunity to study drug effects from patient population data. However, confounding factors such as concomitant medications, patient demographics, patient medical histories, and reasons for prescribing a drug often are uncharacterized in spontaneous reporting systems, and these omissions can limit the use of quantitative signal detection methods used in the analysis of such data. Here, we present an adaptive data-driven approach for correcting these factors in cases for which the covariates are unknown or unmeasured and combine this approach with existing methods to improve analyses of drug effects using three test data sets. We also present a comprehensive database of drug effects (Offsides) and a database of drug-drug interaction side effects (Twosides). To demonstrate the biological use of these new resources, we used them to identify drug targets, predict drug indications, and discover drug class interactions. We then corroborated 47 (P < 0.0001) of the drug class interactions using an independent analysis of electronic medical records. Our analysis suggests that combined treatment with selective serotonin reuptake inhibitors and thiazides is associated with significantly increased incidence of prolonged QT intervals. We conclude that confounding effects from covariates in observational clinical data can be controlled in data analyses and thus improve the detection and prediction of adverse drug effects and interactions.