tbuckley/cabot-search huggingface dataset:
Decreased bioavailability of digoxin due to hypocholesterolemic interventions.
Authors: D D Brown, R P Juhl, S L Warner
Journal: Circulation (1978)

This study tested the hypothesis that hypocholesterolemic interventions interfere with the bioavailability of orally administered digoxin.Using single dose studies of bioavailability, cumulative six-day urinary digoxin excretion (ex- pressed as a percentage of each individual's control value) was 103% with a normal fiber diet, 82% with a high fiber diet, 83% with 4 g of cholestyramine, 69% with 8 g of cholestyramine, 80% with 8 g cholestyramine administered eight hours before digoxin, 92% with 8 g of cholestyramine administered eight hours after digoxin and 80% after completion of two weeks of treatment with para-aminosalicylic acid.Analysis of the urinary excretion data and associated serum levels revealed significant interference with the absorption of digoxin in all instances except for administration of digoxin either with a normal fiber diet or administration eight hours before cholestyramine.The cholestyramine-digoxin interaction was further studied using steady-state investigation of bioavailability.Serum levels and daily urinary digoxin excretions (expressed as a percentage of each individual's control value) were: 75% and 80% for digoxin administered simultaneously with 4 g of cholestyramine daily; 69% and 86% for digoxin administered simultaneously with the first daily dose of cholestyramine given as 4 g, four times a day, and 96% and 93% with cholestyramine 8 g twice a day, eight hours before and eight hours after digoxin ingestion.Serum levels and urinary excretions for all three cholestyramine interventions were significantly less than control.The results of the single dose and steady-state experiments demonstrate that cholestyramine's reduction of digoxin oral bioavailability is related to the dose of cholestyramine and the proximity of the time of administration of the two drugs.
Distribution of prostaglandins in gastric and duodenal mucosa of healthy subjects and duodenal ulcer patients: effects of aspirin and paracetamol.
Authors: S J Konturek, W Obtulowicz, E Sito, J Oleksy, S Wilkon, A Kiec-Dembinska
Journal: Gut (1981)

The distribution of mucosal PGE2-like activity was determined by bioassay technique in the body and antrum of the stomach and in the duodenum of healthy subjects and duodenal ulcer patients before and after administration of aspirin, paracetamol, or histamine. In healthy subjects, the oxyntic, antral and duodenal mucosa was found to be capable of generating large amounts of PGE2, which were not significantly different from those found in duodenal ulcer patients. No correlation was found between the generation of PGE2 and gastric acid secretory status or serum gastrin level. Aspirin-and to a much lesser extent, paracetamol-caused a dramatic reduction in the ability of the gastric mucosa to biosynthesis PGE2 and this was accompanied by marked side-effects and injury to the gastric mucosa. Administration of histamine caused small but significant reduction in the biosynthesis of PGE2 but it was accompanied by marked mucosal damage. This study indicates that the gastric and duodenal mucosa is capable of generating PGE2-like activity which may be involved in the mechanism that protects the mucosa against the damage caused by aspirin.
Identification of Tumorigenic Cells in <i>KrasG12D</i>-Induced Lung Adenocarcinoma
Authors: Huan-Chieh Cho, Chao-Yang Lai, Li-En Shao, John Yu
Journal: Cancer Research (2011)

Abstract We established an inducible KrasG12D-driven lung adenocarcinoma in CCSP-rtTA/TetO-Cre/LSL-KrasG12D mice that enable pursuits of the cellular and molecular processes involved in Kras-induced tumorigenesis. To investigate the cellular origin of this cancer, we first report a strategy using fluorescence-activated cell sorting fractionation that could highly enrich bronchiolar Clara and alveolar type II cells, respectively. The EpCAM+MHCII− cells (bronchiolar origin) were more enriched with tumorigenic cells in generating secondary tumors than EpCAM+MHCII+ cells (alveolar origin) in primary tumors that had been already initiated with oncogenic Kras activation. In addition, secondary tumors derived from EpCAM+MHCII− cells showed diversity of tumor locations compared with those derived from EpCAM+MHCII+ cells. In the alveolar region, secondary tumors from EpCAM+MHCII− cells expressed not only bronchiolar epithelial marker, panCK, but also differentiation marker, proSPC, consistent with the notion that cancer-initiating cells display not only the abilities for self-renewal but also the features of differentiation to generate heterogeneous tumors with phenotypic diversity. Furthermore, high level of ERK1/2 activation and colony-forming ability as well as lack of Sprouty-2 expression were also observed in EpCAM+MHCII− cells. Therefore, these results suggest that bronchiolar Clara cells are the origin of cells and tumorigenesis for KrasG12D-induced neoplasia in the lungs. Cancer Res; 71(23); 7250–8. ©2011 AACR.
Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events
Authors: Salim Yusuf, Hans-Christoph Diener, Ralph L. Sacco, Daniel Cotton, Stephanie Ôunpuu, William A. Lawton, Yuko Palesch, Reneé H. Martin, Gregory W. Albers, Philip Bath, Natan Bornstein, Bernard P.L. Chan, Sien-Tsong Chen, Luis Cunha, Björn Dahlöf, Jacques De Keyser, Geoffrey A. Donnan, Conrado Estol, Philip Gorelick, Vivian Gu, Karin Hermansson, Lutz Hilbrich, Markku Kaste, Chuanzhen Lu, Thomas Machnig, Prem Pais, Robin Roberts, Veronika Skvortsova, Philip Teal, Danilo Toni, Cam VanderMaelen, Thor Voigt, Michael Weber, Byung-Woo Yoon
Journal: New England Journal of Medicine (2008)

Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke.In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes.The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10).Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)
Multiple Abnormalities in Glucose and Energy Metabolism and Coordinated Changes in Levels of Adiponectin, Cytokines, and Adhesion Molecules in Subjects With Metabolic Syndrome
Authors: Urpu Salmenniemi, Eija Ruotsalainen, Jussi Pihlajamäki, Ilkka Vauhkonen, Sakari Kainulainen, Kari Punnonen, Esko Vanninen, Markku Laakso
Journal: Circulation (2004)

Detailed metabolic defects in glucose and energy metabolism and abnormalities in a variety of cardiovascular risk factors are largely unknown in subjects with the metabolic syndrome.We characterized the metabolic syndrome in 119 nondiabetic offspring of diabetic probands. Cardiovascular risk factors, including cytokines and adhesion molecules, were measured. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp and indirect calorimetry; intra-abdominal fat and subcutaneous fat were assessed by CT; and maximal oxygen consumption was measured with a bicycle ergometer test. By applying factor analysis, we identified a single factor, the metabolic syndrome factor, from the following variables: 2-hour glucose, fasting insulin, body mass index, waist, HDL cholesterol, triglycerides, and mean blood pressure. Subjects with the highest factor score were defined as having the metabolic syndrome. During hyperinsulinemia, the highest factor score was associated with decreased rates of glucose oxidation and nonoxidative glucose disposal, high rates of lipid oxidation, low energy expenditure, and impaired suppression of free fatty acids during hyperinsulinemia. Furthermore, the metabolic syndrome was associated with a high amount of visceral fat, hypoadiponectinemia, a low maximum oxygen uptake, and high levels of C-reactive protein, proinflammatory cytokines, and adhesion molecules.The metabolic syndrome is characterized by an excess of intra-abdominal fat, hypoadiponectinemia, insulin resistance in skeletal muscle and adipose tissue, multiple defects in glucose and energy metabolism, and elevated levels of cytokines and adhesion molecules.
Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma
Authors: Audrey Lamora, Julie Talbot, Gwenola Bougras, Jérôme Amiaud, Marion Leduc, Julie Chesneau, Julien Taurelle, Verena Stresing, Marie Cécile Le Deley, Marie Françoise Heymann, Dominique Heymann, Françoise Redini, Franck Verrecchia
Journal: Clinical Cancer Research (2014)

Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastasis is present at diagnosis. Because transforming growth factor-β (TGFβ) has been shown to promote metastasis in many solid tumors, we investigated the effect of the natural TGFβ/Smad signaling inhibitor Smad7 and the TβRI inhibitor SD-208 on osteosarcoma behavior.By using a mouse model of osteosarcoma induced by paratibial injection of cells, we assessed the impact of Smad7 overexpression or SD-208 on tumor growth, tumor microenvironment, bone remodeling, and metastasis development.First, we demonstrated that TGFβ levels are higher in serum samples from patients with osteosarcoma compared with healthy volunteers and that TGFβ/Smad3 signaling pathway is activated in clinical samples. Second, we showed that Smad7 slows the growth of the primary tumor and increases mice survival. We furthermore demonstrated that Smad7 expression does not affect in vitro osteosarcoma cell proliferation but affects the microarchitectural parameters of bone. In addition, Smad7-osteosarcoma bone tumors expressed lower levels of osteolytic factors such as RANKL, suggesting that Smad7 overexpression affects the "vicious cycle" established between tumor cells and bone cells by its ability to decrease osteoclast activity. Finally, we showed that Smad7 overexpression in osteosarcoma cells and the treatment of mice with SD208 inhibit the development of lung metastasis.Taken together, these results demonstrate that the inhibition of the TGFβ/Smad signaling pathway may be a promising therapeutic strategy against tumor progression of osteosarcoma, specifically against the development of lung metastasis.
Response to Letter Regarding Article “Effect Size Estimates of Lifestyle and Dietary Changes on All-Cause Mortality in Coronary Artery Disease Patients: A Systematic Review”
Authors: Jolein A. Iestra, PhD, Yvonne T. van der Schouw, Diederick E. Grobbee, Wija A. van Staveren, Daan Kromhout, Hendriek C. Boshuizen
Journal: Circulation (2006)

The letter by Colquhoun et al points to the fact that during the publication of our review, 1 simultaneous reports of an international research fraud investigation appeared, raising suspicion of the work of R.B. Singh.In our review, we used 3 publications by this author, which describe the dietary effects on mortality in coronary artery disease patients: 1 study on body weight management 2 and 2 on combined dietary interventions. 3,4he letter of Colquhoun et al reinforces the view already expressed in our review.Studies on body weight management in coronary artery disease patients are insufficient to provide a reliable estimate of the mortality effect.The study by Singh on this issue 2 was already considered a low-quality study and not used in an effect estimate.We also agree with Colquhoun et al that, as a result of the suspected research fraud, the available data on combined dietary interventions are even more "meager" than previously thought.The remaining randomized controlled trial and cohort study alone are insufficient to provide a reliable effect estimate.The analyses of the following lifestyle factors are unaffected by this problem: smoking cessation, physical activity, and moderate alcohol consumption.For dietary interventions, the situation remains that no reliable effect estimate can be provided for any of the 6 investigated dietary goals, individually or in combination.We, therefore, wholeheartedly endorse the view of Colquhoun et al that there is an urgent need for more evidence from randomized controlled trials in this field and that these trials should be monitored to high-quality standards.
Abstract 5301: Integrative protein-marker prognostic model for early-stage endometrioid endometrial carcinoma
Authors: Han Liang
Journal: Cancer Research (2015)

Abstract Endometrioid endometrial carcinoma (EEC) is the major histological type of endometrial cancer, the most prevalent gynecologic malignancy in USA. EEC recurrence or metastasis is associated with an abysmal prognosis. Early-stage EEC is generally curable, but a subset has high risk of recurrence or metastasis. Prognosis estimation for early-stage EEC mainly relies on clinicopathological characteristics, but is unreliable. We aimed to identify patients with high-risk early-stage EEC who are most likely to benefit from more extensive surgery and adjuvant therapy by building a prognostic model that integrates clinical variables and protein markers. We employed two large, independent EEC datasets as training and validation cohorts, and generated the levels of 186 proteins and phosphoproteins using reverse-phase protein arrays. Using the training samples, we developed a predictive model containing two clinical factors and 18 protein markers and optimized the risk group classification. Kaplan-Meier survival analyses in the validation cohort confirmed an improved prognostic power. Compared with clinical variables (stage, grade, and patient age), only the risk groups defined by the integrative model were consistently significant in both univariate and multivariate analyses across both cohorts. Our prognostic model is potentially of high clinical value for stratifying patients with early-stage EEC and optimizing their treatment strategies. Note: This abstract was not presented at the meeting. Citation Format: Han Liang, UT MD Anderson RPPA/TCGA working group. Integrative protein-marker prognostic model for early-stage endometrioid endometrial carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5301. doi:10.1158/1538-7445.AM2015-5301
Chylomicron remnant clearance from the plasma is normal in familial hypercholesterolemic homozygotes with defined receptor defects.
Authors: D C Rubinsztein, J C Cohen, G M Berger, D R van der Westhuyzen, G A Coetzee, W Gevers
Journal: Journal of Clinical Investigation (1990)

The retinyl palmitate fat tolerance test was used to measure chylomicron remnant clearance in 10 normal subjects (apolipoprotein E [apo E] isotypes 3 or 4 only), 6 normolipidemic apo E2/2 homozygotes and 5 familial hypercholesterolemic homozygotes. Skin fibroblasts with fully upregulated LDL receptors from the latter subjects degraded rabbit 125I-beta VLDL in vitro at rates ranging from less than 10-48% of normal. Experiments in vivo revealed no significant differences between the normal and homozygous familial hypercholesterolemic (FHH) subjects in chylomicron remnant clearance assessed on the basis of "areas under the curves" for retinyl palmitate levels present in post-prandial serum, chylomicron remnants (Sf. less than 1,000), or chylomicrons (Sf. greater than 1,000). Remnant clearance was greatly decreased at all times in the apo E2/2 homozygotes, indicative of an important degree of flux control exerted by a receptor-mediated step involving apo E as ligand. The absence of any excess remnant accumulation in FHH subjects with varying "impairment" of LDL receptor-mediated degradation of apo E-containing lipoproteins, permits the conclusion that chylomicron remnants are initially cleared from the plasma by apo E-recognizing receptors which are genetically distinct from LDL receptors.
PYROGENIC THERAPY: WITH REMARKS ON COLLOIDAL METALS
Authors: A. G. Auld
Journal: BMJ (1918)

THE term "pyrogen" was first used by Burdon-Sanderson in 1875 to signify a fever-producing substance wlxichl lhe had prepared.Such substances, both protein and non- protein, have since tllen received ample recognition, tlhough not from the tlherapeutic side.The subject.lhowever, is one of high practical importance, and in many cases brilliant results may be obtained.Early in 1915 I began tlhe clinical investigation of various colloidal metals parenterally introduced.They were received from different sources and included those produced by both clhemical and electrical methods.Tlle first attempts were limited to subcutaneous injections, gold, platinunm, silver, and copper being chiefly used.Tlje results were meagre and uncertain.Sometiwles sliglht elevations of temperature followed tthe injections.'rle next attempts were instigated by a consideration of the catalytic action of certain metals in relation to the oxidative processes in thje peroxide-peroxidase system.It seemned conceivable that under local conditions of defective oxidation tlje introduction, if possible, of a new peroxidase mialgt be beneficial, especially if there was some bar to the effective action of tlle natural peroxidase, wwhichl may be regarded as the iron iDn the -haemoglobin anid in the tissues.To tlhis end I employed colloidal manganous lhydroxide intravenously.Tile results were
Neurobiological Measures of Schizotypal Personality Disorder: Defining an Inhibitory Endophenotype?
Authors: Kristin S. Cadenhead, Gregory A. Light, Mark A. Geyer, Jennifer E. McDowell, David L. Braff
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Subjects with schizotypal personality disorder demonstrate deficits in inhibition when assessed on prepulse inhibition, P50 suppression, and antisaccade paradigms. This study determined if distinct subgroups of subjects with schizotypal personality disorder could be identified on the basis of performance on these measures and whether endophenotypes could be defined for future genetic study by using measures of inhibitory function. METHOD: Prepulse inhibition, P50 suppression, and antisaccade paradigms were assessed in 21 subjects with schizotypal personality disorder. RESULTS: Seven subjects with schizotypal personality disorder had deficits on each paradigm; seven had no deficits on any paradigm. P50 and antisaccade deficits were present in five of the same subjects and significantly correlated. CONCLUSIONS: These results suggest that P50 and antisaccade performance reflects a common endophenotype and that prepulse inhibition identifies a separate endophenotype reflecting different neurobiological substrate(s) in subjects with schizotypal personality disorder. This pattern may generalize to schizophrenia spectrum disorder patients.
Model Averaging and Bayes Factor Calculation of Relaxed Molecular Clocks in Bayesian Phylogenetics
Authors: W. L. S. Li, A. J. Drummond
Journal: Molecular Biology and Evolution (2011)

We describe a procedure for model averaging of relaxed molecular clock models in Bayesian phylogenetics. Our approach allows us to model the distribution of rates of substitution across branches, averaged over a set of models, rather than conditioned on a single model. We implement this procedure and test it on simulated data to show that our method can accurately recover the true underlying distribution of rates. We applied the method to a set of alignments taken from a data set of 12 mammalian species and uncovered evidence that lognormally distributed rates better describe this data set than do exponentially distributed rates. Additionally, our implementation of model averaging permits accurate calculation of the Bayes factor(s) between two or more relaxed molecular clock models. Finally, we introduce a new computational approach for sampling rates of substitution across branches that improves the convergence of our Markov chain Monte Carlo algorithms in this context. Our methods are implemented under the BEAST 1.6 software package, available at http://beast-mcmc.googlecode.com.
Targeting the c-Met Pathway Potentiates Glioblastoma Responses to γ-Radiation
Authors: Bachchu Lal, Shuli Xia, Roger Abounader, John Laterra
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Resistance to current cytotoxic therapies limits the treatment of most solid malignancies. This results, in part, from the overactivation of receptor tyrosine kinases and their downstream pathways in tumor cells and their associated vasculature. In this report, we ask if targeting the multifunctional mitogenic, cytoprotective, and angiogenic scatter factor/hepatocyte growth factor (SF/HGF)/c-Met pathway potentiates antitumor responses to γ-radiation. Experimental Design: Endogenous expression of SF/HGF and c-Met was targeted in U87 MG human malignant glioma cells and xenografts using chimeric U1/ribozymes. The effects of U1/ribozymes ± γ-radiation on glioma cell proliferation, apoptosis, xenograft growth, and animal survival were examined. Results: U1/ribozymes knocked down SF/HGF and c-Met mRNA and protein levels, sensitized cells to γ-radiation (P &amp;lt; 0.005), and enhanced radiation-induced caspase-dependent cytotoxicity in vitro (P &amp;lt; 0.005). Intravenous U1/ribozyme therapy as liposome/DNA complexes or radiation alone modestly and transiently inhibited the growth of s.c. U87 xenografts. Combining the therapies caused tumor regression and a 40% tumor cure rate. In animals bearing intracranial xenografts, long-term survival was 0% in response to radiation, 20% in response to intratumoral adenoviral-based U1/ribozyme delivery, and 80% (P &amp;lt; 0.0005) in response to combining U1/ribozymes with radiation. This apparent synergistic antitumor response was associated with a ∼70% decrease in cell proliferation (P &amp;lt; 0.001) and a ∼14- to 40-fold increase in apoptosis (P &amp;lt; 0.0001) within xenografts. Conclusions: Targeting the SF/HGF/c-Met pathway markedly potentiates the antiglioma response to γ-radiation. Clinical trials using novel SF/HGF/c-Met pathway inhibitors in glioma and other malignancies associated with c-Met activation should ultimate include concurrent radiation and potentially other cytotoxic therapeutics.