tbuckley/cabot-search huggingface dataset:
An Abnormal Mitochondrial–Hypoxia Inducible Factor-1α–Kv Channel Pathway Disrupts Oxygen Sensing and Triggers Pulmonary Arterial Hypertension in Fawn Hooded Rats
Authors: Sébastien Bonnet, Evangelos D. Michelakis, Christopher J. Porter, Miguel A. Andrade-Navarro, Bernard Thébaud, Sandra Bonnet, Alois Haromy, Gwyneth Harry, Rohit Moudgil, M. Sean McMurtry, E. Kenneth Weir, Stephen L. Archer
Journal: Circulation (2006)

Background— The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain. Methods and Results— Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1. PAH began after 20 weeks of age, causing death by &amp;60 weeks. FHR/BN1 did not develop PAH. FHR pulmonary arterial smooth muscle cells (PASMCs) had a rarified reticulum of hyperpolarized mitochondria with reduced expression of electron transport chain components and superoxide dismutase-2. These mitochondrial abnormalities preceded PAH and persisted in culture. Depressed mitochondrial reactive oxygen species (ROS) production caused normoxic activation of hypoxia inducible factor (HIF-1α), which then inhibited expression of oxygen-sensitive, voltage-gated K + channels (eg, Kv1.5). Disruption of this mitochondrial-HIF-Kv pathway impaired oxygen sensing (reducing hypoxic pulmonary vasoconstriction, causing polycythemia), analogous to the pathophysiology of chronically hypoxic Sprague-Dawley rats. Restoring ROS (exogenous H 2 O 2 ) or blocking HIF-1α activation (dominant-negative HIF-1α) restored Kv1.5 expression/function. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, corrected the mitochondrial-HIF-Kv pathway in FHR-PAH and human PAH PASMCs. Oral dichloroacetate regressed FHR-PAH and polycythemia, increasing survival. Chromosome 1 genes that were dysregulated in FHRs and relevant to the mitochondria-HIF-Kv pathway included HIF-3α (an HIF-1α repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1α activation; and reduced expression/activity of HIF-3α, cytochrome c oxidase, and superoxide dismutase-2. Conclusions— FHRs have a chromosome 1 abnormality that disrupts a mitochondria-ROS-HIF-Kv pathway, leading to PAH. Similar abnormalities occur in idiopathic human PAH. This study reveals an intersection between oxygen-sensing mechanisms and PAH. The mitochondria-ROS-HIF-Kv pathway offers new targets for PAH therapy.
Haemorrhagic necrosis of small intestine and acute pancreatitis following open-heart surgery
Authors: E. H. Horton, S. K. Murthy, R. M. E. Seal
Journal: Thorax (1968)

Five cases of haemorrhagic necrosis of the small intestine occurring after valve replacement under cardiopulmonary bypass are described. In one case, in addition to the above, there was an unusual complication, namely acute pancreatitis. The possible causes are discussed. The importance of hypotension before, during, or after bypass, or in the post-operative phase, is stressed.
Microsatellite Null Alleles and Estimation of Population Differentiation
Authors: Marie-Pierre Chapuis, Arnaud Estoup
Journal: Molecular Biology and Evolution (2006)

Microsatellite null alleles are commonly encountered in population genetics studies, yet little is known about their impact on the estimation of population differentiation. Computer simulations based on the coalescent were used to investigate the evolutionary dynamics of null alleles, their impact on FST and genetic distances, and the efficiency of estimators of null allele frequency. Further, we explored how the existing method for correcting genotype data for null alleles performed in estimating FST and genetic distances, and we compared this method with a new method proposed here (for FST only). Null alleles were likely to be encountered in populations with a large effective size, with an unusually high mutation rate in the flanking regions, and that have diverged from the population from which the cloned allele state was drawn and the primers designed. When populations were significantly differentiated, FST and genetic distances were overestimated in the presence of null alleles. Frequency of null alleles was estimated precisely with the algorithm presented in Dempster et al. (1977). The conventional method for correcting genotype data for null alleles did not provide an accurate estimate of FST and genetic distances. However, the use of the genetic distance of Cavalli-Sforza and Edwards (1967) corrected by the conventional method gave better estimates than those obtained without correction. FST estimation from corrected genotype frequencies performed well when restricted to visible allele sizes. Both the proposed method and the traditional correction method have been implemented in a program that is available free of charge at http://www.montpellier.inra.fr/URLB/. We used 2 published microsatellite data sets based on original and redesigned pairs of primers to empirically confirm our simulation results.
The role of apoptosis in therapy and prophylaxis of epithelial tumours by nonsteroidal anti-inflammatory drugs (NSAIDs)
Authors: L.F. Fecker, E. Stockfleth, I. Nindl, C. Ulrich, T. Forschner, J. Eberle
Journal: British Journal of Dermatology (2007)

Summary In addition to having anti-inflammatory activities, nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit neoplastic cell proliferation by inducing apoptosis. Diclofenac is the anti-neoplastic compound in diclofenac 3% gel (SolarazeTM) used for topical treatment of actinic keratosis (AK). Main target of NSAIDs seems to be the inhibition of cyclo-oxygenase-2 (COX-2), which is overexpressed in several epithelial tumours and catalyses the synthesis of prostaglandins. The precise mechanism of action of diclofenac in cutaneous cells is still unclear, but induction of apoptosis is a key effect of anti-neoplastic drugs, including NSAIDs. In this paper we give an overview of the anti-tumoural activities of NSAIDs with emphasis on induction of apoptosis. Cyclo-oxygenase-2-mediated synthesis of prostaglandin E2 (PGE2) leads to activation of mitogen-activated protein kinase (MAPK), as well as phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Induction of the anti-apoptotic Bcl-2 and Mcl-1, as well as activation of the caspase-8 inhibitor cFLIP have been reported. In addition, altered lipid concentrations in the cytoplasmic membrane may modulate death receptor activities. Downregulation of both the intrinsic mitochondrial and the extrinsic pathways have been reported. Our data demonstrate induced apoptosis and activation of the caspase cascade in three of four cutaneous squamous cell carcinoma (SCC) cell lines, after treatment with diclofenac plus hyaluronic acid and diclofenac alone; one cell line remained nonresponsive. The effects were less pronounced in normal keratinocytes and cytotoxic effects were not seen. Detailed analysis of apoptosis pathways employed by diclofenac in these cells may help to improve therapeutic strategies and to overcome possible mechanisms that are involved in nonresponsiveness.
Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits
Authors: Hassan S. Dashti, Jack L. Follis, Caren E. Smith, Toshiko Tanaka, Marta Garaulet, Daniel J. Gottlieb, Adela Hruby, Paul F. Jacques, Jessica C. Kiefte-de Jong, Stefania Lamon-Fava, Frank A.J.L. Scheer, Traci M. Bartz, Leena Kovanen, Mary K. Wojczynski, Alexis C. Frazier-Wood, Tarunveer S. Ahluwalia, Mia-Maria Perälä, Anna Jonsson, Taulant Muka, Ioanna P. Kalafati, Vera Mikkilä, José M. Ordovás
Journal: Diabetes Care (2015)

OBJECTIVE Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations. RESEARCH DESIGN AND METHODS We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. RESULTS We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (&amp;lt;7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P &amp;lt; 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m2 higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to &amp;lt;9 h). CONCLUSIONS Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.
<i>Salmonella typhimurium</i> Lacking Ribose Chemoreceptors Localize in Tumor Quiescence and Induce Apoptosis
Authors: Rachel W. Kasinskas, Neil S. Forbes
Journal: Cancer Research (2007)

Abstract The effectiveness of most chemotherapeutics is limited by their inability to penetrate deep into tumor tissue and their ineffectiveness against quiescent cells. Motile Salmonella typhimurium, which are specifically attracted to compounds produced by quiescent cancer cells, could overcome this therapeutic barrier. We hypothesized that individual chemoreceptors target S. typhimurium to specific tumor microenvironments. To test this hypothesis, we used time-lapse fluorescent microscopy and tumor cylindroids to quantify the accumulation of chemotaxis machinery knockouts, including strains lacking individual cell surface chemoreceptors, chemotaxis signal transduction pathway enzymes, and the flagella and motor assemblies. To measure the extent of apoptosis induced by individual bacterial strains, caspase-3 activity was measured as a function of time. Our results showed how chemoreceptors directed bacterial chemotaxis within cylindroids: the aspartate receptor initiated chemotaxis toward cylindroids, the serine receptor initiated penetration, and the ribose/galactose receptor directed S. typhimurium toward necrosis. In addition, strains lacking proper flagella constructs, signal transduction proteins, or active motor function did not chemotax toward tumor cylindroids, indicating that directed chemotaxis is necessary to promote accumulation in tumors. By deleting the ribose/galactose receptor, bacterial accumulation localized to tumor quiescence and had a greater individual effect on inducing apoptosis than wild-type S. typhimurium. This new understanding of the mechanisms of Salmonella migration in tumors will allow for the development of bacterial therapies with improved targeting to therapeutically inaccessible regions of tumors. [Cancer Res 2007;67(7):3201–9]
Chronic Fatigue in Type 1 Diabetes: Highly Prevalent but Not Explained by Hyperglycemia or Glucose Variability
Authors: Martine M. Goedendorp, Cees J. Tack, Elles Steggink, Lotte Bloot, Ellen Bazelmans, Hans Knoop
Journal: Diabetes Care (2013)

OBJECTIVE Fatigue is a classical symptom of hyperglycemia, but the relationship between chronic fatigue and diabetes has not been systematically studied. We investigated prevalence, impact, and potential determinants of chronic fatigue in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS Out of 324 randomly selected T1DM outpatients, 214 participated in this cross-sectional observational study. Participants were compared with age- and sex-matched population-based controls. Chronic fatigue, functional impairments, current health status, comorbidity, diabetes-related factors, and fatigue-related cognitions and behaviors were assessed with questionnaires, and HbA1c values and comorbidity were assessed with medical records. Sixty-six patients underwent continuous glucose monitoring combined with an electronic fatigue diary for 5 days. Acute fatigue and four glucose parameters were determined: mean, variability, and relative time spent in hypoglycemia and hyperglycemia. RESULTS T1DM patients were significantly more often chronically fatigued (40%; 95% CI 34-47%) compared with matched controls (7%; 95% CI 3-10%; P < 0.001). Chronically fatigued patients had significantly more functional impairments. Fatigue was the most troublesome symptom. Age, depression, pain, sleeping problems, low self-efficacy concerning fatigue, and physical inactivity were significantly associated with chronic fatigue. Chronically fatigued patients spent slightly less time in hypoglycemia (proportion 0.07 ± 0.06 vs. 0.12 ± 0.10; P = 0.025). Glucose parameters were not related to acute fatigue. CONCLUSIONS Chronic fatigue is highly prevalent and clinically relevant in T1DM. Its significant relationship with cognitive behavioral variables and weak association with blood glucose levels suggests that behavioral interventions could be helpful in managing chronic fatigue in T1DM.
Glabellar red dots in frontal fibrosing alopecia: a further clinical sign of vellus follicle involvement
Authors: R. Pirmez, A. Donati, N.S. Valente, C.T. Sodré, A. Tosti
Journal: British Journal of Dermatology (2013)

Journal Article Glabellar red dots in frontal fibrosing alopecia: a further clinical sign of vellus follicle involvement Get access R. Pirmez, R. Pirmez Sector of Dermatology Federal University of Rio de Janeiro Rio de Janeiro Brazil Search for other works by this author on: Oxford Academic Google Scholar A. Donati, A. Donati Department of Dermatology University of São Paulo São Paulo Brazil Search for other works by this author on: Oxford Academic Google Scholar N.S. Valente, N.S. Valente Department of Dermatology University of São Paulo São Paulo Brazil Search for other works by this author on: Oxford Academic Google Scholar C.T. Sodré, C.T. Sodré Sector of Dermatology Federal University of Rio de Janeiro Rio de Janeiro Brazil Search for other works by this author on: Oxford Academic Google Scholar A. Tosti A. Tosti Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami FL U.S.A Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 170, Issue 3, 1 March 2014, Pages 745–746, https://doi.org/10.1111/bjd.12683 Published: 01 March 2014
Phase I Study of the Angiogenesis Inhibitor BIBF 1120 in Patients with Advanced Solid Tumors
Authors: Klaus Mross, Martin Stefanic, Daniela Gmehling, Annette Frost, Franziska Baas, Clemens Unger, Ralph Strecker, Jürgen Henning, Birgit Gaschler-Markefski, Peter Stopfer, Lothar de Rossi, Rolf Kaiser
Journal: Clinical Cancer Research (2009)

BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived growth factors, and fibroblast growth factors. This phase I, accelerated titration study assessed the maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamic effects of BIBF 1120.Sixty-one patients with advanced cancers received BIBF 1120 in successive cohorts. Twenty-five received 50 to 450 mg once daily and 36 received 150 to 300 mg twice daily in 4-week treatment courses interspersed by 1 week of washout. Dynamic contrast-enhanced magnetic resonance imaging assessed antiangiogenic effect in 42 patients.Most frequent BIBF 1120-related adverse events were mostly mild to moderate (Common Toxicity Criteria grade 1-2) nausea (68.9%), vomiting (45.9%), and diarrhea (44.3%). The majority of dose-limiting adverse events of Common Toxicity Criteria grade 3 or 4 were reversible liver enzyme elevations. The maximum tolerated dose was 250 mg of BIBF 1120 for once and twice daily dosing. BIBF 1120 was absorbed moderately fast (t(max) = 1-3 hours at steady state), with no deviation from dose linearity and no decrease of exposure over time. The gMean terminal half-life was from 13 to 19 hours. One complete and two partial responses occurred in patients with renal cell cancer (n = 2) and colorectal cancer (n = 1). Dynamic contrast-enhanced magnetic resonance imaging showed a significant reduction in tumor blood flow in 55% of evaluable patients.BIBF 1120 dosed continuously displayed a favorable safety and pharmacokinetics profile, and first efficacy signals were observed. Twice daily dosing permitted increased drug exposure without additional toxicity. Two hundred milligrams BIBF 1120 twice daily is the recommended dose for phase II monotherapy studies.
Sleep-disordered breathing and stroke: is there a rationale for treatment?
Authors: O. Parra
Journal: European Respiratory Journal (2001)

The association between sleep-disordered breathing (SDB) and stroke cannot be attributed to chance. Indeed, if a link between SDB and cardiovascular disease were demonstrated 1–5, the absence of a relationship with stroke would be surprising. Although we still lack definitive and consistent data from large epidemiological surveys, multiple studies using a variety of methodologies have shown a high prevalence of SDB following stroke, especially obstructive sleep apnoea (OSA) 6–13. This prevalence is greater than expected, bearing in mind the available epidemiological data 14, 15. Nevertheless, these data must be interpreted with caution since stroke patients have a high mean age and the number of obstructive events increases with age, without clinical relevance 16, 17. Moreover, case-control studies have also demonstrated a significantly higher prevalence of SDB in patients with stroke than in controls 8, 9, 11.

SDB may be regarded as a consequence (mainly central events) 18, 19 or as a cause (mainly obstructive events) 13 of stroke. Given the availability of an effective and safe treatment for OSA 20–24, nasal continuous positive airway pressure (nCPAP) could modify the incidence of stroke (if SDB is regarded as a risk factor) or the outcome of these patients (if SDB is considered as a prognostic factor). In this issue, Wessendorf et al. 25 and Sandberg et al. 26 have endeavoured to treat stroke and SDB patients with nCPAP. The resulting data are the first to show a beneficial effect of this treatment in these patients, thereby suggesting the feasibility of introducing nCPAP in such patients, in whom cognitive impairment and physical disability may constitute important drawbacks, and in whom excessive daytime sleepiness does not always justify treatment 27. Despite concerns about some of …
Coronary Artery Disease Is Common in Nonuremic, Asymptomatic Type 1 Diabetic Islet Transplant Candidates
Authors: Peter A. Senior, Robert C. Welsh, Charlotte G. McDonald, Breay W. Paty, A.M. James Shapiro, Edmond A. Ryan
Journal: Diabetes Care (2005)

OBJECTIVE—Coronary artery disease (CAD) is the most common cause of death in patients with type 1 diabetes. Asymptomatic CAD is common in uremic diabetic patients, but its prevalence in nonuremic type 1 diabetic patients is unknown. The prevalence of CAD was determined by coronary angiography and the performance of noninvasive cardiac investigation evaluated in type 1 diabetic islet transplant (ITX) candidates with preserved renal function. RESEARCH DESIGN AND METHODS—A total of 60 consecutive type 1 diabetic ITX candidates (average age 46 years [mean 24–64], 23 men, and 47% ever smokers) underwent coronary angiography, electrocardiographic stress testing (EST), and myocardial perfusion imaging (MPI) in a prospective cohort study. CAD was indicated on angiography by the presence of stenoses &amp;gt;50%. Models to predict CAD were examined by logistic regression. RESULTS—Most subjects (53 of 60) had no history or symptoms of CAD; 23 (43%) of these asymptomatic subjects had stenoses &amp;gt;50%. CAD was associated with age, duration of diabetes, hypertension, and smoking. Although specific, EST and MPI were not sensitive as predictors of CAD on angiography (specificity 0.97 and 0.93, sensitivity 0.17 and 0.04, respectively) but helped identify two of three subjects requiring revascularization. EST and MPI did not enhance logistic regression models. A clinical algorithm to identify low-risk subjects who may not require angiography was highly sensitive but was applicable only to a minority (n = 8, sensitivity 1.0, specificity 0.27, negative predictive value 1.0). CONCLUSIONS—Nonuremic type 1 diabetic patients with hypoglycemic unawareness and/or metabolic lability referred for ITX are at high risk for asymptomatic CAD despite negative noninvasive investigations. Aggressive management of cardiovascular risk factors and further investigation into optimal cardiac risk stratification in type 1 diabetes are warranted.
Microbiota Regulates Eosinophils In The Small Intestine
Authors: Rodrigo Jimenez-Saiz, Tina Walker-Fattouh, Melissa E. Gordon, Waleed S. Ahmed, Breanne Dale, Talveer S. Mandur, Joshua Kong, Derek K. Chu, Roland Kolbeck, Alison A. Humbles, Elena F. Verdu, Manel Jordana
Journal: Journal of Allergy and Clinical Immunology (2014)
Computer-Assisted Detection and Screening Mammography: Where's the Beef?
Authors: D. A. Berry
Journal: JNCI Journal of the National Cancer Institute (2011)

Screening for cancer presents inferential issues that are among the most difficult in science. Whether screening should be recommended and for whom is seldom clear, despite extensive experience in randomized trials, in observational studies, and in ordinary practice. “Finding early” is the easy part. Cancers found early by screening and by improvements in screening technology may or may not be worth the finding. In general, improvements in screening mammography lead to finding more cancers and/or decreasing the number of falsepositive results by improving sensitivity or specificity, respectively. A more important consideration is whether the finding improves the patient’s lot, that is, is identifying a particular cancer and treating it earlier doing the woman a favor? Perhaps, the cancer was not lethal, and without the new technology, it would not have been found for many years. A woman having such a cancer could have spent these years “cancer free” with no decrement in survival. Indeed, the cancer might never have been found otherwise, resulting in overdiagnosis. We know that the incremental cancers found