tbuckley/cabot-search huggingface dataset:
Molecular Therapy for Obesity and Diabetes Based on a Long-Term Increase in Hepatic Fatty-Acid Oxidation §Δ
Authors: Josep M. Orellana-Gavaldà, Laura Herrero, Maria Ida Malandrino, Astrid Pañeda, Maria Sol Rodríguez-Peña, Harald Petry, Guillermina Asins, Sander Van Deventer, Fausto G. Hegardt, Dolors Serra
Journal: Hepatology (2010)

Abstract Obesity-induced insulin resistance is associated with both ectopic lipid deposition and chronic, low-grade adipose tissue inflammation. Despite their excess fat, obese individuals show lower fatty-acid oxidation (FAO) rates. This has raised the question of whether burning off the excess fat could improve the obese metabolic phenotype. Here we used human-safe nonimmunoreactive adeno-associated viruses (AAV) to mediate long-term hepatic gene transfer of carnitine palmitoyltransferase 1A (CPT1A), the key enzyme in fatty-acid β-oxidation, or its permanently active mutant form CPT1AM, to high-fat diet-treated and genetically obese mice. High-fat diet CPT1A- and, to a greater extent, CPT1AM-expressing mice showed an enhanced hepatic FAO which resulted in increased production of CO2, adenosine triphosphate, and ketone bodies. Notably, the increase in hepatic FAO not only reduced liver triacylglyceride content, inflammation, and reactive oxygen species levels but also systemically affected a decrease in epididymal adipose tissue weight and inflammation and improved insulin signaling in liver, adipose tissue, and muscle. Obesity-induced weight gain, increase in fasting blood glucose and insulin levels, and augmented expression of gluconeogenic genes were restored to normal only 3 months after AAV treatment. Thus, CPT1A- and, to a greater extent, CPT1AM-expressing mice were protected against obesity-induced weight gain, hepatic steatosis, diabetes, and obesity-induced insulin resistance. In addition, genetically obese db/db mice that expressed CPT1AM showed reduced glucose and insulin levels and liver steatosis. Conclusion : A chronic increase in liver FAO improves the obese metabolic phenotype, which indicates that AAV-mediated CPT1A expression could be a potential molecular therapy for obesity and diabetes. (Hepatology 2011)
Comparison of two commercial interferon- assays for diagnosing Mycobacterium tuberculosis infection
Authors: J. Y. Lee, H. J. Choi, I-N. Park, S-B. Hong, Y-M. Oh, C-M. Lim, S. D. Lee, Y. Koh, W. S. Kim, D. S. Kim, W. D. Kim, T. S. Shim
Journal: European Respiratory Journal (2006)

The clinical usefulness of ex vivo interferon-γ assays may largely depend on the assay format and epidemiological status of tuberculosis (TB) in the region studied. From July 2004 to June 2005 a prospective comparison study was undertaken at a tertiary referral hospital in South Korea. The results of tuberculin skin tests (TST) and the commercially available QuantiFERON-TB Gold (QFT-G) and T SPOT-TB (SPOT) assays were compared in an intermediate TB-burden country. Of the 224 participants studied, results from all three tests (TST, QFT-G, and SPOT) were available in 218; 87 with active TB and 131 at a low risk for TB. Using 10 mm as a cut-off for TST, SPOT sensitivity (96.6%) was significantly higher than that seen for TST (66.7%) and QFT-G (70.1%). QFT-G showed superior specificity over TST (91.6 versus 78.6%). Although the specificity of QFT-G was higher than that of SPOT (91.6 versus 84.7%), the difference was not statistically significant. Whilst some differences were found in the performance of the two commercialised interferon-γ assays, they seemed to be superior in their detection of Mycobacterium tuberculosis infection compared with tuberculin skin tests. The most appropriate choice of interferon-γ assay to use may depend on the clinical setting.
Hypermethylation of <i>let-7a-3</i> in Epithelial Ovarian Cancer Is Associated with Low Insulin-like Growth Factor-II Expression and Favorable Prognosis
Authors: Lingeng Lu, Dionyssios Katsaros, Irene A. Rigault de la Longrais, Olga Sochirca, Herbert Yu
Journal: Cancer Research (2007)

MicroRNAs (miRNA) are endogenous noncoding small RNAs that regulate the activity of mRNAs. Many miRNA genes, including let-7a-3, are located in CpG islands, suggesting possible epigenetic regulation of their expression. Promoter CpG island methylation of tumor suppressor genes is involved in cancer development and progression. Using real-time methylation-specific PCR and real-time reverse transcription-PCR, we analyzed DNA methylation in the let-7a-3 gene and miRNA expression of let-7a in 214 patients with epithelial ovarian cancer to assess the effect of let-7a-3 methylation on the expressions of let-7a as well as a possible target of let-7 regulation, insulin-like growth factor-II (IGF-II). The association of let-7a-3 methylation with patient survival outcomes was also evaluated. let-7a-3 methylation was detected in epithelial ovarian cancer, and the expression of let-7a was slightly affected by the methylation, but the effect was not substantial. The methylation of let-7a-3, however, was inversely correlated with IGF-II expression and positively with insulin-like growth factor binding protein-3 (IGFBP-3) expression. Patients with methylated let-7a-3 seemed to have reduced risk for death compared with those without, and the association was independent of patient age at surgery, tumor grade, disease stage, and IGF-II or IGFBP-3 expression. No association was found for let-7a-3 methylation and disease progression. These results suggest that the let-7a-3 gene is methylated and the methylation may affect IGF-II expression and the survival of ovarian cancer patients. Further investigation of the role of miRNAs and their regulation in cancer is warranted.
Genetic control of macrophage functions. I. Polygenic regulation of phagocytosis stimulation produced by Glyceryl Trioleate.
Authors: D Mouton, Y Bouthillier, N Feingold, J Feingold, C Decreusefond, C Stiffel, G Biozzi
Journal: The Journal of Experimental Medicine (1975)

The phagocytic index K, established from the rate of blood clearance of colloidal carbon, measures the phagocytic activity of RE macrophages in contact with the circulating blood. The intravenous injection of glyceryl trioleate (triolein) produces a marked stimulation of the phagocytic activity of RE macrophages. This response is higher in the female than in the male mice. The phenotypic character "responsiveness of macrophage to triolein" presents large individual variants in population of random bred albinos mice. This character is submitted to polygenic regulation. Starting from a foundation population of 25 males and 25 females random bred albinos, mice, two lines were separated by selective breeding for the character "responsiveness to triolein": a "high" responder line, KTH, and a "low" responder line, KTL. After 26 consecutive generations of selective breeding, KTH mice present a very high response to triolein while KTL mice are almost irresponsive. The heritability of this character (h2) calculated from the interline divergence is of 12% plus or minus 1. This value of h2 indicates that the character investigated is determined by the cumulative effect of a group of about 27 independently segregating loci. The distribution of the character in (KTH plus KTL)F1 and their backcrosses with parental lines suggests that low responsiveness is dominant over high responsiveness. The genetic regulation of responsiveness to triolein is independent from the dose administered. These results are discussed in relation to the importance of genetic factors controlling macrophage functions involved in lipid metabolism and in the specific mechanisms of immunity.
Red Blood Cells: A Neglected Compartment in Pharmacokinetics and Pharmacodynamics
Authors: Peter H. Hinderling
Journal: Pharmacological Reviews (1997)

The significance of studying the kinetics of drug partitioning into red blood cells (RBCsb) in animals and humans is not fully appreciated, although the importance of routine determination of rate and extent of partitioning of investigational drugs has been stressed ([Lee et al., 1981b][1]; [
Perception of Offspring Risk for Type 2 Diabetes Among Patients With Type 2 Diabetes and Their Adult Offspring
Authors: Masakazu Nishigaki, Koji Kobayashi, Takako Hitomi, Taeko Yokomura, Mitsunao Yokoyama, Naoto Seki, Keiko Kazuma
Journal: Diabetes Care (2007)

Relatives of type 2 diabetic patients are at higher risk for type 2 diabetes, as they are likely to share genetic predisposition and have similar lifestyle habits (1). To actively involve high-risk individuals in prevention, recognition of disease risk is crucial (2). Some studies have suggested that Japanese are genetically predisposed to diabetes (3,4), so recognition of risk by high-risk Japanese individuals is particularly important. In addition, patients with diseases involving genetic predisposition need to advise and warn their offspring about risks associated with the disease (5,6). Diabetic parents must therefore recognize the high-risk status of their offspring, but no studies have examined risk perception of parents and their offspring in Japan.

This self-administered questionnaire survey was conducted to clarify perceptions of Japanese type 2 diabetic patients regarding risk of diabetes in their offspring, as well as perceptions of adult offspring about their own risk for diabetes.

Subjects in the present study comprised 164 pairs of type 2 diabetic patients (aged <75 years) receiving treatment at a general hospital's diabetes clinic located in the suburbs of Tokyo, Japan, and their offspring (aged ≥20 but <50 years with no diabetes or glucose intolerance). After obtaining written informed consent to participate in the study, the patient and offspring completed an anonymous questionnaire separately, with a unique ID to identify …
Bias in phylogenetic tree reconciliation methods: implications for vertebrate genome evolution
Authors: Matthew W Hahn
Journal: Genome biology (2007)

Comparative genomic studies are revealing frequent gains and losses of whole genes via duplication and pseudogenization. One commonly used method for inferring the number and timing of gene gains and losses reconciles the gene tree for each gene family with the species tree of the taxa considered. Recent studies using this approach have found a large number of ancient duplications and recent losses among vertebrate genomes.I show that tree reconciliation methods are biased when the inferred gene tree is not correct. This bias places duplicates towards the root of the tree and losses towards the tips of the tree. I demonstrate that this bias is present when tree reconciliation is conducted on both multiple mammal and Drosophila genomes, and that lower bootstrap cut-off values on gene trees lead to more extreme bias. I also suggest a method for dealing with reconciliation bias, although this method only corrects for the number of gene gains on some branches of the species tree.Based on the results presented, it is likely that most tree reconciliation analyses show biases, unless the gene trees used are exceptionally well-resolved and well-supported. These results cast doubt upon previous conclusions that vertebrate genome history has been marked by many ancient duplications and many recent gene losses.
Serum ghrelin is inversely associated with risk of subsequent oesophageal squamous cell carcinoma
Authors: Gwen Murphy, Farin Kamangar, Demetrius Albanes, Frank Z Stanczyk, Stephanie J Weinstein, Philip R Taylor, Jarmo Virtamo, Christian C Abnet, Sanford M Dawsey, Neal D Freedman
Journal: Gut (2011)

<h3>Background</h3> Gastric atrophy, as determined by a low serum pepsinogen I:II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, is also produced in the gastric fundic glands may be a marker of gastric atrophy, but its association with OSCC is not known. <h3>Methods</h3> To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, the authors conducted a nested case–control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. ORs and 95% CIs were calculated using conditional logistic regression with adjustment for potential confounders. <h3>Results</h3> For individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate OR of subsequent OSCC was 6.83 (95% CI 1.46 to 31.84). These associations were dose dependent (p value for trend =0.005 for both), and independent of the effects of low pepsinogen I:II ratio and <i>Helicobacter pylori</i> infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, although they become attenuated after 10 years. <h3>Conclusion</h3> Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC.
Protein 1 (Clara cell protein) serum levels in lung cancer patients receiving chemotherapy
Authors: H Nomori, H Horio, R Kobayashi, S Morinaga, Y Hirabayashi
Journal: European Respiratory Journal (1995)

As many antineoplastic drugs can cause injury to alveolar pneumocytes, Clara cells (nonciliated, nonmucous epithelial cells of the bronchioles) may also be damaged by such drugs. Protein 1 (P1) is an alpha-microprotein secreted by Clara cells. The effect of antineoplastic drugs on Clara cells is examined by the measurement of serum levels of P1 in patients with lung cancer receiving chemotherapy. Serum levels of P1 were studied in 36 patients with lung cancer, before chemotherapy and 5-7, 10-12 and 14-18 days after chemotherapy. One hundred and eight healthy subjects, matched by sex and age, acted as controls. There was no significant difference in P1 serum levels between patients with lung cancer and healthy controls. P1 serum levels decreased significantly 5-7 and 10-12 days after chemotherapy, recovering thereafter. We conclude that P1 serum levels do not differ between lung cancer patients and healthy controls, and that antineoplastic drugs inhibit the synthesis or secretion of P1 by Clara cells in the early period after the administration of medication.
Sp-1 and c-Myc Mediate Lysophosphatidic Acid–Induced Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Cells via a Hypoxia-Inducible Factor-1–Independent Mechanism
Authors: Yuanda Song, Jinhua Wu, Regina A. Oyesanya, Zendra Lee, Abir Mukherjee, Xianjun Fang
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Lysophosphatidic acid (LPA), which is present in ascites of ovarian cancer patients, stimulates expression of vascular endothelial growth factor (VEGF). VEGF is essential for the development and abdominal dissemination of ovarian cancer. We examined how LPA drives VEGF expression to gain a better understanding of tumor angiogenesis under normoxic conditions. Experimental Design: ELISA, Northern blotting, immunoblotting, quantitative PCR, and promoter reporter analysis in combination with small interfering RNA and pharmacologic inhibitors were used to examine LPA-induced VEGF expression and the underlying mechanisms. Results: LPA stimulated expression of multiple VEGF variants. A 123-bp fragment proximal to the transcriptional initiation site was identified to be functional promoter region responsible for the response to LPA. The fragment harbors consensus sites for several transcription factors including c-Myc and Sp-1 but not hypoxia-inducible factor-1. Blockade of Rho, ROCK, or c-Myc reduced LPA-dependent VEGF production and promoter activation, suggesting that the G12/13-Rho-ROCK-c-Myc cascade partially contributes to VEGF induction by LPA. More significantly, the multiple Sp-1 sites within the responsive region of the VEGF promoter were essential for LPA-mediated transcription. LPA induced Sp-1 phosphorylation and DNA-binding and transcriptional activities. The silencing of Sp-1 expression with small interfering RNA or inhibition of Sp-1 with pharmacologic inhibitors blocked VEGF production induced by LPA. Conclusions: LPA stimulates hypoxia-inducible factor-1-independent VEGF expression to promote tumor angiogenesis through activation of the c-Myc and Sp-1 transcription factors.
Intestinal β-galactosidases
Authors: Gary M. Gray, Nilda A. Santiago
Journal: Journal of Clinical Investigation (1969)

Previous studies based on work in the rat and preliminary experiments with human intestine have suggested that two beta-galactosidases are present in small intestine, and it is believed that only one of these enzymes is a lactase important for the digestion of dietary lactose. The high prevalence of intestinal lactase deficiency in man prompted more complete study of these enzymes. Human intestinal beta-galactosidases were studied by gel filtration on Sephadex G-200 and Biogel P-300 as well as by density gradient ultracentrifugation. Gel filtration produced partial separation into three peaks of enzyme activity, but much activity against synthetic substrates was lost. Only the trailing peak with specificity for synthetic beta-galactosides was completely separated from the other enzymes. Thus gel filtration was not a suitable preparative procedure for biochemical characterization. Density gradients separated the enzymes more completely, and they were designated according to their sedimentation rates and further characterized. Enzyme I has a molecular weight of 280,000, pH optimum of 6.0, and specificity for lactose of at least five times that for cellobiose or synthetic substrates. A second lactase, enzyme II, possesses slightly greater activity against lactose than for some synthetic substrates and is incapable of splitting cellobiose. Further, it has a lower pH optimum (4.5) and is present in two molecular species (molecular weights 156,000 and 660,000). Enzyme III shows specificity only for synthetic beta-galactosides but has a pH activity curve identical with enzyme I and a molecular weight of 80,000. Whereas human liver and kidney contain a beta-galactosidase with the same biochemical characteristics as intestinal enzyme II, enzymes I and III appear to be peculiar to intestine, and enzyme I most probably represents the lactase of importance in the mucosal digestion of dietary lactose. The following paper considers this further in terms of the biochemical change in intestinal lactase deficiency.
Ear Disease in Langage Laboratories
Authors: F. P. Thomson
Journal: BMJ (1964)

The authors explore the relative importance of the three primary drivers of target date fund (TDF) performance: equity (or market) exposures (which across a series9 vintages combine to form a glide path), style exposures (intrastock and intrabond allocations), and other investment selection decisions (e.g., manager selection and the active/passive decision, as well as any other residual risk exposures). They find that overall equity exposure drives only about 25% of the variation in returns across TDFs versus approximately 30% for style and 45% for selection, on average. Consequently, the analysis of the riskiness of a given TDF must be based on more than the overall weight given to equites.
Long-term Skeletal Muscle Protection After Gene Transfer in a Mouse Model of LGMD-2D
Authors: Christina A Pacak, Glenn A Walter, Gabe Gaidosh, Nathan Bryant, Melissa A Lewis, Sean Germain, Cathryn S Mah, Kevin P Campbell, Barry J Byrne
Journal: Molecular Therapy (2007)

Limb girdle muscular dystrophy (LGMD) describes a group of inherited diseases resulting from mutations in genes encoding proteins involved in maintaining skeletal muscle membrane stability. LGMD type-2D is caused by mutations in alpha-sarcoglycan (sgca). Here we describe muscle-specific gene delivery of the human sgca gene into dystrophic muscle using an adeno-associated virus 1 (AAV1) capsid and creatine kinase promoter. Delivery of this construct to adult sgca(-/-) mice resulted in localization of the sarcoglycan complex to the sarcolemma and a reduction in muscle fiber damage. Sgca expression prevented disease progression as observed in vivo by T(2)-weighted magnetic resonance imaging (MRI) and confirmed in vitro by decreased Evan's blue dye accumulation. The ability of recombinant AAV-mediated gene delivery to restore normal muscle mechanical properties in sgca(-/-) mice was verified by in vitro force mechanics on isolated extensor digitorum longus (EDL) muscles, with a decrease in passive resistance to stretch as compared with untreated controls. In summary, AAV/AAV-sgca gene transfer provides long-term muscle protection from LGMD and can be non-invasively evaluated using magnetic resonance imaging.
Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A
Authors: K.-O. Larsen, B. Lygren, I. Sjaastad, K. A. Krobert, K. Arnkvaern, G. Florholmen, A.-K. R. Larsen, F. O. Levy, K. Tasken, O. H. Skjonsberg, G. Christensen
Journal: Cardiovascular Research (2008)

Chronic obstructive pulmonary disease with alveolar hypoxia is associated with diastolic dysfunction in the right and left ventricle (LV). LV diastolic dysfunction is not caused by increased afterload, and we recently showed that reduced phosphorylation of phospholamban at serine (Ser) 16 may explain the reduced relaxation of the myocardium. Here, we study the mechanisms leading to the hypoxia-induced reduction in phosphorylation of phospholamban at Ser16.In C57Bl/6j mice exposed to 10% oxygen, signalling molecules were measured in cardiac tissue, sarcoplasmic reticulum (SR)-enriched membrane preparations, and serum. Cardiomyocytes isolated from neonatal mice were exposed to interleukin (IL)-18 for 24 h. The beta-adrenergic pathway in the myocardium was not altered by alveolar hypoxia, as assessed by measurements of beta-adrenergic receptor levels, adenylyl cyclase activity, and subunits of cyclic AMP-dependent protein kinase. However, alveolar hypoxia led to a significantly higher amount (124%) and activity (234%) of protein phosphatase (PP) 2A in SR-enriched membrane preparations from LV compared with control. Serum levels of an array of cytokines were assayed, and a pronounced increase in IL-18 was observed. In isolated cardiomyocytes, treatment with IL-18 increased the amount and activity of PP2A, and reduced phosphorylation of phospholamban at Ser16 to 54% of control.Our results indicate that the diastolic dysfunction observed in alveolar hypoxia might be caused by increased circulating IL-18, thereby inducing an increase in PP2A and a reduction in phosphorylation of phospholamban at Ser16.