tbuckley/cabot-search huggingface dataset:
Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling
Authors: K Witte
Journal: Cardiovascular Research (2000)

Objectives: Patients with chronic heart failure frequently show blunted circadian blood pressure profiles. The mechanisms involved in the loss of physiological day–night variation are still unclear, but a continuously active sympathetic nervous system could play a role. The present study evaluated long-term consequences of rat heart failure on cardiovascular circadian patterns in vivo, and on density and function of cardiac β-adrenoceptor subtypes in vitro, as a marker of cardiac adrenergic drive. Methods: Heart failure in rats was induced by coronary artery ligation leading to infarct sizes of >30% of left ventricular circumference. Blood pressure and heart rate were monitored for 10 weeks after infarction using radiotelemetry. Density and function of cardiac β1 and β2-adrenoceptors were measured by radioligand binding and adenylyl cyclase stimulation. Results: During the activity period at night blood pressure and heart rate were lower in rats with heart failure than in sham controls, leading to reduced night–day variation in the heart failure group. Depression of circadian rhythmicity in blood pressure was found over the whole study period, while that in heart rate occurred with a lag-time of several weeks. In failing left ventricles β-adrenoceptors showed reduced high affinity agonist binding, a shift in the β1:β2 ratio towards the β2-subtype, and decreased β1-adrenergic stimulation of adenylyl cyclase. In right ventricles no differences were found between failing and control rats. The blunted nocturnal increase in blood pressure and heart rate as well as β1-adrenergic desensitization were correlated with the severity of left ventricular dysfunction. Conclusions: Heart failure in rats leads to disturbed circadian patterns in blood pressure and heart rate, and to desensitization of cardiac β1-adrenoceptors, indicating chronic sympathetic overactivity.
Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men
Authors: Joel S. Finkelstein, Hang Lee, Sherri-Ann M. Burnett-Bowie, J. Carl Pallais, Elaine W. Yu, Lawrence F. Borges, Brent F. Jones, Christopher V. Barry, Kendra E. Wulczyn, Bijoy J. Thomas, Benjamin Z. Leder
Journal: New England Journal of Medicine (2013)

Current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, estradiol, or both account for clinical manifestations.
Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy
Authors: Ying Li, Shuai Zhang, Xiaoying Zhang, Jing Li, Xiaojie Ai, Li Zhang, Daohai Yu, Shuping Ge, Yizhi Peng, Xiongwen Chen
Journal: Cardiovascular Research (2014)

AimsTo determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.
The Genotype–Phenotype Map of Yeast Complex Traits: Basic Parameters and the Role of Natural Selection
Authors: Wei-Chin Ho, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2014)

Most phenotypic traits are controlled by many genes, but a global picture of the genotype-phenotype map (GPM) is lacking.For example, in no species do we know generally how many genes affect a trait and how large these effects are.It is also unclear to what extent GPMs are shaped by natural selection.Here we address these fundamental questions using the reverse genetic data of 220 morphological traits in 4,718 budding yeast strains, each of which lacks a nonessential gene.We show that 1) the proportion of genes affecting a trait varies from <1% to >30%, averaging 6%, 2) most traits are impacted by many more small-effect genes than large-effect genes, and 3) the mean effect of all nonessential genes on a trait decreases precipitously as the estimated importance of the trait to fitness increases.An analysis of 3,116 yeast gene expression traits in 754 gene-deletion strains reveals a similar pattern.These findings illustrate the power of genome-wide reverse genetics in genotype-phenotype mapping, uncover an enormous range of genetic complexity of phenotypic traits, and suggest that the GPM of cellular organisms has been shaped by natural selection for mutational robustness.
Transitions in cardiac isomyosin expression during differentiation of the embryonic chick heart.
Authors: L J Sweeney, R Zak, F J Manasek
Journal: Circulation Research (1987)

The expression of different isoforms of the contractile protein myosin plays a major role in determining contractile characteristics in both cardiac and skeletal muscle in the adult. There is little evidence pertaining to putative changes in myosin phenotype during cardiac embryogenesis or if such changes could play a role in modulating the contractile characteristics of the developing heart. We examined isomyosin expression during cardiogenesis in the chick by indirect immunofluorescence microscopy with monoclonal antibodies to adult ventricular and atrial myosin heavy chains. Antibody specificity was characterized in the adult on the basis of immunofluorescence localization, ELISA, and protein blot immunoassay. Results show that the early embryonic chick heart has a different myosin phenotype than the later embryonic or adult heart. Both the embryonic ventricular and atrial myocardia initially expressed a myosin heavy chain that was recognized by antibody specific (in the adult) for ventricular myosin heavy chain. The ventricles remained reactive throughout life with the ventricular antibody, but reactivity of the atrial myocardium was confined to the initial 6 days of embryonic development. On the other hand, reactivity of the embryonic heart with multiple antibodies specific (in the adult) for atrial myosin was confined to the atrial myocardium throughout development. Thus, the distribution of myosin isoforms became similar to that of the adult myocardium by the time the embryonic heart achieved a 4-chambered configuration at 6 days in ovo.
Mesenchymal Stem Cells Regulate Blood-Brain Barrier Integrity Through TIMP3 Release After Traumatic Brain Injury
Authors: Tyler Menge, Yuhai Zhao, Jing Zhao, Kathryn Wataha, Michael Gerber, Jianhu Zhang, Phillip Letourneau, John Redell, Li Shen, Jing Wang, Zhalong Peng, Hasen Xue, Rosemary Kozar, Charles S. Cox, Aarif Y. Khakoo, John B. Holcomb, Pramod K. Dash, Shibani Pati
Journal: Science Translational Medicine (2012)

The matrix metalloproteinase inhibitor TIMP3 mediates the beneficial effects of mesenchymal stem cells on the blood-brain barrier of the injured mouse brain.
Culture-Negative Neutrocytic Ascites: A Variant of Spontaneous Bacterial Peritonitis
Authors: Bruce A. Runyon, John C. Hoefs
Journal: Hepatology (1984)

A review of the medical records of patients diagnosed as having “spontaneous bacterial peritonitis” (SBP) revealed 18 episodes of culture-negative neutrocytic ascites (CNNA) in 17 patients. The following criteria were all required in order to qualify for this diagnosis: (i) an ascitic fluid neutrophil count greater than 500 cells per mm 3 ; (ii) negative ascitic fluid culture (5); (iii) absence of an intraabdominal source of infection; (iv) no antibiotic treatment within 30 days, and (v) no evidence of pancreatitis. Five patients had positive blood cultures. Two patients with CNNA had SBP in the past, and two other patients, who survived the episode of CNNA, subsequently developed SBP. Clinical signs and symptoms of patients with CNNA were not different from those of 32 patients with 33 episodes of culture-positive SBP. The mortality of CNNA (50%) was not different from that of SBP (70%). Because of the high mortality and because of the similarity of CNNA to SBP, it is presumed that many patients with CNNA have bacterial infection of their ascitic fluid, and it is recommended that they be treated with antibiotics.
Plasma PGE-2 levels and altered cytokine profiles in adherent peripheral blood mononuclear cells in non-small cell lung cancer (NSCLC).
Authors: Giovanna E Hidalgo, Li Zhong, Dennis E Doherty, Edward A Hirschowitz
Journal: Molecular Cancer (2002)

PGE-2 is constitutively produced by many non-small cell lung cancers (NSCLC) and its immunosuppressive effects have been linked to altered immune responses in lung cancer. We asked whether elevated levels of plasma PGE-2 correlated with monocyte IL10 production in the NSCLC environment. Looking for correlation in NSCLC patient blood we assayed plasma from NSCLC patients for PGE2 and IL10; we further evaluated production of IL10 by adherent mononuclear cells from a subset of these patients looking for an altered cytokine profile. Our initial in vitro experiments show that monocyte IL10 induction correlates with tumor cell PGE-2 production, confirming similar reports in the literature. Data show plasma PGE-2 levels in 38 NSCLC patients are elevated compared to normal controls. Plasma IL10 levels were not significantly elevated; however, adherent monocytes derived from NSCLC patient blood did produce significantly more IL10 in 24 hr primary culture than those from normal controls (p < 0.01). The association of elevated plasma PGE-2 and monocyte derived IL-10 was not significant. Elevated plasma PGE-2 and monocyte IL10 production are associated with NSCLC. The biological significance to elevated PGE-2 levels in NSCLC are unclear. Further investigation of each as a nonspecific marker for NSCLC tumor is warranted.
Aging and arteriosclerosis. I. Development of myointimal hyperplasia after endothelial injury.
Authors: R J Hariri, D R Alonso, D P Hajjar, D Coletti, M E Weksler
Journal: The Journal of Experimental Medicine (1986)

Old Fischer 344 rats are more susceptible to vascular lesions after arterial endothelial injury than are young animals. Thus, 20-26-mo-old Fischer 344 rats developed greater and more persistent intimal proliferative lesions than did 2-5-mo-old rats after aortic endothelial denudation. 3 d after deendothelialization, intimal thickness was increased two-fold in both old and young animals. However, 14 d after endothelial injury, intimal thickness had increased nearly five times in old animals, but had regressed to normal in young animals. Intimal thickness of young aortic grafts transplanted into young recipients did not differ significantly from adjacent host aorta or autotransplanted aortic segments 6 wk after surgery. In contrast, intimal thickness of old grafts transplanted into young recipients was eight times greater than adjacent young host aorta 6 wk after surgery. The density of cell nuclei in the intima of old grafts was also much greater than that in young grafts. Thus, in two experimental models of vascular injury, old rats have consistently had greater myointimal hyperplasia than young rats. The increased proliferative response of aortic smooth muscle cells after vascular injury of old animals may contribute to the increased prevalence of vascular disease with age.
White piedra: evidence for a synergistic infection
Authors: K.M. ELLNER, MOLLIE E. McBRIDE, D.C. KALTER, J.A. TSCHEN, J.E. WOLF
Journal: British Journal of Dermatology (1990)

To determine the relative roles of coryneform bacteria and Trichosporon beigelii in the pathogenesis of genital white piedra, scrotal hair from 10 subjects was studied. Hairs were examined by light microscopy to determine the relative proportions of each organism, and were also cultured for coryneforms and yeast. Histologically, hair nodules from five out of nine cases showed a mixture of yeasts and bacteria, four had bacteria alone, and none showed yeast alone. Five strains of T. beigelii were cultured, two strains of Saccharomyces cerevisiae and 22 strains of coryneforms. The isolates were tested for synergism by a plate-overlay method. Growth of coryneforms occurred over and around sections of the plate inoculated with T. beigelii but not around the control yeast, S. cerevisiae. There were strain differences in the stimulatory response of both T. beigelii and coryneform strains. In reverse experiments coryneforms did not enhance growth of T. beigelii. It was concluded that white piedra is a mixed infection caused by the synergistic action between T. beigelii and a specific coryneform bacteria resulting in invasion of the hair cuticle and cortex.
Oxidized low-density lipoprotein depletes PKCα and attenuates reactive oxygen species formation in monocytes/macrophages
Authors: R KOHL, S PREIS, A VONKNETHEN, B BRUNE
Journal: Cardiovascular Research (2006)

Objective: Preexposure of macrophages to oxidized low-density lipoprotein (oxLDL) attenuates formation of reactive oxygen species (ROS) upon stimulation with phorbol 12-myristate 13-acetate (PMA) or acute exposure to oxLDL. We examined whether attenuation of the oxidative burst is attributed to down-regulation of protein kinase C α (PKCα).
Qa-2–Dependent Selection of Cd8α/α T Cell Receptor α/β+ Cells in Murine Intestinal Intraepithelial Lymphocytes
Authors: Gobardhan Das, Dina S. Gould, Mathew M. Augustine, Gladis Fragoso, Edda Scitto, Iwona Stroynowski, Luc Van Kaer, Danny J. Schust, Hidde Ploegh, Charles A. Janeway
Journal: The Journal of Experimental Medicine (2000)

Murine intestinal intraepithelial lymphocytes (iIELs) are made up of a heterogeneous mix of T cells with unique phenotypes. Whereas CD8+ T cells in peripheral lymphoid organs use CD8α/β and are selected on MHC class Ia molecules, a majority of iIELs use CD8α/α. Here, we report that the presence of CD8α/α TCR-α/β cells in iIELs is independent of classical MHC class I molecules Kb and Db, as illustrated by their presence in Kb/Db double-knockout mice and in mice lacking a nonclassical MHC class I molecule, CD1d. Most strikingly, their presence is decreased by ∼70% in mice lacking transporter associated with antigen processing (TAP). The TAP-dependent nonclassical MHC class I molecule Qa-2 is strongly implicated in the presence of these cells, as inferred from the low numbers of CD8α/α TCR-α/β T cells in mice deficient in Qa-2 genes. Second, a Qa-2–transgenic mouse made in a Qa-2− strain showed an increase in the numbers of CD8α/α cells among its iIELs. Thus, the presence of CD8α/α TCR-α/β cells in iIELs is mainly dependent on the nonclassical MHC class I molecule Qa-2.
Lipid composition of bile in diabetics and obesity-matched controls.
Authors: G B Haber, K W Heaton
Journal: Gut (1979)

Duodenal bile from 27 diabetes was compared with samples from healthy subjects matched for age, sex, and body mass index. Cholesterol saturation and the molar percentages of bile acids, phospholipids, and cholesterol were not significantly different. Most bile samples were supersaturated in both groups. The maturity onset diabetics who were almost all obese had more saturated bile than the slimmer juvenile onset patients. Body fatness and plasma triglyceride levels were both positively correlated with the cholesterol saturation of bile in the controls but not in the diabetics. Bile was less concentrated in female diabetics than in controls, which is consistent with impaired gallbladder emptying. It is possible that the increased prevalence of gallstones in diabetics is due not so much to diabetes itself as to the frequently associated obesity.
Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index
Authors: Lisa Martin, Laura Birdsell, Neil MacDonald, Tony Reiman, M. Thomas Clandinin, Linda J. McCargar, Rachel Murphy, Sunita Ghosh, Michael B. Sawyer, Vickie E. Baracos
Journal: Journal of Clinical Oncology (2013)

Emerging evidence suggests muscle depletion predicts survival of patients with cancer.At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models.Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001).CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.
A key role for Fut1-regulated angiogenesis and ICAM-1 expression in K/BxN arthritis
Authors: Mohammad A Amin, Phillip L Campbell, Jeffrey H Ruth, Takeo Isozaki, Bradley J Rabquer, W Alex Stinson, Martin O'Brien, Gautam Edhayan, Ray A Ohara, Jonathon Vargo, Steven E Domino, Alisa E Koch
Journal: Annals of the Rheumatic Diseases (2014)

Angiogenesis contributes to the pathogenesis of rheumatoid arthritis. Fucosyltransferases (Futs) are involved in angiogenesis and tumour growth. Here, we examined the role of Fut1 in angiogenesis and K/BxN serum transfer arthritis.We examined Fut1 expression in human dermal microvascular endothelial cells (HMVECs) by quantitative PCR. We performed a number of angiogenesis assays to determine the role of Fut1 using HMVECs, Fut1 null (Fut1(-/-)), and wild type (wt) endothelial cells (ECs) and mice. K/BxN serum transfer arthritis was performed to determine the contribution of Fut1-mediated angiogenesis in Fut1(-/-) and wt mice. A static adhesion assay was implemented with RAW264.7 (mouse macrophage cell line) and mouse ECs. Quantitative PCR, immunofluorescence and flow cytometry were performed with Fut1(-/-) and wt ECs for adhesion molecule expression.Tumour necrosis factor-α induced Fut1 mRNA and protein expression in HMVECs. HMVECs transfected with Fut1 antisense oligodeoxynucleotide and Fut1(-/-) ECs formed significantly fewer tubes on Matrigel. Fut1(-/-) mice had reduced angiogenesis in Matrigel plug and sponge granuloma angiogenesis assays compared with wt mice. Fut1(-/-) mice were resistant to K/BxN serum transfer arthritis and had decreased angiogenesis and leucocyte ingress into inflamed joints. Adhesion of RAW264.7 cells to wt mouse ECs was significantly reduced when Fut1 was lacking. Fut1(-/-) ECs had decreased intercellular adhesion molecule-1 (ICAM-1) expression at mRNA and protein levels compared with wt ECs. ICAM-1 was also decreased in Fut1(-/-) arthritic ankle cryosections compared with wt ankles.Fut1 plays an important role in regulating angiogenesis and ICAM-1 expression in inflammatory arthritis.
Automated analysis of reticulocytes using fluorescent staining with both acridine orange and an immunofluorescence technique
Authors: Paul A. Seligman, Robert H. Allen, Stefan J. Kirchanski, Peter J. Natale
Journal: American Journal of Hematology (1983)

Abstract We have used an automated system to measure serial reticulocyte samples from phlebotomized rats and rats treated with the chemotherapeutic agent actinomycin‐D. In performing the automated samples, we utilized two different methods. The first method employed a fluorescent dye, acridine orange, which stains RNA in a manner similar to supravital stains presently used in performing reticulocyte counts. The second method is unique in that we utilized an immunofluorescent assay with antitransferrin recptor antibody which identifies the transferrin receptor found on the cell surface of reticulocytes but not on mature red cells. Both methods gave reproducible values in estimating the increase in reticulocytes seen after phlebotomy and the initial reticulocytopenia followed by recovery of the peripheral blood reticulocyte count seen after treatment with actinomycin‐D. Also, since the antitransferrin receptor antibody appears to recognize the more immature reticulocytes, both methods taken together may provide an estimate of the maturity of a population of reticulocytes.
Targeting insulin-like growth factor axis in hepatocellular carcinoma
Authors: Jennifer Wu, Andrew X Zhu
Journal: Journal of Hematology & Oncology (2011)

The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins. The essential role of IGF axis in hepatocellular carcinoma (HCC) has been illustrated in HCC cell lines and in animal xenograft models. Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC. Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation. This review describes the most up-to-date understanding of this complex axis in HCC, and provides relevant information on clinical trials targeting the IGF axis in HCC with a focus on anti-IGF-1R approach. IGF axis is increasingly recognized as one of the most relevant pathways in HCC and agents targeting this axis can potentially play an important role in the treatment of HCC.
THE PROTEASOME AND PROTEASOME INHIBITORS IN CANCER THERAPY
Authors: Peter M. Voorhees, Robert Z. Orlowski
Journal: The Annual Review of Pharmacology and Toxicology (2005)

The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.