tbuckley/cabot-search huggingface dataset:
Nutlin-3 overcomes arsenic trioxide resistance and tumor metastasis mediated by mutant p53 in Hepatocellular Carcinoma
Authors: Tongsen Zheng, Dalong Yin, Zhaoyang Lu, Jiabei Wang, Yuejin Li, Xi Chen, Yingjian Liang, Xuan Song, Shuyi Qi, Boshi Sun, Changming Xie, Xianzhi Meng, Shangha Pan, Jiaren Liu, Hongchi Jiang, Lianxin Liu
Journal: Molecular Cancer (2014)

Arsenic trioxide has been demonstrated as an effective anti-cancer drug against leukemia and solid tumors both in vitro and in vivo. However, recent phase II trials demonstrated that single agent arsenic trioxide was poorly effective against hepatocellular carcinoma (HCC), which might be due to drug resistance. Mutation detection of p53 gene in arsenic trioxide resistant HCC cell lines was performed. The therapeutic effects of arsenic trioxide and Nutlin-3 on HCC were evaluated both in vitro and in vivo. A series of experiments including MTT, apoptosis assays, co-Immunoprecipitation, siRNA transfection, lentiviral infection, cell migration, invasion, and epithelial-mesenchy-mal transition (EMT) assays were performed to investigate the underlying mechanisms. The acquisition of p53 mutation contributed to arsenic trioxide resistance and enhanced metastatic potential of HCC cells. Mutant p53 (Mutp53) silence could re-sensitize HCC resistant cells to arsenic trioxide and inhibit the metastatic activities, while mutp53 overexpression showed the opposite effects. Neither arsenic trioxide nor Nutlin-3 could exhibit obvious effects against arsenic trioxide resistant HCC cells, while combination of them showed significant effects. Nutlin-3 can not only increase the intracellular arsenicals through inhibition of p-gp but also promote the p73 activation and mutp53 degradation mediated by arsenic trioxide. In vivo experiments indicated that Nutlin-3 can potentiate the antitumor activities of arsenic trioxide in an orthotopic hepatic tumor model and inhibit the metastasis to lung. Acquisitions of p53 mutations contributed to the resistance of HCC to arsenic trioxide. Nutlin-3 could overcome arsenic trioxide resistance and inhibit tumor metastasis through p73 activation and promoting mutant p53 degradation mediated by arsenic trioxide.
Association Between Elevated Serum C-Reactive Protein and Triglyceride Levels in Young Subjects With Type 1 Diabetes
Authors: Ana M. Ladeia, Eridan Stefanelli, Carol Ladeia-Frota, Agnaluce Moreira, Angela Hiltner, Luis Adan
Journal: Diabetes Care (2006)

Cardiovascular disease is the major cause of mortality and morbidity in individuals with diabetes (1,2). Increased plasma concentrations of acute-phase proteins have been reported in adult patients with either type 2 (3,4) or type 1 (5,6) diabetes. However, there have been few studies to determine plasma high-sensitivity C-reactive protein (hs-CRP) levels in young diabetic patients (7,8). This study evaluated the levels of hs-CRP and their correlation with metabolic profile in very young patients with type 1 diabetes.

This sectional study included 45 consecutive young patients (26 boys) who fulfilled the inclusion criteria (diagnosed as type 1 diabetic, followed up at a public health assistance center, serum creatinine level <1.3 mg/dl, and normal thyroid-stimulating hormone values) and 30 healthy subjects (12 boys) matched by age (±3 years) and BMI. Exclusion criteria were hypertension, overweight or obesity, smoking, any infection having been diagnosed during the previous 3 months, and treatment for inflammatory or chronic infectious disease.

Measurements of pulse rate, blood pressure, height and weight, and specific clinical examination of throat, eyes, nose, ears, skin, and feet were performed. Laboratory data included fasting blood glucose, HbA1c (A1C), total cholesterol, HDL and LDL cholesterol, triglycerides, serum creatinine, thyroid-stimulating hormone, and hs-CRP. Hs-CRP was determined by nephelometry.

Differences in the means were evaluated by the Student’s t test. The hs-CRP data were …
Experimental laser phototherapy of the morris 7777 hepatoma in the rat
Authors: Stephen Holt, John Tulip, Douglas Hamilton, Judith Cummins, Anthony Fields, Catherine Dick
Journal: Hepatology (1985)

The tumoricidal effect of the activation of hematoporphyrin derivative (HpD), by an argon-ion-dye-laser (wavelength 630 nm), was investigated in the Buffalo rat bearing subcutaneous implants of the Morris 7777 hepatoma. Tumor growth was monitored by measuring the tumor volume with constant force callipers. In control animals and those that were pretreated with HpD alone (10 or 20 mg per kg by i.p. injection) or laser light alone (2,000 J at 100 mW), a predictable exponential growth pattern of the cancer was observed. Animals were pretreated with HpD (10 mg per kg by i.p. injection) 48 hr prior to the fiberoptic, intratumor delivery of laser radiation (2,000 J at 100 mW), when the tumor had reached a volume greater than 1.5 cm3. Forty-eight hours after combined laser and HpD treatment, the hepatoma underwent coagulation necrosis, and the tumor volume rapidly increased from a mean value of 1.8 ± 0.7 cm3 S.D. to a value of 5.8 ± 1.5 cm3 S.D., compared with a mean of 3.7 ± 0.7 cm3 S.D. in animals who had not received laser phototherapy. Rats treated with HpD and laser light survived longer (mean survival time 48 ± 12 days S.D.) than did the other animals treated with the laser alone or HpD alone (mean survival time 31 S± 16.5 S.D.). Tissue biodistribution studies with tritiated hematoporphyrin derivative, given with doses of 10 and 20 mg per kg of HpD, showed higher concentrations of the dye in the liver, kidneys and spleen than in the tumor at 48 hr after administration of the dye. The ratio of uptake of HpD between the Morris 7777 hepatoma and adjacent muscle was approximately 2:1 in both dose ranges of the dye, implying that HpD does not localize in malignant tissue in a preferential manner. Laser phototherapy with HpD significantly interrupts the growth of the highly malignant Morris 7777 hepatoma and prolongs the survival time of Buffalo rats bearing this neoplasm.
Depletion of Tumor-Associated Macrophages Enhances the Effect of Sorafenib in Metastatic Liver Cancer Models by Antimetastatic and Antiangiogenic Effects
Authors: Wei Zhang, Xiao-Dong Zhu, Hui-Chuan Sun, Yu-Quan Xiong, Peng-Yuan Zhuang, Hua-Xiang Xu, Ling-Qun Kong, Lu Wang, Wei-Zhong Wu, Zhao-You Tang
Journal: Clinical Cancer Research (2010)

To investigate the role of macrophages in tumor progression under sorafenib treatment and to explore whether combination of drugs that deplete macrophages improved the antitumor effect of sorafenib.Tumor growth, lung metastasis, and tumor angiogenesis were observed in HCCLM3-R and SMMC7721, two human hepatocellular carcinoma xenograft nude mouse models, when treated with sorafenib (30 mg/kg daily, n = 6 per group) or a vehicle as control. Macrophage infiltration was measured in the peripheral blood and in sorafenib-treated tumor by immunohistochemistry and flow cytometry with F4/80 antibody and CD11b antibody. The effect of macrophage depletion on tumor angiogenesis and metastasis after sorafenib treatment, using two drug target macrophages, zoledronic acid (ZA) and clodrolip, was measured in the two models of hepatocellular carcinoma.Although sorafenib significantly inhibited tumor growth and lung metastasis, it induced a significant increase in peripheral recruitment and intratumoral infiltration of F4/80- and CD11b-positive cells, which was accompanied with elevation of colony-stimulating factor-1, stromal-derived factor 1alpha, and vascular endothelial growth factor in the tumor and elevation of plasma colony-stimulating factor-1 and mouse vascular endothelial growth factor in peripheral blood, suggesting the role of macrophages in tumor progression under sorafenib treatment. Depletion of macrophages by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis, and lung metastasis compared with mice treated with sorafenib alone. ZA was more effective than clodrolip.Macrophages may have an important role in tumor progression under sorafenib treatment. ZA is promising when combined with sorafenib to enhance its antitumor effect.
American Heart Association Childhood Obesity Research Summit Report
Authors: Stephen R. Daniels, Marc S. Jacobson, Brian W. McCrindle, Robert H. Eckel, Brigid McHugh Sanner
Journal: Circulation (2009)

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are
Prevalence and rate of diagnosis of allergic rhinitis in Europe
Authors: V. Bauchau, S.R. Durham
Journal: European Respiratory Journal (2004)

To measure the prevalence of allergic rhinitis among European adults and the proportion of undiagnosed subjects, a two-step, cross-sectional, population-based survey in Belgium, France, Germany, Italy, Spain, and the UK was undertaken. Step one of the study involved screening for allergic rhinitis by telephone interview, based on history of symptoms and/or self-awareness of the condition. Step two undertook confirmation of allergic rhinitis in a subset of the subjects screened positive; this was performed by a clinical diagnosis conducted in three to five clinical centres per country, including specific immunoglobulin E tests and a disease-specific questionnaire. A total of 9,646 telephone interviews were conducted between February and April 2001. Self-awareness of allergic rhinitis was reported by 19% of the subjects. Physician-based diagnosis of allergic rhinitis was reported by 13% of the subjects. In step two, 725 clinical assessments were conducted between May and August 2001. A total of 411 of patients, who underwent step two, had investigator-confirmed allergic rhinitis. Among patients with investigator-confirmed allergic rhinitis, 45% had not reported a previous diagnosis by a physician. Prevalence of subjects with clinically confirmable allergic rhinitis estimated by combining step one and step two data ranged from 17% in Italy to 29% in Belgium with an overall value of 23%. This large-scale study confirms that allergic rhinitis has a high prevalence in western Europe and is frequently undiagnosed.
Repetitive myocardial stunning in pigs is associated with the increased expression of inducible and constitutive nitric oxide synthases
Authors: C Baker
Journal: Cardiovascular Research (1999)

Nitric oxide (NO) has complex effects on myocardial function particularly following ischaemia-reperfusion. The goal of this study was to examine the result of repetitive myocardial stunning on myocardial NO release and expression of inducible (iNOS) and constitutive (eNOS) NO synthases.Propofol anaesthetised pigs underwent ten, 2-min episodes of circumflex artery occlusion (n = 6) or acted as sham operated controls (n = 4). Measurements of segment shortening demonstrated a fall in function in the ischaemic territory to 52.5 +/- 7.3% (mean +/- S.E.M.) of baseline shortening 30 min after the stunning stimulus, recovering to 92 +/- 8.7% 5.5 h later. Function remained stable in sham controls. The change in venous-arterial [NO] between baseline and 6 h reperfusion was found to be significantly different between the two groups (0.2 +/- 0.7 in stunned vs. -4.3 +/- 1.6 microM in shams; P < 0.02). Western blotting and band optical density used to compare tissue from stunned territory (S), non-stunned territory (IC) and sham control animals (SC) demonstrated this was associated with an increase in the expression of both iNOS (S: 93 +/- 13.4, IC: 37 +/- 2.4 and SC: 25 +/- 4 [arbitrary units], P < 0.01 and P = 0.031) and eNOS (S: 104 +/- 7.4, IC; 62.5 +/- 7.4 and SC; 75.7 +/- 0.6, P < 0.03 and P < 0.01) in stunned myocardium. Immunocytochemistry localised iNOS reactivity to vascular smooth muscle cells and cardiomyocytes in stunned tissue and eNOS reactivity to endothelial cells.Recovery from repetitive myocardial stunning is associated with the increased expression of both iNOS and eNOS and would be compatible with a protective role for both these enzymes. This finding has possible relevance for both the late window of ischaemic preconditioning and myocardial hibernation.
Prevention of Antigenically Drifted Influenza by Inactivated and Live Attenuated Vaccines
Authors: Suzanne E. Ohmit, John C. Victor, Judy R. Rotthoff, Esther R. Teich, Rachel K. Truscon, Laura L. Baum, Bhavya Rangarajan, Duane W. Newton, Matthew L. Boulton, Arnold S. Monto
Journal: New England Journal of Medicine (2006)

The efficacy of influenza vaccines may decline during years when the circulating viruses have antigenically drifted from those included in the vaccine.We carried out a randomized, double-blind, placebo-controlled trial of inactivated and live attenuated influenza vaccines in healthy adults during the 2004-2005 influenza season and estimated both absolute and relative efficacies.A total of 1247 persons were vaccinated between October and December 2004. Influenza activity in Michigan began in January 2005 with the circulation of an antigenically drifted type A (H3N2) virus, the A/California/07/2004-like strain, and of type B viruses from two lineages. The absolute efficacy of the inactivated vaccine against both types of virus was 77% (95% confidence interval [CI], 37 to 92) as measured by isolating the virus in cell culture, 75% (95% CI, 42 to 90) as measured by either isolating the virus in cell culture or identifying it through real-time polymerase chain reaction, and 67% (95% CI, 16 to 87) as measured by either isolating the virus or observing a rise in the serum antibody titer. The absolute efficacies of the live attenuated vaccine were 57% (95% CI, -3 to 82), 48% (95% CI, -7 to 74), and 30% (95% CI, -57 to 67), respectively. The difference in efficacy between the two vaccines appeared to be related mainly to reduced protection of the live attenuated vaccine against type B viruses.In the 2004-2005 season, in which most circulating viruses were dissimilar to those included in the vaccine, the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic illnesses from influenza in healthy adults. The live attenuated vaccine also prevented influenza illnesses but was less efficacious. (ClinicalTrials.gov number, NCT00133523.)
Rheumatoid arthritis, a complex multifactorial disease: On the way toward individualized medicine
Authors: Michael O. Glocker, Reinhard Guthke, Jörn Kekow, Hans-Jürgen Thiesen
Journal: Medicinal Research Reviews (2005)

With the availability of the human genome sequence and those of related species like chimpanzee, mouse, and rat, data driven research for tackling the molecular grounds of rheumatoid arthritis (RA), a multifactorial polygenic disease, can be considered a realistic challenge to the scientific community. A comprehensive research strategy is presented enabling the integration of multiple research efforts on studying autoimmunity by so called systems biology approaches. An integrative scientific concept is discussed of how to unravel molecular mechanisms of complex diseases by making use of state-of-the-art methodologies in functional and comparative genomics. A continuous interchange of data-driven and hypothesis-driven research is adjoined to determine the nature of rheumatic diseases with autoimmune background. Instead of studying single genes and proteins, RNA and protein microarray profiles are currently obtained in numerous research projects producing read-outs termed gene signatures rather than DNA and/or protein markers. A comprehensive study of the RNA, protein, and metabolite regimes is undertaken that eventually will lead to a "holistic" view of how all respective molecules, pathways and cells themselves interact with each other. Some of the above mentioned research aspects have already been studied by the authors, hopefully leading to new diagnostics and therapeutics in the future. © 2003 Wiley Periodicals, Inc. Med Res Rev.
We can't fill in answers to philosophical questions
Authors: Lloyd Kaufman
Journal: Behavioral and Brain Sciences (1998)

The target article discusses the classic blind spot, scotomas, subjective contours, and other so-called filling-in phenomena. Its purpose is to evaluate the idea that some theories of filling-in amount to tacit acceptance of Cartesian materialism and a form of psychophysical isomorphism. Pessoa et al. reject what is termed structural isomorphism as well as Cartesian materialism, but claim that neural processes adduced as underlying filling-in may be acceptable without implying isomorphism. The article supports the idea of perceiving as an active constructive process. However, the various subthemes are not clearly related to each other. Topological psychophysical isomorphism is indeed untenable, but the tacit assumption that filling-in enjoys any kind of unique status with respect to illuminating philosophical questions is doubtful.
Heparin‐induced thrombocytopenia and fatal thrombosis in a patient with activated protein C resistance
Authors: J. Gardyn, P. Sorkin, Y. Kluger, S. Kabili, J. M. Klausner, A. Zivelin, A. Eldor
Journal: American Journal of Hematology (1995)

Abstract We report a 20‐year‐old woman who developed heparin‐induced thrombocytopenia (HIT) associated with devastating and fatal multiorgan thrombosis. The patient, her mother, and her brother were found to have resistance to activated protein C (APC), and the congenital thrombophilia in this family was verified by the finding of the Arg 506 Gln mutation in factor V. This is the first case of HIT and APC resistance. The consequences of this association are discussed.
cAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy
Authors: Eric Morel, Andrea Marcantoni, Monique Gastineau, Rikke Birkedal, Francesca Rochais, Anne Garnier, Anne-Marie Lompré, Grégoire Vandecasteele, Frank Lezoualc’h
Journal: Circulation Research (2005)

cAMP is one of the most important second messenger in the heart. The discovery of Epac as a guanine exchange factor (GEF), which is directly activated by cAMP, raises the question of the role of this protein in cardiac cells. Here we show that Epac activation leads to morphological changes and induces expression of cardiac hypertrophic markers. This process is associated with a Ca2+-dependent activation of the small GTPase, Rac. In addition, we found that Epac activates a prohypertrophic signaling pathway, which involves the Ca2+ sensitive phosphatase, calcineurin, and its primary downstream effector, NFAT. Rac is involved in Epac-induced NFAT dependent cardiomyocyte hypertrophy. Blockade of either calcineurin or Rac activity blunts the hypertrophic response elicited by Epac indicating these signaling molecules coordinately regulate cardiac gene expression and cellular growth. Our results thus open new insights into the signaling pathways by which cAMP may mediate its biological effects and identify Epac as a new positive regulator of cardiac growth.
Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-γ Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes
Authors: Anne Fougerat, Stéphanie Gayral, Pierre Gourdy, Alexia Schambourg, Thomas Rückle, Matthias K. Schwarz, Christian Rommel, Emilio Hirsch, Jean-François Arnal, Jean-Pierre Salles, Bertrand Perret, Monique Breton-Douillon, Matthias P. Wymann, Muriel Laffargue
Journal: Circulation (2008)

Background— The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-γ (PI3Kγ) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kγ in the cardiovascular system suggest that PI3Kγ plays a role in atherosclerosis. Methods and Results— Here, we demonstrate that a specific PI3Kγ inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E–deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor–deficient mice. Furthermore, PI3Kγ levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor–deficient mice transplanted with wild-type or PI3Kγ-deficient bone marrow demonstrated that functional PI3Kγ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kγ activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. Conclusions— These data identify PI3Kγ as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.
Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.
Authors: F Sallusto, M Cella, C Danieli, A Lanzavecchia
Journal: The Journal of Experimental Medicine (1995)

We have previously demonstrated that human peripheral blood low density mononuclear cells cultured in granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 develop into dendritic cells (DCs) that are extremely efficient in presenting soluble antigens to T cells. To identify the mechanisms responsible for efficient antigen capture, we studied the endocytic capacity of DCs using fluorescein isothiocyanate-dextran, horseradish peroxidase, and lucifer yellow. We found that DCs use two distinct mechanisms for antigen capture. The first is a high level of fluid phase uptake via macropinocytosis. In contrast to what has been found with other cell types, macropinocytosis in DCs is constitutive and allows continuous internalization of large volumes of fluid. The second mechanism of capture is mediated via the mannose receptor (MR), which is expressed at high levels on DCs. At low ligand concentrations, the MR can deliver a large number of ligands to the cell in successive rounds. Thus, while macropinocytosis endows DCs with a high capacity, nonsaturable mechanism for capture of any soluble antigen, the MR gives an extra capacity for antigen capture with some degree of selectivity for non-self molecules. In addition to their high endocytic capacity, DCs from GM-CSF + IL-4-dependent cultures are characterized by the presence of a large intracellular compartment that contains high levels of class II molecules, cathepsin D, and lysosomal-associated membrane protein-1, and is rapidly accessible to endocytic markers. We investigated whether the capacity of DCs to capture and process antigen could be modulated by exogenous stimuli. We found that DCs respond to tumor necrosis factor alpha, CD40 ligand, IL-1, and lipopolysaccharide with a coordinate series of changes that include downregulation of macropinocytosis and Fc receptors, disappearance of the class II compartment, and upregulation of adhesion and costimulatory molecules. These changes occur within 1-2 d and are irreversible, since neither pinocytosis nor the class II compartment are recovered when the maturation-inducing stimulus is removed. The specificity of the MR and the capacity to respond to inflammatory stimuli maximize the capacity of DCs to present infectious non-self antigens to T cells.
Factors affecting statistical power in the detection of genetic association
Authors: D. Gordon
Journal: Journal of Clinical Investigation (2005)

The mapping of disease genes to specific loci has received a great deal of attention in the last decade, and many advances in therapeutics have resulted. Here we review family-based and population-based methods for association analysis. We define the factors that determine statistical power and show how study design and analysis should be designed to maximize the probability of localizing disease genes.