tbuckley/cabot-search huggingface dataset:
Effects of Interferon Alpha on Vascular Endothelial Growth Factor Gene Transcription and Tumor Angiogenesis
Authors: Z. von Marschall, A. Scholz, T. Cramer, G. Schafer, M. Schirner, K. Oberg, B. Wiedenmann, M. Hocker, S. Rosewicz
Journal: JNCI Journal of the National Cancer Institute (2003)

Interferon alpha (IFN-alpha) has antiangiogenic activity, although the underlying mechanism of action is unclear. Because human neuroendocrine (NE) tumors are highly vascularized and sensitive to IFN-alpha, we investigated whether the therapeutic effects of IFN-alpha result from an inhibition of angiogenesis mediated by a decrease in vascular endothelial growth factor (VEGF) gene expression.VEGF gene and protein expression was analyzed in NE tumors by immunohistochemistry and in NE tumor cell lines by quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). VEGF promoter-reporter gene constructs containing various deletions or mutations and gel shift assays were used to identify minimal promoter requirements and potential transcription factors. A xenograft nude mouse model (five mice per group) was used to determine the effect of IFN-alpha on tumor growth (NE Bon cells and pancreatic Capan-1 cells) and microvessel density. Liver metastases from eight patients with NE tumors were analyzed for microvessel density, VEGF mRNA content, and VEGF plasma levels before and after initiation of IFN-alpha therapy.NE tumors and cell lines expressed VEGF mRNA and secreted VEGF protein. In vitro, IFN-alpha decreased transcription of VEGF gene expression through an Sp1- and/or Sp3-dependent inhibition of VEGF promoter activity. Compared with vehicle treatment in mice, IFN-alpha inhibited tumor growth by 36% and reduced microvessel density from 56 (95% confidence interval [CI] = 49 to 69) to 37 per x400 Field (95% CI = 32 to 41, P =.015). Patients with NE tumors had lower VEGF plasma levels and reduced VEGF mRNA levels and microvessel density in liver metastasis biopsy material after IFN-alpha treatment.IFN-alpha confers its antitumor activity, at least in part, by its antiangiogenic activity, which results from Sp1- and/or Sp3-mediated inhibition of VEGF gene transcription.
Ischaemia induced development of functional coronary collateral circulation in ponies
Authors: K. S RUGH, H. E GARNER, D. G HATFIELD, J. R MIRAMONTI
Journal: Cardiovascular Research (1987)

Journal Article Ischaemia induced development of functional coronary collateral circulation in ponies Get access KARLA S RUGH, KARLA S RUGH From the John M Dalton Research Center and Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar HAROLD E GARNER, HAROLD E GARNER From the John M Dalton Research Center and Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar DANIEL G HATFIELD, DANIEL G HATFIELD From the John M Dalton Research Center and Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar JOE R MIRAMONTI JOE R MIRAMONTI From the John M Dalton Research Center and Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 21, Issue 10, October 1987, Pages 730–736, https://doi.org/10.1093/cvr/21.10.730 Published: 01 October 1987 Article history Received: 01 October 1986 Accepted: 12 May 1987 Published: 01 October 1987
Effects of <scp>l</scp> -Arginine on Fibroblast Growth Factor 2–Induced Angiogenesis in a Model of Endothelial Dysfunction
Authors: Pierre Voisine, Jian Li, Cesario Bianchi, Tanveer A. Khan, Marc Ruel, Shu-Hua Xu, Jun Feng, Audrey Rosinberg, Tamer Malik, Yasunari Nakai, Frank W. Sellke
Journal: Circulation (2005)

Background— Nitric oxide availability, which is decreased in advanced coronary artery disease associated with endothelial dysfunction, is an important mediator of fibroblast growth factor-2 (FGF-2)–induced angiogenesis. This could explain the disappointing results of FGF-2 therapy in clinical trials despite promising preclinical studies. We examined the influence of l -arginine supplementation to FGF-2 therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. Methods and Results— Eighteen pigs were fed either a normal (NORM, n=6) or high cholesterol diet, with (HICHOL-ARG, n=6) or without (HICHOL, n=6) l -arginine. All pigs underwent ameroid placement on the circumflex artery and 3 weeks later received surgical FGF-2 treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by immunohistochemistry. FGF-2, fibroblast growth receptor-1, endothelial-derived nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and syndecan-4 levels were determined by immunoblotting. Pigs from the HICHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by l -arginine supplementation. FGF-2 treatment was ineffective in the HICHOL group (circumflex/left anterior descending blood flow ratios: 1.01 (rest) and 1.01 (pace), after and before treatment). Addition of l -arginine improved myocardial perfusion in response to FGF-2 at rest (ratio 1.13, P =0.02 versus HICHOL) but not during pacing (ratio 0.94, P =NS), and was associated with increased protein levels of iNOS and eNOS. Conclusion— l -arginine supplementation can partially restore the normal response to endothelium-dependent vasorelaxants and myocardial perfusion in response to FGF-2 treatment in a swine model of hypercholesterolemia-induced endothelial dysfunction. These findings suggest a role for l -arginine in combination with FGF-2 therapy for end-stage coronary artery disease.
Immunoblotting detection of gamma-catenin (plakoglobin) antibody in the serum of a patient with paraneoplastic pemphigus
Authors: M. Ishii, J. Izumi, H. Fujiwara, M. Ito, M. Hamada
Journal: British Journal of Dermatology (2001)

Journal Article Immunoblotting detection of γ‐catenin (plakoglobin) antibody in the serum of a patient with paraneoplastic pemphigus Get access M. Ishii, M. Ishii Department of Dermatology, Niigata University School of Medicine, Asahimachi‐dori 1, Niigata 951‐8510, Japan Search for other works by this author on: Oxford Academic Google Scholar J. Izumi, J. Izumi Department of Dermatology, Niigata University School of Medicine, Asahimachi‐dori 1, Niigata 951‐8510, Japan Search for other works by this author on: Oxford Academic Google Scholar H. Fujiwara, H. Fujiwara Department of Dermatology, Niigata University School of Medicine, Asahimachi‐dori 1, Niigata 951‐8510, Japan Search for other works by this author on: Oxford Academic Google Scholar M. Ito, M. Ito Department of Dermatology, Niigata University School of Medicine, Asahimachi‐dori 1, Niigata 951‐8510, Japan Search for other works by this author on: Oxford Academic Google Scholar M. Hamada M. Hamada Department of Dermatology, Niigata Rosai Hospital, Joetsu, Japan Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 144, Issue 2, 1 February 2001, Pages 377–379, https://doi.org/10.1046/j.1365-2133.2001.04031.x Published: 01 February 2001
Blockade of the Intermediate-Conductance Calcium-Activated Potassium Channel as a New Therapeutic Strategy for Restenosis
Authors: Ralf Köhler, Heike Wulff, Ines Eichler, Marlene Kneifel, Daniel Neumann, Andrea Knorr, Ivica Grgic, Doris Kämpfe, Han Si, Judith Wibawa, Robert Real, Klaus Borner, Susanne Brakemeier, Hans-Dieter Orzechowski, Hans-Peter Reusch, Martin Paul, K. George Chandy, Joachim Hoyer
Journal: Circulation (2003)

Background— Angioplasty stimulates proliferation and migration of vascular smooth muscle cells (VSMC), leading to neointimal thickening and vascular restenosis. In a rat model of balloon catheter injury (BCI), we investigated whether alterations in expression of Ca 2+ -activated K + channels (K Ca ) contribute to intimal hyperplasia and vascular restenosis. Methods and Results— Function and expression of K Ca in mature medial and neointimal VSMC were characterized in situ by combined single-cell RT-PCR and patch-clamp analysis. Mature medial VSMC exclusively expressed large-conductance K Ca (BK Ca ) channels. Two weeks after BCI, expression of BK Ca was significantly reduced in neointimal VSMC, whereas expression of intermediate-conductance K Ca (IKCa1) channels was upregulated. In the aortic VSMC cell line, A7r5 epidermal growth factor (EGF) induced IKCa1 upregulation and EGF-stimulated proliferation was suppressed by the selective IKCa1 blocker TRAM-34. Daily in vivo administration of TRAM-34 to rats significantly reduced intimal hyperplasia by ≈40% at 1, 2, and 6 weeks after BCI. Two weeks of treatment with the related compound clotrimazole was equally effective. Reduction of intimal hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content. Conclusions— The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.
Validation of FEV6 in the elderly: correlates of performance and repeatability
Authors: V Bellia, C Sorino, F Catalano, G Augugliaro, N Scichilone, R Pistelli, C Pedone, R Antonelli-Incalzi
Journal: Thorax (2007)

<h3>Background:</h3> Forced expiratory volume in 6 s (FEV<sub>6</sub>) has been proposed as a more easily measurable parameter than forced vital capacity (FVC) to diagnose airway disease using spirometry. A study was undertaken to estimate FEV<sub>6</sub> repeatability, to identify correlates of a good quality FEV<sub>6</sub> measurement and of volumetric differences between FEV<sub>6</sub> and FVC in elderly patients. <h3>Methods:</h3> 1531 subjects aged 65–100 years enrolled in the SA.R.A project (a cross-sectional multicentre non-interventional study) were examined. FEV<sub>6</sub> was measured on volume-time curves that achieved satisfactory start-of-test and end-of-test criteria. Correlates of FEV<sub>6</sub> achievement were assessed by logistic regression. <h3>Results:</h3> Valid FEV<sub>6</sub> and FVC measurements were obtained in 82.9% and 56.9%, respectively, of spirometric tests with an acceptable start-of-test criterion. Female sex, older age, lower educational level, depression, cognitive impairment and lung restriction independently affected the achievement of FEV<sub>6 </sub>measurement. Good repeatability (difference between the best two values &lt;150 ml) was found in 91.9% of tests for FEV<sub>6</sub> and in 86% for FVC; the corresponding figures in patients with airway obstruction were 94% and 78.4%. Both FEV<sub>6</sub> and FVC repeatability were affected by male sex and lower education. Male sex, airway obstruction and smoking habit were independently associated with greater volumetric differences between FEV<sub>6</sub> and FVC. <h3>Conclusions:</h3> In elderly patients, FEV<sub>6</sub> measurements are more easily achievable and more reproducible than FVC although 1/6 patients in this population were unable to achieve them.
Social-psychological predictors of self-reported actual and intended physical activity in a university workforce sample.
Authors: S Biddle, M Goudas, A Page
Journal: British Journal of Sports Medicine (1994)

This study investigated the social-psychological predictors of self-reported actual and intended physical activity in a university workforce sample. Based on the 'Theory of Planned Behaviour', but with additional variables of benefits, barriers and self-efficacy, it was found that both intended and actual activity could be predicted but only when strenuous activity was considered. In addition, the predictors were different for men and women. Specifically, the best predictors of intention to exercise were attitude, perceived control, benefits and self-efficacy for women, but only attitude for men. Predicting self-reported strenuous activity for women were intention and self-efficacy, and for men intention and attitude. Theoretical and practical implications for attitude research and exercise promotion are discussed.
Advances in Targeting Human Epidermal Growth Factor Receptor-2 Signaling for Cancer Therapy
Authors: Funda Meric-Bernstam, Mien-Chie Hung
Journal: Clinical Cancer Research (2006)

Abstract Human epidermal growth factor receptor (HER)-2 is a member of the HER tyrosine kinase family, which regulates cell growth and proliferation. HER-2 is overexpressed in 20% to 30% of breast cancers and has been associated with an aggressive phenotype and a poorer prognosis, making it an appealing therapeutic target. Since 1998, the anti-HER-2 antibody trastuzumab has been used for the treatment of women with HER-2-positive metastatic breast cancer. Results from large trials have established a role for trastuzumab in the adjuvant setting for the treatment of high-risk primary breast cancer as well. Tyrosine kinase inhibitors that target HER-2 are also very promising therapies and are likely to be incorporated into clinical practice in the near future. HER-2-targeted therapies represent a major step forward in achieving our goal of delivering individualized targeted therapy for breast cancer. However, there are many unanswered questions about the optimal use of these agents. Ongoing research will better elucidate the best combination therapies to overcome resistance to HER-2-targeted agents and will help identify patients at high enough risk to warrant their toxicity.
An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic
Authors: Ariel Fernández, Angela Sanguino, Zhenghong Peng, Eylem Ozturk, Jianping Chen, Alejandro Crespo, Sarah Wulf, Aleksander Shavrin, Chaoping Qin, Jianpeng Ma, Jonathan Trent, Yvonne Lin, Hee-Dong Han, Lingegowda S. Mangala, James A. Bankson, Juri Gelovani, Allen Samarel, William Bornmann, Anil K. Sood, Gabriel Lopez-Berestein
Journal: Journal of Clinical Investigation (2007)

Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity.
REPROGRAMMING OF THE IMMUNE SYSTEM DURING ZINC DEFICIENCY
Authors: Pamela J. Fraker, Louis E. King
Journal: Annual Review of Nutrition (2004)

Thymic atrophy, lymphopenia, and compromised cell- and antibody-mediated responses that cause increased rates of infections of longer duration are the immunological hallmarks of zinc deficiency (ZD) in humans and higher animals. As the deficiency advances, a reprogramming of the immune system occurs, beginning with the activation of the stress axis and chronic production of glucocorticoids that accelerate apoptosis among pre-B and -T cells. This reduces lymphopoiesis and causes atrophy of the thymus. In contrast, myelopoiesis is preserved, thereby providing protection for the first line of immune defense or innate immunity. Changes in gene expression for cytokines, DNA repair enzymes, zinc transporters, signaling molecules, etc., suggest that cells of the immune system are attempting to adapt to the stress of suboptimal zinc. Better understanding of the molecular and cellular changes made in response to inadequate zinc should lead to the development of immunotherapeutic interventions.
Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance
Authors: David S. Ludwig, Nicholas A. Tritos, Jason W. Mastaitis, Rohit Kulkarni, Efi Kokkotou, Joel Elmquist, Bradford Lowell, Jeffrey S. Flier, Eleftheria Maratos-Flier
Journal: Journal of Clinical Investigation (2001)

Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity.
Mutual Regulation between Raf/MEK/ERK Signaling and Y-Box–Binding Protein-1 Promotes Prostate Cancer Progression
Authors: Kenjiro Imada, Masaki Shiota, Kenichi Kohashi, Kentaro Kuroiwa, YooHyun Song, Masaaki Sugimoto, Seiji Naito, Yoshinao Oda
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Y-box–binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial–mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer. Experimental Design: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses. Results: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527–20.508; P &amp;lt; 0.0001]. Conclusion: We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics. Clin Cancer Res; 19(17); 4638–50. ©2013 AACR.
Increased Expression and Activity of RhoA Are Associated With Increased DNA Synthesis and Reduced p27 <sup>Kip1</sup> Expression in the Vasculature of Hypertensive Rats
Authors: Tammy M. Seasholtz, Tong Zhang, Michael R. Morissette, Amy L. Howes, Amy H. Yang, Joan Heller Brown
Journal: Circulation Research (2001)

Abstract— We have previously shown that the function of the small G protein Rho is required for vascular smooth muscle cell proliferation and migration. We hypothesized that changes in Rho or Rho signaling might contribute to enhanced vascular proliferative responses associated with hypertension. Western blot analysis revealed that total RhoA expression was ≈2-fold higher in aortas, tail arteries, and aortic smooth muscle cells (ASMCs) obtained from adult male spontaneously hypertensive rats (SHR) compared with those from Wistar Kyoto rats (WKY). An increase in active GTP-bound RhoA was detected in aortic homogenates by affinity precipitation with the RhoA effector rhotekin and by examining RhoA-[ 35 S]GTPγS binding. RhoA protein and activity were also increased in vessels from rats treated with N -nitro- l -arginine methyl ester to increase blood pressure. Thrombin-stimulated RhoA activation was also significantly greater in ASMCs from SHR. As a functional correlate of these changes in Rho signaling, thrombin-stimulated DNA synthesis was enhanced in tail arteries and ASMCs from SHR. Expression of the cyclin-dependent kinase inhibitor p27 Kip1 was decreased by two thirds in SHR, and this decrease was mimicked in ASMCs by expression of a constitutively active (GTPase-deficient) mutant of RhoA. Wortmannin (10 nmol/L) fully inhibited the decrease in p27 Kip1 induced by RhoA, and a membrane-targeted catalytic subunit of phosphatidylinositol-3 kinase (PI3K [p110 CAAX ]) decreased p27 Kip1 expression, suggesting that RhoA signals through PI3K. These data provide evidence that RhoA brings about changes in DNA synthesis through reduced expression of p27 Kip1 , mediated in part via PI3K, and suggest that increases in RhoA expression and activity contribute to the enhanced vascular responsiveness observed in hypertension.