tbuckley/cabot-search huggingface dataset:
Overexpression of Vascular Endothelial Growth Factor and the Development of Post-Transplantation Cancer
Authors: Aninda Basu, Alan G. Contreras, Dipak Datta, Evelyn Flynn, Liling Zeng, Herbert T. Cohen, David M. Briscoe, Soumitro Pal
Journal: Cancer Research (2008)

Abstract Cancer is an increasing and major problem after solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors. We propose that the effect of calcineurin inhibitors on the expression of vascular endothelial growth factor (VEGF) leads to an angiogenic milieu that favors tumor growth. Here, we used 786-0 human renal cancer cells to investigate the effect of cyclosporine (CsA) on VEGF expression. Using a full-length VEGF promoter-luciferase construct, we found that CsA markedly induced VEGF transcriptional activation through the protein kinase C (PKC) signaling pathway, specifically involving PKCζ and PKCδ isoforms. Moreover, CsA promoted the association of PKCζ and PKCδ with the transcription factor Sp1 as observed by immunoprecipitation assays. Using promoter deletion constructs, we found that CsA-mediated VEGF transcription was primarily Sp1 dependent. Furthermore, CsA-induced and PKC-Sp1–mediated VEGF transcriptional activation was partially inhibited by von Hippel-Lindau protein. CsA also promoted the progression of human renal tumors in vivo, wherein VEGF is overexpressed. Finally, to evaluate the in vivo significance of CsA-induced VEGF overexpression in terms of post-transplantation tumor development, we injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully MHC mismatched cardiac transplants. We observed that therapeutic doses of CsA increased tumor size and VEGF mRNA expression and also enhanced tumor angiogenesis. However, coadministration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. Collectively, these findings define PKC-mediated VEGF transcriptional activation as a key component in the progression of CsA-induced post-transplantation cancer. [Cancer Res 2008;68(14):5689–98]
Long-Term Risk of Colorectal Cancer After Negative Colonoscopy
Authors: Hermann Brenner, Jenny Chang-Claude, Christoph M. Seiler, Michael Hoffmeister
Journal: Journal of Clinical Oncology (2011)

Purpose Colonoscopy is thought to be a powerful and cost-effective tool to reduce colorectal cancer (CRC) incidence and mortality. Empirical evidence for overall and risk group–specific definition of screening intervals is sparse. We aimed to assess the risk of CRC according to time since negative colonoscopy, overall, and by sex, smoking, and family history of CRC, in a large population-based case-control study. Patients and Methods In all, 1,945 patients with CRC and 2,399 population controls were recruited in 22 hospitals and through population registers in the Rhine-Neckar region of Germany from 2003 to 2007. Data on history of colonoscopy and important covariates were obtained by personal interviews and from medical records. Results Compared with people who had never undergone colonoscopy, people with a previous negative colonoscopy had a strongly reduced risk of CRC. Adjusted odds ratios for time windows of 1 to 2, 3 to 4, 5 to 9, 10 to 19, and 20+ years after negative colonoscopy were 0.14 (95% CI, 0.10 to 0.20), 0.12 (95% CI, 0.08 to 0.19), 0.26 (95% CI, 0.18 to 0.39), 0.28 (95% CI, 0.17 to 0.45), and 0.40 (95% CI, 0.24 to 0.66), respectively. Low risks even beyond 10 years after negative colonoscopy were observed for both left- and right-sided CRC and in all risk groups assessed except current smokers, who had a risk similar to that of never smokers with no previous colonoscopy 10 or more years after a negative colonoscopy. Conclusion These results support suggestions that screening intervals for CRC screening by colonoscopy could be longer than the commonly recommended 10 years in most cases, perhaps even among men and people with a family history of CRC, but probably not among current smokers.
Performance on a Virtual Reality Spatial Memory Navigation Task in Depressed Patients
Authors: Neda F. Gould, M. Kathleen Holmes, Bryan D. Fantie, David A. Luckenbaugh, Daniel S. Pine, Todd D. Gould, Neil Burgess, Husseini K. Manji, Carlos A. Zarate
Journal: American Journal of Psychiatry (2007)

Findings on spatial memory in depression have been inconsistent. A navigation task based on virtual reality may provide a more sensitive and consistent measure of the hippocampal-related spatial memory deficits associated with depression.Performance on a novel virtual reality navigation task and a traditional measure of spatial memory was assessed in 30 depressed patients (unipolar and bipolar) and 19 normal comparison subjects.Depressed patients performed significantly worse than comparison subjects on the virtual reality task, as assessed by the number of locations found in the virtual town. Between-group differences were not detected on the traditional measure. The navigation task showed high test-retest reliability.Depressed patients performed worse than healthy subjects on a novel spatial memory task. Virtual reality navigation may provide a consistent, sensitive measure of cognitive deficits in patients with affective disorders, representing a mechanism to study a putative endophenotype for hippocampal function.
Exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence: a population-based birth cohort study
Authors: Ulrike Gehring, Alet H Wijga, Gerard Hoek, Tom Bellander, Dietrich Berdel, Irene Brüske, Elaine Fuertes, Olena Gruzieva, Joachim Heinrich, Barbara Hoffmann, Johan C de Jongste, Claudia Klümper, Gerard H Koppelman, Michal Korek, Ursula Krämer, Dieter Maier, Erik Melén, Göran Pershagen, Dirkje S Postma, Marie Standl, Andrea von Berg, Josep M Anto, Jean Bousquet, Thomas Keil, Henriette A Smit, Bert Brunekreef
Journal: The Lancet Respiratory Medicine (2015)
Using Sindbis Viral Vectors for Specific Detection and Suppression of Advanced Ovarian Cancer in Animal Models
Authors: Jen-Chieh Tseng, Alicia Hurtado, Herman Yee, Brandi Levin, Christopher Boivin, Marta Benet, Stephanie V. Blank, Angel Pellicer, Daniel Meruelo
Journal: Cancer Research (2004)

Abstract We studied the therapeutic value of Sindbis vectors for advanced metastatic ovarian cancer by using two highly reproducible and clinically accurate mouse models: a SCID xenograft model, established by i.p. inoculation of human ES-2 ovarian cancer cells, and a syngenic C57BL/6 model, established by i.p. inoculation of mouse MOSEC ovarian cancer cells. We demonstrate through imaging, histologic, and molecular data that Sindbis vectors systemically and specifically infect/detect and kill metastasized tumors in the peritoneal cavity, leading to significant suppression of the carcinomatosis in both animal models. Use of two different bioluminescent genetic markers for the IVIS Imaging System permitted demonstration, for the first time, of an excellent correlation between vector delivery and metastatic locations in vivo. Sindbis vector infection and growth suppression of murine MOSEC tumor cells indicate that Sindbis tumor specificity is not attributable to a species difference between human tumor and mouse normal cells. Sindbis virus is known to infect mammalian cells using the Mr 67,000 laminin receptor. Immunohistochemical staining of tumor cells indicates that laminin receptor is elevated in tumor versus normal cells. Down-regulated expression of laminin receptor with small interfering RNA significantly reduces the infectivity of Sindbis vectors. Tumor overexpression of the laminin receptor may explain the specificity and efficacy that Sindbis vectors demonstrate for tumor cells in vivo. We show that incorporation of antitumor cytokine genes such as interleukin-12 and interleukin-15 genes enhances the efficacy of the vector. These results suggest that Sindbis viral vectors may be promising agents for both specific detection and growth suppression of metastatic ovarian cancer.
Synthesis of urea after stimulation with amino acids: relation to liver function.
Authors: H Vilstrup
Journal: Gut (1980)

Hepatic urea synthesis is the organism9s main channel for the disposal of nitrogen and it may be an 9essential9 liver function. In six control subjects and five patients with cirrhosis of the liver urea synthesis was studied during continuous infusion for six to 24 hours of about 3 mmol alpha-amino nitrogen/h X kg body weight. The urea synthesis rate was calculated in intervals of two hours as urinary excretion with correction for accumulation in the total body water and for hydrolysis of urea in the gut. The peripheral venous plasma alpha-amino nitrogen concentration increased from 3 to about 14 mmol/l and the urea nitrogen synthesis rate from 25 to about 215 mmol/h. In all cases the urea synthesis rate rose linearly with the alpha-amino concentration throughout the examined range. The slope of this linear relationship is an expression of the hepatic conversion of alpha-amino nitrogen to urea nitrogen (9functional hepatic nitrogen clearance9). The functional hepatic nitrogen clearance was 22.4 l/h in control subjects and 13.7 1/h (P &lt; 0.025) in the patients with cirrhosis. It was correlated with quantitative measures of the liver function (the galactose elimination capacity, r = 0.84, and the clearance of antipyrine, 4 = 0.80). These observations, while confirming the abundant capacity of the urea synthesis system, imply that a given urea synthesis rate requires a higher alpha-amino level in patients with reduced liver function.
Interactions among ACE, kinins and NO
Authors: W Linz
Journal: Cardiovascular Research (1999)

Time for primary review 22 days. 

Angiotensin converting enzyme (ACE) is a transmembrane zinc metallopeptidase that cleaves carboxy-terminal dipeptides from several peptides and is expressed in great amounts in vascular endothelial cells [1,2]. A soluble form of the enzyme is found in plasma which is presumably derived from the membrane-bound form by proteolytic cleavage [3]. ACE plays a major role in the regulation of the vascular tone by converting the biological inactive decapeptide angiotensin I (ANG I) into the vasoconstrictor and proliferative octapeptide angiotensin II (ANG II). In a similar manner, ACE inactivates the vasodilatory nonapeptide bradykinin (BK), which derives from a number of different sources [4].

Endothelium-derived or exogenously added BK exerts its vasodilatory action through stimulation of endothelial B2 kinin receptors thereby causing the synthesis and release of vasodilator substances such as endothelium-derived hyperpolarizing factor (EDHF) [5], prostacyclin and nitric oxide (NO) [6]. Many of the effects of NO on platelets [7], smooth muscle cells [8], and cardiac myocytes [9,10] are mediated by activation of soluble guanylyl cyclase to synthesize cyclic GMP. The biological function of soluble guanylyl cyclase and NO/cyclic GMP in endothelial cells is not yet completely understood. One function of endothelial cyclic GMP may be a negative feed-back mechanism to turn off further NO synthesis [11,12]. Changes in the synthesis of ACE, BK and NO are associated with a number of cardiovascular conditions including hypertension, atherosclerosis or coronary heart disease. ACE inhibitors are able to treat these diseases by both, accumulation of endothelium-derived kinins and the inhibition of ANG II [13,14].

The separate effects of ACE, kinins as well as NO on the cardiovascular system have been thoroughly investigated and described. Since only a small amount of information is available concerning the physiological/pathophysiological significance of … 

* Corresponding author. Tel.: +49-69-305-6868, fax: +49-69-305-81252 wolfgang.linz{at}hmrag.com
Sphingosine Kinase Inhibitors and Cancer: Seeking the Golden Sword of Hercules
Authors: Susan Pyne, Robert Bittman, Nigel J. Pyne
Journal: Cancer Research (2011)

Abstract There is considerable evidence that sphingosine kinases play a key role in cancer progression, which might involve positive selection of cancer cells that have been provided with a survival and growth advantage as a consequence of overexpression of the enzyme. Therefore, inhibitors of sphingosine kinase represent a novel class of compounds that have potential as anticancer agents. Poor inhibitor potency is a major issue that has precluded successful translation of these compounds into the clinic. However, recent discoveries have shown that sphingosine kinase 1 is an allosteric enzyme and that some inhibitors offer improved effectiveness by inducing proteasomal degradation of the enzyme or having nanomolar potency. Herein, we provide a perspective about these recent developments and highlight the importance of translating basic pharmacologic and biochemical findings on sphingosine kinase into new drug discovery programs for treatment of cancer. Cancer Res; 71(21); 6576–82. ©2011 AACR.
γδ T Cells from Tolerized αβ T Cell Receptor (TCR)–deficient Mice Inhibit Contact Sensitivity-Effector T Cells In Vivo, and Their Interferon-γ Production In Vitro
Authors: Marian Szczepanik, Laurel R. Anderson, Hiroko Ushio, Wlodzimierz Ptak, Michael J. Owen, Adrian C. Hayday, Philip W. Askenase
Journal: The Journal of Experimental Medicine (1996)

Contact sensitivity (CS) responses to reactive hapten Ag, such as picryl chloride (PCl) or oxazolone (OX), are classical examples of T cell–mediated immune responses in vivo that are clearly subject to multifaceted regulation. There is abundant evidence that downregulation of CS may be mediated by T cells exposed to high doses of Ag. This is termed high dose Ag tolerance. To clarify the T cell types that effect CS responses and mediate their downregulation, we have undertaken studies of CS in mice congenitally deficient in specific subsets of lymphocytes. The first such studies, using αβ T cell–deficient (TCRα−/−) mice, are presented here. The results clearly show that TCRα−/− mice cannot mount CS, implicating αβ T cells as the critical CS-effector cells. However, TCRα−/− mice can, after high dose tolerance, downregulate α+/+ CS-effector T cells adoptively transferred into them. By mixing ex vivo and then adoptive cell transfers in vivo, the active downregulatory cells in tolerized α−/− mice are shown to include γδ TCR+ cells that also can downregulate interferon-γ production by the targeted CS-effector cells in vitro. Downregulation by γδ cells showed specificity for hapten, but was not restricted by the MHC. Together, these findings establish that γδ T cells cannot fulfill CS-effector functions performed by αβ T cells, but may fulfill an Ag-specific downregulatory role that may be directly comparable to reports of Ag-specific downregulation of IgE antibody responses by γδ T cells. Comparisons are likewise considered with downregulation by γδ T cells occurring in immune responses to pathogens, tumors, and allografts, and in systemic autoimmunity.
Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab
Authors: Marinella Clerico, Irene Schiavetti, Stefania F. De Mercanti, Federico Piazza, Dario Gned, Vincenzo Brescia Morra, Roberta Lanzillo, Angelo Ghezzi, Anna Bianchi, Giuseppe Salemi, Sabrina Realmuto, Patrizia Sola, Francesca Vitetta, Paola Cavalla, Damiano Paolicelli, Maria Trojano, Maria Pia Sormani, Luca Durelli
Journal: JAMA Neurology (2014)

The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS).To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS.The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab.Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod.The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year.No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery.This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug.Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.
Heterogeneity of Left Ventricular Wall Thickening Mechanisms
Authors: Allen Cheng, Tom C. Nguyen, Marcin Malinowski, George T. Daughters, D. Craig Miller, Neil B. Ingels
Journal: Circulation (2008)

Myocardial fibers are grouped into lamina (or sheets) 3 to 4 cells thick. Fiber shortening produces systolic left ventricular (LV) wall thickening primarily by laminar extension, thickening, and shear, but the regional variability and transmural distribution of these 3 mechanisms are incompletely understood.Nine sheep had transmural radiopaque markers inserted into the anterior basal and lateral equatorial LV. Four-dimensional marker dynamics were studied with biplane videofluoroscopy to measure circumferential, longitudinal, and radial systolic strains in the epicardium, midwall, and endocardium. Fiber and sheet angles from quantitative histology allowed transformation of these strains into transmural contributions of sheet extension, thickening, and shear to systolic wall thickening. At all depths, systolic wall thickening in the anterior basal region was 1.6 to 1.9 times that in the lateral equatorial region. Interestingly, however, systolic fiber shortening was identical at each transmural depth in these regions. Endocardial anterior basal sheet thickening was >2 times greater than in the lateral equatorial region (epicardium, 0.16+/-0.15 versus 0.03+/-0.06; endocardium, 0.45+/-0.40 versus 0.17+/-0.09). Midwall sheet extension was >2 times that in the lateral wall (0.22+/-0.12 versus 0.09+/-0.06). Epicardial and midwall sheet shears in the anterior wall were approximately 2 times higher than in the lateral wall (epicardium, 0.14+/-0.07 versus 0.05+/-0.03; midwall, 0.21+/-0.12 versus 0.12+/-0.06).These data demonstrate fundamentally different regional contributions of laminar mechanisms for amplifying fiber shortening to systolic wall thickening. Systolic fiber shortening was identical at each transmural depth in both the anterior and lateral LV sites. However, systolic wall thickening of the anterior site was much greater than that of the lateral site. Fiber shortening drives systolic wall thickening, but sheet dynamics and orientations are of great importance to systolic wall thickening. LV wall thickening and its clinical implications pivot on different wall thickening mechanisms in various LV regions. Attempts to implant healthy contractile cells into diseased hearts or to surgically manipulate LV geometry need to take into account not only cardiomyocyte contraction but also transmural LV intercellular architecture and geometry.
Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler®
Authors: O. Johnell, R. Pauwels, C-G. Löfdahl, L.A. Laitinen, D.S. Postma, N.B. Pride, S.V. Ohlsson
Journal: European Respiratory Journal (2002)

There is a need for studying the effects of long-term inhaled corticosteroid therapy on bone mineral density (BMD) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease (COPD). Patients (n=912, mean age 52 yrs) with mild COPD (mean forced expiratory volume in one second (FEV 1 ) 77% of predicted; mean FEV 1 /slow vital capacity ratio 62%) were randomized to receive budesonide 400 µg, or placebo twice daily via Turbuhaler®. BMD was measured at the L2–L4 vertebrae and the femoral neck, trochanter and Ward's triangle by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24 and 36 months (n=161). Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment (n=653). Previous fractures were present at baseline in 43 budesonide-treated patients (13.4%) and 38 placebo-treated patients (11.5%). New fractures occurred in five budesonide-treated patients, compared with three in the placebo group (p=0.50). There were no significant changes in BMD at any site in budesonide-treated patients, compared with the placebo group, during the course of the study. Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin. In the present study, involving a large group of patients with chronic obstructive pulmonary disease, long-term treatment with budesonide 800 µg·day −1 via Turbuhaler® had no clinically significant effects on bone mineral density or fracture rates.
Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis
Authors: Eileen S. Alexander, Lisa J. Martin, Margaret H. Collins, Leah C. Kottyan, Heidi Sucharew, Hua He, Vincent A. Mukkada, Paul A. Succop, J. Pablo Abonia, Heather Foote, Michael D. Eby, Tommie M. Grotjan, Alexandria J. Greenler, Evan S. Dellon, Jeffrey G. Demain, Glenn T. Furuta, Larry E. Gurian, John B. Harley, Russell J. Hopp, Amir Kagalwalla, Ajay Kaul, Kari C. Nadeau, Richard J. Noel, Philip E. Putnam, Karl F. von Tiehl, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2014)