tbuckley/cabot-search huggingface dataset:
Endoglin Regulates Cyclooxygenase-2 Expression and Activity
Authors: Mirjana Jerkic, Juan V. Rivas-Elena, Juan F. Santibanez, Marta Prieto, Alicia Rodríguez-Barbero, Fernando Perez-Barriocanal, Miguel Pericacho, Miguel Arévalo, Calvin P.H. Vary, Michelle Letarte, Carmelo Bernabeu, Jose M. López-Novoa
Journal: Circulation Research (2006)

The endoglin heterozygous (Eng(+/-)) mouse, which serves as a model of hereditary hemorrhagic telangiectasia (HHT), was shown to express reduced levels of endothelial NO synthase (eNOS) with impaired activity. Because of intricate changes in vasomotor function in the Eng(+/-) mice and the potential interactions between the NO- and prostaglandin-producing pathways, we assessed the expression and function of cyclooxygenase (COX) isoforms. A specific upregulation of COX-2 in the vascular endothelium and increased urinary excretion of prostaglandin E(2) were observed in the Eng(+/-) mice. Specific COX-2 inhibition with parecoxib transiently increased arterial pressure in Eng(+/-) but not in Eng(+/+) mice. Transfection of endoglin in L6E9 myoblasts, shown previously to stimulate eNOS expression, led to downregulation of COX-2 with no change in COX-1. In addition, COX-2 promoter activity and protein levels were inversely correlated with endoglin levels, in doxycyclin-inducible endothelial cells. Chronic NO synthesis inhibition with N(omega)-nitro-l-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng(+/+) mice. N(omega)-nitro-l-arginine methyl ester also increased COX-2 expression and promoter activity in doxycyclin-inducible endoglin expressing endothelial cells, but not in control cells. The level of COX-2 expression following transforming growth factor-beta1 treatment was less in endoglin than in mock transfected L6E9 myoblasts and was higher in human endothelial cells silenced for endoglin expression. Our results indicate that endoglin is involved in the regulation of COX-2 activity. Furthermore, reduced endoglin levels and associated impaired NO production may be responsible, at least in part, for augmented COX-2 expression and activity in the Eng(+/-) mice.
MicroRNA-181b regulates NF-κB–mediated vascular inflammation
Authors: Xinghui Sun, Basak Icli, Akm Khyrul Wara, Nathan Belkin, Shaolin He, Lester Kobzik, Gary M. Hunninghake, Miguel Pinilla Vera, Timothy S. Blackwell, Rebecca M. Baron, Mark W. Feinberg
Journal: Journal of Clinical Investigation (2012)

EC activation and dysfunction have been linked to a variety of vascular inflammatory disease states. The function of microRNAs (miRNAs) in vascular EC activation and inflammation remains poorly understood. Herein, we report that microRNA-181b (miR-181b) serves as a potent regulator of downstream NF-κB signaling in the vascular endothelium by targeting importin-α3, a protein that is required for nuclear translocation of NF-κB. Overexpression of miR-181b inhibited importin-α3 expression and an enriched set of NF-κB–responsive genes such as adhesion molecules VCAM-1 and E-selectin in ECs in vitro and in vivo. In addition, treatment of mice with proinflammatory stimuli reduced miR-181b expression. Rescue of miR-181b levels by systemic administration of miR-181b “mimics” reduced downstream NF-κB signaling and leukocyte influx in the vascular endothelium and decreased lung injury and mortality in endotoxemic mice. In contrast, miR-181b inhibition exacerbated endotoxin-induced NF-κB activity, leukocyte influx, and lung injury. Finally, we observed that critically ill patients with sepsis had reduced levels of miR-181b compared with control intensive care unit (ICU) subjects. Collectively, these findings demonstrate that miR-181b regulates NF-κB–mediated EC activation and vascular inflammation in response to proinflammatory stimuli and that rescue of miR-181b expression could provide a new target for antiinflammatory therapy and critical illness.
From Bench to Bedside
Authors: IAN W. RODGER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The discovery of leukotrienes dates back to the period between 1938 and 1940. During this period Kellaway, Feldberg, Trethewie, and Holden published the results of a series of experiments on snake venoms that led them to conclude that there is formed from tissue constituents by enzymic action of the venoms a 'slow-reaction smooth muscle-stimulating substance' which may largely determine the nature of the responses (1, 2). It was, however, in their seminal paper in 1940, using guinea pigs sensitized to egg albumin, that Kellaway and Trethewie (3) coined the term SRS and concluded that SRS was formed by the action of antigen upon sensitized tissue. It was not until some 20 yr later, when Brocklehurst was performing elegant experiments on perfused guinea pig lungs, that he confirmed the release of SRS-like activity on anaphylactic challenge of sensitized tissue (4). In his article Brocklehurst named this biological material slow-reacting substance of anaphylaxis (SRS-A) to differentiate it from other material that could induce slow-reacting contractions. Thus, the term SRS-A was born. Despite intensive research efforts by a wide variety of scientists it was not until 1979 that the chemical constituents of SRS-A were identified, by B. Samuelsson and colleagues at the Karolinska Institute in Stockholm, as the cysteinyl leukotrienes (LTs), namely LTC 4 , LTD 4 , and LTE 4  (5, 6). In the period up until the chemical elucidation of SRS-A it had become progressively more widely accepted that SRS-A played a pivotal role in the bronchoconstriction that is one of the hallmarks of acute asthma attacks. Thus, the seminal discovery that the cysteinyl leukotrienes were the active principle of SRS-A and the elucidation of their biosynthetic pathway from arachidonic acid were key events that provided a rational basis for the design of molecules designed to interfere with these events. Not surprisingly, several pharmaceutical companies (e.g., Merck, ICI [now Zeneca], Abbott, Smith Kline & French [now SmithKline Beecham], Bayer, Lilly, Ono, Ciba Geigy [now Novartis]) mounted research programs that were designed to discover molecules that either inhibited leukotriene biosynthesis or blocked the receptors via which the leukotrienes exerted their effects. The purpose of this article is to review some of the hurdles that are an inevitable component of the drug discovery process. In the interests of brevity, focus is directed particularly at the discovery of drugs by Merck designed to antagonize the cysteinyl leukotriene receptors. This focus, however, in no way diminishes or dismisses the significance of the complementary approach of inhibiting leukotriene biosynthesis, far from it. Indeed, 5-lipoxygenase-activating protein (FLAP) inhibitors have been developed by several companies including Merck (7, 8), and a direct 5-lipoxygenase inhibitor, zileuton, by Abbott (9).
PKC-β1 Mediates Glucose-Induced Akt Activation and TGF-β1 Upregulation in Mesangial Cells
Authors: Dongcheng Wu, Fangfang Peng, Baifang Zhang, Alistair J. Ingram, Darren J. Kelly, Richard E. Gilbert, Bo Gao, Joan C. Krepinsky
Journal: Journal of the American Society of Nephrology (2009)

Accumulation of glomerular matrix is a hallmark of diabetic nephropathy. The serine/threonine kinase Akt mediates glucose-induced upregulation of collagen I in mesangial cells through transactivation of the EGF receptor (EGFR). In addition, in renal tubular cells, glucose-induced secretion of TGF-β requires phosphoinositide-3-OH kinase, suggesting a possible role for Akt in the modulation of TGF-β expression, but the mechanisms of Akt activation and its involvement in TGF-β regulation are unknown. Here, in primary mesangial cells, high glucose induced AktS473 phosphorylation, which correlates with its activation, in a protein kinase C β (PKC-β)-dependent manner. Glucose led to PKC-β1 membrane translocation and association with Akt, and PKC-β1 immunoprecipitated from glucose-treated cells phosphorylated recombinant Akt on S473. PKC is known to mediate glucose-induced TGF-β1 upregulation through the transcription factor AP-1; here, inhibitors of phosphoinositide-3-OH kinase, PKC-β and Akt, and dominant-negative Akt all prevented glucose-induced activation of AP-1 and upregulation of TGF-β1. Finally, pharmacologic and dominant negative inhibition of EGFR blocked glucose-induced activation of PKC-β1, phosphorylation of AktS473, activation of AP-1, and upregulation of TGF-β1. <i>In vivo</i>, the PKC-β inhibitor ruboxistaurin prevented Akt activation in the renal cortex of diabetic rats. In conclusion, PKC-β1 is an Akt S473 kinase in glucose-treated mesangial cells, and TGF-β1 transcriptional upregulation requires EGFR/PKC-β1/Akt signaling. New therapeutic approaches for diabetic nephropathy may result from targeting components of this pathway, particularly the initial EGFR transactivation.
Dacarbazine, Cisplatin, and Interferon-Alfa-2b With or Without Interleukin-2 in Metastatic Melanoma: A Randomized Phase III Trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group
Authors: Ulrich Keilholz, Cornelis J.A. Punt, Martin Gore, Wim Kruit, Poulam Patel, Danielle Lienard, Jose Thomas, Thomas M. Proebstle, Alexander Schmittel, Dirk Schadendorf, Thierry Velu, Sylvie Negrier, Ulrich Kleeberg, Frederic Lehman, Stefan Suciu, Alexander M.M. Eggermont
Journal: Journal of Clinical Oncology (2005)

Based on phase II trial results, chemoimmunotherapy combinations have become the preferred treatment for patients with metastatic melanoma in many institutions. This study was performed to determine whether interleukin-2 (IL-2) as a component of chemoimmunotherapy influences survival of patients with metastatic melanoma.Patients with advanced metastatic melanoma were randomly assigned to receive dacarbazine 250 mg/m2 and cisplatin 30 mg/m2 on days 1 to 3 combined with interferon-alfa-2b 10 x 10(6) U/m2 subcutaneously on days 1 through 5 without (arm A) or with (arm B) a high-dose intravenous decrescendo regimen of IL-2 on days 5 through 10 (18 x 10(6) U/m2/6 hours, 18 x 10(6) U/m2/12 hours, 18 x 10(6) U/m2/24 hours, and 4.5 x 10(6) U/m2 for 3 x 24 hours). Treatment cycles were repeated in the absence of disease progression every 28 days to a maximum of four cycles.Three hundred sixty-three patients with advanced metastatic melanoma were accrued. The median survival was 9 months in both arms, with a 2-year survival rate of 12.9% and 17.6% in arms A and B, respectively (P = .32; hazard ratio, 0.90; 95% CI, 0.72 to 1.11). There was also no statistically significant difference regarding progression-free survival (median, 3.0 v 3.9 months) and response rate (22.8% v 20.8%).Despite its activity in melanoma as a single agent or in combination with interferon-alfa-2b, the chosen schedule of IL-2 added to the chemoimmunotherapy combination had no clinically relevant activity.
Sunbed use by children aged 8-18 years in Denmark in 2008: a cross-sectional study
Authors: A.F. Krarup, B. Køster, C. Thorgaard, A. Philip, I.H. Clemmensen
Journal: British Journal of Dermatology (2011)

Journal Article Sunbed use by children aged 8–18 years in Denmark in 2008: a cross‐sectional study Get access A.F. Krarup, A.F. Krarup Department of Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, DK‐2100 Copenhagen, Denmark E‐mail: annkra@cancer.dk Search for other works by this author on: Oxford Academic Google Scholar B. Køster, B. Køster Department of Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, DK‐2100 Copenhagen, Denmark Search for other works by this author on: Oxford Academic Google Scholar C. Thorgaard, C. Thorgaard Department of Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, DK‐2100 Copenhagen, Denmark Search for other works by this author on: Oxford Academic Google Scholar A. Philip, A. Philip Department of Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, DK‐2100 Copenhagen, Denmark Search for other works by this author on: Oxford Academic Google Scholar I.H. Clemmensen I.H. Clemmensen Department of Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, DK‐2100 Copenhagen, Denmark Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 165, Issue 1, 1 July 2011, Pages 214–216, https://doi.org/10.1111/j.1365-2133.2011.10352.x Published: 01 July 2011
E-Predict: a computational strategy for species identification based on observed DNA microarray hybridization patterns.
Authors: Anatoly Urisman, Kael F Fischer, Charles Y Chiu, Amy L Kistler, Shoshannah Beck, David Wang, Joseph L DeRisi
Journal: Genome biology (2005)

Abstract DNA microarrays may be used to identify microbial species present in environmental and clinical samples. However, automated tools for reliable species identification based on observed microarray hybridization patterns are lacking. We present an algorithm, E-Predict, for microarray-based species identification. E-Predict compares observed hybridization patterns with theoretical energy profiles representing different species. We demonstrate the application of the algorithm to viral detection in a set of clinical samples and discuss its relevance to other metagenomic applications.
Breast Differentiation and Its Implication in Cancer Prevention
Authors: Jose Russo, Daniel Mailo, Yun-Fu Hu, Gabriela Balogh, Fathima Sheriff, Irma H. Russo
Journal: Clinical Cancer Research (2005)

Sporadic breast cancer is a fatal disease most frequently diagnosed in American women from all ethnic groups, suggesting that primary prevention should be the ultimate goal for breast cancer control. We have developed a novel paradigm for breast cancer prevention arising from the well-established knowledge that an early first full-term pregnancy protects the breast against neoplastic transformation, as well as from our studies of the biological principle underlying this protection. We have shown experimentally that the first pregnancy induces the expression of a specific genomic signature in the breast that results from the completion of a cycle in this organ's differentiation driven by the reproductive process. This signature, in turn, is a biomarker associated with a possible overall lifetime decrease in breast cancer risk. We have shown in an experimental model that a short treatment with human chorionic gonadotropin, a placental hormone secreted during pregnancy, induces the same genomic signature that occurs in pregnancy, inhibiting not only the initiation but also the progression of mammary carcinomas, and stopping the development of early lesions such as intraductal proliferations and carcinoma in situ. These observations indicate that human chorionic gonadotropin given for a very short period, only until this genomic signature is acquired, has significant potential as a chemopreventive agent, protecting the normal cell from becoming malignant. This is a novel concept which challenges the current knowledge that a chemopreventive agent needs to be given for a long period of time to suppress a metabolic pathway or abrogate the function of an organ.
Cytokeratin 10 and Cytokeratin 19: Predictive Markers for Poor Prognosis in Hepatocellular Carcinoma Patients after Curative Resection
Authors: Xin-Rong Yang, Yang Xu, Guo-Ming Shi, Jia Fan, Jian Zhou, Yuan Ji, Hui-Chuan Sun, Shuang-Jian Qiu, Bing Yu, Qiang Gao, Yi-Zhou He, Weng-Zhen Qin, Rong-Xin Chen, Guo-Huan Yang, Bing Wu, Qing Lu, Zhi-Quan Wu, Zhao-You Tang
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Cytokeratin 10 (CK10) was found to be expressed differently in human hepatocellular carcinoma (HCC) cell lines with different metastatic potentials in our previous research. The aim of this study was to assess the value of CK10 alone or in combination with cytokeratin 19 (CK19) in predicting tumor recurrence after curative resection in HCC patients. Experimental Design: CK10 expression in stepwise metastatic HCC cell lines and tumor tissues from 50 HCC patients was investigated using immunofluorescence assay, quantitative real-time reverse transcription-PCR, and Western blot analyses. Tumor tissue microarrays of 300 HCC patients who underwent curative resection between 1997 and 2000 were used to detect the expressions of CK10 and CK19. Clinicopathologic data for these patients were evaluated. The prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. Results: CK10 was overexpressed in the high metastatic HCC cell line and in tumor tissues of recurrent patients. Both univariate and multivariate analyses revealed that CK10 was a significant predictor for overall survival (OS) and disease-free survival, and that CK19 was a significant predictor for OS. CK10 expression was correlated with poor prognosis regardless of α-fetoprotein, tumor-node-metastasis stage, and vascular invasion. The 7-year OS and disease-free survival rates in CK10+ and/or CK19+ patients were 30.0% and 37.6%, respectively, which were significantly lower than that of CK10−/CK19− patients (56.1% and 60.0%, respectively; P &amp;lt; 0.001). Conclusion: CK10 is associated with HCC invasiveness. CK10 alone, or in combination with CK19, can be a novel predictor for poor prognosis of HCC patients after curative resection.
Cyclic adenosine monophosphate response to prostaglandin E2 on subpopulations of human lymphocytes.
Authors: J S Goodwin, P A Kaszubowski, R C Williams
Journal: The Journal of Experimental Medicine (1979)

Receptors for prostaglandin E2 or histamine were measured on subpopulations of human lymphocytes, using the cyclic AMP increase after exposure to prostaglandin or histamine as an indicator for the presence of receptors. The cyclic AMP response to prostaglandin E2 was similar in unfractionated lymphocytes and the T-enriched and T-depleted fractions. Within the T-enriched population, T cells bearing a receptor for the Fc portion of IgG (T gamma-cells) had a 27.4-fold rise in cyclic AMP after exposure to prostaglandin E2, whereas the remaining T cells (non-T gamma cells) had a fourfold increase. It would appear that prostaglandin receptors are concentrated on a small subfraction of T gamma cells, comprising approximately 15% of the T-cell population. The cyclic AMP response to histamine was less than twofold in all lymphocyte fractions.
THE ISOLATED PERFUSED BOVINE LIVER
Authors: Niles D. Chapman, Patrick D. Goldsworthy, Wade Volwiler, Lloyd M. Nyhus, Andrew J. Martinis
Journal: The Journal of Experimental Medicine (1961)

1. A procedure is described for surgically isolating and artificially perfusing the liver of the young bovine. Heparinized autogenous blood from the hepatectomized animal diluted with Krebs-Ringer-bicarbonate solution is employed as the perfusate. 2. This preparation has been satisfactorily reproducible in this laboratory in more than 90 separate sequential perfusions. Absence of a sensitive hepatic venous smooth musculature contributes to the ability to maintain satisfactory perfusion for as long as 24 hours. 3. The perfusate was usually maintained bacterially free for at least the first 12 hours of perfusion without the use of antibiotics. The perfusate was maintained at normal body temperature and, by varying the CO2 content of the oxygenating gas, within a physiological pH range. The importance of these features when studying problems of intermediary biochemistry and ultrastructure is emphasized. 4. The liver of the bovine calf is sufficiently large to permit (a) simultaneous and independent perfusion through the hepatic artery and portal vein, and (b) repeated sampling of hepatic tissue without interruption of the circulation. 5. Excellent, viable condition of the isolated liver, throughout many hours of perfusion, was demonstrated by steady state of oxygen consumption, efficient clearance of bromsulphalein dye, continuous secretion of bile, constancy of blood flows and pressures, and very minimal alterations from normal in histologic and ultrastructural detail.
Randomized, Double-Blind, Controlled Trial of Early Endoscopic Ultrasound–Guided Celiac Plexus Neurolysis to Prevent Pain Progression in Patients With Newly Diagnosed, Painful, Inoperable Pancreatic Cancer
Authors: Jonathan M. Wyse, Marco Carone, Sarto C. Paquin, Mariana Usatii, Anand V. Sahai
Journal: Journal of Clinical Oncology (2011)

Celiac plexus neurolysis (CPN) is currently used as salvage therapy for morphine-resistant pancreatic cancer pain. Endoscopic ultrasound-guided CPN (EUS-CPN) can be performed early, at the time of EUS. We hypothesized that early EUS-CPN would reduce pain and morphine consumption, increase quality of life (QOL), and prolong survival.Patients were eligible if referred for EUS for suspected pancreatic cancer with related pain. If EUS and EUS-guided fine-needle aspiration cytology confirmed inoperable adenocarcinoma, patients were randomly assigned to early EUS-CPN or conventional pain management. Pain scores (7-point Likert scale), morphine equivalent consumption, and QOL scores (Digestive Disease Questionnaire-15) were assessed at 1 and 3 months.Five hundred eighty eligible patients were seen between April 2006 and December 2008. Ninety-six patients were randomly assigned (48 patients per study arm). Pain relief was greater in the EUS-CPN group at 1 month and significantly greater at 3 months (difference in mean percent change in pain score = -28.9 [95% CI, -67.0 to 2.8], P = .09, and -60.7 [95% CI, -86.6 to -25.5], P = .01, respectively). Morphine consumption was similar in both groups at 1 month (difference in mean change in morphine consumption = -1.0 [95% CI, -47.7 to 49.2], P = .99), but tended toward lower consumption at 3 months in the neurolysis group (difference in mean change in morphine consumption = -49.5 [95% CI, -127.5 to 7.0], P = .10). There was no effect on QOL or survival.Early EUS-CPN reduces pain and may moderate morphine consumption in patients with painful, inoperable pancreatic adenocarcinoma. EUS-CPN can be considered in all such patients at the time of diagnostic and staging EUS.
Sensory Adaptation in Naive Peripheral CD4 T Cells
Authors: Katy Smith, Benedict Seddon, Marco A. Purbhoo, Rose Zamoyska, Amanda G. Fisher, Matthias Merkenschlager
Journal: The Journal of Experimental Medicine (2001)

T cell receptor interactions with peptide/major histocompatibility complex (pMHC) ligands control the selection of T cells in the thymus as well as their homeostasis in peripheral lymphoid organs. Here we show that pMHC contact modulates the expression of CD5 by naive CD4 T cells in a process that requires the continued expression of p56lck. Reduced CD5 levels in T cells deprived of pMHC contact are predictive of elevated Ca2+ responses to subsequent TCR engagement by anti-CD3 or nominal antigen. Adaptation to peripheral pMHC contact may be important for regulating naive CD4 T cell responsiveness.