tbuckley/cabot-search huggingface dataset:
Clinical Significance of CD99 Down-Regulation in Gastric Adenocarcinoma
Authors: Jung Hyun Lee, Seok-Hyung Kim, Li-Hui Wang, Yoon-La Choi, Young Chul Kim, Jin Hee Kim, Tae Sung Park, Yun-Chul Hong, Young Kee Shin
Journal: Clinical Cancer Research (2007)

Abstract Purpose: CD99 is a cell adhesion molecule associated with human tumors. The aim of the present study was to characterize its role in the development and progression of human gastric adenocarcinoma. Experimental Design: The expression of CD99 was investigated in 283 gastric adenocarcinomas and related lesions and 9 gastric carcinoma cell lines. We also analyzed the methylation status of CD99 gene by using methylation-specific PCR and examined loss of heterozygosity (LOH) of this gene locus by using an intragenic marker. Moreover, we assessed whether SP1, a positive transcription factor for CD99, is expressed in these samples. Results: We found that the decreased expression of CD99 was strongly associated with poor survival and unfavorable clinicopathologic variables. Promoter region methylation (15 of 89, 16.9%) and LOH (21 of 74, 28.4%) were observed and significantly associated with CD99 down-regulation (P &amp;lt; 0.05). In addition, most of the gastric adenocarcinoma cases with CD99 down-regulation had reduced expression of SP1 (47 of 103, 45.6%; P &amp;lt; 0.01). This relationship between CD99 and SP1 was consolidated by using SP1 small interfering RNA transfection experiment and CD99 promoter luciferase assay. Furthermore, we showed that CD99 down-regulation was associated with proliferation and migration in gastric carcinoma cell line. Conclusion: These observations suggest that CD99 down-regulation is a critical event in the progression of gastric adenocarcinoma, and CD99 promoter methylation, CD99 LOH, and SP1 down-regulation were responsible for the down-regulation of CD99.
DDB2: A Novel Regulator of NF-κB and Breast Tumor Invasion
Authors: Marie Ennen, Remi Klotz, Nadège Touche, Sophie Pinel, Claire Barbieux, Vanessa Besancenot, Emilie Brunner, Denise Thiebaut, Alain C. Jung, Sonia Ledrappier, Lionel Domenjoud, Joseph Abecassis, François Plénat, Stéphanie Grandemange, Philippe Becuwe
Journal: Cancer Research (2013)

The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-κB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-κB activity by upregulating expression of IκBα by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IκBα gene expression restored NF-κB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting.
Diffusing capacity and pulmonary capillary blood flow at hyperbaric pressures.
Authors: J R Nairn, G G Power, R W Hyde, R E Forster, C J Lambertsen, J Dickson
Journal: Journal of Clinical Investigation (1965)

tissue in milliliters (VT) was measured by plotting the acetylene disappearance with different times of breath holding in each subject (4). The concentrations of neon, carbon monoxide, and acetylene were approximately constant in the inspired mixture, being 0.5%, 0.4%, and 0.5%, respectively, with a balance of oxygen and nitrogen. Four separate inspired mixtures were employed in which the oxygen concentrations were 6%, 21%, 60%, and 98%o. By breathing different concentrations of oxygen for a few breaths followed by a breath of one of the inspired mixtures described, the alveolar oxygen tension of the subject during the breath holding period could be varied at will. Neon, carbon monoxide, acetylene, and carbon dioxide
Interferon gamma upregulates its own gene expression in mouse peritoneal macrophages.
Authors: P Di Marzio, P Puddu, L Conti, F Belardelli, S Gessani
Journal: The Journal of Experimental Medicine (1994)

Interferon gamma (IFN-gamma) exerts a variety of immunoregulatory effects on several cell targets. It is generally assumed that IFN-gamma is specifically produced by T and large granular lymphocytes. In this study, we show that IFN-gamma is constitutively expressed in resting mouse peritoneal macrophages (PM). Treatment of PM with cycloheximide results in a significant accumulation of IFN-gamma mRNA, suggesting that a short-lived IFN-gamma mRNA accumulates when protein synthesis is inhibited. Moreover, treatment of PM with IFN-gamma also results in a clear-cut accumulation of this mRNA. This effect is not observed in murine lymphocytes from mesenteric lymph nodes (which instead produce IFN-gamma after phytohemagglutinin treatment) and in mouse cell lines. The treatment of PM with IFN-gamma also results in secretion of IFN-gamma after 24-48 h. The upregulation of IFN-gamma expression is also found in PM from anti-asialo GM1-treated nude mice. We suggest that the ability of PM to produce this IFN-gamma is indicative of an autocrine mechanism. The macrophage IFN-gamma may play a role in the regulation of cell differentiation and immune response.
Clinical Ecology
Authors: Yank D. Coble
Journal: JAMA (1992)

PHYSICIANS who practice clinical ecology believe that exposure to low levels of environmental substances present in the air or ingested from food and liquids causes in susceptible individuals a variety of ill-defined symptoms affecting nearly every organ system. <h3>MULTIPLE CHEMICAL SENSITIVITY SYNDROME</h3> Most physicians who practice clinical ecology (clinical ecologists) maintain that a number of patients have the multiple chemical sensitivity syndrome (MCSS) (also called clinical ecological illness, environmental illness, chemical AIDS [acquired immunodeficiency syndrome], 20th-century disease, environmental hypersensitivity disease, total allergy syndrome, and cerebral allergy).<sup>1-10</sup>Clinical ecology has been defined as the orientation in medicine in which physicians primarily work with patients to uncover the cause-and-effect relationship between their ill health and food or low-level chemical exposure.<sup>9</sup>Other definitions have been offered and no general agreement exists that clinical ecology and MCSS are synonymous.<sup>8-10</sup>The lack of a clear definition or diagnostic test for MCSS has
Phase II Study of Bevacizumab Plus Temozolomide During and After Radiation Therapy for Patients With Newly Diagnosed Glioblastoma Multiforme
Authors: Albert Lai, Anh Tran, Phioanh L. Nghiemphu, Whitney B. Pope, Orestes E. Solis, Michael Selch, Emese Filka, William H. Yong, Paul S. Mischel, Linda M. Liau, Surasak Phuphanich, Keith Black, Scott Peak, Richard M. Green, Cynthia E. Spier, Tatjana Kolevska, Jonathan Polikoff, Louis Fehrenbacher, Robert Elashoff, Timothy Cloughesy
Journal: Journal of Clinical Oncology (2010)

Purpose This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity. Patients and Methods Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison. Results The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials. Conclusion Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.
Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy
Authors: M Suzuki
Journal: Cardiovascular Research (1998)

Objective: The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF). Methods: We measured the plasma levels of ET-1 and compared the effects of ET-1 (10−10–10−8 M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF. Results: With CHF, the plasma levels of ET-1 (19.7±6.3 vs. 4.1±0.5 fmol/ml, p<0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8–16%) and the peak velocity of shortening (dL/dtmax, 20–35%; p<0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9–13%) and in the velocity of relengthening, dR/dtmax (10–14%; p<0.05). The myocytes' dR/dtmax also decreased by 8–10% (p<0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20–23%, p<0.0 1). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine). Conclusion: ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.
Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis
Authors: J P Iredale, R C Benyon, M J Arthur, W F Ferris, R Alcolado, P J Winwood, N Clark, G Murphy
Journal: Hepatology (1996)

Liver fibrosis results from a relative imbalance between synthesis and degradation of matrix proteins. We have previously described release of the protein collagenase inhibitor, tissue inhibitor of metalloproteinase–1 (TIMP–1), by culture–activated human hepatic stellate cells (HSCs). In this study, we have investigated the relative expression of TIMP–1 and interstitial collagenase in culture–activated rat HSCs and rat models of liver injury and fibrosis. The complementary DNA (cDNA) for rat TIMP–1 was obtained by homology polymerase chain reaction (PCR) and sequenced. By Northern analysis using this probe, TIMP–1 messenger RNA (mRNA) expression was up–regulated with HSC activation by culture on plastic as defined by cellular expression of procollagen–1. Interstitial collagenase mRNA was expressed in early 1. Interstitial collagenase mRNA was expressed in early culture (&lt;4 days) but became undetectable in more activated cells (7–21 days). By activity assay of serum–free cell–conditioned media, TIMP–1 was found to be released in increasingly concentrations with duration of culture on plastic. Expression of TIMP–1 interstitial collagenase, and procollagen–1 mRNAs were studied in rat models of biliary and parenchymal injury (bile duct ligation and CC14 administration) by ribonuclease protein assay. TIMP–1 mRNA expression was increased at 6, 24 hours, and 3 days after bile duct ligation and was also shown to rise in acute CC14 liver injury and remain elevated as the liver became fibrotic. TIMP–1 expression preceded procollagen–1 expression in both models. In contrasts, interstitial collagenase mRNA levels remained similar to control values throughout both models of liver injury. Total cellular RNA from hepatocytes, HSCs, and kupffer cells freshly isolated from livers after acute CC14 injury was subjected to Northern analysis. TIMP–1 transcripts were observed in nonparenchymal cells only. We suggest that increased expression of TIMP–1 relative to interstitial collagenase by HSCs may promote progression of liver fibrosis in these rat models by preventing degradation of secreted collagens.
Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2
Authors: Stefan Werner, Benedikt Brors, Julia Eick, Elsa Marques, Vivian Pogenberg, Annabel Parret, Dirk Kemming, Antony W. Wood, Henrik Edgren, Hans Neubauer, Thomas Streichert, Sabine Riethdorf, Upasana Bedi, Irène Baccelli, Manfred Jücker, Roland Eils, Tanja Fehm, Andreas Trumpp, Steven A. Johnsen, Juha Klefström, Matthias Wilmanns, Volkmar Müller, Klaus Pantel, Harriet Wikman
Journal: Cancer Discovery (2015)

Regulatory pathways that drive early hematogenous dissemination of tumor cells are insufficiently defined. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to define patients with early disseminated breast cancer and identified low retinoic acid-induced 2 (RAI2) expression to be significantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERα, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells.We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors. We specified the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer.
Interferon Alpha Adjuvant Therapy in Patients With High-Risk Melanoma: A Systematic Review and Meta-analysis
Authors: S. Mocellin, S. Pasquali, C. R. Rossi, D. Nitti
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundBased on previous meta-analyses of randomized controlled trials (RCTs), the use of interferon alpha (IFN-α) in the adjuvant setting improves disease-free survival (DFS) in patients with high-risk cutaneous melanoma. However, RCTs have yielded conflicting data on the effect of IFN-α on overall survival (OS).
Effects of Continuous Positive Airway Pressure on Cerebral Vascular Response to Hypoxia in Patients with Obstructive Sleep Apnea
Authors: Glen E. Foster, Patrick J. Hanly, Michele Ostrowski, Marc J. Poulin
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

The mechanism leading to increased risk of stroke in patients with obstructive sleep apnea (OSA) is unknown. It may occur through alteration in the regulation of cerebral blood flow, reflected in part by the response of the cerebral vasculature to hypoxia. We hypothesized that the cerebrovascular response to hypoxia is reduced in patients with OSA.To determine the cerebral blood flow response to hypoxia in patients with OSA.The cerebral blood flow response to 20 minutes of isocapnic hypoxia was measured in eight male patients with OSA before and after 4 to 6 weeks of continuous positive airway pressure (CPAP) therapy and in 10 matched healthy control subjects.The cerebral blood flow response to hypoxia was significantly lower in patients with OSA compared with control subjects (0.56 +/- 0.10 vs. 0.97 +/- 0.09% [mean +/- SE] change in blood flow velocity per % desaturation; p=0.007). After CPAP therapy, the cerebral blood flow response to hypoxia was similar between patients with OSA and control subjects (1.08 +/- 0.15 vs. 0.92 +/- 0.13% change in blood flow velocity per % desaturation; p=0.4). Moderately strong correlations were found between the cerebral blood flow response to hypoxia and the apnea-hypopnea index (r=-0.57; p=0.04) and nocturnal oxyhemoglobin saturation (r=0.48; p=0.01).The cerebral blood flow response to hypoxia is significantly reduced in patients with OSA. Treatment of OSA with CPAP increases the cerebral blood flow response to hypoxia to normal levels. An attenuated cerebrovascular response to hypoxia in patients with OSA may contribute to their elevated risk of stroke.
Resveratrol is superior to dexamethasone in suppressing cytokine release from human airway smooth muscle cells exposed to lipoteichoic acid in COPD
Authors: Jürgen Knobloch, Chiara Wahl, Maria Feldmann, Erich Stoelben, David Jungck, Andrea Koch
Journal: European Respiratory Journal (2013)

Lipoteichoic acid (LTA) from gram-positive bacteria induces cytokine expression. This contributes to infection defense, but also increases steroid-resistant airway inflammation in COPD leading to exacerbations. Alternative anti-inflammatory therapies are required, and the plant polyphenol resveratrol (Res) is currently under discussion. Res is an activator of sirtuins, the class III of histone deacetylases (HDACs).  Hypothesis: human airway smooth muscle cells (HASMCs) release COPD-related cytokines in response to LTA; Res is superior to the steroid dexamethasone (Dex) in suppressing these cytokines.  Ex vivo-cultivated HASMCs of patients with COPD were treated with Res or Dex before stimulation with LTA. CCL2, GM-CSF, IL-6 and IL-8 were analyzed in supernatants by ELISA. Drug effects were investigated in dose-response experiments in the absence and presence of trichostatin A (TSA, blocks class I/II HDACs) and EX527 (blocks the sirtuin SIRT1).  In dose-response tests, LTA induced robust releases of CCL2, GM-CSF, IL-6, and IL-8 (each p max : 87% vs. 65% reduction), IL-6 (82% vs. 69%) and IL-8 (52% vs. 8%) in LTA-exposed HASMCs. Both drugs similarly reduced GM-CSF. Res effects were partially reversed by EX527 (p  HASMCs contribute to the enhancement of airway inflammation in COPD exacerbations caused by bacterial infections. In HASMCs, Res suppresses cytokine expression via activation of SIRT1, but Dex via class I/II HDACs. Res might be superior to steroids in therapy of exacerbations.
Estrogen-Receptor Status and Outcomes of Modern Chemotherapy for Patients With Node-Positive Breast Cancer
Authors: Donald A. Berry, Constance Cirrincione, I. Craig Henderson, Marc L. Citron, Daniel R. Budman, Lori J. Goldstein, Silvana Martino, Edith A. Perez, Hyman B. Muss, Larry Norton, Clifford Hudis, Eric P. Winer
Journal: JAMA (2006)

made in the treatment of early stage breast cancer.In patients with hormonesensitive tumors, tamoxifen reduces the risk of recurrence and death by more than 30%. 1 Moreover, treatment with aromatase inhibitors in place of or sequentially with tamoxifen further reduces the risk of recurrence in postmenopausal women with estrogenreceptor (ER)-positive tumors. [2]][4] In the absence of treatment, ER status is a weak prognostic factor, but it is a strong predictive factor in the sense that it identifies patients who may benefit from endocrine therapy.With appropriate endocrine therapy, patients with ER-positive disease have substantially better prognoses as a group than do those with ER-negative disease.Evidence is accumulating that improvements in chemotherapy disproportionately benefit patients with ER-
Glutamate mediates platelet activation through the AMPA receptor
Authors: Craig N. Morrell, Henry Sun, Masahiro Ikeda, Jean-Claude Beique, Anne Marie Swaim, Emily Mason, Tanika V. Martin, Laura E. Thompson, Oguz Gozen, David Ampagoomian, Rolf Sprengel, Jeffrey Rothstein, Nauder Faraday, Richard Huganir, Charles J. Lowenstein
Journal: The Journal of Experimental Medicine (2008)

Glutamate is an excitatory neurotransmitter that binds to the kainate receptor, the N-methyl-D-aspartate (NMDA) receptor, and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR). Each receptor was first characterized and cloned in the central nervous system (CNS). Glutamate is also present in the periphery, and glutamate receptors have been identified in nonneuronal tissues, including bone, heart, kidney, pancreas, and platelets. Platelets play a central role in normal thrombosis and hemostasis, as well as contributing greatly to diseases such as stroke and myocardial infarction. Despite the presence of glutamate in platelet granules, the role of glutamate during hemostasis is unknown. We now show that activated platelets release glutamate, that platelets express AMPAR subunits, and that glutamate increases agonist-induced platelet activation. Furthermore, we demonstrate that glutamate binding to the AMPAR increases intracellular sodium concentration and depolarizes platelets, which are important steps in platelet activation. In contrast, platelets treated with the AMPAR antagonist CNQX or platelets derived from GluR1 knockout mice are resistant to AMPA effects. Importantly, mice lacking GluR1 have a prolonged time to thrombosis in vivo. Our data identify glutamate as a regulator of platelet activation, and suggest that the AMPA receptor is a novel antithrombotic target.