Life Sciences Commons^™

Xk Aprosencephaly And Anencephaly In Sibs, Phillip Townes, Karen Reuter, E. Rosquete, B. Magee

B. Dale Magee

Recent studies have suggested a causal and pathogenetic relationship between holoprosencephaly and anencephaly. In support of the proposed relationship we report a sibship that includes anencephalic male twins and a female infant with a severe form of alobar holoprosencephaly, radial aplasia, and oligodactyly. The upper limb and brain malformations are considered to represent aprosencephaly syndrome. The coexistence of anencephaly and aprosencephaly within a sibship suggests that XK aprosencephaly syndrome may be an autosomal recessive disorder.

Imp3 Expression Is Associated With Poor Outcome And Epigenetic Deregulation In Intrahepatic Cholangiocarcinoma, Yuanyuan Gao, Michelle Yang, Zhong Jiang, Bruce A. Woda, Arthur M. Mercurio, Jianjie Qin, Xinli Huang, Feng Zhang

Arthur M. Mercurio

IMP3 is a fetal protein not expressed in normal adult tissues. IMP3 is an oncoprotein and a useful biomarker for a variety of malignancies and is associated with reduced overall survival of a number of them. IMP3 expression and its prognostic value for patients with intrahepatic cholangiocarcinoma (ICC) have not been well investigated. The molecular mechanism underlying IMP3 expression in human cancer cells remains to be elucidated. Here we investigated IMP3 expression in ICC and adjacent nonneoplastic liver in 72 unifocal primary ICCs from a single institute by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction. IMP3 was specifically expressed in …

Chronic Alcohol-Induced Microrna-155 Contributes To Neuroinflammation In A Tlr4-Dependent Manner In Mice, Dora Lippai, Shashi Bala, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

INTRODUCTION: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-alpha (TNFalpha), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1beta). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-kappaB (NF-kappaB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs) play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. AIM: To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. METHODS: Wild type (WT), miR-155- and TLR4-knockout (KO) mice received 5% ethanol-containing or isocaloric …

Another Armed Cd4(+) T Cell Ready To Battle Hepatocellular Carcinoma, Roniel Cabrera, Gyongyi Szabo

Gyongyi Szabo

No abstract provided.

Parental Mastery Of Continuous Subcutaneous Insulin Infusion Skills And Glycemic Control In Youth With Type 1 Diabetes, Kathleen Mitchell, Kimberley Johnson, Karen Cullen, Mary M. Lee, Olga T. Hardy

Mary M. Lee

OBJECTIVE: The purpose of this study is to determine whether parental knowledge of the continuous subcutaneous insulin infusion (CSII) device affects glycemic control as measured by hemoglobin A1c (A1C) level. SUBJECTS AND METHODS: Parents of children with type 1 diabetes mellitus (T1DM) using CSII completed a 14-item questionnaire. Questions 1-10 were knowledge-based questions that required the parent to extract specific information from their child's CSII device. Questions 11-14 asked parents to provide a self-assessment of their CSII knowledge. RESULTS: Twenty-two parents of youth with T1DM participated in the study. Ten of the youth were in the Low-A1C group (A1C/=8%). Parents …

The Genome Of Anopheles Darlingi, The Main Neotropical Malaria Vector, Osvaldo Marinotti, Adam R. Wespiser, Daniel R. Caffrey, Douglas T. Golenbock, Neal S. Silverman

Neal Silverman

Anopheles darlingi is the principal neotropical malaria vector, responsible for more than a million cases of malaria per year on the American continent. Anopheles darlingi diverged from the African and Asian malaria vectors approximately 100 million years ago (mya) and successfully adapted to the New World environment. Here we present an annotated reference A. darlingi genome, sequenced from a wild population of males and females collected in the Brazilian Amazon. A total of 10 481 predicted protein-coding genes were annotated, 72% of which have their closest counterpart in Anopheles gambiae and 21% have highest similarity with other mosquito species. In …

Prediction Of Dengue Disease Severity Among Pediatric Thai Patients Using Early Clinical Laboratory Indicators, James A. Potts, Robert V. Gibbons, Alan L. Rothman, Anon Srikiatkhachorn, Stephen J. Thomas, Pra-On Supradish, Stephenie C. Lemon, Daniel H. Libraty, Sharone Green, Siripen Kalayanarooj

Sharone Green

BACKGROUND: Dengue virus is endemic in tropical and sub-tropical resource-poor countries. Dengue illness can range from a nonspecific febrile illness to a severe disease, Dengue Shock Syndrome (DSS), in which patients develop circulatory failure. Earlier diagnosis of severe dengue illnesses would have a substantial impact on the allocation of health resources in endemic countries. METHODS AND FINDINGS: We compared clinical laboratory findings collected within 72 hours of fever onset from a prospective cohort children presenting to one of two hospitals (one urban and one rural) in Thailand. Classification and regression tree analysis was used to develop diagnostic algorithms using different …

Mitochondrial Antiviral Signaling Protein Defect Links Impaired Antiviral Response And Liver Injury In Steatohepatitis In Mice, Timea Csak, Angela Dolganiuc, Karen Kodys, Bharath Nath, Jan Petrasek, Shashi Bala, Dora Lippai, Gyongyi Szabo

Gyongyi Szabo

Mitochondrial dysfunction is a pathogenic feature of nonalcoholic steatohepatitis (NASH). NASH complicates hepatotropic viral disease. The mitochondrial antiviral signaling protein (MAVS) is the adapter of helicase receptors involved in sensing double-stranded RNA (dsRNA). We hypothesized that impaired MAVS function may contribute to insufficient antiviral response and liver damage in steatohepatitis. We identified reduced MAVS protein levels and increased MAVS association with the proteasome subunit alpha type 7 (PSMA7) in livers from mice given a methionine-choline-deficient (MCD) diet. Decreased association of MAVS with mitochondria and increased cytosolic cytochrome c indicated mitochondrial damage in steatohepatitis. In vivo administration of the synthetic dsRNA …

An Essential Role For Monocyte Chemoattractant Protein-1 In Alcoholic Liver Injury: Regulation Of Proinflammatory Cytokines And Hepatic Steatosis In Mice, Pranoti Mandrekar, Aditya Ambade, Arlene Lim, Gyongyi Szabo, Donna Catalano

Gyongyi Szabo

The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as …

Fatty Acid And Endotoxin Activate Inflammasomes In Mouse Hepatocytes That Release Danger Signals To Stimulate Immune Cells, Timea Csak, Michal Ganz, Justin Pespisa, Karen Kodys, Angela Dolganiuc, Gyongyi Szabo

Gyongyi Szabo

The pathogenesis of nonalcoholic steatohepatitis (NASH) and inflammasome activation involves sequential hits. The inflammasome, which cleaves pro-interleukin-1beta (pro-IL-1beta) into secreted IL-1beta, is induced by endogenous and exogenous danger signals. Lipopolysaccharide (LPS), a toll-like receptor 4 ligand, plays a role in NASH and also activates the inflammasome. In this study, we hypothesized that the inflammasome is activated in NASH by multiple hits involving endogenous and exogenous danger signals. Using mouse models of methionine choline-deficient (MCD) diet-induced NASH and high-fat diet-induced NASH, we found up-regulation of the inflammasome [including NACHT, LRR, and PYD domains-containing protein 3 (NALP3; cryopyrin), apoptosis-associated speck-like CARD-domain containing …

Evidence That Distinct States Of The Integrin Alpha6beta1 Interact With Laminin And An Adam, M. S. Chen, E. A. Almeida, A. P. Huovila, Y. Takahashi, Leslie M. Shaw, Arthur M. Mercurio, J. M. White

Arthur M. Mercurio

Integrins can exist in different functional states with low or high binding capacity for particular ligands. We previously provided evidence that the integrin alpha6beta1, on mouse eggs and on alpha6-transfected cells, interacted with the disintegrin domain of the sperm surface protein ADAM 2 (fertilin beta). In the present study we tested the hypothesis that different states of alpha6beta1 interact with fertilin and laminin, an extracellular matrix ligand for alpha6beta1. Using alpha6-transfected cells we found that treatments (e.g., with phorbol myristate acetate or MnCl2) that increased adhesion to laminin inhibited sperm binding. Conversely, treatments that inhibited laminin adhesion increased sperm binding. …

Transcriptional Activation Of Integrin Beta6 During The Epithelial-Mesenchymal Transition Defines A Novel Prognostic Indicator Of Aggressive Colon Carcinoma, Richard C. Bates, David I. Bellovin, Courtney Brown, Elizabeth Maynard, Bingyan Wu, Hisaaki Kawakatsu, Dean Sheppard, Peter Oettgen, Arthur M. Mercurio

Arthur M. Mercurio

We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelial-mesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the beta6 integrin subunit and a consequent induction of alphavbeta6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-beta and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of beta6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of …

The Activation Dependent Adhesion Of Macrophages To Laminin Involves Cytoskeletal Anchoring And Phosphorylation Of The Alpha 6 Beta 1 Integrin, Leslie M. Shaw, Jeanne M. Messier, Arthur M. Mercurio

Arthur M. Mercurio

Macrophages require activation with either PMA (Mercurio, A. M., and L. M. Shaw. 1988. J. Cell Biol. 107:1873-1880) or interferon-gamma (Shaw, L. M., and A. M. Mercurio. 1989. J. Exp. Med. 169:303-308) to adhere to a laminin substratum. In the present study, we identified an integrin laminin receptor on macrophages and characterized cellular changes that occur in response to PMA activation that facilitate laminin adhesion. A monoclonal antibody (GoH3) that recognizes the integrin alpha 6 subunit (Sonnenberg, A., H. Janssen, F. Hogervorst, J. Calafat, and J. Hilgers. 1987. J. Biol. Chem. 262:10376-10383) specifically inhibited adhesion to laminin-coated surfaces. This antibody …

Glycogen Synthase Kinase-3 Is An Endogenous Inhibitor Of Snail Transcription: Implications For The Epithelial-Mesenchymal Transition, Robin E. Bachelder, Sang-Oh Yoon, Clara Franci, Antonio Garcia De Herreros, Arthur M. Mercurio

Arthur M. Mercurio

We report that the activity of glycogen synthase kinase-3 (GSK-3) is necessary for the maintenance of the epithelial architecture. Pharmacological inhibition of its activity or reducing its expression using small interfering RNAs in normal breast and skin epithelial cells results in a reduction of E-cadherin expression and a more mesenchymal morphology, both of which are features associated with an epithelial-mesenchymal transition (EMT). Importantly, GSK-3 inhibition also stimulates the transcription of Snail, a repressor of E-cadherin and an inducer of the EMT. We identify NFkappaB as a transcription factor inhibited by GSK-3 in epithelial cells that is relevant for Snail expression. …

Release Of Camp Gating By The Alpha6beta4 Integrin Stimulates Lamellae Formation And The Chemotactic Migration Of Invasive Carcinoma Cells, Kathleen L. O'Connor, Leslie M. Shaw, Arthur M. Mercurio

Arthur M. Mercurio

The alpha6beta4 integrin promotes carcinoma in-vasion by its activation of a phosphoinositide 3-OH (PI3-K) signaling pathway (Shaw, L.M., I. Rabinovitz, H.H.-F. Wang, A. Toker, and A.M. Mercurio. Cell. 91: 949-960). We demonstrate here using MDA-MB-435 breast carcinoma cells that alpha6beta4 stimulates chemotactic migration, a key component of invasion, but that it has no influence on haptotaxis. Stimulation of chemotaxis by alpha6beta4 expression was observed in response to either lysophosphatidic acid (LPA) or fibroblast conditioned medium. Moreover, the LPA-dependent formation of lamellae in these cells is dependent upon alpha6beta4 expression. Both lamellae formation and chemotactic migration are inhibited or "gated" by …

Body Mass Index, Treatment Practices, And Mortality In Patients With Acute Heart Failure, Timothy Fitzgibbons, Olga Hardy, Darleen Lessard, Joel Gore, Jorge Yarzebski, Robert Goldberg

Jorge L. Yarzebski

OBJECTIVES: Obesity is associated with an increased risk of heart failure (HF). Among patients presenting with acute HF, however, differences in clinical characteristics, treatment regimens, and short-term prognosis of varying weights are largely unknown, particularly from a broader population-based perspective. METHODS: A total of 3722 patients admitted with acute HF to 11 greater Worcester (Massachusetts, USA) hospitals during 1995 and 2000 were categorized as being lean (n = 216), normal weight (n = 1465), overweight (n = 1007), or obese (n = 1034) at the time of hospitalization. RESULTS: Obese patients with decompensated HF were significantly younger (mean age = …

Multidecade-Long Trends (1986-2005) In The Utilization Of Coronary Reperfusion And Revascularization Treatment Strategies In Patients Hospitalized With Acute Myocardial Infarction: A Community-Wide Perspective, Jared Wasser, Robert Goldberg, Frederick Spencer, Jorge Yarzebski, Joel Gore

Jorge L. Yarzebski

OBJECTIVES: The objectives of our community-wide investigation were to describe multidecade-long trends (1986-2005) in the utilization of thrombolytic therapy, percutaneous coronary interventions, and coronary artery bypass graft surgery in patients hospitalized with acute myocardial infarction (AMI). METHODS: The study sample consisted of 9422 greater Worcester (MA) residents hospitalized with confirmed AMI at all metropolitan Worcester medical centers in 11 annual periods between 1986 and 2005. RESULTS: Increases in the utilization of percutaneous coronary interventions were observed between 1986 (2.0%) and 2005 (50.7%) with the most rapid increases beginning in the late 1990s. Utilization of coronary artery bypass graft surgery during …

Long-Term Trends In The Use Of Coronary Reperfusion Strategies In Acute Myocardial Infarction: A Community-Wide Perspective, Robert Goldberg, Frederick Spencer, Joseph Okolo, Darleen Lessard, Jorge Yarzebski, Joel Gore

Jorge L. Yarzebski

BACKGROUND: The objectives of our study were to examine long-term (1986-2003) trends in the use of percutaneous coronary interventions (PCI) and thrombolytic therapy in the management of patients hospitalized with acute myocardial infarction (AMI) while our secondary study goal was to examine factors associated with use of these coronary reperfusion strategies. While there have been considerable changes in the management of patients hospitalized with AMI over time, limited contemporary data are available about changing trends in the use of different coronary reperfusion strategies, particularly from the more generalizable perspective of a population-based investigation. METHODS: The study sample consisted of 9,422 …

Use Of Do-Not-Resuscitate Orders In Patients With Kidney Disease Hospitalized With Acute Myocardial Infarction, Joline Chen, Jonathan Sosnov, Darleen Lessard, Jorge Yarzebski, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

BACKGROUND: Patients with kidney disease are at increased risk for adverse health outcomes in comparison to patients without kidney disease. Therefore, patients with kidney disease may have greater use of do-not-resuscitate (DNR) orders than patients without kidney disease in the setting of an acute illness. We examined the association between advanced kidney disease and use of DNR orders in patients admitted with an acute myocardial infarction (AMI) to all greater Worcester, MA, hospitals as part of an epidemiological study.

METHODS: Use of DNR orders in 4,033 Worcester residents hospitalized with AMI at 11 greater Worcester medical centers during 1997, 1999, …

Treatment Practices And Outcomes Of Patients With Established Peripheral Arterial Disease Hospitalized With Acute Myocardial Infarction In A Community Setting, Frederick Spencer, Darleen Lessard, Chyke Doubeni, Jorge Yarzebski, Joel Gore, Robert Goldberg

Jorge L. Yarzebski

BACKGROUND: There are little contemporary data available describing the hospital and long-term outcomes of patients with peripheral arterial disease (PAD) who are hospitalized with acute myocardial infarction (AMI). The objectives of our population-based study were to examine the hospital and long-term outcomes, as well as the use of different treatment practices, among patients with established PAD who were hospitalized with AMI. METHODS: The study sample consisted of 4480 patients hospitalized with AMI at all Worcester, Mass, medical centers in 4 alternate years between 1997 and 2003. RESULTS: Among the metropolitan Worcester residents hospitalized with AMI, 13.5% had a history of …