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Shunts, channels and lipoprotein endosomal traffic： a new model of cholesterol homeostasis in the hepatocyte

The Journal of Biomedical Research 2017年第2期31卷 95-107页

作者： robert scott kiss Allan Sniderman Research Institute of the McGill University Health Centre Montreal Quebec H4A 3J1 Canada Department of Medicine McGill University Montreal Quebec H4A 3J1 Canada

The liver directs cholesterol metabolism in the organism. All the major fluxes of cholesterol within the body involve the liver： dietary cholesterol is directed to the liver; cholesterol from peripheral cells goes to the liver; the liver is a major site of cholesterol synthesis for the organism; cholesterol is secreted from the liver within the bile, within apoB lipoproteins and translocated to nascent HDL. The conventional model of cholesterol homeostasis posits that cholesterol from any source enters a common, rapidly exchangeable pool within the cell, which is in equilibrium with a regulatory pool. Increased influx of cholesterol leads rapidly to decreased synthesis of cholesterol. This model was developed based on in vitro studies in the fibroblast and validated only for LDL particles. The challenges the liver must meet in vivo to achieve cholesterol homeostasis are far more complex. Our model posits that the cholesterol derived from three different lipoproteins endosomes has three different fates： LDL-derived cholesterol is largely recycled within VLDL with most of the cholesterol shunted through the hepatocyte without entering the exchangeable pool of cholesterol; high density lipoprotein-derived CE is transcytosed into bile; and chylomicron remnant-derived cholesterol primarily enters the regulatory pool within the hepatocyte. These endosomal channels represent distinct physiological pathways and hepatic homeostasis represents the net result of the outcomes of these distinct channels. Our model takes into account the distinct physiological challenges the hepatocyte must meet, underlie the pathophysiology of many of the apoB dyslipoproteinemias and account for the sustained effectiveness of therapeutic agents such as statins.

关键词： ACAT2 cholesterol hepatocyte HMGCR LDLR

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Rab proteins implicated in lipid storage and mobilization

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The Journal of Biomedical Research 2014年第3期28卷 169-177页

作者： robert scott kiss Tommy Nilsson Department of Medicine McGill University Research Institute of McGill University Health Centre

Abnormal intracellular accumulation or transport of lipids contributes greatly to the pathogenesis of human diseases. In the liver, excess accumulation of triacylglycerol （TG） leads to fatty liver disease encompassing steatosis, steatohepatitis and fibrosis. This places individuals at risk of developing cirrhosis, hepatocellular carcinoma or hepatic decompensation and also contributes to the emergence of insulin resistance and dyslipidemias affecting many other organs. Excessive accumulation of TG in adipose tissue contributes to insulin resistance as well as to the release of cytokines attracting leucocytes leading to a pro-inflammatory state. Pathological accumulation of cholesteryl ester （CE） in macrophages in the arterial wall is the progenitor of atherosclerotic plaques and heart disease. Overconsumption of dietary fat, cholesterol and carbohydrates explains why these diseases are on the increase yet offers few clues for how to prevent or treat individuals. Dietary regimes have proven futile and barfing surgery, no realistic alternatives are at hand as effective drugs are few and not without side effects. Overweight and obesity-related diseases are no longer restricted to the developed world and as such, constitute a global problem. Development of new drugs and treatment strategies are a priority yet requires as a first step, elucidation of the molecular pathophysiology underlying each associated disease state. The lipid droplet （LD）, an up to now over- looked intracellular organelle, appears at the heart of each pathophysiology linking key regulatory and metabolic processes as well as constituting the site of storage of both TGs and CEs. As the molecular machinery and mechanisms of LDs of each cell type are being elucidated, regulatory proteins used to control various cellular processes are emerging. Of these and the subject of this review, small GTPases belonging to the Rab protein family appear as important molecular switches used in the regulation of the in

关键词： lipid droplet rab protein effector GTPase GAP GEF

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Calibration of the Albian/Cenomanian Boundary by Ammonite Biostratigraphy:*** Interior

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Acta Geologica Sinica(English Edition) 2007年第6期81卷 940-948页

作者： robert W.scott University of Tulsa and Precision Stratigraphy Associates

Calibration of numerical ages to the geological time scale is a long scientific pursuit that requires the integration of multiple data sets. A case study of the Albian/Cenomanian stage boundary, also the Lower/Upper Cretaceous series boundary, illustrates the calibration process. The numerical age of this boundary has shifted from 96 Ma to 99 Ma over a time span of nearly fifty years. Recalibration resulted first from improvements in radiometric dating, and later from inferences about ammonite phylogeny, and most recently from radiometric dates of newly discovered volcanic beds interbedded with diagnostic guide fossils. However, the calibration process continues with study of cosmopolitan dinoflagellates.

关键词： Albian/Cenomanian ammonite biostratigraphy age calibration

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Gastrointestinal manifestations of systemic mastocytosis

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World Journal of Gastroenterology 2008年第45期14卷 7005-7008页

作者： Jason K Lee scott J Whittaker robert A Enns Peter Zetler Internal Medicine University of British Columbia St. Paul's Hospital Division of Gastroenterology University of British Columbia St. Paul's Hospital Division of Pathology University of British Columbia

Systemic mastocytosis (SM) is a rare disease with abnormal proliferation and infiltration of mast cells in the skin, bone marrow, and viscera including the mucosal surfaces of the digestive tract. Gastrointestinal (GI) symptoms occur in 14%-85% of patients with systemic mastocytosis. The GI symptoms may be as frequent as the better known pruritis, urticaria pigmentosa, and flushing. In fact most recent studies show that the GI symptoms are especially important clinically due to the severity and chronicity of the effects that they produce. GI symptoms may include abdominal pain, diarrhea, nausea, vomiting, and bloating. A case of predominantly GI systemic mastocytosis with unique endoscopic images and pathologic confirmation is herein presented, as well as a current review of the GI manifestations of this disease including endoscopic appearances. Issues such as treatment and prognosis will not be discussed for the purposes of this paper.

关键词： Systemic mastocytosis Idiopathic diarrhea Gastrointestinal manifestations

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Role of ion channels in gastrointestinal cancer

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World Journal of Gastroenterology 2019年第38期25卷 5732-5772页

作者： Kyle J Anderson robert T Cormier Patricia M scott Department of Biomedical Sciences University of Minnesota Medical School

In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer *** functions of ion channels in the gastrointestinal(GI)tract influence a variety of cellular processes,many of which overlap with these hallmarks of *** this review we focus on the roles of the calcium(Ca^2+),sodium(Na^+),potassium(K^+),chloride(Cl^-)and zinc(Zn^2+)transporters in GI cancer,with a special emphasis on the roles of the KCNQ1 K+channel and CFTR Cl-channel in colorectal cancer(CRC).Ca^2+is a ubiquitous second messenger,serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle,apoptosis,and *** members of the TRP superfamily,including TRPM8,TRPM7,TRPM6 and TRPM2,have been implicated in GI cancers,especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon ***-gated sodium channels(VGSCs)are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle *** VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC *** have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer ***2+transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers,in particular,ZIP4 up-regulation in pancreatic cancer(PC).More than 70 K+channel genes,clustered in four families,are found expressed in the GI tract,where they regulate a range of cellular processes,including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal *** distinct types of K+channels are found dysregulated in the GI *** are hERG1 upregulation in PC,gastric cancer(GC)and CRC,leading to enhanced cancer angiogenesis and invasion,and KCNQ1 down-regulation in CR

关键词： Ion channels Gastrointestinal cancer Colorectal cancer Gastric cancer Pancreatic cancer Esophageal cancer Hepatocellular carcinoma Prognostic biomarker Novel therapies Clinical targets

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Late Cretaceous chronostratigraphy(Turonian—Maastrichtian):SK1 core Songliao Basin,China

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Geoscience Frontiers 2012年第4期3卷 357-367页

作者： robert W. scott Xiaoqiao Wan Chengshan Wang Qinghua Huang Department of Geosciences University of Tulsa and Precision Stratigraphy Associates Tulsa OK 74104 USA State Key Laboratory of Biogeology and Environmental Geology China University of Geosciences. Beijing 100083. China Exploration and Development Research Institute of Daqing Oil.field Company Ltd. Daqing 163712. China

Non-marine ostracodes, charophytes and palynomorphs are abundant in most Cretaceous lacustrine basins of Easl Asia. However, their ranges are not directly integrated with marine biota that defines the Cretaceous stages. Non-biotic events st, ch as magnetochrons and radiometric ages in these terrestrial deposits enable their correlation with marine strata. The SKI north and south compositcd cores in the Songliao Basin present a continuous section of Upper Cretaceous non-marine fossil and magneto- chron successions in superposed order. These chronostratigraphic events are integrated with marine events by an XIY graphic plot between the core data and a global database of Global Section and Stratotype Points （GSSP） and key reference sections. This plot projects stage boundaries in marine sections into the SKI section and interpolates numerical ages to the tirst and last occurrences of biota and to lithostratigraphic boundaries. This stratigraphic experiment tests and relines age calibrations based on both manual interpo- lation of depths to numerical ages and cyclostratigraphy. Ages derived by interpolation are similar and ages by cyclostratigraphy are older because stage boundaries are calibrated to a different age scale.

关键词： Upper Cretaceousstratigraphy:East Asia Songliao Basin:Numerical ages ofpalynomorphs:Ostracodes-Charophytes

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Cretaceous Oceanic Red Beds （CORB）, response to paleoclimatic/paleoceanographic global changes and regional tectonics Workshop of IGCP 463 ＆ 494

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Episodes 2006年第1期29卷 49-51页

作者： robert W. scott Chengshan Wang Xiumian Hu Tulsa University Cleveland Oklahoma 74020 USA China University of Geosciences Beijing 100083 Beijing CHINA Nanjing University210093 Nanjing CHINA

Members of IGCP 463, Cretaceous Oceanic Red Beds （CORBs）, held their fourth workshop in Switzerland, and members of IGCP Project 494, Dysoxic to oxic change in midCretaceous Tethyan oceanic sedimentation, held their third workshop. The joint workshops consisted of a day and a half of presentations of current scientific results and a halfday planning the next year＇s work flow. Afterwards many participants joined the oneday field trip ＂Aptian, Albian, and Cenomanian sedimentation in the Swiss Prealps＂ led by Michel Caron, Luc Braillard, Andre Strasser, and Corinne Saudan, which preceded the 7th International Symposium on the Cretaceous, 5-9 September, 2005. Projects 463 ＆ 494 also sponsored oral and poster sessions at the Symposium entitled, ＂Cretaceous Oceanic Red Beds＂.

关键词：区域构造学全球变化海洋层白垩纪

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Hepatitis B and C infection and liver disease trends among human immunodeficiency virus-infected individuals

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World Journal of Gastroenterology 2011年第14期17卷 1807-1816页

作者： Susan E Buskin Elizabeth A Barash John D scott David M Aboulafia robert W Wood Public Health-Seattle and King County WA 98104United States University of Washington SeattleWA 98195United States Harborview Medical Center SeattleWA 98104United States Virginia Mason Medical Center SeattleWA 98101United States

AIM:To examine trends in and correlates of liver disease and viral hepatitis in an human immunodeficiency virus (HIV)-infected cohort. METHODS:The multi-site adult/adolescent spectrum of HIV-related diseases (ASD) followed 29 490 HIVinfected individuals receiving medical care in 11 U.S. metropolitan areas for an average of 2.4 years,and a total of 69 487 person-years,between 1998 and 2004. ASD collected data on the presentation,treatment,and outcomes of HIV,including liver disease,hepatitis screening,and hepatitis diagnoses. RESULTS:Incident liver disease,chronic hepatitis B virus (HBV),and hepatitis C virus (HCV) were diagnosed in 0.9,1.8,and 4.7 per 100 person-years. HBV and HCV screening increased from fewer than 20% to over 60% during this period of observation (P < 0.001). Deaths occurred in 57% of those diagnosed with liver disease relative to 15% overall (P < 0.001). Overall 10% of deaths occurred among individuals with a diagnosis of liver disease. Despite care guidelines promoting screening and vaccination for HBV and screening for HCV,screening and vaccination were not universally conducted or,if conducted,not documented. CONCLUSION:Due to high rates of incident liver disease,viral hepatitis screening,vaccination,and treatment among HIV-infected individuals should be a priority.

关键词： Human immunodeficiency virus Hepatitis B Hepatitis C Liver disease

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Advances in minimally invasive treatment of hemorrhagic and ischemic stroke

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Neural Regeneration Research 2016年第2期11卷 228-229页

作者： robert C.Rennert J.scott Pannell Alexander A.Khalessi Department of Neurosurgery University of California - San Diego

Cerebrovascular diseases,including ischemic and hemorrhagic strokes,affect more than 6 million US adults *** cause high rates of morbidity and mortality due to the central nervous system’s sensitivity to disruptions in blood flow,and are refractory to traditional surgical interventions.A variety of minimally invasive surgical and endovascular approaches have recently been developed to improve patient outcomes following stroke.

关键词： Advances in minimally invasive treatment of hemorrhagic and ischemic stroke ICH

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Inpatient capsule endoscopy leads to frequent incomplete small bowel examinations

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World Journal of Gastroenterology 2012年第36期18卷 5051-5057页

作者： Cemal Yazici John Losurdo Michael D Brown scott Oosterveen robert Rahimi Ali Keshavarzian Leila Bozorgnia Ece Mutlu Department of Medicine Mercy Hospital and Medical CenterChicagoIL 60616United States Division of Digestive Diseases and Nutrition Rush University Medical CenterChicagoIL 60612United States WellSpan Gastroenterology YorkPA 17403United States Division of Digestive and Liver Diseases University of Texas Southwestern Medical CenterDallasTX 75390United States Department of Pediatrics Los Angeles County-University of Southern California HospitalLos AngelesCA 9003United States

AIM： To examine the predictive factors of capsule en- doscopy （CE） completion rate （CECR） including the ef- fect of inpatient and outpatient ***： We identified 355 consecutive patients who completed CE at Rush University Medical Center between March 2003 and October 2005. Subjects for CE had either nothing by mouth or clear liquids for the afternoon and evening of the day before the pro- cedure. CE exams were reviewed by two physicians who were unaware of the study hypotheses. After retrospective analysis, 21 cases were excluded due to capsule malfunction, prior gastric surgery, endoscopic capsule placement or insufficient data. Of the remain- ing 334 exams [264 out-patient （OP）, 70 in-patient （IP）], CE indications, findings, location of the patients [IP vs OP and intensive care unit （ICU） vs general medical floor （GMF）] and gastrointestinal transit times were analyzed. Statistical analysis was completed us- ing SPSS version 17 （Chicago, IL）. Chi-square, t test or fisher exact-tests were used as appropriate. Multivari- ate logistic regression analysis was used to identify variables associated with incomplete CE exams. RESULTS： The mean age for the entire study popula- tion was 54.7 years. Sixty-one percent of the study population was female, and gender was not different between IPs vs OPs （P = 0.07）. The overall incomplete CECR was 14% in our study. Overt obscure gastroin- testinal bleeding （OGB） was significantly more com- mon for the IP CE （P = 0.0001）, while abdominal pain and assessment of IBD were more frequent indications for the OP CE exams （P = 0.002 and P = 0.01, respec- tively）. Occult OGB was the most common indication and arteriovenous malformations were the most com- mon finding both in the IPs and OPs. The capsule did not enter the small bowel （SB） in 6/70 IPs and 8/264 OPs （P = 0.04）. The capsule never reached the cecum in 31.4% （22/70） of IP vs 9.5% （25/ 264） of OP ex- aminations （P 〈 0.001）. The mean gastric transit time （GTT） was delayed

关键词： Capsule endoscopy Completion rate Inpa-tient Outpatient Hospitalization

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