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Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction

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World Journal of Gastroenterology 2018年第16期24卷 1748-1765页

作者： michelle l boland Stephanie Oldham Brandon B boland Sarah Will Jean-Martin lapointe Silvia Guionaud Christopher J Rhodes James l Trevaskis Cardiovascular and Metabolic Diseases MedImmune LLC Pathology MedImmune Ltd. Pathology Drug Safety and MetabolismIMED Biotech UnitAstraZeneca

AIM To comprehensively evaluate mitochondrial(dys) function in preclinical models of nonalcoholic steatohepatitis(NASH).METHODS We utilized two readily available mouse models of nonalcoholic fatty liver disease(NAFlD) with or without progressive fibrosis: lep^(ob)/lep^(ob)(ob/ob) and FATZO mice on high trans-fat, high fructose and high cholesterol(AMlN) diet. Presence of NASH was assessed using immunohistochemical and pathological techniques, and gene expression profiling. Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence, and function was assessed by measuring oxidative capacity in primary hepatocytes, and respiratory control and proton leak in isolated mitochondria. Oxidative stress was measured by assessing activity and/or expression levels of Nrf1, Sod1, Sod2, catalase and 8-OHdG. RESUlTS When challenged with AMlN diet for 12 wk, ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia. NASH development was associated with hepatic mitochondrial abnormalities, similar to those previously observed in humans, including mitochondrial accumulation and increased proton leak. AMlN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice. Despite similar mitochondrial phenotypes, we found that ob/ob mice developed more advanced hepatic fibrosis. Activity of superoxide dismutase(SOD) was increased in ob/ob AMlN mice, whereas FATZO mice displayed increased catalase activity, irrespective of diet. Furthermore, 8-OHd G, a marker of oxidative DNA damage, was significantly increased in ob/ob AMlN mice compared to FATZO AMlN mice. Therefore, antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57 Bl6 J control mice, but significantly perturbed in ob/ob mice. CONClUSION Oxidative stress, and/or the capacity to compensate for increased oxidative stress, in the setting of mitochondrial dysfunction, is a key factor for development of hepatic injury

关键词： Nonalcoholic steatohepatitis Steatosis Fibrosis Mitochondrial function Oxidative stress

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Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source

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World Journal of Gastroenterology 2019年第33期25卷 4904-4920页

作者： michelle l boland Denise Oro Kirstine S T■lb■l Sebastian T Thrane Jens Christian Nielsen Taylor S Cohen David E Tabor Fiona Fernandes Andrey Tovchigrechko Sanne S Veidal Paul Warrener Bret R Sellman Jacob Jelsing Michael Feigh Niels Vrang James l Trevaskis Henrik H Hansen Cardiovascular Renal and Metabolic DiseasesMedImmuneGaithersburgMD 20878United States Pharmacology GubraH■rsholm DK-2970Denmark

BACKGROUND The trans-fat containing AMlN(amylin liver non-alcoholic steatohepatitis,NASH)diet has been extensively validated in C57Bl/6J mice with or without the lep^ob/lep^ob(ob/ob)mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH.Due to a recent ban on trans-fats as food additive,there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57Bl/6J mice.AIM To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.METHODS Male ob/ob mice were fed AMlN diet or a modified AMlN diet with trans-fat(Primex shortening)substituted by equivalent amounts of palm oil[Gubra amylin NASH,(GAN)diet]for 8,12 and 16 wk.C57Bl/6J mice were fed the same diets for 28 wk.AMlN and GAN diets had similar caloric content(40%fat kcal),fructose(22%)and cholesterol(2%)level.RESUlTS The GAN diet was more obesogenic compared to the AMlN diet and impaired glucose tolerance.Biopsy-confirmed steatosis,lobular inflammation,hepatocyte ballooning,fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMlN diet.C57Bl/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.CONClUSION Substitution of Primex with palm oil promotes a similar phenotype of biopsyconfirmed NASH in ob/ob and C57Bl/6J mice,making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments.

关键词： Non-alcoholic steatohepatitis High-fat diet Mouse model Histopathology Fibrosis liver biopsy liver transcriptome

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ONECUT2 as a key mediator of androgen receptorindependent cell growth and neuroendocrine differentiation in castration-resistant prostate cancer

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Cancer Drug Resistance 2022年第1期5卷 165-170页

作者： WonSeok William Choi Julia l.boland Jianqing lin Division of Hematology/Oncology and Department of Medicine George Washington University HospitalGeorge Washington University School of Medicine and Health SciencesWashingtonDC 20037USA

Despite androgen dependence in a majority of castration-resistant prostate cancers,some cancer cells are independent of androgen receptor(AR)function,a feature of heterogeneity in prostate cancer.One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer(NEPC).This manuscript will focus on the new finding of human one cut domain family member 2(ONECUT2)transcription factor and its role in castration resistance,especially in NEPC.

关键词： Prostate cancers castration resistant ONECUT2 androgen receptor-independence neuroendocrine differentiation

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A comparison of the nutritive value of perennial ryegrass,perennial ryegrass and white clover and multispecies-based farmlet systems

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Grassland Research 2023年第2期2卷 129-139页

作者： Shona Baker Mary B.lynch Fionnuala Godwin Tommy M.boland Alexander C.O.Evans Paul N.C.Murphy Alan K.Kelly Helen Sheridan11 UCD School of Agriculture and Food Science University College DublinBelfieldIreland Teagasc Environmental Research Centre Johnstown Castle Co.WexfordIreland UCD Earth Institute University College DublinBelfieldIreland

Background:limited information is available regarding the nutritive value and structural characteristics of multispecies swards when rotationally grazed.Methods:Three farmlet types were investigated in terms of their nutritive value:lolium perenne(lP);l.perenne+Trifolium repens(lP+TR);and a multispecies sward containing grasses,legumes and herbs(MSS).Farmlets were stocked with beef steers(2.5 livestock units ha−1),grazed on a 1 ha scale to 6 cm(MSS)and 4 cm(lP and lP+TR)residuals.Results:A greater ash concentration was found in MSS than lP(84 vs.75 g kg−1 DM).Both lP+TR and MSS had higher crude protein and lower neutral detergent fibre concentrations than lP.The relative ranking of water soluble carbohydrate and dry matter(DM)concentration was lP>lP+TR>MSS.Despite the leaf component of the lP farmlet contributing more to herbage DM,the organic matter digestibilities of the swards were similar.Conclusions:The MSS and lP+TR farmlets achieved similar forage quality under intensive grazing to lP.However,it is worth noting that MSS had a higher concentration of acid detergent lignin,which can negatively impact digestibility.Further investigation is needed to determine optimal grazing management practices that can minimise the effects of higher lignin concentration on digestibility in multispecies swards.

关键词： forage herbs forage quality grazing cattle legumes multispecies swards nitrogen sustainability

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Mutation of the Arabidopsis Calmodulin-like Protein CMl37 Deregulates the Jasmonate Pathway and Enhances Susceptibility to Herbivory

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Molecular Plant 2014年第12期7卷 1712-1726页

作者： Sandra S. Scholz Jyothilakshmi Vadassery Monika Heyer Michael Reichelt Kyle W. Bender Wayne A. Snedden Wilhelm boland Axel Mithofer Department of Bioorganic Chemistry Max Planck Institute for Chemical Ecology Hans-Knoll-StraBe 8 07745 Jena Germany Department of Biochemistry Max Planck Institute for Chemica Eco ogy Hans-Knoll-StraBe 8 07745 Jena Germany Department of Plant Biology University of Illinois Urbana IL 61801 USA Department of Biology Queen's University Kingston Ontario Canada Canada K7L 3N6

Throughout their life, plants are challenged by various abiotic and biotic stress factors. Among those are attacks from herbivorous insects. The molecular mechanisms underlying the detection of herbivores and the subsequent signal transduction are not well understood. As a second messenger, fluxes in intracellular Ca2＋ levels play a key role in mediating stress response pathways. Ca2＋ signals are decoded by Ca2＋ sensor proteins such as calmodulin-like proteins （CMls）. Here, we demonstrate that recombinant CMl37 behaves like a Ca2＋ sensor in vitro and, in Arabidopsis, AtCMl37 is induced by mechanical wounding as well as by infestation with larvae of the generalist lepidopteran herbivore Spodoptera littoralis. loss of function of CMl37 led to a better feeding performance of larvae suggesting that CMl37 is a positive defense regulator. No herbivory-induced changes in secondary metabolites such as glucosinolates or flavonoids were detected in cml37 plants, although a significant reduction in the accumulation of jasmonates was observed, due to reduced expression of JAR1 mRNA and cellular enzyme activity. Consequently, the expression of jasmonate-responsive genes was reduced as well. Summarizing, our results suggest that the Ca2＋ sensor protein, CMl37, functions as a positive regulator in Ca2＋ signaling during herbivory, connecting Ca2＋ and jasmonate signaling.

关键词： herbivory oral secretion jasmonates cytosolic calcium calmodulin-like proteins.

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long-term persistence of T cell memory to HBsAg after hepatitis B vaccination

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World Journal of Gastroenterology 2004年第2期10卷 260-263页

作者： Ru-XiangWang GreetJ.boland JanvanHattum GijsbertC.deGast ShenyangCenterforDiseaseControlandPrevention Shenyang110031LiaoningProvinceChina DepartmentofGastroenterology UniversityHospitalUtrechttheNetherlands NetherlandsCancerInstitute AmsterdamtheNetherlands

AIM:To determine if the T cell memory to HBsAg can persist for a long time after hepatitis B (HB) vaccination.METHODS: Thirty one vaccine recipients who werehealthcare workers (18 females and 13 males aged 34-58 years) from Utrecht University Hospital, Netherlands, and had previously received a standard course of vaccination for hepatitis B were investigated and another 9 unvaccinated healthy volunteers from the same hospital were used as the control.Blood samples were taken just before the experiment to test serum anti-HBs levels and the subjects were classified into different groups according to their serum titers of antiHBs and vaccination history.Their peripheral blood mononuclear cells (PBMC) were isolated from freshly heparinized venous blood and the proliferative response of T lymphoo/tes to the recombinant hepatitis B surface antigen (HBsAg) was investigated.RESUlTS: Positive serum anti-HBs was found in 61.3%(19/31) vaccine recipients and a significant in vitro lymphocyte proliferative response to recombinant HBsAg was observed in all the vaccinees with positive anti-HBs.Serum anti-HBs level≤10IU/l was found in 38.7% (12/31) subjects.In this study, we specially focused on lymphocyte proliferative response to recombinant HBsAg in those vaccine recipients with serum anti-HBsAg less than 10IU/l.Most of them had received a standard course of vaccination about 10 years before. T lymphocyte proliferative response was found positive in 7 of the 12 vaccine recipients.These results confirmed that HBsAg-specific memory T cells remained detectable in the circulation for a long time after vaccination,even when serum anti-HBs level had been undetectable.CONClUSION: The T cell memory to HBsAg can persist for at least 10 years after HB vaccination. Further booster injection is not necessary in healthy responders to HB vaccine.

关键词：乙型肝炎病毒乙肝表面抗原 T细胞存贮器存活率血清学检查细胞增殖

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Genetic factors for differentiated thyroid cancer in French Polynesia:new candidate loci

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Precision Clinical Medicine 2023年第2期6卷 57-66页

作者： Monia Zidane Marc Haber Thérèse Truong Frédérique Rachédi Catherine Ory Sylvie Chevillard Hélène Blanché Robert Olaso Anne boland Éric Conte Mojgan Karimi Yan Ren Constance Xhaard Vincent Souchard Jacques Gardon Marc Taquet André Bouville Jean-François Deleuze Vladimir Drozdovitch Florent de Vathaire Jean-Baptiste Cazier University Paris-Saclay UVSQInsermGustave RoussyCESPTeam"Radiations Epidemiology"Villejuif 94805France Centre for Computational Biology University of BirminghamBirmingham B152TTUK Institute of Cancer and Genomic Sciences University of BirminghamBirmingham B152TTUK University Paris-Saclay UVSQInsermGustave RoussyCESPTeam"Exposome and Heredity"Villejuif 94805France Endocrinology Unit Territorial Hospital TaaoneF-98713PapeeteTahiti 98713French Polynesia CEA Laboratoire de Cancérologie FondamentaleInstitut de Biologie François JacobiRCMSREITLaboratoire de Cancérologie Expérimentale(LCE)UniversitéParis-SaclayFontenay aux Roses 92265France Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain Paris 75010France UniversitéParis-Saclay CEACentre National de Recherche en Génomique HumaineEvry 91057France U.S.R.2003(CNRS/UPF) Faa’aTahiti 98702France University of lorraine INSERM CIC 1433Nancy CHRUINSERM U1116Nancy 54500France Hydrosciences Montpellier Research Institute for DevelopmentCNRSUniversity of MontpellierMontpellier 62307France Research Institute for Development Center IRD on TahitiArueTahiti 98713French Polynesia National Cancer Institute(retired) BethesdaMD 20892USA Division of Cancer Epidemiology and Genetics National Cancer InstituteNIHDHHSBethesdaMD 20892USA

Background:Populations of French Polynesia(FP),where France performed atmospheric tests between 1966 and 1974,experience a high incidence of differentiated thyroid cancer(DTC).However,up to now,no sufficiently large study of DTC genetic factors in this population has been performed to reach definitive conclusion.This research aimed to analyze the genetic factors of DTC risk among the native FP populations.Methods:We analyzed more than 300000 single nucleotide polymorphisms(SNPs)genotyped in 283 DTC cases and 418 matched controls born in FP,most being younger than 15 years old at the time of the first nuclear tests.We analyzed the genetic profile of our cohort to identify population subgroups.We then completed a genome-wide analysis study on the whole population.Results:We identified a specific genetic structure in the FP population reflecting admixture from Asian and European populations.We identified three regions associated with increased DTC risk at 6q24.3,10p12.2,and 17q21.32.The lead SNPs at these loci showed respective p-values of 1.66×10^(−7),2.39×10^(−7),and 7.19×10^(−7) and corresponding odds ratios of 2.02,1.89,and 2.37.Conclusion:Our study results suggest a role of the loci 6q24.3,10p12.2 and 17q21.32 in DTC risk.However,a whole genome sequencing approach would be better suited to characterize these factors than genotyping with microarray chip designed for the Caucasian population.Moreover,the functional impact of these three new loci needs to be further explored and validated.

关键词： differentiated thyroid cancer population genetics genetic susceptibility

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蛋白酶抑制剂联合疗法与围生期HIV-1感染儿童的疾病严重程度及生活质量

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世界核心医学期刊文摘（儿科学分册） 2006年第6期2卷 54-56页

作者： Storm D.S. boland M.G. Gortmaker S.l. 唐彦 Franois-Xavier Bagnoud Center Bergen Building 65 Bergen St Newark NJ 07101-1709 United States Dr.

Objectives. This study examines quality of life (QOl) among school-aged children with perinatally acquired HIV infection and compares QOl outcomes between treatment groups that differ according to the use of protease inhibitor (PI) combination therapy (PI therapy). To gain insights into how PI therapy might influence QOl, associations between severity of illness and QOl were also investigated. Methods. Cross-sectional data for 940 children, 5 to 18 years of age, who were enrolled in Pediatric AIDS Clinical Trials Group late Outcomes Protocol 219 were used to examine domains of caregiver-reported QOl, as assessed with the General Health Assessment for Children, during 1999. The General Health Assessment for Children is an age-specific, modular, QOl assessment that was developed for the study with previously validated measures. QOl differences between treatment groups were estimated with linear and logistic regressions that controlled for sociodemographic characteristics (age, gender, raceethnicity, maternalcaregiver education, and respondent) and severity-of-illness indicators related to receipt of PI therapy (AIDS status, log10 CD4+cell counts, and height-for-age z scores). Results. The mean age of participants was 9.7 years. Most children were non-Hispanic black (54%) or Hispanic (31%), and 49%of the participants were female. At the 1999 study visit, ～14%of children had severe immune suppression ( lls), whereas 62%of children had ≥25%CD4+cells, ie, no immune suppression. Participants did exhibit some lag in growth, with mean height and weight z scores of-0.70 and-0.20, respectively. Twentyeight percent of the children were reported to have met criteria for AIDS at study entry (1993-1999). When treatment groups were compared, children receiving PI therapy (72%) were older, had lower CD4 +cell percentages, and had lower height and weight z scores than did those receiving non-PI therapies. They were also more likely to have met criteria for AIDS at study entry. The most commonly used PIs were ritonavir (

关键词： HIV-1感染疾病严重程度蛋白酶抑制剂学龄儿童围生期感染生活质量联合疗法 CD4^+细胞计数 logistic回归分析 QOl量表

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读后续写中的二语句法协同效应研究——来自中国学习者产出英语运动构式的证据

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Chinese Journal of Applied linguistics 2021年第3期44卷 292-313,430页

作者：王敏甘桥朱莉·博兰德西安交通大学外国语学院 (美国)密歇根大学心理学系

本研究考察任务模式对读后续写中句法协同效应的影响。研究采用前测-干预-后测的实验设计,目标结构为英语方式动词运动构式。90名中国大学生参加实验并被随机分配至两个实验组或控制组。两个实验组在干预阶段完成一个图片故事续写任务,... 详细信息

本研究考察任务模式对读后续写中句法协同效应的影响。研究采用前测-干预-后测的实验设计,目标结构为英语方式动词运动构式。90名中国大学生参加实验并被随机分配至两个实验组或控制组。两个实验组在干预阶段完成一个图片故事续写任务,但任务模式不同:多轮组所要续写的故事被切分为若干片段,每轮呈现一个,被试续写该片段,然后开始下一轮,反复多次,直到整个故事构建完整;单轮组续写同一个故事,但故事的前半段一次性呈现给被试,被试读完之后,续写后半段。结果表明,读后续写中存在句法协同而且该效应会持续到两周以后,多轮组的协同效应强于单轮组。研究揭示出二语结构协同与互动强度有关,互动强则协同强。

关键词：读后续写句法协同任务模态互动强度运动事件构式中的方式动词二语学习

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24例纵隔和胸腔脂肪肉瘤的临床病理和分子遗传学研究:强调少见的多样性组织学特征(英)

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诊断病理学杂志 2013年第2期20卷 M0004-M0004页

作者： boland JM 段瑞解放军306医院病理科

发生于纵隔的脂肪肉瘤罕见，多数此类研究报道早于当前基于遗传学的分类系统。作者报告了60年间遇到的一组胸部脂肪肉瘤的临床和分子遗传学特征，使用最新的WHO分类对24例确诊病例进行再分类，使用荧光原位杂交检测了部分病例CPM基因扩... 详细信息

发生于纵隔的脂肪肉瘤罕见，多数此类研究报道早于当前基于遗传学的分类系统。作者报告了60年间遇到的一组胸部脂肪肉瘤的临床和分子遗传学特征，使用最新的WHO分类对24例确诊病例进行再分类，使用荧光原位杂交检测了部分病例CPM基因扩增和／或DDIT3基因重排。24例中13例为男性，1l例为女性（中位年龄53岁，范围15～73岁）。其中8例是高分化脂肪肉瘤，6例为去分化脂肪肉瘤（3例CPM＋），7例多形性脂肪肉瘤（2例CPM-，1例DDIT3-），2例黏液性脂肪肉瘤，1例不能分类的脂肪肉瘤（CPM和DDIT3均一）。

关键词：去分化脂肪肉瘤分子遗传学临床病理组织学特征纵隔多样性多形性脂肪肉瘤黏液性脂肪肉瘤

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