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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

关键词： Nonalcoholic steatohepatitis Steatosis Fibrosis Mitochondrial function Oxidative stress

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Cancer stem cell plasticity and tumor hierarchy

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World Journal of Stem Cells 2015年第1期7卷 27-36页

作者： Marina Carla Cabrera Robert E Hollingsworth Elaine M Hurt medimmune LLC Department of Oncology ResearchGaithersburg MD 20878 United States

The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell(CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cel s harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.

关键词： Cancer stem cells Stem cell Plasticity Tumor hierarchy Microenvironment Immune-mediatedtherapies Epithelial-to-mesenchymal transition

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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 *** 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 *** To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated *** 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 *** and GAN diets had similar caloric content(40%fat kcal),fructose(22%)and cholesterol(2%)*** The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose ***-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 *** 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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B7-H7 (HHLA2) inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling

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Cellular & Molecular Immunology 2021年第6期18卷 1503-1511页

作者： Sadiye Amcaoglu Rieder Jingya Wang Natalie White Ariful Qadri Catherine Menard Geoffrey Stephens Jodi LKarnell Christopher ERudd Roland Kolbeck Present address:Viela Bio GaithersburgMDUSA Universite de Montreal MontrealQCCanada medimmune/AstraZeneca GaithersburgMDUSA Biopharmaceuticals Early RIAAstraZenecaGaithersburgMDUSA Biopharmaceuticals Early RIAAstraZenecaGaithersburgMDUSA View author publications

Modulation of T-cell responses has played a key role in treating cancers and autoimmune ***,understanding how different receptors on T cells impact functional outcomes is *** influence of B7-H7(HHLA2)and CD28H(TMIGD2)on T-cell activation remains *** we examined global transcriptomic changes in human T cells induced by *** through TCR with OKT3 and B7-H7 resulted in modest fold changes in the expression of select genes;however,these fold changes were significantly lower than those induced by OKT3 and B7-1 *** transcriptional changes induced by OKT3 and B7-H7 were insufficient to provide functional stimulation as measured by evaluating T-cell proliferation and cytokine ***,B7-H7 was coinhibitory when simultaneously combined with TCR and CD28 *** inhibitory activity was comparable to that observed with ***,in physiological assays using T cells and APCs,blockade of B7-H7 enhanced T-cell activation and proliferation,demonstrating that this ligand acts as a break *** work defines that the transcriptomic changes induced by B7-H7 are insufficient to support full costimulation with TCR signaling and,instead,B7-H7 inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling.

关键词： T cell inhibition Checkpoint pathway T cell transcriptomics

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A single dose pharmacokinetic and pharmacodynamic study of MEDI3617 in cynomolgus monkeys

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中国药理学与毒理学杂志 2013年第3期 544-544页

作者： LIU Yong-zhen WU Chi-yuan LU Hong YU Hong REN Jin Centre for Drug Safety Evaluation and Research Shanghai Institute of Materia Medica medimmune LLC.HaywardCA 94545USA

OBJECTIVE MEDI3617 is a candidate pharmacological agent under development by *** study is designed to assess pharmacokinetic profiles and to fully characterize total and free angiopoietin-2(Ang2) responses after a single intravenous(IV) administration in cynomolgus *** Four male naive cynomolgus monkeys were assigned to this *** animals were given a single dose of 6 mg·kg-1 MEDI3617 via IV administration for approximately 30 *** recovery period was 56 *** samples were taken at different time points to assess exposure of MEDI3617 and to fully characterize total and free Ang2 responses after a single IV *** Peak serum MEDI3617 concentration was attained generally at the first PK time point(1 h) post IV administration and declined biphasically *** observed mean values for maximum concentration was(213 ± 38) mg·L-1,area under the serum concentration-time curve from time 0 to infinity was(1280 ± 288) mg·L-1.d-1,clearance was(4.87 ± 1.15) ***-1.d-1,and half-life was(3.25 ± 0.672) *** changes in free Ang2 levels were *** Ang2 concentrations were suppressed immediately after dosing(1 h) and quickly recovered back to baseline after approximately 12 *** Ang2 concentrations accumulated with a maximum accumulation of approximate 100 fold from baseline and recovered back to baseline after approximately 56 d after dosing.

关键词： pharmacokinetic MEDI3617 pharmacodynamic

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Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone

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Bone Research 2018年第2期6卷 189-196页

作者： Julie E.Pickett John M.Thompson Agnieszka Sadowska Christine Tkaczyk Bret R.Sellman Andrea Minola Davide Corti Antonio Lanzavecchia Lloyd S.Miller Daniel LJ Thorek Division of Nuclear Medicine and Molecular Imaging Department of Radiology and Radiological ScienceJohns Hopkins University School of MedicineGaithersburgMDUSA Department of Orthopaedic Surgery Johns Hopkins University School of MedicineBaltimoreMD 21205USA Department of Infectious Disease MedImmune LLCGaithersburgMDUSA Humabs Bio Med SA BellinzonaSwitzerland Institute for Research in Biomedicine Universitàdella Svizzera italianaBellinzonaSwitzerland Department of Dermatology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Division of Infectious Disease Department of MedicineJohns Hopkins University School of MedicineBaltimoreMDUSA Cancer Molecular and Functional Imaging Program Department of OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21205USA

Discriminating sterile inflammation from infection, especially in cases of aseptic loosening versus an actual prosthetic joint infection, is challenging and has significant treatment implications. Our goal was to evaluate a novel human monoclonal antibody（mAb） probe directed against the Gram-positive bacterial surface molecule lipoteichoic acid（LTA）. Specificity and affinity were assessed in vitro. We then radiolabeled the anti-LTA mAb and evaluated its effectiveness as a diagnostic imaging tool for detecting infection via immuno PET imaging in an in vivo mouse model of prosthetic joint infection（PJI）. In vitro and ex vivo binding of the anti-LTA mAb to pathogenic bacteria was measured with Octet, ELISA, and flow cytometry. The in vivo PJI mouse model was assessed using traditional imaging modalities, including positron emission tomography（PET） with [^（18）F]FDG and [^（18）F]Na F as well as X-ray computed tomography（CT）, before being evaluated with the zirconium-89-labeled antibody specific for LTA（[^（89）Zr]SAC55）.The anti-LTA mAb exhibited specific binding in vitro to LTA-expressing bacteria. Results from imaging showed that our model could reliably simulate infection at the surgical site by bioluminescent imaging, conventional PET tracer imaging, and bone morphological changes by CT. One day following injection of both the radiolabeled anti-LTA and isotype control antibodies, the anti-LTA antibody demonstrated significantly greater（P 〈 0.05） uptake at S. aureus-infected prosthesis sites over either the same antibody at sterile prosthesis sites or of control non-specific antibody at infected prosthesis sites. Taken together, the radiolabeled anti-LTA mAb, [^（89）Zr]SAC55, may serve as a valuable diagnostic molecular imaging probe to help distinguish between sterile inflammation and infection in the setting of PJI. Future studies are needed to determine whether these findings will translate to human PJI.

关键词： Zr Molecularly specific detection bacterial lipoteichoic acid diagnosis prosthetic infection bone LTA SAC PET FDG tracer

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Coronavirus disease 2019 (COVID-19), MERS and SARS: Similarity and difference

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Journal of Acute Disease 2020年第5期9卷 194-199页

作者： Zeinab Mohseni Afshar Soheil Ebrahimpour Mostafa Javanian Veerendra Koppolu VeneelaKrishna Rekha Vasigala Amir Hossein Hasanpour Arefeh Babazadeh Clinical Research Development Center Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran Infectious Diseases and Tropical Medicine Research Center Health Research InstituteBabol University of Medical SciencesBabolI.R.Iran Scientist Biopharmaceutical Development medimmune Gaithersburg MD20878 USA Rangaraya Medical College NTR University of Health SciencesKakinadaIndia Student Research Committee Babol University of Medical SciencesBabolIran

SARS-CoV-2 is the causative agent of *** its outbreak in December 2019,COVID-19 has swept the *** 17 July 2020,the World Health Organization(WHO)had confirmed 13?119?239 cases and 573?752 deaths,and the numbers are still *** evidence shows that COVID-19 is lower than severe acute respiratory syndrome and Middle East respiratory syndrome in terms of severity and mortality risk,although the infections are particularly more severe in patients with underlying medical *** bulk of COVID-19 patients had close contact with confirmed cases,but an exact origin and specific transmission for COVID-19 are still *** there is no approved antiviral treatment for COVID-19 infection,proper prevention and control practices are essential to control the *** have an insight view of COVID-19,we summarized and compared the etiology,clinical manifestations,diagnosis,treatment,and prevention measures of COVID-19,severe acute respiratory syndrome,and Middle East respiratory syndrome.

关键词： COVID-19 Middle East respiratory syndrome Severe acute respiratory syndrome Coronavirus

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