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Phosphatidylserine externalized on the colonic capillaries as a novel pharmacological target for IBD therapy

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Signal Transduction and Targeted Therapy 2021年第7期6卷 2186-2195页

作者： Xuerui Zhang Lulu Song Lin Li Banghui Zhu Lina Huo Zhaoqing Hu Xinran Wang Jie Wang Mengyue Gao Jing Zhang Zichun Hua The State Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjingChina Changzhou High-Tech Research institute of Nanjing University and Jiangsu Target Pharma Laboratories inc ChangzhouChina School of Biopharmacy China Pharmaceutical UniversityNanjingChina

Inflammatory bowel disease(IBD)is a chronic and relapsing disorder for many people associated with poor *** there are some clinical drugs for IBD treatment,the development of effective therapeutics on IBD patients has always been ***,we show that externalized phosphatidylserine(PS)is observed on the surface of colonic *** A5(ANXA5)with high affinity for PS has a good targeting to the colon and effectively alleviates experimental *** contrast,ANXA5 mutant(A5m)lacking the PS-binding ability,has no accumulation in the colon and no therapeutic effects on *** investigations indicate that ANXA5 reduces the inflammatory cell infiltration by inhibiting endothelial cell activation dependent on PS-binding *** the increasing of PS exposure on activated HUVECs(human umbilical vein endothelial cells),ANXA5 binding induces the internalization of TLR4 via PS-dependent *** provide new insights on the molecular mechanism of ANXA5 for its anti-inflammatory *** data suggest that PS-externalization is a potential target of ANXA5 aiming at targeted drug delivery(TDD)for IBD treatment.

关键词： colonic colon drugs

Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment

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World Journal of Hepatology 2016年第31期8卷 1318-1326页

作者： Lydia Shuk Yee Tang Jack Masur Zayani Sims Amy Nelson Anu Osinusi Anita Kohli Sarah Kattakuzhy Michael Polis Shyam Kottilil institute of Human Virology Division of Infectious Diseases University of Maryland School of Medicine Critical Care Medicine Department Clinical CenterNational Institutes of Health Gilead Sciences inc Creighton University School of Medicine St Joseph’s Hospital Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases National Institutes of Health

AIMTo study impact of baseline mental health disease on hepatitis C virus (HCV) treatment; and Beck’s Depression Inventory (BDI) changes with sofosbuvir- and interferon-based therapy. METHODSThis is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and naïve to HCV therapy. Two of the studies included HCV mono-infected participants only (SPARE, SYNERGY-A), and 3 included human immunodeficiency virus (HIV)/HCV co-infected participants only (ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon (IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease (MHD) were identified (defined as either a DSM IV diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response (SVR) and adherence (pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher’s Exact, and t-test with significance defined as a P value less than 0.05. RESULTSBaseline characteristics did not differ significantly between all participa

关键词： Sofosbuvir Direct acting antivirals Directly acting antiviral Hepatitis C Mental health disease Depression Interferon Beck&rsquo s Depression Inventory

Implications of metabolism-driven myeloid dysfunctions in cancer therapy

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Cellular & Molecular Immunology 2021年第4期18卷 829-841页

作者： Laura Strauss Valentina Guarneri Alessandra Gennari Antonio Sica Department of Immunopharmacology and Immuno Oncology EMD Serono Research&Development InstituteInc.80119545A Middlesex TurnpikeBillericaMA 01821USA Department of Surgery Oncology and GastroenterologyUniversity of PadovaPadovaItaly Veneto institute of Oncology-IRCCS PaduaItalyPadovaItaly Division of Oncology Department of Translational MedicineUniversity of Eastern PiedmontNovaraItaly Department of Pharmaceutical Sciences University of Eastern PiedmontA.Avogadrovia Bovio 6NovaraItaly Humanitas Clinical and Research Center IRCCSVia Manzoni 56RozzanoMilanItaly

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid *** chronic inflammatory states,including cancer,this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils,macrophages,and dendritic cells(DCs),thus giving rise to a decline in the antitumor effector lymphoid ***-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors,resulting in unresolved and chronic *** pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool,which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor ***,persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer,as well as to the severity of a broad range of diseases,including metabolic syndrome and autoimmune and infectious *** aims of this review are to(1)define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients,(2)discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes,and(3)explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor *** propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects(irAEs)for current therapeutic strategies,including immune checkpoint inhibitor(ICI)therapy.

关键词： Myelopoiesis Tumor-associated macrophages Myeloid-derived suppressor cells Metabolism Cancer therapy

Accurate and generalizable quantitative scoring of liver steatosis from ultrasound images via scalable deep learning

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World Journal of Gastroenterology 2022年第22期28卷 2494-2508页

作者： Bowen Li Dar-In Tai Ke Yan Yi-Cheng Chen Cheng-Jen Chen Shiu-Feng Huang Tse-Hwa Hsu Wan-Ting Yu Jing Xiao Lu Le Adam P Harrison Research and Development PAII Inc.BethesdaMD 20817United States Department of Gastroenterology and Hepatology Chang Gung Memorial HospitalLinkou Medical CenterTaoyuan 33305Taiwan Division of Molecular and Genomic Medicine National Health Research InstituteTaoyuan 33305Taiwan Research and Development Ping An Insurance GroupShenzhen 518001GuangdongChina

BACKGROUND Hepatic steatosis is a major cause of chronic liver ***-dimensional(2D)ultrasound is the most widely used non-invasive tool for screening and monitoring,but associated diagnoses are highly *** To develop a scalable deep learning(DL)algorithm for quantitative scoring of liver steatosis from 2D ultrasound *** Using multi-view ultrasound data from 3310 patients,19513 studies,and 228075 images from a retrospective cohort of patients received elastography,we trained a DL algorithm to diagnose steatosis stages(healthy,mild,moderate,or severe)from clinical ultrasound *** was validated on two multiscanner unblinded and blinded(initially to DL developer)histology-proven cohorts(147 and 112 patients)with histopathology fatty cell percentage diagnoses and a subset with FibroScan *** also quantified reliability across scanners and *** were evaluated using Bland-Altman and receiver operating characteristic(ROC)*** The DL algorithm demonstrated repeatable measurements with a moderate number of images(three for each viewpoint)and high agreement across three premium ultrasound *** diagnostic performance was observed across all viewpoints:Areas under the curve of the ROC to classify mild,moderate,and severe steatosis grades were 0.85,0.91,and 0.93,*** DL algorithm outperformed or performed at least comparably to FibroScan control attenuation parameter(CAP)with statistically significant improvements for all levels on the unblinded histology-proven cohort and for“=severe”steatosis on the blinded histology-proven *** The DL algorithm provides a reliable quantitative steatosis assessment across view and scanners on two multi-scanner *** performance was high with comparable or better performance than the CAP.

关键词： Ultrasound Liver steatosis Deep learning Screening Computer-aided diagnosis

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癌症筛查之未来

上海预防医学 2017年第3期29卷 245-247页

作者： Cheryll C.Thomas Thomas B.Richards Marcus Plescia Faye L.Wong Rachel Ballard Theodore R.Levin Bruce N.Calonge Otis W.Brawley John Iskander 徐海燕(翻译) 陆仁敏(审校) 蔡颖(审校) Division of Cancer Prevention and Control National Center for Chronic Disease Prevention and Health PromotionCDC National Cancer institute The Permanente Medical Group Inc.and Kaiser Permanente Medical CenterWalnut Creek and AntiochCalifornia The Colorado Trust American Cancer Society Office of the Associate Director for Science CDC 不详

1引言癌症已成为美国的第二大致死病因,52%的人死于肺癌、支气管癌、女性乳腺癌、宫颈癌、结直肠癌、口腔及咽喉癌、前列腺癌和皮肤癌（黑色素瘤）。19世纪30年代,包括宫颈癌在内的子宫癌,位居美国女性癌症死亡第一位。50年代,随着巴氏... 详细信息

1引言癌症已成为美国的第二大致死病因,52%的人死于肺癌、支气管癌、女性乳腺癌、宫颈癌、结直肠癌、口腔及咽喉癌、前列腺癌和皮肤癌（黑色素瘤）。19世纪30年代,包括宫颈癌在内的子宫癌,位居美国女性癌症死亡第一位。50年代,随着巴氏涂片技术（Pap test）的应用,可以在细胞水平检测宫颈的变化,宫颈癌死亡率显著降低,这是第一个癌症筛查检测技术。此后,已有多种影像学检查（例如乳腺癌钼靶X线、内窥镜检查和计算机体层扫描）和实验室检测方法（粪便隐血试验）用于癌症筛检。

关键词：筛查方法女性乳腺癌巴氏涂片癌死亡率结直肠癌致死病因钼靶黑色素瘤计算机体层扫描粪便隐血试验

Chemokines and Chemokine Receptors as Novel Therapeutic Targets in Rheumatoid Arthritis (RA):Inhibitory Effects of Traditional Chinese Medicinal Components

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Cellular & Molecular Immunology 2004年第5期1卷 336-342页

作者： Xinchen JoostJ.Oppenheim O.M.ZackHoward BasicResearchProgram SAIC-FrederickIncUSA. LaboratoryofMolecularImmunoregulation CenterforCancerResearchNationalCancerInstitute-FrederickFrederickMaryland21702-1201USA.

Chemokines belong to a large family of inflammatory cytokines responsible for migration and accumulation of leukocytes at inflammatory *** the past decade,accumulating evidence indicated a crucial role for chemokines and chemokine receptors in the pathophysiology of rheumatoid arthritis(RA).RA is a chronic autoimmune disease in which the synovial tissue is heavily infiltrated by *** play an important role in the infiltration,localization,retention of infiltrating leukocytes and generation of ectopic germinal centers in the inflamed *** evidence also suggests that identification of inhibitors directly targeting chemokines or their receptors may provide a novel therapeutic strategy in *** Chinese medicines(TCMs) have a long history in the treatment of inflammatory joint *** basis for the clinical benefits of TCM remains largely *** studies have led to the identification of numerous novel chemokine/chemokine receptor inhibitors present in anti-inflammatory *** of these inhibitors were previously reported by other researchers to have anti-arthritic effect,which may be attributable,at least in part,to their inhibitory effect on chemokine and/or chemokine ***,identification of agents capable of targeting chemokine/chemokine receptor interactions has suggested a mechanism of action for several TCM components and provided a means of identifying additional anti-RA ***,this approach may lead to the discovery of new inhibitors of chemokines or chemokine receptors that can be used to treat diseases associated with inappropriately overactive chemokine mediated inflammatory *** & Molecular Immunology.2004;1(5):336-342.

关键词： chemokine receptor rheumatoid arthritis traditional Chinese medicine

The use of tlamutin premix in feed to control CRD complex in broilers in Indonesia:a field trial

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The use of tlamutin premix in feed to control CRD complex in...

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

The 15th World Veterinary Poultry Congress

作者： M.Soeripto Andriani J.Raharjo H.Bantoro M.Valks Research institute for Veterinary Science Bogor. Research institute for Veterinary Science Bogor. PT Novartis Biochemie Jakarta PT Novartis Biochemie Jakarta Novartis Animal Health inc Switzerland

＜正＞The purpose of this trial is to test the efficacy and safety of a compatible dose of Tiamutin+amoxicillin premix in combination with monensin for the control of chronic respiratory disease complex（CRDC）in the Indonesian field circumstances.A number of 630 day-old chickens were divided into 3 groups and each group

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Translational Neurodegeneration 2022年第1期11卷 917-930页

作者： Manish Verma Britney N.Lizama Charleen T.Chu Department of Pathology University of Pittsburgh School of MedicinePittsburghPA 15261USA Department of Ophthalmology University of Pittsburgh School of MedicinePittsburghPA 15261USA Pittsburgh institute for Neurodegenerative Diseases University of Pittsburgh School of MedicinePittsburghPA 15261USA McGowan institute for Regenerative Medicine University of Pittsburgh School of MedicinePittsburghPA 15261USA Center for Protein Conformational Diseases University of PittsburghPittsburghPA 15261USA Center for Neuroscience University of PittsburghPittsburghPA 15261USA Present Address:Astellas Pharma inc. 9 Technology DriveWestboroughMA 01581USA.

Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory ***,high levels of glutamatergic input elicit excitotoxicity,contribut-ing to neuronal cell death following acute brain injuries such as stroke and *** excitotoxic cell death has also been implicated in some neurodegenerative disease models,the role of acute apoptotic cell death remains controversial in the setting of chronic ***,it is clear that excitatory synaptic dysregula-tion contributes to neurodegeneration,as evidenced by protective effects of partial N-methyl-D-aspartate receptor ***,we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease,Alzheimer’s disease,amyotrophic lateral sclerosis and Huntington’s *** contrast to classic excitotoxicity,emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic *** discuss mechanisms that regulate mitochondrial calcium uptake and release,the impact of LRRK2,PINK1,Parkin,beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters,and the role of autophagic mitochondrial loss in axodendritic ***,we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix,thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic *** the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems,a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

关键词： Mitochondrial calcium Mitochondrial calcium uniporter NCLX antiporter Parkinson’s disease Alzheimer’s disease LRRK2 PINK1 Beta-amyloid Mitophagy Excitotoxicity Amyotrophic lateral sclerosis Huntington’s disease Glucocerebrosidase

Golgi protein-73:A biomarker for assessing cirrhosis and prognosis of liver disease patients

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World Journal of Gastroenterology 2020年第34期26卷 5130-5145页

作者： Nikolaos K Gatselis Tamás Tornai Zakera Shums Kalliopi Zachou Asterios Saitis Stella Gabeta Roger Albesa Gary L Norman Mária Papp George N Dalekos Department of Medicine and Research Laboratory of Internal Medicine National Expertise Center of Greece in Autoimmune Liver DiseasesGeneral University Hospital of LarissaLarissa 41110Greece institute of Internal Medicine and Hepatology Larissa 41447Greece Department of Internal Medicine Division of GastroenterologyUniversity of DebrecenFaculty of MedicineDebrecen H-4032Hungary Department of Research and Development Inova DiagnosticsInc.San DiegoCA 92131United States

BACKGROUND Reliable biomarkers of cirrhosis,hepatocellular carcinoma(HCC),or progression of chronic liver diseases are *** this context,Golgi protein-73(GP73)also called Golgi phosphoprotein-2,was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial *** a result,GP73 expression was found primarily in biliary epithelial cells,with only slight detection in ***,in patients with acute or chronic liver diseases and especially in HCC,the expression of GP73 is significantly up-regulated in *** far,few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease *** To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease *** GP73 serum levels were retrospectively determined by a novel GP73 ELISA(QUANTA Lite®GP73,Inova Diagnostics,inc.,Research Use Only)in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa,Greece(n=366)and Debrecen,Hungary(n=266).Aspartate aminotransferase(AST)/Platelets(PLT)ratio index(APRI)was also calculated at the relevant time points in all *** hundred and three patients had chronic hepatitis B,183 chronic hepatitis C,198 alcoholic liver disease,28 autoimmune cholestatic liver diseases,15 autoimmune hepatitis,and 5 with other liver-related *** duration of follow-up was 50(57)mo[median(interquartile range)].The development of cirrhosis,liver decompensation and/or HCC during follow-up were assessed according to internationally accepted *** particular,the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein(AFP)determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic *** increased serum levels of GP73(>20 units)were detected at initial evaluation in 277 out of

关键词： Biomarker Golgi protein-73 Hepatic fibrosis Cirrhosis Hepatocellular carcinoma Hepatitis B Hepatitis C Aspartate aminotransferase/Platelets ratio index score