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Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome

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World Journal of Gastrointestinal Surgery 2015年第4期7卷 60-66页

作者： Helen C miller mark Kidd irvin m modlin Patrizia Cohen Roberto Dina Panagiotis Drymousis Panagiotis Vlavianos Günter Klöppel Andrea Frilling Department of Surgery and Cancer Imperial College LondonLondon W12 0HSUnited Kingdom Department of Surgery Yale UniversityNew HavenCT 06510United States Emeritus Yale University School of MedicineNew HavenCT 06510United States Department of Histopathology Imperial College LondonLondon W12 0HSUnited Kingdom Department of Gastroenterology Imperial College LondonLondon W12 0HSUnited Kingdom Department of Pathology Technical University of Munich81675 MunichGermany

Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of nonspecific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. more recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. Octreo Scan was negative. Serum glucagon was elevated to 66 pmol/L(normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene(GCGR) sequencing revealed a heterozygous deletion,K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.

关键词： Hyperglucagonemia Glucagon receptorgene mutation Adenomatosis Pancreas

神经内分泌肿瘤68Ga-DOTATATE显像新观点:图像解读、体内分布、辐射内照射剂量及分子机制

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中华核医学与分子影像杂志 2019年第8期39卷 504-512页

作者：胡桂兰庞芮(译) 霍力(审校) Lisa Bodei Valentina Ambrosini Ken Herrmann irvin modlin 首都医科大学附属北京世纪坛医院核医学科 100038 中国医学科学院、北京协和医学院北京协和医院核医学科、核医学分子靶向诊疗北京市重点实验室 100730 molecular Imaging and Therapy Service Department of RadiologyMemorial Sloan Kettering Cancer CenterNew YorkNew York Nuclear medicine Department of Experimental Diagnostic and Specialized MedicineUniversity of Bologna and S.Orsola-Malpighi HospitalBolognaItaly Department of molecular and medical Pharmacology David Geffen School of Medicine at UCLALos AngelesCalifornia Klinik für Nuklearmedizin Universitatsklinikum EssenEssenGermany Yale University School of medicine Department of SurgeryNew HavenConnecticut

利用68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-D-苯丙氨酸1-酪氨酸3-苏氨酸8-奥曲肽(DOTATATE)PET/CT显像对表达生长抑素受体(SSTR)的肿瘤进行定位,就必须将图像信息有效地与患者诊疗过程相结合,包括临床病史、组织病理学、生物... 详细信息

利用68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-D-苯丙氨酸1-酪氨酸3-苏氨酸8-奥曲肽(DOTATATE)PET/CT显像对表达生长抑素受体(SSTR)的肿瘤进行定位,就必须将图像信息有效地与患者诊疗过程相结合,包括临床病史、组织病理学、生物标志物、肿瘤分期和分级以及已知的影像学检查结果,另外还要考虑到患者已完成的治疗及检查对68Ga-DOTATATE图像的影响(如影响正常生理性分布并导致假阳性结果)。该文针对68Ga-DOTATATE PET/CT显像在图像采集、分析、神经内分泌肿瘤诊断方案及治疗中的价值提供指导意见。

关键词：内分泌神经内分泌肿瘤学肽 68Ga-DOTATATE 生物分布

CTGF, intestinal stellate cells and carcinoid fi brogenesis

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World Journal of Gastroenterology 2007年第39期13卷 5208-5216页

作者： m Kidd Im modlin mD Shapiro RL Camp Sm mane W Usinger JR murren Departments of Surgery Yale University School of Medicine New Haven Connecticut 06520-8062 United States Departments of Pathology Yale University School of Medicine New Haven Connecticut 06520-8062 United States Departments of Affymetrix Resource Keck Biotechnology Resource Laboratory Yale University School of Medicine New Haven Connecticut 06520-8062 United States Fibrogen Inc San Francisco CA United States Departments of medical Oncology Yale University School of Medicine New Haven Connecticut 06520-8062 United States

AIm： To investigate the role of small intestinal carcinoid tumor-derived fibrotic mediators, TGFβ1 and CTGF, in the mediation of fibrosis via activation of an ＂intestinal＂ stellate cell. mETHODS： GI carcinoid tumors were collected for Q RT-PCR analysis of CTGF and TGFβ1. markers of stellate cell desmoplasia were identified in peritoneal fibrosis by immunohistochemistry and stellate cells cultured from fresh resected fibrotic tissue. CTGF and TGFβ1 were evaluated using quantitative tissue array profiling （AQUA analysis） in a GI carcinoid tissue microarray （TmA） with immunostaining and correlated with clinical and histologically documented fibrosis. Serum CTGF was analyzed using a sandwich ELISA assay. RESULTS： message levels of both CTGF and TGFβ1 in SI carcinoid tumors were significantly increased （〉 2-fold, P 〈 0.05） versus normal mucosa and gastric （non-fibrotic） carcinoids. Activated stellate cells and markers of stellate cell-mediated fibrosis （vimentin, desmin） were identified in histological fibrosis. An intestinal stellate cell was immunocytochemically and biochemically characterized and its TGFβ1 （10-7m） initiated CTGF transcription response （〉 3-fold, P 〈 0.05） demonstrated. In SI carcinoid tumor patients with documented fibrosis, TmA analysis demonstrated higher CTGF immunostaining （AQUA Score： 92 ± 8, P 〈0.05）, as well as elevated TGFβ1 （90.6 ± 4.4, P 〈 0.05）. Plasma CTGF （normal 12.5 ± 2.6 ng/mL） was increased in SI carcinoid tumor patients （31 ± 10 ng/mL, P 〈 0.05） compared to non-fibrotic GI carcinoids （〈 15 ng/mL） CONCLUSION： SI carcinoid tumor fibrosis is a CTGF/ TGFβl-mediated stellate cell-driven fibrotic response. The delineation of the biology of fibrosis will facilitate diagnosis and enable development of agents to obviate its local and systemic complications.

关键词： Carcinoid Connective tissue growth factor fibrosis Small intestine Stellate cell TGFI

Comparison of hepatitis C virus testing recommendations in high-income countries

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World Journal of Hepatology 2018年第10期10卷 743-751页

作者： Risha irvin Kathleen Ward Tracy Agee Noele P Nelson Claudia Vellozzi David L Thomas Alexander J millman Division of Infectious Diseases Johns Hopkins University School of Medicine Division of Viral Hepatitis Centers for Disease Control and Prevention

AIm To investigate hepatitis C virus(HCV) testing recommendations from the United States and other high-income *** A comprehensive search for current HCV testing recommendations from the top quartile of United Nations Human Development Index(HDI) countries(very high HDI) was performed using Google and reviewed from may 1-October 30, 2014 and re-reviewed April 1-October 2, 2017. RESULTS Of the 51 countries identified, 16 had HCV testing recom-mendations from a government body or recommendations issued collaboratively between a government and a medical organization. Of these 16 countries, 15 had HCV testing recommendations that were primarily risk-based and highlight behaviors, exposures, and conditions that are associated with HCV transmission in that region. In addition to risk-based testing, the HCV Guidance Panel(United States) incorporates recommendations for aone-time test for individuals born during 1945-1965(the birth cohort) without prior ascertainment of risk into their guidance. In addition to the United States, six other countries either have an age-based testing recommendation or recommend one-time testing for all adults independent of risk factors typical of the region. CONCLUSION This review affirmed the similarities of the HCV Guidance Panel's guidance with those of recommendations from very high HDI countries.

关键词： Hepatitis C Testing Recommendations mass screening Guidelines

Overview of the Prevalence and Associated Risk, Factors of Lifestyle Diseases in University Students

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International Journal of Clinical medicine 2017年第5期8卷 344-352页

作者： Damar Nagheer Rachael irvin Novie Younger-Coleman Department of medical Sciences Biochemistry Section The University of the West Indies Mona Campus Mona Jamaica

Background: The prevalence of lifestyle diseases is increasing rapidly in Youths (17 - 25 yrs). Factors such as poor diet, little or no physical exercise, and smoking are major contributors to this increase. Lifestyle diseases in youths present a timeline challenge as disease duration is longer and financial burden more costly. Aim: To analyse and synthesize published literature on the prevalence of and risk factors associated with four lifestyle diseases—obesity, hypertension, diabetes and cancer—in university/college students worldwide. Results: The literature indicates that among lifestyle diseases in university/college students, overweight/obesity (Body mass Index > 25 kg/m2) had the highest prevalence of 45.6% and duration of approximately 5 years. Cardiovascular diseases and hypertension had lower prevalence rates but prehypertension which lingers >4 years was at 32.0%. Type 1 diabetes mellitus (T1Dm) had a fairly high prevalence in college students (21.7%);type 2 diabetes mellitus (T2Dm) was found in much lower percentage (12.95%). Cancer had the lowest prevalence of >2% but was increasing in most regions based on the presence of multiple risk factors. Conclusion: Increase prevalence of these diseases in youths indicates that young people are at high risk of developing these diseases due to poor early lifestyle habits. Early corrective measures can reduce the burden of many lifestyle diseases.

关键词： Dm1 (Diabetes mellitus Type 1) Dm2 (Diabetes mellitus Type 2) WHR (Waist-Hip Ratio) Obesity World Health Organization (WHO)

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胃泌素瘤的诊断与处理

国际外科学杂志 1984年第4期11卷 194-196页

作者： modlin I m 夏云节

早期对胃泌素瘤病人的研究表明,这是一种难治的、多发性、侵袭性的复发性消化性溃疡,与一般有广泛转移的胰岛细胞瘤有关.现已认识到,高酸的大量分泌及其并发症系循环中高浓度的胃泌素所致,这些胃泌素由胰腺内分泌瘤产生.本综合征首先由Z... 详细信息

早期对胃泌素瘤病人的研究表明,这是一种难治的、多发性、侵袭性的复发性消化性溃疡,与一般有广泛转移的胰岛细胞瘤有关.现已认识到,高酸的大量分泌及其并发症系循环中高浓度的胃泌素所致,这些胃泌素由胰腺内分泌瘤产生.本综合征首先由Zollinger和Ellison描述.其发病率在丹麦为每年每百万人中有一人.美国每年35万例新发病的消化性溃疡中,胃泌素瘤所占比例虽小,但有意义.胃泌素瘤至少60%为恶性.手术时50%以上病人已有肝转移.而且,50%以上病人胰腺内可见多发性病变或转移灶.术后,有50%的病人复发.因此

关键词：胃泌素瘤病人十二指肠胃窦消化性溃疡小肠消化道溃疡胃肠病激发试验促胰液素

Phosphorylcholine polymer nanocapsules prolong the circulation time and reduce the immunogenicity of therapeutic proteins

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Nano Research 2016年第4期9卷 1022-1031页

作者： Sheng Liang Yang Liu Xin Jin Gan Liu Jing Wen Linlin Zhang Jie Li Xubo Yuan irvin S.Y. Chen Wei Chen Hui Wang Linqi Shi Xinyuan Zhu Yunfeng Lu Department of Nuclear medicine Xinhua HospitalAffiliated to Shanghai Jiao Tong University Shanghai Jiao Tong University Shanghai 200092 China Department of Chemical and Biomolecular Engineering University of California Los Angeles CA 90095 USA Department of microbiology Immunology and Molecular Genetics University of California Los Angeles CA 90095 USA Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) Key Laboratory of Functional Polymer Materials of Ministry of Education and State Key Laboratory of Medicinal Chemical Biology Institute of Polymer Chemistry Nankai University Tianjin 30007 I China School of Chemistry and Chemical Engineering ShanghaiJiao Tong University Shanghai 200240 China School of materials Science and Engineering Key Laboratory of Composite and Functional Materials Tianjin University Tianjin 300072 China Beiiina Institute ofBiatechnoloav. Beiiina 100071. China

Protein therap34 wherein therapeutic proteins are delivered to treat disorders, is considered the safest and most direct approach for treating diseases. However, its applications are highly limited by the paucity of efficient strategies for delivering proteins and the rapid clearance of therapeutic proteins in vivo after their administration. Here, we demonstrate a novel strategy that can significantly prolong the circulation time of therapeutic proteins as well as minimize their immunogenicity. This is achieved by encapsulating individual protein molecules with a thin layer of crosslinked phosphorylcholine polymer that resists protein adsorption. Through extensive cellular studies, we demonstrate that the crosslinked phosphorylcholine polymer shell effectively prevents the encapsulated protein from being phagocytosed by macrophages, which play an essential role in the clearance of nanoparfides in vivo. moreover, the polymer shell prevents the encapsulated protein from being identified by immune cells. As a result, immune responses against the therapeutic protein are effectively suppressed. This work describes a feasible method to prolong the circulation time and reduce the immunogenicity of therapeutic proteins, which may promote the development and application of novel protein therapies in the treatment of diverse diseases.

关键词： protein nanocapsule,protein delivery,protein therapy long-circulation,stealth therapeutic

Type I Interferon Responses to Bacterial Infections

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Type I Interferon Responses to Bacterial Infections

Diet-Induced Alteration of the murine Intestinal microbiome Following Antibiotic Ablation

第八届全国免疫学学术大会

作者：程根宏 Kislay Parvatiyar Zhiqiang Zhang Songying Ouyang Rosane m Teles Robert L modlin Zhi-Jie Liu Yongjun Liu 美国加州大学洛杉矶分校微生物与免疫遗传学系 Department of microbiology Immunology and Molecular Genetics University of CaliforniaLos Angeles CA 90095 USA Baylor Institute for Immunology Research Baylor Research Institute 3434 Live Oak StDallas TX 75204 USA Institute of Biophysics Chinese Academy of Science Division of Dermatology Department of Medicine David Geffen School of MedicineUniversity of CaliforniaLos Angeles CA 90095 USA

In response to infections by pathogens such as bacteria and viruses,host pattern recognition receptors(P R R)can recognize conserved structural motifs in pathogens,initiate innate immune responses and also instruct adaptive immune responses to combat infecting *** families of P R Rs,including Toll-like Recptor(TLR),Nod-like receptor(NLR)and Retinoic acid inducible gene-I( RIG-I)like receptor( RLR),are differentially expressed in immune and non-immune *** individual P R Rs conduct their specific biological functions through the activation of overlapping and distinct signal transduction and gene expression networks,which we called gene programs.

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Advances in microbiology 2017年第7期7卷 545-564页

作者： Adam irvin Andrew Cockburn Donald A. Primerano Jim Denvir Goran Boskovic Aniello m. Infante Gary D. Wu Christopher F. Cuff Department of microbiology Immunology and Cell Biology Robert C. Byrd Health Sciences Center West Virginia University Morgantown WV USA Department of Biomedical Sciences Robert C. Byrd Biotechnology Science Center Joan C. Edwards School of Medicine Marshall University Huntington WV USA Department of Biostatistics Robert C. Byrd Health Sciences Center West Virginia University Morgantown WV USA Division of Gastroenterology Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

mouse models of antibiotic-induced ablation of the intestinal microbiome have been used to study the microbiome in health and disease. The fecal microbiomes of mice treated with broad-spectrum antibiotics while being fed different laboratory chows were analyzed by Gram stain, quantitative flow cytometry, bacterial cell culture, next generation sequencing of the V3 regions of the 16S ribosomal RNA (rRNA) gene, microscopy, and sequence analysis of the tuf gene. Noncultivatable gram-positive cocci and cultivatable yeast were the microorganisms most readily detected in feces of antibiotic-treated mice fed a defined diet that utilizes casein as a protein source, maltodextrin 10 and sucrose as sources of carbohydrates, and lard as the major source of fat. High-throughput sequencing of the variable regions of the 16S rRNA gene and tuf gene sequencing identified the major bacterial phylotype as Lactococcus. The mouse chow was heavily laden with noncultivatable Lactococcus, which dominated the intestinal flora after consumption. The microbiome of antibiotic-treated mice fed a grain-based diet (mainly wheat, corn and alfalfa) consisted predominantly of a member of the Enterobacteriaceae identified as Escherichia coli, and yeast was not detected by culture or Gram stain. Appearance of intestinal yeast by culture and Gram stain was dependent on the specific chow, although yeast was not detected by culture or Gram stain in the chow. We conclude that bacteria found in food sources can influence qualitative and quantitative assessments of the fecal microbiome, at least in the context of antibiotic therapy, and potentially confound molecular studies that assess the effects of diet on the intestinal ecology. Not surprisingly, different food sources can influence the microbiome, particularly in the context of antibiotic-mediated ablation of the intestinal microbiome. Whether and how the food-derived dead bacteria alter intestinal physiology needs to be determined.

关键词： mouse Intestinal microbiome Antibiotics Diet Lactococcus