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Inflammatory bowel disease:Therapeutic limitations and prospective of the stem cell therapy

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World Journal of Stem Cells 2020年第10期12卷 1050-1066页

作者： Rangnath Mishra Punita Dhawan Anand S Srivastava Amar B Singh Institute of Stem Cell Therapy and Research San DiegoCA 92122United States Department of Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNE 68118United States fred and Pamela Buffett cancer center OmahaNE 68118United States VA Nebraska-Western Iowa Health Care System OmahaNE 68118United States

Inflammatory bowel disease(IBD),consisting primarily of ulcerative colitis and Crohn’s disease,is a group of debilitating auto-immune disorders,which also increases the risk of colitis-associated ***,due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs(e.g.,approximately 30%non-responders to anti-TNFαagents),and related serious side effects,about half of all IBD patients(in millions)turn to alternative treatment *** this regard,mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved ***,despite the increasing clinical realization of the significance of the concept of mucosal healing,its regulation and means of therapeutic targeting remain largely ***,stemcell therapy,which uses hematopoietic stem cells or mesenchymal stem cells,remains a promising *** cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory *** overreaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing ***,by differentiating into the mature intestinal epithelial cells,the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction,the root cause of the *** this article,we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.

关键词： Crohn′s disease Ulcerative colitis Mesenchymal stem cells Hematopoietic stem cells Mucosal healing

A pilot study of the association between genetic polymorphisms involved in estrogen signaling and infant male genital phenotypes

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Asian Journal of Andrology 2012年第5期14卷 766-772页

作者： Sheela Sathyanarayana Shanna H Swan Federico M Farin Hui-Wen Wilkerson Michael Bamshad Richard Grady Chuan Zhou Stephen M Schwartzy Department of Pediatrics University of WashingtonSeattleWA 98195USA center for Child Health Behaviorand DevelopmentSeattle Children's Research InstituteSeattleWA 98105USA Department of Preventive Medicine Mount Sinai School of MedicineNew YorkNY 10029USA Department of Environmental and Occupational Health Sciences University of WashingtonSeattleWA 98195USA Department of Genome Sciences University of WashingtonSeattleWA 98195USA Division of Pediatric Urology Seattle Children's HospitalSeattleWA 98105USA Department of Epidemiology University of WashingtonSeattleWA 98195USA Epidemiology Program Fred Hutchinson Cancer Research CenterSeattleWA 98109USA

Single nucleotide polymorphisms （SNPs） in genes that influence development of the male reproductive tract have been associated with male genitourinary abnormalities. However, no studies have tested the relationship between SNPs and intermediate phenotypes such as anogenital distance （AGD）, anoscrotal distance （ASD） and penile width （PW）. We tested whether 24 common SNPs in eight genes that influence male genital development were associated with intermediate phenotypes in 106 healthy male infants from the Study for Future Families. We used DNA from buccal smears and linear regression models to assess the relationship between anogenital measurements and SNP genotypes with adjustment for covariates. We found that the rs2077647 G allele, located in the coding region of estrogen receptor alpha （ESR1）, was associated with a shorter AGD （P=0.02; -7.3 mm, 95% confidence interval （CI）： -11.6 to -3.1）, and the rs10475 T allele, located in the 3＇ untranslated region of activating transcription factor 3 （ATF3）, was associated with a shorter ASD （-4.3 mm, 95% Ch -7.2 to -1.4）, although this result was not significant （P=0.07） after controlling for multiple comparisons. We observed no association between PW and the SNPs tested. Minor alleles for two SNPs in genes that regulate estrogen signaling during male genital development were associated with AGD and ASD, although the significance of the association was marginal. Our findings suggest that AGD and ASD are influenced by heritable factors in genes known to be associated with frank male genital abnormalities such as hvpospadias and crvotorchidism.

关键词： gene hypospadias male phenotype polymorphism reproductive

Projected effectiveness of HIV detection during early infection and rapid ART initiation among MSM and transgender women in Peru: A modeling study

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Infectious Disease Modelling 2019年第1期4卷 73-82页

作者： Dobromir Dimitrov Daniel Wood Angela Ulrich David A.Swan Blythe Adamson Javier R.Lama Jorge Sanchez Ann Duerr Vaccine and Infectious Diseases Division Fred Hutchinson Cancer Research CenterSeattleWAUSA Department of Global Health University of WashingtonSeattleWAUSA Comparative Health Outcomes Policy&Economics(CHOICE)InstituteUniversity of WashingtonSeattleWAUSA Asociacion Civil Impacta Salud y Educacion LimaPeru Centro de Investigaciones Tecnologicas Biomedicas y MedioambientalesUniversidad Mayor de San MarcosLimaPeru

Background:The Sabes study,a treatment as prevention intervention in Peru,tested the hypothesis that initiating antiretroviral therapy(ART)early in HIV infection when viral load is high,would markedly reduce onward HIV transmission among high-risk men who have sex with men(MSM)and transgender women(TW).We investigated the potential population-level benefits of detection of HIV early after acquisition and rapid initiation of ***:We designed a transmission dynamic model to simulate the HIV epidemic among MSM and TW in Peru,calibrated to data on HIV prevalence and ART coverage from 2004 to *** assessed the impact of an intervention starting in 2018 in which up to 50%of the new infections were diagnosed within three months of acquisition and initiated on ART within 1 month of *** estimated the impact of the intervention over 20 years using the cumulative prevented fraction of new HIV infections compared to scenarios without ***:Our model suggests that only 19%of the infected MSM and TW are virally suppressed in 2018 and 35%e40%of the new HIV infections are transmitted from contacts with acutely-infected *** intervention reaching 10%of all acutely infected MSM and TW is projected to prevent 13.3%[Uncertainty interval:11.9%e14.3%]of the new infections over 20 years and reduce HIV incidence in 2038 by 24%.Reaching 50%of all acutely infected MSM and TWwill increase the prevalence of viral suppression in 2038 to 59%and prevent 41%of expected infections over 20 *** 50%of the high-risk MSM and TW in acute phase would reduce HIV incidence in 2038 by 60%and prevent 36%of new infections between 2018 and ***:Early detection of HIV infections and rapid initiation of ART among MSM is desirable as it would increase the effectiveness of the HIV prevention program in *** high-risk MSM and TW will be highly efficient.

关键词： Mathematical model Antiretroviral therapy HIV incidence HIV prevention

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

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Frontiers of Medicine 2021年第2期15卷 275-291页

作者： Na Qin Yuancheng Li Cheng Wang Meng Zhu Juncheng Dai Tongtong Hong Demetrius Albanes Stephen Lam Adonina Tardon Chu Chen Gary Goodman Stig EBojesen Maria Teresa Landi Mattias Johansson Angela Risch H-Erich Wichmann Heike Bickeboller Gadi Rennert Susanne Arnold Paul Brennan John KField Sanjay Shete Loic Le Marchand Olle Melander Hans Brunnstrom Geoffrey Liu Rayjean JHung Angeline Andrew Lambertus AKiemeney Shan Zienolddiny Kjell Grankvist Mikael Johansson Neil Caporaso Penella Woll Philip Lazarus Matthew BSchabath Melinda CAldrich Victoria LStevens Guangfu Jin David CChristiani Zhibin Hu Christopher IAmos Hongxia Ma Hongbing Shen Department of Epidemiology Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjing 211166China State Key Laboratory of Reproductive Medicine Center for Global HealthNanjing Medical UniversityNanjing 211166China Department of Bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing 211166China Jiangsu Key Lab of cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer MedicineNanjing Medical UniversityNanjing 211166China China International Cooperation center for Environment and Human Health School of Public HealthNanjing Medical UniversityNanjing 211166China Division of cancer Epidemiology and Genetics National Cancer InstituteBethesdaMD 20892-9304USA Department of Integrative Oncology British Columbia Cancer AgencyVancouverBC V5Z 1L3Canada Faculty of Medicine University of Oviedo and CIBERESPOviedo 33006Spain Program in Epidemiology Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleWA 98109-1024USA Public Health Sciences Division Swedish Cancer InstituteSeattleWA 98026USA Department of Clinical Biochemistry Copenhagen University HospitalCopenhagen DK-1017Denmark National cancer Institute BethesdaMD 20892-9304USA Genetic Epidemiology Group International Agency for Research on CancerLyon 69372France cancer center Cluster Salzburg at PLUS Department of Molecular BiologyUniversity of SalzburgHeidelberg 5020Austria Institute of Medical Informatics Biometry and EpidemiologyChair of EpidemiologyLudwig Maximilians UniversityMunichBavaria 80539Germany Department of Genetic Epidemiology University Medical Center GoettingenGoettingen 37075Germany Technion Faculty of Medicine Carmel Medical CenterHaifa 3448516Israel Markey cancer center University of KentuckyLexingtonKY 40506-0054USA Department of Molecular and Clinical cancer Medicine Roy Castle Lung Cancer Research ProgrammeThe University of Liverpool Institute of Translational MedicineLiverpool L697Z

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely *** integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility *** identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive *** factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was *** annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency *** results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

关键词： lung cancer genome-wide association study function annotation immune homologous recombination repair deficiency genetic heterogeneity

天然杀伤(NK)细胞与靶细胞相互作用的研究

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分子细胞生物学报 1987年第2期 40-49页

作者：丰美福 C.S.Henney 中国科学院北京动物研究所美国fred hutchinson cancer Research center

本文对NK细胞与正常的,以及经低温、加热、超声、辐射、单糖、蛋白酶、和/或环己亚胺处理的靶细胞(AV、1C2、YAC-1、R.1.1,R.1.X)的相互作用进行了研究。并且与混合淋巴细胞培养产生的细胞毒作用进行了比较。试验并对来自L 5178 Y的一... 详细信息

本文对NK细胞与正常的,以及经低温、加热、超声、辐射、单糖、蛋白酶、和/或环己亚胺处理的靶细胞(AV、1C2、YAC-1、R.1.1,R.1.X)的相互作用进行了研究。并且与混合淋巴细胞培养产生的细胞毒作用进行了比较。试验并对来自L 5178 Y的一对变株AV(NK不敏感株)和1C2(NK敏感株)作了FACS分析。结果表明:NK细胞对多种瘤细胞均有杀伤作用,不受H-2限制,NK细胞介导的这一细胞毒作用可能需要一个完整的,有代谢活性的靶细胞结构。蛋白酶和环己亚胺处理能显著降低NK细胞的活性。FACS分析结果表明:1C2能特异地与抗Gg 3cer糖脂的单抗结合,而AV则不能。以上提示:NK细胞有它一定的识别作用。糖蛋白和/或糖脂可能是NK细胞所识别的靶的结构。

关键词： NK targets.Interaction.Recognition structure.

Application of Proteomics to cancer Molecular Diagnostics

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中国肺癌杂志 2009年第6期12卷 I0005-I0005页

作者： Sam HANASH fred hutchinson cancer Research center Washington USA

Strategies to achieve personalized medicine and improve public health encompass assessment of an individual's risk for disease,

关键词：肿瘤诊断学临床治疗

Mismatch repair enzyme expression in primary and castrate resistant prostate cancer

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Asian Journal of Urology 2016年第4期3卷 223-228页

作者： Belinda Nghiem Xiaotun Zhang Hung-Ming Lam Lawrence DTrue Ilsa Coleman Celestia SHigano Peter SNelson Colin CPritchard Colm Morrissey Department of Urology University of WashingtonSeattleWAUSA State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacao(SAR)China Department of Pathology University of WashingtonSeattleWAUSA Divison of Human Biology Fred Hutchinson Cancer Research CenterSeattleWAUSA Department of Medicine University of WashingtonSeattleWAUSA Department of Laboratory Medicine University of WashingtonSeattleWAUSA

Objective:Although the utility of immunohistochemistry(IHC)for assessing mismatch repair(MMR)protein expression has been demonstrated in solid tumors including primary prostate cancer(PCa),its utility has not been assessed in castration-resistant PCa(CRPC).Methods:Tissue microarrays were constructed from 127 radical prostatectomies and 155 CRPC metastases from 50 ***(MLH1,MSH2,MSH6,and PMS2)expression was assessed by IHC and gene expression *** between MMR protein expression in PCa and CRPC and biochemical recurrence(BCR)or time from diagnosis to death respectively were ***:There was no correlation between levels of MMR protein and *** of MSH2 and MSH6 was the most pronounced at 15%and 22%in PCa and 17.8%and 16%in CRPC patients,***2 and MSH6 protein were absent in 9.4%and 8%of PCa and CRPC *** of individual MMR proteins did not correlate with BCR or time from diagnosis to *** absent MSH2/MSH6 in CRPC was associated with shorter time to death(pZ0.0006).Loss of MSH2 was verified at the gene expression *** finding correlated with microsatellite instability previously reported in this CRPC cohort.

关键词： Mismatch repair Castration resistant prostate cancer MLH1 MSH2 MSH6 PMS2

激素治疗的长期应用及不同治疗方案与乳腺癌发病危险的关系

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美国医学会杂志（中文版） 2004年第5期23卷 240-244页

作者：李颖郁琦 Division of Public Health Sciences fred hutchinson cancer Research center Seattle Wash and Department of Epidemiology School of Public Health and Community Medicine Division of Public Health Sciences fred hutchinson cancer Research center Seattle Wash Department of Epidemiology School of Public Health and Community Medicine Division of Human Biology Department of Pathology School of Medicine University of Washington Seattle Division of Public Health Sciences fred hutchinson cancer Research center Seattle Wash Department of Epidemiology School of Public Health and Community Medicine Division of Public Health Sciences

背景：妇女应用雌孕激素联合替代治疗(combined estrogen and progestine hormone replacement therapy，CHRT)会增加乳腺癌的危险；然而，目前仍缺乏长期使用和不同治疗方案所致危险性的资料。目的：通过组织病理学类型及激素受体状况... 详细信息

背景：妇女应用雌孕激素联合替代治疗(combined estrogen and progestine hormone replacement therapy，CHRT)会增加乳腺癌的危险；然而，目前仍缺乏长期使用和不同治疗方案所致危险性的资料。目的：通过组织病理学类型及激素受体状况，评估CHRT应用时间及方式与乳腺癌的关系。设计：人群病例．对照研究。地点：华盛顿州西部三个县。参试者：自1997年4月1日至1999年5月31日，975例65～79岁诊断为侵袭性乳腺癌的妇女(组织学：196例小叶癌，656例导管癌，114例其他组织类型以及9例非特异组织学类型；雌激素受体(ER)／孕激素受体(PR)状况：646例ER+／PR+，147例ER+／PR-，101例ER-／PR-[6例ER-／PR+和75例ER／PR状况不明者未包括于本研究中]，1007例正常人作为对照。主要观察指标：发生侵袭性乳腺小叶癌、乳腺导管癌以及ER+／PR+、ER+／PR-和ER-／PR-乳腺癌的危险。结果：应用非对抗性雌激素替代治疗(estrogen replacement therapy，ERT)的妇女(仅用ERT者)，即使应用25年以上，乳腺癌发病危险无明显增加(尽管其相关优势比与可能存在微弱影响并非不一致)。曾经应用CHRT者(包括也使用过ERT的CHRT使用者)乳腺癌危险性增加1．7倍(95％可信区间[CI]，1．3～2．2)，其中包括侵袭性小叶癌危险性增加2．7倍(95％CI，1．7～4．3)，侵袭性导管癌增加1．5倍(95％CI，1．1～2．0)，ER+／PR+乳腺癌危险性增加2．0倍(95％CI，1．5～2．7)。危险性增加在较长期使用CHRT的妇女最为明显，应用CHRT在5～14．9年和≥15年者，侵袭性导管癌的危险性分别增加1．5倍(95％CI，1．0～2．3)和1．6倍(95％CI，1．0～2．6)，侵袭性小叶癌的危险性则分别增加了3．7倍(95％CI，2．0～6．6)和2．6倍(95％CI，1．3～5．3)。在按期使用和连续使用CHRT的妇女，相关程度大致相似。任何使用方式均不增加ER+／PR-和ER-／PR-肿瘤的危险性；然而，由于这些肿瘤患者的数量少，限制了我们发现可能联系的把握度。结论：研究资料提示，CHRT的使用，无论是按期或者持续使用孕激素，均与乳腺癌特别是侵袭性小叶癌危险性增加相关。

关键词：乳腺癌侵袭性 PR ERT 危险性导管癌发病危险资料发现

A boronate-based modular assembly nanosystem to block the undesirable crosstalk between hepatic stellate cells and Kupffer cells

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Bioactive Materials 2023年第7期25卷 569-579页

作者： Huizhen Jia Ling Ding Ao Yu Weimin Tang Siyuan Tang Chuhan Zhang David Oupický center for Drug Delivery and Nanomedicine Department of Pharmaceutical SciencesCollege of PharmacyUniversity of Nebraska Medical CenterOmahaNE68198USA

Crosstalk between Kupffer cells(KCs)and hepatic stellate cells(HSCs)plays an important role in multiple liver disease conditions,including the formation of liver fibrosis in alcohol-associated liver disease(AALD).Therapeutic targeting of the KC-HSC crosstalk is a prime target for therapeutic ***,a novel modular nanosystem was designed and prepared through the self-assembly utilizing boric acid and catechol interactions to prepare polymers modified with a CXCR4-inhibiting *** polymers were used to encapsulate anti-miR-155 and to block the undesirable crosstalk between HSCs and KCs by downregulating miR-155 expression in KCs with the parallel inhibition of CXCR4 signaling in activated *** combined inhibition of miR-155 and CXCR4 at two different liver cell types achieved improved antifibrosis effects in a mouse model of AALD *** finding highlights the key role that blocking the undesirable crosstalk between HSCs and KCs plays in reversing AALD fibrosis as well as demonstrates a proof-of-concept approach for designing and constructing multifunctional delivery nanosystems using orthogonal functional modules based on the understanding of disease mechanisms.

关键词： Nanoparticles miRNA CXCR4 Liver fibrosis Undesirable crosstalk Modular assembly