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Inflammation-associated microsatellite alterations:Mechanisms and significance in the prognosis of patients with colorectal cancer

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World Journal of Gastrointestinal Oncology 2018年第1期10卷 1-14页

作者： Minoru Koi Stephanie S Tseng-Rogenski John M Carethers Department of Internal Medicine and Comprehensive Cancer Center University of MichiganAnn ArborMI 48109-5368United States

Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair(MMR). About 15% of sporadic colorectal cancers(CRCs) manifest hypermethylation of the DNA MMR gene MLH1, resulting in mono-and di-nucleotide frameshifts to classify it as microsatellite instability-high(MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic nonMSI-H CRCs demonstrate frameshifts at di-and tetra-nucleotide microsatellites to classify it as MSIlow/elevated microsatellite alterations at selected tetranucleotide repeats(EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement. The trigger for MSH3 displacement appears to be inflammation and/or oxidative stress, and unlike MSI-H CRC patients, patients with MSI-L/EMAST CRCs show poor prognosis. These inflammatory-associated microsatellite alterations are a consequence of the local tumor microenvironment, and in theory, if the microenvironment is manipulated to lower inflammation, the microsatellite alterations and MSH3 dysfunction should be corrected. Here we describe the mechanisms and significance of inflammatory-associated microsatellite alterations, and propose three areas to deeply explore the consequences and prevention of inflammation's effect upon the DNA MMR system.

关键词： Microsatellite instability Microsatellite stable Elevated microsatellite alterations at selected tetranucleotide repeats Colorectal cancer Mismatch repair Inflammation MSH3

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Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

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World Journal of Gastroenterology 2015年第31期21卷 9253-9261页

作者： John M Carethers Elena M Stoffel Division of Gastroenterology Department of Internal MedicineUniversity of Michigan

Hereditary non-polyposis colorectal cancer(HNPCC) was previously synonymous with Lynch syndrome; however,identification of the role of germline mutations in the DNA mismatch repair(MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer(CRC). Broadly,HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability(MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome(germline MMR mutation),Lynch-like syndrome(biallelic somatic MMR mutations),constitutional MMR deficiency syndrome(biallelic germline MMR mutations),and sporadic MSI CRC(somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions,others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.

关键词： Hereditary non-polyposis colorectal cancer Lynch s

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A vestigial pathway for sex differences in immune regulation

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Cellular & Molecular Immunology 2017年第7期14卷 578-580页

作者： Yun Liang J Michelle Kahlenberg Johann E Gudjonsson Department of Dermatology University of MichiganAnn ArborMI 48109USA Division of Rheumatology Department of Internal MedicineUniversity of MichiganAnn ArborMI 48109USA

Autoimmune diseases have a strikingly higher prevalence in women compared to men,with approximately 80%of individuals affected with autoimmune diseases being *** nature of this sex-bias has remained unclear,but sex hormones have previously been implicated as the leading underlying *** this research highlight,we discuss a recently identified transcription factor。

关键词： diseases autoimmune prevalence

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“Autoinflammatory psoriasis”-genetics and biology of pustular psoriasis

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Cellular & Molecular Immunology 2021年第2期18卷 307-317页

作者： Ranjitha Uppala Lam C.Tsoi Paul W.Harms Bo Wang Allison C.Billi Emanual Maverakis J.Michelle Kahlenberg Nicole L.Ward Johann E.Gudjonsson Graduate Program in Immunology University of MichiganAnn ArborMIUSA Department of Dermatology University of MichiganAnn ArborMIUSA Department of Pathology University of MichiganAnn ArborMIUSA Department of Dermatology University of CaliforniaDavisSacramentoCAUSA Division of Rheumatology Department of Internal MedicineUniversity of MichiganAnn ArborMIUSA a.alfred taubman medical research institute Ann ArborMIUSA Departments of Nutrition and Dermatology Case Western Reserve UniversityClevelandOHUSA

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical *** psoriasis,which is the most common manifestation of psoriasis,is located on one end of the spectrum,dominated by adaptive immune responses,whereas the rarer pustular psoriasis lies on the opposite end,dominated by innate and autoinflammatory immune *** recent years,genetic studies have identified six genetic variants that predispose to pustular psoriasis,and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis *** this review,we discuss the presentation and clinical subtypes of pustular psoriasis,contribution of genetic predisposing variants,critical role of the IL-36 family of cytokines in disease pathophysiology,and treatment perspectives for pustular *** further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

关键词： Pustular psoriasis Genetics IL-36 Autoinflammation Clinical features Histology

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海藻糖及其在眼科的研究进展

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国际眼科杂志 2008年第11期8卷 2316-2318页

作者：高洪瑞蒋华济南军区总医院眼科中国山东省济南市250031

海藻糖(trehalose,TRH)是一种具有独特抗脱水、抗冷冻、抗高渗保护作用的非特异性生物保护剂,可在严酷环境下保护生物体的组织和大分子的功能和活性,在眼液制剂、干眼症治疗、角膜保存等方面有较大的研究进展。本文就TRH的生物特性及在... 详细信息

海藻糖(trehalose,TRH)是一种具有独特抗脱水、抗冷冻、抗高渗保护作用的非特异性生物保护剂,可在严酷环境下保护生物体的组织和大分子的功能和活性,在眼液制剂、干眼症治疗、角膜保存等方面有较大的研究进展。本文就TRH的生物特性及在眼科的研究进展情况作一综述。

关键词：海藻糖眼液制剂干眼症角膜保存

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