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Pre-operative visceral adipose tissue radiodensity is a potentially novel prognostic biomarker for early endoscopic post-operative recurrence in Crohn’s disease

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World Journal of Gastrointestinal Surgery 2024年第3期16卷 740-750页

作者： Phillip Gu Shishir Dube Norman Gellada So Yung Choi Susan Win Yoo Jin Lee Shaohong Yang Talin Haritunians Gil Y Melmed Eric A Vasiliauskas Niru Bonthala Gaurav Syal Andres J Yarur David Ziring Shervin Rabizadeh Phillip Fleshner Cindy Kallman Suzanne Devkota Stephan R Targan Dalin Li Dermot PB McGovern Department of Medicine Cedars-Sinai Medical CenterLos AngelesCA 90048United States Department of Imaging Cedars-Sinai Medical CenterLos AngelesCA 90048United States Department of Biostatistics Shared Resource Cedars-Sinai Medical CenterLos AngelesCA 90048United States Department of Internal Medicine Keimyung University School of MedicineDaegu 42601South Korea Department of Medicine University of California at Los AngelesLos AngelesCA 90095United States Department of Medicine University of California at San DiegoSan DiegoCA 92093United States Department of Pediatrics Cedars-Sinai Medical CenterLos AngelesCA 90048United States Department of Surgery Cedars-Sinai Medical CenterLos AngelesCA 90048United States

BACKGROUND Evidence suggests inflammatory mesenteric fat is involved in post-operative recurrence(POR)of Crohn’s disease(CD).However,its prognostic value is INTRODUCTION Crohn’s disease(CD)is a debilitating chronic immune-mediated inflammatory disease(IMID)of the gastrointestinal tract that is increasing in incidence and prevalence globally[1].CD patients often undergo surgery for disease-related complic-ations and/or medically refractory ***,surgery is not curative,and many patients develop post-operative recurrence(POR)of CD with a significant proportion eventually requiring additional *** advances in early detection and therapeutics,the contemporary 10-year risk of surgery has improved from 50%to 26%,but the risk of recurrent surgery has remained unchanged at 30%,suggesting a need to improve post-operative management strategies[2].Presently,there are two accepted strategies to mitigate POR,but each have potential ***,patients start early post-operative pharmacologic prophylaxis within 4-6 wk after *** strategy can potentially overtreat a subset of patient who may not develop long-term disease recurrence off ***,these patients are at risk of medication-related adverse events and the direct and indirect costs associated with therapy with little or no benefit[3].The second strategy is performing early colonoscopy within 6-12 months after surgery and escalating therapy based on FOOTNOTES Author contributions:Gu P is the guarantor of the article and was involved in concept and design,data collection,statistical analysis,drafting of manuscript,and final approval of manuscript;Dube S and Choi SY were involved in statistical analysis,drafting of the manuscript,and final approval of manuscript;Gellada N,Win S,Lee YJ and Yang S were involved in the data collection,drafting of the manuscript,and final approval of manuscript;Haritunians T and Li D were involved in data analysis and interpretation,drafting

关键词： Crohn’s disease Surgery Visceral adipose tissue Mesenteric adipose tissue Creeping fat Computed tomography

Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK

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International Journal of Oral Science 2024年第3期16卷 471-485页

作者： Dexuan Zhuang Shuangshuang Wang Huiting Deng Yuxin Shi Chang Liu Xue Leng Qun Zhang Fuxiang Bai Bin Zheng Jing Guo Xunwei Wu School and Hospital of Stomatology Cheeloo College of MedicineShandong University&Shandong Key Laboratory of Oral Tissue Regeneration&Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration&Shandong Provincial Clinical Research Center for Oral DiseasesJinanChina Engineering Laboratory for Biomaterials and Tissue Regeneration Ningbo Stomatology HospitalSavaid Stomatology SchoolHangzhou Medical CollegeNingboChina cedars-sinai Cancer Institute Department of Biomedical SciencesCedars-Sinai Medical CenterLos AngelesCAUSA

The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new *** has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC *** found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in ***-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC ***,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC ***,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of *** summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell *** study supports the potential clinical utility of phenformin for OSCC treatment in the future.

关键词： drugs treatment AMPK DDI

Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease

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World Journal of Gastroenterology 2011年第37期17卷 4166-4173页

作者： Kara Bradford David Q Shih Department of Medicine Cedars Sinai Medical Center inflammatory bowel and Immunobiology Research Institute Cedars-Sinai Medical Center

The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) *** reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and *** to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse *** strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to *** this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.

关键词： Azathioprine Drug levels inflammatory bowel disease 6-Mercaptopurine Thiopurine

Immunopathogenesis of inflammatory bowel disease

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World Journal of Gastroenterology 2008年第3期14卷 390-400页

作者： David Q Shih Stephan R Targan cedars-sinai inflammatory bowel disease center Los Angeles CA United States Department of Medicine Division of Digestive Diseases University of California Los Angeles CA United States cedars-sinai inflammatory bowel disease center Los Angeles CA United States

Crohn＇s disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn＇s disease and T-helpero2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.

关键词： Crohn's disease Ulcerative colitis Innate andadaptive immune system

Association between Exposure to Metals during Pregnancy,Childhood Gut Microbiome,and Risk of Intestinal Inflammation in Late Childhood

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Environment & Health 2024年第10期2卷 739-749页

作者： Vishal Midya Manasi Agrawal Jamil M.Lane Chris Gennings Leonid Tarassishin Libni A.Torres-Olascoaga Joseph Eggers Jill K.Gregory Mellissa Picker Inga Peter Jeremiah J.Faith Manish Arora Martha M.Tellez-Rojo Robert O.Wright Jean-Frederic Colombel Shoshannah Eggers Department of Environmental Medicine and Climate Science Icahn School of Medicine at Mount SinaiNew York 10029-6574New YorkUnited States Division of Gastroenterology Icahn School of Medicine at Mount SinaiNew York 10029-6574New YorkUnited States center for Molecular Prediction of inflammatory bowel disease(PREDICT) Department of Clinical MedicineAalborg UniversityCopenhagen 9220Denmark Department of Genetics and Genomic Sciences Icahn School of MedicineNew York 10029-6574New YorkUnited States center for Research on Nutrition and Health National Institute of Public HealthCuernavaca 62508Mexico Department of Immunology and Immunotherapy Icahn School of Medicine at Mount SinaiNew York 10029-6574New YorkUnited States Department of Epidemiology University of Iowa College of Public HealthIowa City 52242 IowaUnited States Instructional Technology Group Icahn School of Medicine at Mount SinaiNew York 10029-6574New YorkUnited States

Alterations to the gut microbiome and exposure to metals during pregnancy have been suggested to impact inflammatory bowel ***,how prenatal exposure to metals eventually results in long-term effects on the gut microbiome,leading to subclinical intestinal inflammation,particularly during late childhood,has not been *** is also unknown whether such an interactive effect drives a specific subgroup of children toward elevated susceptibility to intestinal *** used an amalgamation of machine-learning techniques with a regression-based framework to explore if children with distinct sets of gut microbes and certain patterns of exposure to metals during pregnancy(metal−microbial clique signature)had a higher likelihood of intestinal inflammation,measured based on fecal calprotectin(FC)in late *** obtained samples from a well-characterized longitudinal birth cohort from Mexico City(n=108),*** the second and third trimesters of pregnancy,11 metals were measured in whole *** microbial abundances and FC were measured in stool samples from children 9−11 years of *** FC was defined as having FC above 100μg/g of *** identified subgroups of children in whom microbial and metal−microbial clique signatures were associated with elevated FC(false discovery rate(FDR)<0.05).In particular,we found two metal−microbial clique signatures significantly associated with elevated FC:(1)low cesium(Cs)and copper(Cu)in the third trimester and low relative abundance of Eubacterium ventriosum(OR[95%CI]:10.27[3.57,29.52],FDR<0.001)and(2)low Cu in the third trimester and high relative abundances of Roseburia inulinivorans and Ruminococcus torques(OR[95%CI]:7.21[1.81,28.77],FDR<0.05).This exploratory study demonstrates that children with specific gut microbes and specific exposure patterns to metals during pregnancy may have higher fecal calprotectin levels in late childhood,denoting an elevated risk of intestinal inflammation.

关键词： exposome metals machine learning microbiome environmental epidemiology intestinal inflammation

Excess non-COVID-19-related mortality among inflammatory bowel disease decedents during the COVID-19 pandemic

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World Journal of Gastroenterology 2024年第20期30卷 2677-2688页

作者： Sarah Rotondo-Trivette Xin-Yuan He Jamil S Samaan Fan Lv Emily Truong Michaela Juels Anthony Nguyen Xu Gao Jian Zu Yee Hui Yeo Fan-Pu Ji Gil Y Melmed Department of Medicine Cedars-Sinai Medical CenterLos AngelesCA 90048United States Department of Infectious disease The Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710004Shaanxi ProvinceChina Karsh Division of Gastroenterology and Hepatology Department of Medicine Cedars-Sinai Medical CenterLos AngelesCA 90048United States School of Mathematics and Statistics Xi’an Jiaotong UniversityXi’an 710049Shaanxi ProvinceChina David Geffen School of Medicine University of CaliforniaLos AngelesLos AngelesCA 90095United States Division of Gastroenterology The Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710004Shaanxi ProvinceChina National and Local Joint Engineering Research center of Biodiagnosis and Biotherapy The Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710004Shaanxi ProvinceChina Key Laboratory of Surgical Critical Care and Life Support(Xi’an Jiaotong University) Ministry of EducationXi’an 710004Shaanxi ProvinceChina

BACKGROUND The coronavirus disease 2019(COVID-19)pandemic disrupted healthcare in the United *** To investigate COVID-19-related and non-COVID-19-related death and characteristics associated with excess death among inflammatory bowel disease(IBD)*** We performed a register-based study using data from the National Vital Statistics System,which reports death data from over 99%of the United States population,from January 1,2006 through December 31,***-related deaths among adults 25 years and older were stratified by age,sex,race/ethnicity,place of death,and primary cause of *** and actual age-standardized mortality rates(ASMRs)per 100000 persons were *** 49782 IBD-related deaths occurred during the study ***-COVID-19-related deaths increased by 13.14%in 2020 and 18.12%in 2021[2020 ASMR:1.55 actual vs 1.37 predicted,95%confidence interval(CI):1.26-1.49;2021 ASMR:1.63 actual vs 1.38 predicted,95%CI:1.26-1.49].In 2020,non-COVID-19-related mortality increased by 17.65%in ulcerative colitis(UC)patients between the ages of 25 and 65 and 36.36%in non-Hispanic black(NHB)Crohn’s disease(CD)*** the pandemic,deaths at home or on arrival and at medical facilities as well as deaths due to neoplasms also *** IBD patients suffered excess non-COVID-19-related death during the *** death was associated with younger age among UC patients,and with NHB race among CD *** death at home or on arrival and due to neoplasms suggests that delayed presentation and difficulty accessing healthcare may have led to increased IBD mortality.

关键词： inflammatory bowel disease Ulcerative colitis Crohn’s disease COVID-19 Excess death Race Sex Disparities

Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients

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World Journal of Gastroenterology 2017年第40期23卷 7265-7273页

作者： Daniel Lew Soon Man Yoon Xiaofei Yan Lori Robbins Talin Haritunians Zhenqiu Liu Dalin Li Dermot PB McGovern Department of Medicine Cedars-Sinai Medical Center F. Widjaja Foundation inflammatory bowel and Immunobiology Research Institute Cedars-Sinai Medical Center Department of Gastroenterology Cedars-Sinai Medical Center

AIM To study the type and frequency of adverse events associated with anti-tumor necrosis factor(TNF)therapy and evaluate for any serologic and genetic *** This study was a retrospective review of patients attending the inflammatory bowel disease(IBD) centers at cedars-sinai IBD center from 2005-2016. Adverse events were identified via chart review. IBD serologies were measured by ELISA. DNA samples were genotyped at cedars-sinai using Illumina Infinium Immunochipv1 array per manufacturer's protocol. SNPs underwent methodological review and were evaluated using several SNP statistic parameters to ensure optimal allele-calling. Standard and rigorous QC criteria were applied to the genetic data, which was generated using immunochip. Genetic association was assessed by logistic regression after correcting for population *** Altogether we identified 1258 IBD subjects exposed to anti-TNF agents in whom Immunochip data were available. 269/1258 patients(21%) were found to have adverse events to an anti-TNF-α agent that required the therapy to be discontinued. 25% of women compared to 17% of men experienced an adverse event. All adverse events resolved after discontinuing the antiTNF agent. In total: n = 66(5%) infusion reactions; n = 49(4%) allergic/serum sickness reactions; n = 19(1.5%) lupus-like reactions, n = 52(4%) rash, n = 18(1.4%) infections. In Crohn's disease, Ig A ASCA(P = 0.04) and Ig G-ASCA(P = 0.02) levels were also lower in patients with any adverse events, and anti-I2 level in ulcerative colitis was significantly associated with infusion reactions(P = 0.008). The logistic regression/human annotation and network analyses performed on the Immunochip data implicated the following five signaling pathways: JAK-STAT(Janus Kinase-signal transducer and activator of transcription), measles, IBD, cytokine-cytokine receptor interaction, and toxoplasmosis for any adverse event. CONCLUSION Our study shows 1 in 5 IBD patients experience an

关键词： Genetic associations inflammatory bowel disease Anti-tumor necrosis factor Adverse events

A case of steroid-dependent myeloid granulocytic sarcoma masquerading as Crohn's disease

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World Journal of Gastroenterology 2011年第19期17卷 2446-2449页

作者： Lola Y Kwan Stephan R Targan David Q Shih Division of Gastroenterology and Hepatology University of Rochester Medical CenterRochesterNY 14642United States inflammatory bowel disease center and Immunobiology Research Institute Cedars-Sinai Medical CenterLos AngelesCA 90048United States cedars-sinai inflammatory bowel and Immunobiology Research Institute 8700 Beverly Blvd.Suite 4066Los AngelesCA 90048United States

Small bowel tumors and Crohn's disease are common causes of small bowel *** stage neoplasms can easily be mistaken for Crohn's ***,thorough work-ups including imaging studies and endoscopic evaluation with biopsies are critical for accurate *** we report a case of an otherwise healthy female with progressive onset of multiple,recurrent obstructive symptoms secondary to terminal ileal narrowing who was referred for management of steroid-dependent Crohn's *** thorough evaluation,the diagnosis was revised to myeloid granulocytic sarcoma involving the terminal *** this case,a delay in diagnosis can be detrimental for prognosis,as myeloid granulocytic sarcoma is highly predictive of underlying acute myeloid leukemia and needs urgent referral for chemotherapy and/or resection.

关键词： Crohn's disease Myeloid sarcoma Ileum Steroids

Cell-cell interactions and communication dynamics in lung fibrosis

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2024年第2期2卷 63-71页

作者： Ting Xie Jiurong Liang Barry Stripp Paul W.Noble Division of Pulmonary and Critical Care Medicine Department of MedicineWomen’s Guild Lung InstituteCedars-Sinai Medical CenterLos AngelesCA 90048USA

Cell-cell interactions are essential components of coordinated cell function in lung *** diseases involve altered cell-cell interactions and communication between different cell types,as well as between subsets of cells of the same *** identification and understanding of intercellular signaling in lung fibrosis offer insights into the molecular mechanisms underlying these interactions and their implications in the development and progression of lung fibrosis.A comprehensive cell atlas of the human lung,established with the facilita-tion of single-cell RNA transcriptomic analysis,has enabled the inference of intercellular communications using ligand-receptor *** this review,we provide a comprehensive overview of the modified cell-cell commu-nications in lung *** highlight the intricate interactions among the major cell types within the lung and their contributions to *** insights presented in this review will contribute to a better understand-ing of the molecular mechanisms underlying lung fibrosis and may guide future research efforts in developing targeted therapies for this debilitating disease.

关键词： Cell–cell interaction Lung fibrosis Lung homeostasis Targeted therapies