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IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion

Cellular & Molecular Immunology 2021年第9期18卷 2199-2210页

作者： Sadiq Umar Karol Palasiewicz Katrien van Raemdonck Michael V.Volin Bianca Romay MAsif Amin Ryan K.Zomorrodi Shiva Arami Mark Gonzalez Vikram Rao Brian Zanotti David A.Fox Nadera Sweiss Shiva Shahrara Jesse Brown va medical center ChicagoIL60612USA Department of Medicine Division of RheumatologyUniversity of Illinois at ChicagoChicagoIL60612USA Department of Microbiology and Immunology Midwestern UniversityDowners GroveIL60515USA Division of Rheumatology and Clinical Autoimmunity center of Excellence University of MichiganAnn ArborMI481096USA Department of Orthopedic Surgery University of Illinois at ChicagoChicagoIL60612USA Pfizer Research CambridgeMA02139USA

Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis(RA)patients could reflect activation of innate immune ***,we show that a TLR7 GU-rich endogenous ligand,miR-Let7b,potentiates synovitis by amplifying RA monocyte and fibroblast(FLS)***-Let7b ligation to TLR7 in macrophages(MΦs)and FLSs expanded the synovial inflammatory ***,secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell *** showed that IRAK4 inhibitor(i)therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦor FLS activation,as well as monokine-modulated Th1/Th17 cell ***4i therapy also disrupted RA osteoclastogenesis,which was amplified by miR-Let7b ligation to joint myeloid ***,the effectiveness of IRAK4i was compared with that of a TNF inhibitor(i)or anti-IL-6R treatment in collagen-induced arthritis(CIA)and miR-Let7b-mediated *** found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480+iNOS+MΦs,the expression of certain monokines,and Th1 cell ***,these biologic therapies were unable to alleviate miR-Let7b-induced *** superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480+iNOS+MΦs,vimentin+fibroblasts,and CD3+T cells,in addition to negating the expression of a wide range of monokines,including IL-12,MIP2,and IRF5 and Th1/Th17 *** conclusion,IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.

关键词： TLR7 MΦs RA FLSs osteoclasts T cells IRAK4

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Current research status of transarterial therapies for hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2024年第9期16卷 3752-3760页

作者： Mao-Ting Zhou Peng Zhang Qi Mao Xiao-Qin Wei Lin Yang Xiao-Ming Zhang Department of Radiology Interventional Medical CenterScience and Technology Innovation CenterThe Affiliated Hospital of North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina School of medical Imaging North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina

With continuous advancements in interventional radiology,considerable progress has been made in transarterial therapies for hepatocellular carcinoma(HCC)in recent years,and an increasing number of research papers on transarterial therapies for HCC have been *** this editorial,we comment on the article by Ma et al published in the recent issue of the World Journal of Gastrointestinal Oncology:“Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable HCC”.We focus specifically on the current research status and future directions of transarterial *** the future,more studies are needed to determine the optimal transarterial local treatment for *** the emergence of checkpoint immunotherapy modalities,it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.

关键词： Hepatocellular carcinoma Transarterial therapies Transarterial chemoembolization Hepatic artery infusion chemotherapy Transarterial embolization Transarterial radioembolization

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Centralized Lung Nodule Management at A VeteransHospital Using A Multidisciplinary Lung NoduleEvaluation Team(LNET)

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中国肺癌杂志 2018年第11期21卷 828-832页

作者： William R.WRIGHTSON Umar GAUHAR Fred HENDLER Teresa JOINER Jennifer PENDLETON Robley Rex Veterans Affairs (va)medical center LouisvilleKentuckyUSA

Introduction: Lung nodules are frequently identified on imaging studies and can represent early lung cancers. We instituted the Lung Nodule Evaluation Team(LNET) to optimize management of these nodules by a lung specialist physician. All lung nodules identified by a radiologist prompted a direct consultation to this service. We report our initial experience with this process. Methods: This is a retrospective review of patients with lung nodules at a single institution from 2008 to 2015. Since October 2014, lung nodules >3 mm identified on computed tomography(CT) scanning of the chest generate an automatic consult to LNET from the radiology service. Demographic, nodule and follow up data was entered into a surveillance database and ***: There were 1,873 patients identified in the database. Of these, 900 patients were undergoing active surveillance. Consults increased from 5.5 to 93 per month after the start of the new consult program. Lung nodules were identified on 64% of chest CT scans. Prior to the direct radiology consult the average size of a nodule was 1.7 cm and 0.7 cm after. The overall time from initial nodule imaging to initiating a management plan by a thoracic specialist physician was 3.7 days. Conclusion: Assessment of lung nodules by a specialist physician is important to ensure appropriate long term management and optimize utilization of diagnostic interventions. A direct radiology consult to a specialized team of chest physicians decreased the time in initiating a management plan, identified smaller nodules and may lead to a more judicious use of health care resources in the management of lung nodules.

关键词： Lung nodule Cancer Mulfidiscliplinary

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One Year After First Spontaneous Bacterial Peritonitis:Who Survives?

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Journal of Clinical and Translational Hepatology 2021年第5期9卷 603-604页

作者： Atoosa Rabiee Washington DC va medical center Washington DCUSA

Spontaneous bacterial peritonitis(SBP)is defined as infection in ascites fluid without evidence of an intra-abdominal treatable source.1 Diagnosis is confirmed by presence of≥250 cells/mm3 polymorphonuclear cells(PMNs).2 Although SBP responds well to appropriate antibiotic treatment,in patients with underlying cirrhosis severe enough to develop SBP,long-term prognosis is ***-hospital non-infectionrelated mortality is 20–40%and 1-and 2-year mortality rates are 70%and 80%,respectively.

关键词： mortality infection ascites

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Inhibiting ceramide synthase 5 expression in microglia decreases neuroinflammation after spinal cord injury

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Neural Regeneration Research 2025年第10期20卷 2955-2968页

作者： Wei Zhang Yubao Lu Ruoqi Shen Yingjie Wu Chenrui Liu Xingxing Fang Liangming Zhang Bin Liu Limin Rong Department of Spine Surgery The Third Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong ProvinceChina National medical Products Administration(NMPA)Key Laboratory for Quality Research and Evaluation of Cell Products GuangzhouGuangdong ProvinceChina Guangdong Provincial center for Quality Control of Minimally Invasive Spine Surgery GuangzhouGuangdong ProvinceChina Guangdong Provincial center for Engineering and Technology Research of Minimally Invasive Spine Surgery GuangzhouGuangdong ProvinceChina

Microglia,the resident monocyte of the central nervous system,play a crucial role in the response to spinal cord ***,the precise mechanism remains *** investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury,we performed single-cell RNA sequencing dataset analysis,focusing on changes in microglial *** found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis,sphingomyelin metabolism,and neuroinflammation at high ***,we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord ***,we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron *** ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced ***,ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling *** ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological ***2g7 formed a“bridge”between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling ***,these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3,thereby exerting neuroprotective effects.

关键词： ceramide synthase 5 gasdermin D microglia neuroinflammation NLRP3 nuclear factor kappa B Pla2g7 pyroptosis sphingomyelin metabolism spinal cord injury

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Macrophages are the primary effector cells in IL-7-induced arthritis

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Cellular & Molecular Immunology 2020年第7期17卷 728-740页

作者： Seung-jae Kim Huan J.Chang Michael VVolin Sadiq Umar Katrien van Raemdonck Aimee Chevalier Karol Palasiewicz John W.Christman Suncica Volkov Shiva Arami Mehrdad Maz Anjali Mehta Ryan K.Zomorrodi David A.Fox Nadera Sweiss Shiva Shahrara Division of Rheumatology Jesse Brown VAMedical CenterChicagoIL 60612USA Department of Medicine Division of RheumatologyUniversity of Illinois at ChicagoChicagoIL 60612USA Department of Microbiology and Immunology Chicago College of Osteopathic MedicineMidwestern UniversityDowners GroveIL 60515USA Pulmonary Critical Care and Sleep MedicineOhio State University Wexner Medical CenterDavis Heart and Lung Research InstituteColumbusOH 43210USA Division of Allergy Clinical Immunology and RheumatologyThe University of Kansas Medical CenterKansas CityKS 66160USA Division of Rheumatology and Clinical Autoimmunity center of Excellence University of MichiganAnn ArborMI 481096USA

Synovial macrophages are crucial in the development of joint inflammation and bone damage;however, the pathways that controlmacrophage remodeling in inflammatory M1 cells or bone-eroding osteoclasts are not fully understood. We determined thatelevated IL-7R/CD127 expression is the hallmark of rheumatoid arthritis (RA) M1 macrophages and that these cells are highlyresponsive to interleukin-7 (IL-7)-driven osteoclastogenesis. We established that lipopolysaccharide (LPS), interferon-γ (IFNγ), andtumor necrosis factor-α (TNFα), the classic M1 macrophage mediators, enhance IL-7R expression in RA and murine *** local expression of IL-7 provokes arthritis, predominantly through escalating the number of F480^(+)iNOS^(+) cells rather than CD3^(+)T cells. Ectopic LPS injection stabilizes IL-7-induced arthritis by increasing myeloid IL-7R expression, in part via IFNγ ***, in RAG−/− mice, IL-7-mediated arthritis is suppressed because of the reduction in myeloid IL-7R expression due to the lackof IFNγ. Moreover, the amelioration of IL-7-induced arthritis by anti-TNF therapy is due to a decrease in the number of cells in theunique F480^(+)iNOS^(+)IL-7R^(+)CCL5^(+) subset, with no impact on the F480^(+)Arginase^(+) cell or CD3^(+) T cell frequency. Consistent with thepreclinical findings, the findings of a phase 4 study performed with RA patients following 6 months of anti-TNF therapy revealedthat IL-7R expression was reduced without affecting the levels of IL-7. This study shifts the paradigm by discovering that IL-7-induced arthritis is dependent on F480^(+)iNOS^(+)IL-7R^(+)CCL5^(+) cell function, which activates TH-1 cells to amplify myeloid IL-7Rexpression and disease severity.

关键词： myeloid elevated inflammation

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Endoscopic options for treatment of dysplasia in Barrett's esophagus

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World Journal of Gastrointestinal Endoscopy 2015年第19期7卷 1311-1317页

作者： R Brooks vance Kerry B Dunbar va north Texas Healthcare System Dallas VA Medical Center University of Texas Southwestern Medical Center

Recent advances in the endoscopic treatment of dysplasia in Barrett's esophagus(BE) have allowed endoscopists to provide effective and durable eradication therapies. This review summarizes the available endoscopic eradication techniques for dysplasia in patients with BE including endoscopic mucosal resection, endoscopic submucosal dissection, photodynamic therapy, argon plasma coagulation, radiofrequency ablation and cryotherapy.

关键词： Dysplasia Barrett's esophagus Endoscopictherapy Endoscopic mucosal resection Radiofrequencyablation Endoscopy Photodynamic therapy

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Targeting the SUMO pathway for neuroprotection in brain ischaemia

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Stroke & vascular Neurology 2016年第3期1卷 101-107页

作者： Wei Yang Huaxin Sheng Haichen Wang Multidisciplinary Neuroprotection Laboratories Department of AnesthesiologyDuke University Medical CenterDurhamNorth CarolinaUSA Multidisciplinary Neuroprotection Laboratories Department of NeurologyDuke University Medical CenterDurhamNorth CarolinaUSA

Small ubiquitin-like modifier(SUMO)conjugation(SUMOylation)is a post-translational protein modification that modulates almost all major cellular processes,and has been implicated in many human diseases.A growing body of evidence from in vitro and in vivo studies demonstrates that increasing global levels of SUMO conjugated proteins(global SUMOylation)protects cells against ischaemia-induced damage,while suppressing global SUMOylation promotes cell injury after ***,SUMOylation has emerged as a potential therapeutic target for neuroprotection in brain ischaemia,including global brain ischaemia and focal brain ischaemia(ischaemic stroke).Here,we summarise findings on the role of SUMOylation in human diseases,brain ischaemia in particular,and review recent developments in drug discovery targeting SUMOylation with a major focus on its neuroprotective applications.

关键词： protective diseases SUMO

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Combination of transarterial radioembolization with atezolizumab and bevacizumab for intermediate and advanced staged hepatocellular carcinoma:A preliminary report of safety and feasibility

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Journal of Interventional Medicine 2023年第4期6卷 186-192页

作者： Qian Yu Yating Wang Ethan Ungchusri Mikin Patel Divya Kumari Thuong van Ha Anjana Pillai Chih-yi Liao Osman Ahmed Department of Radiology University of Chicago Medical CenterUniversity of ChicagoChicagoIL60637USA Hematology and Oncology Ascension Providence HospitalSouthfieldMI48075USA Division of Gastroenterology Hepatologyand NutritionDepartment of MedicineUniversity of Chicago Medical CenterUniversity of ChicagoChicagoIL60637USA Hematology and Oncology Department of MedicineUniversity of Chicago Medical CenterUniversity of ChicagoChicagoIL60637USA

Purpose:The IMbrave150 PhaseⅢtrial demonstrated superiority of atezolizumab and bevacizumab(Atezo/Bev)over sorafenib for unresectable hepatocellular carcinoma(HCC).The present study aims to evaluate the feasibility of TARE in combination with Atezo/Bev for treatment of intermediate and advanced staged ***:Retrospective review at a single institution was performed between May 2021 and December *** who received TARE using yttrium-90(Y90)with concomitant or sequential Atezo/Bev systemic treatment were *** following outcomes were retrieved:overall survival(OS),radiologic tumor response,progression-free survival,technical adverse events related to TARE,and toxicity based on the National Cancer Institute–Common Terminology Criteria for Adverse Events version ***:Ten consecutive patients with intermediate(n=4)and advanced stage HCC(n=6)were treated with TARE and sequential/concomitant Atezo/*** control was achieved in all TARE-treated target lesions(100%).Overall disease progression occurred in 4 patients with PFS of 78.8%and 66.7%at 6-and 12-months,*** patients died at follow-up,with 6-month and 12-month OS rates of 90.0%and 77.1%,***(75%)patients with intermediate stage disease were downstaged into Milan *** patient developed grade 3 transaminitis and hypoglobulinemia,while Atezo/Bev was switched to Lenvatinib in another patient due to immunotherapy related ***:This study demonstrates initial safety and feasibility of combined TARE with Atezo/Bev for intermediate/advanced stage *** prospective studies with larger sample size are warranted.

关键词： Hepatocellular carcinoma Immunotherapyc Radioembolization Yttrium-90

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Endoscopic transgastric drainage of a gastric wall abscess after endoscopic submucosal dissection

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World Journal of Gastroenterology 2014年第4期20卷 1119-1122页

作者： Osamu Dohi Moyu Dohi Ken Inoue Yasuyuki Gen Masayasu Jo Kazuhiko Tokita Department of Gastroenterology and Hepatology North Medical Center Kyoto Prefectural University of Medicine

A 63-year-old woman was referred to our hospital for further examination because of an incidental finding of early gastric *** submucosal dissection(ESD)was successfully performed for complete resection of the *** the first post-ESD day,the patient suddenly complained of abdominal pain after an episode of *** computed tomography(CT)showed delayed perforation after *** patient was conservatively treated with an intravenous proton pump inhibitor and *** the fifth post-ESD day,CT revealed a gastric wall abscess in the gastric *** revealed a gastric fistula at the edge of the post-ESD ulcer,and pus was found flowing into the *** intradrainage stent and an extradrainage nasocystic catheter were successfully inserted into the abscess for endoscopic transgastric *** the procedure,the clinical symptoms and laboratory test results improved *** months later,a follow-up CT scan showed no collection of ***,the intradrainage stent was *** the gastric wall abscess recurred 2 wk after stent removal,it recovered soon after endoscopic transgastric ***,after stent removal and oral antibiotic treatment for 1 mo,no recurrence of the gastric wall abscess was found.

关键词： Gastric wall abscess Transgastric drainage Delayed perforation Endoscopic submucosal dissection Early gastric cancer

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