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Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-κB Signaling

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Journal of Clinical and Translational Hepatology 2024年第6期12卷 539-550页

作者： Xiaohui Xu Jinmei Feng Xin Wang Xin Zeng Ying Luo Xinyu He Meihua Yang Tiewei Lv Zijuan Feng Liming Bao Li Zhao Daochao Huang Yi Huang Institute of Pediatrics Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Pediatric Metabolism and Inflammatory DiseasesChongqingChina Department of Cardiology Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersNational Clinical Key Cardiovascular SpecialtyLaboratory of Children’s Important Organ Development and Diseases of Chongqing Municipal Health CommissionChongqingChina Department of Laboratory Medicine Chongqing Western HospitalChongqingChina Key Laboratory of Molecular Biology for Infectious Diseases Ministry of EducationInstitute for Viral HepatitisChongqing Medical UniversityChongqingChina Department of Laboratory Medicine The Third People’s Hospital of ChengduChengduSichuanChina Departments of Neurology Epilepsy CenterBarnes-Jewish Hospital and Washington University School of MedicineSt.LouisMOUSA Department of Clinical Pathology and Laboratory Medicine Weill Cornell Medical College of Cornell UniversityNew YorkNYUSA Departments of Medicine(Oncology) Washington University School of MedicineSt.LouisMOUSA

Background and Aims:Hepatic fibrosis(HF)is a critical step in the progression of hepatocellular carcinoma(HCC).Gene associated with retinoid-IFN-induced mortality 19(GRIM19),an essential component of mitochondrial respiratory chain complex I,is frequently attenuated in various human cancers,including ***,we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF ***:GRIM19 expression was evaluated in normal liver tissues,hepatitis,hepatic cirrhosis,and HCC using human liver disease spectrum tissue *** studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein-9(Cas9)lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in *** performed flow cytometry,immunofluorescence,immunohistochemistry,western blotting,and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced ***:Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues,including hepatitis,cirrhosis,and HCC ***-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in *** addition,GRIM19 loss caused chronic liver injury through reactive oxygen species(ROS)-mediated oxidative stress,resulting in aberrant NF-κB activation via an IKK/IKB partner in ***-more,GRIM19 loss activated NLRP3-mediated IL33 signaling administration of the NLRP3 inhibitor MCC950 dramatically via the ROS/NF-κB pathway in *** alleviated GRIM19 loss-driven HF in ***:The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-κB signaling,providing potential therapeutic approaches for earlier HF prevention.

关键词： Liver fibrosis GRIM19 Reactive Oxygen Species NF-κB NLRP3 inflammasome IL33.

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Beyond just a tight fortress:contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

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Signal Transduction and Targeted Therapy 2020年第1期5卷 328-339页

作者： Ashenafi Bulle Kian-Huat Lim Division of Oncology Department of Internal MedicineBarnes-Jewish Hospital and The Alvin J.Siteman Comprehensive Cancer CenterWashington University School of MedicineSt.LouisMO 63110USA

Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma(PDAC).Therapeutics that target the driver mutations,especially the KRAS oncoprotein and its effector cascades,have been *** is increasing clear that the extensive fibro-inflammatory stroma(or desmoplasia)of PDAC plays an active role in the progression and therapeutic resistance of *** desmoplastic stroma is composed of dense extracellular matrix(ECM)deposited mainly by the cancer-associatedfibroblasts(CAFs)and infiltrated with various types of immune *** dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC *** addition,mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms,particularly engagement of the epithelial-mesenchymal transition(EMT)*** of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapyinduced ***,we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in *** discussed the experimental models that are currently employed and best suited to study EMT in PDAC,which are instrumental in increasing the chance of successful clinical translation.

关键词： stroma transition render

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Additive Manufacturing:Incremental Improvements to a Disruptive Technology

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Accounts of Materials Research 2021年第8期2卷 574-576页

作者： John E.barnes Kevin Slattery The barnes Global Advisors PittsburghPennsylvaniaUnited States The barnes Global Advisors St.LouisMissouriUnited States

Additive Manufacturing(AM)is disruptive and complex not only in its nature but also in what it can *** have always had difficulty absorbing complexity and disruption due to our skeptical nature and need to *** being a 3-dimensional solution is simply an example of how AM is disruptive because people are adept at thinking in two *** a technology as transformative as AM to progress,some assumptions have to be made and certain approximations have to be asserted and held to be true until they can be revisited *** we weigh the societal benefit that AM can and will bring,efficiency comes to the *** could be efficiency of energy use,efficiency of materials utilization,or efficiency in designs that are lighter and then use less *** matter what form efficiency takes,it impacts *** achieve a greater impact,AM must become more pervasive,and for it to become more pervasive,it must become more *** additional source of complexity in AM is the sheer number of process variables,such as feedstock,energy source,part geometry,and postprocessing,with more than 100 identified,1 not including the interrelationships between these *** similar numbers are present in other manufacturing processes,such as forging and casting,civilization has had between 200 and 5000 years to understand the variables in these processes,which is longer than society wants to wait in the case of AM.

关键词： casting Additive absorbing

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Safety and efficacy outcomes of the Xen45 Gel Stent use for refractory glaucoma:a surgery series from surgeon trainees at a tertiary teaching hospital

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Eye and Vision 2020年第1期7卷 47-57页

作者： Karen Hong John Lind Arsham Sheybani Department of Ophthalmology and Visual Sciences Washington University School of MedicineSt.LouisMOUSA barnes-Jewish Center for Outpatient Health 4901 Forest Park AvenueSt LouisMO 63110USA

Background:To study the effect of an ab interno gelatin stent(XEN45 Gel Stent,Allergan Inc.,Irvine,California,USA)on intraocular pressure(IOP)as placed by glaucoma fellowship trainees in eyes with refractory ***:A prospective noncomparative study at a tertiary training center on 28 unique eyes undergoing ab interno gelatin stent implantation by glaucoma fellowship *** was collected at baseline and postoperatively at day 1,week 1,and months 1,3,5,and *** outcome was mean IOP *** outcomes included change in number of glaucoma medication classes and visual *** outcomes included needling *** success was defined by achieving≥20%reduction in IOP with the same or fewer classes of antiglaucoma medications from baseline without the need for secondary surgical intervention and/or stent ***:At baseline,28.6%(8/28)of the subjects had prior failed incisional glaucoma surgery in a study population that was 54%African-American,with 78%with severe glaucoma(average mean deviation of−14.58 dB).Thirteen subjects terminated their clinic visits before their 12-month postoperative visit,leaving 15 subjects for end point *** IOP went from 21.6 mmHg(range 12.0–31.0,SD 6.6)at baseline to 12.5 mmHg(range 7.0–19.0,SD 3.6),a 42.1%reduction(p<0.007).All subjects decreased the number of medication classes they were taking with an average reduction of 3.8(range 2–5,SD 0.9)to 1.3(range 0–3,SD 1.0)classes,or a 65.8%decrease(p<0.006).Crude surgical success was 80.0%for the 15 subjects that followed up at 12 *** Kaplan-Meier cumulative probability of success for all 28 subjects at 12 months was 70.4%(95%CI:44.7–85.8%).Regardless of the length of follow-up,21.4%(6/28)met failure criteria:3 subjects failed because they required secondary surgical intervention,and the other 3 did not have adequate IOP *** bleb needling rate was 28.6%(8/28)and repeat was 17.9%(5/28).Conclusions:Compared to the re

关键词： XEN Investigational devices Glaucoma Gelatin stent Ab interno surgery Minimally invasive glaucoma surgery Subconjunctival drainage Gelatin microstent

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Stroma-targeting strategies in pancreatic cancer:Past lessons,challenges and prospects

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World Journal of Gastroenterology 2021年第18期27卷 2105-2121页

作者： Faran Polani Patrick M Grierson Kian-Huat Lim Division of Oncology Department of Internal MedicineBarnes-Jewish Hospital and The Alvin J.Siteman Comprehensive Cancer CenterWashington University School of MedicineSaint LouisMO 63110United States

Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after *** treatment resistance is perhaps the most significant factor that underlies the poor prognosis of *** date,combination chemotherapy remains the mainstay of treatment for most PDAC *** to other cancer types,treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and *** from typically harboring genetic alterations that to date remain undruggable and are drivers of treatment resistance,PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment ***,emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental *** conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor *** advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells,stromal fibroblasts,and immune *** new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this ***,we provide a concise review on lessons learned from past stromatargeting strategies,new challenges revealed from recent preclinical and clinical studies,as well as new prospects in the treatment of PDAC.

关键词： Stroma Pancreatic cancer Treatment resistance Cancer-associated fibroblasts Clinical trials

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Cancer vaccines:shared tumor antigens return to the spotlight

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Signal Transduction and Targeted Therapy 2020年第1期5卷 324-325页

作者： Lijin Li S.Peter Goedegebuure William Gillanders Department of Surgery Washington University School of MedicineSt LouisMOUSA The Alvin J.Siteman Cancer Center at barnes-Jewish Hospital and Washington University School of Medicine St LouisMOUSA

Sahin et *** reported interim data from a phase 1 clinical trial(NCT02410733)treating melanoma patients with a RNAlipoplex vaccine(RNA-LPX),targeting melanoma TAA.1 The trial is a multicenter,non-randomized,open-label,dose-escalation trial designed to evaluate the safety and tolerability of BNT111 targeting four melanoma TAA(NY-ESO-1,MAGE-A3,tyrosinase,and TPTE).Secondary endpoints include vaccine-induced immune responses and clinical response of patients with measurable disease.

关键词： vaccine melanoma clinical

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Stress repair mechanism activity explains inflammation and apoptosis

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Advances in Bioscience and Biotechnology 2012年第4期3卷 459-503页

作者： Lewis S. Coleman barnes Dental Surgery Center 2626 S. Mooney Blvd Visalia Ca.

A review of modern evidence using Internet resources has identified the Stress Repair Mechanism (SRM) postulated by Hans Selye in 1951. SRM activity regulates thrombin generation to govern tissue maintenance, tissue repair, hemodynamic physiology, inflammation, and apoptosis. Thrombin utilizes ATP to energize coagulation, capillary hemostasis, chemotaxis, immune activity, mitosis, metabolism, angiogenesis, and the release of chemokines, cytokines, bradykinins, and prostaglandins that enable cell-to-cell communications, promote perfusion, loosen cell connections, and sensitize nociceptors during tissue repair. The orchestration of these diverse activities by the SRM explains the disparate elements of the inflammation syndrome, including dolor (pain), rubor (redness), calor (heat), tumor (swelling), and Functio laesa (loss of function). Inflammation resolves as tissue repair nears completion and declining SRM activity restores thrombin to maintenance levels. As thrombin levels decline below a critical threshold, repair cells undergo apoptosis and clots disintegrate. Apoptosis shrinks granulation tissues to enable wound closure. Apoptosis also facilitates embryological development. Occult systemic SRM hyperactivity due to sepsis, surgery, trauma, chemicals, pain, fear, and emotional memories causes inflammatory effects that manifest as the fever, edema, malignancy, organ disruption, eclampsia, Multi-System Organ Failure (MS-OF), Systemic Inflammatory Response Syndrome (SI-RS), Adult Respiratory Distress Syndrome (ARDS), Disseminated Intravascular Coagulation (DIC) and other pathologies.

关键词： Selye Stress Inflammation Atherosclerosis Tissue Repair Hemodynamic

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复地震道属性的遗传分类

复地震道属性的遗传分类

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美国勘探地球物理学家学会第67届年会

作者： Arthur E．barnes 杨红霞 barnes Geophysical Research

振幅和相位是最基本的复地震道属性,其它属性都是由此求得。得出的属性可以是一维、二维、或三维的,可以在时间或深度域计算,可以是瞬时或局部的。由时间数据产生的时间属性属于地球物理学范畴;由深度数据产生的深度属性属于地质学范畴...

振幅和相位是最基本的复地震道属性,其它属性都是由此求得。得出的属性可以是一维、二维、或三维的,可以在时间或深度域计算,可以是瞬时或局部的。由时间数据产生的时间属性属于地球物理学范畴;由深度数据产生的深度属性属于地质学范畴。瞬时属性按点计算;局部属性在窗口内计算。这些分类是属性遗传分类的基础。地震数据和分析目标决定了相应的应用属性。一维的时间属性应该用于未偏移数据的地球物理学分析,而二维和三维深度属性应该用于偏移数据的地质学解释。

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Success of photodynamic therapy in palliating patients with nonresectable cholangiocarcinoma: A systematic review and meta-analysis

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World Journal of Gastroenterology 2017年第7期23卷 1278-1288页

作者： Harsha Moole Harsha Tathireddy Sirish Dharmapuri Vishnu Moole Raghuveer Boddireddy Pratyusha Yedama Sowmya Dharmapuri Achuta Uppu Naveen Bondalapati Abhiram Duvvuri Department of Medicine University of Illinois College of Medicine Department of Medicine Wilkes-Barre Veterans Affairs Medical Center Department of Medicine NTR University of Health Sciences Department of Medicine Albert Einstein College of Medicine Department of Medicine Barnes Jewish Christian Medical GroupChristian Hospital Division of Gastroenterology and Hepatology Kansas City Veteran Affairs Medical Center

To perform a systematic review and meta-analysis on clinical outcomes of photodynamic therapy (PDT) in non-resectable *** studies compared outcomes with photodynamic therapy and biliary stenting (PDT group) vs biliary stenting only (BS group) in palliation of non-resectable cholangiocarcinoma. Articles were searched in MEDLINE, PubMed, and EMBASE. Pooled proportions were calculated using fixed and random effects model. Heterogeneity among studies was assessed using the I2 *** studies (n = 402) that met inclusion criteria were included in this analysis. The P for χ2 heterogeneity for all the pooled accuracy estimates was > 0.10. Pooled odds ratio for successful biliary drainage (decrease in bilirubin level > 50% within 7days after stenting) in PDT vs BS group was 4.39 (95%CI: 2.35-8.19). Survival period in PDT and BS groups were 413.04 d (95%CI: 349.54-476.54) and 183.41 (95%CI: 136.81-230.02) respectively. The change in Karnofsky performance scores after intervention in PDT and BS groups were +6.99 (95%CI: 4.15-9.82) and -3.93 (95%CI: -8.63-0.77) respectively. Odds ratio for post-intervention cholangitis in PDT vs BS group was 0.57 (95%CI: 0.35-0.94). In PDT group, 10.51% (95%CI: 6.94-14.72) had photosensitivity reactions that were self-limiting. Subgroup analysis of prospective studies showed similar results, except the incidence of cholangitis was comparable in both *** palliation of unresectable cholangiocarcinoma, PDT seems to be significantly superior to BS alone. PDT should be used as an adjunct to biliary stenting in these patients.

关键词： Photodynamic therapy Biliary stenting Unresectable cholangiocarcinoma Outcome Systematic review Meta-analysis

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Handbook of clinical laboratory testing during pregnancy 1

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丛书名： Current Clinical Pathology

2004年

作者： Ann M. Gronowski foreword by Gillian Lockitch.

ISBN: (数字)9781592597871

ISBN: (纸本)9781588292704

Practicing specialists in pathology, laboratory medicine, and obstetrics comprehensively summarize the latest scientific findings and their experiences in the use and interpretation of laboratory testing in patients who are pregnant or experiencing recurrent pregnancy loss. Topics of interest include the effects of normal physiological changes on test results, test selection for diagnosis, changes in reference ranges, monitoring the pregnant patient, new technologies, and the limitations of laboratory testing. The authors not only clearly explain currently used test methods and technologies for the nontechnical reader, but also provide comprehensive details for laboratory professionals. The comprehensive appendix that compiles published normal reference ranges by first, second, and third trimester consttitutes an excellent resource for professionals caring for pregnant women

关键词： Prenatal Diagnosis

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