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Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

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World journal of Gastroenterology 2024年第25期30卷 3182-3184页

作者： jeffrey A Lowell Michael j Farber keith Sultan Department of Medicine Zucker School of Medicine at HofstraNorth Shore University Hospital-Long Island Jewish Medical CenterManhassetNY 11030United States Preclinical Studies New York Institute of Technology College of Osteopathic MedicineGlen HeadNY 11545United States Division of Gastroenterology Northwell HealthNorth Shore University Hospital and Long Island Jewish Medical CenterGreat NeckNY 10021United States

Inflammatory bowel disease(IBD)is entering a potentially new era of combined *** et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this *** importance of controlled trials should be stressed in establishing new treatment *** prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

关键词： Inflammatory bowel disease Biologics Immunomodulators Dual-therapy Combination therapy

EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

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Signal Transduction and Targeted Therapy 2024年第2期9卷 679-692页

作者： keith Al-Hasani Safiya Naina Marikar Harikrishnan Kaipananickal Scott Maxwell jun Okabe Ishant Khurana Thomas Karagiannis julia j.Liang Lina Mariana Thomas Loudovaris Thomas Kay Assam El-Osta Epigenetics in Human Health and Disease Program Baker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of Diabetes Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of Science STEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR Biomedical Laboratory Science Department of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark

β-cells are a type of endocrine cell found in pancreatic islets that synthesize,store and release *** type 1 diabetes(T1D),T-cells of the immune system selectively destroy the insulin-producingβ-*** of these cells leads to a lifelong dependence on exogenous insulin administration for ***,there is an urgent need to identify novel therapies that stimulateβ-cell growth and induceβ-cell *** and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-cells for T1D owing to their inherent differentiation *** transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 *** the present study,we show that transient stimulation of exocrine cells,derived from juvenile and adult T1D donors to the FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell *** transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin *** EZH2 is fundamental toβ-cell regenerative *** pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex *** pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration ofβ-like cell function.

关键词： EZH2 struction inhibitors

Hepatic vein reconstruction during hepatectomy:A feasible and underused technique

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 421-427页

作者： Manish Ahuja Kunal joshi Chris Coldham Paulo Muiesan Bobby Dasari Manuel Abradelo Ravi Marudanayagam Darius Mirza john Isaac David Bartlett Nikolaos A Chatzizacharias Robert P Sutcliffe keith j Roberts Department of HPB and Liver Transplant Surgery University Hospitals Birmingham NHS Foundation TrustBirminghamUK Institute of Immunology and Immunotherapy University of BirminghamBirminghamUK

Complete surgical resection(R0)of liver tumors,primary or metastatic,remains the main objective in management of primary and metastatic liver tumors[1].Tumors invading to the proximity of the hepatic venous outflow pose a peculiar challenge to achieve R0 resections,because this location may render a tumor *** median survival of patients with liver tumor without surgery is less than 12 months[2].Even with surgery,post-hepatectomy liver failure and subsequently increased mortality are the main problems associated with complex resection[3].Moreover,when the vein is affected,vein resection and subsequent reconstruction are *** resection is a standard practice in liver resection and transplantation[4],for example,hepatic vein reconstruction during a living-donor liver transplant,porto-mesenteric axis reconstruction during resection of advanced pancreatic cancer and caval reconstruction during resection of retroperitoneal ***,novel techniques like total hepatic vascular exclusion(HVE)[5],veno-venous bypass[6]and ex vivo hepatic resection[7,8]have facilitated curative resections of tumors close to one or more major hepatic veins.

关键词： hepatectomy surgery mortality

Management of distal cholangiocarcinoma with arterial involvement: Systematic review and case series on the role of neoadjuvant therapy

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World journal of Gastrointestinal Surgery 2024年第8期16卷 2689-2701页

作者： Lewis A Hall Duncan Loader Santiago Gouveia Marta Burak james Halle-Smith Peter Labib Moath Alarabiyat Ravi Marudanayagam Bobby V Dasari keith j Roberts Syed S Raza Michail Papamichail David C Bartlett Robert P Sutcliffe Nikolaos A Chatzizacharias Department of Hepatopancreatobiliary Surgery and Liver Transplantation University Hospitals Birmingham NHS Foundation TrustBirmingham B152GWUnited Kingdom Institute of Immunology and Immunotherapy University of BirminghamBirmingham B152TTUnited Kingdom College of Medical and Dental Sciences University of BirminghamBirmingham B152TTUnited Kingdom Institute of Clinical Sciences University of BirminghamBirmingham B152TTUnited Kingdom

BACKGROUND The use of neoadjuvant therapy(NAT)in distal cholangiocarcinoma(dCCA)with regional arterial or extensive venous involvement,is not widely accepted and evidence is *** To synthesise evidence on NAT for dCCA and present the experience of a highvolume tertiary-centre managing dCCA with arterial *** A systematic review was performed according to PRISMA guidance to identify all studies reporting outcomes of patients with dCCA who received *** patients from 2017 to 2022 who were referred for NAT for dCCA at our centre were retrospectively collected from a prospectively maintained *** characteristics,NAT type,progression to surgery and oncological outcomes were *** Twelve studies were *** definition of“unresectable”locally advanced dCCA was *** studies reported outcomes for 9 patients who received NAT for dCCA with extensive vascular involvement.R0 resection rate ranged between 0 and 100%but without survival benefit in most *** studies considered either NAT in resectable dCCA or inclusive with extrahepatic *** presented case series includes 9 patients(median age 67,IQR 56-74 years,male:female 5:4)referred for NAT for borderline resectable or locally advanced *** patients progressed to surgery and 2 were *** patient died at 14 months with evidence of recurrence at 6 months and the other died at 51 months following recurrence 6 months *** Evidence for benefit of NAT is *** on criteria for uniform definition of resectability for dCCA is *** propose using the established National-Comprehensive-Cancer-Network®criteria for pancreatic ductal adenocarcinoma.

关键词： Cholangiocarcinoma Neoadjuvant therapy Arterial involvement Locally advanced Systematic review

Prehospital transdermal glyceryl trinitrate for ultra- acute ischaemic stroke: data from the RIGHT- 2 randomised sham- controlled ambulance trial

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Stroke & Vascular Neurology 2024年第1期9卷 38-49,I0035-I0046页

作者： jason Philip Appleton Lisa j Woodhouse Craig S Anderson Sandeep Ankolekar Lesley Cala Mark Dixon Timothy j England Kailash Krishnan Grant Mair keith W Muir john Potter Christopher I Price Marc Randall Thompson G Robinson Christine Roffe Else C Sandset jeffrey L Saver Angela Shone Aloysius Niroshan Siriwardena joanna M Wardlaw Nikola Sprigg Philip M Bath Stroke University Hospitals Birmingham NHS Foundation TrustBirminghamUK Institute of Applied HealthResearch University of Birmingham College of Medical and Dental SciencesBirminghamUK Stroke Trials Unit Mental Health and Clinical NeurosciencesUniversity of NottinghamNottinghamUK Faculty of Medicine The George Institute for Global HealthSydneyNew South WalesAustralia The George Institute China at Peking University Health Science Center BeijingChina Neurology Royal Prince Alfred HospitalSydney Health PartnersSydneyNew South WalesAustralia Department of Neurology King's College Hospital NHS Foundation TrustLondonUK Faculty of Health and Medical Sciences University of Western AustraliaCrawleyWestern AustraliaAustralia East Midlands Ambulance Service NHS Trust NottinghamUK Stroke Queen's Medical CentreNottingham University Hospitals NHS TrustNottinghamUK Centre for Clinical Brain Sciences Dementia Research InstituteUniveristy of EdinburghEdinburghUK Institute of Neurology and Psychology University of GlasgowGlasgowUK Bob Champion Research and Education Building University of East AngliaNorwichUK Institute of Neuroscience Newcastle UniversityNewcastle upon TyneUK Department of Neurology Leeds Teaching Hospitals NHS TrustLeedsUK Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre University of LeicesterLeicesterUK Stroke Research in Stoke Institute for Science and Technology in MedicineKeele UniversityStoke-on TrentUK Department of Neurology Oslo University HospitalOsloNorway Research and Development Norwegian Air Ambulance FoundationOsloNorway Department of Neurology and Comprehensive Stroke Center David Geffen School of MedicineUCLALos AngelesCaliforniaUSA Research and Graduate Services University of NottinghamNottinghamUK Community and Health Research Unit University of LincolnLincolnUK

Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is ***,we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2).Methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4hours of *** primary outcome was a shift in scores on the modified Rankin scale(mRS)at day *** outcomes included death;a global analysis(Wei-Lachin test)containing Barthel Index,EuroQol-5D,mRS,telephone interview for cognitive status-modified and Zung depression scale;and neuroimaging-determined‘brain frailty’*** were reported as n(%),mean(SD),median[IQR],adjusted common OR(acOR),mean difference or Mann-Whitney difference(MWD)with 95%*** 597 of 1149(52%)patients had a final diagnosis of ischaemic stroke;age 75(12)years,premorbid mRS>2107(18%),Glasgow Coma Scale 14(2)and time from onset to randomisation 67[45,108]***‘brain frailty’was common:median score 2[2,3](range 0–3).At day 90,GTN did not influence the primary outcome(acOR for increased disability 1.15,95%CI 0.85 to 1.54),death or global analysis(MWD 0.00,95%CI-0.10 to 0.09).In subgroup analyses,there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1hour of symptom onset and in those with more severe *** In patients who had an ischaemic stroke,ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital *** IS ALREADY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those w

关键词： Glasgow nitrate random

RNA m^(6)A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression

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Genes & Diseases 2024年第1期11卷 382-396页

作者： Zheng Zhang Keren Zhou Li Han Andrew Small jianhuang Xue Huilin Huang Hengyou Weng Rui Su Brandon Tan Chao Shen Wei Li Zhicong Zhao Ying Qing Xi Qin Kitty Wang keith Leung Mark Boldin Chun-Wei Chen David Ann Zhijian Qian Xiaolan Deng jianjun Chen Zhenhua Chen Department of Systems Biology Beckman Research Institute of City of HopeMonroviaCA 91016USA Irell and Manella Graduate School of Biological Sciences Beckman Research Institute of City of HopeDuarteCA 91010USA Gehr Family Center for Leukemia Research City of HopeDuarteCA 91010USA Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060China Guangzhou Laboratory GuangzhouGuangdong 510005China Bioland Laboratory GuangzhouGuangdong 51005China Department of Liver Surgery Renji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of Diabetes Complications and Metabolism Beckman Research Institute of City of HopeDuarteCA 91010USA Department of Biochemistry and Molecular Biology University of FloridaGainesvilleFL 32603USA Tongji Hospital Affiliated to Tongji University Frontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China School of Pharmacy China Medical UniversityShenyangLiaoning 110001China

As the most common internal modification of mRNA,Ne-methyladenosine(m^(6)A)and its regulators modulate gene expression and play critical roles in various biological and patholog-ical processes including *** was reported previously that m^(6)A methyltransferase(writer),methyltransferase-like 3(METTL3)adds m^(6)A in primary microRNAs(pri-miRNAs)and fa-cilitates its processing into precursor miRNAs(pre-miRNAs).However,it is unknown whether m^(6)A modification also plays a role in the maturation process of pre-miRNAs and(if so)whether such a function contributes to ***,we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia(AML)patients,especially in relapsed patients,and plays an onco-genic role in ***,YTHDF2 promotes expression of miR-126-3p(also known as miR-126,as it is the main product of precursor miR-126(pre-miR-126)),a miRNA that was reported as an oncomiRNA in AML,through facilitating the processing of pre-miR-126 into mature ***,YTHDF2 recognizes m^(6)A modification in pre-miR-126 and recruits AGO2,a regulator of pre-miRNA processing,to promote the maturation of ***2 posi-tively and negatively correlates with miR-126 and miR-126's downstream target genes,respec-tively,in AML patients,and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis,indi-cating that miR-126 is a functionally important target of YTHDF2 in ***,our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the ther-apeutic potential of targeting this axis for AML treatment,but also suggest that m^(6)A plays a role in pre-miRNA processing that contributes to tumorigenesis.

关键词： AML miR-126 N^(6)-methyladenosine Pre-miRNA maturation YTHDF2

SIMAP500: A novel risk score to identify recipients at higher risk of hepatocellular carcinoma recurrence following liver transplantation

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World journal of Transplantation 2024年第3期14卷 132-143页

作者： Amr Alnagar Nekisa Zakeri Konstantinos Koilias Rosemary E Faulkes Rachel Brown Owen Cain M Thamara P R Perera keith j Roberts Rebeca Sanabria-Mateos David C Bartlett Yuk Ting Ma Shivan Sivakumar Shishir Shetty Tahir Shah Bobby V M Dasari Department of HBP and Liver Transplantation Surgery Queen Elizabeth HospitalUniversity Hospitals BirminghamBirmingham B152GWUnited Kingdom Centre for Liver Research Institute of Biomedical ResearchBirmingham B152TTUnited Kingdom Department of Hepatology Queen Elizabeth HospitalUniversity Hospitals BirminghamBirmingham B152GWUnited Kingdom Department of Pathology University Hospitals Birmingham NHS Foundation TrustBirmingham B152GWUnited Kingdom Department of Oncology Queen Elizabeth HospitalUniversity Hospitals of BirminghamBirmingham B152GWUnited Kingdom

BACKGROUND Recurrence of hepatocellular carcinoma(HCC)following liver transplantation(LT)has a devastating influence on recipients’survival;however,the risk of recur-rence is not routinely *** stratification is vital with a long LT waiting time,as that could influence the recurrence despite strict listing *** This study aims to identify predictors of recurrence and develop a novel risk pre-diction score to forecast HCC recurrence following *** A retrospective review of LT for HCC recipients at University Hospitals Bir-mingham between july 2011 and February *** and multivariate analyses were performed to identify recurrence predictors,based on which the novel SIMAP500(satellite nodules,increase in size,microvascular invasion,AFP>500,poor differentiation)risk score was *** 234 LTs for HCC were performed with a median follow-up of 5.3 *** developed in 25 patients(10.7%).On univariate analyses,RETREAT score>3,α-fetoprotein(AFP)at listing 100-500 and>500,bridging,increased tumour size between imaging at the listing time and explant histology,increase in the size of viable tumour between listing and explant,presence of satellite nodules,micro-and macrovascular invasion on explant and poor differentiation of tumours were significantly associated with recurrence,based on which,the SIMAP500 risk score is *** SIMAP500 demonstrated an excellent predictive ability(c-index=0.803)and outper-formed the RETREAT score(c-index=0.73).SIMAP500 is indicative of the time to disease *** SIMAP500 risk score identifies the LT recipients at risk of HCC *** stratification allows patient-centric post-transplant surveillance *** validation of the score is recommended.

关键词： Liver transplantation Hepatocellular carcinoma Recurrence Survival

Archaeolithoporella and Tubiphytes : Affinties and Paleoecology in Permian Reefs of South China

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Science China Chemistry 1994年第6期37卷 723-743页

作者：王生海范嘉松 j.keith Rigby Institute of Geology Academia Sinica Beijing 100029 PRO Department of Geology Brigham Young University Provo 84602 Utah USA

Archaeolithoporella is one of the most important Permian reef-building organisms, but itsaffinity has long been controversial. It was first reported in japan and was considered as a coralline red alga. Since then it has been recognized in Permian reefs in other parts of the world. Many researchers have studied the materials they had found and the japanese holotype specimen. Most have concluded that it is a problematic alga. or just a problematica because of weak criteria for definition. Some have even considered it inorganic. However, relict cellular structures and microtubular laminae found in well-preserved specimens from Permian reefs in South China strongly support a coralline red algal affinity for the *** situ preserved Archaeolithoporella is restricted within the typical framework facies and it occurs most abundantly in syndepositionally cemented framestones. This suggests that Archaeolithoporella required a firm substrate and clear but agitated sea water. Archaeolithoporella is often found in cavities , implying that it was accustomed to cryptic biotopes. Archaeolithoporella is a most important encrusting organism helping other frame-building organisms to form rigid wave-resistant *** is another component of Permian reefs of South China and its affinity has also been enigmatic. This genus was established in 1956, based on material from Russia, and was originally placed in the blue-green algae. Several affinities have been subsequently proposed for it, but most researchers consider it as a problematic alga or a problematica. However, the structure of this organism, especially the various types of central tubes and well-organized bodies, opposes the algal affinity.A comparison of Tubiphytes with some modern sponges suggests that Tubiphytes belongs to the class Demospongiae in the phylum of Porifera. It is an animal rather than a plant. It is obvious that more than one genus is described under the term 'Tubiphytes. 'Tubiphytes is quite ab

关键词： Archaeolithoporella and Tubiphytes South China.

The practice of mine ventilation engineering

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International journal of Mining Science and Technology 2015年第2期25卷 165-169页

作者： Wallace keith Prosser Brian Stinnette j.Daniel Mine Ventilation Services Inc.

The practice of ventilation is continually evolving with new technological advances developed in the mining *** recent years the advances in diesel engine technologies,ventilation modeling software,and ventilation management capacities have redefined the historical methods used to evaluate *** advances re-evaluate previous methods used to calculate the airflow requirements for the dilution of diesel exhaust *** software has become an integral part of planning and developing ventilation systems in partnership with graphical mine design software packages to generate realistic representations of the *** advances in ventilation control strategies through remote sensors and monitoring capabilities have been developed to results in cost *** there has been much advancement in mine ventilation technology,the practices and basic ventilation principals enacted through the ventilation engineer cannot be placated with technological advances only.

关键词： Modern ventilation Ventilation on demand Diesel Airflow evaluation Monitoring system