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The lysine methyltransferase SMYD2 facilitates neointimal hyperplasia by regulating the HDAC3-SRF axis

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Acta Pharmaceutica Sinica B 2024年第2期14卷 712-728页

作者： Xiaoxuan Zhong Xiang Wei Yan Xu Xuehai Zhu Bo Huo Xian Guo Gaoke Feng Zihao Zhang Xin Feng Zemin Fang Yuxuan Luo Xin Yi Ding-Sheng Jiang division of Cardiovascular Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Key Laboratory of organ transplantation Ministry of EducationNHC Key Laboratory of Organ TransplantationChinese Academy of Medical SciencesWuhan 430030China School of Life Science and Technology Key Laboratory of Developmental Genes and Human DiseaseSoutheast UniversityNanjing 210096China Department of Cardiology Renmin Hospital of Wuhan UniversityWuhan 430060China

Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary heart disease.Here,we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum-and PDGF-BB-induced vascular smooth muscle cells(VSMCs),and in tissues of carotid artery injury-induced neointimal hyperplasia.Smyd2 overexpression in VSMCs(Smyd2-vTg)facilitates,but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice.Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor(SRF)target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation.HDAC3 directly interacts with and deacetylates SRF,which enhances SRF transcriptional activity in VSMCs.Moreover,SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter.RGFP966,a specific inhibitor of HDAC3,not only counteracts the pro-proliferation effect of SMYD2 overexpression on VSMCs,but also inhibits carotid artery injury-induced neointima formation in mice.HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner.Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.

关键词： Neointimaformation Histonemethylation Histoneacetylation SRFacetylation SMYD2 HDAC3 LLY-507 RGFP966

In search of a pan-coronavirus vaccine:next-generation vaccine design and immune mechanisms

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Cellular & Molecular Immunology 2024年第2期21卷 103-118页

作者： S.Cankat M.U.Demael L.Swadling division of Infection and Immunity Institute of Immunity and TransplantationUniversity College LondonPears BuildingLondon NW32PPUK

Members of the coronaviridae family are endemic to human populations and have caused several epidemics and pandemics in recent history.In this review,we will discuss the feasibility of and progress toward the ultimate goal of creating a pan-coronavirus vaccine that can protect against infection and disease by all members of the coronavirus family.We will detail the unmet clinical need associated with the continued transmission of SARS-CoV-2,MERS-CoV and the four seasonal coronaviruses(HCoV-OC43,NL63,HKU1 and 229E)in humans and the potential for future zoonotic coronaviruses.We will highlight how first-generation SARS-CoV-2 vaccines and natural history studies have greatly increased our understanding of effective antiviral immunity to coronaviruses and have informed next-generation vaccine design.We will then consider the ideal properties of a pan-coronavirus vaccine and propose a blueprint for the type of immunity that may offer cross-protection.Finally,we will describe a subset of the diverse technologies and novel approaches being pursued with the goal of developing broadly or universally protective vaccines for coronaviruses.

关键词： Vaccine Coronavirus Cross-reactive immunity Cross-protection Universal

SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation

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Cancer Communications 2024年第3期44卷 384-407页

作者： Shiyu Zhang Xing Jia Haojiang Dai Xingxin Zhu Wenfeng Song Suchen Bian Hao Wu Shinuo Chen Yangbo Tang Junran Chen Cheng Jin Mengqiao Zhou Haiyang Xie Shusen Zheng Penghong Song division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China National Health Commission Key Laboratory of Combined Multi-organ transplantation HangzhouZhejiangP.R.China Key Laboratory of the Diagnosis and Treatment of organ transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical SciencesHangzhouZhejiangP.R.China Key Laboratory of organ transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiangP.R.China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China

Background:Liver cancer is a malignancy with high morbidity and mortality rates.Serpin family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many tumors.In this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.Methods:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver can-cer.Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of patients.DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells.RNA sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis.Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.Results:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA methylation.SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer.SERPINE2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and angiogenesis.IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with EGFR.Mechanistically,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,c-Cbl.Additionally,EGFR was activated in liver cancer cells after sorafenib treatment,and SER-PINE2 knockdown-induced EGFR downregulation sig

关键词： liver cancer metastasis DNA methylation SERPINE2 EGFR c-Cbl ubiquitination

Mechanical upper bowel obstruction caused by a large trichobezoar in a young woman: A very unusual case report

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World Journal of Clinical Cases 2024年第4期12卷 777-781页

作者： Magdalena Scherrer Peter Kornprat Robert Sucher Johanna Muehlsteiner Doris Wagner Department of Surgery Division for GeneralVisceral and Transplantation SurgeryMedical University of GrazGraz 8036Austria Department of Surgery Clinic RohrbachRohrbach 4150Austria

BACKGROUND Bezoars usually compile human fibers and debris.A special form of bezoar in case of psychologically altered individuals is the trichobezoar.It consists of voluntarily swallowed hair bulks and is normally removed via gastroscopy.Trichobezoars leading to ileus have rarely been reported.CASE SUMMARY A 24-year-old female patient presented to the emergency room with abdominal pain,nausea,and vomiting for 3 d.Her previous medical and psychiatric history was unremarkable.Laboratory analysis showed iron deficiency anemia,leukocytosis,and elevated liver enzymes.An abdominal CT scan revealed a dense structure in the patients’stomach which turned out to be a huge trichobezoar completely obstructing the pylorus.The trichobezoar had to be removed surgi-cally.During her postoperative course,a subcutaneous seroma formed.After a single puncture,the rest of the recovery process was unremarkable,and the patient recovered fully.CONCLUSION A mechanical bowel obstruction is a potentially life-threatening event for every patient.In our case a young female was suffering from severe symptoms of an obstruction which might have resulted in serious harm without successful surgical management.

关键词： Rapunzel syndrome Hair ingestion Gastroscopy Bezoar Case report

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

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World Journal of transplantation 2024年第1期14卷 72-83页

作者： Maurizio Salvadori Giuseppina Rosso Department of Renal transplantation Careggi University HospitalFlorence 50139TuscanyItaly division of Nephrology San Giovanni di Dio HospitalFlorence 50143ToscanaItaly

Gut microbiota is often modified after kidney transplantation.This principally happens in the first period after transplantation.Antibiotics and,most of all,immunosuppressive drugs are the main responsible.The relationship between immunosuppressive drugs and the gut microbiota is bilateral.From one side immunosuppressive drugs modify the gut microbiota,often generating dysbiosis;from the other side microbiota may interfere with the immunosuppressant pharmacokinetics,producing products more or less active with respect to the original drug.These phenomena have influence over the graft outcomes and clinical consequences as rejections,infections,diarrhea may be caused by the dysbiotic condition.Corticosteroids,calcineurin inhibitors such as tacrolimus and cyclosporine,mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known.In contrast is well known how the gut microbiota may interfere with glucocorticoids,which may be transformed into androgens.Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus.The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase,may be transformed into the inactive product.

关键词： Immunosuppressive therapy Kidney transplantation Gut microbiota Dysbiosis Pathobionts Graft outcomes

The interplay of drug therapeutics and immune responses to SARS-CoV-2

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Cellular & Molecular Immunology 2024年第2期21卷 197-200页

作者： Valeria Fumagalli Matteo Iannacone division of Immunology Transplantationand Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilanItaly Vita-Salute San Raffaele University MilanItaly Experimental Imaging Centre IRCCS San Raffaele Scientific InstituteMilanItaly

The SARS-CoV-2 pandemic has necessitated rapid therapeutic and preventative responses.While vaccines form the frontline of defense,antiviral treatments such as nirmatrelvir have emerged as vital adjunctive measures,particularly for those unable or unwilling to be vaccinated.This review delves into the potential influence of nirmatrelvir on enduring immunity.In parallel,the potential of drug repurposing is explored,with bisphosphonates being examined for their possible effects against COVID-19 due to their immunomodulatory properties.The importance of rigorous clinical trials and careful interpretation of preliminary data is emphasized.

关键词： SARS-CoV-2 Nirmatrelvir Bisphosphonates Adaptive immunity Drug repurposing

Routine utilization of machine perfusion in liver transplantation:Ready for prime time?

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World Journal of Gastroenterology 2024年第11期30卷 1488-1493页

作者： Alessandro Parente Keyue Sun Philipp Dutkowski AM James Shapiro Andrea Schlegel Department of Surgery Division of TransplantationUniversity of Alberta HospitalEdmonton T6G 2B7Canada Immunity and Inflammation Lerner Research InstituteClevelandOH 44195United States Swiss Hepato-Pancreato-Biliary Center Department of Visceral and Transplantation SurgeryUniversity Hospital ZurichZurich 8091Switzerland Immunity and Inflammation Digestive Disease and Surgery InstituteClevelandOH 44195United States

The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation.Robust evidence from numerous randomized controlled trials has been pooled by meta-analyses,providing the highest available evidence on the protective effect of machine perfusion(MP)over static cold storage in liver transplantation(LT).Based on a protective effect with less complications and improved graft survival,the field has seen a paradigm shift in organ preservation.This editorial focuses on the role of MP in LT and how it could become the new“gold standard”.Strong collaborative efforts are needed to explore its effects on long-term outcomes.

关键词： Liver transplantation Machine perfusion Viability assessment Hypothermic oxygenated perfusion Normothermic machine perfusion

Engineered stem cells by emerging biomedical stratagems

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Science Bulletin 2024年第2期69卷 248-279页

作者： Jinglin Wang Xiaoxuan Zhang Hanxu Chen Haozhen Ren Min Zhou Yuanjin Zhao Department of Vascular Surgery.Nanjing Drum Tower Hospital Affliated Hospital of Medical SchoolNanjing UniversityNanjing 210008China division of Hepatobiliary Surgery and transplantation Surgery Department of General SurgeryNanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096China Shenzhen Research Institute Southeast UniversityShenzhen 518038China

Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders.As the safety of stem cell transplantation having been demonstrated in numerous clinical trials,various kinds of stem cells are currently utilized in medical applications.Despite the achievements,the therapeutic benefits of stem cells for diseases are limited,and the data of clinical researches are unstable.To optimize tthe effectiveness of stem cells,engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities,paving the way for the next generation of stem cell therapies.This review offers a detailed analysis of engineered stem cells,including their clinical applications and potential for future development.We begin by briefly introducing the recent advances in the production of stem cells(induced pluripotent stem cells(ipsCs),embryonic stem cells(ESCs),mesenchymal stem cells(MSCs)and hematopoietic stem cells(HSCs).Furthermore,we present the latest developments of engineered strategies in stem cells,including engineered methods in molecular biology and biomaterial fields,and their application in biomedical research.Finally,we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications.

关键词： Stem cells Genetic modification Biomaterials Microfluidics organ-on-a-chip Bioprinting

The outcomes and safety of patients undergoing endoscopic retrograde cholangiopancreatography combining a single-use cholangioscope and a single-use duodenoscope:A multicenter retrospective international study

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Hepatobiliary & Pancreatic Diseases International 2024年第1期23卷 71-76页

作者： Alessandro Fugazza Matteo Colombo Michel Kahaleh V.Raman Muthusamy Bick Benjamin Wim Laleman Carmelo Barbera Carlo Fabbri Jose Nieto Abed Al-Lehibi Mohan Ramchandani Amy Tyberg Haroon Shahid Avik Sarkar Dean Ehrlich Stuart Shermand Cecilia Binda Marco Spadaccini Andrea Iannone Kareem Khalaf Nageshwar Reddy Andrea Anderloni Alessandro Repici division of Gastroenterology and Digestive Endoscopy Humanitas Research Hospital-IRCCSVia Manzoni 5620089RozzanoMilanoItaly Gastroenterology Rutgers Robert Wood JohnsonNew BrunswickNew JerseyUSA Vatche and Tamar Manoukian division of Digestive Diseases University of CaliforniaLos Angeles School of Medicine at UCLALos AngelesCaliforniaUSA division of Digestive and Liver Disorders Indiana University School of MedicineIndianapolisINUSA Department of Gastroenterology and Hepatology University Hospitals LeuvenKU Leuven3000 LeuvenBelgium U.O.C.di Gastroenterologia ed Endoscopia Digestiva Ospedale Giuseppe MazziniASL TeramoItaly Gastroenterology and Digestive Endoscopy Unit Forlì-Cesena HospitalsAUSL RomagnaForlì-CesenaItaly Borland Groover Clinic JacksonvilleFloridaUSA Department of Gastroenterology and Hepatology King Fahad Medical CityRiyadhSaudi Arabia Asian Institute of Gastroenterology HyderabadIndia Section of Gastroenterology Department of Emergency and Organ TransplantationUniversity of BariBari 70124Italy Department of Biomedical Sciences Humanitas UniversityVia Rita Levi Montalcini 420090Pieve EmanueleMilanItaly

Background: Duodenoscope-related multidrug-resistant organism(MDRO) infections raise concerns. Disposable duodenoscopes have been recently introduced in the market and approved by regulatory agencies with the aim to reduce the risk of endoscopic retrograde cholangiopancreatography(ERCP) associated infections. The aim of this study was to evaluate the outcome of procedures performed with single-use duodenoscopes in patients with clinical indications to single-operator cholangiopancreatoscopy. Methods: This is a multicenter international, retrospective study combining all patients who underwent complex biliopancreatic interventions using the combination of a single-use duodenoscope and a single-use cholangioscope. The primary outcome was technical success defined as ERCP completion for the intended clinical indication. Secondary outcomes were procedural duration, rate of cross-over to reusable duodenoscope, operator-reported satisfaction score(1 to 10) on performance rating of the single-use duodenoscope, and adverse event(AE) rate. Results: A total of 66 patients(26, 39.4% female) were included in the study. ERCP was categorized according to ASGE ERCP grading system as 47(71.2%) grade 3 and 19(28.8%) grade 4. The technical success rate was 98.5%(65/66). Procedural duration was 64(interquartile range 15-189) min, cross-over rate to reusable duodenoscope was 1/66(1.5%). The satisfaction score of the single-use duodenoscope classified by the operators was 8.6 ± 1.3 points. Four patients(6.1%) experienced AEs not directly related to the single-use duodenoscope, namely 2 post-ERCP pancreatitis(PEP), 1 cholangitis and 1 bleeding.Conclusions: Single-use duodenoscope is effective, reliable and safe even in technically challenging procedures with a non-inferiority to reusable duodenoscope, making these devices a viable alternative to standard reusable equipment.

关键词： Single-operator cholangioscopy Single-use duodenoscope Endoscopic retrograde cholangiopancreatography Indeterminate biliary stricture Difficult biliary stones