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Contactin-associated protein-like 2(CNTNAP2)mutations impair the essentialα-secretase cleavages,leading to autism-like phenotypes

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1625-1636页

作者： Qing Zhang Mengen Xing Zhengkai Bao Lu Xu Yang Bai Wanqi Chen Wenhao Pan Fang Cai Qunxian Wang Shipeng Guo Jing Zhang Zhe Wang Yili Wu Yun Zhang Jia-Da Li Weihong Song Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Zhejiang Key Laboratory of Alzheimer's DiseaseZhejiang Provincial Clinical Research Center for Mental DisordersSchool of Mental Health and Wenzhou Kangning HospitalThe Second Affiliated Hospital and Yuying Children's HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325035China Townsend Family Laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Chongqing Key Laboratory of Translational medical Research in Cognitive Development and Learning and Memory Disorders Ministry of Education Key Laboratory of Child Development and DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China Center for medical genetics Hunan Key Laboratory of Animal Models for Human DiseasesHunan Key Laboratory of Medical GeneticsHunan International Scientific and Technological Cooperation Base of Animal Models for Human DiseasesSchool of Life SciencesCentral South UniversityChangsha 410078 HunanChina The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053Chin

Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its ***,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain *** this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM10/17-dependent a-secretase and presenilindependent *** identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96,and the main a-cleavage product C79 by ADAM10 is required for the subsequent y-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the a-cleavage to generate C79,and the inhibition leads to ASDIlike repetitive and social behavior abnormalties in the Cntnap2l1254T knock-in ***,exogenous expression of 79 improves autism-ike phenotypes in the Cntnap2^(11254T) knock-in and Cntnap2^(-/-)knockout *** data demonstrates that the a-secretase is essential for CNTNAP2 processing and its *** study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

关键词： NAP2 cleavage subsequent

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Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141,DDHD2,and LHFPL5

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Frontiers of Medicine 2024年第1期18卷 81-97页

作者： Liwei Sun Xueting Yang Amjad Khan Xue Yu Han Zhang Shirui Han Xiaerbati Habulieti Yang Sun Rongrong Wang Xue Zhang McKusick-Zhang Center for Genetic Medicine State Key Laboratory for Complex Severe and Rare DiseasesInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing100005China Chongqing Key Laboratory of Human Embryo Engineering Center for Reproductive MedicineNational Key Clinical Speciality Construction Project(Obstetrics and Gynecology)Chongqing Health Center for Women and ChildrenChongqing400013China Chongqing Clinical Research Center for Reproductive Medicine Women and Children’s Hospital of Chongqing Medical UniversityChongqing400013China Faculty of Biological Sciences Department of ZoologyUniversity of Lakki MarwatKhyber Pakhtunkhwa28420Pakistan Institute for medical genetics and Applied Genomics University of TübingenTübingen72076Germany Alexander von Humboldt fellowship Foundation Berlin10117Germany Department of Pediatrics The First Affiliated Hospital of Guangxi Medical UniversityNanning530000China Department of Laboratory Medicine State Key Laboratory for Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing100730China

Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and *** variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic ***,a Pakistani family with parental consanguinity was presented,characterized with severe intellectual disability(ID),spastic paraplegia,and *** mapping,integrated single nucleotide polymorphism(SNP)array,whole-exome sequencing,and whole-genome sequencing were performed,and homozygous variants in TMEM141(c.270G>A,***90^(*)),DDHD2(c.411+767_c.1249-327del),and LHFPL5(c.250delC,***84^(*))were identified.A Tmem141^(***90^(*)/***90^(*))mouse model was *** studies showed impairments in learning ability and motor *** slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje *** electron microscopy showed abnormal mitochondrial ***,studies on a human in vitro neuronal model(SH-SY5Y cells)with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function,possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse ***,panoramic variation analysis revealed that multilocus genomic variations of TMEM141,DDHD2,and LHFPL5 together caused variable phenotypes in ***,the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

关键词： neurodevelopmental disorder autosomal recessive intellectual disability consanguinity spastic paraplegia hearing loss TMEM141

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Allelic reprogramming of chromatin states in human early embryos

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National Science Review 2024年第03期11卷 58-71页

作者： Shenli Yuan Lei Gao Wenrong Tao Jianhong Zhan Gang Lu Jingye Zhang Chuanxin Zhang Lizhi Yi Zhenbo Liu Zhenzhen Hou Min Dai Han Zhao Zi-Jiang Chen Jiang Liu Keliang Wu Center for Reproductive Medicine Shandong University CAS Key Laboratory of Genome Sciences and Information Collaborative Innovation Center of Genetics and Development Beijing Institute of Genomicsand China National Center for BioinformationChinese Academy of Sciences University of Chinese Academy of Sciences CUHK-SDU Joint Laboratory on Reproductive genetics School of Biomedical Sciences the Chinese University of Hong Kong Key Laboratory of Reproductive Endocrinology of the Ministry of Education Shandong University Center for Reproductive Medicine Ren Ji Hospital School of Medicine Shanghai Jiao Tong University CAS Center for Excellence in Animal Evolution and genetics Chinese Academy of Sciences

The reprogramming of parental epigenomes in human early embryos remains elusive. To what extent the characteristics of parental epigenomes are conserved between humans and mice is currently unknown. Here,we mapped parental haploid epigenomes using human parthenogenetic and androgenetic embryos. Human embryos have a larger portion of genome with parentally specific epigenetic states than mouse *** allelic patterns of epigenetic states for orthologous regions are not conserved between humans and mice. Nevertheless, it is conserved that maternal DNA methylation and paternal H3K27me3 are associated with the repression of two alleles in humans and mice. In addition, for DNA-methylation-dependent imprinting, we report 19 novel imprinted genes and their associated germline differentially methylated regions. Unlike in mice, H3K27me3-dependent imprinting is not observed in human early ***, allele-specific epigenomic reprogramming is different in humans and mice.

关键词： human embryo epigenetics reprogramming DNA methylation H3K27me3 chromatin accessibility

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Experimental models for cancer brain metastasis

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Cancer Pathogenesis and Therapy 2024年第1期2卷 15-23页

作者： Zihao Liu Shanshan Dong Mengjie Liu Yuqiang Liu Zhiming Ye Jianhao Zeng Maojin Yao Guangzhou Institute of Respiratory Disease The First Affiliated Hospital of Guangzhou Medical UniversityChina State Key Laboratory of Respiratory DiseaseGuangzhouGuangdong 510182China Department of medical genetics and Cell Biology GMU-GIBH Joint School of Life SciencesGuangzhou Medical UniversityGuangzhouGuangdong 511436China Department of Microbiology Immunologyand Cancer BiologyUniversity of Virginia Health SystemCharlottesvilleVA 22908USA

Brain metastases are a leading cause of cancer-related ***,progress in their treatment has been limited over the past decade,due to an incomplete understanding of the underlying biological *** accurate in vitro and in vivo models to recapitulate the complexities of brain metastasis offers the most promising approach to unravel the intricate cellular and physiological processes ***,we present a comprehensive review of the currently accessible models for studying brain *** introduce a diverse array of in vitro and in vivo models,including cultured cells using the Transwell system,organoids,microfluidic models,syngeneic models,xenograft models,and genetically engineered *** have also provided a concise summary of the merits and limitations inherent to each model while identifying the optimal contexts for their effective *** review serves as a comprehensive resource,aiding researchers in making well-informed decisions regarding model selection that align with specific research questions.

关键词： Brain metastases Blood-brain barrier Animal model In vitro model

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Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

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Genes & Diseases 2024年第1期11卷 413-429页

作者： Dongsheng Zhang Wenjuan Tang Haitao Niu William Tse Hai-Bin Ruan Helmut Dolznig Thomas Knosel Friedrich Karl-Heinz Madeleine Themanns Jiang Wang Mingquan Song Lee Denson Lukas Kenner Richard Moriggl Yi Zheng Xiaonan Han Division of Hematology and Oncology Division of Cancer BiologyDepartment of MedicineMetroHealth Medical Center(MHMC)Case Western Reserve University(CWRU)School of MedicineClevelandOH 44109USA Cancer Genomics and Epigenomics Program Case Comprehensive Cancer CenterCase Western Reserve University(CWRU)ClevelandOH 44106USA Division of Gastroenterology Hepatology and NutritionCincinnati Children’s Hospital Medical Center(CCHMC)CincinnatiOH 45229USA Children’s Hospital of Fudan University Shanghai 201102China School of Medicine Jinan UniversityGuangzhouGuangdong 510632China Laboratory Animal Science(ILAS) Chinese Academy of Medical Science(CAMS)and Peking Union Medical College(PUMC)Beijing 100006China Department of Integrative Biology and Physiology University of Minnesota Medical SchoolMinneapolisMI 55455USA Institute of medical genetics Medical University of ViennaVienna 1040Austria Institute of Pathology Ludwig-Maximilians-University MunichMunich 80539Germany Institute of Biochemistry II University Hospital JenaJena 07743Germany Laboratory Animal Pathology University of Veterinary Medicine ViennaVienna 1210Austria Department of Pathology University of CincinnatiCincinnatiOH 45221USA Department of Gastroenterology The Affiliated Hospital of Qingdao UniversityQingdaoShandong 266005China Department of Pathology Medical University of ViennaVienna 1040Austria Ludwig Boltzmann Institute for Cancer Research Vienna 1090Austria medical University of Vienna Vienna 1040Austria Institute of Animal Breeding and genetics University of Veterinary Medicine ViennaVienna 1210Austria Division of Experimental Hematology CCHMCCincinnatiOH 45229USA

CDC42 controls intestinal epithelial(IEC)stem cell(IESC)*** aberrant CDC42 initiates intestinal inflammation or neoplasia is *** utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and *** specimens were collected to determine the levels of CDC42 in IBD or colorectal ***42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient ***,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC *** studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD *** Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt *** Cdc42 depletion markedly enhanced irra-diation-or chemical-induced *** or inhibition of Cdc42 reduced colonic Lgr5+IESC *** conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal *** monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.

关键词： Cell divisioncycle 42(CDC42) Colitis Colorectal cancer(CRC) Inflammatory bowel diseases(IBD) Intestinal epithelial cell(IEC) Intestinal epithelial stem cell(IESC) Irradiation

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Congenital Disseminated Pyogenic Granuloma:A Case With Numerous Mucocutaneous and Visceral Lesions

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Maternal-Fetal Medicine 2024年第3期6卷 190-195页

作者： Siavash Ghaderi-Sohi Behnaz Moradi Mahboobeh Shirazi Rahil Rahimi Romina Ravanbakhsh Ariana Kariminejad Elham Feizabad Kariminejad-Najmabadi Pathology&genetics Center Tehran ***Iran Department of Radiology Advanced Diagnostic and Interventional Radiology Research Center(ADIR)Tehran University of Medical SciencesTehran ***Iran Yas Complex Hospital Tehran University of Medical SciencesTehran ***Iran Nikan Hospital Tehran ***Iran

Congenital disseminated pyogenic granuloma(CDPG)is characterized by eruptive disseminated or localized lesions,which may arise spontaneously or secondary to predisposing *** rarer is the occurrence of CDPG with numerous lesions affecting variable organs,which develop during the fetal *** report describes the case of a 32-week-old fetus presenting with severe hydrocephalus and vascular intracranial and right lung masses on magnetic resonance *** labor occurred at the 32^(nd)week due to preterm premature rupture of membranes,and the newborn died due to cardiac dysfunction within 2 hours *** subsequent autopsy revealed multiple violaceous to dark red papules,nodules,pedunculated and un-pedunculated mucocutaneous masses,as well as two brain lesions,a lung lesion,a thoracic wall intramuscular mass,and a pyloric *** examination and immunohistochemical evaluation for glucose transporter 1(GLUT1)confirmed the diagnosis of *** represents a rare condition with an elusive etiology and limited reports in the *** diagnosis from multifocal infantile hemangioma,based on GLUT1 negativity of CDPG,is imperative due to differing clinical course and treatment *** report underscores a severe case of CDPG characterized by preterm labor and demise shortly after delivery,notable for its extensive involvement across multiple organs,including the brain,lung,intestine,musculoskeletal system,mucosal,and numerous cutaneous sites.

关键词： Pyogenic Granuloma Congenital Hemangioma

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Fine-needle aspiration technique under endoscopic ultrasound guidance:A technical approach for RNA profiling of pancreatic neoplasms

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2663-2672页

作者： Sabina Sherafedinovna Seyfedinova Olga Aleksandrovna Freylikhman Polina Sergeevna Sokolnikova Konstantin Aleksandrovich Samochernykh Anna Aleksandrovna Kostareva Olga Viktorovna Kalinina Evgeniy Gennadievich Solonitsyn Research Laboratory of Digestive Cancer Almazov Medical Research CentreSaint-Petersburg 197341Russia Research Laboratory of Molecular and Cellular Modeling and Gene Therapy Almazov Medical Research CentreSaint-Petersburg 197341Russia Head of Russian Neurosurgical Institute Named after Prof.A.L.Polenova Russian Neurosurgical Institute Named after Prof.A.L.PolenovaSaint-Petersburg 191014Russia Head of Institute of Molecular Biology and genetics Almazov National Medical Research CentreSaint-Petersburg 197341Russia Research Laboratory of Autoimmune and Autoinflammatory Diseases Almazov National Medical Research CentreSaint-Petersburg 197341Russia

BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma(PDAC)has been a longstanding *** prognosis of patients with PDAC depends on the stage at *** is necessary to identify biomarkers for the detection and differentiation of pancreatic tumors and optimize PDAC sample preparation procedures for DNA and RNA *** molecular studies are done using paraffin-embedded blocks;however,the integrity of DNA and RNA is often compromised in this ***,RNA isolated from human pancreatic tissue samples is generally of low quality,in part,because of the high concentration of endogenous pancreatic RNAse activity *** To assess the potential of endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA)to obtain specimens from pancreatic neoplasms for subsequent RNA molecular profiling,including next-generation sequencing(NGS).METHODS Thirty-four EUS-FNA samples were included in this study:PDAC(n=15),chronic pancreatitis(n=5),pancreatic cysts(n=14),mucinous cysts(mucinous cystic neoplasia/intraductal papillary mucinous neoplasia)n=7,serous cystic neoplasms n=5,and pseudocysts n=*** material consisted of cyst fluid and cyst wall samples obtained by through-the-needle biopsy(TTNB).Samples were stored at -80℃ until *** purity(A260/230,A260/280 ratios),concentration,and integrity(RIN)were ***-time polymerase chain reaction was conducted on all samples,and small RNA libraries were prepared from solid mass *** RNA was successfully extracted from 29/34(85%)EUS-FNA samples:100% pancreatic adenocarcinoma samples,100% chronic pancreatitis samples,70% pancreatic fluid cyst samples,and 50%TTNB *** relative expression of GAPDH and HPRT were obtained for all successfully extracted RNA samples(n=29)including lowquality RNA *** concentration and nonoptimal RIN values(no less than 3)of RNA extracted from EUS-FNA samples did not prevent NGS library *** suitability of cyst fluid samples

关键词： Endoscopic ultrasound-guided,fine-needle aspiration Pancreatic cancer Pancreatic cysts RNA extraction Through-the-needle biopsy Next-generation sequencing

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Preimplantation genetic testing for embryos predisposed to hereditary cancer:Possibilities and challenges

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Cancer Pathogenesis and Therapy 2024年第1期2卷 1-14页

作者： Mohammed H.Albujja Maher Al-Ghedan Lakshmidevi Dakshnamoorthy Josep Pla Victori Department of Forensic Sciences Naif Arab University for Security SciencesRiyadh 11452Saudi Arabia genetics Laboratory Thuriah Medical CenterRiyadh 11523Saudi Arabia Department of Genetic Counselling VI-RMA GlobalValencia 46004Spain

Preimplantation genetic testing(PGT),which was developed as an alternative to prenatal genetic testing,allows couples to avoid pregnancies with abnormal chromosomes and the subsequent termination of the affected *** used for early onset monogenic conditions,PGT is now used to prevent various types of inherited cancer conditions based on the development of PGT technology,assisted reproductive techniques(ARTs),and in vitro fertilization(IVF).This review provides insights into the potential benefits and challenges associated with the application of PGT for hereditary cancer and provides an overview of the existing literature on this test,with a particular focus on the current challenges related to laws,ethics,counseling,and ***,this review predicts the future potential applications of this *** PGT may be utilized to predict and prevent hereditary cancer,each case should be comprehensively *** motives of couples must be assessed to prevent the misuse of this technique for eugenic purposes,and non-pathogenic phenotypes must be carefully *** cases that require this technology should also be carefully considered based on legal and ethical *** may be the preferred treatment for hereditary cancer cases;however,such cases require careful case-by-case ***,this study concludes that multidisciplinary counseling and support for patients and their families are essential to ensure that PGT is a viable option that meets all legal and ethical concerns.

关键词： Preimplantation genetic testing Hereditary cancer Late-onset diseases Ethics Legal restrictions

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Transcriptomic analysis reveals that NIBAN1 overexpression is associated with BRAF^(V600E)mutation and increases the aggressiveness of thyroid cancer

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Genes & Diseases 2024年第4期11卷 16-19页

作者： Paula Diana Thaise Nayane Ribeiro Carneiro Janete Maria Cerutti Reginaldo Massanobu Kuroshu Gianna Maria Griz Carvalheira Division of genetics Department of Morphology and GeneticsEscola Paulista de MedicinaUniversidade Federal de Sao PauloSao PauloRua Botucatu740Edificio Leitaoda Cunha1AndarSao PauloSP04023900Brazil Genetic Bases of Thyroid Tumors Laboratory Division of GeneticsDepartment of Morphology and GeneticsEscola Paulista de MedicinaUniversidade Federal de Sao PauloPedro de Toledo 66911AndarSao PauloSP 04039-032Brazil Institute of Science and Technology Universidade Federal de Sao PauloAv Cesare Mansueto Giulio Lattes1201Eugenio deMelloSaoJose dos CamposSP12247-014Brazil

NIBAN1 overexpression has been reported in a widerange of thyroid carcinoma subtypes,and in other cancers,while it is not expressed in thyroid benign lesions and normal thy-roid.1-3 However,the mechanism associated with its expression and prognostic value remains *** this study,six independent cohorts were enrolled,in which NIBAN1 expression was evaluated.A total of 583patients with thyroid tumors,326 patients with skin cancers,293 patients with colorectal carcinoma,and 189 patients with lung carcinoma were analyzed.

关键词： BRAF lesions BAN

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Mesenchymal stem cell therapy for liver fibrosis need“partner”:Results based on a meta-analysis of preclinical studies

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World Journal of Gastroenterology 2024年第32期30卷 3766-3782页

作者： Yan Xu Xue-Song Wang Xiao-Lei Zhou Wen-Ming Lu Xing-Kun Tang Yu Jin Jun-Song Ye Subcenter for Stem Cell Clinical Translation First Affiliated Hospital of Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina School of Rehabilitation Medicine Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine Gannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina Department of medical genetics School of MedicineTongji UniversityShanghai 200092China Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases Ministry of EducationGannan Medical UniversityGanzhou 341000Jiangxi ProvinceChina

BACKGROUND The efficacy of mesenchymal stem cells(MSCs)in treating liver fibrosis has been demonstrated in several clinical ***,their low survival and liver implantation rates remain *** recent years,a large number of studies in animal models of liver fibrosis have shown that MSCs combined with drugs can improve the efficacy of MSCs in the treatment of liver fibrosis alone and inhibit its progression to end-stage liver *** has inspired new ways of thinking about treating liver *** To investigate the effectiveness and mechanisms of MSCs combined with drugs in treating liver *** Data sources included four electronic databases and were constructed until January *** subjects,interventions,comparators,outcomes,and study design principle were used to screen the literature,and the quality of the literature was evaluated to assess the risk of *** randomised controlled trials were selected,and the final 13 studies were included in the final *** A total of 13 studies were included after *** analysis showed that MSCs combined with drug therapy significantly improved liver function,promoted the repair of damaged liver tissues,reduced the level of liver fibrosis-related indexes,and effectively ameliorated hepatic fibrosis by modulating the hepatic inflammatory microenvironment,promoting the homing of MSCs,and regulating the relevant signaling pathways,and the treatment efficacy was superior to MSCs ***,the combined treatment statistics showed no amelioration in serum albumin levels(standardized mean difference=0.77,95%confidence interval:-0.13 to 1.68,P=0.09).CONCLUSION In conclusion,MSCs combined with drugs for treating liver fibrosis effectively make up for the shortcomings of MSCs in their therapeutic ***,due to the different drugs,the treatment mechanism and effect also ***,more randomized controlled trials are needed to compare the therapeutic effic

关键词： drugs alone partner

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