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Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide

World Journal of Diabetes 2015年第6期6卷 807-827页

作者： Emanuel Monteiro Candeias Inês Carolina Sebastio Susana Maria Cardoso Sónia Catarina Correia Cristina isabel Carvalho Ana isabel plácido Maria Sancha Santos Catarina Resende Oliveira paula isabel Moreira Ana isabel Duarte CNC-Center for Neuroscience and Cell Biology Rua Larga Faculty of Medicine (1st Floor) University of Coimbra Institute for Interdisciplinary Research (IIIUC) University of Coimbra Casa Costa Alem?o-Pólo II Rua D Francisco de Lemos 3030-789 Coimbra Portugal Faculty of Medicine University of Coimbra Life Sciences Department University of Coimbra Largo Marquês de Pombal 3004-517 Coimbra Portugal Institute of Biochemistry Faculty of Medicine University of Coimbra Institute of physiology Faculty of Medicine University of Coimbra

Long-acting glucagon-like peptide-1(GLp-1) analogues marketed for type 2 diabetes(T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2 D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLp-1 receptors(GLp-1R) are expressed throughout the central nervous system and GLp-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLp-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions(e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLp-1 mimetics class of anti-T2 D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLp-1R agonist highly resistant to dipeptidyl peptidase-4 degradation(thereby having an increased half-life) and whose systemic GLp-1R activity is comparable to that of native GLp-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2 D, stroke and Alzheimer disease(AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia in

关键词： Type 2 diabetes Glucagon-like peptide-1 Gut Brain Insulin Liraglutide Alzheimer disease Neuroprotection

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Enforced pGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity

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Cellular & Molecular Immunology 2021年第7期18卷 1761-1771页

作者： Nina Dumauthioz Benjamin Tschumi Mathias Wenes Bastien Marti Haiping Wang Fabien Franco Wenhui Li isabel CLopez-Mejia Lluis Fajas ping-Chih Ho Alena Donda pedro Romero Lianjun Zhang Translational Tumor Immunology Group Ludwig Cancer ResearchUniversity of LausanneEpalingesSwitzerland Department of Fundamental Oncology University of LausanneEpalingesSwitzerland Department of Fundamental Oncology University of LausanneEpalingesSwitzerland Ludwig Cancer Research Institute Lausanne BranchEpalingesSwitzerland Center for Systems Medicine Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical College100005BeijingChina Suzhou Institute of Systems Medicine SuzhouJiangsu215123China Center for Integrative Genomics University of LausanneLausanneSwitzerland

Memory CD8 T cells can provide long-term protection against tumors,which depends on their enhanced proliferative capacity,self-renewal and unique metabolic rewiring to sustain cellular ***,memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic *** contrast,tumor-infiltrating lymphocytes(TILs)display severe metabolic defects,which may underlie their functional ***,we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha(pGC-1α),the master regulator of mitochondrial biogenesis(MB),favors CD8 T cell central memory formation rather than resident memory ***-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide ***,CD8 T cells with enhanced pGC-1αexpression provide stronger antitumor immunity in a mouse melanoma ***,TILs overexpressing pGC-1αmaintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free ***,our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation,metabolic fitness,and antitumor immunity in vivo.

关键词： pGC-1α Mitochondria CD8 Memory Anti-tumor immunity

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Alpha-1 antitrypsin deficiency and pi^(*)Z allele as important co-factors in the development of liver fibrosis

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World Journal of Hepatology 2024年第8期16卷 1099-1110页

作者： Ana isabel Ferreira Catarina Guimarães Vitor Macedo Silva Sofia Xavier Joana Magalhães JoséCotter Department of Gastroenterology Hospital da Senhora da Oliveira-GuimarãesGuimarães 4835-044Portugal Life and Health Sciences Research Institute School of MedicineUniversity of MinhoBraga 4710-057Portugal Life and Health Sciences Research Institute/3B’s PT Government Associate LaboratoryBraga 4710-057Portugal Department of pulmonology Hospital Senhora da Oliveira-GuimarãesGuimarães 4835-044Portugal

BACKGROUND Alpha-1 antitrypsin deficiency(AATD)is a codominant autosomal hereditary condition that predisposes patients to the development of lung and/or liver disease,and pi*Z allele is the most clinically relevant *** To evaluate the impact of clinical parameters and AATD phenotypes,particularly the pi*Z allele,in liver *** Cross-sectional cohort study including consecutive patients with AATD followed in pulmonology or Hepatology *** Included 69 patients,49.3%had pi*MZ phenotype and 10.1%pi**** age≥55 years,age at diagnosis≥41 years and AAT at diagnosispredicted a nonalcoholic fatty liver disease fibrosis score(NFS)not excluding advanced fibrosis[area under the curve(AUC)=0.840,ppp=0.025].An age≥50 years and age at diagnosis≥41 years predicted a fibrosis-4 index of moderate to advanced fibrosis(AUC=0.831,pppatients with hypertension,type 2 diabetes mellitus(DM),dyslipidaemia,metabolic syndrome,and regular alcohol consumption were more likely to have a NFS not excluding advanced fibrosis(pp=0.002,p=0.008,pp=0.033).patients with at least one pi*Z allele and type 2 DM were 8 times more likely to have liver stiffness measurement≥7.1 kpa(p=0.040).CONCLUSION Risk factors for liver disease in AATD included an age≥50 years,age at diagnosis≥41 years,metabolic risk factors,regular alcohol consumption,at least one pi*Z allele,and AAT value at diagnosispatients to use in primary care,selecting those to be referred to Hepatology consultation.

关键词： Alpha-1 antitrypsin deficiency Liver fibrosis Nonalcoholic fatty liver disease fibrosis score Fibrosis-4 index Liver stiffness measurement

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Comparison of white‑to‑white measurements using four devices and their determination of ICL sizing

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Eye and Vision 2024年第5期10卷 28-40页

作者： Robert Edward T.Ang Edward Kenneth F.Reyes Fernando Amado J.Ayuyao Jr Maria isabel N.Umali Emerson M.Cruz Asian Eye Institute Phinma PlazaRockwell Center8Th Floor1200 MakatiPhilippines Cardinal Santos Medical Center 10 Wilson St.Greenhills1502 San JuanPhilippines

Background:To compare the measurements obtained from the Orbscan II,IOLMaster 700,pentacam AXL,and Castroviejo caliper and their effects on calculating the recommended implantable collamer lens(ICL)size and postoperative vault ***:This is a retrospective cross-sectional study of patients who underwent ICL surgery by a single surgeon from March 1,2018 to July 31,*** were reviewed for the anterior chamber depth(ACD)and white-to-white(WTW)measurements obtained from the Orbscan II,IOLMaster 700,pentacam AXL,and Castroviejo caliper(WTW only).These were used to calculate the recommended ICL *** actual ICL size implanted,and vault measurements obtained one month postoperatively were also ***:One hundred seven eyes with a mean age of 27.9±7.7 years were included in the *** WTW measurements were significantly different between devices(pper having the lowest value(11.45±0.04 mm).Mean ACD measurements were the lowest in Orbscan II(3.12±0.25 mm)and the highest in pentacam AXL(3.16±0.24 mm).The pentacam AXL produced an ICL size similar to the Orbscan in 69.2%of *** IOLMaster yielded an ICL measurement one size larger than Orbscan-based calculations in 64.5%of *** the Orbscan WTW and ACD,the desired vault of 0.25 to 0.75 mm and 0.25 to 1.00 mm was achieved in 70%and 91%of eyes,*** caliper WTW to IOLMaster 700 or pentacam AXL WTW increases the percentage of achieving the desired vault to 80%,similar to the ***:The Orbscan II,IOLMaster 700,and pentacam AXL cannot be used interchangeably for calculating ICL *** the WTW from caliper measurement with the ACD of the IOLMaster 700 or pentacam AXL could improve ICL sizing and achieve a higher percentage of eyes with the desired vault.

关键词： ICL vault Orbscan II IOLMaster 700 pentacam AXL Caliper

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低渗核黄素在圆锥角膜患者角膜交联术中的应用（英文）

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国际眼科杂志 2020年第2期20卷 211-216页

作者： Ana Sofia Lopes Diana Silva Susana Henriques peter pego Cristina Vendrell isabel prieto Hospital professor Doutor Fernando Fonseca EpE Amadora-Sintra眼科

目的:比较圆锥角膜患者角膜交联(CXL)、等渗(IR)和低渗核黄素(HR)的结果。方法:回顾性研究,包括29例29眼圆锥角膜患者行角膜交联术,IR组15眼,HR组14眼。参数分析包括(随访1a):最佳矫正视力(BCVA),球体和柱体,中央和较薄处角膜厚度,平均... 详细信息

目的:比较圆锥角膜患者角膜交联(CXL)、等渗(IR)和低渗核黄素(HR)的结果。方法:回顾性研究,包括29例29眼圆锥角膜患者行角膜交联术,IR组15眼,HR组14眼。参数分析包括(随访1a):最佳矫正视力(BCVA),球体和柱体,中央和较薄处角膜厚度,平均和最大角膜曲率(分别为Km和Kmax),并发症及进展。结果:观察到两组的BCVA提高:治疗前IR组为0.26±0.57,HR组为0.47±0.72。术后1a,IR组为0.13±0.79,HR组为0.29±1.52,IR组BCVA更高(p=0.018)。术后1mo,两组中央角膜厚度(μm)均减少,但在接下来的数月中增加:术前IR组为497±28μm,HR组为432±14μm;术后1a,IR组为480±31μm,HR组为424±15μm。较薄处角膜厚度也是如此,术前IR组为487±29μm,HR组为410±20μm;术后1a,IR组为468±33μm,HR组为413±13μm。两组中Km和Kmax均降低。每组6眼呈现短暂的混浊,无持续性混浊。结论:在中央角膜厚度<400μm的患者中,HR的使用似乎是一个有效的替代执行传统CXL的技术。

关键词：圆锥角膜交联术核黄素薄角膜

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Diagnostic accuracy of cardiac computed tomography angiography for myocardial infarction

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World Journal of Radiology 2013年第8期5卷 295-303页

作者： Monvadi B Srichai Hersh Chandarana Robert Donnino Irene isabel p Lim Christianne Leidecker James Babb Jill E Jacobs Department of Cardiology Medstar Georgetown University Hospital Department of Radiology New York University School of Medicine Department of Medicine (Cardiology Division) New York University School of Medicine Department of General Surgery New York University School of Medicine Siemens AG Healthcare Sector91301 Forchheim

AIM:To investigate diagnostic accuracy of high,low and mixed voltage dual energy computed tomography(DECT) for detection of prior myocardial infarction(MI).METHODS:Twenty-four consecutive patients(88% male,mean age 65 ± 11 years old) with clinically documented prior MI(> 6 mo) were prospectively recruited to undergo late phase DECT for characterization of their *** tomography(CT) examinations were performed using a dual source CT system(64-slice Definition or 128-slice Definition FLASH,Siemens Healthcare) with initial first pass and 10 min late phase image *** the 17-segment model,regional systolic function was analyzed using first pass CT as normal or abnormal(hypokinetic,akinetic,dyskinetic).Regions with abnormal systolic function were identified as infarct *** phase DE scans were reconstructed into:140 kVp,100 kVp,mixed(120 kVp) images and iodine-only *** the same 17-segment model,each dataset was evaluated for possible(grade 2) or definite(grade 3) late phase myocardial enhancement *** regression for correlated data was used to compare reconstructions in terms of the accuracy for detecting infarct segments using late myocardial hyperenhancement ***:All patients reported prior history of documented myocardial infarction,with most occurring more than 5 years prior(n = 18;75% of cohort).Fiftyfive of 408(13%) segments demonstrated abnormal wall motion and were classified as *** remaining 353 segments were classified as non-infarcted segments.A total of 1692 segments were analyzed for late phase enhancement abnormalities,with 91(5.5%) segments not interpretable due to *** grades 2 and 3 compared to grade 3 only enhancement abnormalities demonstrated significantly higher sensitivity and similar specificity for detection of infarct segments for all reconstructions *** of different voltage acquisitions demonstrated the highest diagnostic performance for th

关键词： Myocardial infarction Dual energy computed tomography Cardiac computed tomography angiography Ischemic heart disease Late enhancement computed tomography

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Genotoxicity evaluation of two derived products from Allium extracts: s-propylmercaptocysteine and s-propyl mercaptoglutathione

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FOOD BIOSCIENCE 2023年第3期53卷 1603-1611页

作者： Cascajosa-Lira, Antonio Medrano-padial, Concepcion prieto, Ana isabel Banos, Alberto de la Torre, Jose M. Jos, Angeles Camean, Ana M. Univ Seville Fac Farm Area Toxicol Prof Garcia Gonzalez 2 Seville 41012 Spain DMC Res Ctr Camino Jayena 82 Alhendin 18620 Spain

propyl-propane-thiosulfonate (pTSO) is one of the main organosulfur compounds present in Allium essential oils with a widely documented biological activity. For this reason, it could be used as a food and feed additive in the agri-food industry. A genotoxicity evaluation of substances and their metabolites present in food is necessary to guarantee the consumer's health following the recommendations of the European Food Safety Authority (EFSA). To evaluate the toxicological profile of derivatives of pTSO, the cytotoxicity, an Ames test, a micronucleus test and the comet assay were performed. Results showed that non-cytotoxic effects were observed in Caco-2 exposed to s-propyl mercaptocysteine (CSSp) and s-propyl mercaptoglutathione (GSSp) (0-450 mu M). The mutagenicity index remained in the range of 0.6-1.4 for both compounds, showing no mutagenic effects for the concentrations of 5000-312.5 mu g GSSp/plate and 250-15.63 mu g CSSp/plate. Moreover, the % binucleated cells with micronuclei were 1.3-2.2 and 1.6-2.7 for GSSp and GSSp, respectively. For comet assays there was no DNA-genotoxic or oxidative damage in a concentration range of 112.5-450 mu M. Therefore, we can conclude that these compounds are not genotoxic at the conditions tested. These results support that the presence of CSSp and GSSp in the food/ feed is not of concern, although further studies are needed to complete their safety profile.

关键词： Cytotoxicity Genotoxicity Mutagenicity Organosulfur compounds Allium propyl-propane-thiosulfonate

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Immediate effect of high-intensity exercise on brain-derived neurotrophic factor in healthy young adults:A systematic review and meta-analysis

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Journal of Sport and Health Science 2022年第3期11卷 367-375页

作者： Rubén Fernández-Rodríguez CeliaÁlvarez-Bueno isabel A.Martínez-Ortega Vicente Martínez-Vizcaíno Arthur Eumann Mesas Blanca Notario-pacheco Health and Social Research Center Universidad de Castilla-La ManchaCuenca 16071Spain Universidad politécnica y Artística del paraguay Asunción 2024Paraguay Faculty of Medicine Universidad Autónoma de ChileTalca 3460000Chile postgraduate program in public Health Universidad Estadual de LondrinaLondrina 86051-990Brazil

Background Although brain-derived neurotrophic factor(BDNF)has been identified as a molecular biomarker of the neurophysiological effects induced by exercise,the acute effects of high-intensity exercise(HIE)on BDNF levels are *** study aims to estimate the immediate effects of HIE on BDNF levels in healthy young *** A systematic search was conducted in the MEDLINE,Scopus,Cochrane CENTRAL,and SpORTDiscuss databases up to December *** controlled trials(RCTs)and non-RCTs reporting pre-post changes in serum or plasma BDNF after an acute intervention of HIE compared to a control condition were *** effect sizes(p-ESs)and 95%confidence intervals(95%CIs)were calculated for RCTs using a random effects model with Stata/SE(Version 15.0;StataCorp.,College Station,TX,USA).The preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were *** registration number:*** A total of 22 studies with 552 individuals(age range:20-31 years;59.1%male)were *** meta-analysis included 10 RCTs that reported valid outcome *** BDNF levels were observed when HIE interventions were compared with non-exercise(p-ES=0.55,95%CI:0.12-0.98;I^(2)=25.7%;n=4 studies)and light-intensity exercise(p-ES=0.78,95%CI:0.15-1.40;I^(2)=52.4%;n=3 studies)but not moderate-intensity exercise(p-ES=0.93,95%CI:-0.16 to 2.02;I^(2)=88.5%;n=4 studies)*** In comparison to non-exercise or light-intensity exercises,an immediate increase in BDNF levels may occur when young adults perform *** the benefits obtained maximizing circulating BDNF when performing HIE and its potential effects on brain health,our findings suggest that HIE could be recommended by clinicians as a useful exercise strategy to healthy adults.

关键词： Cognition Exercise Neurogenesis Neuroplasticity

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plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia

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Translational Neurodegeneration 2021年第4期10卷 666-677页

作者： Nuole Zhu Miguel Santos-Santos Ignacio lllán-Gala Victor Montal Teresa Estellés isabel Barroeta Miren Altuna Javier Arranz Laia Muñoz Olivia Belbin isabel Sala Maria Belén Sánchez-Saudinós Andrea Subirana Laura Videla Jordi pegueroles Rafael Blesa Jordi Clarimón Maria Carmona-Iragui Juan Fortea Alberto Lleó Daniel Alcolea Sant pau Memory Unit Department of NeurologyInstitut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant PauUniversitat Autònoma de Barcelona08041 BarcelonaSpain Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas(CIBERNED) 28031 MadridSpain Autonomous University of Barcelona 08913 BarcelonaSpain Fundación Catalana Sindrome de Down Centre Mèdic Down08029 BarcelonaSpain

Background:Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative *** of glial fibrillary acidic protein(GFAp),an astrocytic damage marker,may help advance our understanding of different neurodegenerative *** this study,we investigated the diagnostic performance of plasma GFAp(pGFAp),plasma neurofilament light chain(pNfL)and their combination for frontotemporal dementia(FTD)and Alzheimer's disease(AD)and their clinical utility in predicting disease ***:pGFAp and pNfL concentrations were measured in 72 FTD,56 AD and 83 cognitively normal(CN)participants using the Single Molecule Array *** the 211 participants,199 underwent cerebrospinal(CSF)analysis and 122 had magnetic resonance *** compared cross-sectional biomarker levels between groups,studied their diagnostic performance and assessed correlation between CSF biomarkers,cognitive performance and cortical *** prognostic performance was investigated,analyzing cognitive decline through group comparisons by ***:Unlike pNfL,which was increased similarly in both clinical groups,pGFAp was increased in FTD but lower than in AD(all pplasma markers improved the diagnostic performance to discriminate FTD from AD(area under the curve[AUC]:combination 0.78;pGFAp 0.7;pNfL 0.61,all ppGFAp correlated with cognition,CSF and plasma NfL,and cortical thickness(all ppGFAp was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD(1.40 points annually,hazard ratio[HR]3.82,ppoints annually,HR 2.26,ppGFAp and pNfL levels differ in FTD and AD;and their combination is useful for distinguishing between the two *** could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.

关键词： Glial fibrillary acidic protein Neurofilament Frontotemporal dementia plasma biomarkers

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pSMA配体的前列腺癌pET显像

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中华核医学与分子影像杂志 2019年第2期39卷 121-128页

作者：黎翔(译) 杨卫东(译) 汪静(审校) Sarah M.Schwarzenboeck isabel Rauseher Christina Bluemel Wolfgang p.Fendler Steven p. Rowe Martin G.pomper Ali Asfhar-Oromieh Ken Herrrnann Matthias Eiber 第四军医大学第一附属医院核医学科西安710032 Klinik fur Nuklearmedizin Universitatsklinikum EssenEssenGermany Department of Nuclear Medicine Rostock University Medical CentreRostockGermany Department of Nuclear Medicine Klinikum rechts der Isar Technical University of MunichMunichGermany Department of Nuclear Medicine University Hospital Wurzburg Wurzburg Germany Department of Molecular and Medical pharmacology David Geffen School of Medicine at UCLALos AngelesCalifornia Department of Nuclear Medicine Lndwig-Maximilians-University of MunichMunichGermany Russell H.Morgan Department of Radiology and Radiological Science Johns Hopkins University School of MedicineBaltimoreMaryland Department of Nuclear Medicine Heidelberg University HospitalHeidelbergGermany Clinical Cooperation Unit Nuclear Medicine German Cancer Research CentreHeidelbergGermany

近年来,用68Ga和18F标记pET显像剂靶向前列腺特异膜抗原(pSMA)逐渐受到重视。多项回顾性研究指出,与常规影像相比,pSMA配体前列腺癌pET/CT显像具有较高的检测效能,前列腺癌生化复发已被世界多个地区确立为pSMA配体前列腺癌pET/CT显像的... 详细信息

近年来,用68Ga和18F标记pET显像剂靶向前列腺特异膜抗原(pSMA)逐渐受到重视。多项回顾性研究指出,与常规影像相比,pSMA配体前列腺癌pET/CT显像具有较高的检测效能,前列腺癌生化复发已被世界多个地区确立为pSMA配体前列腺癌pET/CT显像的临床适应证。对于高危原发前列腺癌,越来越多的证据表明该显像方式有助于探测隐匿性淋巴结和前列腺癌骨转移;对于原发和复发性前列腺癌的临床适应证,初步研究证实其对临床管理有着重要影响;另有证据表明,其对前列腺内的肿瘤定位、治疗分期和特定临床情况下的晚期病灶治疗监测将成为未来的适应证。随着有关生理性和病理性摄取模式和误区文献数量的剧增,pSMA配体pET显像报告的标准也在不断改进。文章旨在对pSMA配体pET显像的现状进行概述,包括显像程序和解释、临床适应证、诊断潜力及其对治疗计划的影响。

关键词：前列腺癌 pET/CT pSMA

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