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Recombinant adeno-associated virus-mediated delivery of antisense angiotensin Ⅱ receptor 1 gene attenuates hypertension development

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Acta Pharmacologica Sinica 2007年第11期28卷 1737-1745页

作者： Xu-guang LI~2,Jiang-tao YAN~2,Xi-zheng XU,Jia-ning wang,Li-ming cheng,tao wang,Ping ZUO,Dao-wen wang~3Institute of Hypertension and Department of Internal Medicine,Tongji Hospital,Tongji Medical College,Huazhong University of Science andTechnology,Wuhan 430030,China Institute of Hypertension and Department of Internal Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Aim:The renin-angiotensin system plays a crucial role in the development andestablishment of hypertension,and the pharmacological blockade of the systemresults in a reduction in blood *** the present study,we investigatedwhether the effects of a novel,double-stranded,recombinant adeno-associatedvirus vector (rAAV)-mediated antisense angiotensin Ⅱ receptor 1 (AT1R) geneefficiently prevents the development of hypertension induced by a high-salt dietin adult,male Sprague-Dawley (SD) ***:A rAAV was prepared with acassette containing a cytomegalovirus promoter and partial cDNA (660 base pairs)for the AT1R inserted in the antisense direction (rAAV-AT1-AS).A single tail veininjection of the rAAV-AT1-AS or rAAV-GFP (green fluorescent protein,a reportergene) was performed in adult,male SD *** weeks after injection,the animalswere fed a diet containing 8% NaCl,and the systolic blood pressure was measuredweekly using the tail-cuff method for 12 ***:The high-salt dietinduced a significant rise in systolic blood pressure in the rAAV-GFP-treatedanimals;however,the rAAV-AT1-AS treatment attenuated the rise in blood pres-sure (142.7±4.5 mmHg vs 117±3.8 mmHg,P<0.01),and the hypotensive effect wasmaintained until the experiments ended at 12 *** the rAAV-GFP-treatedanimals AT1was overexpressed in various tissues,especially in the aorta andkidney at mRNA levels;in contrast,rAAV-AT1-AS treatment markedly ***,rAAV-AT1-AS treatment prevented target organdamages from hypertension,including cardiac dysfunction and renal injury com-pared to the rAAV-GFP ***:These results suggest that rAAV-mediated anti-AT1delivery attenuates the development of hypertension and pro-tects against renal injury and cardiac remodeling.

关键词： hypertension gene therapy angiotensin Ⅱ receptor 1 antisense double-stranded recombinant adeno-associated virus vector

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基于Toll样信号通路探讨FSE对大鼠乳腺炎的治疗作用

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中国兽医学报 2024年第7期44卷 1521-1525+1570页

作者：成晓丽曹璐王桃姚丹张勇甘肃农业大学动物医学院甘肃省动物生殖生理及繁殖调控重点试验室

旨在探讨连翘提取物(Forsythia suspensa extracts, FSE)对金黄色葡萄球菌诱导大鼠乳腺上皮细胞炎症损伤的保护机制。选择哺乳期大鼠50只，随机分为5组，每组10只：空白对照组(第4对乳腺注射生理盐水),模型组(第4对乳腺注射金黄色葡萄... 详细信息

旨在探讨连翘提取物(Forsythia suspensa extracts, FSE)对金黄色葡萄球菌诱导大鼠乳腺上皮细胞炎症损伤的保护机制。选择哺乳期大鼠50只，随机分为5组，每组10只：空白对照组(第4对乳腺注射生理盐水),模型组(第4对乳腺注射金黄色葡萄球菌菌液各100μL),高剂量组(第4对乳腺注射菌液24 h后，1～7 d灌胃FSE 3.750 g/(kg·d)),中剂量组(第4对乳腺注射菌液24 h后，1～7 d灌胃FSE 1.875 g/(kg·d)),低剂量组(第4对乳腺注射菌液24 h后，1～7 d灌胃FSE 0.935 g/(kg·d)),末次给药24 h后采集血样后处死。结果显示，模型组乳腺组织严重受损，乳腺组织中检测到核因子κB抑制物激酶β(IKKβ)、髓样分化因子88(MyD88)、核因子κB(NF-κB)、Toll样受体4(TLR4) mRNA表达量显著升高(P<0.05)。FSE中、高剂量与模型组相比，乳腺组织中IKKβ、MyD88、NF-κB、TLR4蛋白的相对表达量显著降低(P<0.05)。因此，FSE可能通过抑制Toll样信号通路改善金黄色葡萄球菌诱导的大鼠乳腺上皮细胞炎症反应，降低下游通路蛋白IKKβ、MyD88、NF-κB、TLR4的表达，从而发挥抗炎作用。

关键词：连翘金黄色葡萄球菌乳腺炎 TLR4 MyD88 大鼠

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Gastrointestinal manifestations of critical ill heatstroke patients and their associations with outcomes:A multicentre,retrospective,observational study

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World Journal of Gastroenterology 2024年第4期30卷 346-366页

作者： Yu-Cong wang Xin-Yang Jin Zheng Lei Xiao-Jiao Liu Yu Liu Bang-Guo Zhang Jian Gong Lie-tao wang Lv-Yuan Shi Ding-Yuan Wan Xin Fu Lu-Ping wang Ai-Jia Ma Yi-Song cheng Jing Yang Min He Xiao-Dong Jin Yan Kang Bo wang Zhong-Wei Zhang Qin Wu Department of Critical Care Medicine West China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina School of Pharmacy Macao University of Science and TechnologyMacao 999078China Department of Critical Care Medicine The First People's Hospital of Ziyang CityZiyang 641399Sichuan ProvinceChina Department of Critical Care Medicine The First People's Hospital of Guanghan CityChengdu 618399Sichuan ProvinceChina Department of Critical Care Medicine Lezhi County Traditional Chinese Medicine HospitalChengdu 641599Sichuan ProvinceChina Department of Critical Care Medicine Chengdu Qingbaijiang District People's HospitalChengdu 610399Sichuan ProvinceChina Department of Critical Care Medicine Ziyang People's HospitalChengdu 641399Sichuan ProvinceChina

BACKGROUND Extreme heat exposure is a growing health problem,and the effects of heat on the gastrointestinal(GI)tract is *** study aimed to assess the incidence of GI symptoms associated with heatstroke and its impact on *** To assess the incidence of GI symptoms associated with heatstroke and its impact on *** Patients admitted to the intensive care unit(ICU)due to heatstroke were included from 83 *** history,laboratory results,and clinically relevant outcomes were recorded at ICU admission and daily until up to day 15,ICU discharge,or *** symptoms,including nausea/vomiting,diarrhoea,flatulence,and bloody stools,were *** characteristics of patients with heatstroke concomitant with GI symptoms were *** regression analyses were performed to determine significant predictors of GI *** A total of 713 patients were included in the final analysis,of whom 132(18.5%)patients had at least one GI symptom during their ICU stay,while 26(3.6%)suffered from more than one *** with GI symptoms had a significantly higher ICU stay compared with those *** mortality of patients who had two or more GI symptoms simultaneously was significantly higher than that in those with one GI *** logistic regression analysis revealed that older patients with a lower GCS score on admission were more likely to experience GI *** The GI manifestations of heatstroke are common and appear to impact clinically relevant hospitalization outcomes.

关键词： Extreme heat Flatulence Sunstroke Intensive care units Diarrhea

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Reliable intracavity reflection for self-injection locking lasers and microcomb generation

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Photonics Research 2024年第5期12卷 I0001-I0010页

作者： BItao SHEN XUGUANG ZHANG YIMENG wang ZIHAN tao HAOWEN SHU HUAJIN CHANG WENCAN LI YAN ZHOU Zhangfeng Ge RUIXUAN CHEN BOWEN BAI LIN CHANG XINGJUN wang State Key Laboratory of Advanced Optical Communications System and Networks School of ElectronicsPeking UniversityBeijing 100871China Peng cheng Laboratory Shenzhen 518055China Peking University Yangtze Delta Institute of Optoelectronics Nantong 226010China Frontiers Science Center for Nano-optoelectronics Peking UniversityBeijing 100871China

Self-injection locking has emerged as a crucial technique for coherent optical sources,spanning from narrow linewidth lasers to the generation of localized *** technique involves key components,namely a laser diode and a high-quality cavity that induces narrow-band reflection back into the laser ***,in prior studies,the reflection mainly relied on the random intracavity Rayleigh backscattering,rendering it unpredictable and unsuitable for large-scale production and wide-band *** this work,we present a simple approach to achieve reliable intracavity reflection for self-injection locking to address this challenge by introducing a Sagnac loop into the *** method guarantees robust reflection for every resonance within a wide operational band without compromising the quality factor or adding complexity to the fabrication *** a proof of concept,we showcase the robust generation of narrow linewidth lasers and localized microcombs locked to different resonances within a normal-dispersion ***,the existence and generation of localized patterns in a normal-dispersion cavity with broadband forward–backward field coupling is first proved,as far as we know,both in simulation and in *** research offers a transformative approach to self-injection locking and holds great potential for large-scale production.

关键词： intracavity injection locking

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Multiple pulp stones emerge across all teeth during mixed dentition:A case report

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World Journal of Clinical Cases 2024年第22期12卷 5189-5195页

作者： Yuan Lv Jie Zhu cheng-tao Fu Le Liu Jing wang Yan-Feng Li Department of Stomatology China Aerospace Science&Industry Corporation 731 HospitalBeijing 100074China School of Medicine Huzhou UniversityHuzhou 313204Zhejiang ProvinceChina Department of Stomatology The Fourth Medical CentreChinese People's Liberation Army General HospitalBeijing 100048China

BACKGROUND This paper reports a rare presentation of multiple pulp stones(PSs)emerging in all teeth during mixed *** offers valuable insights into the clinical diagnosis,treatment,and prognosis of multiple PSs,shedding light on their occurrence during the mixed dentition *** SUMMARY A 10-year-old girl presented with repeated pain in the mandibular right posterior *** examination revealed carious lesions,abnormal tooth shapes,and anomalies in tooth *** examinations showed multiple PSs with diverse shapes,sizes,and quantities in all teeth,alongside anomalies in tooth shape and *** canal therapy was initiated,but the patient initially lacked timely *** return for treatment completion,an extracted tooth revealed irregular calculus within the pulp *** This case underscores the importance of considering multiple PSs in mixed dentition,necessitating comprehensive evaluation and management strategies.

关键词： Mixed dentition Multiple pulp stones Pulp calcification Cone-beam computed tomography Case report

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Tenecteplase versus alteplase in treatment of acute ST-segment elevation myocardial infarction:A randomized non-inferiority trial

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Chinese Medical Journal 2024年第3期137卷 312-319页

作者： Xingshan Zhao Yidan Zhu Zheng Zhang Guizhou tao Haiyan Xu Guanchang cheng Wen Gao Liping Ma Liping Qi Xiaoyan Yan Haibo wang Qingde Xia Yuwang Yang Wanke Li Juwen Rong Limei wang Yutian Ding Qiang Guo Wanjun Dang Chen Yao Qin Yang Runlin Gao Yangfeng Wu Shubin Qiao Department of Cardiology Beijing Jishuitan HospitalCapital Medical UniversityThe Fourth Clinical Medical College of Peking UniversityBeijing 100035China Peking University Clinical Research Institute Peking University First HospitalBeijing 100191China Department of Cardiology The First Hospital of Lanzhou UniversityLanzhouGansu 730013China Department of Cardiology The First Affiliated Hospital of Liaoning Medical UniversityJinzhouLiaoning 110002China Department of Cardiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100037China Department of Cardiology Huaihe Hospital of Henan UniversityKaifengHenan 450001China Department of Cardiology Bayannur HospitalBayannurInner Mongolia 015208China Department of Cardiology Puyang People’s HospitalPuyangHenan 457099China Department of Cardiology Xingtai Third HospitalXingtaiHebei 054099China Department of Cardiology Lintao County People’s HospitalDingxiGansu 730599China Department of Cardiology Dancheng County People’s HospitalZhoukouHenan 477150China Department of Cardiology The First People’s Hospital of LingbaoSanmenxiaHenan 472500China Department of Cardiology Shanyin County People’s HospitalShuozhouShanxi 036999China Department of Cardiology Uxin Banner People’s HospitalOrdosInner Mongolia 017399China Department of Cardiology Lingqiu County People’s HospitalDatongShanxi 034499China Department of Cardiology Huaibin County People’s HospitalXinyangHenan 464411China Department of Cardiology Tianzhu County People’s HospitalWuweiGansu 733200China Guangzhou Recomgen Biotech Co. LtdGuangzhouGuangdong 510530China

Background:A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator(rhTNK-tPA)has previously shown its preliminary efficacy in ST elevation myocardial infarction(STEMI)*** study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase(rt-PA)in Chinese patients with ***:In this multicenter,randomized,open-label,non-inferiority trial,patients with acute STEMI were randomly assigned(1:1)to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 *** primary endpoint was recanalization defined by thrombolysis in myocardial infarction(TIMI)flow grade 2 or *** secondary endpoint was clinically justified *** endpoints included 30-day major adverse cardiovascular and cerebrovascular events(MACCEs)and safety ***:From July 2016 to September 2019,767 eligible patients were randomly assigned to receive rhTNK-tPA(n=384)or rt-PA(n=383).Among them,369 patients had coronary angiography data on TIMI flow,and 711 patients had data on clinically justified *** used a–15%difference as the non-inferiority efficacy *** comparison to rt-PA,both the proportion of patients with TIMI grade 2 or 3 flow(78.3%[148/189]vs.81.7%[147/180];differences:–3.4%;95%confidence interval[CI]:–11.5%,4.8%)and clinically justified recanalization(85.4%[305/357]vs.85.9%[304/354];difference:–0.5%;95%CI:–5.6%,4.7%)in the rhTNK-tPA group were *** occurrence of 30-day MACCEs(10.2%[39/384]vs.11.0%[42/383];hazard ratio:0.96;95%CI:0.61,1.50)did not differ significantly between *** safety outcomes significantly differed between ***:rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery,a validated surrogate of clinical outcomes,among Chinese patients with acute ***

关键词： Thrombolytic therapy rhTNK-tPA Randomized controlled trial ST elevation myocardial infarction

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Evaluation of genetic response of mesenchymal stem cells to nanosecond pulsed electric fields by whole transcriptome sequencing

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World Journal of Stem Cells 2024年第3期16卷 305-323页

作者： Jian-Jing Lin Tong Ning Shi-cheng Jia Ke-Jia Li Yong-Can Huang Qiang Liu Jian-Hao Lin Xin-tao Zhang Department of Sports Medicine and Rehabilitation Peking University Shenzhen HospitalShenzhen 518036Guangdong ProvinceChina Institute of Medical Science The Second HospitalCheeloo College of MedicineShandong UniversityJinan 250033Shandong ProvinceChina Department of Biomedical Engineering Institute of Future TechnologyPeking UniversityBeijing 100871China Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies Peking University Shenzhen HospitalShenzhen 518036Guangdong ProvinceChina Arthritis Clinical and Research Center Peking University People’s HospitalBeijing 100044China

BACKGROUND Mesenchymal stem cells(MSCs)modulated by various exogenous signals have been applied extensively in regenerative medicine ***,nanosecond pulsed electric fields(nsPEFs),characterized by short duration and high strength,significantly influence cell phenotypes and regulate MSCs differentiation via multiple ***,we used transcriptomics to study changes in messenger RNA(mRNA),long noncoding RNA(lncRNA),microRNA(miRNA),and circular RNA expression during nsPEFs *** To explore gene expression profiles and potential transcriptional regulatory mechanisms in MSCs pretreated with *** The impact of nsPEFs on the MSCs transcriptome was investigated through whole transcriptome *** were pretreated with 5-pulse nsPEFs(100 ns at 10 kV/cm,1 Hz),followed by total RNA *** transcript was normalized by fragments per kilobase per *** change and difference significance were applied to screen the differentially expressed genes(DEGs).Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to elucidate gene functions,complemented by quantitative polymerase chain reaction *** In total,263 DEGs were discovered,with 92 upregulated and 171 *** were predominantly enriched in epithelial cell proliferation,osteoblast differentiation,mesenchymal cell differentiation,nuclear division,and wound *** cellular components,DEGs are primarily involved in condensed chromosome,chromosomal region,actin cytoskeleton,and *** aspect of molecular functions,DEGs are mainly involved in glycosaminoglycan binding,integrin binding,nuclear steroid receptor activity,cytoskeletal motor activity,and steroid *** real-time polymerase chain reaction confirmed targeted transcript *** Our systematic investigation of the wide-ranging transcriptional pattern modulated by nsPEFs revealed the differential expression of 26

关键词： Nanosecond pulsed electric fields Whole transcriptome sequencing Mesenchymal stem cells Genetic response Stem cell engineering

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Safety and efficacy of Kaffes intraductal self-expanding metal stents in the management of post-liver transplant anastomotic strictures

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World Journal of Transplantation 2024年第2期14卷 88-98页

作者： Chee Lim Jonathan Ng Babak Sarraf Rhys Vaughan Marios Efthymiou Leonardo Zorron cheng tao Pu Sujievvan Chandran Department of Gastroenterology and Hepatology Austin HealthMelbourne HeidelbergVIC 3084Australia Melbourne Medical School The University of MelbourneMelbourne ParkvilleVIC 3052Australia

BACKGROUND Endoscopic management is the first-line therapy for post-liver-transplant anas-tomotic *** the optimal duration of treatment with plastic stents has been reported to be 8-12 months,data on safety and duration for metal stents in this setting is *** to limited access to endoscopic retrograde cholan-giopancreatography(ERCP)during the coronavirus disease 2019 pandemic in our centre,there was a change in practice towards increased usage and length-of-stay of the Kaffes biliary intraductal self-expanding stent in patients with suitable *** was mainly due to the theoretical benefit of Kaffes stents allowing for longer indwelling periods compared to the traditional plastic *** Adult liver transplant recipients aged 18 years and above who underwent ERCP were retrospectively identified during a 10-year period through a database *** admissions post-Kaffes stent insertion were identified manually through electronic and scanned medical *** main outcome was the incidence of complications when stents were left indwelling for 3 months vs 6 *** efficacy was calculated via rates of stricture recurrence between patients that had stenting courses for≤120 d or>120 *** During the study period,a total of 66 ERCPs with Kaffes insertion were performed in 54 patients throughout their stenting *** 33 ERCPs,the stent was removed or exchanged on a 3-month *** pancreatitis,perfor-ations or deaths *** post-ERCP complications were similar between the 3-month(abdominal pain and intraductal migration)and 6-month(abdominal pain,septic shower and embedded stent)groups-6.1%vs 9.1%respectively,P=*** strictures resolved at the end of the stenting course,but the stenting course was variable from 3 to 22 *** recurrence rate for stenting courses lasting for up to 120 d was 71.4%and 21.4%for stenting courses of 121 d or over(P=0.03).There were 28 patients that were treated with a sin

关键词： Liver transplantation Cholangiopancreatography Endoscopic retrograde Constriction Pathologic Self expandable metallic stents Bile duct diseases Cholestasis

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Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

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Acta Pharmaceutica Sinica B 2024年第2期14卷 533-578页

作者： Xiaopeng Peng Zhihao Hu Limei Zeng Meizhu Zhang Congcong Xu Benyan Lu chengpeng tao Weiming Chen Wen Hou Kui cheng Huichang Bi Wanyi Pan Jianjun Chen College of Pharmacy Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of EducationGannan Medical UniversityGanzhou 314000China College of Basic Medicine Gannan Medical UniversityGanzhou 314000China Guangdong Provincial Key Laboratory of New Drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

关键词： Epigenetic Degrader PROTAC Molecularglue Hydrophobic tagging

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Early detection of pancreatic cancer in patients with recurrent pancreatitis:A case report

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World Journal of Clinical Cases 2024年第19期12卷 3936-3941页

作者： cheng Wei Yi-Chen Li Hong-tao Jin De-Feng Li Li-Sheng wang Jun Yao Department of Gastroenterology Shenzhen People’s HospitalThe Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and TechnologyShenzhen 518020Guangdong ProvinceChina Department of Emergency Shenzhen People’s HospitalThe Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and TechnologyShenzhen 518020Guangdong ProvinceChina Department of Pathology Shenzhen People’s HospitalThe Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and TechnologyShenzhen 518020Guangdong ProvinceChina

BACKGROUND Pancreatic cancer presents a challenge with its low early diagnosis and treatment rates,leading to high metastasis and mortality *** median survival time for advanced pancreatic cancer is a mere 3 ***,there's hope:small pancreatic cancers diagnosed at an early stage(T1)or those less than or equal to 1 cm in diameter boast an impressive 5-year survival rate of nearly 100%.This underscores the critical importance of early pancreatic cancer detection for significantly improving *** SUMMARY Pancreatic cancer,a malignant tumor of the digestive tract,poses challenges in both diagnosis and treatment due to its occult and atypical clinical ***,patients with recurrent pancreatitis should be vigilant,as it may be indicative of pancreatic cancer,particularly in middle-aged and elderly ***,we presented the case of a patient who experienced recurrent acute pancreatitis within a span of 2 *** the initial episode of pancreatitis,routine imaging failed to identify the cause of pancreatic ***,upon recurrence of acute pancreatitis,endoscopic ultrasonography(EUS)revealed a space-occupying lesion approximately 1 cm in size in the pancreatic *** EUS coupled with fine-needle aspiration examination demonstrated atypical pancreatic gland ***,the patient underwent surgery and was diagnosed with an intraductal papillary mucinous tumor of the pancreas(severe epithelial dysplasia,focal cancer).CONCLUSION We recommend EUS for patients with recurrent pancreatitis of unknown etiology to exclude early pancreatic cancer.

关键词： Pancreatic cancer Endosonographic ultrasonography Early diagnosis Case report

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