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Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes

Acta Pharmaceutica Sinica B 2024年第4期14卷 1693-1710页

作者： Xiong Chen Jinfu Qian Shiqi Liang Jianchang Qian Wu Luo Yujuan Shi Hong Zhu Xiang Hu Gaojun Wu Xiaokun Li Guang Liang Department of Endocrinology the First Affiliated HospitalWenzhou Medical UniversityWenzhou 325035China Chemical Biology Research Center School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou 325035China Department of Wound Repair the First Affiliated HospitalWenzhou Medical UniversityWenzhou 325035China Department of Cardiology the First Affiliated HospitalWenzhou Medical UniversityWenzhou 325035China School of Pharmaceutical Sciences Hangzhou Medical CollegeHangzhou 311399China

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

关键词： Diabetic cardiomyopathy Protein tyrosine kinases FGFR1 Cardiomyocytes Inflammatory responses Toll-like receptor4 c-Src NFkB

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Efficacy of radiofrequency ablation combined with sorafenib for treating liver cancer complicated with portal hypertension and prognostic factors

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World Journal of Gastroenterology 2024年第11期30卷 1533-1544页

作者： Li-Min Yang Hong-Juan Wang Shan-Lin Li Guan-Hua Gan Wen-Wen Deng Yong-Sheng Chang Lian-Feng Zhang Department of Gastroenterology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina Department of Gastroenterology Zhoukou Central Hospital of Henan ProvinceZhoukou 466000Henan ProvinceChina Department of Gastroenterology The First Affiliated Hospital of Xinxiang Medical CollegeXinxiang 453000Henan ProvinceChina

BACKGROUND Patients with liver cancer complicated by portal hypertension present complex challenges in *** To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this *** Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group(n=50)and a control group(n=50)according to the treatment *** research group received radiofrequency ablation(RFA)in combination with sorafenib,and the control group only received *** short-term efficacy of both the research and control groups was *** function and portal hypertension were compared before and after ***-fetoprotein(AFP),glypican-3(GPC-3),and AFP-L3 levels were compared between the two groups prior to and after *** occurrence of adverse reactions in both groups was *** 3-year survival rate was compared between the two *** data were compared between the survival and non-surviving *** identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension,multivariate logistic regression analysis was *** When comparing the two groups,the research group's total effective rate(82.00%)was significantly greater than that of the control group(56.00%;P<0.05).Following treatment,alanine aminotransferase and aspartate aminotransferase levels increased,and portal vein pressure decreased in both *** degree of improvement for every index was substantially greater in the research group than in the control group(P<0.05).Following treatment,the AFP,GPC-3,and AFP-L3 levels in both groups decreased,with the research group having significantly lower levels than the control group(P<0.05).The incidence of diarrhea,rash,nausea and vomiting,and fatigue in the research group was significantly great

关键词： Radiofrequency ablation Sorafenib Liver cancer Portal hypertension Efficacy Prognosis analysis

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Pancreatic panniculitis as the first presentation of pancreatic ductaladenocarcinoma

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Hepatobiliary & Pancreatic Diseases International 2024年第1期23卷 106-108页

作者： Wei-Fang Zhu Shan Fang Jian-Jun Qiao Department of Dermatology the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

To the Editor:Pancreatic panniculitis,also known as pancreatic fat necrosis or enzymatic panniculitis,is a rare type of panniculitis that occurs in 0.3%−3%of patients with pancreatic disease such as acute or chronic pancreatitis and pancreatic carcinoma,especially acinar cell carcinoma[1,2].The clinical manifestations are nonspecific erythema tender nodules.

关键词： Pancreatic acute adenocarcinoma

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An artificial intelligence diabetes management architecture based on 5G

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Digital Communications and Networks 2024年第1期10卷 75-82页

作者： Ruochen Huang Wei Feng Shan Lu Tao shan Changwei Zhang Yun Liu Department of Geriatrics The First Affiliated Hospital of Nanjing Medical UniversityNanjing210096China Department of Information The First Afliated Hospital of Nanjing Medical UniversityNanjing210096China Department of Medical Informatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166China Department of Outpatient The First Affiliated Hospital of Nanjing Medical UniversityNanjing210096China Jiangsu Key Laboratory of Wireless Communications Nanjing University of Posts and TelecommunicationsNanjing210003China

Along with the development of 5G network and Internet of Things technologies,there has been an explosion in personalized healthcare *** the 5G and Artificial Intelligence(Al)is introduced into diabetes management architecture,it can increase the efficiency of existing systems and complications of diabetes can be handled more effectively by taking advantage of *** this article,we propose a 5G-based Artificial Intelligence Diabetes Management architecture(AIDM),which can help physicians and patients to manage both acute complications and chronic *** AIDM contains five layers:the sensing layer,the transmission layer,the storage layer,the computing layer,and the application *** build a test bed for the transmission and application ***,we apply a delay-aware RA optimization based on a double-queue model to improve access efficiency in smart hospital wards in the transmission *** application layer,we build a prediction model using a deep forest *** on real-world data show that our AIDM can enhance the efficiency of diabetes management and improve the screening rate of diabetes as well.

关键词： Diabetes 5G Artificial intelligence Deep forest Smart hospital ward

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MPZL1 as an HGF/MET signaling amplifier promotes cell migration and invasion in glioblastoma

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Genes & Diseases 2024年第5期11卷 70-73页

作者： Haimin Song Bowen Ni Xuetao Peng Weijuan Xu Shaochun Yang Runwei Yang Ziyu Wang Kaishu Li Rui Lin Yunxiao Zhang Jinglin Guo Kezhi Wu Guangwei Shi Jichao Sun Chunming He Yawei Liu Department of Neurosurgery The First Affiliated Hospital of Gannan Medical UniversityGanzhouJiangxi 341000China Department of Neurosurgery&Medical Research Center Shunde HospitalSouthern Medical University(The First People’s Hospital of Shunde Foshan)FoshanGuangdong 528300China Medical Research Center Shunde HospitalSouthern Medical University(The First People’s Hospital of Shunde Foshan)FoshanGuangdong 528300China Bidding and Procurement Office Shunde HospitalSouthern Medical University(The First People’s Hospital of Shunde Foshan)FoshanGuangdong 528300China Department of Neurosurgery Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong 510515China Department of Neurosurgery The Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuanGuangdong 511518China Department of Neurosurgery The First Affiliated Hospital of Shantou University Medical CollegeShantouGuangdong 515041China Department of Geriatrics Shenzhen People’s Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdong 518020China

The extremely poor prognosis of patients is largely due to hepatocyte growth factor(HGF)/MET signaling,which promotes migration and invasion of glioblastoma(IDH wildtype;GBM;WHO grade 4).1,2 Clinical trials targeting MET,the only receptor of HGF,have yielded unimpressive results in GBM.3,4 Here we found that HGF induced strong chemotaxis on GBM cells,but MET expression was extremely ***,therefore,used single-cell RNA sequencing(scRNA-seq)coupled with label-free proteome profiling to identify membrane proteins associated with HGF/MET signaling amplification in GBM and to provide a novel modulator,MPZL1,for HGF/MET-targeted therapy.

关键词： invasion prognosis Clinical

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A deep learning model based on contrast-enhanced computed tomography for differential diagnosis of gallbladder carcinoma

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 376-384页

作者： Fei Xiang Qing-Tao Meng Jing-Jing Deng Jie Wang Xiao-Yuan Liang Xing-Yu Liu Sheng Yan Department of Hepatobiliary Pancreatic Surgery Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Radiology Affiliated Chuzhou First People’s HospitalAnhui Medical UniversityChuzhou 239000China

Background:Gallbladder carcinoma(GBC)is highly malignant,and its early diagnosis remains *** study aimed to develop a deep learning model based on contrast-enhanced computed tomography(CT)images to assist radiologists in identifying ***:We retrospectively enrolled 278 patients with gallbladder lesions(>10 mm)who underwent contrast-enhanced CT and cholecystectomy and divided them into the training(n=194)and validation(n=84)*** deep learning model was developed based on ResNet50 *** and clinical models were built based on support vector machine(SVM)*** comprehensively compared the performance of deep learning,radiomics,clinical models,and three ***:Three radiomics features including LoG_3.0 gray-level size zone matrix zone variance,HHL firstorder kurtosis,and LHL gray-level co-occurrence matrix dependence variance were significantly different between benign gallbladder lesions and GBC,and were selected for developing radiomics *** regression analysis revealed that age≥65 years[odds ratios(OR)=4.4,95%confidence interval(CI):2.1-9.1,P37 U/mL(OR=4.0,95%CI:1.6-10.0,P=0.003)were significant clinical risk factors of *** deep learning model achieved the area under the receiver operating characteristic curve(AUC)values of 0.864(95%CI:0.814-0.915)and 0.857(95%CI:0.773-0.942)in the training and validation datasets,which were comparable with radiomics,clinical models and three *** sensitivity of deep learning model was the highest both in the training[90%(95%CI:82%-96%)]and validation[85%(95%CI:68%-95%)]***:The deep learning model may be a useful tool for radiologists to distinguish between GBC and benign gallbladder lesions.

关键词： Gallbladder carcinoma Computed tomography Deep learning Radiomics

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Promotion and Mechanism of Acupotomy on Chondrocyte Autophagy in Knee Osteoarthritis Rabbits

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Chinese Journal of Integrative Medicine 2024年第9期30卷 809-817页

作者： LU Man MENG De-hong SHE Ze-yu WU Xian XIA Shuai YANG Kai-ning LIU Cun-bin LI Tao YANG Yong-hui The first affiliated hospital of Anhui University of Chinese Medicine Hefei230031China The Second affiliated hospital of Anhui University of Chinese Medicine Hefei230038China Department of Acupotomy Rehabilitation Anhui Provincial Hospital of Integrated Traditional Chinese and Western MedicineHefei230031China

Objective:To explore the effect of acupotomy intervention on autophagy of chondrocytes in rabbits with knee osteoarthritis(KOA),and to determine the possible mechanisms of acupotomy to alleviate cartilage ***:The modified Videman method was used to construct a KOA rabbit *** modeling,40 rabbits were randomly divided into 4 groups by a random number table:control;KOA(model);KOA+acupotomy(acupotomy),and KOA+sham acupotomy(sham),10 in each *** a 3-week treatment course,the knee joint activity was determined by the modified Lequesne MG ***-eosin staining staining was used to examine the morphological changes of *** of chondrocytes was observed by transmission electron *** surface morphology of cartilage tissue was observed by scanning electron *** mRNA and protein levels of AMP kinase/mammalian target of rapamycin/Unc-51(AMPK/mTOR/ULK1)signal pathway key proteins,autophagy-related factor Beclin-1 and microtubule-associated protein 1A/1B light chain 3(LC3)in rabbit knee cartilage were assessed by real-time fluorescence quantitative polymerase chain reaction and Western blot,***:The modified Lequesne MG score of acupotomy group was significantly lower than that of model group(P<0.05).Pathological results showed that chondrocyte autophagy decreased and cartilage surface was rough in the model group,which recovered after acupotomy *** mRNA expressions of AMPK,ULK1,Beclin-1 and the protein levels of p-AMPK,p-ULK1,Beclin-1,and LC3Ⅱ/LC3Ⅰwere decreased in the model group,while the mRNA and protein expressions of mTOR were increased(P<0.01).However,acupotomy treatment reversed these abnormal changes(P<0.05).Conclusions:Acupotomy could effectively up-regulate the expressions of AMPK,ULK1 and Beclin1,reduce the expression of mTOR,promote autophagy,and alleviate joint *** is a promising complementary and alternative therapy for KOA.

关键词： acupotomy knee asteoarthritis autophagy AMPK/mTOR/ULK1 signaling pathway rabbit

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T-tube bridging fistula jejunal anastomosis for treatment of pancreatic lumbar dorsal fistula after necrotizing pancreatitis

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 428-430页

作者： Su-Lai Liu Guo-Guang Li Wei Cheng Chuang Peng Ying-Hui Song Department of Hepatobiliary Surgery Hunan Provincial People’s Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangsha 410000China

Infectious pancreatic necrosis causes external pancreatic fistula in some ***,external pancreatic fistula requires fistula-gastric and/or intestinal anastomosis,and digestive endoscopic interventional treatment[1–3].It is especially difficult to treat external pancreatic fistulas with small fistulas where the external fistula is located in the lower *** common treatment is to remove the body and tail of the pancreas and the *** operation is very traumatic.A new pancreatic fistula may still occur at the pancreatic *** above operations may lead to unnecessary resection of the spleen,colon injury and other *** order to solve this problem,we innovatively used T-tube bridging fistula jejunal anastomosis plus continuous negative pressure suction to treat three cases of external pancreatic fistulas in the lower back,and all of them achieved good results.

关键词： fistula anastomosis spleen

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Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia

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Genes & Diseases 2024年第5期11卷 140-162页

作者： Xudong Li Wei Li Yanli Zhang Linping Xu Yongping Song Department of Hematology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhouHenan 450008China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China Department of Hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China

The advent of tyrosine kinase inhibitors(TKI)targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia(CML),greatly prolonged the life of CML patients,and improved their ***,TKI resistance is still a major problem with CML patients,reducing the efficacy of treatment and their quality of *** resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent ***,the main clinical strategy addressing TKI resistance is to switch to newly developed ***,data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance ***,finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system(UPS)has emerged as a *** UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological *** recent years,the study of UPS in hematological malignant tumors has resulted in effective treatments,such as bortezomib in the treatment of multiple myeloma and mantle cell *** CML,the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL,interfering with CML-related signaling pathways,and negatively or positively affecting leukemia stem *** of these molecules may help overcome TKI resistance and treat *** this review,the mechanism of TKI resistance is briefly described,the components of UPS are introduced,existing studies on UPS participating in TKI resistance are listed,and UPS as the therapeutic target and strategies are discussed.

关键词： Chronic myeloid leukemia Deubiquitinases E3 ligase PROTAC TKI resistance Ubiquitin-proteasome system

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The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

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Neural Regeneration Research 2024年第4期19卷 800-806页

作者： Xinxin Wang Yushu Hu Renshi Xu Medical College of Nanchang University Department of Neurology Jiangxi Provincial People's HospitalThe First Affiliated Hospital of Nanchang Medical CollegeThe Clinical College of Nanchang Medical College

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory ***,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the *** disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized *** TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral *** review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

关键词： amyotrophic lateral sclerosis axonal transport liquid-liquid phase separation noncellular autonomous functions oxidative stress pathogenesis post-translational modification protein quality control system stress granules TAR DNA-binding protein 43(TDP-43)

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