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Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

Acta Pharmaceutica Sinica B 2024年第3期14卷 1302-1316页

作者： Xinyuan Xu Qian Zhang Xufeng Wang Jing Jin Chengwei Wu Li Feng Xiuyan Yang Mingzhu Zhao Yingyi Chen Shaoyong Lu Zhen Zheng Xiaobing Lan Yi Wang Yan Zheng Xuefeng Lu Qiufen Zhang Jian Zhang State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Medicinal Chemistry and BioinformaticsCenter Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefei 230026China Department of Assisted Reproduction Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China College of Pharmacy Ningxia Medical UniversityYinchuan 750004China Department of pancreatic Surgery Shanghai General HospitalShanghai Key Laboratory of Pancreatic DiseaseInstitute of Pancreatic DiseaseShanghai Jiao Tong University School of MedicineShanghai 200080China

pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour ***6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic ***,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be ***,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/***,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/*** allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural ***,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver *** our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic *** not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

关键词： SIRT6 Inhibitor Allosteric Selectivity Cocrystal pancreatic cancer metastasis

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Lower-order transgressive-regressive cycles within a higher-order transgression at the basin margin: an aberrant intercalation of palaeosol and biostromal ichnofabrics from the early Miocene Kutch Basin, India

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Journal of Palaeogeography 2024年第4期13卷 906-923页

作者： Ayush Srivastava Sudipta Dasgupta Seema Singh Bombay Ichnos research group Department of Earth SciencesIndian Institute of Technology Bombay (IIT Bombay) Department of Geology Panjab University

The Chhasra Formation (CF) of Kutch Basin exemplifies a typical mixed siliciclastic-carbonate system with alternations of biostromal carbonate and fine-grained siliciclastic beds. The CF is subdivided into two members: the lower Claystone (CM) and the upper Siltstone(SM) member. Three CM outcrops (P1-P3) comprising buried palaeosols that formed under a specific environmental set-up involving imperfectly to poorly drained conditions, are exposed along the Berwali River. The biostromal carbonate beds, alternating with the palaeosols, contain invertebrate bioclasts(bivalves, gastropods, echinoids, etc.) and are characterized by a paucispecific firmground Thalassinoides ichnofabric. At section P1, below the contact between the underlying palaeosol and overlying carbonate, Thalassinoides transforms into firmground Gyrolithes inside the palaeosol forming a compound ichnotaxon. The palaeosol intervals of sections P1 and P2 consist of a Vondrichnus-Termitichnus-root trace ichnofabric defining the Termitichnus ichnofacies. At section P3, lenses of fully bioturbated siltstones with a monospecific firmground Thalassinoides ichnofabric can be observed within an overall silty palaeosol horizon, thereby, locally cross-cutting the pedogenic features. The ichnofabrics of section P3 indicate polyphase pedogenesis with three stages:(1) initial stage: pedogenesis in siltstone of undefined depositional affinity which was obscured by pedogenic processes,(2) transient stage: recurring marine incursions and colonization by crustaceans within the lens-shaped palaeotopographic depressions overprinting the palaeosol, and (3) final stage: subaerial exposure and another preserved phase of pedogenesis. The CM shows an apparent low-order T-R(transgressive-regressive) cyclicity within a 3rd-order TST (transgressive systems tract) that is supported by pedogenic intensity, ichnofabrics, and reciprocal sedimentation near the Miocene basin margin, though the cyclicity can be the result of both autoge

关键词： Palaeosol Biostrome Ichnofabrics Chhasra Formation Transgressive–regressive cycles TST Kutch (Kachchh) Basin

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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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Identifying the risk factors for pancreatic fistula after laparoscopic pancreaticoduodenectomy in patients with pancreatic cancer

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World Journal of Gastrointestinal Surgery 2024年第6期16卷 1609-1617页

作者： Hang Xu Qing-Cai Meng Jie Hua Wei Wang Department of pancreatic Surgery Fudan University Shanghai Cancer CenterShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China

BACKGROUND Laparoscopic pancreaticoduodenectomy(LPD)is a surgical procedure for treating pancreatic cancer;however,the risk of complications remains high owing to the wide range of organs involved during the surgery and the difficulty of *** fistula(PF)is a major complication that not only increases the risk of postoperative infection and abdominal hemorrhage but may also cause multi-organ failure,which is a serious threat to the patient’s *** study hypothesized the risk factors for PF after *** To identify the risk factors for PF after laparoscopic pancreatoduodenectomy in patients with pancreatic *** We retrospectively analyzed the data of 201 patients admitted to the Fudan University Shanghai Cancer Center between August 2022 and August 2023 who underwent LPD for pancreatic *** the basis of the PF’s incidence(grades B and C),patients were categorized into the PF(n=15)and non-PF groups(n=186).Differences in general data,preoperative laboratory indicators,and surgery-related factors between the two groups were compared and analyzed using multifactorial logistic regression and receiver-operating characteristic(ROC)curve *** The proportions of males,combined hypertension,soft pancreatic texture,and pancreatic duct diameter≤3 mm;surgery time;body mass index(BMI);and amylase(Am)level in the drainage fluid on the first postoperative day(Am>1069 U/L)were greater in the PF group than in the non-PF group(Pgroup was lower than that in the non-PF group(all P24.91 kg/m²[odds ratio(OR)=13.978,95%confidence interval(CI):1.886-103.581],hypertension(OR=8.484,95%CI:1.22-58.994),soft pancreatic texture(OR=42.015,95%CI:5.698-309.782),and operation time>414 min(OR=15.41,95%CI:1.63-145.674)were risk factors for the development of PF after LPD for pancreatic cancer(all P<0.05).The areas under the ROC curve for BMI,

关键词： pancreatic cancer Laparoscopy pancreaticoduodenectomy pancreatic fistula Risk factors Receiver-operating characteristic curve

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Potential role of hippocampal neurogenesis in spinal cord injury induced post-trauma depression

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Neural Regeneration research 2024年第10期19卷 2144-2156页

作者： Ying Ma Yue Qiao Xiang Gao Spinal Cord and Brain Injury research group Stark Neuroscience Research InstituteIndianapolisINUSA Department of Neurological Surgery Indiana University School of MedicineIndianapolisINUSA Department of Neurology Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The largescale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.

关键词： antidepressants chronic pain depression exercise hippocampal neurogenesis inflammation inhibition neuroinflammation physical activity deficits social isolation spinal cord injury

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Alarm Log Data Augmentation Algorithm Based on a GAN Model and Apriori

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Journal of Computer Science & Technology 2024年第4期39卷 951-966页

作者： Yang Yang Yu-Ting Li Yong-Hua Huo Zhi-Peng Gao Lan-Lan Rui State Key Laboratory of Network and Switching Technology Beijing University of Posts and TelecommunicationsBeijing 100876China The 54th research Institute of China Electronics Technology group Corporation Shijiazhuang 050081China

The complexity of alarm detection and diagnosis tasks often results in a lack of alarm log *** to the strong rule associations inherent in alarm log data,existing data augmentation algorithms cannot obtain good results for alarm log *** address this problem,this paper introduces a new algorithm for augmenting alarm log data,termed APRGAN,which combines a generative adversarial network(GAN)with the Apriori *** generates alarm log data under the guidance of rules mined by the rule ***,we propose a new dynamic updating mechanism to alleviate the mode collapse problem of the *** addition to updating the real reference dataset used to train the discriminator in the GAN,we dynamically update the parameters and the rule set of the Apriori algorithm according to the data generated in each *** extensive experimentation on two public datasets,it is demonstrated that APRGAN surpasses other data augmentation algorithms in the domain with respect to alarm log data augmentation,as evidenced by its superior performance on metrics such as BLEU,ROUGE,and METEOR.

关键词： data augmentation alarm log data Apriori generative adversarial network(GAN)

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GLOBAL BOUND ON THE GRADIENT OF SOLUTIONS TO p-LAPLACE TYPE EQUATIONS WITH MIXED DATA

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Acta Mathematica Scientia 2024年第4期44卷 1394-1414页

作者： Minh-Phuong TRAN The-Quang TRAN Thanh-Nhan NGUYEN Applied Analysis research group Faculty of Mathematics and StatisticsTon Duc Thang UniversityHo Chi Minh CityVietnam Nguyen Huu Huan High School Thu Duc CityVietnam group of Analysis and Applied Mathematics Department of MathematicsHo Chi Minh City University of EducationVietnam

In this paper,the study of gradient regularity for solutions of a class of elliptic problems of p-Laplace type is *** particular,we prove a global result concerning Lorentz-Morrey regularity of the non-homogeneous boundary data problem:-div((s^(2)+|▽u|^(2)p-2/2)▽u)=-div(|f|^(p-2)f)+g inΩ,u=h in■Ω,with the(sub-elliptic)degeneracy condition s∈[0,1]and with mixed data f∈L^(p)(Q;R^(n)),g∈Lp/(p-1)(Ω;R^(n))for p∈(1,n).This problem naturally arises in various applications such as dynamics of non-Newtonian fluid theory,electro-rheology,radiation of heat,plastic moulding and many *** on the idea of level-set inequality on fractional maximal distribution functions,it enables us to carry out a global regularity result of the solution via fractional maximal *** to the significance of M_(α)and its relation with Riesz potential,estimates via fractional maximal functions allow us to bound oscillations not only for solution but also its fractional derivatives of orderα.Our approach therefore has its own interest.

关键词： gradient estimates p-Laplace quasilinear elliptic equation fractional maximal operators Lorentz-Morrey spaces

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Fabrication,Microstructure and Mechanical Properties of in situ GNPs Reinforced Magnesium Matrix Composites

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Acta Metallurgica Sinica(English Letters) 2024年第3期37卷 561-569页

作者： Peitang Zhao Xuejian Li Hailong Shi Xiaoshi Hu Chunlei Zhang Chao Xu Xiaojun Wang The 38th research Institute of China Electronics Technology group Corporation Hefei 230088China National Key Laboratory of Precision Hot Processing of Metal Harbin Institute of TechnologyHarbin 150001China

Graphene reinforced magnesium matrix composites have wide applications in automotive,electronics,aerospace and military fields due to the fascinating mechanical ***,it is difficult to realize the high strength and ductility *** this work,the in situ liquid-state method was utilized to prepare GNPs/Mg6Zn composites via CO_(2)/Mg chemical *** strength of the GNPs/Mg6Zn composites was improved with increasing content of the ***,the composites also exhibit a notable plastic deformation stage,and especially the ductility of 0.12 GNPs/Mg6Zn composites reaches 27.6%.Therefore,this novel preparation method has great potential application for fabricating Mg matrix composites with high strength and high ductility.

关键词： Magnesium matrix composite In situ composite Microstructure Mechanical properties

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Pollen analysis reveals the effects of uncovered interactions,pollen-carrying structures,and pollinator sex on the structure of wild bee-plant networks

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Insect Science 2024年第3期31卷 971-988页

作者： Clément Tourbez Carmelo Gómez-Martínez MiguelÁngel Gonzalez-Estévez Amparo Lazaro Mediterranean Institute for Advanced Studies(UIB-CSIC) Global Change Research GroupEsporlesBalearic IslandsSpain Department of Biology Ecology AreaUniversity of the Balearic/slandsPalmaSpain

Pollination networks are increasingly used to model the complexity of interactions between pollinators and flowering plants in *** methods exist to sample these interactions,with direct observations of plant-pollinator contacts in the field being by far the most *** the identification of pollen carried by pollinators allows uncovering interactions and increasing sample sizes,the methods used to build pollen-transport networks are variable and their effect on network structure remains *** understand how interaction sampling influences the structure of networks,we analyzed the pollen found on wild bees from eight communities across Mallorca Island and investigated the differences in pollen loads between bee body parts(scopa ***)and *** then assessed how these differences,as well as the uncovered interactions not detected in the field,influenced the structure of wild bee-plant *** identified a higher quantity and diversity of pollen in the scopa than in the rest of the female body,but these differences did not lead to differences in structure between plant-pollination(excluding scopa pollen)and bee-feeding interaction(including scopa pollen)***,networks built with pollen data were richer in plant species and interactions and showed lower modularity and specialization(H2'),and higher nestedness than visitation networks based on field *** interactions with plants were stronger compared to those of males,although not ***,females were more generalist(low d')and tended to be more central in interaction networks,indicating their more key role structuring pollination networks in comparison to *** study highlights the importance of palynological data to increase the resolution of networks,as well as to understand important ecological questions such as the differences between plant-pollination and bee-feeding interaction networks,and the role of sexes in pollination.

关键词： palynology pollen-transport networks pollination role of bee sexes sampling methodology visitation networks

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

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

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

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

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

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