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A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

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Acta Pharmaceutica Sinica B 2024年第1期14卷 223-240页

作者： Lei Sun Arabella h.wan Shijia Yan Ruonian Liu Jiarui Li Zhuolong Zhou Ruirui Wu Dongshi Chen Xianzhang Bu Jingxing Ou Kai Li Xiongbin Lu Guohui wan Zunfu Ke Department of Pathology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation National Engineering Research Center for New Drug and Druggability(Cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA Department of Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Department of hepatic Surgery and Liver Transplantation Center Third Affiliated HospitalOrgan Transplantation InstituteSun Yat-sen UniversityOrgan Transplantation Research Center of Guangdong ProvinceGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhou 510630China Guangdong Provincial Key Laboratory of Liver Disease Research Guangzhou 510630China Department of Ultrasound Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Melvin and Bren Simon Comprehensive Cancer Center Indiana UniversityIndianapolisIN 46202USA

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug ***,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant *** and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing *** screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO ***,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX ***,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

关键词： Lenvatinib Drug resistance high-throughput screening Drug discovery Patient-derived model Romidepsin EGFR Liver cancer

Revealing the correlation between structure evolution and electrochemical performance of high-voltage lithium cobalt oxide

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Journal of Energy Chemistry 2021年第3期30卷 786-794页

作者： Jiajia wan Jianping Zhu Yuxuan Xiang Guiming Zhong Xiangsi Liu Yixiao Li kelvin h.L.Zhang Chaoyu hong Jianming Zheng Kai wang Yong Yang Collaborative Innovation Center of Chemistry for Energy Materials State Key Laboratory for Physical Chemistry of Solid SurfaceCollege of Chemistry and Chemical EngineeringXiamen UniversityXiamen 361005FujianChina Xiamen Institute of Rare Earth Materials Haixi InstitutesChinese Academy of SciencesXiamen 361021FujianChina Department of Chemical and Biochemical Engineering College of Chemistry and Chemical EngineeringXiamen UniversityXiamen 361005FujianChina Ningde Amperex Technology Ltd Ningde 352100FujianChina School of Energy Xiamen UniversityXiamen 361005FujianChina

Lithium cobalt oxide(LCO)is the dominating cathode materials for lithium-ion batteries(LIBs)deployed in consumer electronic devices for its superior volumetric energy density and electrochemical *** constantly increasing demands of higher energy density urge to develop high-voltage LCO via a variety of ***,the corresponding modification mechanism,especially the influence of the long-and short-range structural transitions at high-voltage on electrochemical performance,is still not well understood and needs further *** on ss-NMR,in-situ X-ray diffraction,and electrochemical performance results,it is revealed that the h3 to h1-3 phase transition dictates the structural reversibility and stability of LCO,thereby determining the electrochemical *** introduction of La and Al ions could postpone the appearance of h1-3 phase and induce various types of local environments to alleviate the volume variation at the atomic level,leading to better reversibility of the h1-3 phase and smaller lattice strain,and significantly improved cycle *** a comprehensive long-range,local,and electronic structure characterization enables an in-depth understanding of the structural evolution of LCO,providing a guiding principle for developing high-voltage LCO for high energy density LIBs.

关键词： Lithium cobalt oxide high-voltage In-situ XRD Solid-state NMR Structure change

MicroBTC:Efficient,Flexible and Fair Micropayment for Bitcoin Using hash Chains

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Journal of Computer Science & Technology 2019年第2期34卷 403-415页

作者： Zhi-Guo wan Robert h.Deng David Lee Ying Li School of Computer Science and Technology Shandong University Qingdao 266237 China School of Information Systems Singapore Management University Singapore 188065 Singapore School of Business Singapore University of Social Sciences Singapore 599494 Singapore Beijing Institute of Tracking and Telecommunications Technology Beijing 100094 China

While Bitcoin gains increasing popularity in different payment scenarios,the transaction fees make it difficult to be applied to *** the wide applicability of micropayment,it is crucial for all cryptocurrencies including Bitcoin to provide effective support *** light of this,a number of low-cost micropayment schemes for Bitcoin have been proposed recently to reduce micropayment *** schemes,however,suffer from drawbacks such as high computation cost,inflexible payment value,and possibly unfair *** paper proposes two new micropayment schemes,namely the basic MicroBTC and the advanced MicroBTC,for Bitcoin by integrating the hash chain technique into cryptocurrency *** basic MicroBTC realizes micropayment by exposing hash pre-images on the hash chain one by one,and it can also make arbitrary micropayments by exposing multiple hash *** further design the advanced MicroBTC to achieve non-interactive refund and efficient hash chain *** analyze the complexity and security of the both MicroBTC schemes and implement them using the Bitcoin source *** experiments were conducted to validate their performance,and the result showed that a micropayment session can be processed within about 18 ms for the basic MicroBTC and 9 ms for the advanced MicroBTC on a *** schemes enjoy great efficiency in computation and flexibility in micropayments,and they also achieve fairness for both the payer and the payee.

关键词： blockchain micropayment cryptocurrency hash chain Bitcion

Chloride content and ph value in the pore solution of concrete under carbonation

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Journal of Zhejiang University-Science A(Applied Physics & Engineering) 2013年第1期14卷 71-78页

作者： Xiao-mei wan Folker h. WITTMANN Tie-jun ZhAO hong FAN Aedificat Institute Freiburg Freiburg D-79100 Germany School of Civil Engineering Qingdao Technological University

Chloride content and the ph value of the pore solution in the neighborhood of steel reinforcement are decisive pa- rameters for initiation and rate of corrosion. The pore solution of cement mortar and hardened cement paste has been expressed from the pore space by high pressure in the investigation. The influence of the water-cement ratio, age, and addition of chloride to the fresh mix on chloride content in the pore solution has been determined by ion chromatography. At the same time the ph value of the pore solution has been determined. The dissolved chloride content decreases with increase in the water-cement ratio. The amount of bound chloride increases with time, but it decreases with decreasing content of dissolved chloride in the pore solution. A significant influence of carbonation on the dissolved chloride content of the pore solution has been observed. With complete carbonation, the dissolved chloride content in cement mortar and hardened cement paste increases by a factor between 2 and 12. The bound chloride decreases by 27%--54%. As expected, the ph value decreases from around 13.2 to as low as 8.0 due to car- bonation. It can be concluded that carbonation not only lowers the ph value but liberates bound chloride. This is one obvious reason why the combined action of chloride penetration and carbonation accelerates steel corrosion and shortens the service life of reinforced concrete structures.

关键词： Chloride Pore solution Carbonation ph value

Cellular senescence in musculoskeletal homeostasis,diseases,and regeneration

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Bone Research 2021年第4期9卷 444-455页

作者： Mei wan Elise F.Gray-Gaillard Jennifer h.Elisseeff Department of Orthopaedic Surgery The Johns Hopkins University School of MedicineBaltimoreMDUSA Translational Tissue Engineering Center Wilmer Eye Institute and the Department of Biomedical EngineeringThe Johns Hopkins UniversityBaltimoreMDUSA

Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders,which represent the leading global cause of *** senescence was initially described by hayflick et *** 1961 as an irreversible nondividing state in in vitro cell culture *** now know that cellular senescence can occur in vivo in response to various stressors as a heterogeneous and tissue-specific cell state with a secretome phenotype acquired after the initial growth *** the past two decades,compelling evidence from preclinical models and human data show an accumulation of senescent cells in many components of the musculoskeletal *** senescence is therefore a defining feature of age-related musculoskeletal disorders,and targeted elimination of these cells has emerged recently as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration of the skeleton and skeletal *** this review,we summarize evidence of the role of senescent cells in the maintenance of bone homeostasis during childhood and their contribution to the pathogenesis of chronic musculoskeletal disorders,including osteoporosis,osteoarthritis,and *** highlight the diversity of the senescent cells in the microenvironment of bone,joint,and skeletal muscle tissue,as well as the mechanisms by which these senescent cells are involved in musculoskeletal *** addition,we discuss how identifying and targeting senescent cells might positively affect pathologic progression and musculoskeletal system regeneration.

关键词： skeletal homeostasis dividing

Classification of iatrogenic bile duct injury

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hepatobiliary & Pancreatic Diseases International 2007年第5期6卷 459-463页

作者： wan-Yee Lau Eric C.h.Lai Department of Surgery the Chinese University of Hong KongShatinNew TerritoriesHong Kong SARChina

BACKGROUND: Iatrogenic bile duct injury continues to be an important clinical problem, resulting in serious morbidity, and occasional mortality, to patients. The ease of management, operative risk, and outcome of bile duct injuries vary considerably, and are highly dependent on the type of injury and its location. This article reviews the various classification systems of bile duct injury. DATA SOURCES: A Medline, PubMed database search was performed to identify relevant articles using the keywords 'bile duct injury', 'cholecystectomy', and 'classification'. Additional papers were identified by a manual search of the references from the key articles. RESULTS: Traditionally, biliary injuries have been classified using the Bismuth's classification. This classification, which originated from the era of open surgery, is intended to help the surgeons to choose the appropriate technique for the repair, and it has a good correlation with the final outcome after surgical repair. however, the Bismuth's classification does not encompass the whole spectrum of injuries that are possible. Bile duct injury during laparoscopic cholecystectomy tends to be more severe than those with open cholecystectomy. Strasberg's classification made Bismuth's classification much more comprehensive by including various other types of extrahepatic bile duct injuries. Our group, Bergman et al, Neuhaus et al, Csendes et al, and Stewart et al have also proposed other classification systems to complement the Bismuth's classification. CONCLUSIONS: None of the classification system is universally accepted as each has its own limitation. hopefully, a universally accepted comprehensive classification system will be published in the near future.

关键词： laparoscopic cholecystectomy bile duct injury bile duct stricture bile leak classification

Development and controversies of adjuvant therapy for pancreatic cancer

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hepatobiliary & Pancreatic Diseases International 2008年第2期7卷 121-125页

作者： wan-Yee Lau Eric C.h.Lai Faculty of Medicine the Chinese University of Hong Kong Prince of Wales Hospital Shatin New TerritoriesHong Kong SAR China

BACKGROUND: Pancreatic cancer is an aggressive malignancy with a dismal prognosis. Radical surgery provides the only chance for a cure with a 5-year survival rate of 7%-25%. An effective adjuvant therapy is urgently needed to improve the surgical outcome. This review describes the current status of adjuvant therapy for pancreatic cancer, and highlights its controversies. DATA SOURCES: A Medline database search was performed to identify relevant articles using the keywords 'pancreatic neoplasm', and 'adjuvant therapy'. Additional papers were identified by a manual search of the references from the key articles. RESULTS: Eight prospective randomized controlled trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation for pancreatic cancer could be identified. The results for adjuvant regimens based on systemic 5-fluorouracil with or without external radiotherapy were conflicting. The recent two RCTs on gemcitabine based regimen gave promising results. CONCLUSIONS: Based on the available data, no standard adjuvant therapy for pancreatic cancer can be established yet. The best adjuvant regimen remains to be determined in large-scale RCTs. Future trials should use a gemcitabine based regimen.

关键词： pancreatic neoplasm pancreatectomy adjuvant therapy radiotherapy chemotherapy

hepatocellular carcinoma: current management and recent advances

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hepatobiliary & Pancreatic Diseases International 2008年第3期7卷 237-257页

作者： wan-Yee Lau Eric C. h. Lai Faculty of Medicine The Chinese University of Hong Kong Prince of Wales Hospital Shatin New Territories Hong Kong SAR China

BACKGROUND: hepatocellular carcinoma (hCC) is a major health problem worldwide. It is the fifth most common cancer in the world, and the third most common cause of cancer-related death. Without specific treatment, the prognosis is very poor. The goal of management is 'cancer control'-a reduction in its incidence and mortality as well as an improvement in the quality of life of patients with hCC and their families. This article aims to review the current management of hCC and its recent advances. DATA SOURCES: A MEDLINE database search was performed to identify relevant article using the keywords 'hepatocellular carcinoma', 'hepatectomy', 'liver transplantation', and 'local ablative therapy'. Additional papers and book chapters were identified by a manual search of the references from the key articles. RESULTS: Liver resection and liver transplantation remain the options that give the best chance of a cure. Recent evidence suggests that local ablative therapy may offer comparable survival results in patients with small hCC, and preserved liver function. Transarterial chemoembolization (TACE) is the most promising palliative modality for unresectable hCC, but other techniques, such as transarterial radioembolization (TARE), and local ablative therapy, have also shown comparable results. CONCLUSIONS: Early diagnosis of hCC remains a key goal in improving the prognosis of patients. During the last two decades, operative mortality and surgical outcome of liver resection and liver transplantation for hCC have improved. Progress also has been made in multi-modality therapy which can increase the chance of survival and improve the quality of life for patients with advanced hCC.

关键词： hepatocellular carcinoma hepatectomy liver transplantation local ablative therapy

Enemy release at range edges:do invasive species escape their herbivores as they expand into new areas?

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Journal of Plant Ecology 2016年第5期9卷 636-647页

作者： Justin S.h.wan Stephen P.Bonser Evolution and Ecology Research Centre School of BiologicalEarth and Environmental SciencesUNSW AustraliaSydneyNew South Wales 2052Australia

Aims We test the hypothesis that invasive plant species at their range edges experience lower herbivory and allocate less to defense at the edge of an expanding range edge than from more central parts of their distribution,during secondary invasion in a new *** plants are often able to spread rapidly through new *** success of invasive species in new ranges is frequently attributed to enemy release in these new areas and associated evolutionary changes minimizing allocation to defense in favor of growth and *** release could also explain rapid advances of invasive species upon arriving in new *** invasive species accumulate enemies over time in a new location,then these species may experience a release from their enemies at expanding range *** release at these range fronts may accelerate range *** We used populations of four woody invasive species within the invaded range,and four native control *** quantified leaf herbivory and leaf physical defense traits at both range central and range edge locations,over two 1-month sampling periods,sampled 7 months *** Findings herbivory at the range edge did not differ to the range center but patterns were not consistent across *** was a trend for lower herbivory at the range edge for Lantana camara,which was reflected in lower leaf ***,leaf toughness was greater at the range edge location across invasive and control *** defenses were different among range locations in a few species,though most species show the same trend,suggesting higher herbivory pressures at the range edge location or differences may be due to climatic *** of *** were significantly less tough at range edges,suggesting that some species can potentially escape their enemies at range ***,our results overall do not support the hypothesis that plants at the edge of their ranges experience reduced impact from their enem

关键词： Australian woodlands enemy release hypothesis herbivory invasion dynamics physical defense range edge