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第11届世界华人药物化学研讨会（ISCMC 2018）

作者： Huiju Tseng Liangchieh Chen Changyi Liu Yunyi Huang Chengchung Yen Jingru Weng Yehlin Lu Wenchi Hou Tony Eight Lin Ihorng Pan Kuokuei Huang Weijan Huang Kaicheng Hsu Program in Biotechnology Research and Development College of PharmacyTaipei Medical University Graduate Institute of Pharmacognosy College of PharmacyTaipei Medical University School of Pharmacy College of PharmacyTaipei Medical University Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and TechnologyTaipei Medical University Department of Marine Technology and Resources College of Marine SciencesSun Yat-sen University Herbal Medicinal Product Div. Industrial Technology Research Institute Ph.D.Program for the Clinical Drug Discovery from Botanical Herbs College of PharmacyTaipei Medical University School of Pharmacy “Defense Medical Center”

Alzheimer's disease(Ad) is a progressive neurodegenerative disorder with multiple ***-amyloid(AB) self-aggregation and overexpression of class IIa histone deacetylases(HdACs) are strongly implicated with Ad *** this study,a series of novel diarylheptanoid derivatives were designed,synthesized and evaluated for use as dual Aβ self-aggregation and class IIa HdAC *** these compounds,4 j,5 c and Se displayed effective inhibitions for AB self-aggregation,HdACS activity and HdAC7 activity with IC50 values of < 10 μ*** compounds contain three common features:(1) a catechol or pyrogallol moiety,(2) a carbonyl linker and(3) an aromatic ring that can function as an HdAC cap and create hydrophobic interactions with Aβ***,compounds 4 j,5 c and 5 e showed no significant cytotoxicity to human neuroblastoma SH-SY5 Y cells and also exhibited neuroprotective effect against H2O2-induced ***,these promising in vitro data highlighted compounds 4 j,5 c and 5 e as lead compounds that are worthy for further investigation.

关键词： Alzheimer's disease Aβ aggregation Histone deacetylase Isoform-selective inhibitors dual inhibitors

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198 The effect of magnolol on the TNF-α/IL-23/Th-17 axis of the imiquimod induced psoriasis-like dermatitis mice

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Journal of Investigative dermatology 2020年第7期140卷 S23-S23页

作者： J. Guo Y. Cheng Y. Ro Z. Wu S. Jee Medical Research Institute Cathay General Hospital New Taipei City Taiwan Fu Jen Catholic University Ph.D. Program in Pharmaceutical Biotechnology New Taipei City Taiwan Department of Dermatology Cathay General Hospital Taipei Taiwan

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Structural insights into the role of N-terminal integrity in phoSL for core-fucosylated N-glycan recognition

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International Journal of Biological Macromolecules 2024年 255卷 128309页

作者： Lou, Yuan-Chao Tu, Cheng-Fen Chou, Chun-Chi Yeh, Hsin-Hong Chien, Chia-Yu Sadotra, Sushant Chen, Chinpan Yang, Ruey-Bing Hsu, Chun-Hua Institute of Biomedical Sciences Academia Sinica Taipei115 Taiwan Department of Agricultural Chemistry National Taiwan University Taipei106 Taiwan Chemical Biology and Molecular Biophysics Taiwan International Graduate Program Academia Sinica Taipei115 Taiwan Institute of Bioinformatics and Structural Biology National Tsing Hua University Hsinchu300 Taiwan Biomedical Translation Research Center Academia Sinica Taipei115 Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei110 Taiwan Genome and Systems Biology Degree Program National Taiwan University and Academia Sinica Taipei106 Taiwan Institute of Biochemical Sciences National Taiwan University Taipei106 Taiwan Center for Computational and Systems Biology National Taiwan University Taipei106 Taiwan

phoSL (pholiota squarrosa Lectin) has an exceptional binding affinity for biomolecules with core-fucosylated N-glycans. This modification involves the addition of fucose to the inner N-acetylglucosamine within the N-glycan structure and is known to influence many physiological processes. Nevertheless, the molecular interactions underlying high-affinity binding of native phoSL to core-fucosylated N-glycans remain largely unknown. In this study, we devised a strategy to produce phoSL with the essential structural characteristics of the native protein (n-phoSL). To do so, a fusion protein was expressed in E. coli and purified. Then, enzymatic cleavage and incubation with glutathione were utilized to recapitulate the native primary structure and disulfide bonding pattern. Subsequently, we identified the residues crucial for n-phoSL binding to core-fucosylated chitobiose (N2F) via NMR spectroscopy. Additionally, crystal structures were solved for both apo n-phoSL and its N2F complex. These analyses suggested a pivotal role of the N-terminal amine in maintaining the integrity of the binding pocket and actively contributing to core-fucose recognition. In support of this idea, the inclusion of additional residues at the N-terminus considerably reduced binding affinity and phoSL cytotoxicity toward breast cancer cells. Taken together, these findings can facilitate the utilization of phoSL in basic research, diagnostics and therapeutic strategies. © 2023 Elsevier B.V.

关键词： Proteins

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VIRTUAL PROTOTYPING USING KNOWLEdGE - BASEd MOdELING ANd SIMULATION TECHNIQUES

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NAVAL ENGINEERS JOURNAL 1993年第3期105卷 201-212页

作者： SHEA, JG The Author:holds bachelor and master of engineering degrees in mechanical engineering a M.Eng. in engineering management and is currently fulfilling requirements for the M.S. and Ph.D. degrees in computer science at the University of Louisville. He is employed as program manager Phalanx Advanced Engineering Development at the Naval Ordnance Station Crane Div. NavSurfWarCen Louisville Ky. During his tenure with Phalanx Mr. Shea has contributed to system reliability improvement system performance upgrading and the development of the Phalanx HOL (RISC) Computer. Mr. Shea is a member of ASNE the Institute of Electrical and Electronics Engineers American Institute of Aeronautics and Astronautics Society for Computer Simulation International Test & Evaluation Association and the Military Operations Research Society.

Knowledge-based modeling and simulation bridges the gap between ''conventional'' artificial intelligence implementations (such as expert systems) and more traditional computer-aided design techniques. We are currently developing software, whose primary function is to capture a user-input design specification and produce a ''virtual'' rapid prototvpe in the form of executable rule-based code. This code can then be exercised either as an interactive part of a hardware-in-the-loop testbed simulator or as a component of an object-oriented ''behavioral'' simulation environment. While the phalanx Testbed is the immediate beneficiary of this work, the techniques described have a wide range of application in the modeling of conceptual design and performance characteristics. This paper describes the system architecture and software tools that we are applying to generate virtual rapid prototypes for use in the phalanx Testbed. Particular attention is paid to defining the intelligent knowledge-capture mechanisms and model generation methodologies that we are using to translate design knowledge and performance requirements into rule-based simulations. The object-oriented programming approach to the merging of ''new'' data with previouslv-captured and stored data is discussed, and the issues of verifying and validating prototypes generated using such partiallv ''reengineered'' models are examined. An application currently in use as an investigative prototype for testbed development, a simple position controller servomechanism used to control the azimuth angle of a target-tracking sensor, is used to illustrate the process.

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Oral anticoagulants and cognitive impairment in patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis

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Thrombosis research 2024年 238卷 132-140页

作者： Lee, Kun-Han Yeh, Jiunn-Tyng Wu, Meng-Lun Yeh, Wan-Yu Lip, Gregory Y.H. Chiang, Chern-En Chen, Chen-Huan Cheng, Hao-Min Department of Orthopaedics and Traumatology Taipei Veterans General Hospital Taipei Taiwan Center for Evidence-based Medicine Taipei Veterans General Hospital Taipei Taiwan Center for Artificial Intelligence in Medicine Chang Gung Memorial Hospital Taoyuan Taiwan Department of Medical Education Taipei Veterans General Hospital Taipei Taiwan Liverpool Centre for Cardiovascular Science University of Liverpool Liverpool John Moores University and Liverpool Heart & Chest Hospital Liverpool United Kingdom Department of Clinical Medicine Aalborg University Aalborg Denmark Department of Internal Medicine Taipei Veterans General Hospital Taipei Taiwan General Clinical Research Center Taipei Veterans General Hospital Taipei Taiwan College of Medicine National Yang Ming Chiao Tung University School of Medicine Taipei Taiwan ReShining Clinic Taipei Taiwan Ph.D. Program of Interdisciplinary Medicine (PIM) National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan Division of Faculty Development Taipei Veterans General Hospital Taipei Taiwan Institute of Public Health and Community Medicine Research Center National Yang Ming Chiao Tung University School of Medicine Taipei Taiwan

Background: This systematic review assesses the likelihood of developing dementia and cognitive impairment in patients with atrial fibrillation (AF) receiving non-vitamin K antagonist oral anticoagulants (NOACs) as opposed to vitamin K antagonists (VKAs). Methods: We performed a systematic review with meta-analysis and trial sequential analysis (TSA), which encompassed both randomized controlled trials (RCTs) and observational studies. The objective was to assess the impact of NOACs and VKAs on the incidence of dementia in individuals diagnosed with AF. Results: Out of 1914 studies that were screened, 31 studies were included in the final analysis, which consisted of nine RCTs or their subsequent post-hoc analyses, in addition to 22 observational studies. The meta-analysis shows that NOACs were associated with a decreased probability of developing dementia of any cause [Rate Ratio (RR): 0.88;95 % confidence interval (95 % CI): 0.82–0.94], especially in patients below the age of 75 (RR: 0.78;95 % CI: 0.73–0.84). Consistent patterns were observed across all forms of dementia and cognitive function decline. The overall evidence indicates notable variability in the outcome with a moderate-to-low degree of certainty. The TSA suggests that the total sample size of the included trials (155,647 patients) was significantly smaller than the required information size of 784,692 patients to discern the true effect of NOAC versus VKA in terms of reducing dementia risk. Conclusion: NOACs may reduce the likelihood of developing dementia in patients with AF, particularly in those under the age of 75. This review highlights the urgent necessity for thorough research to determine the efficacy of NOACs in safeguarding cognitive health. © 2024 Elsevier Ltd

关键词： Anticoagulants Atrial fibrillation Cognitive impairment dementia Non-vitamin K antagonist oral anticoagulants

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Potential PCR amplification bias in identifying complex ecological patterns: Higher species compositional homogeneity revealed in smaller-size coral reef zooplankton by metatranscriptomics

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Molecular Ecology Resources 2024年第3期24卷 e13911-e13911页

作者： Mattos, Felipe M. G. dreyer, Niklas Fong, Chia-Ling Wen, Yung-Hui Victoria Jain, dharmesh de Vivo, Mattia Huang, Yu-Sin Mwihaki, John Karichu Wang, Tzi-Yuan Ho, Ming-Jay Tsai, Isheng Jason Wang, John Chan, Benny K. K. Machida, Ryuji J. Biodiversity Research Center Academia Sinica Taipei Taiwan Department of Life Science National Taiwan Normal University Taipei Taiwan Biodiversity Program Taiwan International Graduate Program Academia Sinica and National Taiwan Normal University Taipei Taiwan Natural History Museum of Denmark Invertebrate Zoology University of Copenhagen Copenhagen Denmark Institute of Plant and Microbial Biology Academia Sinica Taipei Taiwan Ph.D. Program in Microbial Genomics National Chung Hsing University and Academia Sinica Taipei Taiwan Graduate Institute of Biotechnology National Chung Hsing University Taichung Taiwan Molecular and Biological Agricultural Sciences Taiwan International Graduate Program Academia Sinica and National Chung Hsing University Taipei Taiwan

PCR-based high-throughput sequencing has permitted comprehensive resolution analyses of zooplankton diversity dynamics. However, significant methodological issues still surround analyses of complex bulk community samples, not least as in prevailing PCR-based approaches. Marine drifting animals—zooplankton—play essential ecological roles in the pelagic ecosystem, transferring energy and elements to higher trophic levels, such as fishes, cetaceans and others. In the present study, we collected 48 size-fractionated zooplankton samples in the vicinity of a coral reef island with environmental gradients. To investigate the spatiotemporal dynamics of zooplankton diversity patterns and the effect of PCR amplification biases across these complex communities, we first took metatranscriptomics approach. Comprehensive computational analyses revealed a clear pattern of higher/lower homogeneity in smaller/larger zooplankton compositions across samples respectively. Our study thus suggests changes in the role of dispersal across the sizes. Next, we applied in silico PCR to the metatranscriptomics datasets, in order to estimate the extent of PCR amplification bias. Irrespective of stringency criteria, we observed clear separations of size fraction sample clusters in both metatranscriptomics and in silico datasets. In contrast, the pattern—smaller-fractioned communities had higher compositional homogeneity than larger ones—was observed in the metatranscriptomics data but not in the in silico datasets. To investigate this discrepancy further, we analysed the mismatches of widely used mitochondrial CO1 primers and identified priming site mismatches likely driving PCR-based biases. Our results suggest the use of metatranscriptomics or, although less ideal, redesigning the CO1 primers is necessary to circumvent these issues. © 2023 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.

关键词： coral reef diversity in silico PCR metatranscriptomics size fraction zooplankton

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Briastecholides G–J, New Polyoxygenated Briaranes from the Octocoral Briareum Stechei

SSRN

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SSRN 2022年

作者： Sung, Ping-Jyun Huynh, Thanh-Hao Chien, Su-Ying Wen, Zhi-Hong Liaw, Chih-Chuang Tsai, Yu-Chi Department of Marine Biotechnology and Resources National Sun Yat-sen University Kaohsiung804201 Taiwan National Museum of Marine Biology and Aquarium Pingtung944401 Taiwan Instrumentation Center National Taiwan University Taipei106319 Taiwan Institute of Biopharmaceutical Sciences National Sun Yat-sen University Kaohsiung804201 Taiwan Chinese Medicine Research and Development Center China Medical University Hospital Taichung404394 Taiwan Graduate Institute of Natural Products Kaohsiung Medical University Kaohsiung807378 Taiwan Ph. D. Program in Pharmaceutical Biotechnology Fu Jen Catholic University New Taipei City242062 Taiwan

Chemical composition screening of octocoral Briareum stechei , collected from Okinawan waters, led to the isolation of 10 briarane-type diterpenoids, including four previously-undescribed metabolites, briastecholides G–J ( 1 – 4 ), in addition to six known analogues, brianodin A ( 5 ), briarlides G ( 6 ) and P ( 7 ), and violides G, O, and P ( 8 – 10 ). The structures of 1 – 10 were elucidated by spectroscopic methods. Briastecholide d ( 1 ) was found to possess an unprecedented 10/6/5/5-fused tetracyclic scaffold. Furthermore, the absolute configuration of brianodin A ( 5 ) was elucidated for the first time in this study by single-crystal X-ray diffraction analysis. Briaranes 2 and 5 – 8 reduced the release of iNOS to 17.01, 37.95, 28.76, 1.21 and 26.66%, respectively, at a concentration of 10 µM. © 2022, The Authors. All rights reserved.

关键词： Spectroscopic analysis

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In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer

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Protein Science 2024年第6期33卷 e5004-e5004页

作者： Huang, Cheng-Chiao Hsu, Chia-Ming Chao, Min-Wu Hsu, Kai-Cheng Lin, Tony Eight Yen, Shih-Chung Tu, Huang-Ju Pan, Shiow-Lin Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University and Academia Sinica Taipei Taiwan Division of General Surgery Department of Surgery Taipei Medical University Hospital Taipei Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan School of Medicine College of Medicine National Sun Yat-sen University Kaohsiung Taiwan Institute of Biopharmaceutical Sciences College of Medicine National Sun Yat-sen University Kaohsiung Taiwan The Doctoral Program of Clinical and Experimental Medicine College of Medicine National Sun Yat-sen University Kaohsiung Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan TMU Research Center of Drug Discovery Taipei Medical University Taipei Taiwan Warshel Institute for Computational Biology The Chinese University of Hong Kong (Shenzhen) Guangdong Shenzhen China

dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC₅₀) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy. © 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.

关键词： CLK2 drug discovery kinase inhibitor structure-based virtual screening triple-negative breast cancer

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TRPM1 promotes tumor progression in acral melanoma by activating the Ca 2+ /CaMKIIδ/AKT pathway

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Journal of Advanced research 2023年 43卷 45-57页

作者： Chi-Che Hsieh Yue-Chiu Su Kuan-Ying Jiang Takamichi Ito Ting-Wei Li Yumiko Kaku-Ito Shih-Tsung Cheng Li-Tzong Chen daw-Yang Hwang Che-Hung Shen National Institute of Cancer Research National Health Research Institutes Tainan 704 Taiwan Department of Pathology Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka 812-8582 Japan Department of Life Sciences National Cheng Kung University Tainan 704 Taiwan Department of Dermatology Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Dermatology College of Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Internal Medicine Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 807 Taiwan Center for Cancer Research Kaohsiung Medical University Kaohsiung 807 Taiwan Ph.D. Program in Tissue Engineering and Regenerative Medicine Biotechnology Center National Chung Hsing University Taichung 402 Taiwan

Introduction Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. Objectives We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. Methods TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. Results We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca 2+ levels and activated CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo . Conclusions TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca 2+/ CaMKIIδ/AKT pathway.

关键词： Acral melanoma TRPM1 CaMKII Ca 2+ channel

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Intravitreal ranibizumab injection is associated with an increased risk of chronic kidney disease: a population-based study in Taiwan

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Naunyn-Schmiedeberg's Archives of pharmacology 2024年第7期397卷 4799-4808页

作者： Chen, Chang-Hsu Lim, Paik Seong Wu, Tsai-Kun Chuang, Wu-Lung Yu, Teng-Shun Tsai, Fuu-Jen Chen, Chuan-Mu Chang, Kuang-Hsi Ph.D. Program in Translational Medicine National Chung Hsing University Taichung 402 Taiwan Division of Renal Medicine Tungs’ Taichung MetroHarbor Hospital Taichung 435 Taiwan Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung 402 Taiwan Department of Life Sciences College of Life Sciences National Chung Hsing University Taichung 402 Taiwan Post Baccalaureate Medicine National Chung Hsing University Taichung 402 Taiwan Division of Endocrinology and Metabolism Department of Internal Medicine Changhua Christian Hospital Changhua 500 Taiwan Division of Endocrinology and Metabolism Department of Internal Medicine Lukang Christian Hospital Changhua 505 Taiwan Management Office for Health Data China Medical University Hospital Taichung 404 Taiwan College of Medicine China Medical University Taichung 404 Taiwan School of Chinese Medicine College of Chinese Medicine China Medical University Taichung 404 Taiwan Department of Medical Research China Medical University Hospital China Medical University Taichung 404 Taiwan Division of Medical Genetics China Medical University Children’s Hospital Taichung 404 Taiwan Department of Biotechnology and Bioinformatics Asia University Taichung 413 Taiwan The iEGG and Animal Biotechnology Center National Chung Hsing University Taichung 402 Taiwan Department of Medical Research Tungs’ Taichung MetroHarbor Hospital Taichung 435 Taiwan Center for General Education China Medical University Taichung 404 Taiwan General Education Center Nursing and Management Jen-Teh Junior College of Medicine Miaoli 356 Taiwan

Systemic vascular endothelial growth factor (VEGF) blockade has been the top adjunctive chemotherapy since 1990. Anti-VEGF therapy has also been associated with worsened renal function in some patients. However, the association between patient outcomes and use of intravitreal VEGF inhibitors remains controversial. Thus, it is necessary to determine the action mechanism and long-term renal effects of ranibizumab. The National Health Insurance research database (NHIRd) is one of the largest global databases that are extensively used for epidemiological research. NHIRd contains the medical information of all insureds, such as inpatient, outpatient, emergency, and traditional Chinese medicine records. We selected subjects aged ≥ 20 years who recently administered ranibizumab for the ranibizumab cohort. Non-ranibizumab cohort consisted of subjects who did not receive ranibizumab, and the index date was a random date between 2008 and 2018. We excluded subjects with missing sex and age records and those in which the date of primary outcome was before the index date. The two cohorts were matched via 1:1 propensity score matching based on sex, age, index year, hypertension, diabetes mellitus, hyperlipidemia, stroke, coronary artery disease, alcoholism, chronic obstructive pulmonary disease, and age-related macular degeneration, retinal vein occlusion, and diabetic macular edema. Medical confounders were angiotensin I-converting enzyme inhibitors, statins, corticosteroids, VEGF inhibitors including bevacizumab and aflibercept, lithium, amphotericin B, adefovir, NSAIdS, cisplatin, and calcineurin inhibitors. Among 48,248 participants aged ≥ 20 years, 24,136 (50%) received ranibizumab (13,565 male [56.20%] and 10,571 female [43.80%]). Moreover, 24,136 participants who did not receive ranibizumab were matched by age, sex, comorbidities, and medications. Subjects who received ranibizumab exhibited a significantly higher risk of CKd than those who did not receive ranibizumab (adju

关键词： Chronic kidney disease, National Health Insurance research database (NHIRd) Ranibizumab Vascular endothelial growth factor (VEGF)

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