Yue Wu, Zewei Zhang, Haiping Cai, Weiqing Zhang, Linjian Zhang, Zhihong Li, Le Yang, Yafen Chen, Thomas P. Corner, Zhe Song, Jie Yue, Fulai Yang, Xiang Li, Christopher J. Schofield, Xiaojin Zhang
{"title":"Discovery of ZG-2305, an Orally Bioavailable Factor Inhibiting HIF Inhibitor for the Treatment of Obesity and Fatty Liver Disease","authors":"Yue Wu, Zewei Zhang, Haiping Cai, Weiqing Zhang, Linjian Zhang, Zhihong Li, Le Yang, Yafen Chen, Thomas P. Corner, Zhe Song, Jie Yue, Fulai Yang, Xiang Li, Christopher J. Schofield, Xiaojin Zhang","doi":"10.1021/acs.jmedchem.4c01698","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01698","url":null,"abstract":"Genetic loss of the 2-oxoglutarate oxygenase factor inhibiting hypoxia-inducible factor (FIH) enhances both glycolysis and aerobic metabolism. FIH is thus a potential target for adiposity control and improving hepatic steatosis. We describe development of a series of novel, potent, and selective FIH inhibitors that occupy both the FIH catalytic site and a recently defined tyrosine conformational-flip pocket. <b>ZG-2305</b>, with a <i>K</i><sub>i</sub> of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-inducible factor (HIF) prolyl hydroxylase PHD2. Oral administration of <b>ZG-2305</b> in the western-diet induced obesity mouse model results in improved lipid accumulation and recovery from abnormal body weight/hepatic steatosis. Amelioration of nonalcoholic steatohepatitis (NASH) related pathological phenotypes in the HF-CDAA-diet induced NASH mouse model was observed. Preliminary preclinical studies indicate <b>ZG-2305</b> has good pharmacokinetic properties and an acceptable safety profile. The results imply <b>ZG-2305</b> is a promising candidate for treatment of obesity and fatty liver disease.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovery of Arene Ruthenium(II) Complexes as Potential VEGF Inhibitors for Glioblastoma Metastasis Suppression","authors":"Chanling Yuan, Chunguang Zhu, Qingshuang Lv, Jiahui Shi, Jiacheng Wang, Shiqi Gao, Jiayi Qian, Yanhua Chen, Qiong Wu, Wenjie Mei","doi":"10.1021/acs.jmedchem.4c00797","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00797","url":null,"abstract":"Developing drugs for treating glioblastoma has been a significant challenge. Herein, a series of arene ruthenium(II) complexes have been synthesized and investigated as potential candidates to suppress the proliferation and metastasis of glioblastoma. It is found that para-substituent-modified molecules, especially <b>6</b>, exhibit higher antitumor activity than ortho-substituents. Further studies show that <b>6</b> can trigger tumor cell autophagy by regulating the PI3K/AKT/mTOR pathway. Moreover, it is also found that <b>6</b> can induce DNA damage in glioblastoma cells through binding and stabilizing VEGF G-quadruplex DNA. Furthermore, it is confirmed that <b>6</b> can inhibit the proliferation and metastasis of U87-MG glioblastoma cell in situ xenograft in the zebrafish model. Hence, arene ruthenium(II) complexes can be developed as promising therapeutic agents for glioblastoma treatment in the future.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structure-Affinity-Pharmacokinetics Relationships of Novel 18F-Labeled 1,4-Diazepane Derivatives for Orexin 1 Receptor Imaging","authors":"Yui Ishizaka, Hiroyuki Watanabe, Masahiro Ono","doi":"10.1021/acs.jmedchem.4c01090","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01090","url":null,"abstract":"The orexin 1 receptor (OX1R) has been suggested to be involved in the reward and autonomic nervous systems. Positron emission tomography (PET) of OX1R contributes to elucidating its role and developing new drugs. However, there are no useful PET probes for in vivo imaging of OX1R. Here, we newly designed and synthesized <sup>18</sup>F-labeled 1,4-diazepane derivatives and evaluated their utilities as OX1R PET probes. In particular, BTF showed high and selective binding affinity for OX1R. In a biodistribution study using normal mice, [<sup>18</sup>F]BTF exhibited brain uptake, and radioactivity in the brain was significantly decreased by preinjection of unlabeled BTF. In a PET/CT study, it was suggested that [<sup>18</sup>F]BTF has the potential to visualize high-expression regions of OX1R in the normal mouse brain. Collectively, [<sup>18</sup>F]BTF has the fundamental features of an OX1R PET probe, and further studies may lead to the development of more useful probes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cell-Based Screen Identifies a Highly Potent and Orally Available ABCB1 Modulator for Treatment of Multidrug Resistance","authors":"Shuai Wang, Sai-Qi Wang, Xiao-Bing Chen, Qian Xu, Hao Deng, Qiu-Xu Teng, Zhe-Sheng Chen, Xuyao Zhang, Fen-Er Chen","doi":"10.1021/acs.jmedchem.4c01081","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01081","url":null,"abstract":"Targeting ABCB1 is a promising strategy in combating multidrug resistance. Our cell-based phenotypic screening led to the discovery of novel triazolo[1,5-<i>a</i>]pyrimidone-based ABCB1 modulators. Notably, <b>WS-917</b> was identified as a significant contributor to heightened sensitization of human colorectal adenocarcinoma cells (SW620/Ad300) to paclitaxel (IC<sub>50</sub> = 5 nM). Mechanistic elucidation revealed that this compound substantially augmented intracellular paclitaxel and [<sup>3</sup>H]-paclitaxel, concurrently mitigating the efflux of [<sup>3</sup>H]-paclitaxel in SW620/Ad300 through the inhibition of ABCB1 efflux. The cellular thermal shift assay underscored its ability to stabilize ABCB1 through direct binding. Additionally, <b>WS-917</b> induced stimulation of ABCB1 ATPase activity while exhibiting negligible inhibitory effect against CYP3A4. Remarkable was its capacity to enhance the sensitivity of SW620/Ad300 to paclitaxel, as well as the sensitivity of CT26/TAXOL to paclitaxel and PD-L1 inhibitor (Atezolizumab) in vivo, all achieved without inducing observable toxicity. The discovery of <b>WS-917</b> holds promise for the development of more potent ABCB1 modulators.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charline Giroud, Tamas Szommer, Carmen Coxon, Octovia Monteiro, Thomas Grimes, Tryfon Zarganes-Tzitzikas, Thomas Christott, James Bennett, Karly Buchan, Paul E. Brennan, Oleg Fedorov
{"title":"Covalent Inhibitors of S100A4 Block the Formation of a Pro-Metastasis Non-Muscle Myosin 2A Complex","authors":"Charline Giroud, Tamas Szommer, Carmen Coxon, Octovia Monteiro, Thomas Grimes, Tryfon Zarganes-Tzitzikas, Thomas Christott, James Bennett, Karly Buchan, Paul E. Brennan, Oleg Fedorov","doi":"10.1021/acs.jmedchem.4c01320","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01320","url":null,"abstract":"The S100 protein family functions as protein–protein interaction adaptors regulated by Ca<sup>2+</sup> binding. Formation of various S100 complexes plays a central role in cell functions, from calcium homeostasis to cell signaling, and is implicated in cell growth, migration, and tumorigenesis. We established a suite of biochemical and cellular assays for small molecule screening based on known S100 protein–protein interactions. From 25 human S100 proteins, we focused our attention on S100A4 because of its well-established role in cancer progression and metastasizes by interacting with nonmuscle myosin II (NMII). We identified several potent and selective inhibitors of this interaction and established the covalent nature of binding, confirmed by mass spectrometry and crystal structures. <b>5b</b> showed on-target activity in cells and inhibition of cancer cell migration. The identified S100A4 inhibitors can serve as a basis for the discovery of new cancer drugs operating via a novel mode of action.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amrendra Kumar, Sivanna Chithanna, Yuexin Li, Xiaowei Zhang, Rozalia A. Dodean, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Xiannu Jin, Ravi Chetree, Cameron Blount, William E. Dennis, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Susan Leed, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla
{"title":"Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines","authors":"Amrendra Kumar, Sivanna Chithanna, Yuexin Li, Xiaowei Zhang, Rozalia A. Dodean, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Xiannu Jin, Ravi Chetree, Cameron Blount, William E. Dennis, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Susan Leed, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla","doi":"10.1021/acs.jmedchem.4c02093","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02093","url":null,"abstract":"Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure–activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic <i>Plasmodium</i> parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic <i>Plasmodium yoelii</i> infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage <i>Plasmodium berghei</i> sporozoite-induced infection in mice.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to “Discovery of Novel Histone Deacetylase 6 (HDAC6) Inhibitors with Enhanced Antitumor Immunity of Anti-PD-L1 Immunotherapy in Melanoma”","authors":"Xiaopeng Peng, Ling Li, Jingxuan Chen, Yichang Ren, Jin Liu, Ziwen Yu, Hao Cao, Jianjun Chen","doi":"10.1021/acs.jmedchem.4c02486","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02486","url":null,"abstract":"In our study to investigate the impact of two newly synthesized compounds (XP5 and XP19) alongside a positive control drug (CAY10603) on the expression levels of various target proteins─specifically, AC-α-Tubulin, α-Tubulin, SMC3, Ac-H3, H3, Ac-SMC3, and apoptosis-related antibodies (Ac-Ku70, Ku70, Bcl-2, Bax)─we conducted a series of experiments on different tumor cell lines, including Jurkat-T cells and B16-F10 cells. This comprehensive analysis yielded a substantial amount of experimental data and protein bands. Regrettably, during the assembly of Figure 7 and Figure 8 in the original manuscript, we inadvertently used a wrong image of Ac-Ku70 and Ku70 in Figure 7A and of Ac-SMC3, SMC3, and Ac-H3 in Figure 8E,F. Upon recent and careful review of the original manuscript, we identified this error and have replaced the wrong image with the correct one in the corrected Figure 7 and Figure 8. This corrected result still demonstrates that XP5 and XP19 can upregulate the expression levels of acetylated Ku70 significantly and dose-dependently but showed no effect on the Ku70 levels and had little effect on the levels of acetyl-SMC3 and acetyl-H3, and these corrections do not change the scientific conclusions of the article in any way. Figure 7. Analysis of acetylated Ku70, Ku70, Bcl-2, and Bax by Western blot. Jurkat T cells were treated with dimethyl sulfoxide (DMSO) or XP5, and XP19 for 6 h. The levels of acetylated Ku70, Ku70, Bcl-2, and Bax were examined by Western blot (A). Quantitative analysis of the levels of acetylated Ku70 (B), Bcl-2 (C), and Bax (D). All data are representative of three independent experiments and shown as mean ± SD. ***<i>p</i> < 0.001, **<i>p</i> < 0.01, *<i>p</i> < 0.05 compared with the control group, <sup>###</sup><i>p</i> < 0.001. One-way ANOVA for the above analysis, Dunnett test. Figure 8. Analysis of acetylated α-tubulin/acetylated-SMC3 and acetylated-H3 by Western blot. The levels of acetyl-α-tubulin (Ac-α-Tub) and α-tubulin in B16-F10 cells (A) and Jurkat T cells (B) treated with DMSO or XP5, XP19, and CAY10603 for 6 h. Quantitative analysis of the level of acetyl-α-tubulin (Ac-α-Tub) by Western blotting assay obtained in B16-F10 cells (C) and Jurkat T cells (D). The levels of acetylated-SMC3, total SMC3, acetylated-H3, and total H3 in B16-F10 cells (E) and Jurkat T cells (F) treated with DMSO or XP5, XP19, and CAY10603 for 6 h. All data are representative of three independent experiments and shown as mean ± SD. ***<i>p</i> < 0.001, **<i>p</i> < 0.01 compared with the control group, <sup>###</sup><i>p</i> < 0.001, <sup>&</sup><i>p</i> < 0.05, <sup>&&</sup><i>p</i> < 0.01. One-way ANOVA for the above analysis, Dunnett test. We have now corrected the original Figure 7 and Figure 8, and all authors have agreed to the changes. We apologize for any confusion this may have caused and appreciate your understanding as we make these necessary corrections to ensure the integrity of our","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vladimir Aladinskiy, Chris Kruse, Luoheng Qin, Eugene Babin, Yaya Fan, Georgiy Andreev, Heng Zhao, Yanyun Fu, Man Zhang, Yan Ivanenkov, Alex Aliper, Alex Zhavoronkov, Feng Ren
{"title":"Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis","authors":"Vladimir Aladinskiy, Chris Kruse, Luoheng Qin, Eugene Babin, Yaya Fan, Georgiy Andreev, Heng Zhao, Yanyun Fu, Man Zhang, Yan Ivanenkov, Alex Aliper, Alex Zhavoronkov, Feng Ren","doi":"10.1021/acs.jmedchem.4c01580","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01580","url":null,"abstract":"Traf2- and Nck-interacting kinase (TNIK) has been identified as a promising therapeutic target for the treatment of fibrosis-driven diseases. Utilizing a structure-based drug design workflow, we developed a series of potent TNIK inhibitors that modulate the conformation of the gatekeeper Met105 side chain and access the TNIK back pocket. The lead optimization efforts culminated in the discovery of the recently reported compound <b>4</b> (INS018_055), a novel TNIK inhibitor. This molecule demonstrated excellent activity in both enzymatic and cell-based assays, along with high selectivity in a kinome panel. Further, <i>in vitro</i> and <i>in vivo</i> preclinical studies revealed favorable <i>in vitro</i> and <i>in vivo</i> DMPK properties. Results from multiple cell-based and animal models proved that compound <b>4</b> exhibits considerable antifibrotic and anti-inflammatory efficacy. Currently, phase II clinical trials of compound <b>4</b> are underway for the treatment of idiopathic pulmonary fibrosis (IPF).","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advancing Cancer Immunotherapy through Engineering New PD-L1 Degraders: A Comprehensive Study from Small Molecules to PD-L1-Specific Peptide–Drug Conjugates","authors":"Zekun Zeng, Zhiwei Yang, Chenghao Li, Shujing Liu, Wei Wei, Ye Zhou, Simeng Wang, Mengjun Sui, Mengdan Li, Shumei Lin, Yangyang Cheng, Peng Hou","doi":"10.1021/acs.jmedchem.4c01652","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01652","url":null,"abstract":"Despite the considerable achievements of antibodies targeting PD-1/PD-L1 in cancer immunotherapy, limitations in antitumor immune response and pharmacokinetics hinder their clinical adoption. Small molecules toward PD-L1 degradation signifies an innovative avenue to modulate PD-1/PD-L1 axis. Herein, we unveil a comprehensive engineering involving the development of new PD-L1 degraders based on the berberine (BBR) and palmatine (PMT) bioactive frameworks and explore their translational potential for cancer immunotherapy using a peptide-drug conjugate strategy. Chemical modifications at the O-9 position of PMT dramatically enhance the PD-L1 degradation capacity. Further conjugation of PMT degraders with an anti-PD-L1 peptide featuring disulfide linkers enables efficient GSH-specific prodrug activation, yielding synergistic immunotherapeutic benefits through both external PD-L1 blockade and internal PD-L1 degradation mechanisms. This work elucidates the compelling charm of the discovery and application of PD-L1 degraders, offering solutions to the challenges in advancing cancer immunotherapy in widespread clinics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yam B. Poudel, Ruchita R. Thakore, Eugene P. Chekler
{"title":"Correction to “The New Frontier: Merging Molecular Glue Degrader and Antibody–Drug Conjugate Modalities To Overcome Strategic Challenges”","authors":"Yam B. Poudel, Ruchita R. Thakore, Eugene P. Chekler","doi":"10.1021/acs.jmedchem.4c02447","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02447","url":null,"abstract":"The authors regret an inadvertent error in Figure 1 where in both label 3, the “lysosome” should read “late endosome”. We apologize for the inconvenience. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}