Journal of pharmaceutical and biomedical analysis最新文献

{"title":"Characterization of main degradation products from dendrobine under stress conditions by multistage cleavage of UPLC-ESI-IT-TOF.","authors":"Hengju Zhou, Meiling Zeng, Keyong Geng, Zaipeng Chen, Zhijia Tang, Jianwei Xu, Xiaoyan Zhang, Wei Zhou","doi":"10.1016/j.jpba.2025.116663","DOIUrl":"10.1016/j.jpba.2025.116663","url":null,"abstract":"<p><p>Dendrobine is a sesquiterpene alkaloid primarily used in the treatment of inflammatory diseases, immune system disorders, and conditions related to oxidative stress. To understand the possible degradation pathways of dendrobine for its quality control, we conducted an in-depth investigation of its degradation products using forced degradation methods. The separation of dendrobine and its degradation products was achieved on a Shim-pack XR-ODS III (75 mm × 2 mm, 1.6 µm) column with a methanol-water mixture as the mobile phase under isocratic conditions, the isolated compounds were examined in positive ion mode with an ion trap-time of flight mass spectrometer (IT-TOF). In order to obtain in-depth structural information about the degradation products, mass spectrometry was performed using a five-stage fragmentation approach. This method allowed for thorough structural clarification via several rounds of selective fragmentation and high-resolution detection. System control and data acquisition were managed using LCMSsolution 3.81 software. The results showed that dendrobine undergoes significant degradation under oxidative, acidic, hydrolytic and thermal conditions, resulting in the formation of several degradation products with notable structural changes. Under oxidative conditions, dendrobine primarily generates two degradation products with mass increases of 16 Da and 32 Da, indicating mono-oxidation and di-oxidation reactions. Acidic degradation led to the identification of three degradation products, including a novel compound with an 18 Da mass increase, suggesting potential hydrolysis or dehydration reactions. Hydrolytic and thermal conditions resulted in the formation of two and three degradation products, respectively, with structural changes indicating possible molecular cleavage and reorganization mechanisms. In contrast, dendrobine exhibited strong stability under alkaline and photolytic conditions, with no significant degradation products detected. Detailed characterization of the degradation products via multi-stage mass spectrometry revealed key reaction pathways and mechanisms involved in dendrobine's degradation, providing critical insights for assessing its chemical stability and optimizing storage conditions.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116663"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of an UPLC-MS/MS method with polarity switching for simultaneous determination of 14 antiepileptic drugs and 2 metabolites in human serum.","authors":"Xiao-Han Peng, Yan-Lin Zhao, Zhong Huang, Xin-Feng Xia, Kun Wang, Peng Jin, Yan Du, Dao-Quan Tang","doi":"10.1016/j.jpba.2024.116655","DOIUrl":"10.1016/j.jpba.2024.116655","url":null,"abstract":"<p><p>Currently, treatment with antiepileptic drugs (AEDs) is still the first choice for epileptic patients, while monitoring their blood concentrations is undoubtedly beneficial for minimizing their adverse side effects and optimizing their therapeutic effects. In this study, an ultra-high performance liquid chromatography coupled with tandem mass spectrometry with polarity switching was developed and validated for simultaneous determination of 14 AEDs and 2 active metabolites in human serum. Olanzapine was selected as the internal standard. One-step protein precipitation using methanol containing 0.05 % formic acid was used to treat sample, and the supernatant was injected for analysis without further evaporation and reconstitution. Chromatographic separation was performed on an Aglient Zorbax Eclipse Plus C18 (50 mm × 2.1 mm, 1.8 μm) column with gradient methanol and 0.1 % formic acid in water as mobile phase. Multi-reaction monitoring was performed for quantification of 16 analytes in polarity switching mode. Matrix-matched calibration curves of 16 analytes presented good linearity within the test concentration range (r > 0.99). The intra- and inter-run accuracies and precisions at the lower limit of quantification, and low, medium and high quality control levels were all less than 20 % or 15 %, respectively. The extraction recovery, matrix effect, and stability were all acceptable under detected conditions. Finally, this method was successfully applied in the quantitation of target analytes in the serum of patients received AEDs.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116655"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for the metabolic activation of higenamine to quinone methide and ortho-quinone metabolites in vitro and in vivo using liquid chromatography tandem mass spectrometry.","authors":"Hui Wang, Lihua Xin, Pengyi Hou, Shiwei Sun, Jiang Zheng, Wei Wang","doi":"10.1016/j.jpba.2024.116634","DOIUrl":"10.1016/j.jpba.2024.116634","url":null,"abstract":"<p><p>Higenamine (HG), a naturally occurring benzyltetrahydroisoquinoline alkaloid, has been revealed a variety of biological activities and is extensively utilized in dietary supplements. Currently, HG is under investigation in phase I clinical trials, however, the liver metabolism of HG has so far not been fully elucidated. The present study aimed to identify reactive metabolites of HG using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Four glutathione (GSH) conjugates (M1-M4) and four cysteine conjugates (M5-M8) derived from reactive metabolites of HG were detected in GSH/cysteine-fortified mouse/human microsomal incubations. The cysteine conjugates were chemically synthesized for structural elucidation using manganese dioxide as the oxidizing agent. The reactive metabolites of HG were identified as quinone methide, hydroxyquinone methide, and ortho-quinone based on the fragmentation patterns of cysteine conjugates. Multiple CYP450 enzymes including CYP2D6, CYP3A4, and CYP2E1 were mediated in the formation of quinone methide, with the major role assigned to CYP2D6. While the oxidation of catechol to ortho-quinone metabolite and the subsequent isomerization into hydroxyquinone methide were independent of CYP450 isoforms. In addition, these electrophilic metabolites were found to react with biliary GSH and cysteine residues of hepatic protein in HG-treated mice. The in vitro and in vivo evidence of the metabolic activation of HG to quinone methide and ortho-quinone metabolites raised health concerns regarding the consumption of HG-containing supplements.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116634"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual recombinase polymerase amplification system combined with lateral flow immunoassay for simultaneous detection of Staphylococcus aureus and Vibrio parahaemolyticus.","authors":"Yan Zhang, Xiaofeng Liu, Jiawei Luo, Hua Liu, You Li, Juan Liu, Lemei Zhu, Jinbin Wang, Haijuan Zeng","doi":"10.1016/j.jpba.2024.116621","DOIUrl":"10.1016/j.jpba.2024.116621","url":null,"abstract":"<p><p>Development of a highly sensitive visualization platform for multiplex genetic detection could significantly improve efficiency and reliability of on-site detection of foodborne pathogens. In this study, coupling recombinase polymerase amplification (RPA) with lateral flow immunoassay (LFIA) readout system was proposed for Staphylococcus aureus and Vibrio parahaemolyticus detection. Taking the advantage of the isothermal amplification of RPA, dual primers modified with different labeling groups were designed to realize target signal amplification. LFIA coated with anti-digoxigenin antibody and streptavidin as test line 1 and 2 were designed to detect the two RPA products. The proposed method (dual RPA-LFIA) could realize visual detection using LFIA through rapid RPA amplification within 20 min, exhibiting a lowest detection limit of 4.6 × 10² CFU/mL for Staphylococcus aureus and Vibrio parahaemolyticus. The dual RPA-LFIA is characterized by simultaneous detection of dual targets in one RPA reaction and colorimetric readout through LFIA, thus ensuring high sensitivity and efficiency, and showing great potential to address the on-site detection of foodborne pathogens in the future.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116621"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomic profiling of the febrile rat hypothalamus by the intervention of Artemisia japonica extracts.","authors":"Xiaodong Zhang, Suqing Zhao, Yuxue Ma, Wen Kang, Wenbin Zhou, Chen Zhang, Zeper Abliz","doi":"10.1016/j.jpba.2024.116588","DOIUrl":"10.1016/j.jpba.2024.116588","url":null,"abstract":"<p><p>Artemisia species have been regarded as an important source of ethnic medicinal plants, such as A. annua and A. capillaris, both of which are widely used in clinical treatment. The clinical efficacy of A. japonica is similar to that of A. capillaris, but fewer pharmaceutical studies have been reported. Given that the extracts of A. japonica were observed to reduce the rectal temperature of febrile rats induced by LPS, this study was designed to demonstrate this regulatory effect of the extracts, with a particular focus on the lipidomic profiling of the febrile rat hypothalamus. A total of 72 differential metabolites were filtered out and the association between lipid profiling and potential mechanism was explored. Sphingolipid, glycerophospholipid, arachidonic acid and ether lipid metabolism pathways were significantly enriched. TNF-α, IL-6 and PGE₂ cytokines in the hypothalamus were significantly downregulated by the intervention of the extracts of A. japonica. Enzymatic reaction enrichment analysis suggested that PEMT and COX-2 might be potential targets of the efficacy, and which were testified to be downregulated by the ELISA assay under the extracts intervention.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116588"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deeper insights into the stability of oxylipins in human plasma across multiple freeze-thaw cycles and storage conditions.","authors":"Maria Moran-Garrido, Sandra M Camunas-Alberca, Jorge Sáiz, Ana Gradillas, Ameer Y Taha, Coral Barbas","doi":"10.1016/j.jpba.2024.116587","DOIUrl":"10.1016/j.jpba.2024.116587","url":null,"abstract":"<p><p>Oxylipins are signaling lipids derived from the oxidation of polyunsaturated fatty acids (PUFAs). In lipidomic studies, human plasma may be subjected to various storage conditions and freeze-thaw cycles, which may impact the analysis of these compounds. In this study, we used liquid chromatography coupled with mass spectrometry (LC-MS) to examine the influence of up to five freeze-thaw cycles (FTCs) on free and total (mostly esterified) oxylipins in human plasma and the influence of temperature and storage duration (4 °C for up to 120 h and -20 °C and -80 °C for 1-98 days) in the presence or absence of butylated hydroxytoluene (BHT) on extracted oxylipins stored in LC-MS amber vials. In fresh plasma subjected to several FTCs, approximately 48 % of the detected free oxylipins were significantly altered by the third cycle, with increases in cytochrome P450 (CYP450) and lipoxygenase (LOX)-derived compounds and reductions in trihydroxylated oxylipins. In contrast, multiple FTCs did not significantly alter esterified oxylipins. At 4 °C, the extracted oxylipins did not change significantly for up to 120 h (5 days). Oxylipin levels remained stable for 98 days at -80 °C but decreased by 98 days at -20 °C. The antioxidant activity of butylated hydroxytoluene (BHT) did not influence oxylipin stability at 4 °C for 120 h or at -80 °C for 98 days, but it reduced oxylipin degradation at -20 °C at 98 days. Conversely, prostaglandin F_2α (PGF_2α) exhibited substantial increases at -20 °C and -80 °C, independent of BHT. This study demonstrates that (i) unlike free oxylipins, the esterified oxylipin pool remains stable following repeated FTCs, (ii) extracted oxylipins are stable at 4 °C for up to 120 h and at -80 °C for up to 98 days, but not at -20 °C for 98 days, and (iii) BHT may minimize oxylipin degradation of sample extracts stored at -20 °C. This study provides a framework for measuring oxylipins under various freeze-thaw and storage conditions.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116587"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic and molecular basis of flavonoid biosynthesis in Lycii fructus: An integration of metabolomic and transcriptomic analysis.","authors":"Limei Tong, Yinxiu Jiang, Xinrun Zhang, Xia Zhang, Wenhua Zhang, Gang Ren, Zhanping Chen, Yuling Zhao, Sheng Guo, Hui Yan, Yang Pan, Jin-Ao Duan, Fang Zhang","doi":"10.1016/j.jpba.2024.116653","DOIUrl":"10.1016/j.jpba.2024.116653","url":null,"abstract":"<p><p>Flavonoids serve as bioactive components and contribute to medicinal and nutritional profile of Lycii fructus. However, there is limited information regarding the influence of ecological environments on the flavonoid biosynthesis pathway. In this study, we integrated transcriptome sequencing and metabonomic techniques across three distinct cultivation regions to elucidate the processes of flavonoids biosynthesis and the associated gene expression levels in L. fructus. LC-MS/MS based metabolomics revealed significant variations in metabolite profiles including 43 differential flavonoid metabolites, predominantly consisting of flavanol compounds across diverse regions. Additionally, 154 significantly differentially expressed genes (DEGs) were categorized in the flavonoid biosynthesis identified by de novo transcriptome assembly. Transcription factors C2C2 MYB, NAC, WRKY, AP2/ERF and B3 superfamily were the mainly hub genes regulating the flavonoids biosynthesis. The flavonoid pathway was built through integrated analysis of DEGs and DAMs to illustrate the molecular mechanism of flavonoid biosynthesis. Precipitation and temperature may serve as the primary environmental factors that affected the flavonoids variations. This study proposed a schematic of flavonoid biosynthesis in L. fructus, and further provided evidence for environmental response of L. fructus.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116653"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A simple automated assay format for measuring multiple immune checkpoint inhibitors.","authors":"Ragnhild V Nome, Øystein Flatebø, Sigurd Leinæs Bøe, Rolf Anton Klaasen, Elin Aamdal, Marius Normann, Nils Bolstad, David John Warren","doi":"10.1016/j.jpba.2024.116657","DOIUrl":"10.1016/j.jpba.2024.116657","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have improved survival rates in oncology, but there is a rising concern for immune-related adverse health outcomes. Monitoring drug serum concentration would enable tailored dosing, however this strategy has not yet been evaluated for ICIs. Fully automated analyte capture assays with time-resolved fluorometry using protein A as tracer, were developed for three different ICIs; the cytotoxic T lymphocyte Antigen-4 (CTLA4) inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) and the Programmed Death-1 (PD-1) inhibitors nivolumab (Opdivo; Bristol-Myers Squibb) and pembrolizumab (Keytruda; Merck). Drug trough levels were measured in serum samples from ICI-treated patients. Measuring ranges were 1-100 mg/L for all three drugs. Automation allowed for 110 samples to be analyzed in < 4 h. Median drug trough-levels after 5-7 weeks of treatment were 20 (range <1.0-45) mg/L for ipilimumab (n = 113), 60 (range 14-75) mg/L) for nivolumab (n = 21) and 19 (range 7.4-39) mg/L for pembrolizumab (n = 20). Routine drug concentration monitoring for ipilimumab, nivolumab and pembrolizumab is feasible using fully automated analyte capture assays constructed with commercially available reagents. The large drug serum concentration ranges in samples from real-world patients, should be further investigated to assess the clinical relevance of ICI concentration monitoring.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116657"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Untargeted metabolomics combined with lipidomics revealed the effects of myocardial infarction and exercise rehabilitation on blood circulation metabolism of patients based on liquid chromatography-mass spectrometry.","authors":"Na Wang, Huimin Li, Hao Wu, Zilin Xia, Dabing Ren, Yunmei Zhang, Yan Zhao, Hong Zhang, Ke Zhuang, Lunzhao Yi","doi":"10.1016/j.jpba.2024.116651","DOIUrl":"10.1016/j.jpba.2024.116651","url":null,"abstract":"<p><p>Myocardial infarction (MI) is a major cause of death worldwide. Exercise rehabilitation (ER) is a powerful tool to improve life quality and prognosis of MI patients. Herein, we developed an untargeted metabolomics combined with lipidomics method to qualitatively and quantitatively detect metabolites in plasma. A total of 475 metabolites were annotated according to MS, MS/MS, and quantified by internal standard method. Moreover, medical statistical methods combined with chemometrics were used for metabolomics data mining and interpretation of clinical issues (matched Cohort 1, n = 90, Cohort 2, n = 6). The results illustrated that abnormal lipid metabolism is the most significant metabolic disorder for MI patients. And, three metabolic pathways, bile secretion, HIF-1 signaling pathway, and glutathione metabolism were uncovered in MI patients. Furthermore, glutamine, Phenylacetylglutamine (PAGln) and lysophosphatidylcholine (LPCs) were revealed as the essential biomarkers for ER of MI patients. Our findings revealed the metabolic landscape of MI and metabolic alterations after ER, will underlay potential applications of plasma metabolites in the detection of MI and optimization of ER program.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116651"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation and elimination of noncovalent artificial aggregates during non-reduced capillary electrophoresis-sodium dodecyl sulfate analysis of a multi-specific antibody.","authors":"Jianhui Cheng, Qianchuan Lv, Yuanzhao Ji, Chunling Zhou, Jifen Guo, Xinxin Li, Jianzhong Hu","doi":"10.1016/j.jpba.2025.116673","DOIUrl":"10.1016/j.jpba.2025.116673","url":null,"abstract":"<p><p>Capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) is widely used in the biopharmaceutical industry for monitoring purity and analyzing impurities. The accuracy of the method may be compromised by artificial species resulting from sample preparation or electrophoresis separation due to suboptimal conditions. During non-reduced CE-SDS analysis of a multispecific antibody (msAb), named as multispecific antibody C (msAb-C), a cluster of unexpected peaks was observed after the main peak. The corrected peak area ratio of these peaks showed a strong dependence on loaded protein concentration, which affected the accurate assessment of the purity of msAb-C. After investigation, the unexpected peaks were identified as artifacts produced during electrophoresis separation. These artifacts can be mitigated by three different strategies: 1) adding a more hydrophobic surfactant, sodium hexadecyl sulfate (SHS), to the sample and/or sieving gel buffer; 2) reducing the sample loading amount; and 3) increasing the capillary separation temperature to above 40 ℃. We adopted strategy 1) and strategy 3), and successfully developed an optimal non-reduced CE-SDS method for the accurate and reliable purity assessment of msAb-C samples. These strategies of optimizing non-reduced CE-SDS can be used in developing quality control methods for other therapeutic bispecific/multispecific antibodies.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"255 ","pages":"116673"},"PeriodicalIF":3.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}