Drug Resistance Updates最新文献

{"title":"Why and how citrate may sensitize malignant tumors to immunotherapy","authors":"Philippe Icard ,&nbsp;Mathilde Prieto ,&nbsp;Antoine Coquerel ,&nbsp;Ludovic Fournel ,&nbsp;Joseph Gligorov ,&nbsp;Johanna Noel ,&nbsp;Adrien Mouren ,&nbsp;Anthony Dohan ,&nbsp;Marco Alifano ,&nbsp;Luca Simula","doi":"10.1016/j.drup.2024.101177","DOIUrl":"10.1016/j.drup.2024.101177","url":null,"abstract":"<div><div>Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101177"},"PeriodicalIF":15.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of purine metabolism reverses macrophage immunosuppression and enhances anti-tumor immunity in non-small cell lung cancer","authors":"Li Yang ,&nbsp;Aitian Li ,&nbsp;Weina Yu ,&nbsp;Huishang Wang ,&nbsp;Lei Zhang ,&nbsp;Dan Wang ,&nbsp;Ying Wang ,&nbsp;Ru Zhang ,&nbsp;Qingyang Lei ,&nbsp;Zhangnan Liu ,&nbsp;Shanshan Zhen ,&nbsp;Haiming Qin ,&nbsp;Yaqing Liu ,&nbsp;Yang Yang ,&nbsp;Xian-Lu Song ,&nbsp;Yi Zhang","doi":"10.1016/j.drup.2024.101175","DOIUrl":"10.1016/j.drup.2024.101175","url":null,"abstract":"<div><h3>Aims</h3><div>Immune checkpoint blockade therapy is not effective in most patients with non-small cell lung cancer (NSCLC) due to the immunosuppressive tumor microenvironment. Macrophages are key components of tumor-infiltrating immune cells and play a critical role in immunosuppression, which can be mediated by cell-intrinsic metabolism. This study aimed to evaluate whether macrophages regulate NSCLC progression through metabolic crosstalk with cancer cells and affect immunotherapy efficacy.</div></div><div><h3>Methods</h3><div>The macrophage landscape of NSCLC tissues were analyzed by single-cell sequencing and verified through flow cytometry and immunofluorescence. Multiplex assay, single-cell sequencing data, ELISA, immunofluorescence, and RNA-seq et al. were used to investigate and verify the mechanism of macrophage-mediated metabolic regulation on immunosuppression. The tumor-bearing model was established in C57BL/6 J mice to explore in vivo efficacy.</div></div><div><h3>Results</h3><div>We found that tumor tissue-derived macrophages exhibited an anti-inflammatory phenotype and had a prognostic value for NSCLC. NSCLC cell-secreted CXCL8 recruited macrophages from peritumor tissues to tumor sites and promoted programmed death-ligand 1 (PD-L1) expression by activating purine metabolism with increasing xanthine dehydrogenase and uric acid production. Moreover, purine metabolism-mediated macrophage immunosuppression was dependent on NLRP3/caspase-1/IL-1β signaling. Blockade of purine metabolism signaling enhanced anti-tumor immunity and the efficacy of anti-PD-L1 therapy.</div></div><div><h3>Conclusions</h3><div>Collectively, our findings reveal a key role of purine metabolism in macrophage immunosuppression and suggest that blockade of purine metabolism combined with immune checkpoint blockade could provide synergistic effects in NSCLC treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101175"},"PeriodicalIF":15.8,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721164","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":"Post-translational modifications in drug resistance","authors":"Chenggui Miao ,&nbsp;Yurong Huang ,&nbsp;Cheng Zhang ,&nbsp;Xiao Wang ,&nbsp;Bing Wang ,&nbsp;Xinyue Zhou ,&nbsp;Yingqiu Song ,&nbsp;Peng Wu ,&nbsp;Zhe-Sheng Chen ,&nbsp;Yibin Feng","doi":"10.1016/j.drup.2024.101173","DOIUrl":"10.1016/j.drup.2024.101173","url":null,"abstract":"<div><div>Resistance to antitumor drugs, antimicrobial drugs, and antiviral drugs severely limits treatment effectiveness and cure rate of diseases. Protein post-translational modifications (PTMs) represented by glycosylation, ubiquitination, SUMOylation, acetylation, phosphorylation, palmitoylation, and lactylation are closely related to drug resistance. PTMs are typically achieved by adding sugar chains (glycosylation), small proteins (ubiquitination), lipids (palmitoylation), or functional groups (lactylation) to amino acid residues. These covalent additions are usually the results of signaling cascades and could be reversible, with the triggering mechanisms depending on the type of modifications. PTMs are involved in antitumor drug resistance, not only as inducers of drug resistance but also as targets for reversing drug resistance. Bacteria exhibit multiple PTMs-mediated antimicrobial drug resistance. PTMs allow viral proteins and host cell proteins to form complex interaction networks, inducing complex antiviral drug resistance. This review summarizes the important roles of PTMs in drug resistance, providing new ideas for exploring drug resistance mechanisms, developing new drug targets, and guiding treatment plans.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101173"},"PeriodicalIF":15.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-driven visualization tool for analyzing data and predicting drug-resistant outbreaks","authors":"Yoshiyasu Takefuji","doi":"10.1016/j.drup.2024.101174","DOIUrl":"10.1016/j.drup.2024.101174","url":null,"abstract":"<div><div>A tool was developed to identify potential disease outbreaks using pathogen and serotype data. By analyzing isolate numbers and comparing them to a two-year average, the tool highlights anomalies suggestive of outbreaks. When applied to Salmonella data, it revealed potential outbreaks related to specific serotypes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101174"},"PeriodicalIF":15.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693878","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":"Autophagy in cancer development, immune evasion, and drug resistance","authors":"Xuegang Niu ,&nbsp;Qi You ,&nbsp;Kaijian Hou ,&nbsp;Yu Tian ,&nbsp;Penghui Wei ,&nbsp;Yang Zhu ,&nbsp;Bin Gao ,&nbsp;Milad Ashrafizadeh ,&nbsp;Amir Reza Aref ,&nbsp;Alireza Kalbasi ,&nbsp;Israel Cañadas ,&nbsp;Gautam Sethi ,&nbsp;Vinay Tergaonkar ,&nbsp;Lingzhi Wang ,&nbsp;Yuanxiang Lin ,&nbsp;Dezhi Kang ,&nbsp;Daniel J. Klionsky","doi":"10.1016/j.drup.2024.101170","DOIUrl":"10.1016/j.drup.2024.101170","url":null,"abstract":"<div><div>Macroautophagy/autophagy is a highly conserved evolutionary mechanism involving lysosomes for the degradation of cytoplasmic components including organelles. The constitutive, basal level of autophagy is fundamental for preserving cellular homeostasis; however, alterations in autophagy can cause disease pathogenesis, including cancer. The role of autophagy in cancer is particularly complicated, since this process acts both as a tumor suppressor in precancerous stages but facilitates tumor progression during carcinogenesis and later stages of cancer progression. This shift between anti-tumor and pro-tumor roles may be influenced by genetic and environmental factors modulating key pathways such as those involving autophagy-related proteins, the PI3K-AKT-MTOR axis, and AMPK, which often show dysregulation in tumors. Autophagy regulates various cellular functions, including metabolism of glucose, glutamine, and lipids, cell proliferation, metastasis, and several types of cell death (apoptosis, ferroptosis, necroptosis and immunogenic cell death). These multifaceted roles demonstrate the potential of autophagy to affect DNA damage repair, cell death pathways, proliferation and survival, which are critical in determining cancer cells’ response to chemotherapy. Therefore, targeting autophagy pathways presents a promising strategy to combat chemoresistance, as one of the major reasons for the failure in cancer patient treatment. Furthermore, autophagy modulates immune evasion and the function of immune cells such as T cells and dendritic cells, influencing the tumor microenvironment and cancer’s biological behavior. However, the therapeutic targeting of autophagy is complex due to its dual role in promoting survival and inducing cell death in cancer cells, highlighting the need for strategies that consider both the beneficial and detrimental effects of autophagy modulation in cancer therapy. Hence, both inducers and inhibitors of autophagy have been introduced for the treatment of cancer. This review emphasizes the intricate interplay between autophagy, tumor biology, and immune responses, offering insights into potential therapeutic approaches that deploy autophagy in the cancer suppression.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101170"},"PeriodicalIF":15.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721174","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":"Modeling the epidemiologic impact of age-targeted vaccination for drug-resistant tuberculosis","authors":"Pei-Yao Zhai ,&nbsp;Zhi-Xian Chen ,&nbsp;Ting Jiang ,&nbsp;Jian Feng ,&nbsp;Bin Zhang ,&nbsp;Xiao Zang ,&nbsp;Yan-Lin Zhao ,&nbsp;Gang Qin","doi":"10.1016/j.drup.2024.101172","DOIUrl":"10.1016/j.drup.2024.101172","url":null,"abstract":"<div><div>This study used a calibrated mathematical model to evaluate age-specific tuberculosis (TB) vaccination strategies, for drug-resistant (DR)-TB management in China. Prioritizing elderly vaccination significantly reduced multidrug-resistant or rifampicin-resistant TB incidence and mortality, while avoiding the need for second-line treatment, offering a promising approach to mitigate DR-TB burden by 2050.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101172"},"PeriodicalIF":15.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zebrafish patient-derived xenograft system for predicting carboplatin resistance and metastasis of ovarian cancer","authors":"Feifeng Song ,&nbsp;Xiaofen Yi ,&nbsp;Xiaowei Zheng ,&nbsp;Zhentao Zhang ,&nbsp;Linqian Zhao ,&nbsp;Yan Shen ,&nbsp;Ye Zhi ,&nbsp;Ting Liu ,&nbsp;Xiaozhen Liu ,&nbsp;Tong Xu ,&nbsp;Xiaoping Hu ,&nbsp;Yiwen Zhang ,&nbsp;Huafeng Shou ,&nbsp;Ping Huang","doi":"10.1016/j.drup.2024.101162","DOIUrl":"10.1016/j.drup.2024.101162","url":null,"abstract":"<div><h3>Aims</h3><div>Ovarian cancer (OC) remains a significant challenge in oncology due to high rates of drug resistance and disease relapse following standard treatment with surgery and platinum-based chemotherapy. Despite the widespread use of these treatments, no effective biomarkers currently exist to identify which patients will respond favorably to therapy. This study introduces a zebrafish patient-derived xenograft (PDX) system, capable of replicating both the carboplatin response and metastatic behavior observed in OC patients, within a rapid 3-day assay period.</div></div><div><h3>Methods</h3><div>Two OC cell lines: carboplatin-sensitive (A2780) and resistant (OVCAR8) were used to assess differential responses to treatment in murine and zebrafish xenograft models. Tumor tissues from 16 OC patients were implanted into zebrafish embryos to test carboplatin responses and predict metastasis. Additionally, eight clinical OC samples were directly implanted into zebrafish embryos as part of a proof-of-concept demonstration.</div></div><div><h3>Results</h3><div>The zebrafish xenografts accurately reflected the carboplatin sensitivity and resistance patterns seen in <em>in vitro</em> and murine models. The zebrafish PDX model demonstrated a 67 % success rate for implantation and a 100 % success rate for engraftment. Notably, the model effectively distinguished between metastatic and non-metastatic disease, with an area under the ROC curve (AUC) of 0.818. Furthermore, the zebrafish PDX model showed a high concordance with patient-specific responses to carboplatin.</div></div><div><h3>Conclusions</h3><div>This zebrafish PDX model offers a fast, accurate, and clinically relevant platform for evaluating carboplatin response and predicting metastasis in OC patients. It holds significant potential for advancing personalized medicine, allowing for more precise therapeutic outcome predictions and individualized treatment strategies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101162"},"PeriodicalIF":15.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMOD3 accelerated resistance to immunotherapy in KRAS-mutated pancreatic cancer through promoting autophagy-dependent degradation of ASCL4","authors":"Zhiwei He ,&nbsp;Dijie Zheng ,&nbsp;Futang Li ,&nbsp;Liwen Chen ,&nbsp;Changhao Wu ,&nbsp;Zhirui Zeng ,&nbsp;Chao Yu","doi":"10.1016/j.drup.2024.101171","DOIUrl":"10.1016/j.drup.2024.101171","url":null,"abstract":"<div><div>The high prevalence of KRAS mutations in pancreatic cancer (PC) is widely acknowledged and results in the resistance of targeted ferroptosis therapy and immunotherapy. Herein, via a CRISPR/Cas9 library screen, the effects of ferroptosis agonists were increased in KRAS-mutant PC cells upon knockout of tropomodulin 3 (TMOD3), while these effects were not observed in KRAS-wild-type cells. Increased levels of TMOD3 were found in PC tissues, particularly in those with KRAS mutations. The increase in TMOD3 expression was facilitated by KRAS via the ETS transcription factor ELK1. Liquid chromatography–mass spectrometry (LC/MS) showed that TMOD3 increased acyl-CoA synthetase long chain family member 4 (ACSL4) protein expression and fatty acid metabolism. Mechanistically, TMOD3 promoted F-actin polymerization, thereby facilitating the fusion of autophagosomes with lysosomes, increasing the degradation of the ACSL4 protein, and augmenting the ferroptosis-inducing effects of RSL3. These effects of TMOD3 were counteracted by the administration of cytochalasin, the removal of the α2 domain of TMOD3, or the introduction of a mutation at S71. Cangrelor, an FDA-approved drug, can target TMOD3. In a mouse model, the suppression of TMOD3 using cangrelor or gene silencing technology resulted in increased infiltration of CD8+ T cells into tumor tissues with KRAS mutations and exhibited a synergistic effect with the PD-1 antibody. In conclusion, TMOD3 was found to inhibit ferroptosis and induced the resistance to PD-1 antibody by facilitating the fusion of autophagosomes and lysosomes through the promotion of F-actin polymerization in KRAS-mutant PC. TMOD3 was identified as a novel target for PC therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101171"},"PeriodicalIF":15.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632056","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":"Revolutionising infection control: building the next generation of phage banks","authors":"Braira Wahid,&nbsp;Muhammad Salman Tiwana,&nbsp;Akhtar Ali","doi":"10.1016/j.drup.2024.101143","DOIUrl":"10.1016/j.drup.2024.101143","url":null,"abstract":"<div><div>The escalating global burden of antimicrobial resistance (AMR) represents a critical public health challenge. This rise in antibiotic resistance is concomitant with heightened antibiotic consumption, with an estimated annual usage of 100,000 to 200,000 tons. A recent systematic review, which analysed data from 204 countries, reported that AMR was responsible for 4.95 million deaths in 2019 (<span><span>Murray et al., 2022</span></span>). The growing threat of AMR is imposing a significant financial burden on the global economy, with the CDC reporting an additional annual cost of $20 billion in the U.S. and €9 billion in Europe. The emerging field of bacteriophage therapy offers promising potential as a game-changer in the era of AMR. However, existing literature reveals numerous research gaps and technological challenges, including insufficient information on phage pharmacology, genomics, and a lack of preclinical and clinical data. In addition to conducting further research to address existing knowledge gaps, establishing phage banks in clinical facilities could be a transformative advancement in the fight against AMR.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101143"},"PeriodicalIF":15.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100765","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":"Targeting NQO1 induces ferroptosis and triggers anti-tumor immunity in immunotherapy-resistant KEAP1-deficient cancers","authors":"Zhennan Yuan ,&nbsp;Xueying Wang ,&nbsp;Boyu Qin ,&nbsp;Rulong Hu ,&nbsp;Rui Miao ,&nbsp;Yang Zhou ,&nbsp;Lei Wang ,&nbsp;Tong Liu","doi":"10.1016/j.drup.2024.101160","DOIUrl":"10.1016/j.drup.2024.101160","url":null,"abstract":"<div><div>Immunotherapy has revolutionized cancer treatment, yet the efficacy of immunotherapeutic approaches remains limited. Resistance to ferroptosis is one of the reasons for the poor therapeutic outcomes in tumors with Kelch-like ECH-associated protein 1 (KEAP1) mutations. However, the specific mechanisms by which KEAP1-mutant tumors resist immunotherapy are not fully understood. In this study, we showed that the loss of function in KEAP1 results in resistance to ferroptosis. We identified NAD(P)H Quinone Dehydrogenase 1 (NQO1) as a transcriptional target of nuclear factor erythroid 2–related factor 2 (NRF2) and revealed that inducing NQO1-mediated ferroptosis in KEAP1-deficient tumors triggers an antitumor immune cascade. Additionally, it was found that NQO1 protein levels could serve as a candidate biomarker for predicting sensitivity to immunotherapy in clinical tumor patients. We validated these findings in several preclinical tumor models. Overall, KEAP1 mutations define a unique disease phenotype, and targeting its key downstream molecule NQO1 offers new hope for patients with resistance to immunotherapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101160"},"PeriodicalIF":15.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142552011","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}