{"title":"Selective killing of castration-resistant prostate cancer cells by formycin A via the ATF4–CHOP axis","authors":"Tomoki Takei, Yuki Hamamura, Hiroshi Hongo, Etsu Tashiro, Masaya Imoto, Takeo Kosaka, Mototsugu Oya","doi":"10.1111/cas.16349","DOIUrl":"10.1111/cas.16349","url":null,"abstract":"<p>Prostate cancer is initially androgen-dependent but often relapses to an androgen-independent state called castration-resistant prostate cancer (CRPC). Currently approved therapies have limited efficacy against CRPC, highlighting the need for novel therapeutic strategies. To address this need, we conducted a drug screen in our previously established aggressive CRPC cell model. We found that formycin A induced cell death in CRPC model cells but not in parental prostate cancer cells. In addition, formycin A upregulated death receptor 5 through the induction of endoplasmic reticulum stress, activating the “extrinsic” apoptosis pathway in CRPC model cells. Moreover, formycin A showed in vivo antitumor efficacy against CRPC xenografts in castrated nude mice. Thus, our findings highlight the potential of formycin A as a CRPC therapeutic.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 12","pages":"3997-4007"},"PeriodicalIF":4.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16349","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Decreased PU.1 expression in mature B cells induces lymphomagenesis","authors":"Shinya Endo, Nao Nishimura, Kosuke Toyoda, Yoshihiro Komohara, Joaquim Carreras, Hiromichi Yuki, Takafumi Shichijo, Shikiko Ueno, Niina Ueno, Shinya Hirata, Yawara Kawano, Kisato Nosaka, Masashi Miyaoka, Naoya Nakamura, Ai Sato, Kiyoshi Ando, Hiroaki Mitsuya, Koichi Akashi, Daniel G. Tenen, Jun-ichirou Yasunaga, Masao Matsuoka, Yutaka Okuno, Hiro Tatetsu","doi":"10.1111/cas.16344","DOIUrl":"10.1111/cas.16344","url":null,"abstract":"<p>Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non-Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by <i>Spi1</i>, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non-germinal center B-cell-like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional <i>Spi1</i> knockout mice using <i>Cγ1-Cre</i> mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B-cell lymphomas. In contrast, no wild-type mice developed B-cell lymphoma. In addition, RNA-seq analysis of lymphoma cells from <i>Cγ1-Cre Spi1</i><sup><i>F/F</i></sup> mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral-transduced <i>Spi1</i> rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B-cell lymphoma development.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 12","pages":"3890-3901"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy","authors":"Shinsei Yumoto, Haruki Horiguchi, Tsuyoshi Kadomatsu, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata, Toshiro Moroishi, Hideo Baba, Yuichi Oike","doi":"10.1111/cas.16348","DOIUrl":"10.1111/cas.16348","url":null,"abstract":"<p>Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor “immunophenotypes” governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 12","pages":"3846-3858"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models","authors":"Ryo Tsumura, Takahiro Anzai, Yoshikatsu Koga, Hiroki Takashima, Yasuhiro Matsumura, Masahiro Yasunaga","doi":"10.1111/cas.16335","DOIUrl":"10.1111/cas.16335","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) have been recognized as a promising class of cancer therapeutics. Tissue factor (TF), an initiator of the blood coagulation pathway, has been investigated regarding its relationship with cancer, and several preclinical and clinical studies have presented data on anti-TF ADCs, including tisotumab vedotin, which was approved in 2021. However, the feasibility of other payloads in the design of anti-TF ADCs is still unclear because no reports have compared payloads with different cytotoxic mechanisms. For ADCs targeting other antigens, such as Her2, optimizing the payload is also an important issue in order to improve in vivo efficacy. In this study, we prepared humanized anti-TF Ab (clone.1084) conjugated with monomethyl auristatin E (MMAE) or deruxtecan (DXd), and evaluated the efficacy in several cell line- and patient-derived xenograft models of pancreatic cancer. As a result, optimizing the drug / Ab ratio was necessary for each payload in order to prevent pharmacokinetic deterioration and maximize delivery efficiency. In addition, MMAE-conjugated anti-TF ADC showed higher antitumor effects in tumors with strong and homogeneous TF expression, while DXd-conjugated anti-TF ADC was more effective in tumors with weak and heterogeneous TF expression. Analysis of a pancreatic cancer tissue array showed weak and heterogeneous TF expression in most TF-positive specimens, indicating that the response rate to pancreatic cancer might be higher for DXd- than MMAE-conjugated anti-TF ADC. Nevertheless, our findings indicated that optimizing the ADC payloads individually in each patient could maximize the potential of ADC therapeutics.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 12","pages":"3986-3996"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Real-world genome profiling in Japanese patients with pancreatic ductal adenocarcinoma focusing on HRD implications","authors":"Toshifumi Doi, Takeshi Ishikawa, Tomoki Sakakida, Junichiro Itani, Daiki Sone, Ryuichi Morita, Seita Kataoka, Hayato Miyake, Yuya Seko, Kanji Yamaguchi, Michihisa Moriguchi, Yoshio Sogame, Hideyuki Konishi, Kyoko Murashima, Masahiro Iwasaku, Koichi Takayama, Yoshito Itoh","doi":"10.1111/cas.16329","DOIUrl":"10.1111/cas.16329","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges due to its high mortality, making it a critical area of research. This retrospective observational study aimed to analyze real-world data from comprehensive genome profiling (CGP) of Japanese patients with PDAC, mainly focusing on differences in gene detection rates among panels and the implications for homologous recombination deficiency (HRD) status. This study enrolled 2568 patients with PDAC who had undergone CGP between June 2019 and December 2021 using data from the nationwide Center for Cancer Genomics and Advanced Therapeutics database. Two types of CGP assays (tissue and liquid biopsies) were compared and a higher detection rate of genetic abnormalities in tissue specimens was revealed. HRD-related gene alterations were detected in 23% of patients, with <i>BRCA1/2</i> mutations accounting for 0.9% and 2.9% of patients, respectively. Treatment outcome analysis indicated that patients with <i>BRCA1/2</i> mutations had a longer time to treatment discontinuation with FOLFIRINOX than gemcitabine plus nab-paclitaxel as first-line therapy (9.3 vs. 5.6 months, <i>p</i> = 0.028). However, no significant differences were observed in the treatment response among the other HRD-related genes. Logistic regression analysis identified younger age and family history of breast, prostate, and ovarian cancers as predictive factors for HRD-related gene alterations. Despite the lack of progression-free survival data and the inability to discriminate between germline and somatic mutations, this study provides valuable insights into the clinical implications of CGP in Japanese patients with PDAC. Further research is warranted to optimize panel selection and elucidate the efficacy of platinum-based therapies depending on the HRD status.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 11","pages":"3729-3739"},"PeriodicalIF":4.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"BBOX1-AS1 promotes gastric cardia adenocarcinoma progression via interaction with CtBP2 to facilitate the epithelial–mesenchymal transition process","authors":"Wenxu Zou, Qing Yin, Wei Guo, Zhiming Dong, Yanli Guo","doi":"10.1111/cas.16350","DOIUrl":"10.1111/cas.16350","url":null,"abstract":"<p>It is recognized that lncRNA BBOX1-AS1 exerts a crucial oncogenic property in several cancer types. However, the functions and underlying mechanisms of BBOX1-AS1 in the epithelial–mesenchymal transition (EMT) process of gastric cardia adenocarcinoma (GCA) have remained unclarified. The findings of this study demonstrated that GCA tissues had elevated BBOX1-AS1 expression levels, which was associated with a worse prognosis in GCA patients. BBOX1-AS1 dramatically enhanced cell proliferation, invasion, and TGF-β1-induced the EMT process in vitro. Further mechanism analysis revealed that BBOX1-AS1 could combine with CtBP2 and strengthen the interaction of CtBP2 and ZEB1. BBOX1-AS1 might regulate the E-cadherin expression through CtBP2/ZEB1 transcriptional complex-mediated transcriptional repression, further affecting the activation of the Wnt/β-catenin pathway and the EMT process. Overall, our findings demonstrate that BBOX1-AS1 might act as an lncRNA associated with EMT for facilitating GCA advancement via interaction with CtBP2 to facilitate the activation of Wnt/β-catenin pathway and the EMT process, which indicated that it might function as an exploitable treatment target for GCA patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 12","pages":"3875-3889"},"PeriodicalIF":4.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer SciencePub Date : 2024-09-23DOI: 10.1111/cas.16357
{"title":"Correction to “Expression of concern: Hydroxychavicol, a Piper betle leaf component, induces apoptosis of CML cells through mitochondrial reactive oxygen species-dependent JNK and endothelial nitric oxide synthase activation and overrides imatinib resistance”","authors":"","doi":"10.1111/cas.16357","DOIUrl":"10.1111/cas.16357","url":null,"abstract":"<p><i>Cancer Science</i> 115, no. 6 (2024): 2086–2086, https://doi.org/10.1111/cas.16155.</p><p>The originally published version of this Expression of Concern has been updated to include new information raised to us by a third party. The additional text is found below:</p><p>“Subsequently, additional concerns have been raised about Figure 1e DAPI panels, that show high similarity with images from the authors' previous publication, and about Figure 3b HCH subpanel, which includes highly similar cellular sections. The authors were unable to provide a satisfactory explanation, and due to the elapsed time, the original images and the raw data of the manuscript were no longer available.”</p><p>The online version of the originally published Expression of Concern has been corrected accordingly.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 12","pages":"4081"},"PeriodicalIF":4.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Interpretable machine learning model predicting immune checkpoint inhibitor-induced hypothyroidism: A retrospective cohort study","authors":"Su-Yan Zhu, Tong-Tong Yang, Yi-Zhuo Zhao, Yu Sun, Xiao-Meng Zheng, Hong-Bin Xu","doi":"10.1111/cas.16352","DOIUrl":"10.1111/cas.16352","url":null,"abstract":"<p>Hypothyroidism is a known adverse event associated with the use of immune checkpoint inhibitors (ICIs) in cancer treatment. This study aimed to develop an interpretable machine learning (ML) model for individualized prediction of hypothyroidism in patients treated with ICIs. The retrospective cohort of patients treated with ICIs was from the First Affiliated Hospital of Ningbo University. ML methods applied include logistic regression (LR), random forest classifier (RFC), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver-operating characteristic curve (AUC) was the main evaluation metric used. Furthermore, the Shapley additive explanation (SHAP) was utilized to interpret the outcomes of the prediction model. A total of 458 patients were included in the study, with 59 patients (12.88%) observed to have developed hypothyroidism. Among the models utilized, XGBoost exhibited the highest predictive capability (AUC = 0.833). The Delong test and calibration curve indicated that XGBoost significantly outperformed the other models in prediction. The SHAP method revealed that thyroid-stimulating hormone (TSH) was the most influential predictor variable. The developed interpretable ML model holds potential for predicting the likelihood of hypothyroidism following ICI treatment in patients. ML technology offers new possibilities for predicting ICI-induced hypothyroidism, potentially providing more precise support for personalized treatment and risk management.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 11","pages":"3767-3775"},"PeriodicalIF":4.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cholesterol synthesis is essential for the growth of liver metastasis-prone colorectal cancer cells","authors":"Kumiko Taniguchi, Kei Sugihara, Takashi Miura, Daisuke Hoshi, Susumu Kohno, Chiaki Takahashi, Eishu Hirata, Etsuko Kiyokawa","doi":"10.1111/cas.16331","DOIUrl":"10.1111/cas.16331","url":null,"abstract":"<p>Metastasis to the liver is a leading cause of death in patients with colorectal cancer. To investigate the characteristics of cancer cells prone to metastasis, we utilized an isogenic model of BALB/c and colon tumor 26 (C26) cells carrying an active <i>KRAS</i> mutation. Liver metastatic (LM) 1 cells were isolated from mice following intrasplenic transplantation of C26 cells. Subsequent injections of LM1 cells generated LM2 cells, and after four cycles, LM4 cells were obtained. In vitro, using a perfusable capillary network system, we found comparable extravasation frequencies between C26 and LM4 cells. Both cell lines showed similar growth rates in vitro. However, C26 cells showed higher glucose consumption, whereas LM4 cells incorporated more fluorescent fatty acids (FAs). Biochemical analysis revealed that LM4 cells had higher cholesterol levels than C26 cells. A correlation was observed between fluorescent FAs and cholesterol levels detected using filipin III. LM4 cells utilized FAs as a source for cholesterol synthesis through acetyl-CoA metabolism. In cellular analysis, cholesterol accumulated in punctate regions, and upregulation of NLRP3 and STING proteins, but not mTOR, was observed in LM4 cells. Treatment with a cholesterol synthesis inhibitor (statin) induced LM4 cell death in vitro and suppressed LM4 cell growth in the livers of nude mice. These findings indicate that colorectal cancer cells prone to liver metastasis show cholesterol-dependent growth and that statin therapy could help treat liver metastasis in immunocompromised patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 11","pages":"3817-3828"},"PeriodicalIF":4.5,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Improved platelet separation performance from whole blood using an acoustic fluidics system","authors":"Kazuko Sakai, Shuta Ohara, Junko Tanaka, Kenichi Suda, Takamichi Muramatsu, Chihiro Uematsu, Yasuhiro Tsutani, Tetsuya Mitsudomi, Kazuto Nishio","doi":"10.1111/cas.16337","DOIUrl":"10.1111/cas.16337","url":null,"abstract":"<p>This study investigated the effectiveness of acoustic separation for platelet analysis in patients with non–small-cell lung cancer (NSCLC), comparing it with traditional centrifugation methods. In total, 10 patients with NSCLC and 10 healthy volunteers provided peripheral blood samples, which were processed using either acoustic separation or centrifugation to isolate platelets. The study included whole transcriptome analysis of platelets, peripheral blood mononuclear cells, and tumor tissue samples, employing hierarchical clustering and Gene Ontology analysis to explore gene expression differences. Acoustic separation proved more efficient than centrifugation in terms of platelet yield, recovery rate, and RNA yield. Gene expression profiles of platelets from patients with NSCLC showed distinct patterns compared with healthy volunteers, indicating tumor-influenced alterations. Gene Ontology analysis revealed enrichment in pathways associated with platelet activation and the tumor microenvironment. This finding indicates the potential of acoustic isolation in platelet separation and its relevance in understanding the unique gene expression profile of platelets in patients with NSCLC. The findings of this study suggested that platelets from cancer patients separated by acoustic techniques exhibited tumor-specific alterations and provided new insights into the diagnosis of cancer in platelet analysis systems in clinical practice.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 11","pages":"3795-3803"},"PeriodicalIF":4.5,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}