Cancer & Metabolism最新文献

{"title":"Sustained reductions in valine and isoleucine mediate anti-cancer pharmacological effects of inhibiting amino acid transporter LAT1 in cancer cells.","authors":"Kou Nishikubo, Ryuichi Ohgaki, Hiroki Okanishi, Minhui Xu, Yoshikatsu Kanai","doi":"10.1186/s40170-025-00415-0","DOIUrl":"10.1186/s40170-025-00415-0","url":null,"abstract":"<p><strong>Background: </strong>L-type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids (LNAAs), is highly upregulated in various cancers and represents a promising therapeutic target. The first-in-class LAT1-specific inhibitor, nanvuranlat (JPH203, KYT-0353), has exhibited potent anti-cancer effects and is under clinical evaluation. However, alterations in the amino acid availability in cancer cells underlying its pharmacological activities remain to be elucidated.</p><p><strong>Methods: </strong>Amino acids in nanvuranlat-treated cancer cells were measured by high-performance liquid chromatography. LAT1 knockdown was performed using siRNA. To mimic LAT1 inhibition, cancer cells were incubated in culture media lacking specific LNAA(s) reduced by nanvuranlat. The consequences of these treatments were compared by cell-based assays, including analyses of amino acid contents, cell growth, amino acid-related signaling pathways, cell cycle, ATP production rate, and transcriptomes by RNA sequencing. Metabolome of nanvuranlat-treated and untreated cells was compared by mass spectrometry. The effects of nanvuranlat on amino acid composition were also examined in three-dimensional cancer cell spheroids.</p><p><strong>Results: </strong>Both pharmacological and genetic inhibition of LAT1 preferentially and continuously reduced valine, isoleucine, and tryptophan in pancreatic cancer MIA PaCa-2 cells. Nanvuranlat induced similar alterations in intracellular amino acids in multiple cancer cell lines. Depletion of these amino acids from culture media selectively lowered their intracellular concentrations, recapitulating the effects of nanvuranlat on cell growth, amino acid-related mTORC1/GAAC signaling pathways, and cell cycle. Deprivation of valine or isoleucine exhibited more pronounced impacts than tryptophan in all assays. As a novel pharmacological action of nanvuranlat mediated by the reductions in valine and isoleucine, we revealed downregulation of multiple genes in the TCA cycle and respiratory chain, accompanied by a decreased mitochondrial ATP production rate. Consistently, metabolomics revealed broad decreases in the TCA cycle intermediates by LAT1 inhibition. Nanvuranlat also similarly influenced the amino acid levels in cancer cell spheroids.</p><p><strong>Conclusions: </strong>Reductions in valine and isoleucine in cancer cells primarily account for the multifaceted anti-cancer pharmacological activities of LAT1 inhibition by nanvuranlat. This study establishes the molecular basis for LAT1-targeted therapy and highlights growth-promoting processes in cancer cells that can be exploited pharmacologically by modulating the availability of specific amino acids.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"46"},"PeriodicalIF":5.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12673697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cdk5 regulates glutamine metabolism in colorectal cancer via the EZH2-GLS1 axis.","authors":"Qilong Wu, Xiaotong Zhu, Xinxin Wan, Xinjie Lu, Jiayan Chen, Zhe Ying, Yan Li, Xing Hu, Jiahai Lu, Yongliang Lou, Xiang Li","doi":"10.1186/s40170-025-00414-1","DOIUrl":"10.1186/s40170-025-00414-1","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production-collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":" ","pages":"1"},"PeriodicalIF":5.3,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12790122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix composition and glucose availability cooperatively determine cancer spheroid bioenergetics in 3D hydrogels.","authors":"Paula Guerrero-López, Gorana Drobac, Eduardo A Silva, Hanne R Hagland, José Manuel García-Aznar","doi":"10.1186/s40170-025-00413-2","DOIUrl":"10.1186/s40170-025-00413-2","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"45"},"PeriodicalIF":5.3,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12628585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: A role of arginase-1-expressing myeloid cells in cachexia.","authors":"Apsana Lamsal, Sonja Benedikte Andersen, Unni Nonstad, Natalie Jayne Kurganovs, Richard Je Skipworth, Geir Bjørkøy, Kristine Pettersen","doi":"10.1186/s40170-025-00412-3","DOIUrl":"10.1186/s40170-025-00412-3","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"44"},"PeriodicalIF":5.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12593791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming in diffuse intrinsic pontine gliomas (DIPG): dual inhibition of mitochondrial oxidative phosphorylation and lactate metabolism to enhance anti-tumor and radiosensitizing effects in DIPG cells.","authors":"Han Shen, Quy-Susan Huynh, Faiqa Mudassar, Cecilia Chang, Brian Gloss, Prunella Ing, Shiyong Ma, Harriet Gee, Eric Hau, Kristina M Cook","doi":"10.1186/s40170-025-00411-4","DOIUrl":"10.1186/s40170-025-00411-4","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"43"},"PeriodicalIF":5.3,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12570633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay between malic enzyme 2, de novo serine synthesis, and the malate-aspartate shuttle drives metabolic adaptation in triple-negative breast cancer.","authors":"Jin Heon Jeon, Mark D Slayton, Ben Krinkel, Olamide Animasahun, Ajay Shankaran, Fulei Wuchu, Minal Nenwani, Zackariah Farah, Julia Burke, Abhinav Achreja, Brisilda Nilaj, Kerslee Kohagen, Yi-Hsien Eu, Alyssa Rosenfeld, Mason Collard, Liwei Bao, Xu Cheng, Celina Kleer, Christopher Squire, Kerry Loomes, Deepak Nagrath, Sofia D Merajver","doi":"10.1186/s40170-025-00410-5","DOIUrl":"10.1186/s40170-025-00410-5","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"42"},"PeriodicalIF":5.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The integration of single-cell and metabolomics reveals the increase of oxidative phosphorylation during the liver metastasis of colorectal cancer.","authors":"Tianyu Liu, Sizheng Sun, Yicheng Huang, Yiming E, Wenyuan Li, Fanggui Xu, Zhengxia Liu, Xiagang Luo, Chen Lu, Chunzhao Yu","doi":"10.1186/s40170-025-00408-z","DOIUrl":"10.1186/s40170-025-00408-z","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is among the most prevalent malignant tumors, with liver metastasis as the leading cause of mortality. Although metabolic reprogramming is known to play a crucial role in tumor metastasis, our understanding of this process during colorectal cancer liver metastasis (CRLM) remains limited.</p><p><strong>Methods: </strong>A stepwise mouse model of CRC liver metastasis was developed, and metabolomic profiling was performed to verify model stability and identify metabolic changes. Single-cell RNA sequencing (scRNA-seq) was used to assess oxidative phosphorylation (OXPHOS) activity within the metastatic tumor microenvironment (TME). Additionally, spatial transcriptomics (ST) was conducted to elucidate the spatial distribution of metabolic phenotypes within metastatic sites. Finally, in vivo experiments were conducted by administering TGFβ inhibitor (LY2157299) or OXPHOS inhibitor (IACS-010759) to evaluate the potential for liver metastasis, and in vitro, the functions of HCT116 and SW620 cells were assessed through Transwell assays and oxygen consumption rate (OCR) measurements.</p><p><strong>Results: </strong>Metabolomic profiling revealed heightened tricarboxylic acid (TCA) cycle activity in liver metastases. ScRNA-seq analysis showed increased OXPHOS in metastatic cells, including a highly malignant cell subtype characterized by augmented OXPHOS. Further analysis identified a significant upregulation of OXPHOS associated with TGFβ pathway activation. ST localized this OXPHOS -enriched subtype within metastatic tissue. Both in vivo and in vitro experiments demonstrate that inhibition of TGFβ signaling reduces OXPHOS activity, thereby attenuating the progression of colorectal cancer liver metastasis.</p><p><strong>Conclusions: </strong>This study identifies OXPHOS upregulation as a key metabolic alteration during CRC liver metastasis, which could be induced by TGFβ signaling pathway. These findings contribute to a refined understanding of CRC metabolic adaptation in liver metastases and may inform therapeutic strategies targeting OXPHOS in advanced CRC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"41"},"PeriodicalIF":5.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pressure-adjusted static compression: aerobic metabolism and microvascular perfusion in the context of chemotherapy-induced neuropathy.","authors":"Betty Lischke, Josef Mohammad, René Rheimann, Anne Schraplau, Antonia Haspel, André Schmidt-Lucke, Sebastian Ochsenreither, Ulrich Keller, Helmut Habazettl, Caroline Schmidt-Lucke","doi":"10.1186/s40170-025-00409-y","DOIUrl":"10.1186/s40170-025-00409-y","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy-induced peripheral neuropathy (CIPN) involves impaired microvascular neuronal perfusion and reduced bioenergetics. Compression and cryotherapy are potential preventive measures, yet their mechanism of acral temperature reduction remains unclear. This study aims to unravel the effects of pressure-adjusted static compression (PSC) on aerobic metabolic and endothelial responses in patients undergoing chemotherapy (CTX).</p><p><strong>Methods: </strong>Cancer patients with CTX above the CIPN-threshold dose (n = 24, 50% male; age 64 [61-71] years) and healthy controls (n = 53, 45% male; age 23 (18 to 87) years) had PSC applied on upper extremities. Tissue oxygenation and metabolism were derived by measuring oxygen supply (O₂Hb), oxygen demand (HHb), tissue oxygenation (TOI) and microvascular perfusion (THb) with quantitative time-resolved near-infrared spectroscopy (NIRS) and temperature with thermography. Effects were compared to cryoapplication and intermittent pneumatic compression (IPC). Endothelial function was quantified during vascular occlusion test (VOT).</p><p><strong>Results: </strong>PSC, in contrast to undersized surgical gloves (SG), uniformly creates pressure on hands and leads to a more pronounced reduction of hand temperature. Furthermore, PSC significantly increased microvascular perfusion, O₂-supply and reduced O₂-demand and aerobic metabolism, thus raised local tissue oxygenation (p < 0.05 each). CTX lead to impaired metabolic and vascular reaction to PSC with only significant reduction of O₂-demand (p < 0.05) during PSC. PSC is preferable regarding comfort (p < 0.05) compared to SG. Cooling of hands (cooling gloves) had different action (p < 0.001) to PSC with significantly reduced microvascular perfusion, O₂-supply and O₂-demand (p < 0.05 each). Comparable local significant effects (p < 0.05) were seen during IPC. CTX exhibited endothelial dysfunction with impaired microvascular reactivity, which limited their capacity to enhance tissue oxygenation.</p><p><strong>Conclusions: </strong>Reduction of oxygen demand represents an important mechanism in interventions targeting prevention of CIPN. PSC, comparable to cryoapplication and IPC attenuates energy metabolism and enhances tissue oxygenation. PSC's impact on the combination of vascular and energy metabolism suggests its potential to alleviate CIPN burden. These findings support PSC's role in reducing acral CIPN through distinct mechanisms.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"40"},"PeriodicalIF":5.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.","authors":"Renan Fl Vieira, Sawyer R Sanchez, Menusha Arumugam, Peyton D Mower, Meghan C Curtin, Abigail E Jackson, Molly R Gallop, Jillian Wright, Alexis Bowles, Gregory S Ducker, Keren I Hilgendorf, Amandine Chaix","doi":"10.1186/s40170-025-00407-0","DOIUrl":"10.1186/s40170-025-00407-0","url":null,"abstract":"<p><p>Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology, and, while obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 and Py230 orthotopic models of obesity-accelerated BC growth in immune-competent mice, we investigated the role of systemic lipids on tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in individuals with obesity.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"39"},"PeriodicalIF":5.3,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.","authors":"Xu Han, Laura C Kim, Nicholas P Lesner, Xuanyan Cai, Tran Ngoc Van Le, M Celeste Simon","doi":"10.1186/s40170-025-00389-z","DOIUrl":"10.1186/s40170-025-00389-z","url":null,"abstract":"<p><strong>Background: </strong>Lipid homeostasis is critical for pancreatic adenocarcinoma (PDAC) cell survival under hypoxic and nutrient-deprived conditions. Hypoxia inhibits unsaturated lipid biosynthesis, compelling cancer cells to depend on exogenous unsaturated lipids to counteract saturated lipid-induced toxicity. Our previous work revealed that cancer-associated fibroblasts (CAFs) secrete unsaturated lipids, primarily lysophosphatidylcholines (LPCs), to alleviate lipotoxic stress in PDAC cells. Here, we conducted a drug screen to identify compounds that bypass the rescue effect of exogenous LPCs on cancer cell survival under stress.</p><p><strong>Methods: </strong>We employed high-throughput screening of a bioactive chemical library with 3,336 compounds, including FDA-approved drugs and drug-like molecules against defined molecular targets. Two assays were performed: a cytotoxicity assay to exclude indiscriminately toxic compounds at 1 μM and an LPC crosstalk inhibition assay to identify compounds that selectively reduce cancer cell viability in the presence of LPCs under stress conditions.</p><p><strong>Results: </strong>CB-839, a glutaminase inhibitor, was identified as the most effective compound, selectively inhibiting the LPC-mediated rescue of PDAC cell viability effect without intrinsic cytotoxicity. Mechanistic studies revealed that CB-839 induces cell death by activating the pro-apoptotic ATF4/CHOP pathway, reducing antioxidant production, and increasing reactive oxygen species (ROS). While CB-839 showed limited efficacy against PDAC tumor cells alone in vivo, it modestly inhibited tumor growth in a PDAC-CAF co-implanted subcutaneous mouse model, highlighting its potential to disrupt CAF-mediated nutrient support. Additionally, glutamine antagonists showed more potent tumor-suppressive effects than CB-839.</p><p><strong>Conclusion: </strong>Our findings emphasize the importance of glutamine metabolism inhibition in suppressing tumor growth and disrupting CAF-mediated crosstalk. We further underscore the potential of glutamine antagonist prodrugs as a strategy to target metabolic vulnerabilities in PDAC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"13 1","pages":"38"},"PeriodicalIF":5.3,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}