Cancer heterogeneity and plasticity最新文献

{"title":"Hippo-YAP/TAZ signaling in gastric cancer: orchestrating epithelial-stromal heterogeneity, plasticity, and therapy resistance.","authors":"Junsong Zhao, Curt Balch, Dipti Athavale, Yanting Zhang, Xiaodan Yao, Mikel Ghelfi, Madeline B Torres, Young Ki Hong, Jamin Morrison, Francis Spitz, Generosa Grana, Shumei Song","doi":"10.47248/chp2603030008","DOIUrl":"10.47248/chp2603030008","url":null,"abstract":"<p><p>Gastric cancer is a lethal malignancy with highly variable clinical behavior, reflecting both inter-tumor diversity and marked heterogeneity within individual lesions. Large-scale genomics data (including TCGA and ACRG) has delineated recurring molecular subtypes, while expression- and immunohistochemistry-based schemes provide clinically practical surrogates. However, single-cell and spatial profiling reveal that most tumors comprise multiple malignant epithelial states alongside diverse cancer-associated fibroblast (CAF) and immune programs that vary spatially, evolve during progression, and are remodeled by therapy. The Hippo pathway effectors YAP and TAZ act as central integrators of oncogenic, inflammatory, and mechanical cues that coordinate these dynamic states. In gastric cancer, YAP/TAZ activity is enriched in diffuse/EMT-like and mesenchymal phenotypes, associates with peritoneal dissemination, and contributes to immune evasion and treatment resistance. Here, we link YAP/TAZ activity to gastric cancer subtype heterogeneity and emphasize two interconnected dimensions: (i) cell heterogeneity, encompassing coexisting epithelial lineage states and CAF subsets within tumors; and (ii) cell plasticity, highlighting reversible transitions that enable invasion, metastasis, and drug resistance. Finally, we propose a framework of YAP/TAZ-governed epithelial-stromal ecotypes and discuss implications for biomarkers and rational combination strategies incorporating Hippo-targeted agents with chemotherapy, stromal modulation, and immunotherapy.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"3 3","pages":"0008"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keratin 5 expression defines a niche-supported hierarchy in tubo-ovarian cancer.","authors":"Zhiyu Tian, Karen McLean","doi":"10.47248/chp2603020006","DOIUrl":"10.47248/chp2603020006","url":null,"abstract":"<p><p>Tubo-ovarian high-grade serous carcinoma (HGSC) is characterized by extreme cellular heterogeneity. A tumorigenic subset of cancer-propagating cells (CPC) with stem-like properties coexists with a large population of non-cancer-propagating cells (non-CPC), but the functional interplay between these two cell types remains poorly understood. In this issue, Bidarimath et al. identify keratin 5 (KRT5) as a marker of CPC in HGSC and propose a niche model in which osteopontin (OPN) sustains KRT5-positive CPC through interactions with KRT5-negative, non-tumorigenic cells. By combining in vitro, in vivo, and patient-derived data, the study links a supportive tumor microenvironment to the maintenance of a phenotypically defined CPC population.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13271655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148274493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP1 depletion enhances TAZ and its complexation with TEAD4 and AP-1 heterodimer C-JUN/FOSB in gastric cancer progression and metastasis.","authors":"Jingjing Wu, Dipti Athavale, Curt Balch, Junsong Zhao, Gengyi Zou, Yibo Fan, Yanting Zhang, Joseph Zhao, Mikel Ghelfi, Anthony Pompetti, Gennaro Calendo, Ailing Scott, Shan Shao, Xiaodan Yao, Melissa Pool Pizzi, Christopher Vellano, Vladimir Khazak, Sheng Zhang, Timothy A Yap, Shilpa S Dhar, Raghav Sundar, Francis Spitz, Generosa Grana, Jaffer A Ajani, Shumei Song","doi":"10.47248/chp2603010003","DOIUrl":"10.47248/chp2603010003","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of the Hippo signaling pathway, characterized by aberrant activation of the transcriptional coactivators YAP1 and TAZ, drives tumor progression, immunosuppression, and metastasis. Hippo pathway components are emerging therapeutic targets in several solid tumors, however, the expression profiles of Hippo coactivators YAP1, TAZ, and their transcriptional factors TEAD1-4 in gastric cancer peritoneal metastases (GCPMs), and their therapeutic value, are unknown. In this study, we sought to determine the expression status of YAP1, TAZ, and TEAD1-4 in GCPMs and to evaluate whether dual targeting of YAP1 and TAZ provides superior antitumor activity compared with inhibition of either coactivator alone.</p><p><strong>Methods: </strong>Expression of YAP1, TAZ, and TEAD1-4 was examined in GCPMs by single-cell RNA sequencing and co-immunofluorescent staining. Functional studies using genetic knockout and antisense oligonucleotide (ASO) inhibition of YAP1 or TAZ were performed to assess antineoplastic effects <i>in vitro</i> and <i>in vivo</i>. Co-immunoprecipitation and luciferase reporter assays were used to characterize YAP1/TAZ interactions with TEADs and AP-1 components (JUN and FOSB) and to quantify transcriptional activity. Antitumor efficacy was validated in patient-derived xenograft (PDX) and KP-Luc2 syngeneic models.</p><p><strong>Results: </strong>YAP1, TAZ, and TEADs1- 4 were highly coexpressed in GCPMs and correlated with poor survival. YAP1 inhibition alone elicited compensatory upregulation of TAZ, while combined inhibition of both coactivators maximally repressed cell proliferation and invasion <i>in vitro</i>, and tumor growth <i>in vivo</i>. Increased TAZ complexation with TEAD4 and AP-1 (c-JUN and FOSB) heterodimer was observed following YAP1 knockdown or pharmacological ASO inhibition. Dual inhibition of YAP1 and TAZ was required to maximally suppress YAP1/TAZ expression and reduce their nuclear accumulation, transactivation of TEAD, and activation of downstream genes.</p><p><strong>Conclusions: </strong>These findings show that combined YAP1 and TAZ inhibition holds promise for the treatment of GCPM, a highly lethal disease with an urgent need for novel treatment options.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13334769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148440688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keratin 5 marks cancer-propagating cells sustained by an osteopontin-producing niche in high-grade serous ovarian carcinoma.","authors":"Mallikarjun Bidarimath, Coulter Q Ralston, Nandini Bidarimath, Ian M Rose, Darianna Colina, Elisa Schmoeckel, Andrew K Godwin, Doris Mayr, Lora H Ellenson, Andrea Flesken-Nikitin, Alexander Yu Nikitin","doi":"10.47248/chp2603020005","DOIUrl":"10.47248/chp2603020005","url":null,"abstract":"<p><p>High-grade serous carcinoma (HGSC) is the most common and aggressive form of ovarian cancer. Advanced HGSCs exhibit pronounced cellular heterogeneity, including a subset of cancer-propagating cells (CPCs, also known as cancer stem cells) that are highly tumorigenic and display stem cell-associated properties such as self-renewal and chemoresistance. In contrast, a substantial fraction of HGSC cells is non-tumorigenic. The role of these non-cancer-propagating cells (non-CPCs) and their relationship to CPCs remain poorly understood. Here, we demonstrate that neoplastic cells expressing the intermediate filament protein keratin 5 (KRT5) represent bona fide CPCs. KRT5+ cells form cancer organoids over successive passages, are tumorigenic in serial dilution xenograft assays, and are resistant to the antineoplastic agents, doxorubicin and cisplatin. Single-cell lineage-tracing experiments show that KRT5+ CPCs give rise to KRT5- cells. KRT5+ and KRT5- populations exhibit distinct gene expression profiles, with KRT5- cells characterized by expression of SPP1, which encodes the secreted factor osteopontin (OPN). Treatment with OPN enhances HGSC organoid growth and chemoresistance, whereas SPP1 knockdown reverses these effects. Together, these findings support a model in which HGSC contains two hierarchically related cell populations: KRT5+, OPN-responsive CPCs and KRT5-, non-tumorigenic cells that form a niche producing OPN. Inhibiting pathways that sustain this niche may enable reduced dosing of highly toxic chemotherapeutic agents while enhancing therapeutic efficacy in HGSC.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13155427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147871304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular heterogeneity of HPV-associated cancers and strategies to overcome treatment resistance.","authors":"Sara Rasouli, Weiyi Gong, Raegan Wood, Danyal Daneshdoust, Anam Khan, Rani Mahyoob, Chongwen Cao, Zihao Yu, Nagireddy Putluri, Gennady Shvets, Haichang Li, Bo Zhao, Xuefeng Liu, Jenny Li","doi":"10.47248/chp2603010002","DOIUrl":"10.47248/chp2603010002","url":null,"abstract":"<p><p>Human papillomavirus (HPV) is a major driver of global cancer incidence, responsible for nearly all cervical cancers and a significant proportion of oropharyngeal, anal, and other anogenital cancers. Despite the availability of effective vaccines, HPV-associated cancers persist due to persistent infection, immune evasion, and the virus's ability to integrate into the host genome, contributing to molecular heterogeneity and therapeutic resistance. Here, we summarize molecular heterogeneity and the emerging combined therapeutic strategies. High-risk HPV types, notably HPV16 and HPV18, initiate carcinogenesis through persistent infection of epithelial basal cells and through the actions of the E6 and E7 oncoproteins, which disrupt the p53 and Rb pathways, induce telomerase activation, and promote genomic instability. A critical step in the progression to cancer is HPV genome integration, which occurs through DNA damage response pathways and results in heterogeneous insertion patterns that drive oncogene activation, tumor suppressor inactivation, and complex chromosomal rearrangements. Emerging single-cell RNA sequencing studies have highlighted the transcriptional, immune, and spatial heterogeneity of HPV-associated cancers, revealing subpopulations linked to immune escape, therapy resistance, and disease progression. These technologies have uncovered dynamic microenvironmental shifts and distinct immune cell populations, underscoring the importance of cellular and spatial heterogeneity in shaping tumor evolution and treatment response. The \"hit and run\" hypothesis suggests that while HPV oncoproteins are critical in early carcinogenesis, some tumors may lose dependence on viral oncogenes as they accumulate host genomic alterations, complicating detection and treatment strategies. Heterogeneity in HPV integration patterns and the tumor microenvironment contribute to variable treatment outcomes and the development of resistance to monotherapies. To overcome the challenges posed by molecular heterogeneity in HPV-associated cancers, combined therapeutic strategies targeting viral oncoproteins, host genomic vulnerabilities, and immune microenvironment are essential. Integrating single-cell transcriptomic insights with HPV integration profiles highlights how viral and host heterogeneity shape immune escape and therapeutic response, offering a framework for designing personalized combination therapies to improve outcomes in HPV-associated cancers.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147625295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rewiring transcriptional plasticity: the case for dual YAP1 and TAZ targeting in gastric cancer peritoneal metastases.","authors":"Rahul Kumar","doi":"10.47248/chp2603010004","DOIUrl":"10.47248/chp2603010004","url":null,"abstract":"","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13166162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147937120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Transcriptomic and Epitranscriptomic Profiling Identifies THBS1 as A Regulator of Enzalutamide Resistance in Prostate Cancer.","authors":"Emmanuelle Hodara, Lisa Swartz, Aubree Mades, Daniel Bsteh, Tong Xu, Suhn K Rhie, Amir Goldkorn","doi":"10.47248/chp2502020007","DOIUrl":"https://doi.org/10.47248/chp2502020007","url":null,"abstract":"<p><p>Cancer drug resistance arises not only from selection of resistant clones, but also through rapid activation of adaptive transcriptional programs. One mechanism of transcriptional regulation involves N6-methyladenosine (m⁶A) RNA modification, which dynamically regulates mRNA processing and alternative splicing, ultimately impacting cell fate and differentiation. In prostate cancer (PC), resistance to systemic therapies such as the androgen receptor pathway inhibitor (ARPI) enzalutamide is associated with a host of well-documented androgen receptor (AR) alterations, including amplification, mutation, and alternative splicing. Given these functions, we hypothesized that m⁶A modifications play a role in the transition to enzalutamide resistance in PC. To test this, we used methyl-RNA-immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA-seq to identify gene transcripts that were both differentially methylated and differentially expressed between enzalutamide-sensitive and enzalutamide-resistant PC cells. We filtered and prioritized these genes using clinical and functional database tools, including Gene Ontology (GO) enrichment analysis and Gene Set Enrichment Analysis (GSEA), The Cancer Genome Atlas (TCGA), and the Oncology Research Information Network (ORIEN) avatar. Using this approach, we identified 487 transcripts that were both differentially methylated and differentially expressed and validated six of the top 12 candidates via targeted qPCR and MeRIP-PCR. One of these, <i>THBS1</i>, was found to have increased m⁶A level associated with decreased transcript levels in enzalutamide-resistant cells, a finding recapitulated in publicly available preclinical and clinical data. Moreover, in enzalutamide-sensitive cells, depletion of <i>THBS1</i> by siRNA-knockdown induced resistance to enzalutamide. While <i>THBS1</i> has previously been implicated in aggressive PC phenotypes, we now show that <i>THBS1</i> downregulation directly contributes to a rapid transition to enzalutamide resistance, suggesting a novel role for this gene in PC hormonal therapy resistance. These results constitute the first comprehensive epitranscriptomic profiling of ARPI resistance and identify <i>THBS1</i> as a potential driver of acute resistance in prostate cancer.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"2 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating Solid Tumor Heterogeneity: The Promise and Challenges of Antibody-Drug Conjugates.","authors":"Ashley A Duhon, Karen McLean","doi":"10.47248/chp2502040017","DOIUrl":"10.47248/chp2502040017","url":null,"abstract":"<p><p>Antibody drug conjugates (ADCs) are changing the landscape of cancer therapy. These agents contain an antibody directed at a tumor cell surface antigen linked to a cytotoxic payload that is released following complex internalization and processing by the lysosome. To date, seven ADCs have been approved by the Federal Drug Administration for the treatment of solid tumors and an additional seven ADCs are approved in hematologic malignancies; because of the unique aspects of solid tumor therapy, this review will focus specifically on ADCs for solid malignancies. Review of the design of these solid tumor ADCs highlights the successful evolution of ADC treatment to date, including selection of antigen target, chemical linker features, and payload. In this review, we focus on how spatial and temporal intratumoral heterogeneity uniquely limits durable efficacy of ADC therapy. We consider strategies to overcome these hurdles, including improved characterization of clinical samples for optimal ADC selection, improvements in ADC design, and combinatorial therapy. These preclinical and clinical efforts seek to overcome the challenges of tumor heterogeneity to improve ADC options and outcomes in the treatment of solid tumor malignancies.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12668522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell Cycle Plasticity and Heterogeneity: An Underappreciated Feature of Cancer and Treatment Response.","authors":"Erik S Knudsen, Thomas N O'Connor, Agnieszka K Witkiewicz","doi":"10.47248/chp2502030015","DOIUrl":"10.47248/chp2502030015","url":null,"abstract":"<p><p>Progression through the mammalian cell cycle is a highly regulated process to maintain tissue homeostasis. The key regulators of cell cycle transitions are cyclin-dependent kinase (CDK)/Cyclin complexes that phosphorylate substrates such as the RB tumor suppressor to facilitate cellular division. The regulation of G1/S is of particular significance in cancer and is affected by numerous tumor suppressors and oncogenes. Historically, the cell cycle was viewed as a rigidly regulated process, but recent evidence has revealed significant flexibility and differential CDK/Cyclin dependencies across tumor types. These heterogeneous features of cell cycle control have implications for the etiology of different tumor types as well as the response to multiple therapeutic modalities. Most notably, adaptive responses in cell cycle regulatory circuits can contribute to acquired resistance in a variety of contexts, underscoring the importance for tumor biology and disease treatment.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"2 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12525970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Cancer Biology: Highlights from the 2025 FASEB SRC on Cellular Plasticity in Cancer.","authors":"Hans Clevers, Ankur Sharma, Sendurai A Mani, Anna Golebiewska, Axel Behrens, Wai Leong Tam, Loic P Deleyrolle, Huiping Liu, Karuna Ganesh, Walid T Khaled, Shaheen Sikandar, Terence K Lee, Tyler E Miller, Dean G Tang, Sheila Singh, Vivian S W Li, Justin D Lathia, Stephanie Ma","doi":"10.47248/chp2502040018","DOIUrl":"10.47248/chp2502040018","url":null,"abstract":"<p><p>The inaugural FASEB Science Research Conference (SRC) on Cellular Plasticity in Cancer was held in May 2025 in Hong Kong SAR, China. This event brought together leading experts to discuss cutting-edge research centered on cancer cell plasticity. The conference featured comprehensive presentations covering a broad spectrum of topics, including oncofetal reprogramming in tumor development and progression, mechanisms regulating cancer cell plasticity, metabolic reprogramming and its role in tumor progression, cancer cell plasticity during metastasis, cancer stem cell programs within the tumor microenvironment, tumor plasticity and immune evasion, as well as innovative therapeutic strategies aimed at targeting stem cell-like states, modulating cancer cell states, and effectively controlling disease progression. It is anticipated that the insights gained from this meeting will catalyze further advancements in cancer biology and therapy.</p>","PeriodicalId":520023,"journal":{"name":"Cancer heterogeneity and plasticity","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12599846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}