Experimental Hematology & Oncology最新文献

{"title":"Ibrutinib and acalabrutinib use and risk of incident atrial fibrillation: a propensity-matched analysis.","authors":"Joachim Alexandre, Jonaz Font, Thibault Lenormand, Sylvain Chantepie, Hippolyte Bardet, Gandhi Damaj, Charles Dolladille, Damien Legallois, Angélique Da-Silva, Paul Milliez, Arnaud Bisson, Laurent Fauchier","doi":"10.1186/s40164-025-00619-6","DOIUrl":"10.1186/s40164-025-00619-6","url":null,"abstract":"<p><p>Ibrutinib and acalabrutinib are both associated with an increased risk of atrial fibrillation (AF); however, the comparative risk of AF between these 2 BTK inhibitors remains largely unknown. Our primary aim was to evaluate the risk of incident AF in patients exposed to ibrutinib compared to those exposed to acalabrutinib. Using the TriNetX research network database, we established a retrospective cohort of adult patients (≥ 18 years) previously diagnosed with a B-cell malignancy (using ICD-10-CM codes) in whom a first BTKi introduction occurred between January 1st, 2013 (first patient exposed to ibrutinib in TriNetX) and July 1st, 2024. Patients were divided into 2 groups based on their exposure to ibrutinib or acalabrutinib. After propensity score matching (PSM) across 37 covariates, Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to compare the 2 matched groups. The appropriateness of the proportional hazard assumption was examined and risk differences (RDs) were used if appropriate. Results were summarized with the use of Kaplan-Meier survival curves. Follow-up started from 1 day after first BTKi introduction and continued over a 6-year follow-up period. A cohort of 12,449 patients exposed to ibrutinib and 4,131 to acalabrutinib were included in the study. After PSM, 4,090 patients remained in each group (1:1). During a mean duration of BTKi exposure of 2.3 ± 1.8 years, we found a significantly higher risk of incident AF in the ibrutinib group compared to the acalabrutinib group (RD 0.09, 95% CI 0.07-0.10). This difference was consistent across subgroups (age ≤ or > 75 and lower or higher baseline cardiovascular risk of developing AF). In conclusion, among patients with B-cell malignancies, the risk of developing incident AF is increased when treated with ibrutinib compared to acalabrutinib.Trial registration ClinicalTrial registration number: NCT06561243.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"29"},"PeriodicalIF":9.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556426","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":"Mesothelin-targeted CAR-T cells secreting NKG2D-BiTEs exhibit potent efficacy against triple-negative breast cancer.","authors":"Muhammad Auwal Saliu, Qi Wang, Mansur Dabai Salisu, Yuanfeng Ren, Pengchao Zhang, Rabiatu Bako Suleiman, Bingbing Cao, Yiqiao Xu, Xudong Liu, Frederic Lluis, Maoxuan Liu, Xiaochun Wan","doi":"10.1186/s40164-025-00621-y","DOIUrl":"10.1186/s40164-025-00621-y","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited treatment options. Chimeric antigen receptor (CAR)-T cell therapy holds promise, but its efficacy is hindered by tumor antigen escape and heterogeneity. To address these challenges, we developed a novel bispecific T cell engagers CAR-T (BiTEs CAR-T) targeting Mesothelin (MSLN) and secreting NKG2D-Bispecific T cell Engagers (BiTEs) to engage NKG2D ligands (NKG2DL). Analysis of TNBC tissues using The Cancer Genome Atlas and tumor microarrays revealed high but weakly correlated expression of MSLN and NKG2DL, making them ideal targets for dual engagement. To reduce immunogenicity and enhance stability, we used a nanobody and the natural receptor NKG2D as antigen-binding domains instead of traditional scFvs in the CAR construct. The secreted BiTEs could promote the cytotoxicity of untransduced T cells against NKG2DL + tumor cells. In vitro, BiTEs CAR-T cells exhibited superior cytotoxicity, T cell activation, and cytokines production against heterogeneous target cells compared to MSLN CAR-T. In vivo, BiTEs CAR-T cells demonstrated potent antitumor activity in zebrafish and murine TNBC models, significantly reducing tumor burden and prolonging survival without detectable toxicity. These findings suggest that BiTE CAR-T cells offer a highly promising therapeutic strategy for TNBC by addressing antigen heterogeneity and immune escape mechanisms, with promising translational potential for clinical application.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"27"},"PeriodicalIF":9.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540816","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":"CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy.","authors":"Pengchao Zhang, Xuejia Feng, Xiangyun Niu, Zhongming Liu, Minghui Li, Maoxuan Liu, Dehong Yan, Guizhong Zhang, Xiaochun Wan","doi":"10.1186/s40164-025-00618-7","DOIUrl":"10.1186/s40164-025-00618-7","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-NK therapy holds great potential for tumor treatment, but current CAR designs are primarily optimized for T cells, raising concerns about their suitability for NK cells. This study compared two dominant CAR designs used in T cells-CD28-CD3ζ (28z) and 4-1BB-CD3ζ (BBz)-and found that CD28 costimulation offers superior functionality in NK cells. 28z CAR-NK cells exhibited significantly better activation, cytotoxicity, and in vivo anti-tumor efficacy than BBz CAR-NK cells, with similar persistence and tumor infiltration. 28z CAR more effectively recruited the ZAP70 kinase and upregulated multiple key factors involved in immune activation, potentially augmenting CAR-NK cell function. MAP3K8, a kinase involved in inflammation and the MAPK signaling pathway, was identified as a critical mediator in enhancing 28z CAR-NK cell function. Silencing or inhibiting MAP3K8 impaired the anti-tumor activity of 28z CAR-NK cells, while its overexpression substantially improved the function of BBz CAR-NK cells. These findings provide new insights into how CD28 costimulation boosts CAR-NK cell efficacy, supporting its use into NK cell-specific CARs for cancer immunotherapy, and highlight MAP3K8 as a potential target for optimizing BBz CAR-NK cell therapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"28"},"PeriodicalIF":9.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540813","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":"IRF1 is a core transcriptional regulatory circuitry member promoting AML progression by regulating lipid metabolism.","authors":"Fenli Zhang, Zhiheng Li, Fang Fang, Yixin Hu, Zhixu He, Yanfang Tao, Yizhen Li, Zimu Zhang, Bi Zhou, Ying Yang, Yumeng Wu, Yijun Wu, Zhongling Wei, Ailian Guo, Ling Xu, Yongping Zhang, Xiaolu Li, Yan Li, Chunxia Yang, Man Zhou, Jian Pan, Shaoyan Hu, Xiaoyan Yang","doi":"10.1186/s40164-025-00612-z","DOIUrl":"10.1186/s40164-025-00612-z","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) is a prevalent malignancy of the hematologic system. Despite advancements in therapeutic approaches, significant heterogeneity and therapeutic resistance pose substantial challenges to treatment. Tumors driven by core transcription factors through super-enhancers can establish core transcriptional regulatory circuits (CRCs) that modulate oncogene expression programs. Identifying CRC is crucial for understanding disease-related transcriptional regulation. This study sought to predict and establish a CRC model for AML, identify genes critical for AML survival and explore their regulatory mechanisms in AML progression.</p><p><strong>Methods: </strong>The dbCoRC tool was used for predictive analysis of H3K27ac ChIP-seq data from 11 AML samples to construct and validate the CRC model in AML patients. To elucidate the functional role of the CRC member IRF1, we utilized short hairpin RNA (shRNA) to knock down IRF1 in AML cells. RNA-seq, CUT&Tag and lipidomics technologies were subsequently used to investigate the regulatory roles and downstream mechanisms of IRF1 in AML.</p><p><strong>Results: </strong>This study established a core transcriptional regulatory circuit consisting of IRF1, ELF1, ETV6, RUNX2, and MEF2D, which formed an interconnected autoregulatory loop. Further investigations revealed up-regulated expression of IRF1 in AML patients, which was associated with poor prognosis. Inhibition of IRF1 expression resulted in decreased AML cell proliferation and induced apoptosis, indicating its essential role in the survival of AML cells. Additionally, this study revealed that IRF1 directly regulates the transcription of key genes such as FASN, SCD, and SREBF1 for lipid synthesis, thereby affecting lipid metabolism in AML cells.</p><p><strong>Conclusion: </strong>In summary, this study identified IRF1 as a novel core transcription factor involved in AML pathogenesis. IRF1 collaborates with ELF1, ETV6, RUNX2, and MEF2D to form a core transcriptional regulatory circuit that promotes AML progression. Furthermore, we demonstrated that IRF1 directly regulates the expression of key genes involved in lipid metabolism, influencing the synthesis of diverse lipid molecules crucial for AML survival.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"25"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536835","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":"Dickkopf-1 promotes tumor progression of gefitinib- resistant non-small cell lung cancer through cancer cell-fibroblast interactions.","authors":"Munkyung Choi, Yong June Choi, Young Joo Lee, Yujeong Lee, Jin-Haeng Chung, Keon Wook Kang","doi":"10.1186/s40164-025-00616-9","DOIUrl":"10.1186/s40164-025-00616-9","url":null,"abstract":"<p><strong>Background: </strong>Cancer cell-secreted proteins play a critical role in tumor progression and chemoresistance by influencing intercellular interactions within the tumor microenvironment. Investigating the intratumoral functions of these secretory proteins may provide insights into understanding and treating chemoresistant cancers. This study aims to identify potential anticancer target(s) in gefitinib-resistant non-small cell lung cancer (NSCLC), with a focus on secretory proteins and their effects on intercellular interactions.</p><p><strong>Methods: </strong>Differentially expressed secretory proteins were identified in gefitinib-resistant human NSCLC cell lines (PC9-GR and HCC827-GR), revealing an elevation in Dickkopf-1 (DKK1) expression and secretion. To elucidate the role of DKK1 in gefitinib-resistant cancer, the anticancer effects of a neutralizing antibody against DKK1 were evaluated in tumors comprising either cancer cells alone or cancer cells co-injected with human lung fibroblasts (MRC-5). Following the confirmation of the importance of cancer cell-fibroblast interactions in the protumorigenic activity of DKK1, the fibroblast traits modulated by DKK1 were further analyzed.</p><p><strong>Results: </strong>Gefitinib-resistant NSCLC cells exhibited increased DKK1 protein expression. Although elevated DKK1 levels were linked to poor prognosis, DKK1 did not directly affect cancer cell proliferation. However, DKK1 blockade showed significant anticancer effects in gefitinib-resistant tumors containing lung fibroblasts, suggesting that DKK1's pro-tumorigenic roles are mediated through cancer cell-fibroblast interactions. DKK1 altered fibroblast characteristics, enhancing inflammatory fibroblast traits while diminishing myofibroblast traits in tumor microenvironment. These DKK1-induced changes were mediated via activation of the c-JUN pathway in fibroblasts. Moreover, DKK1 was identified as a potential anticancer target across various cancer types beyond gefitinib-resistant lung cancer.</p><p><strong>Conclusions: </strong>This study clarifies that DKK1 mediates interactions between cancer cells and fibroblasts in gefitinib-resistant lung cancer, contributing to tumor progression. Therefore, we propose DKK1 as a promising anticancer target for the treatment of gefitinib-resistant NSCLC.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"24"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536822","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":"TLR7/8 signaling activation enhances the potency of human pluripotent stem cell-derived eosinophils in cancer immunotherapy for solid tumors.","authors":"Sheng Zhu, Zhengyang Zhou, Ruixin Gu, Zixin Zhao, Yingfeng Zhang, Yudi Miao, Qi Lei, Tianxing Liu, Guokai Wang, Chenyi Dai, Yi Huo, Jinghao You, Lejun Lv, Cheng Li, Ming Yin, Chengyan Wang, Hongkui Deng","doi":"10.1186/s40164-025-00613-y","DOIUrl":"10.1186/s40164-025-00613-y","url":null,"abstract":"<p><strong>Background: </strong>Efficient tumor T-cell infiltration is crucial for the effectiveness of T-cell-based therapies against solid tumors. Eosinophils play crucial roles in recruiting T cells in solid tumors. Our group has previously generated induced eosinophils (iEOs) from human pluripotent stem cells and exhibited synergistic efficacy with CAR-T cells in solid tumor inhibition. However, administrated eosinophils might influx into inflammatory lungs, posing a potential safety risk. Mitigating the safety concern and enhancing efficacy is a promising development direction for further application of eosinophils.</p><p><strong>Methods: </strong>We developed a new approach to generate eosinophils with enhanced potency from human chemically reprogrammed induced pluripotent stem cells (hCiPSCs) with the Toll-like receptor (TLR) 7/8 signaling agonist R848.</p><p><strong>Results: </strong>R848-activated iEOs (R-iEOs) showed significantly decreased influx to the inflamed lungs, indicating a lower risk of causing airway disorders. Furthermore, these R-iEOs had enhanced anti-tumor functions, preferably accumulated at tumor sites, and further increased T-cell infiltration. The combination of R-iEOs and CAR-T cells suppressed tumor growth in mice. Moreover, the chemo-trafficking signaling increased in R-iEOs, which may contribute to the decreased lung influx of R-iEOs and the increased tumor recruitment of T cells.</p><p><strong>Conclusion: </strong>Our study provides a novel approach to alleviate the potential safety concerns associated with eosinophils while increasing T-cell infiltration in solid tumors. This finding offers a prospective strategy for incorporating eosinophils to improve CAR-T-cell immunotherapy for solid tumors in the future.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"26"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536836","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":"TET2 downregulation enhances the antitumor efficacy of CD19 CAR T cells in a preclinical model.","authors":"Yeongrin Kim, Moonjung Jeun, Heung Kyoung Lee, Ji U Choi, Simon Park, Chi Hoon Park","doi":"10.1186/s40164-025-00609-8","DOIUrl":"10.1186/s40164-025-00609-8","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy has demonstrated significant clinical efficacy in patients with hematologic cancers. However, long-term follow-up studies indicate that only 50% of patients remain in complete remission after three years. To overcome these limitations, we investigated a strategy to enhance the antitumor activity of CAR T cells through gene modification. Based on previous research results demonstrating that CAR T cells with disrupted TET2, a methylcytosine dioxygenase, exhibit enhanced antitumor effects compared to conventional CAR T, we developed CAR T cells in which TET2 is downregulated by TET2 shRNA. Among the screened TET2-specific shRNAs, TET2-shRNA-1 was identified as the most effective sequence for gene silencing. Using this sequence, we constructed an all-in-one vector co-expressing CD19 CAR and TET2 shRNA. In vitro studies demonstrated that TET2 knockdown CD19 CAR T cells exhibited comparable cytolytic activity against CD19-positive cancer cells compared to conventional CD19 CAR T cells. However, interestingly, in xenograft mouse model using NSG mice, TET2 knockdown CAR T cells showed significantly improved antitumor activity compared to conventional CAR T cells. Our study demonstrates that shRNA-mediated knockdown of TET2 is a promising strategy to enhance the antitumor activity of CD19 CAR T cells in a preclinical model.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"23"},"PeriodicalIF":9.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515202","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":"A proinflammatory response and polarized differentiation of stromal elements characterizes the murine myeloma bone marrow niche.","authors":"Hussein Ghamlouch, Dylan C Gagler, Patrick Blaney, Eileen M Boyle, Yubao Wang, Jason Avigan, Jinyoung Choi, Ola Landgren, Aristotelis Tsirigos, Francesco Maura, Gareth J Morgan, Faith E Davies","doi":"10.1186/s40164-025-00606-x","DOIUrl":"10.1186/s40164-025-00606-x","url":null,"abstract":"<p><strong>Background: </strong>The bone marrow (BM) niche contains non-hematopoietic elements including mesenchymal stromal cells (MSC) and bone marrow endothelial cells (BMEC) which provide mechanical support, and control hematopoietic cell growth and differentiation. Although it is known that multiple myeloma (MM) cells interact closely with the BM microenvironment, little is known about the impact of MM on non-hematopoietic niche-forming cells.</p><p><strong>Methods: </strong>To address the role of the niche in MM pathogenesis, we utilized the 5TGM1 murine model. During the asymptomatic precursor stage of the model, we isolated the rare non-hematopoietic cells and performed single cell RNA sequencing. Using in-silico methods we characterized the individual cellular components of the niche, their relative abundance and differentiation state before and after exposure to MM cells as well as their intercellular interactions.</p><p><strong>Results: </strong>MM engraftment increased the abundance of MSC-lineage cells, BMECs and enhanced endothelial to mesenchymal transition. An inflammatory and oxidative stress signal was identified together with polarization of MSC differentiation away from osteocyte formation towards adipocytes which provide growth factors that are known to support MM expansion. BMEC differentiation was polarized towards sinusoidal endothelial cells with a pro-angiogenic/pro-inflammatory phenotype.</p><p><strong>Conclusions: </strong>MM cells impact the BM niche by generating a pro-inflammatory microenvironment with MSC differentiation being changed to generate cell subsets that favor MM growth and survival. In order to induce remission and improve long-term outcome for MM patients these inflammatory and oxidative stress signals need to be reduced and normal niche differentiation trajectories restored.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"22"},"PeriodicalIF":9.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515200","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":"Suppression of CYLD by HER3 confers ovarian cancer platinum resistance via inhibiting apoptosis and by inducing drug efflux.","authors":"Ye Zhang, Jian-Ge Qiu, Wei Wang, Fan-Li Sun, Xue Wang, Wen-Jing Liu, Xiao-Yu Jia, Hongbin Ji, Lin Wang, Bing-Hua Jiang","doi":"10.1186/s40164-025-00620-z","DOIUrl":"10.1186/s40164-025-00620-z","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) is the most pathogenic gynecological malignant tumor in the world. Due to the difficulty of early diagnosis, most of patients developed chemo-resistance and recurrence during/after chemotherapy.</p><p><strong>Methods: </strong>CCK8 and flow cytometry were utilized to assess drug sensitivity and apoptosis in parental and drug resistant cell lines. CYLD knockdown or overexpressed cells were employed to investigate its regulatory involvement in DDP resistance. Clinical tumor samples have been utilized to investigate the clinical relevance of CYLD. The drug synergistic effects were investigated through drug combination methods and a nude mice model with ABCB1 inhibitor or HER3 inhibitor.</p><p><strong>Results: </strong>In this study, we found that CYLD levels were significantly reduced in DDP-resistant cancer tissues and cells compared to the normal tissues and cells. CYLD knockdown in DDP-sensitive cells was sufficient to converse the cells to become DDP resistant by reducing cell apoptosis through increasing Bcl-XL and inhibiting Bax, and by increasing drug efflux via upregulating ABCB1 expression. HER3 expression levels were substantially higher in resistant cancer tissues and cells, and HER3 was the upstream facilitator of suppressing CYLD expression via STAT3 signaling. Furthermore, overexpression of CYLD in resistant cells increased sensitivity to platinum-based chemotherapy both in vitro and in vivo. ABCB1 was a key downstream target of CYLD for regulating tumor growth and therapeutic resistance both in vitro and in vivo, CYLD knockdown promoted the translocation of p65 to nucleus which increased ABCB1 expression through transcriptional activation. High expression levels of HER3 rendered CYLD suppression, consequently, mediated DDP resistance by blocking cell apoptosis pathways and promoting the drug efflux in ovarian cancer.</p><p><strong>Conclusions: </strong>Our findings identify novel HER3/CYLD/ABCB1 axis that regulate tumor growth and DDP resistance, which may be used as potential novel therapeutic target(s) to overcome ovarian cancer DDP resistance.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"21"},"PeriodicalIF":9.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515201","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":"Bridging therapy with histotripsy prior to liver transplantation for hepatocellular carcinoma: a first case report.","authors":"Melis Uysal, Chase J Wehrle, Christopher Coppa, Suneel Kamath, Smitha Krishnamurthi, Charles Martin, Mohamed El Hag, Mazhar Khalil, Masato Fujiki, Andrea Schlegel, Charles Miller, Koji Hashimoto, Federico Aucejo, David Ch Kwon, Jaekeun Kim","doi":"10.1186/s40164-025-00604-z","DOIUrl":"10.1186/s40164-025-00604-z","url":null,"abstract":"<p><strong>Background: </strong>Histotripsy is a novel, non-invasive, non-ionizing, and non-thermal ablation technique that disrupts tumors using acoustic cavitation. We report the first use of Histotripsy as bridging therapy prior to liver transplant for hepatocellular carcinoma (HCC) treated with histotripsy.</p><p><strong>Case presentation: </strong>A 59-year-old woman presented with Metabolic-Associated Steatotic Liver Disease (MASLD) cirrhosis (labMELD = 14), hepatic encephalopathy, and a single 2 cm OPTN V lesion in the left lateral segment consistent with HCC. The patient underwent histotripsy treatment of the lesion as bridging therapy before receiving liver transplantation. Histopathology analysis of the explanted liver showed total necrosis of the treated area, with no residual viable tissue tumor.</p><p><strong>Conclusion: </strong>This case demonstrates the potential utility of histotripsy as an effective bridging therapy for patients with combined cirrhosis and hepatocellular carcinoma (HCC) awaiting liver transplantation, with complete tumor necrosis on explant pathology demonstrating its therapeutic efficacy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"20"},"PeriodicalIF":9.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500096","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}