Pub Date : 2025-03-08DOI: 10.1016/j.tranon.2025.102338
Rui Ding , Yang Li , Yu Zhang , Xun Li , Yunjian Song , Xinliang Gu , Xianjuan Shen , Shaoqing Ju
Gastric cancer is one of the malignant tumors with the highest morbidity and mortality rates worldwide. Yet, there is a lack of diagnostic markers with high sensitivity in the clinic. tRNA-derived small RNAs are a novel type of non-coding small RNAs, which are abundant in tumor cells and body fluids. In this study, we explored the potential of 3′-tRFArg as a tumor marker for the diagnosis of GC. Differential expression of 3′-tRFArg was screened by high-throughput sequencing, and Quantitative real-time PCR confirmed its low expression in GC serum with good stability. Differential expression of serum 3′-tRFArg could distinguish between GC patients, gastritis patients, and healthy donors and was significantly correlated with clinical pathological features such as tumor differentiation, lymph node metastasis, and TNM staging. The receiver operating characteristic curve showed that 3′-tRFArg had a higher diagnostic value compared with conventional biomarkers, especially in the diagnosis of early gastric cancer. In conclusion, our results suggest that 3′-tRFArg can serve as a highly sensitive biomarker with a certain value for monitoring tumor development and prognosis.
{"title":"Comprehensive assessment of serum 3′-tRFArg as a novel diagnostic biomarker for gastric cancer","authors":"Rui Ding , Yang Li , Yu Zhang , Xun Li , Yunjian Song , Xinliang Gu , Xianjuan Shen , Shaoqing Ju","doi":"10.1016/j.tranon.2025.102338","DOIUrl":"10.1016/j.tranon.2025.102338","url":null,"abstract":"<div><div>Gastric cancer is one of the malignant tumors with the highest morbidity and mortality rates worldwide. Yet, there is a lack of diagnostic markers with high sensitivity in the clinic. tRNA-derived small RNAs are a novel type of non-coding small RNAs, which are abundant in tumor cells and body fluids. In this study, we explored the potential of 3′-tRF<sup>Arg</sup> as a tumor marker for the diagnosis of GC. Differential expression of 3′-tRF<sup>Arg</sup> was screened by high-throughput sequencing, and Quantitative real-time PCR confirmed its low expression in GC serum with good stability. Differential expression of serum 3′-tRF<sup>Arg</sup> could distinguish between GC patients, gastritis patients, and healthy donors and was significantly correlated with clinical pathological features such as tumor differentiation, lymph node metastasis, and TNM staging. The receiver operating characteristic curve showed that 3′-tRF<sup>Arg</sup> had a higher diagnostic value compared with conventional biomarkers, especially in the diagnosis of early gastric cancer. In conclusion, our results suggest that 3′-tRF<sup>Arg</sup> can serve as a highly sensitive biomarker with a certain value for monitoring tumor development and prognosis.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102338"},"PeriodicalIF":5.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580306","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}
Pub Date : 2025-03-08DOI: 10.1016/j.tranon.2025.102353
Ming-Yu Chou , Muh-Hwa Yang
The emergence of molecularly targeted therapies and immunotherapies has revolutionized cancer treatment, yet the optimal sequencing of these modalities remains debated. While targeted therapies often induce initial immunostimulatory effects, the development of resistance is accompanied by dynamic alterations in the tumor-immune microenvironment. These changes can promote tumor growth, hinder immune surveillance, and contribute to subsequent immunotherapy resistance. This review focuses on solid tumors and summarizes the immunomodulatory effects arising in the context of targeted therapy resistance, highlighting the challenges they pose for the subsequent immunotherapy efficacy.
{"title":"Immunomodulation on tumor immune microenvironment in acquired targeted therapy resistance and implication for immunotherapy resistance","authors":"Ming-Yu Chou , Muh-Hwa Yang","doi":"10.1016/j.tranon.2025.102353","DOIUrl":"10.1016/j.tranon.2025.102353","url":null,"abstract":"<div><div>The emergence of molecularly targeted therapies and immunotherapies has revolutionized cancer treatment, yet the optimal sequencing of these modalities remains debated. While targeted therapies often induce initial immunostimulatory effects, the development of resistance is accompanied by dynamic alterations in the tumor-immune microenvironment. These changes can promote tumor growth, hinder immune surveillance, and contribute to subsequent immunotherapy resistance. This review focuses on solid tumors and summarizes the immunomodulatory effects arising in the context of targeted therapy resistance, highlighting the challenges they pose for the subsequent immunotherapy efficacy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102353"},"PeriodicalIF":5.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579648","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}
Pub Date : 2025-03-08DOI: 10.1016/j.tranon.2025.102346
Zhilong Ma , Jie Hua , Miaoyan Wei , Lin Han , Mingwei Dong , Wangcheng Xie , Tingyi Luo , Qingcai Meng , Wei Wang , Zhenshun Song , Si Shi , Xianjun Yu , Jin Xu
Pancreatic cancer is an aggressive malignancy characterized by rapid progression, unfavorable outcomes, and a low early detection rate. Elucidating the mechanisms underlying the onset and progression of pancreatic tumors is essential for early detection and for developing preventive measures. Even though human rhomboid family-1 (RHBDF) acts as an oncogene in various tumors, the role of RHBDF in pancreatic cancer progression remains unexplored. Here, publicly available datasets, including samples of chronic pancreatitis associated with pancreatic cancer from our center, were used for bioinformatics analyses, including differential expression, survival, and enrichment studies. The findings were validated by immunohistochemical staining and in vitro experiments. We found that RHBDF1 was significantly upregulated in tumor samples relative to adjacent non-tumor and pancreatitis tissues, and its expression increased in correlation with the progression of pancreatitis to cancer. Furthermore, RHBDF1 promoted the proliferation, migration, and invasion of pancreatic cancer cells, and in vivo studies demonstrated that RHBDF1 promoted pancreatic cancer progression, tissue fibrosis, and the formation of new blood vessels. RNA-sequencing and cell functional experiments indicated that RHBDF1 promotes the progression of pancreatic cancer through the SRC-YAP signaling pathway. In summary, the pancreatitis-cancer transformation-related factor, RHBDF1, promotes pancreatic cancer progression by activating the SRC-YAP signaling cascade, indicating that RHBDF1 could be a viable target for the diagnosis and treatment of early-stage pancreatic cancer.
{"title":"The pancreatitis-cancer transformation-related factor, human rhomboid family-1, promotes pancreatic cancer progression through the SRC/YAP signaling pathway","authors":"Zhilong Ma , Jie Hua , Miaoyan Wei , Lin Han , Mingwei Dong , Wangcheng Xie , Tingyi Luo , Qingcai Meng , Wei Wang , Zhenshun Song , Si Shi , Xianjun Yu , Jin Xu","doi":"10.1016/j.tranon.2025.102346","DOIUrl":"10.1016/j.tranon.2025.102346","url":null,"abstract":"<div><div>Pancreatic cancer is an aggressive malignancy characterized by rapid progression, unfavorable outcomes, and a low early detection rate. Elucidating the mechanisms underlying the onset and progression of pancreatic tumors is essential for early detection and for developing preventive measures. Even though human rhomboid family-1 (RHBDF) acts as an oncogene in various tumors, the role of RHBDF in pancreatic cancer progression remains unexplored. Here, publicly available datasets, including samples of chronic pancreatitis associated with pancreatic cancer from our center, were used for bioinformatics analyses, including differential expression, survival, and enrichment studies. The findings were validated by immunohistochemical staining and in vitro experiments. We found that RHBDF1 was significantly upregulated in tumor samples relative to adjacent non-tumor and pancreatitis tissues, and its expression increased in correlation with the progression of pancreatitis to cancer. Furthermore, RHBDF1 promoted the proliferation, migration, and invasion of pancreatic cancer cells, and in vivo studies demonstrated that RHBDF1 promoted pancreatic cancer progression, tissue fibrosis, and the formation of new blood vessels. RNA-sequencing and cell functional experiments indicated that RHBDF1 promotes the progression of pancreatic cancer through the SRC-YAP signaling pathway. In summary, the pancreatitis-cancer transformation-related factor, RHBDF1, promotes pancreatic cancer progression by activating the SRC-YAP signaling cascade, indicating that RHBDF1 could be a viable target for the diagnosis and treatment of early-stage pancreatic cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102346"},"PeriodicalIF":5.0,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580305","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}
Pub Date : 2025-03-07DOI: 10.1016/j.tranon.2025.102334
Zhe Qin , Fangzhou Ye , Jiayi Wang, Jun Jiang, Xiaohong Zhang, Huanqing Li, Li Feng
Background
Cisplatin resistance significantly impedes the treatment of gastric cancer (GC). This work examined the possible therapeutic target status and function of BUB1B in controlling cisplatin resistance.
Methods
Following the identification of differentially expressed genes (DEGs), protein-protein interaction (PPI) network analysis was conducted using datasets from the Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD), GSE51575, and GSE79973. Functional tests assessed the effect of BUB1B overexpression and knockdown on the GC cells. Enrichment analysis and RNA-seq identified pathways linked to BUB1B. Additionally, the function of BUB1B in GC cells resistant to cisplatin in regulating DNA repair was examined, as its relationship with Rad51 inhibitor (B02) in regulating cell cycle, proliferation, and apoptosis. The combined effects of Rad51 suppression and BUB1B overexpression on tumor development in cisplatin-resistant GC cells were further validated in vivo xenograft models.
Results
Significant overexpression of six critical overlapping genes was seen in GC tissues. The GC cell invasion, migration, and proliferation processes were improved by BUB1B overexpression, whereas BUB1B knockdown prevented these outcomes. Genes involved in DNA repair were downregulated by BUB1B knockdown, according to an RNA-seq study. BUB1B overexpression boosted cell survival via modulating cell cycle proteins, but BUB1B knockdown hampered DNA repair and increased death in cisplatin-resistant GC cells. Overexpression of BUB1B enhanced tumor development in vivo and counteracted the inhibitory effects of B02 on cell growth.
Conclusion
BUB1B enhances cisplatin resistance in gastric cancer by regulating DNA repair and cell cycle progression, suggesting that targeting BUB1B may be a feasible therapeutic strategy.
{"title":"BUB1B promotes cisplatin resistance in gastric cancer via Rad51-mediated DNA damage repair","authors":"Zhe Qin , Fangzhou Ye , Jiayi Wang, Jun Jiang, Xiaohong Zhang, Huanqing Li, Li Feng","doi":"10.1016/j.tranon.2025.102334","DOIUrl":"10.1016/j.tranon.2025.102334","url":null,"abstract":"<div><h3>Background</h3><div>Cisplatin resistance significantly impedes the treatment of gastric cancer (GC). This work examined the possible therapeutic target status and function of <em>BUB1B</em> in controlling cisplatin resistance.</div></div><div><h3>Methods</h3><div>Following the identification of differentially expressed genes (DEGs), protein-protein interaction (PPI) network analysis was conducted using datasets from the Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD), GSE51575, and GSE79973. Functional tests assessed the effect of <em>BUB1B</em> overexpression and knockdown on the GC cells. Enrichment analysis and RNA-seq identified pathways linked to <em>BUB1B</em>. Additionally, the function of <em>BUB1B</em> in GC cells resistant to cisplatin in regulating DNA repair was examined, as its relationship with Rad51 inhibitor (B02) in regulating cell cycle, proliferation, and apoptosis. The combined effects of <em>Rad51</em> suppression and <em>BUB1B</em> overexpression on tumor development in cisplatin-resistant GC cells were further validated <em>in vivo</em> xenograft models.</div></div><div><h3>Results</h3><div>Significant overexpression of six critical overlapping genes was seen in GC tissues. The GC cell invasion, migration, and proliferation processes were improved by <em>BUB1B</em> overexpression, whereas <em>BUB1B</em> knockdown prevented these outcomes. Genes involved in DNA repair were downregulated by <em>BUB1B</em> knockdown, according to an RNA-seq study. <em>BUB1B</em> overexpression boosted cell survival via modulating cell cycle proteins, but <em>BUB1B</em> knockdown hampered DNA repair and increased death in cisplatin-resistant GC cells. Overexpression of <em>BUB1B</em> enhanced tumor development <em>in vivo</em> and counteracted the inhibitory effects of B02 on cell growth.</div></div><div><h3>Conclusion</h3><div><em>BUB1B</em> enhances cisplatin resistance in gastric cancer by regulating DNA repair and cell cycle progression, suggesting that targeting <em>BUB1B</em> may be a feasible therapeutic strategy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102334"},"PeriodicalIF":5.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563660","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}
Pub Date : 2025-03-06DOI: 10.1016/j.tranon.2025.102342
Zarema Albakova
Inflammasomes are cytoplasmic macromolecular complexes playing an important role in sensing exogenous and endogenous stimuli. Inflammasome activation leads to IL-1β and IL-18 secretion and pyroptosis. The concept of non-self recognition triggering inflammasome activation has been well-established for myeloid cells. However, increasing evidence suggests the presence of functional inflammasome or inflammasome-related components in lymphocytes. Dysregulated expression of inflammasome contributes to the development of many diseases, including cardiovascular, infectious, neurodegenerative diseases and cancer. Multiple clinical trials are being conducted to assess drugs targeting various inflammasome components. This review discusses current knowledge on inflammasome activation in T, B and NK cells and explores their potential as therapeutic targets. Further understanding inflammasome and pyroptotic pathways in lymphocytes may have implications in the development of novel immunotherapeutic strategies.
{"title":"Inflammasomes in lymphocytes as therapeutic targets","authors":"Zarema Albakova","doi":"10.1016/j.tranon.2025.102342","DOIUrl":"10.1016/j.tranon.2025.102342","url":null,"abstract":"<div><div>Inflammasomes are cytoplasmic macromolecular complexes playing an important role in sensing exogenous and endogenous stimuli. Inflammasome activation leads to IL-1β and IL-18 secretion and pyroptosis. The concept of non-self recognition triggering inflammasome activation has been well-established for myeloid cells. However, increasing evidence suggests the presence of functional inflammasome or inflammasome-related components in lymphocytes. Dysregulated expression of inflammasome contributes to the development of many diseases, including cardiovascular, infectious, neurodegenerative diseases and cancer. Multiple clinical trials are being conducted to assess drugs targeting various inflammasome components. This review discusses current knowledge on inflammasome activation in T, B and NK cells and explores their potential as therapeutic targets. Further understanding inflammasome and pyroptotic pathways in lymphocytes may have implications in the development of novel immunotherapeutic strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102342"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548887","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}
Pub Date : 2025-03-06DOI: 10.1016/j.tranon.2025.102337
Mallory I. Frederick , Elicia Fyle , Anna Clouvel , Djihane Abdesselam , Saima Hassan
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. The only targeted therapeutic approach that has emerged for early TNBC patients with BRCA-mutations (BRCAMUT) are PARP inhibitors (PARPi). In combination, PARPi may benefit a larger cohort of TNBC patients. We used our previously identified 63-gene signature that was associated with PARPi response to identify candidate genes that could be therapeutic targets. We selected FEN1 for further investigation since its knockdown was associated with an increase in G2/M arrest, DNA damage, and apoptosis. We first tested LNT1, a FEN1/EXO1 inhibitor, in a panel of 10 TNBC cell lines. LNT1 sensitivity was identified predominantly in BRCA1-mutant/deficient cell lines. However, the combination of PARPi and LNT1 demonstrated a synergistic or additive effect in 7/10 cell lines, mainly in BRCA1/2 wild-type (BRCAWT) and BRCA2-mutant cell lines, with intrinsic and acquired resistance to PARPi. The greatest synergy was observed in a BRCA2-mutant cell line with acquired resistance to olaparib (HCC1395-OlaR), with a combination index value of 0.20. In the synergistic cell lines, BT549 (BRCAWT) and HCC1395-OlaR, the combination was associated with a rapid progression in DNA replication fork speed, an early and sustained increase in DNA damage in comparison to each of the single-agents. However, in the additive BRCA1/2 wild-type cell lines, MDAMB231 and HCC1806, the combination demonstrated a high DNA damage response that was largely driven by either talazoparib or LNT1. Therefore, targeting FEN1/EXO1 with PARPi is a promising targeted combination approach, particularly in the context of PARPi-resistant and BRCAWT TNBC.
{"title":"Targeting FEN1/EXO1 to enhance efficacy of PARP inhibition in triple-negative breast cancer","authors":"Mallory I. Frederick , Elicia Fyle , Anna Clouvel , Djihane Abdesselam , Saima Hassan","doi":"10.1016/j.tranon.2025.102337","DOIUrl":"10.1016/j.tranon.2025.102337","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. The only targeted therapeutic approach that has emerged for early TNBC patients with BRCA-mutations (BRCA<sup>MUT</sup>) are PARP inhibitors (PARPi). In combination, PARPi may benefit a larger cohort of TNBC patients. We used our previously identified 63-gene signature that was associated with PARPi response to identify candidate genes that could be therapeutic targets. We selected FEN1 for further investigation since its knockdown was associated with an increase in G2/M arrest, DNA damage, and apoptosis. We first tested LNT1, a FEN1/EXO1 inhibitor, in a panel of 10 TNBC cell lines. LNT1 sensitivity was identified predominantly in <em>BRCA1</em>-mutant/deficient cell lines. However, the combination of PARPi and LNT1 demonstrated a synergistic or additive effect in 7/10 cell lines, mainly in <em>BRCA1/2</em> wild-type (BRCA<sup>WT</sup>) and <em>BRCA2</em>-mutant cell lines, with intrinsic and acquired resistance to PARPi. The greatest synergy was observed in a <em>BRCA2</em>-mutant cell line with acquired resistance to olaparib (HCC1395-OlaR), with a combination index value of 0.20. In the synergistic cell lines, BT549 (BRCA<sup>WT</sup>) and HCC1395-OlaR, the combination was associated with a rapid progression in DNA replication fork speed, an early and sustained increase in DNA damage in comparison to each of the single-agents. However, in the additive BRCA1/2 wild-type cell lines, MDAMB231 and HCC1806, the combination demonstrated a high DNA damage response that was largely driven by either talazoparib or LNT1. Therefore, targeting FEN1/EXO1 with PARPi is a promising targeted combination approach, particularly in the context of PARPi-resistant and BRCA<sup>WT</sup> TNBC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102337"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548886","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}
Pub Date : 2025-03-06DOI: 10.1016/j.tranon.2025.102345
Meijin Huang , Xiangqing Zhu , Wenmang Xu , Jun Zhu , Xin Xun , Bin Su , Hong Chen
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. ALK gene rearrangement has been identified in 3 % to 5 % of the patients with NSCLC. Thanks to the advancements in second-generation sequencing technology, an increasing number of novel fusion partners have been identified. In our research, we discovered a rare ALK fusion, TTC7A-ALK, in a patient with advanced lung adenocarcinoma using targeted next-generation sequencing (NGS). After being diagnosed with advanced lung adenocarcinoma with TTC7A-ALK fusion, the patient received crizotinib treatment and achieved a progression-free survival of 29 months. Additonanlly, we conducted further functional analyses on this fusion protein to assess its oncogenic potential. Similar to EML4-ALK, the TTC7A-ALK fusion protein can promote the growth of Ba/F3 cells under IL-3-independent conditions in vitro. In vivo studies demonstrate that the TTC7A-ALK fusion protein could enhance the tumorigenesis of NIH3T3 cells in nude mice, which can be suppressed by crizotinib. Mechanistic studies indicated that the ectopic expression of TTC7A-ALK in 293T cells led to the hyperactivation of downstream MAPK and PI3K/Akt pathways, which can be inhibited by crizotinib. Furthermore, upon tumor progression, the patient transitioned to alectinib, which provided rapid symptom relief and controlled the majority of lesions. Conclusionly, we identified and validated TTC7A-ALK as a oncogenic fusion in NSCLC. The patient demonstrated a significant clinical benefit from sequential treatment with crizotinib and alectinib, highlighting TTC7A-ALK as a novel therapeutic target for ALK inhibitors. These findings extend the spectrum of actionable ALK fusions and promote the inclusion of rare fusion detection in clinical diagnostic processes and treatment strategies.
{"title":"TTC7A-ALK, a novel ALK fusion variant identified in a patient with metastatic lung adenocarcinoma, exhibits excellent response to crizotinib","authors":"Meijin Huang , Xiangqing Zhu , Wenmang Xu , Jun Zhu , Xin Xun , Bin Su , Hong Chen","doi":"10.1016/j.tranon.2025.102345","DOIUrl":"10.1016/j.tranon.2025.102345","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. <em>ALK</em> gene rearrangement has been identified in 3 % to 5 % of the patients with NSCLC. Thanks to the advancements in second-generation sequencing technology, an increasing number of novel fusion partners have been identified. In our research, we discovered a rare <em>ALK</em> fusion, <em>TTC7A-ALK</em>, in a patient with advanced lung adenocarcinoma using targeted next-generation sequencing (NGS). After being diagnosed with advanced lung adenocarcinoma with <em>TTC7A-ALK</em> fusion<em>,</em> the patient received crizotinib treatment and achieved a progression-free survival of 29 months. Additonanlly, we conducted further functional analyses on this fusion protein to assess its oncogenic potential. Similar to <em>EML4-ALK</em>, the <em>TTC7A-ALK</em> fusion protein can promote the growth of Ba/F3 cells under IL-3-independent conditions in vitro. In vivo studies demonstrate that the <em>TTC7A-ALK</em> fusion protein could enhance the tumorigenesis of NIH3T3 cells in nude mice, which can be suppressed by crizotinib. Mechanistic studies indicated that the ectopic expression of <em>TTC7A-ALK</em> in 293T cells led to the hyperactivation of downstream MAPK and PI3K/Akt pathways, which can be inhibited by crizotinib. Furthermore, upon tumor progression, the patient transitioned to alectinib, which provided rapid symptom relief and controlled the majority of lesions. Conclusionly, we identified and validated <em>TTC7A-ALK</em> as a oncogenic fusion in NSCLC. The patient demonstrated a significant clinical benefit from sequential treatment with crizotinib and alectinib, highlighting <em>TTC7A-ALK</em> as a novel therapeutic target for <em>ALK</em> inhibitors. These findings extend the spectrum of actionable <em>ALK</em> fusions and promote the inclusion of rare fusion detection in clinical diagnostic processes and treatment strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102345"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563588","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}
Pub Date : 2025-03-05DOI: 10.1016/j.tranon.2025.102335
Yimin Wu , Lifang Fan , Haixin Shao , Jiale Li , Weiwei Yin , Jing Yin , Weiyu Zhu , Pingyang Zhang , Chaoxue Zhang , Junli Wang
Background
Accurate early diagnosis of ovarian cancer is crucial. The objective of this research is to create a comprehensive model that merges clinical variables, O-RADS, and deep learning radiomics to support preoperative diagnosis and assess its efficacy for sonographers.
Materials and methods
Data from two centers were used: Center 1 for training and internal validation, and Center 2 for external validation. DL and radiomics features were extracted from transvaginal ultrasound images to create a DL radiomics model using the LASSO method. A machine learning model ensemble was created by merging clinical variables, O-RADS scores, and DL radiomics model predictions. The model's effectiveness was evaluated by measuring the area under the receiver operating characteristic curve (AUC) and analyzing its impact on improving the diagnostic skills of sonographers. Moreover, the model's additional usefulness was assessed through integrated discrimination improvement (IDI), net reclassification improvement (NRI), and subgroup analysis.
Results
The ensemble model demonstrated superior diagnostic performance for ovarian cancer compared to standalone clinical models and clinical O-RADS models. Notably, there were significant improvements in the NRI and IDI across all three datasets, with p-values < 0.05. The ensemble model exhibited exceptional diagnostic performance, achieving AUCs of 0.97 in both the internal and external validation sets. Moreover, the implementation of this ensemble model substantially improved the diagnostic precision and reliability of sonographers. The sonographers' average AUC improved by 11 % in the internal validation set and by 7.7 % in the external validation set.
Conclusions
The ensemble model significantly enhances preoperative ovarian cancer diagnosis accuracy and improves sonographers' diagnostic capabilities and consistency.
{"title":"Evaluation of a novel ensemble model for preoperative ovarian cancer diagnosis: Clinical factors, O-RADS, and deep learning radiomics","authors":"Yimin Wu , Lifang Fan , Haixin Shao , Jiale Li , Weiwei Yin , Jing Yin , Weiyu Zhu , Pingyang Zhang , Chaoxue Zhang , Junli Wang","doi":"10.1016/j.tranon.2025.102335","DOIUrl":"10.1016/j.tranon.2025.102335","url":null,"abstract":"<div><h3>Background</h3><div>Accurate early diagnosis of ovarian cancer is crucial. The objective of this research is to create a comprehensive model that merges clinical variables, O-RADS, and deep learning radiomics to support preoperative diagnosis and assess its efficacy for sonographers.</div></div><div><h3>Materials and methods</h3><div>Data from two centers were used: Center 1 for training and internal validation, and Center 2 for external validation. DL and radiomics features were extracted from transvaginal ultrasound images to create a DL radiomics model using the LASSO method. A machine learning model ensemble was created by merging clinical variables, O-RADS scores, and DL radiomics model predictions. The model's effectiveness was evaluated by measuring the area under the receiver operating characteristic curve (AUC) and analyzing its impact on improving the diagnostic skills of sonographers. Moreover, the model's additional usefulness was assessed through integrated discrimination improvement (IDI), net reclassification improvement (NRI), and subgroup analysis.</div></div><div><h3>Results</h3><div>The ensemble model demonstrated superior diagnostic performance for ovarian cancer compared to standalone clinical models and clinical O-RADS models. Notably, there were significant improvements in the NRI and IDI across all three datasets, with p-values < 0.05. The ensemble model exhibited exceptional diagnostic performance, achieving AUCs of 0.97 in both the internal and external validation sets. Moreover, the implementation of this ensemble model substantially improved the diagnostic precision and reliability of sonographers. The sonographers' average AUC improved by 11 % in the internal validation set and by 7.7 % in the external validation set.</div></div><div><h3>Conclusions</h3><div>The ensemble model significantly enhances preoperative ovarian cancer diagnosis accuracy and improves sonographers' diagnostic capabilities and consistency.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102335"},"PeriodicalIF":5.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548901","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}
Pub Date : 2025-03-05DOI: 10.1016/j.tranon.2025.102340
Xinya Zhao , Guoyu Wu , Xufeng Tao , Deshi Dong , Jing Liu
Pancreatic cancer (PC) is a highly invasive tumor characterized by delayed diagnosis, rapid progress, and resistance to chemotherapy. Mitochondria, as the "power chamber" of cells, not only play a central role in energy metabolism but also participate in the production of reactive oxygen species (ROS), calcium signaling, regulation, and differentiation of the cell cycle. The abnormal activity of mitochondria is closely related to the development of PC. In this paper, we discussed the key role of mitochondria in PC, including mitochondrial DNA, mitochondrial biogenesis, mitochondrial dynamics, metabolic regulation, ROS generation, and mitochondrial-dependent apoptosis. We elaborated on the importance of these mitochondrial mechanisms in the development of PC and emphasized the potential of targeted mitochondrial therapy strategies for these mechanisms in the treatment of PC. In addition, this article also reviews the latest developments in innovative drug carriers such as cell-penetrating peptides, nucleic acid aptamers, and nanomaterials, which can achieve precise localization of mitochondria and drug delivery. Therefore, this article comprehensively analyzed the important role of mitochondria in the treatment of PC and clarified the effectiveness and necessity of targeting mitochondria in the treatment of PC.
{"title":"Targeted mitochondrial therapy for pancreatic cancer","authors":"Xinya Zhao , Guoyu Wu , Xufeng Tao , Deshi Dong , Jing Liu","doi":"10.1016/j.tranon.2025.102340","DOIUrl":"10.1016/j.tranon.2025.102340","url":null,"abstract":"<div><div>Pancreatic cancer (PC) is a highly invasive tumor characterized by delayed diagnosis, rapid progress, and resistance to chemotherapy. Mitochondria, as the \"power chamber\" of cells, not only play a central role in energy metabolism but also participate in the production of reactive oxygen species (ROS), calcium signaling, regulation, and differentiation of the cell cycle. The abnormal activity of mitochondria is closely related to the development of PC. In this paper, we discussed the key role of mitochondria in PC, including mitochondrial DNA, mitochondrial biogenesis, mitochondrial dynamics, metabolic regulation, ROS generation, and mitochondrial-dependent apoptosis. We elaborated on the importance of these mitochondrial mechanisms in the development of PC and emphasized the potential of targeted mitochondrial therapy strategies for these mechanisms in the treatment of PC. In addition, this article also reviews the latest developments in innovative drug carriers such as cell-penetrating peptides, nucleic acid aptamers, and nanomaterials, which can achieve precise localization of mitochondria and drug delivery. Therefore, this article comprehensively analyzed the important role of mitochondria in the treatment of PC and clarified the effectiveness and necessity of targeting mitochondria in the treatment of PC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102340"},"PeriodicalIF":5.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548899","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}
Pub Date : 2025-03-03DOI: 10.1016/j.tranon.2025.102339
Ramia J. Salloom , Dania Z. Sahtout , Iman M. Ahmad , Maher Y. Abdalla
Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both in vitro and in vivo models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. In vitro experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. In vivo, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4+ and CD8+ T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes.
{"title":"Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment","authors":"Ramia J. Salloom , Dania Z. Sahtout , Iman M. Ahmad , Maher Y. Abdalla","doi":"10.1016/j.tranon.2025.102339","DOIUrl":"10.1016/j.tranon.2025.102339","url":null,"abstract":"<div><div>Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both <em>in vitro</em> and <em>in vivo</em> models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. <em>In vitro</em> experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. <em>In vivo</em>, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4<sup>+</sup> and CD8<sup>+</sup> T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"54 ","pages":"Article 102339"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548900","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}
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