Translational cancer research最新文献

{"title":"Survival and treatment selection in NUT carcinoma: a population-based study and propensity score-matched comparison with poorly differentiated head and neck squamous cell carcinoma.","authors":"Guoliang Yang, Tingyao Ma, Yixin Jing, Yiming Ding, Xiaohong Chen, Zhigang Huang","doi":"10.21037/tcr-2026-1773","DOIUrl":"https://doi.org/10.21037/tcr-2026-1773","url":null,"abstract":"<p><strong>Background: </strong>NUT carcinoma (NC) is a rare and highly aggressive malignancy that can arise in the head and neck, thorax, and other organs. Large population-based studies remain limited, and survival comparisons with poorly differentiated head and neck squamous cell carcinoma (HNSCC), a common histologic mimic, have not been adequately controlled for baseline clinical imbalance. This study aimed to characterize survival and prognostic factors in NC and to compare survival between head and neck NC and poorly differentiated HNSCC after balancing baseline characteristics.</p><p><strong>Methods: </strong>In this retrospective population-based cohort study, primary NC diagnosed from 2018 to 2023 was identified from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) was analyzed with Kaplan-Meier and Cox models. Landmark analyses and time-dependent Cox modeling assessed treatment-timing bias. Head and neck NC was compared with poorly differentiated HNSCC using propensity score matching (PSM).</p><p><strong>Results: </strong>There were 91 NC patients included, 39 with head and neck disease. After excluding cases with missing matching covariates, 36 head and neck NC cases and 7,633 HNSCC comparators were included in propensity-score analyses. In NC, 61 patients (67.0%) died and median OS was 8 months. Older age, non-head and neck site, distant stage, M1 disease, and larger tumor size were associated with worse OS. In conventional multivariable Cox models, surgery, chemotherapy, and radiotherapy were associated with improved OS. After incorporating landmark and time-dependent approaches, chemotherapy was no longer robust, whereas radiotherapy, surgery, overall treatment status, and stage remained relevant depending on the analytic framework. Before matching, head and neck NC had worse OS than HNSCC; this association was attenuated after balancing measured clinical variables.</p><p><strong>Conclusions: </strong>NC has poor population-based survival, with stage and treatment status as major survival-related factors. The observed survival disadvantage of head and neck NC relative to poorly differentiated HNSCC was attenuated after matching for measured clinical characteristics, but the imprecision of the matched estimates precludes conclusions of prognostic equivalence or exclusion of a clinically important difference.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"695"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-cohort validation of <i>BRAF-PTPRT</i> co-mutation as a predictor of favorable immunotherapy response in melanoma.","authors":"Dongmei Han, Caihong Wu, Dan Wang, Hao Jin, Weishuai Liu","doi":"10.21037/tcr-2026-1745","DOIUrl":"https://doi.org/10.21037/tcr-2026-1745","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade (ICB) has transformed melanoma therapy, but predictive biomarkers remain suboptimal. <i>BRAF</i> is the most common driver mutation, yet its single-gene association with ICB response remains inconsistent. <i>PTPRT</i> loss activates STAT3-driven immunity. We hypothesized that concurrent <i>BRAF</i> and <i>PTPRT</i> mutations (co-mutation) synergistically enhance immunogenicity and predict ICB benefit.</p><p><strong>Methods: </strong>We analyzed three independent cohorts: Memorial Sloan Kettering Cancer Center (MSK) (n=320, ICB-treated), The Cancer Genome Atlas (TCGA) (n=448, mixed treatments), and a combined ICB cohort (CS, n=436). Patients were categorized into four groups: co-mutation, <i>BRAF+/PTPRT-</i>, <i>BRAF-/PTPRT+</i>, double wild-type (WT). Overall survival (OS), tumor mutational burden (TMB), neo-antigen load, clinical benefit, immune infiltration, and transcriptomic pathways were evaluated. A simplified risk score (0-2) was constructed by assigning 1 point for co-mutation and 1 point for high TMB (above median) to predict clinical benefit.</p><p><strong>Results: </strong>In ICB-treated cohorts (MSK and CS), only co-mutation consistently predicted superior OS, while single mutations showed no consistent benefit. Co-mutated tumors exhibited significantly higher TMB and neo-antigen loads, an immune-inflamed microenvironment with elevated M1 macrophages, reduced Tregs, and upregulation of programmed death-ligand 1 (PD-L1), CTLA-4, TIM-3, as well as enrichment of IFN-γ and IL6-JAK-STAT3 pathways. The combined risk score (co-mutation + TMB) predicted clinical benefit with an area under the curve (AUC) of 0.659. Patients with high-risk score (2 points) demonstrated significantly higher clinical benefit rates compared to low-risk score (0 points).</p><p><strong>Conclusions: </strong><i>BRAF-PTPRT</i> co-mutation is a robust, cross-cohort predictive biomarker for ICB response in melanoma. A simple risk score integrating co-mutation and TMB further improves patient stratification. Routine testing of both genes may guide immunotherapy decisions.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"680"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and external validation of an XGBoost-based prognostic model for small cell lung cancer with brain metastases.","authors":"Pei Jiao, Chen Chen, Koudong Zhang, Qian Sun, Can Wang","doi":"10.21037/tcr-2026-1263","DOIUrl":"https://doi.org/10.21037/tcr-2026-1263","url":null,"abstract":"<p><strong>Background: </strong>Patients with small cell lung cancer (SCLC) and brain metastases (BM) have poor and heterogeneous survival outcomes, while existing prognostic tools have shown limited discriminatory performance. We aimed to develop an extreme gradient boosting (XGBoost) based prognostic model and perform preliminary external validation.</p><p><strong>Methods: </strong>Patients with small cell lung cancer and brain metastases (SCLCBM) diagnosed between 2010 and 2020 were identified from the Surveillance, Epidemiology, and End Results (SEER) database for model development and internal testing. External validation was performed in an independent single-center Chinese cohort. Variables screened by univariable Cox regression and retained in multivariable Cox regression analyses were used as predictors in the XGBoost models. Grid search was used for hyperparameter tuning, and candidate parameter combinations were evaluated using 10-fold cross-validation. Model performance was assessed using the areas under the curves (AUCs) and confusion matrices, and SHapley Additive exPlanations (SHAP) analysis was used to interpret model predictions.</p><p><strong>Results: </strong>The study included 7,692 patients from the SEER database and 128 patients in the external validation cohort. The final models incorporated demographic, tumor-related, treatment-related, and metastatic factors, including age, sex, T and N stages, chemotherapy, radiotherapy, surgery, and extracranial metastases. AUCs for 3-, 6-, 12-, and 18-month overall survival (OS) were 0.840, 0.801, 0.738, and 0.759 in the internal testing cohort and 0.779, 0.790, 0.739, and 0.763 in the external cohort, respectively. SHAP analysis consistently ranked chemotherapy as the most influential predictor.</p><p><strong>Conclusions: </strong>The XGBoost models showed moderate discrimination across the evaluated prediction horizons in both the internal testing cohort and a small single-center external cohort. Further validation in larger, prospective, multicenter cohorts is required before clinical use.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"694"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between primary-site surgery and overall survival in non-metastatic and metastatic colorectal cancer: a population-based study using the Surveillance, Epidemiology, and End Results database.","authors":"Xueru Fan, Tianzi Luo, Zelun Li, Xiaoge Wang, Erping Xu","doi":"10.21037/tcr-2026-1108","DOIUrl":"https://doi.org/10.21037/tcr-2026-1108","url":null,"abstract":"<p><strong>Background: </strong>Surgery is central to the management of localized colorectal cancer (CRC), whereas surgical decision-making in metastatic disease is more complex and highly individualized. This study aimed to investigate patterns of primary-site surgery recorded in the Surveillance, Epidemiology, and End Results (SEER) database, reasons for no surgery, patient and tumor characteristics, and observed overall survival (OS) in non-metastatic CRC, with a separate exploratory analysis of surgical patterns in metastatic disease.</p><p><strong>Methods: </strong>CRC tumor records diagnosed between 2006 and 2015 were identified according to prespecified eligibility criteria. Non-metastatic (M0) disease was the primary cohort. Descriptive analyses characterized recorded surgery, reasons for no surgery, baseline features, and survival; multivariable Cox regression, propensity-score matching (PSM), and sensitivity analyses estimated adjusted associations. Metastatic (M1) disease was analyzed separately as an exploratory cohort.</p><p><strong>Results: </strong>Among 14,130 M0 tumor records, five with unknown surgery status were excluded, leaving 13,807 with and 318 without recorded primary-site surgery. Surgery was not recommended in 213 of 318 no-surgery records (67.0%), and the method used to determine regional nodal status differed markedly by surgery status [absolute standardized mean difference (SMD), 2.158]. Median OS was 164 months with recorded surgery and 59 months without recorded surgery (log-rank P<0.001). In the primary Cox model, recorded surgery was associated with a lower average hazard of death over follow-up [hazard ratio (HR), 0.457; 95% confidence interval (CI): 0.397-0.527; P<0.001], but the proportional hazards assumption was not met. PSM yielded 317 pairs; the pair-stratified HR was 0.453 (95% CI: 0.344-0.598; P<0.001), and 60-month OS was 74.1% versus 50.2%. The M1 cohort comprised 694 tumor records. In the 2010-2015 subset (n=467), records without primary-site surgery more often had lung metastasis, bone metastasis, and at least two documented organ sites; four recorded surgical patterns were observed.</p><p><strong>Conclusions: </strong>In M0 disease, no recorded primary-site surgery was uncommon, usually reflected that surgery was not recommended, and was associated with substantially shorter observed survival. This association does not quantify the causal effect of surgery. Heterogeneous metastatic distributions and procedure patterns in M1 disease underscore the need for individualized clinical decision-making rather than routine primary-site surgery based on registry survival comparisons.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"707"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telmisartan enhances anti-PD-1 efficacy in MSS colorectal cancer via modulation of PD-L1 and STAT3 signaling.","authors":"Xin Lin, Jingying Li, Wei Lin","doi":"10.21037/tcr-2026-1409","DOIUrl":"https://doi.org/10.21037/tcr-2026-1409","url":null,"abstract":"<p><strong>Background: </strong>Microsatellite stable (MSS) colorectal cancer (CRC), accounting for over 85% of advanced cases, shows intrinsic resistance to immune checkpoint inhibitors due to an immunosuppressive tumor microenvironment. The renin-angiotensin system (RAS), particularly angiotensin II type 1 receptor (AT1R), has been implicated in tumor progression and immune evasion. This study investigated whether telmisartan, a selective AT1R antagonist, modulates programmed death-ligand 1 (PD-L1) expression and enhances anti-tumor immunity in MSS CRC.</p><p><strong>Methods: </strong>Mismatch repair (MMR) protein expression was characterized in human (SW480, HT29, HCT116) and murine (CT26) CRC cell lines. The effects of telmisartan on cell viability, PD-L1 expression, STAT3 signaling, and migration were evaluated using Cell Counting Kit-8 (CCK-8), Western blotting, and Transwell assays. A CT26 tumor model in BALB/c mice was used to assess therapeutic efficacy alone or combined with pembrolizumab, with immunohistochemical analysis of tumor-infiltrating lymphocytes. Public transcriptomic analysis of The Cancer Genome Atlas (TCGA) CRC data and immune infiltration analysis using the CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) algorithm were further performed.</p><p><strong>Results: </strong>Telmisartan (10-20 μM) reduced PD-L1 expression in both MSS and MSI-H CRC cell lines without significant cytotoxicity. It was associated with increased signal transducer and activator of transcription 3 (STAT3) phosphorylation and reduced cell migration. <i>In vivo</i>, telmisartan inhibited tumor growth, while the combination with pembrolizumab resulted in enhanced antitumor efficacy. These effects were accompanied by increased infiltration of CD3⁺, CD4⁺, and CD8⁺ T cells. Transcriptomic analysis demonstrated positive correlations among AGTR1, STAT3, and CD274 expression, while CIBERSORT analysis revealed AGTR1-associated alterations in immune cell infiltration.</p><p><strong>Conclusions: </strong>Telmisartan may remodel the tumor immune microenvironment, potentially through modulation of PD-L1 expression associated with STAT3 signaling, thereby enhancing the response of MSS CRC to immune checkpoint blockade. These findings suggest that telmisartan could serve as a potential immunotherapy adjuvant for MSS CRC.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"702"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of hepatitis B virus-associated membrane proteins as prognostic biomarkers for hepatocellular carcinoma based on retrospective analysis of integrated membrane proteomics.","authors":"Zichen Liu, Jiaming Wan, Guoli Deng, Mingzhu Zhang, Shaohua Zhang, Qizhi Liu, Liu Ouyang, Shupeng Liu","doi":"10.21037/tcr-2026-0760","DOIUrl":"https://doi.org/10.21037/tcr-2026-0760","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Hepatitis B virus (HBV) infection is one of the major risk factors for hepatocellular carcinoma (HCC) development. Current prognostic assessment of HBV-associated HCC (HBV-HCC) largely relies on clinicopathological parameters, such as tumor stage, liver function, and serum alpha-fetoprotein (AFP) levels, which have limited accuracy in identifying patients at high risk of recurrence or poor survival. Therefore, reliable molecular biomarkers are urgently needed to improve individualized risk stratification and guide postoperative surveillance and therapeutic decision-making. HBV infection induces chronic inflammation through mechanisms such as genomic integration, ultimately leading to HCC. Cell membrane proteins play critical roles in maintaining cellular homeostasis, signal transduction, and immune recognition, and may be importantly involved in HBV-HCC. However, the prognostic significance of HBV-associated membrane proteins has not been sufficiently investigated. This study aimed to identify HBV-associated membrane proteins through integrated proteomic analysis and to evaluate their prognostic value for recurrence-free survival (RFS) and overall survival (OS) in patients with HBV-HCC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;HBV-associated membrane proteins were identified in HepG2 and Hep3B cells using two parallel proteomic approaches: membrane fractionation and &lt;i&gt;Bacillus subtilis&lt;/i&gt; (BS2)-based proximity labeling, both coupled with mass spectrometry (MS). These findings were integrated with proteomic analysis of HBV-HCC tissue samples. Prognostic models for RFS and OS were constructed using machine learning algorithms including least absolute shrinkage and selection operator (LASSO)-Cox (proportional hazards model), random survival forest (RSF), and elastic net (EN).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 98 HBV-associated membrane proteins were identified, including canonical membrane proteins as well as several nuclear and cytoplasmic proteins. Functional annotation revealed numerous tumor-associated molecules, transporters, and enzymes. Univariate and multivariate analyses identified proteins such as POLM and TMEM192 as prognostic factors for RFS, and GLYATL1 and TMEM109 for OS. The prognostic models developed using machine learning achieved receiver operating characteristic (ROC) values exceeding 0.7.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study identified HBV-HCC-related membrane proteins beyond classical localized molecules using membrane fractionation and BS2 proximity labeling, and established robust prognostic models through multiple machine learning approaches. These findings provide potential therapeutic targets and prognostic biomarkers that may improve the clinical management of HBV-HCC patients. However, the single-cohort design, absence of external validation, and potential model optimism preclude claims of clinical robustness or immediate application. Independent multicenter validation and stan","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"687"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two case reports of gastric signet ring cell carcinoma with pulmonary metastasis manifesting as diffuse ground-glass opacities and pleural involvement: an atypical imaging pattern mimicking lung infection.","authors":"Yike Wang, Yingbo Xie, Xuan Yao, Pei Ma, Fengnan Wang, Xinqing Lin, Xiaohong Xie, Ming Liu, Chengzhi Zhou, Zhanhong Xie","doi":"10.21037/tcr-2026-1318","DOIUrl":"https://doi.org/10.21037/tcr-2026-1318","url":null,"abstract":"<p><strong>Background: </strong>Gastric signet ring cell carcinoma (SRCC) typically metastasizes to the liver and peritoneum. Although pulmonary metastasis occurs in approximately 15% of patients with advanced gastric cancer and typically presents as multiple well-circumscribed nodules on chest computed tomography (CT), diffuse ground-glass opacities (GGOs) as the predominant manifestation of SRCC lung metastasis are exceedingly rare. This pattern may pose a diagnostic pitfall by closely mimicking infectious or interstitial lung diseases.</p><p><strong>Case description: </strong>We report two cases of gastric SRCC with pulmonary metastasis presenting primarily with respiratory symptoms and atypical imaging features. Case 1: A 64-year-old woman presented with persistent cough, dyspnea, and chest pain, and denied any preceding gastrointestinal symptoms. Chest CT revealed bilateral diffuse GGOs accompanied by pleural effusion and thickening. Despite empirical antibiotic therapy directed against <i>Streptococcus pyogenes</i> and <i>Klebsiella pneumoniae</i> identified by next-generation sequencing, her symptoms worsened. Positron emission tomography-computed tomography (PET-CT) demonstrated intense metabolic activity [maximum standardized uptake value (SUVmax) 6.2] in the lung lesions and bilateral pleural involvement. Bronchoscopy-guided biopsy confirmed adenocarcinoma with signet ring cell features, and gastroscopy with biopsy of a depressed gastric angle lesion confirmed poorly differentiated gastric adenocarcinoma. She received docetaxel plus oxaliplatin chemotherapy with symptomatic improvement and was discharged. Case 2: A 62-year-old woman presented with exertional dyspnea and intermittent cough, also without preceding gastrointestinal symptoms. CT imaging demonstrated right pleural effusion, pleural thickening, and ground-glass nodules. Empirical antibiotic therapy was ineffective. Pleural fluid analysis revealed elevated carcinoembryonic antigen (CEA; 85.00 µg/mL) and cancer antigen 125 (CA125; 327.00 U/mL). Biopsy of an adnexal mass and gastric lesions confirmed gastric SRCC with pleural and ovarian metastases. She was referred to the oncology department for systemic therapy. Long-term follow-up data for both patients are not available in the medical records.</p><p><strong>Conclusions: </strong>These cases highlight an atypical imaging pattern of gastric SRCC metastasis-diffuse GGOs with pleural involvement-that closely mimics benign lung diseases. In patients without known malignancy who present with unexplained respiratory symptoms, diffuse pulmonary infiltrates, pleural effusion or thickening, and poor response to anti-infective therapy, early lung or pleural biopsy is essential to prevent diagnostic delay and initiate timely systemic oncological treatment.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"720"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic signature of phosphoethanolamine and arginine pathways predicts prognosis and immunotherapy resistance in lung adenocarcinoma.","authors":"Tao Wang, Hongwei Li, Fei Ding","doi":"10.21037/tcr-2026-1553","DOIUrl":"https://doi.org/10.21037/tcr-2026-1553","url":null,"abstract":"<p><strong>Background: </strong>Metabolic reprogramming is a hallmark of lung adenocarcinoma (LUAD). However, the prognostic significance of phosphoethanolamine (pEtn) and arginine metabolism-related genes remains poorly defined. This study aimed to develop and externally validate a pEtn- and arginine metabolism-related gene signature for predicting prognosis in LUAD and to characterize its associations with tumor biology, immune response, and therapeutic sensitivity.</p><p><strong>Methods: </strong>We analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) LUAD (TCGA-LUAD, n=514) and independent Gene Expression Omnibus (GEO) cohorts. Candidate genes were identified from Molecular Signatures Database (MSigDB) gene sets, followed by differential expression, Cox regression, and protein-protein interaction (PPI) analyses. An 18-gene metabolic signature was constructed using least absolute shrinkage and selection operator (LASSO) regression and validated across three external datasets. Functional enrichment, immune infiltration profiling, Tumor Immune Dysfunction and Exclusion (TIDE) analysis, and drug sensitivity prediction, Cancer Therapeutics Response Portal (CTRP), and Genomics of Drug Sensitivity in Cancer (GDSC) were performed to explore biological and therapeutic implications.</p><p><strong>Results: </strong>We identified 114 metabolism-related genes, of which 27 were significantly associated with overall survival (OS). An 18-gene prognostic signature stratified patients into high- and low-risk groups, with high-risk patients showing significantly poorer survival [TCGA: hazard ratio (HR) =2.81, P<0.001; external validation: HR 2.60-3.24, all P<0.01]. High-risk tumors were enriched in cell cycle, glycolysis, and epithelial-mesenchymal transition (EMT) pathways, and exhibited elevated but dysfunctional CD8⁺ T cell infiltration, consistent with immune exclusion and reduced immunotherapy response. Drug sensitivity analysis suggested that high-risk patients may benefit from dasatinib, lovastatin, irinotecan, and talazoparib.</p><p><strong>Conclusions: </strong>An 18-gene metabolic signature demonstrates robust prognostic value in LUAD, linking metabolic reprogramming with tumor aggressiveness, immunotherapy resistance, and drug vulnerability. This model provides a potential tool for risk stratification and personalized treatment.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"706"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinase-based molecular subtyping and a prognostic risk model in colorectal cancer with functional validation of PLK4.","authors":"Chao Shen, Changmin Ding, Xiaofeng Han, Yanzhao Wang","doi":"10.21037/tcr-2026-1446","DOIUrl":"https://doi.org/10.21037/tcr-2026-1446","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) exhibits marked molecular heterogeneity, yet prognostic tools centered specifically on protein kinases remain scarce. This study aimed to identify kinase-related molecular subtypes of CRC and to develop and validate a kinase-based prognostic risk model integrating clinical and immune features.</p><p><strong>Methods: </strong>Transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were integrated to identify prognosis-related kinase genes. Unsupervised consensus clustering was used to define molecular subtypes, and differences in survival, immune infiltration, and immune checkpoint expression between subtypes were assessed. A nine-gene prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression and validated in an independent external cohort. Associations with the consensus molecular subtypes (CMS), tumor mutational burden (TMB), drug sensitivity, and immunotherapy response were analyzed. The expression of core genes was verified by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC cell lines, and the function of <i>PLK4</i> was examined by knockdown experiments.</p><p><strong>Results: </strong>Consensus clustering revealed two distinct kinase-based subtypes with significantly different survival; the poorer-prognosis subtype overlapped predominantly with CMS4 and showed altered immune infiltration. The nine-gene risk model provided reproducible prognostic stratification, remained an independent predictor of survival after adjustment for tumor-node-metastasis (TNM) stage, and was validated in the external validation cohort. Compared with high-risk patients, low-risk patients showed higher TMB and greater predicted responsiveness to immunotherapy and selected chemotherapeutic agents. qRT-PCR confirmed that nine core genes exhibited expression trends consistent with the bioinformatics predictions, and <i>PLK4</i> knockdown consistently inhibited cell proliferation and migration and promoted apoptosis in both HT-29 and HCT116 cells, supporting an oncogenic role.</p><p><strong>Conclusions: </strong>This kinase-based subtyping and prognostic model offers a complementary tool for risk stratification and individualized treatment decisions in CRC. Further multi-omics and <i>in vivo</i> studies are warranted to facilitate clinical translation.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"683"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glaucocalyxin A sensitizes ovarian cancer cells to PARP inhibitors by inducing DNA damage.","authors":"Lingling Zhuang, Lanyan Hu, Qi Chen","doi":"10.21037/tcr-2026-1260","DOIUrl":"https://doi.org/10.21037/tcr-2026-1260","url":null,"abstract":"<p><strong>Background: </strong>Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated therapeutic advantages in ovarian cancer (OC) patients with homologous recombination (HR) deficiency. However, their effectiveness is limited in HR-proficient or acquired resistance tumors. Glaucocalyxin A (GLA) is an ent-kauranoid diterpene with anti-tumor properties. This study aimed to investigate the role and underlying mechanisms of GLA in OC and its potential as a sensitizing agent for PARPi.</p><p><strong>Methods: </strong>The anti-proliferative effect of GLA on OC cells was evaluated both <i>in vitro</i> and <i>in vivo</i>. RNA-sequencing (RNA-seq) was performed to identify GLA-regulated pathways. DNA damage and cell cycle progression were assessed by immunofluorescence, neutral comet assay, and flow cytometry. The expression and activation of key proteins in the DNA damage response (DDR), HR, and Fanconi anemia (FA) pathways were analyzed by western blotting and immunofluorescence. The synergistic effect of GLA combined with the PARPi talazoparib was evaluated <i>in vitro</i> and in SKOV3 xenografts.</p><p><strong>Results: </strong>GLA significantly inhibited OC cell proliferation <i>in vitro</i> and <i>in vivo</i>. RNA-seq analysis revealed that GLA induced G2/M cell cycle arrest and DNA damage. Mechanistically, GLA activated the ATM-Chk2 pathway while suppressing the ATR-Chk1 axis within the DDR. Furthermore, GLA inhibited HR and FA pathways, leading to DNA repair deficiency. Notably, a sequential regimen of GLA followed by talazoparib markedly increased drug responsiveness and DNA damage levels, and synergistically enhanced the anti-tumor effect of PARPi in SKOV3 xenografts.</p><p><strong>Conclusions: </strong>This study identifies GLA as a potential PARPi-sensitizing agent and provides a preclinical rationale for sequential combination therapy to broaden the therapeutic utility of PARPi in HR-proficient OC.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":"15 9","pages":"701"},"PeriodicalIF":2.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}