Search Results (1,012)

Background: RiBi is integral to cell proliferation, and its dysregulation is increasingly recognized as a hallmark of aggressive cancers. We sought to develop and validate a composite “PanRibo-515 score” reflecting RiBi activity across multiple tumor types, assess its prognostic significance, and explore its relationship with immune checkpoint therapy outcomes. Methods: We curated 515 RiBi–associated genes (PanRibo-515) and used a LASSO regression-based strategy on a training dataset (GSE202203) to select the prognostically most relevant subset of 68 genes (OncoRibo-68). Directionality (positive or negative impact on survival) was assigned based on the sign of the LASSO coefficients. We integrated a forward selection approach to identify a refined subset of genes for computing the OncoRibo-68 score. For validation, patients in The Cancer Genome Atlas (TCGA) were stratified into high or low OncoRibo-68 score groups for survival analyses. Additional validation for immunotherapy response was conducted using bioinformatic platforms used for immunotherapy response analysis. Results: A higher OncoRibo-68 score consistently correlated with poorer overall and progression-free survival across multiple cancers. Elevated OncoRibo-68 score was linked to an immunosuppressive tumor microenvironment, but interestingly to increased response to checkpoint inhibitors. Conclusions: Our findings highlight RiBi as an important determinant of tumor aggressiveness and identify the OncoRibo-68 score as a promising biomarker for risk stratification and therapy selection. Future research may evaluate whether targeting RiBi pathways could enhance treatment efficacy, particularly in combination with immunotherapy. Full article

Background: Pleural mesothelioma (PM) is a type of cancer that is difficult to diagnose and treat. Patients may have vastly varying prognoses, and prognostic factors may help guide the clinical approach. As a recently identified biomarker, the pan-Immune-Inflammation-Value (PIV) is a simple, comprehensive, and peripheral blood cell-based biomarker. Methods: The present study represents a retrospective observational analysis carried out within a single-center setting. Ninety-five patients with PM stages I–IV were enrolled in the study. We analyzed the correlation between patients’ demographic characteristics, clinicopathological factors such as histological subtypes, surgery status, tumor thickness, blood-based parameters, and treatment options with their prognoses. PIV was calculated by the following formula: (neutrophil count × monocyte count × platelet count)/lymphocyte count. Additionally, blood-based parameters were used to calculate the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and systemic immune inflammation index (SII). Results: We categorized the patients into two groups, low PIV group (PIV ≤ 732.3) and high PIV group (PIV > 732.3) according to the determined cut-off value, which was defined as the median. It was revealed that high PIV was associated with poor survival outcomes. The median follow-up period was 15.8 months (interquartile range, IQR, 7.1 to 29.8 months). The median overall survival (OS) was significantly longer in patients in the low PIV group (median 29.8 months, 95% confidence interval (CI), 15.6 to 44) than the high PIV group (median 14.7 months, 95% CI, 10.8 to 18.6 p < 0.001). Furthermore, the study revealed that patients with low PIV, NLR, and SII values were more likely to be eligible for surgery and were diagnosed at earlier stages. Additionally, these markers were identified as potential predictors of disease-free survival (DFS) in the surgical cohort and of treatment response across the entire patient population. Conclusions: In addition to well-established clinical factors such as stage, histologic subtype, resectability, and Eastern Cooperative Oncology Group (ECOG) performance status (PS), PIV emerged as an independent and significant prognostic factor of overall survival (OS) in patients with PM. Moreover, PIV also demonstrated a remarkable independent prognostic value for disease-free survival (DFS) in this patient population. Additionally, some clues are provided for conditions such as treatment responses, staging, and suitability for surgery. As such, in this cohort, it has outperformed the other blood-based markers based on our findings. Given its ease of calculation and cost-effectiveness, PIV represents a promising and practical prognostic tool in the clinical management of pleural mesothelioma. It can be easily calculated using routinely available laboratory parameters for every cancer patient, requiring no additional cost or complex procedures, thus facilitating its integration into everyday clinical practice. Full article

Background/Objectives: Although numerous prognostic biomarkers have been proposed for colorectal cancer (CRC), their longitudinal evaluation remains limited. The aim of this study was to investigate longitudinal changes in biomarkers calculated from routinely used laboratory markers and their relationships to common chronic diseases (comorbidities). Methods: A retrospective longitudinal observational study was completed with the inclusion of 817 CRC patients and a total of 4542 measurement points. Pan-immune inflammation value (PIV), prognostic nutritional index (PNI), and systemic immune-inflammation index (SII) were calculated based on complete blood count and albumin measurement data. Results: Longitudinal data analyses confirmed the different values and slopes of the parameters tested at the different endpoints. Survivors had the lowest and most constant PIVs and SII values, and the highest and most slowly decreasing PNI values. Those patients with non-cancerous death had similar values to the previous cohort, but an increase/decrease occurred towards the death event. Patients with CRC-related death had significantly higher PIVs and SII values and significantly lower PNI values (p < 0.0001), and a significant increase/decrease was observed at the early observational periods. The presence of lymph node and/or distant metastases, adjuvant chemotherapy, and hypertension significantly affected PIVs and SII and/or PNI values. The changes in PIVs and SII and PNI values toward pathological values are poor prognostic signs (p < 0.0001). Conclusions: Each of the three calculated markers demonstrates suitability for longitudinal patient follow-up, and their pathological alterations over time serve as valuable prognostic indicators. They may also be useful to detect certain clinicopathological parameters early. Full article

Cancer disparities in low- and middle-income countries (LMICs) arise from multifaceted interactions between environmental exposures, infectious agents, and systemic inequities, such as limited access to care. The exposome, a framework encompassing the totality of non-genetic exposures throughout life, offers a powerful lens for understanding these disparities. In LMICs, populations are disproportionately affected by air and water pollution, occupational hazards, and oncogenic infections, including human papillomavirus (HPV), hepatitis B virus (HBV), Helicobacter pylori (H. pylori), human immunodeficiency virus (HIV), and neglected tropical diseases, such as schistosomiasis. These infectious agents contribute to increased cancer susceptibility and poor outcomes, particularly in immunocompromised individuals. Moreover, climate change, food insecurity, and barriers to healthcare access exacerbate these risks. This review adopts a population-level exposome approach to explore how environmental and infectious exposures intersect with genetic, epigenetic, and immune mechanisms to influence cancer incidence and progression in LMICs. We highlight the critical pathways linking chronic exposure and inflammation to tumor development and evaluate strategies such as HPV and HBV vaccination, antiretroviral therapy, and environmental regulation. Special attention is given to tools such as exposome-wide association studies (ExWASs), which offer promise for exposure surveillance, early detection, and public health policy. By integrating exposomic insights into national health systems, especially in regions such as sub-Saharan Africa (SSA) and South Asia, LMICs can advance equitable cancer prevention and control strategies. A holistic, exposome-informed strategy is essential for reducing global cancer disparities and improving outcomes in vulnerable populations. Full article

Prognostic markers such as overall survival (OS) and tertiary lymphoid structure (TLS) ratios, alongside diagnostic signatures like primary cancer-type classification, provide critical information for treatment selection, risk stratification, and longitudinal care planning across the oncology continuum. However, extracting these signals solely from sparse, high-dimensional multi-omics data remains a major challenge due to heterogeneity and frequent missingness in patient profiles. To address this challenge, we present SeNMo, a self-normalizing deep neural network trained on five heterogeneous omics layers—gene expression, DNA methylation, miRNA abundance, somatic mutations, and protein expression—along with the clinical variables, that learns a unified representation robust to missing modalities. Trained on more than 10,000 patient profiles across 32 tumor types from The Cancer Genome Atlas (TCGA), SeNMo provides a baseline that can be readily fine-tuned for diverse downstream tasks. On a held-out TCGA test set, the model achieved a concordance index of 0.758 for OS prediction, while external evaluation yielded 0.73 on the CPTAC lung squamous cell carcinoma cohort and 0.66 on an independent 108-patient Moffitt Cancer Center cohort. Furthermore, on Moffitt’s cohort, baseline SeNMo fine-tuned for TLS ratio prediction aligned with expert annotations (p < 0.05) and sharply separated high- versus low-TLS groups, reflecting distinct survival outcomes. Without altering the backbone, a single linear head classified primary cancer type with 99.8% accuracy across the 33 classes. By unifying diagnostic and prognostic predictions in a modality-robust architecture, SeNMo demonstrated strong performance across multiple clinically relevant tasks, including survival estimation, cancer classification, and TLS ratio prediction, highlighting its translational potential for multi-omics oncology applications. Full article

Background/Objectives: Upper tract urothelial carcinoma (UTUC) is a rare and biologically distinct subset of urothelial malignancies, comprising approximately 5–10% of urothelial cancers. UTUC presents unique diagnostic and therapeutic challenges, with both a higher likelihood of invasive disease at presentation and a less favorable prognosis compared to urothelial carcinoma of the bladder. Current treatment strategies for UTUC are largely derived from bladder cancer studies, underscoring the need for UTUC-directed research. This review provides a comprehensive overview of UTUC, encompassing diagnostic approaches, systemic and intraluminal therapies, surgical management, and future directions. Methods: A narrative review was conducted synthesizing evidence from guideline-based recommendations, retrospective and prospective clinical studies, and ongoing trials focused on UTUC. Results: Neoadjuvant cisplatin-based chemotherapy is increasingly preferred in UTUC due to the risk of postoperative renal impairment that may preclude adjuvant cisplatin use. Surgical management includes kidney-sparing approaches and radical nephroureterectomy (RNU), with selection guided by tumor risk and patient comorbidities. While endoscopic management (EM) preserves renal function, it carries a higher recurrence and surveillance burden; RNU remains standard for high-risk cases. Systemic therapy for advanced and metastatic UTUC mirrors that of bladder urothelial carcinoma. Enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy over chemotherapy in the EV-302 trial, with improved response rate, progression-free survival, and overall survival across subgroups, including UTUC. For patients ineligible for EV, the CheckMate-901 study supported first-line chemoimmunotherapy with gemcitabine, cisplatin, and nivolumab. Further systemic therapy strategies include maintenance avelumab post-chemotherapy (JAVELIN Bladder 100), targeted therapies such as erdafitinib (THOR trial), and trastuzumab deruxtecan (DESTINY-PanTumor02) in FGFR2/3-altered and HER2-positive disease, respectively. Conclusions: Historically, the therapeutic landscape of UTUC has been extrapolated from bladder cancer; however, ongoing research specific to UTUC is deriving more precise regimens involving the use of immune checkpoint inhibitors, antibody–drug conjugates, and biomarker-driven therapies. Full article

Multiple metrics for read-level DNA methylation pattern analysis have provided new insights into DNA methylation modifications. However, the performance of these metrics and their relationship with DNA methylation ratios in identifying biologically meaningful regions have remained unclear. Here, we systematically benchmarked five read-level DNA methylation metrics using whole-genome bisulfite sequencing data from 59 individuals across six healthy tissue types and six tumor types. We found that DNA methylation concurrence (MCR) effectively captured tissue-specific features independent of the DNA methylation ratios. Regions that exhibited decreased MCR (MCDRs) in tumors were significantly enriched in promoter and intergenic regions and strongly overlapped with tumor-gained chromatin accessibility sites. The further analysis of histone modifications, including H3K4me3, H3K27ac, and H3K9ac, confirmed that MCDRs marked active gene regulatory elements. Motif enrichment analysis revealed a strong preference for CTCF binding within MCDRs. Additionally, 3D genome analysis supported a model in which MCDRs, independent of DNA methylation ratios, contribute to active gene regulation by facilitating CTCF binding and long-range chromatin interactions. Full article

RKIP and LKB1, encoded by PEBP1 and STK11, respectively, have emerged as key regulators of cancer pathophysiology. However, their role in shaping tumor progression through modulation of the tumor microenvironment (TME) is not yet fully understood. To address this, we performed a comprehensive pan-cancer analysis using TCGA transcriptomic data across 33 cancer types, grouped by their tissue of origin. We investigated PEBP1/STK11 co-expression and its association with transcriptomic reprogramming in major TME components, including immune, mechanical, metabolic, and hypoxic subtypes. Our results revealed both positive and inverse correlations between PEBP1/STK11 co-expression and TME-related molecular signatures, which did not align with classical cancer categorizations. In a subset of tumors, PEBP1/STK11 co-expression was significantly associated with improved overall survival and reduced mortality (HR < 1). Notably, we predominantly observed inverse correlations with pro-inflammatory and immunosuppressive chemokines, immune checkpoints, extracellular matrix components, and key regulators of epithelial-to-mesenchymal transition. In contrast, we found positive associations with anti-inflammatory chemokines and their receptors. Importantly, PEBP1/STK11 co-expression was consistently linked to reduced expression of drug resistance genes and greater chemosensitivity across multiple tumor types. Our findings underscore the co-expression of PEBP1 and STK11 as a promising target for future studies aimed at elucidating its potential as a biomarker for prognosis and therapeutic response in precision oncology. Full article

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC. Full article

Background: Thyroid neoplasms exhibit a diverse molecular landscape, and the 2022 WHO classification emphasizes the critical role of molecular profiling in thyroid cancer management; however, comprehensive mutational data from fine-needle aspiration cytology (FNAC) samples using targeted next-generation sequencing (NGS) are still limited, necessitating further investigation to guide clinical practice. Purpose: To characterize the mutational landscape of thyroid neoplasms using targeted NGS of FNAC samples and to assess the clinical implications of molecular profiling. Materials and Methods: This retrospective study included 952 patients with thyroid carcinomaneoplasms who underwent surgery at Sun Yat-sen Memorial Hospital from 2021 to 2023. Preoperative ultrasound, FNAC, and targeted NGS were performed. NGS panels covering 18, 88, and pan-cancer genes were used to analyze FNAC samples. Molecular alterations were correlated with clinical and pathological features. Results: The most frequent mutation was BRAF^V600E (84.45%), followed by RET (6.41%), BRCA1/2 (4.41%) and RAS (4.41%). Patients were categorized into BRAF-like (830 cases), RAS-like (36 cases), high-risk mutations (25 cases), and other mutations (28 cases). High-risk mutations were associated with older age and larger tumor size. BRAF-like tumors had a higher lymph node metastasis rate (58.77%) compared to RAS-like tumors (33.33%). Tumor mutation burden varied significantly among different thyroid neoplasm subtypes. Conclusions: Molecular profiling using targeted NGS of FNAC samples provides valuable insights into the genetic landscape of thyroid neoplasms and has significant clinical implications for diagnosis and personalized treatment strategies. Further validation with paired tumor and plasma samples is warranted. Full article

Breast cancer is a leading cause of central nervous system (CNS) metastases in women, often associated with poor prognosis and limited therapeutic options. However, molecular differences between primary tumors and CNS metastases remain underexplored. We aimed to characterize transcriptomic differences between primary breast tumors and matched CNS metastases and identify immune-related biomarkers associated with metastatic progression and patient outcomes. Transcriptomic profiling was based on 11 matched FFPE sample pairs (primary tumor and CNS metastasis). Paired formalin-fixed paraffin-embedded (FFPE) samples from primary tumors (T1) and CNS metastases (T2) were analyzed using the NanoString nCounter^® platform and the PanCancer IO 360™ Gene Expression Panel. Differential gene expression, Z-score transformation, and heatmap visualization were performed in R. In silico survival analyses for overall survival (OS) and recurrence-free survival (RFS) were conducted using publicly available TCGA and GEO datasets. Forty-five genes were significantly differentially expressed between the T1 and T2 samples. Immune-related genes such as CXCL9, IL7R, CD79A, and CTSW showed consistent downregulation in CNS metastases. High expression of CXCL9 and CD79A was associated with improved OS and RFS, whereas high IL7R and CTSW expression correlated with worse outcomes. These findings indicate immune suppression as a hallmark of CNS colonization. Comparative transcriptomic analysis further underscored the distinct molecular landscapes between primary and metastatic tumors. This study highlights transcriptional signatures associated with breast cancer CNS metastases, emphasizing the role of immune modulation in metastatic progression. The identified genes have potential as prognostic biomarkers and therapeutic targets, supporting the need for site-specific molecular profiling in metastatic breast cancer management. Full article

Background/Objectives: Cell–cell communication (CCC) is a critical process within the tumor microenvironment, governing regulatory interactions between cancer cells and other cellular subpopulations. Aiming to improve the accuracy and completeness of intercellular gene-regulatory network inference, we constructed a novel spatial-resolved gene-regulatory network framework (spGRN). Methods: Firstly, the spatial multi-omics data of colorectal cancer (CRC) patients were analyzed. We precisely located the tumor boundaries and then systematically constructed the spGRN framework to study the network regulation. Subsequently, the key signaling molecules obtained by the spGRN were identified and further validated by the spatial-proteomics dataset. Results: Through the constructed spatial gene regulatory network, we found that in the communication with malignant cells, the highly expressed ligands LIF and LGALS3BP and receptors IL6ST and ITGB1 in fibroblasts can promote tumor proliferation, and the highly expressed ligands S100A8/S100A9 in plasma cells play an important role in regulating inflammatory responses. Further, validation of the key signaling molecules by the spatial-proteomics dataset highlighted the role of these genes in mediating the regulation of boundary-related cells. Furthermore, we applied the spGRN to publicly available single-cell and spatial-transcriptomics datasets from three other cancer types. The results demonstrate that ITGB1 and its target genes FOS/JUN were commonly expressed in all four cancer types, indicating their potential as pan-cancer therapeutic targets. Conclusion: the spGRN was proven to be a useful tool to select signal molecules as potential biomarkers or valuable therapeutic targets. Full article

Inhibitors of the ubiquitin–proteasome system increase proteotoxic stress and have achieved clinical success for multiple myeloma but not for solid cancers such as hepatocellular carcinoma. Our objective is to identify a combination with proteasome inhibitors that enhances proteotoxic stress and apoptotic cell death in hepatocellular carcinoma but with less toxicity to non-cancer cells. We found that rencofilstat, a pan-cyclophilin inhibitor, combined with ixazomib, a proteasome inhibitor, increased apoptotic cell death in hepatocellular carcinoma but not in umbilical vein or dermal fibroblast non-cancer cells. We then analyzed the effects of rencofilstat + ixazomib on XBP1s and PERK, critical factors in the unfolded protein response used by cells to survive proteotoxic stress. Rencofilstat + ixazomib maintained higher expression of XBP1s and genetic models suggested that XBP1s was a pro-survival protein early and pro-death protein at later times. Simultaneously, decreased PERK expression prevented the block in protein synthesis via phospho-eIF2α and likely further amplified proteotoxic stress. Rencofilstat + ixazomib did not have effects on XBP1s or PERK in non-cancer cells. Further genetic experiments revealed the pro-survival roles for cyclophilin A and B in mediating rencofilstat + ixazomib-induced cell death. In the Hep3B xenograft model, rencofilstat + ixazomib significantly inhibited tumor volumes/weights without general toxicity. We conclude that rencofilstat + ixazomib amplified proteotoxic stress in hepatocellular carcinoma past a threshold pro-survival pathways could not tolerate, whereas non-cancer cells were less affected. Full article

Purpose: Previous studies have reported that blood-based inflammatory markers are associated with prognosis in patients with various solid tumors, including colorectal cancer (CRC). The pan-immune inflammation value (PIV) is a novel prognostic biomarker based on blood count. Here, we aimed to study the association between PIV and survival following transarterial radioembolization (TARE) in patients with liver-dominant metastatic colorectal cancer (CLM). Methods: A total of 49 patients with CLM who underwent TARE at the Ankara University Department of Medical Oncology were retrospectively analyzed. The relationship between clinical and laboratory parameters with post-TARE overall survival (OS) was analyzed by multivariate analyses. Results: The median age was 60 years and 71.4% of patients had received at least two lines of chemotherapy. The objective response rate (ORR) was 59.1% following TARE. Patients with hepatic response after TARE treatment demonstrated significantly longer survival compared to non-responders (p: 0.033). The optimal PIV threshold value was calculated as 629 in ROC analyses. This PIV value had 81% sensitivity and 80% specificity for OS prediction (AUC 0.86; 95% CI: 0.75–0.98, p = 0.008). Patients with elevated PIV > 629 had significantly shorter OS (p = 0.002). In the multivariate analysis, adjusted for ECOG PS, TARE response, presence of extrahepatic disease, number of chemotherapy lines, CEA levels and post-TARE NLR and PIV, only low PIV level was associated with longer OS (>629 vs. ≤629; HR: 4.87; 95% CI: 1.32–17.92; p = 0.017). Conclusions: PIV, a blood-based inflammatory score, may reflect the host’s immune response following TARE and serve as a novel predictor of survival. Full article

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy. Full article