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Search Results (383)

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Keywords = colorectal cancer-specific survival

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29 pages, 959 KiB  
Review
Machine Learning-Driven Insights in Cancer Metabolomics: From Subtyping to Biomarker Discovery and Prognostic Modeling
by Amr Elguoshy, Hend Zedan and Suguru Saito
Metabolites 2025, 15(8), 514; https://doi.org/10.3390/metabo15080514 - 1 Aug 2025
Viewed by 256
Abstract
Cancer metabolic reprogramming plays a critical role in tumor progression and therapeutic resistance, underscoring the need for advanced analytical strategies. Metabolomics, leveraging mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, offers a comprehensive and functional readout of tumor biochemistry. By enabling both targeted [...] Read more.
Cancer metabolic reprogramming plays a critical role in tumor progression and therapeutic resistance, underscoring the need for advanced analytical strategies. Metabolomics, leveraging mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, offers a comprehensive and functional readout of tumor biochemistry. By enabling both targeted metabolite quantification and untargeted profiling, metabolomics captures the dynamic metabolic alterations associated with cancer. The integration of metabolomics with machine learning (ML) approaches further enhances the interpretation of these complex, high-dimensional datasets, providing powerful insights into cancer biology from biomarker discovery to therapeutic targeting. This review systematically examines the transformative role of ML in cancer metabolomics. We discuss how various ML methodologies—including supervised algorithms (e.g., Support Vector Machine, Random Forest), unsupervised techniques (e.g., Principal Component Analysis, t-SNE), and deep learning frameworks—are advancing cancer research. Specifically, we highlight three major applications of ML–metabolomics integration: (1) cancer subtyping, exemplified by the use of Similarity Network Fusion (SNF) and LASSO regression to classify triple-negative breast cancer into subtypes with distinct survival outcomes; (2) biomarker discovery, where Random Forest and Partial Least Squares Discriminant Analysis (PLS-DA) models have achieved >90% accuracy in detecting breast and colorectal cancers through biofluid metabolomics; and (3) prognostic modeling, demonstrated by the identification of race-specific metabolic signatures in breast cancer and the prediction of clinical outcomes in lung and ovarian cancers. Beyond these areas, we explore applications across prostate, thyroid, and pancreatic cancers, where ML-driven metabolomics is contributing to earlier detection, improved risk stratification, and personalized treatment planning. We also address critical challenges, including issues of data quality (e.g., batch effects, missing values), model interpretability, and barriers to clinical translation. Emerging solutions, such as explainable artificial intelligence (XAI) approaches and standardized multi-omics integration pipelines, are discussed as pathways to overcome these hurdles. By synthesizing recent advances, this review illustrates how ML-enhanced metabolomics bridges the gap between fundamental cancer metabolism research and clinical application, offering new avenues for precision oncology through improved diagnosis, prognosis, and tailored therapeutic strategies. Full article
(This article belongs to the Special Issue Nutritional Metabolomics in Cancer)
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23 pages, 2002 KiB  
Article
Precision Oncology Through Dialogue: AI-HOPE-RTK-RAS Integrates Clinical and Genomic Insights into RTK-RAS Alterations in Colorectal Cancer
by Ei-Wen Yang, Brigette Waldrup and Enrique Velazquez-Villarreal
Biomedicines 2025, 13(8), 1835; https://doi.org/10.3390/biomedicines13081835 - 28 Jul 2025
Viewed by 471
Abstract
Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of [...] Read more.
Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10−5). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article
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22 pages, 4133 KiB  
Article
Multiomics Signature Reveals Network Regulatory Mechanisms in a CRC Continuum
by Juan Carlos Higareda-Almaraz, Francesco Mattia Mancuso, Pol Canal-Noguer, Kristi Kruusmaa and Arianna Bertossi
Int. J. Mol. Sci. 2025, 26(15), 7077; https://doi.org/10.3390/ijms26157077 - 23 Jul 2025
Viewed by 206
Abstract
Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, [...] Read more.
Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, we profiled LGD and HGD adenomas using EM-seq, and identified a consensus differential methylation signature (DMS) of 626 regions through two independent bioinformatics pipelines. This signature effectively distinguished LGD from HGD in both tissue and plasma-derived cell-free DNA (cfDNA), highlighting specific methylation patterns. Functional annotation indicated enrichment for regulatory elements associated with transcription factor activity and cell signaling. Applying the DMS to the TCGA CRC dataset revealed three tumor subtypes with increasing hypermethylation and one normal cluster. The most hypermethylated subtype exhibited poor survival, high mutation burden, and disrupted transcriptional networks. While overlapping with classical CpG Island Methylator Phenotype (CIMP) categories, the DMS captured a broader spectrum of methylation alterations. These findings suggest that the DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression, enabling the robust stratification of dysplasia severity and tumor subtypes. This signature holds promise for enhancing preclinical detection and molecular classification, and warrants further evaluation in larger prospective cohorts. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Colorectal Cancer)
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34 pages, 6295 KiB  
Article
ROS/Enzyme Dual-Responsive Drug Delivery System for Targeted Colorectal Cancer Therapy: Synergistic Chemotherapy, Anti-Inflammatory, and Gut Microbiota Modulation
by Xin Zhang, Ruonan Lian, Bingbing Fan, Lei Meng, Pengxia Zhang, Yu Zhang and Weitong Sun
Pharmaceutics 2025, 17(7), 940; https://doi.org/10.3390/pharmaceutics17070940 - 21 Jul 2025
Viewed by 434
Abstract
Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral [...] Read more.
Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral drug delivery system, KGM-CUR/PSM microspheres, to achieve precise drug release in CRC and enhance tumor-specific drug accumulation, which leverages high ROS levels in CRC and the β-mannanase overexpression in colorectal tissues. Methods: In this study, we synthesized a ROS-responsive prodrug polymer (PSM) by conjugating polyethylene glycol monomethyl ether (mPEG) and mesalazine (MSL) via a thioether bond. CUR was then encapsulated into PSM using thin-film hydration to form tumor microenvironment-responsive micelles (CUR/PSM). Subsequently, konjac glucomannan (KGM) was employed to fabricate KGM-CUR/PSM microspheres, enabling targeted delivery for colorectal cancer therapy. The ROS/enzyme dual-response properties were confirmed through in vitro drug release studies. Cytotoxicity, cellular uptake, and cell migration were assessed in SW480 cells. In vivo efficacy was evaluated in AOM/DSS-induced CRC mice, monitoring tumor growth, inflammatory markers (TNF-α, IL-1β, IL-6, MPO), and gut microbiota composition. Results: In vitro drug release studies demonstrated that KGM-CUR/PSM microspheres exhibited ROS/enzyme-responsive release profiles. CUR/PSM micelles demonstrated significant anti-CRC efficacy in cytotoxicity assays, cellular uptake studies, and cell migration assays. In AOM/DSS-induced CRC mice, KGM-CUR/PSM microspheres significantly improved survival and inhibited CRC tumor growth, and effectively reduced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and myeloperoxidase (MPO). Histopathological and microbiological analyses revealed near-normal colon architecture and microbial diversity in the KGM-CUR/PSM group, confirming the system’s ability to disrupt the “inflammation-microbiota-tumor” axis. Conclusions: The KGM-CUR/PSM microspheres demonstrated a synergistic enhancement of anti-tumor efficacy by inducing apoptosis, alleviating inflammation, and modulating the intestinal microbiota, which offers a promising stimuli-responsive drug delivery system for future clinical treatment of CRC. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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19 pages, 1049 KiB  
Review
MEK Inhibition in Glioblastoma: Current Perspectives and Future Directions
by Adam Shapira Levy, Jean-Paul Bryant, David Matichak, Shumpei Onishi and Yeshavanth Kumar Banasavadi-Siddegowda
Int. J. Mol. Sci. 2025, 26(14), 6875; https://doi.org/10.3390/ijms26146875 - 17 Jul 2025
Viewed by 336
Abstract
The Mitogen-activated protein kinase kinase (MEK) protein family has dual-specificity protein kinases with a myriad of cellular functions that include but are not limited to cell survival, cell division, immunologic response, angiogenesis, and cellular senescence. MEK is crucial in the MAPK signaling pathway, [...] Read more.
The Mitogen-activated protein kinase kinase (MEK) protein family has dual-specificity protein kinases with a myriad of cellular functions that include but are not limited to cell survival, cell division, immunologic response, angiogenesis, and cellular senescence. MEK is crucial in the MAPK signaling pathway, regulating different organ systems, including the CNS. Increased activation and dysregulation of the MEK pathway is reportedly observed in 30% of all malignancies. The diversity of MEK renders it a prime target for inhibition in treating cancer. MEK inhibition has been studied in the context of melanoma, non-small cell lung cancer, breast cancer, and colorectal cancer, among others. The standard treatment for glioblastoma (resection, temozolomide, and radiation) remains relatively futile, which warrants alternative treatment options. Therefore, MEK inhibition has garnered more attention in recent years as investigators have explored its role in treating the most aggressive and most common primary brain tumor, glioblastoma. MEK inhibitors have shown efficacy in pre-clinical investigations as well as some promise in clinical trials which have demonstrated improved overall and progression-free survival. This underscores the potential of MEK inhibition in glioblastoma therapy and represents an area that likely warrants further research. However, there are few comprehensive and unifying reviews discussing the current state of MEK inhibition in glioblastoma therapy. We begin this review by detailing the normal function of MEK as it pertains to the CNS. We then compiled relevant pre-clinical and clinical studies to investigate recent research discussing the role of MEK inhibition in glioblastoma therapy. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 3rd Edition)
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20 pages, 1063 KiB  
Review
ANGPTL4: A Comprehensive Review of 25 Years of Research
by Pedro Ramos, Qiongyu Shi, Jeremy Kleberg, Chandra K. Maharjan, Weizhou Zhang and Ryan Kolb
Cancers 2025, 17(14), 2364; https://doi.org/10.3390/cancers17142364 - 16 Jul 2025
Viewed by 678
Abstract
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved [...] Read more.
Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that was discovered in 2000 by three independent laboratories. In the ensuing two and a half decades, extensive work has been conducted to determine its physiological and pathological functions. ANGPTL4 has been shown to be involved in many biological processes, including glucose and lipid metabolism, angiogenesis, and wound healing, with implications in diseases such as type 2 diabetes, cardiovascular (e.g., atherosclerosis) and renal diseases, and cancer. For instance, ANGPTL4 is upregulated in several cancers, including renal cell carcinoma, breast cancer, and colorectal cancer. Interestingly, ANGPTL4 has been shown to exhibit both pro-tumor—promoting tumor growth, cell survival, angiogenesis and metastasis—as well as anti-tumor activities, underscoring its complex roles in cancer biology. This review examines the comprehensive biological functions of ANGPTL4 and its contributions to disease mechanisms with a specific emphasis on cancer, as well as its potential as a therapeutic target across different types of human cancers. Full article
(This article belongs to the Section Molecular Cancer Biology)
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9 pages, 393 KiB  
Article
TARE-Induced Pan-Immune Inflammation Value as a Prognostic Biomarker in Liver-Dominant Metastatic Colorectal Cancer
by Bengu Dursun, Burak Demir, Nejat Emre Öksüz, Çiğdem Soydal and Güngör Utkan
J. Clin. Med. 2025, 14(14), 4927; https://doi.org/10.3390/jcm14144927 - 11 Jul 2025
Viewed by 385
Abstract
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 [...] Read more.
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
(This article belongs to the Section Oncology)
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14 pages, 436 KiB  
Article
Laparoscopic Radical Colectomy with Complete Mesocolic Excision Offers Similar Results Compared with Open Surgery
by Vasile V. Bintintan, Vlad Fagarasan, Radu I. Seicean, David Andras, Alexandru I. Ene, Romeo Chira, Adriana Bintintan, Georgiana Nagy, Cristina Petrisor, Simona Cocu, Elena Stefanescu, Ionut Negoi, Adrian Calborean, George C. Dindelegan, Ciprian Silaghi, Iulia Lupan and Gabriel Samasca
Medicina 2025, 61(7), 1231; https://doi.org/10.3390/medicina61071231 - 7 Jul 2025
Viewed by 262
Abstract
Background and Objectives: The technique of complete mesocolic excision (CME) for colonic cancer is being advocated to improve the local control of the disease and increase the long-term survival. However, even with an open approach, CME is a complex technique and has [...] Read more.
Background and Objectives: The technique of complete mesocolic excision (CME) for colonic cancer is being advocated to improve the local control of the disease and increase the long-term survival. However, even with an open approach, CME is a complex technique and has not yet been adopted as standard care. Laparoscopy has been proven to bring significant advantages to colorectal surgery but performing a laparoscopic CME (Lap-CME) for colonic cancer is even more technically demanding than CME in open surgery. The purpose of this study is to evaluate whether Lap-CME can be offered as a standard procedure for patients with colonic cancer and to compare the results with those obtained after a conventional, open technique. Materials and methods: This study included 100 consecutive patients with colonic cancer, who were operated on by the same surgical team using a standardized medial-to-lateral open or laparoscopic complete mesocolic excision technique. The perioperative data was prospectively recorded in a database and retrospectively analyzed with the aim of identifying the proportion of patients that received Lap-CME, to evaluate the success rate of the procedure and to identify whether there are differences in the oncological quality of CME between the laparoscopic and open surgery groups. Results: Most of the patients enrolled in this study were in the advanced stages of the disease, with the incidence of pT3 tumors being 67% and the mean tumor size averaging 4.5 cm. Laparoscopic CME was performed in 39% of cases overall, with 41.4% being right colectomies, 42.5% being left colectomies and 16.1% being transverse colectomies. All of the parameters relevant to the oncological quality of resection, namely total lymph node count, resection margins, or the completeness of resection, were similar between the open and laparoscopic groups both when analyzed for the entire cohort or when analyzed for specific subgroups according to the tumor location (right, transverse, or left colon) or stage of the disease (pT3 or stage III). Conclusions: Laparoscopic complete mesocolic excision for colonic cancer can be offered as a standard procedure by experienced surgical teams in carefully selected patients and provides oncological results similar to those obtained with open surgery. Full article
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16 pages, 1146 KiB  
Review
Wnt Signaling and Circular RNAs in Esophageal and Gastric Cancers: Opportunities for Early Detection and Targeted Therapy
by Piotr Paweł Chmielewski, Bartłomiej Strzelec and Julia Rudno-Rudzińska
J. Clin. Med. 2025, 14(13), 4805; https://doi.org/10.3390/jcm14134805 - 7 Jul 2025
Viewed by 460
Abstract
Aberrant activation of Wnt/β-catenin signaling, frequently caused by oncogenic mutations, plays a crucial role in the development, progression, and therapy resistance of gastric, esophageal, hepatic, pancreatic, and colorectal cancers. Concurrently, circular RNAs (circRNAs), produced by back-splicing of precursor mRNAs (pre-mRNAs), have emerged as [...] Read more.
Aberrant activation of Wnt/β-catenin signaling, frequently caused by oncogenic mutations, plays a crucial role in the development, progression, and therapy resistance of gastric, esophageal, hepatic, pancreatic, and colorectal cancers. Concurrently, circular RNAs (circRNAs), produced by back-splicing of precursor mRNAs (pre-mRNAs), have emerged as critical modulators of this pathway. Accumulating evidence indicates that specific circRNAs regulate Wnt/β-catenin signaling by sponging microRNAs, interacting with RNA-binding proteins, modulating protein function, and altering the expression of pathway components. Some circRNAs are also subject to feedback regulation by Wnt signaling itself. Clinically, tumor-associated circRNAs are present in body fluids and correlate with disease stage, metastatic burden, and patient survival, underscoring their potential as early and minimally invasive biomarkers. Moreover, targeting oncogenic circRNAs has shown promise in preclinical models of Wnt-driven gastrointestinal malignancies. In this review, we summarize the current understanding of the interplay between circRNAs and Wnt/β-catenin signaling in gastric and esophageal cancers. We discuss the translational challenges and emerging opportunities for biomarker development and targeted therapy. Full article
(This article belongs to the Special Issue Gastroesophageal Cancer: Outcomes and Therapeutic Management)
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17 pages, 2089 KiB  
Article
From Mutation to Prognosis: AI-HOPE-PI3K Enables Artificial Intelligence Agent-Driven Integration of PI3K Pathway Data in Colorectal Cancer Precision Medicine
by Ei-Wen Yang, Brigette Waldrup and Enrique Velazquez-Villarreal
Int. J. Mol. Sci. 2025, 26(13), 6487; https://doi.org/10.3390/ijms26136487 - 5 Jul 2025
Cited by 1 | Viewed by 478
Abstract
The rising incidence of early-onset colorectal cancer (EOCRC), particularly among underrepresented populations, highlights the urgent need for tools that can uncover clinically meaningful, population-specific genomic alterations. The phosphoinositide 3-kinase (PI3K) pathway plays a key role in tumor progression, survival, and therapeutic [...] Read more.
The rising incidence of early-onset colorectal cancer (EOCRC), particularly among underrepresented populations, highlights the urgent need for tools that can uncover clinically meaningful, population-specific genomic alterations. The phosphoinositide 3-kinase (PI3K) pathway plays a key role in tumor progression, survival, and therapeutic resistance in colorectal cancer (CRC), yet its impact in EOCRC remains insufficiently explored. To address this gap, we developed AI-HOPE-PI3K, a conversational artificial intelligence platform that integrates harmonized clinical and genomic data for real-time, natural language-based analysis of PI3K pathway alterations. Built on a fine-tuned biomedical LLaMA 3 model, the system automates cohort generation, survival modeling, and mutation frequency comparisons using multi-institutional cBioPortal datasets annotated with clinical variables. AI-HOPE-PI3K replicated known associations and revealed new findings, including worse survival in colon versus rectal tumors harboring PI3K alterations, enrichment of INPP4B mutations in Hispanic/Latino EOCRC patients, and favorable survival outcomes associated with high tumor mutational burden in FOLFIRI-treated patients. The platform also enabled context-specific survival analyses stratified by age, tumor stage, and molecular alterations. These findings support the utility of AI-HOPE-PI3K as a scalable and accessible tool for integrative, pathway-specific analysis, demonstrating its potential to advance precision oncology and reduce disparities in EOCRC through data-driven discovery. Full article
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32 pages, 6839 KiB  
Article
Identification of Novel Molecular Panel as Potential Biomarkers of PAN-Gastrointestinal Cancer Screening: Bioinformatics and Experimental Analysis
by Fatemeh Hajibabaie, Parisa Mohamadynejad, Laleh Shariati, Kamran Safavi and Navid Abedpoor
Biology 2025, 14(7), 803; https://doi.org/10.3390/biology14070803 - 2 Jul 2025
Viewed by 501
Abstract
PAN-gastrointestinal cancers (PAN-GI cancers), including the oral, esophageal, gastric, hepatocellular, pancreatic=, and colorectal cancers, are the leading cause of cancer-related mortality. Despite recent advances in identifying the molecular mechanisms driving these malignancies, the high incidence and recurrence of the PAN-gastrointestinal cancers and the [...] Read more.
PAN-gastrointestinal cancers (PAN-GI cancers), including the oral, esophageal, gastric, hepatocellular, pancreatic=, and colorectal cancers, are the leading cause of cancer-related mortality. Despite recent advances in identifying the molecular mechanisms driving these malignancies, the high incidence and recurrence of the PAN-gastrointestinal cancers and the low survival rates of patients indicate the need to introduce biomarkers for early diagnosis to improve diagnostic and therapeutic approaches. In the present study, using integrated transcriptomics, RNA-Seq and microarray data, from the TCGA and GEO databases, respectively, were combined to discover and validate a global biomarker panel for PAN-gastrointestinal cancers. In order to validate the bioinformatics data, the expression levels of genes in the molecular panel were evaluated using real-time quantitative polymerase chain reaction (qPCR) in tumor tissues of 21 patients with early diagnosis of gastric cancer and colorectal cancer (Stage I and II). By examining the transcriptomic profiles of six types of PAN-gastrointestinal cancers, a network of closely related hub genes (n = 167) with biomarker potential (p value < 0.05) was identified. Also, using ROC curve analysis and the Youden index, a molecular panel consisting of AURKA, CEP55, DTL, and TTK was presented (95% confidence interval and p value < 0.05), which showed exceptional sensitivity and specificity in differentiating malignant tissue from normal tissue (AUC > 80%). The diagnostic efficacy of these markers was confirmed by further validation using qPCR in colorectal and gastric tumor samples (p value < 0.05). In conclusion, a novel molecular signature panel including the AURKA, CEP55, DTL, and TTK genes could improve early cancer detection and diagnostic accuracy, and it may contribute to the treatment outcomes of PAN-gastrointestinal cancer patients. Full article
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14 pages, 1841 KiB  
Article
Validation of Prognostic Circulating Cell-Free RNA Biomarkers HPGD, PACS1, and TDP2 in Colorectal Cancer Through TaqMan qPCR and Correlation Analysis
by Chau Ming Kan, Xiao Meng Pei, Simon Siu Man Ng, Wing Wa Leung, Yee Ni Wong, Hennie Yuk-Lin Cheng, William Chi Shing Cho, Hin Fung Tsang and Sze Chuen Cesar Wong
Curr. Issues Mol. Biol. 2025, 47(7), 508; https://doi.org/10.3390/cimb47070508 - 2 Jul 2025
Viewed by 371
Abstract
Circulating cell-free RNAs (cfRNAs) have emerged as promising non-invasive biomarkers for colorectal cancer (CRC), offering insights into the disease’s prognosis. This study investigates the prognostic significance of the specific cfRNA biomarkers HPGD, PACS1, and TDP2 by employing the Taqman quantitative PCR [...] Read more.
Circulating cell-free RNAs (cfRNAs) have emerged as promising non-invasive biomarkers for colorectal cancer (CRC), offering insights into the disease’s prognosis. This study investigates the prognostic significance of the specific cfRNA biomarkers HPGD, PACS1, and TDP2 by employing the Taqman quantitative PCR (qPCR) to evaluate their expression levels in a cohort of 52 CRC patients. The methodology involved a robust statistical analysis to assess correlations between cfRNA levels and clinical parameters, including survival rates and recurrence incidences. Findings revealed a significant upregulation in the expression of HPGD and PACS1, while TDP2 displayed varying results, indicating a complex role in disease dynamics. Notably, lower expression levels of HPGD were associated with reduced survival, suggesting its potential as a negative prognostic indicator. Conversely, TDP2 levels correlated strongly with increased risks of recurrence, highlighting its clinical relevance in monitoring disease progression. Overall, this study elucidates the intricate interplay between these cfRNAs in the CRC prognosis. The results advocate for further exploratory studies to validate PACS1’s potential as a prognostic marker and reinforce the clinical significance of HPGD and TDP2 in the context of CRC management, positioning them as vital elements in the landscape of molecular oncology. Full article
(This article belongs to the Special Issue Early Molecular Diagnosis and Comprehensive Treatment of Tumors)
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17 pages, 2041 KiB  
Article
Performance and Prognostic Relevance of Lymph Node Assessment by One-Step Nucleic Acid Amplification Assay in Rectal Cancer: A Multicenter Study
by Qing Liu, Sandra Lopez-Prades, Karmele Saez de Gordoa, Maite Rodrigo-Calvo, Mireia Garcia, Juan Ruiz Martin, Angel Romo, Ignacio Pinilla, Jordi Tarragona, Begoña Otero Alen, Jordi Camps, Ivan Archilla and Miriam Cuatrecasas
Cancers 2025, 17(13), 2141; https://doi.org/10.3390/cancers17132141 - 25 Jun 2025
Viewed by 301
Abstract
Background/Objectives: Lymph node metastases (LNM) undetected by standard hematoxylin and eosin (H&E) have been associated with unfavorable prognosis in colorectal cancer. The One-Step Nucleic Acid Amplification (OSNA) assay has demonstrated superior sensitivity in detecting LNM compared to H&E. We aimed to assess the [...] Read more.
Background/Objectives: Lymph node metastases (LNM) undetected by standard hematoxylin and eosin (H&E) have been associated with unfavorable prognosis in colorectal cancer. The One-Step Nucleic Acid Amplification (OSNA) assay has demonstrated superior sensitivity in detecting LNM compared to H&E. We aimed to assess the performance of OSNA in detecting LNM, as well as its prognostic value in rectal cancer (RC) patients. Methods: Lymph nodes (LNs) of patients from 15 centers were analyzed by both H&E and OSNA. The total tumor load (TTL) was defined as the sum of cytokeratin 19 mRNA copies/µL in all LNs from a surgical specimen, using a threshold of 250 copies/μL for OSNA positivity. Cox proportional hazard regression was used to assess the effect of TTL ≥ 250 or 6000 copies/μL on cancer-specific survival (CSS) and recurrence-free survival (RFS), with Firth’s method applied to account for low event rate. Results: A total of 97 RC patients were included. Of these, 84 patients were eligible for survival analysis. The sensitivity and specificity of OSNA, compared to H&E, were 91.7% and 84.7%, respectively. TTL ≥ 6000 versus <6000 copies/μL was related to worse CSS and RFS. When dividing TTL into three groups: ≤250, 250–6000, and >6000 copies/μL, only TTL ≥ 6000 copies/μL was significantly associated with worse CSS and RFS. Conclusions: The OSNA assay is highly sensitive for detecting LNM in RC patients. A TTL of ≥6000 copies/μL could identify a subset of RC patients with worse CSS and RFS who might benefit from adjuvant treatment or intensive surveillance. Full article
(This article belongs to the Section Cancer Pathophysiology)
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18 pages, 1987 KiB  
Article
AI-HOPE-TGFbeta: A Conversational AI Agent for Integrative Clinical and Genomic Analysis of TGF-β Pathway Alterations in Colorectal Cancer to Advance Precision Medicine
by Ei-Wen Yang, Brigette Waldrup and Enrique Velazquez-Villarreal
AI 2025, 6(7), 137; https://doi.org/10.3390/ai6070137 - 24 Jun 2025
Cited by 2 | Viewed by 671
Abstract
Introduction: Early-onset colorectal cancer (EOCRC) is rising rapidly, particularly among the Hispanic/Latino (H/L) populations, who face disproportionately poor outcomes. The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in colorectal cancer (CRC) progression by mediating epithelial-to-mesenchymal transition (EMT), immune evasion, and [...] Read more.
Introduction: Early-onset colorectal cancer (EOCRC) is rising rapidly, particularly among the Hispanic/Latino (H/L) populations, who face disproportionately poor outcomes. The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in colorectal cancer (CRC) progression by mediating epithelial-to-mesenchymal transition (EMT), immune evasion, and metastasis. However, integrative analyses linking TGF-β alterations to clinical features remain limited—particularly for diverse populations—hindering translational research and the development of precision therapies. To address this gap, we developed AI-HOPE-TGFbeta (Artificial Intelligence agent for High-Optimization and Precision Medicine focused on TGF-β), the first conversational artificial intelligence (AI) agent designed to explore TGF-β dysregulation in CRC by integrating harmonized clinical and genomic data via natural language queries. Methods: AI-HOPE-TGFbeta utilizes a large language model (LLM), Large Language Model Meta AI 3 (LLaMA 3), a natural language-to-code interpreter, and a bioinformatics backend to automate statistical workflows. Tailored for TGF-β pathway analysis, the platform enables real-time cohort stratification and hypothesis testing using harmonized datasets from the cBio Cancer Genomics Portal (cBioPortal). It supports mutation frequency comparisons, odds ratio testing, Kaplan–Meier survival analysis, and subgroup evaluations across race/ethnicity, microsatellite instability (MSI) status, tumor stage, treatment exposure, and age. The platform was validated by replicating findings on the SMAD4, TGFBR2, and BMPR1A mutations in EOCRC. Exploratory queries were conducted to examine novel associations with clinical outcomes in H/L populations. Results: AI-HOPE-TGFbeta successfully recapitulated established associations, including worse survival in SMAD4-mutant EOCRC patients treated with FOLFOX (fluorouracil, leucovorin and oxaliplatin) (p = 0.0001) and better outcomes in early-stage TGFBR2-mutated CRC patients (p = 0.00001). It revealed potential population-specific enrichment of BMPR1A mutations in H/L patients (OR = 2.63; p = 0.052) and uncovered MSI-specific survival benefits among SMAD4-mutated patients (p = 0.00001). Exploratory analysis showed better outcomes in SMAD2-mutant primary tumors vs. metastatic cases (p = 0.0010) and confirmed the feasibility of disaggregated ethnicity-based queries for TGFBR1 mutations, despite small sample sizes. These findings underscore the platform’s capacity to detect both known and emerging clinical–genomic patterns in CRC. Conclusions: AI-HOPE-TGFbeta introduces a new paradigm in cancer bioinformatics by enabling natural language-driven, real-time integration of genomic and clinical data specific to TGF-β pathway alterations in CRC. The platform democratizes complex analyses, supports disparity-focused investigation, and reveals clinically actionable insights in underserved populations, such as H/L EOCRC patients. As a first-of-its-kind system studying TGF-β, AI-HOPE-TGFbeta holds strong promise for advancing equitable precision oncology and accelerating translational discovery in the CRC TGF-β pathway. Full article
(This article belongs to the Section Medical & Healthcare AI)
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Article
Palliative Luminal Treatment of Colorectal Cancer Using Endoscopic Calcium-Electroporation: First Case Series from United Kingdom
by Ademola Adeyeye, Olaolu Olabintan, Homira Ayubi, Hao Gao, Aman Saini, Andrew Emmanuel, Bu’Hussain Hayee and Amyn Haji
J. Clin. Med. 2025, 14(12), 4138; https://doi.org/10.3390/jcm14124138 - 11 Jun 2025
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Abstract
Background/Objectives: Colorectal cancer (CRC) is the most common gastrointestinal (GI) malignancy, the second leading cause of cancer-related mortality, and the third most prevalent tumor. Around 20% of cases are metastatic or inoperable at diagnosis, often requiring palliative treatment, which may not be feasible [...] Read more.
Background/Objectives: Colorectal cancer (CRC) is the most common gastrointestinal (GI) malignancy, the second leading cause of cancer-related mortality, and the third most prevalent tumor. Around 20% of cases are metastatic or inoperable at diagnosis, often requiring palliative treatment, which may not be feasible in frail patients. Calcium-electroporation, a less invasive alternative, induces cell death via apoptosis, necrosis, and pyroptosis. This study is the first in the United Kingdom to evaluate the efficacy and safety of endoscopic calcium-electroporation in palliating distal CRC. Methods: Frail patients with inoperable left-sided CRC were included. The diagnosis and staging followed standard guidelines, while frailty was assessed using the performance status (PFS), Charlson comorbidity index (CCI), and American Society of Anesthesiologists (ASA) score. Calcium electroporation was performed via a flexible endoscopy usually under sedation, with symptom relief, quality of life (QoL), survival, and adverse events (AE) monitored. Results: Sixteen patients (median age 84.5) underwent 36 treatments with electroporation over 28 months (November 2022 to March 2025). The incidence of common symptoms was rectal bleeding (75%), constipation (25%), and pain (75%). Nine patients had metastases and three had failed conventional treatments. Symptomatic relief and an improved QoL occurred in 86.7%, with transfusion/iron infusion needs reduced by 91.7%. The median cancer-specific survival was 10 months, with a 94% survival rate. No device-related AE was recorded. One patient died after 11 months due to disease progression while two patients passed away from other medical conditions. Conclusions: Endoscopic calcium electroporation is a safe, palliative option effective for tumor reduction and symptomatic relief in frail CRC patients unfit for conventional therapies. Full article
(This article belongs to the Special Issue Diagnosis, Treatment, and Management of Gastrointestinal Oncology)
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