Search Results (7,802)

Organoid culture represents a sophisticated biological model that surpasses traditional two-dimensional (2D) methods and animal models in physiological relevance and cost-effectiveness. Current organoid systems derive from adult, fetal, and induced pluripotent stem cells, providing innovative platforms for studying organ development, disease pathogenesis, and drug discovery. Recent technological advances now enable respiratory organoids to significantly contribute to respiratory disease research. This review comprehensively synthesizes the development of respiratory organoid models and their applications in studying major respiratory diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and lung cancer. It further evaluates the transformative potential of these models in advancing respiratory disease research. Respiratory organoids uniquely model disease mechanisms and drug responses in human-specific microenvironments, enabling pathogenesis studies of respiratory diseases. They serve as functional platforms for drug screening and personalized therapy development. Future integration of multi-organoid systems with precision medicine promises to redefine respiratory disease research paradigms. Full article

Curcumin is the main active ingredient in Curcuma longa turmeric, with a wide range of biological effects. It shows significant therapeutic potential in the field of stem cell therapy. This article aims to explore the modulatory effects and underlying mechanisms of curcumin on mesenchymal stem cells (MSCs), providing a theoretical basis based on experimental evidence for its clinical application in regenerative medicine. First, the physicochemical properties, main pharmacological activities, and metabolic pathways of curcumin are described. Subsequently, the key molecular mechanisms by which curcumin regulates MSCs are analyzed in depth, demonstrating that curcumin can significantly promote MSC proliferation and inhibit apoptosis by modulating signaling pathways and gene expression. Additionally, curcumin directs the differentiation of MSCs into osteoblasts and chondrocytes. It also inhibits their differentiation into adipocytes, thereby regulating the physiological functions of MSCs such as proliferation, differentiation, and apoptosis. Finally, several main challenges in current research are highlighted. These include the low oral bioavailability of curcumin; the regulatory effects that vary depending on doses and microenvironmental conditions; the underlying mechanisms not being fully elucidated; the research being mostly limited to in vitro cell models and animal experiments; and the lack of quality standards and production process control systems for curcumin preparations. Full article

Mesenchymal stromal cells (MSCs) are intensively investigated in oncology owing to their intrinsic tumor-homing ability and capacity to deliver therapeutic agents directly into the tumor microenvironment (TME). Recent advances in genetic engineering have enabled precise modification of MSCs, allowing controlled expression of therapeutic genes and other cargo delivery, thus improving targeting efficiency. As cellular carriers, MSCs have been engineered to transport oncolytic viruses, suicide genes in gene-directed enzyme prodrug therapy (GDEPT), multifunctional nanoparticles, and therapeutic factors such as IFN-β or TRAIL, while engineered MSC-derived extracellular vesicles (MSC-EVs) offer a promising cell-free alternative. These strategies increase intratumoral drug concentration, amplify bystander effects, and synergize with standard therapies while reducing systemic toxicity. Conversely, accumulating evidence highlights the tumor-promoting properties of MSCs: once recruited by inflammatory and hypoxic cues, they remodel the tumor microenvironment by stimulating angiogenesis, suppressing immune responses, differentiating into cancer-associated fibroblasts, and promoting epithelial-to-mesenchymal transition (EMT), ultimately enhancing invasion, metastasis, and therapy resistance. This duality has sparked both enthusiasm and concern in the oncology field. The present review outlines the paradoxical role of MSCs in oncology—ranging from their potential to promote tumor growth to their emerging utility as vehicles for targeted drug delivery. By highlighting both therapeutic opportunities and biological risks, we aim to provide a balanced perspective on how MSC-based strategies might be refined, optimized, and safely integrated into future cancer therapies. Full article

Background: The management of pediatric inflammatory bowel disease (PIBD) has evolved significantly over the past two decades, transitioning from corticosteroids and immunomodulators to biologic and small-molecule therapies. These advances have aimed not only to control inflammation but also to promote mucosal healing, improve growth, and enhance long-term quality of life. Objectives: This narrative review summarizes current evidence on the efficacy, safety, and clinical applications of biologic and novel small-molecule therapies in PIBD, highlighting emerging trends in personalized and precision-based management. Methods: A literature search was performed across PubMed, Embase, and the Cochrane Library, focusing on studies published within the last five years. Additional data were retrieved from key guidelines and position papers issued by ECCO–ESPGHAN, SIGENP, the FDA, and the EMA. Results: Anti–tumor necrosis factor (TNF) agents such as infliximab and adalimumab remain first-line biologics with proven efficacy in remission induction and maintenance. Newer biologics—vedolizumab, ustekinumab, risankizumab, and mirikizumab—offer alternatives for anti-TNF-refractory cases, showing encouraging short-term results and favorable safety profiles. Although many are approved only for adults with limited pediatric evidence, emerging small molecules—including Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib) and sphingosine-1-phosphate (S1P) modulators (etrasimod)—provide oral, rapidly acting, and non-immunogenic treatment options for refractory disease. Furthermore, the gut microbiome is increasingly recognized as an emerging therapeutic target in PIBD, with growing evidence that host–microbiome interactions can influence both the efficacy and safety of biologics and small-molecule therapies. Conclusions: While biologics and small molecules have transformed PIBD management, challenges remain, including high treatment costs, limited pediatric trial data, and variable access worldwide. Future directions include multicenter pediatric studies, integration of pharmacogenomics, and biomarker-guided precision medicine to optimize early, individualized treatment and improve long-term outcomes. Full article

Platelet-rich plasma (PRP) has been increasingly explored as a biologic strategy for liver repair; however, preclinical studies have evaluated not only intact PRP but also PRP related hemocomponents with distinct biological properties, complicating interpretation and translation of the evidence. A systematic review of experimental studies was conducted to assess the effects of PRP and related hemocomponents in animal models of liver injury, focusing on molecular, metabolic, biochemical, and histological outcomes, and evaluating methodological quality and risk of bias using the Cochrane ROB 2.0 framework. Fourteen eligible studies were identified across toxic, cholestatic, parasitic, radiation-induced, and surgical models. Platelet-based interventions were generally associated with hepatoprotective, antifibrotic, antioxidant, immunomodulatory, and pro-regenerative effects; however, responses were highly context dependent and varied according to injury etiology, disease stage, administration route and timing, and the frequent use of combination therapies. Substantial heterogeneity in the platelet-based products evaluated—including platelet supernatants and lysates—and inconsistent reporting of key compositional parameters limited product classification, cross-study comparability, and mechanistic interpretation, while ROB 2.0 assessments revealed predominantly some concerns of bias. PRP and related hemocomponents show biologically relevant effects in experimental liver injury, but their translational potential is constrained by methodological heterogeneity and inadequate product characterization. Standardized reporting, controlled comparative designs, and clinically relevant models are required to clarify efficacy and support rational translation. Full article

Background: Female patients undergoing radical cystectomy (RC) for bladder cancer have historically presented with more advanced disease and poorer survival outcomes than males. These disparities have been attributed to biological differences, delayed diagnosis, and variations in treatment delivery. Recent data suggest, however, that outcomes may converge when patients are managed in standardized, multidisciplinary, high-volume centers. This study evaluated the influence of gender on perioperative features and oncological outcomes such as disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) at a tertiary uro-oncology center. Methods: We retrospectively reviewed a prospectively maintained database of patients who underwent open or robotic-assisted RC for histologically confirmed urothelial carcinoma between 2014 and 2023 at Guy’s and St. Thomas’ NHS Foundation Trust. Demographic, perioperative, and pathological variables were stratified by gender to assess their association with DFS, DSS, and OS. Results: A total of 887 patients were included: 640 men (72.2%) and 247 women (27.8%), with similar mean age (68.5 vs. 68.1 years) and tumour histology (pure urothelial carcinoma 85% vs. 83%). Men had a higher prevalence of diabetes and chronic kidney disease, but no significant differences were observed in time from referral to surgery (0.93 vs. 1.03 months, p = 0.93), use of neoadjuvant therapy (21.6% vs. 17.3%, p = 0.25), or surgical approach (p = 0.55). Pathological stage distribution was comparable between sexes (pT0–1: 44% vs. 50%; pT2–4: 56% vs. 50%; p = 0.13). Kaplan–Meier analysis revealed no significant gender-related differences in 12-month DFS (77.3% vs. 75.4%, p = 0.20), DSS (85.6% vs. 86.9%, p = 0.56), or OS (81.2% vs. 85.2%, p = 0.70). Conclusion: In this high-volume tertiary center, gender did not independently influence perioperative or survival outcomes following radical cystectomy. These findings suggest that standardized, multidisciplinary management within specialized bladder cancer pathways may mitigate the pathological and survival disparities historically associated with gender. Full article

Background/Objectives: The rates and predictors of clinical remission, a novel and practical therapeutic goal in severe asthma, have been inconsistently reported across studies. Data on clinical remission in Japanese patients remain limited. The aim of this study was to assess the rate of four-component clinical remission and its predictors in Japanese adult patients with severe asthma. Methods: This retrospective study enrolled adult patients with severe asthma who had initiated biologic therapy at least 12 months prior to inclusion at Nagoya City University Hospital. The primary endpoint was the achievement rate of four-component clinical remission, defined as (1) no maintenance oral corticosteroids (OCS); (2) no exacerbations for 12 months; (3) Asthma Control Test (ACT) score ≥ 20; and (4) forced expiratory volume in one second (FEV₁) ≥ 80% of predicted. The secondary endpoint was to identify factors, including airway structural indices measured using chest computed tomography (CT), associated with clinical remission at 12 months. Results: Among 87 patients with severe asthma, 26 (30%) achieved four-component clinical remission after 12 months of biologic therapy. In univariate analysis, clinical remission was more frequently achieved in patients with chronic rhinosinusitis, higher FEV₁ (% predicted), higher blood eosinophil counts, higher ACT scores, fewer exacerbations in the previous year, higher Lund–Mackay scores, and smaller airway wall thickness and luminal areas on CT (all p < 0.05). Multivariate analysis revealed that higher blood eosinophil counts and fewer exacerbations in the previous year were independently associated with clinical remission (both p < 0.05). Conclusions: After 12 months of biologic therapy, 30% of patients with severe asthma achieved four-component clinical remission. Higher blood eosinophil counts and fewer prior exacerbations were associated with higher remission rates. Full article

Melanocytic Tumors of Uncertain Malignant Potential (MELTUMPs) remain among the most challenging entities in dermatopathology due to overlapping morphologic features and marked inter-observer variability. This comprehensive review critically assesses the diagnostic and potential prognostic significance of combining p16 and methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) as a practical surrogate for genomic alterations involving the 9p21 (CDKN2A/MTAP) locus. We analyzed the molecular underpinnings of the CDKN2A/MTAP axis and systematically reviewed existing literature to define an integrated IHC strategy for ambiguous melanocytic lesions. The combined use of p16, a sensitive marker of CDKN2A inactivation, and MTAP, a highly specific marker for homozygous 9p21 deletion, was assessed for its diagnostic complementarity and potential clinical utility. p16 IHC demonstrates high sensitivity but limited specificity due to heterogeneous staining in borderline lesions. In contrast, MTAP loss exhibits near-absolute specificity for CDKN2A/MTAP co-deletion, albeit with lower sensitivity. Concordant loss of both markers strongly supports melanoma or high-risk melanocytoma, while MTAP retention may predict responsiveness to adjuvant interferon therapy. Combined p16/MTAP IHC provides a synergistic, biologically grounded approach that refines diagnostic accuracy in MELTUMPs. This dual-marker algorithm promotes a shift from purely morphology-based evaluation toward a reproducible, molecularly informed classification, improving both diagnostic confidence and patient management. Full article

Although neurological disease is common in people with human immunodeficiency virus (HIV) (PWH), the contributing factors and underlying inflammatory mechanisms remain challenging to identify. Extracellular vesicles (EVs) constitute a relatively uncharacterized modality of intercellular communication and bioactive cargo transport in the setting of viral infection and pathogenesis. EVs carry inflammatory mediators to areas of the periphery during antiretroviral therapy (ART) suppression but are understudied in the brain. Using a biologically relevant simian–human immunodeficiency chimeric virus with a clade D HIV envelope (SHIV.D)-infected rhesus macaque (RM) model of HIV persistence in the central nervous system (CNS), we investigate circulating EV populations and the protein cargo of myeloid-derived EVs during SHIV infection. Using EV flow cytometry to quantify specific EV subpopulations, we found a significant increase in TMEM119+ microglial EVs and CD171+ neuronal EVs in RM plasma during viremia and ART suppression. Using primary RM monocyte-derived macrophages (MDMs), we determined that MDMs increased EV production after SHIV infection. Whole proteomic analysis of these EVs demonstrated that myeloid EVs isolated from SHIV.D-infected MDMs carried significantly increased levels of neuropathogenic and inflammatory proteins. Altogether, these studies improve our understanding of the contribution of myeloid EVs to neurological disease during SHIV/HIV infection. Full article

Background and Objectives: Overweight and obesity is defined as a Body Mass Index (BMI) of 25.0–29.9 kg/m² and ≥30.0 kg/m². The prognostic significance of obesity in metastatic prostate cancer is still unclear, especially between the castration-sensitive (CSPC) and castration-resistant (CRPC) disease states. New evidence suggests that obese patients who get androgen receptor–targeted therapies may have an unexpected survival advantage. This study examined the correlation between body mass index (BMI) and survival outcomes in patients administered androgen receptor pathway inhibitors. Materials and Methods: A retrospective analysis was conducted on a cohort of 167 patients with metastatic prostate cancer treated between 2015 and 2024. BMI was analyzed as both a continuous variable and a categorical variable, which was classified as normal weight, overweight or obese. The primary goal of this study is to compare PFS and OS among BMI groups. We employed Kaplan–Meier survival analysis and Cox regression modeling to evaluate prognostic indicators. The CSPC and CRPC groups were evaluated separately. Results: PFSs for normal, overweight and obese CSPC patients were 11.3, 15.1, 19.5 months, respectively; p = 0.03 but the OS did not differ significantly between BMI groups. OS for normal, overweight and obese CRPC patients were 32.8, 47.6 and 43.4 months, respectively; p = 0.01. There was also a trend toward better PFS, but it was not statistically significant. Multivariate analysis found that obesity (BMI ≥ 30) was a separate protective factor for PFS in CSPC, while high-volume disease was a bad prognostic factor for OS in CRPC. A high Gleason score and ECOG-PS 2 were consistently associated with poor outcomes. Conclusions: Obesity has a phase-dependent prognostic influence in metastatic prostate cancer, providing a PFS advantage in CSPC and an OS benefit in CRPC. These results suggest that there may be an obesity paradox in people who are getting androgen receptor–targeted therapy. Further prospective studies are required to gain a better understanding of the biological reasons for this association. Full article

The functional deterioration of granulosa cells (GCs), essential for follicular growth, steroidogenesis, and oocyte competence, indicates ovarian aging and reduced fertility. An expanding corpus of research indicates that oxidative stress is a primary molecular contributor to granulosa cell dysfunction, culminating in mitochondrial impairment, reduced metabolic support for oocytes, and the activation of regulated apoptotic pathways that end in follicular atresia. Ferroptosis, an emergent type of iron-dependent lipid peroxidation, has been identified as a crucial mechanism contributing to chemotherapy-induced ovarian insufficiency, polycystic ovary syndrome (PCOS), and granulosa cell death in aging ovaries, in addition to conventional apoptosis. The SIRT1-Nrf2 axis acts as a crucial anti-oxidative and anti-ferroptotic system that protects GC viability, maintains mitochondrial homeostasis, and upholds redox equilibrium. SIRT1 promotes mitochondrial biogenesis and metabolic resilience by deacetylating downstream proteins, including FOXO3 and PGC-1α. Nrf2 simultaneously controls the transcriptional activation of detoxifying and antioxidant enzymes, including HO-1, SOD2, NQO1, and GPX4, which are critical inhibitors of ferroptosis. Disruption of SIRT1-Nrf2 signalling accelerates GC senescence, follicular depletion, and reproductive aging. In contrast, pharmaceutical and nutraceutical therapies, including metformin, melatonin, resveratrol, and agents that increase NAD⁺ levels, may reverse ovarian deterioration and reactivate SIRT1-Nrf2 activity. This narrative review highlights innovative treatment prospects for ovarian aging, fertility preservation, and assisted reproduction by synthesising current evidence on ferroptotic pathways, SIRT1-Nrf2 interactions, and oxidative stress in granulosa cells. An understanding of these interrelated biological networks enables the development of tailored therapies that postpone ovarian ageing and enhance reproductive outcomes for women receiving fertility therapy. Full article

Background: Self-amplifying mRNA (sa-mRNA) represents a promising platform for vaccines and gene therapies, offering sustained protein expression at low doses through self-replication. For vaccines targeting respiratory pathogens, pulmonary delivery of sa-mRNA lipid nanoparticles (LNPs) is particularly advantageous, enabling direct delivery to the infection site and induction of mucosal immunity. Objective: In this study, we evaluated the stability of sa-mRNA–LNPs under refrigerated and frozen conditions and developed a dry powder formulation suitable for inhalation, produced by freeze-drying followed by cryomilling with leucine. Methods: sa-mRNA–LNPs formulated in HEPES buffer with 20% (w/v) sucrose were stored for up to 8 weeks as liquid or freeze-dried samples at various temperatures (−80 °C, −20 °C, 4 °C, and 20 °C). Biological stability was assessed by transfection efficiency in HeLa cells, while physical stability was characterized by encapsulation efficiency, zeta potential, particle size, and polydispersity index. Results: Liquid formulations remained stable for at least 8 weeks at −80 °C and −20 °C but rapidly lost stability at 4 °C and 20 °C. Freeze-drying effectively preserved sa-mRNA–LNP functionality and structural integrity for up to 8 weeks at 4 °C, with only minor structural changes. Subsequent cryomilling in the presence of 4 wt-% leucine produced a respirable dry powder while retaining approximately 60% of the original sa-mRNA–LNP functionality. Although cryomilling induced some structural alterations, the remaining functional fraction remained stable during storage. The resulting powders displayed favorable aerosol performance for deep lung delivery, as demonstrated by cascade impaction (MMAD = 4.13 ± 0.26 µm). Conclusions: In conclusion, freeze-drying effectively preserved sa-mRNA–LNP integrity at 4 °C, whereas cryomilling with leucine produced a respirable dry powder suitable for pulmonary delivery, providing a foundation for globally accessible, needle-free sa-mRNA vaccines against respiratory diseases. Full article

A novel lytic bacteriophage, XAN_XB1, was isolated from hospital wastewater through host bacterial enrichment and evaluated for its potential in controlling multidrug-resistant Stenotrophomonas maltophilia infections. Transmission electron microscopy revealed that XAN_XB1 has a long tail, possessing an icosahedral head of ~80 nm in diameter and a tail measuring ~150 nm in length. It produced clear plaques of 0.5–1 mm on host bacterial lawns. Host range analysis demonstrated its ability to infect multiple multidrug-resistant S. maltophilia isolates. Biological characterization showed that the phage is chloroform-insensitive, retains strong lytic activity across a wide temperature (4–60 °C) and pH (3.0–10.0) range, and achieves more rapid host suppression under higher multiplicity of infection (MOI). Whole-genome sequencing determined a ~47 kb double-stranded DNA genome encoding 71 predicted open reading frames, with no known virulence or antibiotic resistance genes. Phylogenetic analysis of MCP and terminase large subunit sequences placed XAN_XB1 in a unique Caudoviricetes, with ANI values below the 95% ICTV threshold verifying its status as a novel phage species. The XAN_XB1 therapy significantly alleviates S. maltophilia infection-induced severe pulmonary inflammatory lesions, high mortality, elevated serum inflammatory factors and massive pulmonary bacterial colonization in male BALB/c mice, confirming its favorable therapeutic effect on such infections. Collectively, these results reveal that is an efficacious candidate for therapeutic development against S. maltophilia infections. Full article

Background/Objectives: Patients with eosinophilic chronic obstructive pulmonary disease (COPD) often remain symptomatic despite optimized triple inhaled therapy. Dupilumab is a fully human monoclonal antibody that blocks the IL-4 receptor alpha subunit, thereby inhibiting IL-4 and IL-13 signaling. Evidence from randomized trials supports dupilumab for add-on treatment of type 2-high COPD, but data referring to short-term effectiveness in clinical practice are quite limited. Methods: We conducted an observational, compassionate-use study enrolling 13 consecutive outpatients with eosinophilic COPD (blood eosinophils ≥ 300 cells/µL) receiving add-on biologic therapy with dupilumab 300 mg every two weeks. Clinical (CAT, mMRC), functional (spirometry and body plethysmography), and inflammatory parameters (blood eosinophils/basophils, fibrinogen, FeNO) were evaluated at baseline and after four weeks of treatment. Safety was monitored after injection in a clinical setting, as well as via weekly phone follow-up. Results: Participants (84.6% male; mean age 67.08 ± 11.42 years) experienced rapid and clinically meaningful improvements at four weeks. CAT score decreased from baseline 21.40 ± 6.22 to 14.00 ± 5.58 (p < 0.001) and mMRC scale from 2.90 ± 0.73 to 1.80 ± 0.63 (p < 0.0001), respectively. Pre-bronchodilator FEV₁ increased from baseline 1.35 ± 0.65 L to 1.59 ± 0.84 L (p < 0.05), and FVC from 2.36 ± 0.92 L to 2.83 ± 1.11 L (p < 0.01). A marked lung deflation was observed: indeed, residual volume declined from baseline 4.17 ± 1.98 L to 3.47 ± 2.07 L (p < 0.05), with a concomitant reduction in specific effective airway resistance (from baseline 3.15 ± 1.77 to 2.43 ± 1.44 kPa·s; p < 0.05) associated with significant increases in mid-expiratory flow (FEF₂₅₋₇₅: from baseline 0.62 ± 0.38 to 0.86 ± 0.71 L/s; p < 0.05) and peak expiratory flow (3.80 ± 1.40 to 4.48 ± 1.79 L/s; p < 0.01). Type 2 inflammatory biomarkers changed as follows: blood eosinophil count fell from baseline 390.0 ± 43.75 to 190.0 ± 65.47 cells/µL (p < 0.001); blood basophil number decreased from baseline 37.50 ± 13.89 to 26.25 ± 13.02 cells/µL (p < 0.001); plasma fibrinogen lowered from baseline 388.4 ± 54.81 to 334.9 ± 72.36 mg/dL (p < 0.01); FeNO levels dropped from baseline 23.95 ± 18.10 to 14.00 ± 2.04 ppb (p < 0.0001). Dupilumab was well tolerated, and no treatment-related serious adverse events or discontinuations were detected. Conclusions: Within an exploratory context of daily medical activity referring to eosinophilic COPD already treated with maximal inhaled therapy, we found relevant therapeutic effects of a four-week add-on treatment with dupilumab. In particular, our patients manifested rapid improvements in symptoms, airflow limitation, and lung hyperinflation, paralleled by significant decrements of type 2 inflammatory signatures. Such encouraging results were associated with a favorable short-term safety profile. However, larger and longer studies are necessary to corroborate these preliminary findings. Full article

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients, FGFR3, NF1, and RPS6KA6 mutations were significantly enriched in tumors not receiving FOLFOX, whereas PDGFRB alterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease, NTRK2 and PDGFRB mutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, including AKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS, and SOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlight NF1, MAPK3, RPS6KA4, and PDGFRB as potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches. Full article