Search Results (783)

Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options. Advances in genomic and transcriptomic research have deepened the understanding of mUC biology, leading to the identification of clinically relevant molecular alterations that represent potential actionable targets. This has broadened the treatment landscape of the disease to include novel agents, such as antibody–drug conjugates (e.g., enfortumab vedotin) and targeted therapies, including the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib. Genomic alterations in FGFR3 are well-established oncogenic drivers in bladder cancer and represent predictive biomarkers of response to FGFR-targeted therapies. The phase III THOR trial demonstrated the clinical benefit of erdafitinib in previously treated mUC patients harboring FGFR3 alterations and supported its subsequent approval by the European Medicines Agency. In this context, accurate molecular profiling is essential to guide patient selection for FGFR inhibitor therapy. Equally important is the standardization and timely implementation of FGFR3 testing in clinical practice to optimize treatment planning. This review addresses key considerations in FGFR3 testing in mUC and discusses how it can be routinely incorporated into clinical practice. Full article

Parkinson’s disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system and α-synuclein (α-syn) pathology, with disease progression driven by convergent mechanisms including neuroinflammation, mitochondrial injury, oxidative stress, and regulated cell-death programs such as ferroptosis. Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) constitute a key signaling system in the central nervous system, influencing not only neuronal survival and glial states but also intersecting with networks governing redox homeostasis and iron metabolism. Accumulating evidence indicates that, beyond classical neurotrophic actions, FGF–FGFR signaling can modulate mitochondrial quality control, glial inflammatory activation, and lipid peroxidation-related processes, thereby reshaping cellular susceptibility to ferroptotic injury. This review summarizes current advances in understanding FGF signaling networks in Parkinson’s disease, synthesizes their potential mechanistic links to the interplay among neuroinflammation, mitochondrial dysfunction, and redox imbalance as well as to ferroptosis regulation, and discusses the experimental basis and translational challenges of targeting the FGF pathway as a disease-modifying therapeutic strategy. Full article

Background/Objectives: The progression and dissemination of CRC are heavily influenced by a subpopulation of tumor cells known as CSCs. This study aimed to identify novel protein membrane antigens expressed by colorectal CSCs and the consequent development of targeted therapies based on monoclonal antibodies directed against the identified antigens. Methods: Integrated bioinformatics analyses were conducted using proprietary CSC gene expression profiles and public colon gene expression databases, leading to the identification of five plasma membrane proteins enriched in CSCs. Genetic immunization in rats was employed to generate monoclonal antibodies (mAbs) targeting these antigens. FGFR4 was prioritized due to its overexpression in colorectal tumors. Its function was characterized in vitro and in vivo through assays evaluating proliferation, colony formation, migration, and tumorigenicity. The anti-FGFR4 antibody 3B6 was selected based on its affinity and ability to inhibit FGFR4 signaling in CSCs. Its therapeutic potential was further assessed in xenograft models, and alterations in downstream signaling were analyzed via Western blot. Results: FGFR4 emerged as a key regulator of CRC CSC proliferation, migration, and tumorigenic capacity. The 3B6 antibody, a high-affinity FGFR4 binder, demonstrated robust in vitro inhibition of CSC features and significant antitumor effects in patient-derived xenograft models. Western blot analysis confirmed the modulation of FGFR4-driven signaling pathways, particularly those involved in epithelial–mesenchymal transition (EMT). Conclusions: This study successfully identified several CSC-selective membrane antigens that can become therapeutic targets in CRC. Among them, we focused on FGFR4 as a promising target and developed the anti-FGFR4 3B6 monoclonal antibody which offers potential for both diagnostic and therapeutic applications. Full article

Urothelial carcinoma represents one of the deadliest urological tumors, due to its biological aggressiveness and the ephemeral response to platinum-based chemotherapy of advanced-stage disease. The use of immune checkpoint inhibitors has positively impacted the prognosis of these patients, although only a proportion of them achieve long lasting disease control. As with other solid tumors, in the last decade, there has been a growing interest in the molecular characterization of urothelial carcinoma in order to identify new therapeutic targets and improve survival in these patients. The aim of this narrative review is to summarize the main evidence available in the literature concerning the role of targeted therapies in urothelial carcinoma, especially focusing on related molecular targets, published data on clinical efficacy, and on future perspectives. Specifically, the effort of this review aims to strengthen the clinical impact of well-known molecular patterns and relative target treatments (such as FGFR inhibitors and Nectin-4-directed antibody–drug conjugates) and to examine the role and preliminary data of drugs targeting biomarkers that are not yet commonly used in clinical practice (such as HER2). Full article

Poorly differentiated gastric carcinoma (PGC) is aggressive, yet subtype-specific genomics are under-characterized. We queried AACR Project GENIE^® (cBioPortal v18.0-public; 12 August 2025) for PGC and analyzed somatic alterations from targeted panels (depth ≥ 100×; variant allele frequency ≥ 5%). Mutation and copy number frequencies were summarized, co-occurrence and exclusivity were tested, and primary versus metastatic tumors were compared using chi-square with Benjamini–Hochberg correction. The cohort included 189 tumors from 188 patients (71% primary; 25% metastatic), with primary and metastatic tumor samples being collected from different patients. Recurrently mutated genes were TP53 (48.7%), CDH1 (31.2%), ARID1A (21.2%), KMT2C (8.5%), and POLD1 (7.4%); additional alterations involved ERBB3, KMT2D, KEL, CDKN2A, and FAT1 (≈1–7%). Amplifications in CCNE1 (8.2%) and FGFR2 (7.6%) were common, alongside gains in MET, MYC, KRAS, and ERBB2 and losses in CDKN2A/CDKN2B, CDH1, and PTEN. Significant co-occurrence was observed for POLD1–KMT2D (p < 0.001), POLD1–ARID1A (p < 0.001), and ARID1A–KMT2D (p < 0.001), while TP53 was mutually exclusive with ARID1A (p = 0.029) and CDH1 (p = 0.041). CDH1 (48.9% vs. 29.6%; p = 0.021) and MLH1 (8.5% vs. 1.5%; p = 0.040) were enriched in metastases, and CCNE1 alterations showed female predominance (p = 2.83 × 10⁻⁴). Several “primary-only” findings likely reflect small denominators and require replication. PGC demonstrates a mutational framework dominated by TP53, CDH1, ARID1A, and recurrent CCNE1/FGFR2 amplifications, underscoring dysregulation of cell cycle and chromatin-remodeling pathways as key drivers. Co-occurrence of POLD1, ARID1A, and KMT2D suggests coordinated disruption of DNA repair and epigenetic regulation, whereas mutual exclusivity of TP53, ARID1A, and CDH1 indicates distinct tumorigenic routes. Metastatic enrichment of CDH1 and MLH1 supports their roles in invasion and therapeutic resistance. Together, these findings highlight candidate biomarkers and actionable pathways warranting validation in larger, multi-omic cohorts to refine precision treatment strategies for this aggressive gastric cancer subtype. Full article

Background: Chronic kidney disease (CKD) markedly increases the risk of cardiovascular events (CVE), yet conventional biomarkers often fail to capture this excess risk. We evaluated whether circulating levels and genetic variability within the FGF19/β-Klotho/FGFR axis contribute to CV risk stratification in CKD. Methods: In 579 CKD patients, plasma FGF19 and β-Klotho concentrations were quantified, and 64 genetic variants across FGF19, KLB, FGFR1, and FGFR4 genes were analyzed. Results: Cluster analysis identified three distinct biomarker profiles, with one cluster—characterized by low/intermediate FGF19 and markedly elevated β-Klotho—showing significantly reduced CV event-free survival. After adjustment for clinical covariates, this cluster was independently associated with higher CV risk [HR = 2.97 (1.12–7.92), p = 0.029]. Two genetic variants also showed independent associations: FGFR1 rs2288696 (protective) [HR = 0.51 (0.27–0.95), p = 0.029] and KLB rs2687971 (risk-increasing) [HR = 2.03 (0.97–4.27), p = 0.046]. A combined CV risk model incorporating biomarker clusters, relevant SNPs, and traditional risk factors achieved good discriminative ability (C-index = 0.80), with the FGF19/β-Klotho cluster showing predictive importance comparable to diabetes and previous CV history. Conclusions: These results indicate that integrating FGF19-Klotho biomarkers with genetic information may improve CV risk prediction in CKD. Full article

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis. Full article

Hypertension remains a major public health concern globally. Accumulating evidence suggests that dietary phosphate (Pi) and fibroblast growth factor 23 (FGF23), a phosphaturic hormone, are involved in blood pressure regulation. Experimental studies have shown that excess Pi consumption, largely from inorganic Pi used as a preservative or flavor enhancer in processed foods, and increased FGF23 may contribute to vascular abnormalities, thereby promoting hypertension. Importantly, recent animal studies have demonstrated that peripheral FGF23 can cross the blood–brain barrier and stimulate FGF receptor 4 (FGFR4)-calcineurin signaling in the brain, contributing to sympathetic overactivation and hypertensive responses during high Pi loading. Additionally, dietary Pi loading leads to suppression of Klotho, which may further contribute to hypertension. Such mechanisms are potentially relevant to chronic kidney disease (CKD), a condition characterized by Pi retention, massively elevated FGF23, sympathetic overactivity, and hypertension. This review highlights current evidence linking Pi-induced FGF23 pathogenically to hypertension, with focus on FGF23 translocation to and FGFR4 signaling in the central nervous system as a potential mechanism and therapeutic target for hypertension associated with high Pi intake and CKD. Full article

Accurate interpretation of missense variants in cancer-associated genes remains a critical challenge in precision oncology, as most sequence-based predictors lack mechanistic explanations. Receptor tyrosine kinases like FGFR2 exemplify this problem: their function depends on conformational dynamics, yet most variants remain classified as variants of uncertain significance (VUS). In this paper we present DyVarMap, an interpretable structural-learning framework that integrates AlphaFold2-based ensemble generation with physics-driven refinement, manifold learning, and supervised classification using five biophysically motivated geometric features. Applied to FGFR2, the framework generates diverse conformational ensembles, identifies metastable states through nonlinear dimensionality reduction, and classifies pathogenicity while providing mechanistic attributions via SHAP analysis. External validation on ten kinase-domain variants yields an AUROC of 0.77 with superior calibration (Brier score = 0.108) compared to PolyPhen-2 (0.125) and AlphaMissense (0.132). Feature importance analysis consistently identifies K659–E565 salt-bridge distance and DFG motif dihedral angles as top predictors, directly linking predictions to known activation mechanisms. Case studies of borderline variants (A628T, E608K, L618F) demonstrate the framework’s ability to provide structurally coherent mechanistic explanations. DyVarMap bridges the gap between static structure prediction and dynamics-aware functional assessment, generating testable hypotheses for experimental validation and demonstrating the value of incorporating conformational dynamics into variant effect prediction for precision oncology. Full article

Alopecia profoundly impacts psychological well-being and quality of life, yet current therapeutic options such as minoxidil and finasteride exhibit limited efficacy. Fibroblast growth factor 7 (FGF-7), also known as keratinocyte growth factor (KGF), is a paracrine growth factor secreted by dermal papilla cells that specifically activates the epithelial receptor FGFR2b. Receptor engagement triggers multiple downstream signaling cascades, including the MAPK/ERK, PI3K/Akt, and Wnt/β-catenin pathways, promoting keratinocyte proliferation, stem cell activation, and the transition of hair follicles into the anagen phase. Both in vitro and in vivo animal studies consistently demonstrate that FGF-7 accelerates telogen-to-anagen transition and enhances follicular regeneration. FGF-7 acts synergistically with insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) to sustain nutrient delivery and cell proliferation. Human scalp studies further reveal a strong association between the FGF-7/FGFR2b signaling and follicular activity; however, clinical trials remain scarce. Topical application of FGF-7 has demonstrated an excellent safety profile, whereas systemic administration necessitates careful monitoring. Future directions include the development of engineering to extend the systemic half-life, advanced delivery systems, and gene or mRNA-based therapeutic approaches. Thus, the FGF-7/FGFR2b axis is a highly compelling molecular target for next-generation hair regeneration therapies. 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

Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9⁺/Fgfr3⁺ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1⁺ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5⁺ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a–Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh–PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint. Full article

Background: Urine cytology remains widely used for surveillance of non-muscle-invasive bladder cancer despite well-known limitations in sensitivity, especially for low-grade tumors. Uromonitor^®, a molecular assay detecting TERT promoter, FGFR3, and KRAS mutations in voided urine, has emerged as a promising adjunct. To evaluate its suitability for routine use, a consolidated assessment of diagnostic performance and a direct comparison with urine cytology are needed. Methods: We conducted a prospectively registered systematic review (PROSPERO CRD420251173244), synthesizing all available studies that evaluated Uromonitor^® for the detection of urothelial carcinoma of the bladder (UCB). Methodological quality was assessed using the QUADAS-2 framework, and certainty of evidence was evaluated following GRADE for diagnostic tests. Sensitivity was prespecified as the primary endpoint. Comparative datasets were identified, and random-effects meta-analyses were performed for sensitivity, specificity, accuracy, and predictive values (PVs). Results: Across eight cohorts evaluating Uromonitor^®, 832 of 3196 patients (26.0%) had histologically confirmed UCB. Aggregated sensitivity was 0.55 (95% CI 0.52–0.58). Specificity was 0.95 (0.94–0.96). Accuracy was 0.85 (0.83–0.86). PPV was 0.79 (0.76–0.82), and NPV was 0.86 (0.84–0.87). Across seven paired datasets, urine cytology demonstrated a sensitivity of 0.42, a specificity of 0.91, an accuracy of 0.78, a PPV of 0.64, and an NPV of 0.81. Pooled odds ratio for sensitivity was 3.16 (0.73–13.76), while diagnostic accuracy yielded 1.71 (1.01–2.90). Differences in specificity and NPV were not statistically significant, whereas the PPV favored Uromonitor^®, reaching statistical significance in pooled analyses. Conclusions: Uromonitor^® demonstrates higher sensitivity and improved accuracy compared with urine cytology, although current performance remains insufficient for stand-alone surveillance. The sensitivity estimate showed very low certainty due to pronounced heterogeneity, underscoring the need for careful interpretation. With advancing DNA recovery methods, incorporation of droplet digital PCR, and rigorous evaluations in prospective multicenter studies, Uromonitor^® may become an integral element of risk-adapted follow-up strategies. Full article

Desmoplastic small round cell tumor (DSRCT) is a rare but aggressive soft tissue sarcoma of the abdomen. With an asymptomatic course and rapid dissemination, DSRCT’s prognosis is poor at diagnosis. This study characterizes the demographic variation and genomic profile of DSRCT to guide studies into diagnosis and treatment. The AACR GENIE database was utilized to identify genetic alterations in DSRCT. Data was queried to identify disease prevalence by different demographic variables. Information was collected on frequency of somatic mutations and copy number alterations, rates of mutation co-occurrence, and mutations seen in primary and metastatic samples. ARID1A, TP53, ATM, TERT, and FGFR4 were the most frequently identified somatic mutations. Copy number alterations seen in DSRCT were commonly homozygous deletions in tumor suppressor genes. Independent of sex, WT1 mutations were most common. Non-White patients saw single occurrences of many mutations but recurrent ones in ANKRD11 and KMT2C. Co-occurrence was found between FGFR4 and EP300. Moreover, primary tumor samples had exclusive mutations in AKAP9, KDM2B, MAGED1, MKI67, PCLO, and TRAF1. Metastatic samples had exclusive mutations in FIP1L1 and NRIP1. Our data highlights mutational variation across demographic cohorts. These patterns are vital to future studies into identifying diagnostic markers or therapeutic targets. Full article

Background/Objectives: Premalignant laryngeal lesions carry a variable risk of malignant transformation to squamous cell carcinoma. Identifying reliable biomarkers that predict malignant transformation could improve patient management and surveillance strategies. The objective of this work is to perform a systematic review of the literature on biomarkers that predict malignant transformation of premalignant laryngeal lesions. Methods: We conducted a systematic review following PRISMA 2020 guidelines. The PubMed, Scopus and Embase databases, and Google Scholar were searched for studies published between January 2011 and November 2025. Studies investigating biomarkers that predict malignant transformation of histopathologically confirmed premalignant laryngeal lesions were included. Risk of bias was assessed using the ROBINS-I tool. Results: From 166 initially identified records, 11 studies met the inclusion criteria, including 730 patients. These studies investigated diverse biomarker categories such as protein markers (cortactin, FAK, NANOG, SOX2, CSPG4), immune markers (tumor-infiltrating lymphocytes, immune gene signatures), microRNAs (miR-183-5p, miR-155-5p, miR-106b-3p), and genetic markers (chromosomal instability, PIK3CA amplification and mutations, FGFR3 mutations). Five studies provided adequate follow-up data on transformation outcomes. Most studies showed a moderate to serious risk of bias primarily due to limited confounder control and incomplete reporting. Conclusions: While several promising biomarker candidates have been identified, the evidence base remains limited due to small sample sizes, heterogeneous methodologies, and inadequate follow-up data. Cortactin/FAK protein expression and immune signatures are the most promising but require validation in larger, well-designed prospective cohorts. Full article