Search Results (248)

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, with a five-year overall survival rate below 10%. While the introduction of multi-agent chemotherapy regimens has improved outcomes marginally, most patients with advanced disease continue to have limited therapeutic options. Molecular profiling has uncovered actionable genomic alterations in select subgroups of PDAC, yet the clinical impact of targeted therapies remains modest. This review aims to provide a clinically oriented synthesis of emerging molecular targets in PDAC, their therapeutic relevance, and practical considerations for biomarker testing, including current FDA and EMA indications. Methods: A narrative review was conducted using data from PubMed, Embase, Scopus, and international guidelines (NCCN, ESMO, ASCO). The selection focused on evidence published between 2020 and 2025, highlighting molecularly defined PDAC subsets and the current status of targeted therapies. Results: Actionable genomic alterations in PDAC include KRAS G12C mutations, BRCA1/2 and PALB2-associated homologous recombination deficiency, MSI-H/dMMR status, and rare gene fusions involving NTRK, RET, and NRG1. While only a minority of patients are eligible for targeted treatments, early-phase trials and real-world data have shown promising results in these subgroups. Testing molecular profiling is increasingly standard in advanced PDAC. Conclusions: Despite the rarity of targetable mutations, systematic molecular profiling is critical in advanced PDAC to guide off-label therapy or clinical trial enrollment. A practical framework for identifying and acting on molecular targets is essential to bridge the gap between precision oncology and clinical management. Full article

Background/Objectives: Emerging studies have indicated the importance of intra-tumoral neuronal signals in tumor progression and immune modulation. However, there is limited insight into neuroimmune crosstalk, and the molecules involved are largely unknown. This study investigates the relationship between tumor-derived neuropeptides and immune modulation in head and neck squamous cell carcinoma (HNSC). Methods: By utilizing neuropeptide databases and web tools leveraging TCGA data, neuropeptides’ expression and their associations with neurotrophic factors, immune cell infiltration, and immune checkpoints were analyzed, followed by survival analysis. Results: Over half of the neuropeptides were expressed in HNSC, with 16% exhibiting differential expression compared to normal counterparts. Notably, differentially expressed neuropeptides showed significant correlations with neurotrophic factors, immune cell infiltration, and checkpoint genes. Further, their expression was significantly different in responder and non-responder patient samples subjected to immune checkpoint therapy. Neuropeptide genes—PTHLH, NMB, GAST, APLN, and LYNX1—were identified and emerged as crucial mediators in neuroimmune crosstalk. Additionally, the neurotrophic gene NTRK1 exhibited extensive correlation with immune checkpoint genes, underscoring the prevalence of neuroimmune crosstalk in HNSC. Conclusions: These findings shed light on the role of tumor-derived neuropeptides in neuroimmune regulation in HNSC, offering valuable insights for future studies to decode the cancer neuroscience of HNSC progression and therapy. Full article

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive syndrome caused by loss-of-function mutations in the Neurotrophic Tyrosine Kinase Receptor 1 gene, characterized by recurrent episodes of infections and unexplained fever, anhidrosis, absence of reactions to noxious stimuli, intellectual disability, self-mutilating behaviors, and damage to many body organs, including the eyes. Main text: We systematically searched the Medline/PubMed, Scopus, and Web of Science databases from their inception until March 2025 for papers describing the clinical manifestations of patients with CIPA. The inclusion criterion was papers reporting ocular manifestations of patients diagnosed with CIPA. We excluded non-English papers or those reporting ocular manifestations of patients diagnosed with syndromes other than CIPA. Also, we excluded review articles, clinical trials, gray literature, or any paper that did not report ocular manifestations of patients with CIPA or that reported patients with previous ocular surgeries. Out of 6243 studies, 28 were included in the final analysis, comprising 118 patients. The mean age was 7.37 years, and males represented 63.5% (n = 75). Of the patients, fifty-six had bilateral ocular manifestations. The most common ocular manifestations were the absence of corneal reflex in 56 patients (47.5%, bilateral in 56), whereas corneal ulcerations were the second most common manifestation in 46 patients (38.98%, bilateral in 8), followed by corneal opacity in 32 patients (27.11%, bilateral in 19). Topical lubricants, topical antibiotics, and lateral tarsorrhaphy were common management modalities for these patients. Absent corneal sensitivity, corneal ulcers, and corneal opacities, among other manifestations, are common ocular presentations in patients with CIPA. Conclusions: Self-mutilation, intellectual disability, decreased lacrimation, and absence of the corneal reflex are factors that may explain the development of these manifestations in CIPA. The early detection of these manifestations can improve patient conditions and prevent further complications, in addition to helping to guide the clinical diagnosis of CIPA in these patients. Full article

Neurotrophins and inflammatory mediators are known to influence endometrial function, but their interplay in luminal epithelial cells remains poorly characterized. In this study, sheep endometrial luminal epithelial cells (SELECs) were treated with nerve growth factor (NGF), lipopolysaccharide (LPS), or both, and the effects on gene expression and prostaglandin secretion were evaluated. NGF stimulation alone induced a clear transcriptional activation of NGF, neurotrophic receptor tyrosine kinase 1 (NTRK1), p75 neurotrophin receptor (p75NTR), cyclooxygenase 2 (COX2), and steroidogenic acute regulatory protein (STAR). LPS treatment selectively increased Toll-like receptor 4 (TLR4), COX2, and insulin-like growth factor binding protein 6 (IGFBP6). Combined NGF and LPS treatment did not enhance the transcriptional response beyond that induced by NGF alone, except for STAR. However, co-treatment resulted in a modest increase in prostaglandin production, particularly prostaglandin F2α (PGF2α), but not prostaglandin E2 (PGE2), compared to single treatments, suggesting a possible post-transcriptional modulation rather than a transcriptional synergy. These findings indicate that NGF acts as the primary transcriptional driver in SELECs, while LPS contributes selectively and may enhance prostaglandin output. The observed increase in prostaglandin production may involve post-transcriptional mechanisms, although this remains to be confirmed. Full article

Oral squamous cell carcinoma (OSCC) remains a significant global health challenge, representing 90% of oral malignancies. Despite therapeutic advances, patient outcomes remain poor, highlighting the need for novel prognostic biomarkers and treatment targets. We investigated the expression patterns of NTRK genes and their corresponding proteins (TrkA, TrkB, and TrkC) in OSCC, analyzing their relationships with clinical outcomes and potential as therapeutic targets. We examined 93 OSCC tissue samples using immunohistochemistry and quantitative real-time PCR. Protein expression was quantified using the H-score method. We analyzed correlations between Trk expression, clinicopathological parameters, and 2-year survival rates using chi-square tests, Mann–Whitney U tests, and Kaplan–Meier survival analysis. TrkA showed near-universal expression (97.8%—91 patients) in OSCC samples, with high expression levels significantly correlating with lower tumor grade (p = 0.014) and improved 2-year survival (p = 0.011). While TrkB and TrkC were expressed in 65.5% and 84.9% of cases, respectively, neither showed significant associations with clinical parameters. NTRK2 and NTRK3 mRNA levels demonstrated a strong positive correlation (R = 0.64, p = 0.002), suggesting coordinated regulation. Our findings establish TrkA as a promising positive prognostic marker in OSCC, warranting investigation as a therapeutic target. The strong correlation between NTRK2 and NTRK3 expression suggests shared regulatory mechanisms in OSCC pathogenesis. Further studies with larger cohorts and longer follow-up periods are needed to validate these findings and explore their therapeutic implications. Full article

Lycopene exhibits a broad spectrum of biological activities with potential therapeutic applications. Despite its established antioxidant and anti-inflammatory properties, the molecular basis for its pharmacological actions remains incompletely defined. Here we investigated the molecular targets, pharmacodynamic feasibility, and tissue-specific expression of lycopene targets using a computational pharmacology approach combined with affinity and protein–protein interaction (PPI) analyses. Lycopene-associated human protein targets were predicted using a Swiss target screening platform. Molecular docking was used to estimate binding affinities, and concentration-affinity (CA) ratios were calculated based on physiologically relevant plasma concentrations (75–210 nM). PPI networks of lycopene targets were constructed to identify highly connected targets, and tissue expression analysis was assessed for high-affinity targets using protein-level data from the Human Protein Atlas database. Of the 94 predicted targets, 37% were nuclear receptors and 18% were Family A G Protein Coupled Receptors (GPCRs). Among the top 15 high-affinity targets, nuclear receptors and GPCRs comprised 40% and 26.7%, respectively. Twenty targets had affinities < 10 μM, with six key targets (MAP2K2, SCN2A, SLC6A5, SCN3A, TOP2A, and TRIM24) showing submicromolar binding. CA ratio analysis identified MAP2K2, SCN2A, and SLC6A5 as pharmacodynamically feasible targets (CA > 1). PPI analysis revealed 32 targets with high interaction and 9 with significant network connectivity. Seven targets (TRIM24, GRIN1, NTRK1, FGFR1, NTRK3, CHRNB4, and PIK3CD) showed both high affinity and centrality in the interaction network. The expression profiling of submicromolar targets revealed widespread tissue distribution for MAP2K2 and SCN3A, while SCN2A, TOP2A, and TRIM24 showed more restricted expression patterns. This integrative analysis identifies a subset of lycopene targets with both high affinity and pharmacological feasibility, particularly MAP2K2, SCN2A, and TRIM24. Lycopene appears to exert its biological effects through modulation of interconnected signalling networks involving nuclear receptors, GPCRs, and ion channels. These findings support the potential of lycopene as a multi-target therapeutic agent and provide a rationale for future experimental and clinical validation. Full article

Background/Objectives: The neurotrophic tropomyosin receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 encode tyrosine kinase receptors, and their fusion genes are known as the oncogenic driver genes for cancer. This study aimed to compare the diagnostic ability of NTRK fusion among five types of multi-cancer genome profiling tests (multi-CGP tests) and determine a useful multi-CGP test for NTRK fusion, recorded in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database in Japan. This study aimed to compare the diagnostic results for NTRK fusions among the five different CGP tests. Methods: A total of 88,688 tumor cases were enrolled in the C-CAT profiling database from 2019 to 2024. The detection frequency of NTRK fusion genes was compared to the results for five multi-CGP tests: NCC Oncopanel, FoundationOne CDx (F1), FoundationOne Liquid (F1L), GenMineTOP (GMT), and Guardant360. Results: NTRK fusion genes were detected in 175 (0.20%) of the 88,688 total cases. GMT, which is equipped with RNA sequencing function, frequently detected NTRK fusion genes (20 of 2926 cases; 0.68%) in comparison with the other four multi-CGP tests that do not have RNA sequencing analysis. GMT showed significantly (p < 0.05) higher diagnostic ability for NTRK fusions compared with the other four multi-CGP tests. Especially, NTRK2 fusion was significantly (p < 0.001) more highly determined by GMT than it was by the other four multi-CGP tests. The detection rates for FGFR1 and FGFR3 were significantly higher in GMT than in other multi-CGP tests. In contrast, the detection rates of the ALK and RET fusion genes were significantly higher in F1L. Conclusions: GMT, which is equipped with RNA sequencing analysis, might show a useful diagnostic ability for NTRK fusions, especially for NTRK2 fusion genes. Full article

Background: Chronic postsurgical pain (CPSP) poses a major clinical challenge due to unresolved links between neurotrophic pathways and endoplasmic reticulum (ER) stress. While Neurotrophic Tyrosine Kinase Receptor Type 1 (NTRK1) modulates ER stress in neuropathic pain, its interaction with Insulin-Like Growth Factor II (IGF2) in CPSP remains uncharacterized, impeding targeted therapy. This study defined the spinal NTRK1-IGF2-ER stress axis in CPSP. Methods: Using a skin/muscle incision–retraction (SMIR) rat model, we integrated molecular analyses and intrathecal targeting of NTRK1 (GW441756) or IGF2 (siRNA). Results: SMIR surgery upregulated spinal NTRK1, IGF2, and ER stress mediators. NTRK1 inhibition reduced both NTRK1/IGF2 expression and ER stress, reversing mechanical allodynia. IGF2 silencing attenuated ER stress and pain but did not affect NTRK1, revealing a unidirectional signaling cascade where NTRK1 drives IGF2-dependent ER stress amplification. These findings expand understanding of stress-response networks in chronic pain. Conclusions: We show that spinal NTRK1 drives IGF2-mediated ER stress to sustain CPSP. The NTRK1-IGF2-ER stress axis represents a novel therapeutic target; NTRK1 inhibitors and IGF2 biologics offer non-opioid strategies for precision analgesia. This work advances CPSP management and demonstrates how decoding unidirectional signaling hierarchies can transform neurological disorder interventions. Full article

Background: High-grade glioma (HGG) is the most common primary malignant brain tumor, with peak incidence in the fifth and sixth decades of life. Although HGG is rare in children, the prognosis remains poor, with a median overall survival (OS) of less than two years. Recently, TRK inhibitors have been approved for the treatment of tumors harboring NTRK gene fusions. In this review, we analyzed data from early clinical trials investigating the use of these agents in patients with HGG. Methods: A systematic literature search was performed in the PubMed database. Studies involving patients with HGG treated with TRK inhibitors were included. We analyzed progression-free survival (PFS), 24-week disease control rate, and complete or partial radiological responses according to the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Sixteen studies comprising 55 patients with HGG harboring NTRK gene fusions (19 adults and 36 children) were included. A statistically significant difference in PFS was observed between pediatric and adult patients treated with TRK inhibitors (17 vs. 8.5 months; p < 0.001). Pediatric patients also exhibited a higher rate of complete or partial radiological response compared to adults (94% vs. 57%). Discussion: Although the available evidence on TRK inhibitors in HGG is limited, the findings of this review highlight a potentially promising role for these agents, particularly in the treatment of pediatric HGGs. Full article

Methods: We retrospectively and cross-sectionally reviewed the cases of 648 patients with a histological diagnosis of colon adenocarcinoma. Of these, 166 had partial molecular studies, and 42 cases were selected based on the availability of the genetic markers targeted in this study. We analyzed the frequency of mutations in these genes, as well as their correlation with microsatellite instability (MSI). Results: A high mutation rate was found in the KRAS gene (52.4%). NRAS mutations were less frequent (8.9%), whereas BRAF mutations were observed in 20.8% of cases. This allowed us to identify a patient subgroup with MSI, representing 12.1% of cases. Among the 42 patients analyzed for KRAS, NRAS, BRAF, and MSI mutations, a significant association was observed between KRAS mutations and microsatellite stability, while no association was found between NRAS mutations and MSI. BRAF mutations showed a statistically significant association with MSI (p < 0.05), with the most common mutation being c.1799T > A, p.Val600Glu. The objective of this study is to demonstrate that the NGS-based method for evaluating MSI is rigorously valid compared to the results obtained using IHC and PCR. Conclusions: Comprehensive NGS profiling from the start improves diagnostic efficiency by saving time, tissue, and costs compared to gene-by-gene analysis. It also enables better molecular characterization and facilitates tailored therapeutic strategies, particularly in identifying candidates for targeted therapy and immunotherapy. This approach supports efficient tumor classification based on using KRAS, BRAF, NTRK, ERBB2, and PIK3CA as key markers, along with MSI status. We recommend that, if initial NGS is not feasible, start with KRAS analysis, then test BRAF and MSI if no mutation is found. Full article

Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder. Methods: We studied a well-defined Australian patient cohort diagnosed via the International Consensus Criteria, recruited by a specialist ME/CFS clinic. The whole-exome sequences of 77 patients were contrasted against genome variation in the 1000 Genome Project’s genome-matched population. Results: Significant associations with ME/CFS were harboured in genes that belong to the Neuroblastoma Breakpoint Family encoding Olduvai (DUF1220) domains, namely NBPF1 (rs3897177, p-value = 3.15 × 10⁻⁸), NBPF10 (rs1553120233, p-value = 9.262 × 10⁻¹³), and NBPF16 (rs200632836, p-value = 1.04 × 10⁻⁶). Other significantly associated variants were detected in the ATR, RSPH10B, ADGRE5-CD97, and NTRK2 genes, among others. Replication of these results was attempted via a GWAS on raw data from a US cohort, which confirmed shared significant associations with variation identified in the PTPRD, CSMD3, RAPGEF5, DCC, ALDH18A1, GALNT16, UNC79, and NCOA3 genes. Conclusions: These genes are involved in cortical neurogenesis, brain evolution, and neuroblastoma, and have been implicated by several studies in schizophrenia and autism. The sharing of these associations by the two cohorts supports their validity and grants the necessity of future studies to evaluate the implications for ME/CFS aetiology. Full article

Lung cancer remains the leading cause of cancer-related death in the US and worldwide. Recent advances in molecular profiling and targeted therapies have revolutionized the management of non-small cell lung cancer (NSCLC), particularly in oncogene-driven subtypes. These therapies selectively target key molecular alterations in EGFR, ALK, KRAS, ROS1, MET, RET, ERBB2 (HER2), BRAF V600E, and NTRK, resulting in substantial improvements in survival rates and quality of life for lung cancer patients. However, disparities in molecular diagnostics and precision treatments persist, disproportionately affecting minority patients. These inequities include underrepresentation in clinical trials, disparities in molecular testing, and barriers to treatment access. The limited participation of racial and ethnic minorities in landmark clinical trials raises concerns about the generalizability of findings and their applicability to diverse populations. In this review, we examine the current landscape of molecular diagnosis and precision medicine in minority patients with oncogene-driven lung cancer, highlighting challenges, opportunities, and future directions for achieving equity in precision oncology. Additionally, we discuss differences in the prevalence of oncologic driver mutations across populations and emphasize the urgent need for greater diversity in clinical research. Addressing these gaps is critical to improving survival outcomes and ensuring equitable access to personalized lung cancer care for all patients. Full article

Traumatic brain injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology Panel to test the hypothesis that idebenone post-treatment mitigates TBI-pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in the peri-lesional cortex at 24 h post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology–biological process (GO:BP) pathways “ephrin receptor signaling” and “dopamine metabolic process”. Gene co-expression analysis correlated levels of microglial complement component 1q (C1q) and the neurotrophin receptor gene Ntrk1 to large (>3-fold) TBI-induced decreases in dopamine receptor genes Drd1 and Drd2 that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, the results suggest that idebenone may enhance TBI-induced microglial number within the first 24 h of TBI and identify ephrin-A and dopamine signaling as novel idebenone targets. Full article

Lung cancer is the leading cause of cancer-related death worldwide, ranking first among men and second among women for both incidence and mortality. Surgery remains the primary treatment for early-stage, resectable non-small cell lung cancer (NSCLC), encompassing stages I and selected cases of stage IIIB. For patients with stage II to III disease, as well as some stage IB tumors, neoadjuvant or adjuvant systemic therapies are recommended. It is well recognized that specific driver gene mutations play a critical role in tumor progression and aggressiveness, and patients with these genetic alterations may benefit from targeted treatment approaches. These alterations are referred to as “druggable”, “targetable”, or “actionable”, representing specific targets for personalized treatments. Tyrosine kinase inhibitors (TKIs) are now the preferred first-line treatment for patients harboring mutations in EGFR, ALK, ROS1, and BRAF. Additionally, targeted therapies exist for patients with alterations in RET, ERBB2, KRAS, MET, and NTRK, either for those who have received prior treatments or as part of ongoing clinical trials. The success of targeted therapies is reshaping treatment approaches for NSCLC with targetable driver gene alterations, both in early-stage and locally advanced settings. This review focuses on current therapeutic strategies that combine targeted therapies with surgical resection in patients with resectable non-small cell lung cancer (NSCLC) harboring actionable driver gene alterations. Full article

Thyroid cancer (TC) remains a prevalent malignancy, with over 820,000 global cases diagnosed in 2022. Differentiated thyroid carcinoma (DTC), primarily papillary and follicular types, accounts for most cases and has a favorable prognosis with total thyroidectomy and radioiodine (RAI) ablation. However, 5–15% of patients develop RAI-refractory (RAI-R) disease, leading to a significantly poorer outcome. For RAI-R patients, treatment decisions depend on disease progression. Active surveillance is suitable for indolent cases, while symptomatic or progressive disease requires systemic therapy. Multikinase inhibitors (MKIs) such as lenvatinib and sorafenib serve as first-line options, with cabozantinib recently approved for resistant cases. Additionally, novel targeted therapies, including RET and NTRK inhibitors, and immune checkpoint inhibitors, are under investigation, offering a personalized approach. A key challenge is determining the optimal timing for systemic therapy, balancing progression-free survival (PFS) benefits against MKI-related toxicities, which significantly impact quality of life (QoL). Molecular testing can identify actionable mutations, guiding therapy selection. Clinical guidelines (ATA, ESMO) recommend initiating treatment based on disease progression and patient condition, integrating strategies such as active surveillance, surgery, and radiotherapy when appropriate. Despite advances, systemic therapies carry significant adverse events (e.g., hypertension, fatigue, gastrointestinal toxicity), necessitating careful monitoring to prevent dose reductions or interruptions. A multidisciplinary approach is essential to optimize patient outcomes and maintain QoL. As targeted therapies continue to evolve, further research is needed to refine treatment sequencing and improve outcomes for RAI-R TC. This review synthesizes current evidence to guide clinical decision-making. Full article