Search Results (647)

Background: Epidermal growth factor receptor (EGFR) mutations are presented in approximately 50% of East Asian populations with advanced non-small cell lung cancer (NSCLC). While EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment, patient outcomes are also influenced by host-related factors. This study aimed to investigate clinical and radiological factors associated with early mortality and develop a prognostic prediction model in advanced EGFR-mutated NSCLC. Methods: A retrospective cohort was conducted in patients with EGFR-mutated NSCLC treated with first line EGFR-TKIs from January 2012 to October 2022 at Chiang Mai University Hospital. Clinical data and radiologic findings at the initiation of treatment were analyzed. A multivariable flexible parametric survival model was used to determine the predictors of death at 18 months. The predicted survival probabilities at 6, 12, and 18 months were estimated, and the model performance was evaluated. Results: Among 189 patients, 84 (44.4%) died within 18 months. Significant predictors of mortality included body mass index <18.5 or ≥23, bone metastasis, neutrophil-to-lymphocyte ratio ≥ 5, albumin-to-globulin ratio < 1, and mean pulmonary artery diameter ≥ 29 mm. The model demonstrated good performance (Harrell’s C-statistic = 0.72; 95% CI: 0.66–0.78). Based on bootstrap internal validation, the optimism-corrected Harrell’s C-statistic was 0.71 (95% CI: 0.71–0.71), derived from an apparent C-statistic of 0.75 (95% CI: 0.74–0.75) and an estimated optimism of 0.04 (95% CI: 0.03–0.04). Estimated 18-month survival ranged from 87.1% in those without risk factors to 2.1% in those with all predictors. A web-based tool was developed for clinical use. Conclusions: The prognostic model developed from fundamental clinical and radiologic parameters demonstrated promising utility in predicting 18-month mortality in patients with advanced EGFR-mutated NSCLC receiving first-line EGFR-TKI therapy. Full article

Bruton Tyrosine Kinase (BTK) has emerged as a critical mediator in the pathophysiology of neuroinflammation associated with neurodegenerative diseases. BTK, a non-receptor tyrosine kinase predominantly expressed in cells of the hematopoietic lineage, modulates B-cell receptor signaling and innate immune responses, including microglial activation. Recent evidence implicates aberrant BTK signaling in the exacerbation of neuroinflammatory cascades contributing to neuronal damage in disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, and Huntington’s disease. Pharmacological inhibition of BTK has shown promise in attenuating microglial-mediated neurotoxicity, reducing pro-inflammatory cytokine release, and promoting neuroprotection in preclinical models. BTK inhibitors, originally developed for hematological malignancies, demonstrate favorable blood–brain barrier penetration and immunomodulatory effects relevant to central nervous system pathology. This therapeutic approach may counteract detrimental neuroimmune interactions without broadly suppressing systemic immunity, thus preserving host defense. Ongoing clinical trials are evaluating the safety and efficacy of BTK inhibitors in patients with neurodegenerative conditions, with preliminary results indicating potential benefits in slowing disease progression and improving neurological outcomes. This review consolidates current knowledge on BTK signaling in neurodegeneration and highlights the rationale for BTK inhibition as a novel, targeted therapeutic strategy to modulate neuroinflammation and mitigate neurodegenerative processes. Full article

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, with oral squamous cell carcinoma (OSCC) accounting for a significant portion of cases. Despite advancements in treatment, only modest gains have been made in HNSCC/OSCC control. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have emerged as targeted therapies for OSCC in clinical trials. However, their clinical efficacy remains a challenge. Cannabidiol (CBD), a non-psychoactive phytochemical from cannabis, has demonstrated anticancer and immunomodulatory properties. CBD induces apoptosis and autophagy and modulates signaling pathways often dysregulated in HNSCC. This review summarizes the molecular mechanisms of EGFR-TKIs and CBD and their clinical insights and further discusses potential implications of combination targeted therapies. 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

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by a dense desmoplastic stroma and a highly immunosuppressive tumor microenvironment (TME). The focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is considered a critical regulator of various cellular processes involved in cancer development. FAK inhibitors (FAKi) have proven to be promising therapeutics for cancer treatment including for pancreatic cancer. As monotherapy, however, FAKi showed only a modest effect in clinical studies. In this study, we investigated the cytotoxicity of six FAKi (Defactinib, CEP-37440, VS-4718, VS-6062, Ifebemtinib and GSK2256098) used in clinical trials on five pancreatic tumor cell lines. We further examined whether their anti-tumor activity can be enhanced by combination with the oncolytic coxsackievirus B3 (CVB3) strain PD-H. IC₅₀ analyses identified Defactinib and CEP-37440 as the most potent inhibitors of tumor cell growth. VS-4718, VS-6062, and Ifebemtinib showed slightly lower activity, while GSK2256098 was largely ineffective. The combination of Defactinib, CEP-37440, VS-4718, and VS-6062 with PD-H resulted in varying effects on cytotoxicity, depending on the cell line and the specific FAKi, ranging from no enhancement to a pronounced increase. Using the Chou–Talalay method, we determined combination indices (CI), revealing synergistic, additive, but also antagonistic interactions between the respective FAKi and PD-H. Considering both oncolytic efficacy and the CI, the greatest enhancement in oncolytic activity was achieved when VS-4718 or CEP-37440 was combined with PD-H. These findings indicate that co-treatment with PD-H can potentiate the therapeutic activity of the selected FAKi and may represent a novel strategy to improve treatment outcomes in PDAC. Full article

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth factor receptor (EGFR) mutations to respond well to EGFR tyrosine kinase inhibitors (TKIs). Due to the high EGFR mutation frequency (up to more than 50%) observed particularly in Asian NSCLC patients, EGFR-TKIs have produced unprecedented clinical responses. Depending on their binding interactions with EGFRs, EGFR-TKIs are classified as reversible (first-generation: gefitinib and erlotinib) or irreversible inhibitors (second-generation: afatinib and dacomitinib; third-generation: osimertinib). While the discovery of osimertinib represents a breakthrough in the treatment of NSCLC, most patients eventually relapse and develop drug resistance. Novel strategies to overcome osimertinib resistance are urgently needed. In Asian countries, the concomitant use of Western medicine and traditional Chinese medicine (TCM) is very common. Ganoderma lucidum (Lingzhi) and Coriolus versicolor (Yunzhi) are popular TCMs that are widely consumed by cancer patients to enhance anticancer efficacy and alleviate the side effects associated with cancer therapy. The bioactive polysaccharides and triterpenes in these medicinal mushrooms are believed to contribute to their anticancer and immunomodulating effects. This review presents the latest update on the beneficial combination of Lingzhi/Yunzhi and EGFR-TKIs to overcome drug resistance. The effects of Lingzhi/Yunzhi on various oncogenic signaling pathways and anticancer immunity, as well as their potential to overcome EGFR-TKI resistance, are highlighted. The potential risk of herb–drug interactions could become critical when cancer patients take Lingzhi/Yunzhi as adjuvants during cancer therapy. The involvement of drug transporters and cytochrome P450 enzymes in these herb–drug interactions is summarized. Finally, we also discuss the opportunities and future prospects regarding the combined use of Lingzhi/Yunzhi and EGFR-TKIs in cancer patients. Full article

Background/Objectives: The fat mass and obesity-associated (FTO) protein demethylates nuclear N6-Methyladenosine (m6A) on mRNA, facilitates tumor growth, and contributes to therapeutic resistance in multiple cancer types. Recent evidence demonstrates several roles of FTO in tumorigenesis. In this study, we seek to explore the role of FTO in non-small cell lung cancer (NSCLC) tumorigenicity and its relationship with epidermal growth factor receptor (EGFR) tyrosine kinase resistance. Methods: We performed qPCR, immunoblotting, viability assays, migration assays, and ATP assays to investigate the functions of FTO in EGFR tyrosine kinase inhibitor (TKI) resistance, specifically to erlotinib, in three NSCLC cell lines harboring either wild-type or mutant EGFR. We also performed immunohistochemistry on lung tumor tissues from patients diagnosed at different stages of NSCLC. Results: Our study found an upregulation of FTO in erlotinib-resistant (ER) cell lines at both the gene and protein levels. FTO inhibition and knockdown significantly reduced cell viability of erlotinib-resistant H2170 and PC9 cells by over 30% when treated with 0.8 µM of Dac51 and about 20% when treated with siFTO. FTO inhibition also slowed down the migration of ER cells, and the effect was even more pronounced when combined with erlotinib. Furthermore, FTO was found to be overexpressed in late-stage NSCLC tumor tissues compared to early-stage tumors, and it was upregulated in patients who smoked. Conclusions: These findings suggest FTO might mediate resistance and tumor growth by augmenting cell proliferation. In addition, FTO can be a potential prognostic marker in NSCLC patients. 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

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown clinical activity for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the development of resistance to EGFR-TKIs is almost inevitable, posing a significant barrier to long-term survival. Local ablative therapy (LAT) may facilitate the prolonged survival of patients with oligometastatic NSCLC. Therapeutic combinations of EGFR-TKIs and LAT for residual disease have been suggested to be potentially effective in EGFR-mutated NSCLC with induced oligometastatic disease, wherein a few lesions remain following initial EGFR-TKI treatment. Various resistance pathways for third-generation EGFR-TKIs including osimertinib, current standard of care for patients with EGFR-mutated NSCLC, have also been identified. In addition to resistance mechanisms, the disease-progression pattern may be an essential element for achieving long-term response and survival. Oligo-progressive disease is a state in which only a few lesions become resistant, whereas many lesions remain controlled with effective systemic therapy. Previous studies have shown that LAT for all oligo-progressive lesions could provide survival benefits. This review discusses the current treatment options and potential future therapeutic developments for patients with EGFR-mutated NSCLC who have synchronous oligometastatic disease, oligo-residual disease during treatment with EGFR-TKIs, and oligo-progressive disease following resistance to EGFR-TKIs. Full article

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives. Full article

Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK gene, such as ETV6::SYK and ITK::SYK, have emerged as rare but potentially targetable genetic events in both myeloid and lymphoid neoplasms. SYK, a non-receptor tyrosine kinase critical for hematopoietic signalling, can become constitutively activated through gene fusions, driving oncogenesis via the PI3K/AKT, MAPK, and JAK-STAT pathways. ETV6::SYK has been primarily associated with myeloid neoplasms, often presenting with eosinophilia, bone marrow dysplasia, and skin involvement. In vitro and in vivo models confirm its leukemogenic potential and identify SYK as a therapeutic target. Although SYK inhibitors like fostamatinib have shown transient efficacy, resistance mechanisms, possibly involving alternative pathway activation, remain a challenge. The ITK::SYK fusion, on the other hand, has been identified in peripheral T-cell lymphomas, particularly of the follicular helper T-cell subtype, with similar pathway activation and potential for targeted intervention. Additional rare SYK fusions, such as PML::SYK and CTLC::SYK, have been reported in myeloid neoplasms and juvenile xanthogranuloma, respectively, expanding the spectrum of SYK-driven diseases. Accumulating evidence supports the inclusion of SYK fusions in future classification systems and highlights the need for broader molecular screening and clinical evaluation of SYK-targeted therapies. Full article

The onset and progression of tumors involve intricate, multifactorial processes. A key component in tumor evolution is the dynamic interaction between cancer cells and the extracellular matrix (ECM). Discoidin Domain Receptors (DDRs), a unique class of collagen-activated receptor tyrosine kinases, serve as critical mediators of cell-ECM communication. Recent studies have uncovered their significant roles in modulating diverse cancer-related processes, including immune responses, cell proliferation, apoptosis, differentiation, metabolic reprogramming, metastasis, and resistance to therapy. This review begins with an overview of the discovery, structural features, and canonical and non-canonical functions of DDRs. It then focuses on the reciprocal regulation between DDRs and collagen in the tumor microenvironment, highlighting how this interplay contributes to cancer progression. Furthermore, we explore the involvement of DDRs in reshaping the tumor immune microenvironment and their influence on various aspects of cancer cell biology. Finally, we summarize the current advances in therapeutic strategies targeting DDRs, offering insights into their potential as biomarkers and drug targets in cancer treatment. Full article

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases globally and most patients receive their diagnosis at advanced or metastatic disease stages. The use of tyrosine kinase inhibitors (TKIs) such as erlotinib (first-generation) and osimertinib (third-generation) to treat NSCLC is possible because of activating mutations in the epidermal growth factor receptor (EGFR). Although osimertinib has shown better results in recent trials, direct and updated comparisons with erlotinib, especially in combination regimens, are still limited. Background/Objectives: This study aimed to compare the efficacy and safety of osimertinib versus erlotinib, both as monotherapies and in combination, in treatment-naïve patients with advanced or metastatic EGFR-mutated NSCLC. Methods: A systematic review and network meta-analysis were conducted following PRISMA-NMA guidelines and registered in PROSPERO (CRD42025649761). PubMed, EMBASE, and Scopus were searched up to February 2025 for randomized controlled trials (RCTs) that compared erlotinib- or osimertinib-based regimens in previously untreated EGFR-mutated advanced NSCLC. Outcomes included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 adverse events. A frequentist random-effects model was used, and treatments were ranked using p-scores. Results: Eleven RCTs (2341 patients) were included. Osimertinib, alone or with chemotherapy, resulted in significantly longer OS compared to erlotinib-based regimens (HR for OS vs. erlotinib: 1.59, 95% CI 1.09–2.31). All osimertinib and erlotinib regimens outperformed chemotherapy for PFS, but no statistically significant differences were observed between osimertinib and erlotinib. Severe adverse events were comparable, though osimertinib ranked highest for safety. The combination of osimertinib with chemotherapy achieved the highest p-scores for both OS and PFS. Conclusions: Osimertinib is associated with superior overall survival and comparable safety versus erlotinib-based strategies in first-line treatment of advanced EGFR-mutated NSCLC. These findings reinforce osimertinib as the preferred first-line option in this setting. Full article

Background/Objectives: Ruptured abdominal aortic aneurysm (RAAA) remains a leading cause of vascular death, with mortality rates approaching 90%. Biomarkers capable of identifying the most at-risk population are urgently needed in the clinic. We aimed to identify potential alterations in the urine proteome that can enable non-invasive detection of abdominal aortic aneurysms (AAA) at high risk of rupture. Methods: We used multiplexed kinase inhibitor beads (MIBs) and quantitative mass spectrometry (MIB/MS) to examine potential biomarkers in urine samples. Quantitative proteomic profiling was conducted using iTRAQ labeling and LC-TEMPO MALDI-TOF/TOF analysis, revealing several dysregulated proteins in the urinary proteome between the two groups. MS and MS/MS data were generated using MALDI TOF/TOF instruments (models 5800 or 4800; AB SCIEX). MS/MS spectra were processed with ProteinPilot™ software version 3.0 (AB SCIEX) and matched against the UniProt/Swiss-Prot database for identification of proteins with an Unused ProtScore >1.3. Statistical tests were performed using R/Bioconductor software and bioinformatics analysis using open-source software. Results: We quantitatively measured activity over 130 kinases from various kinase families using MIB/MS with a threshold of 1.5-fold change in expression. Statistical analysis assigned significance to EPHB6, AXL, EPHB4, DDR1, EPHA2 and EPHB3. All were tyrosine kinases, and the Ephrin receptor type was dominant. The reduced expression of specific kinases identified by MIB/MS analysis was validated by Western blot. Conclusions: This pilot study presents a promising breakthrough in the diagnosis and surveillance of AAA. We identified six dysregulated tyrosine kinases in the urine proteome of patients with RAAAs, suggesting their potential as urinary biomarkers for early detection of AAA at high risk of rupture. However, these preliminary findings require confirmation in larger, prospective cohorts to validate their diagnostic utility and generalizability. Full article

The IgLON family of tumor suppressor genes (TSG) impact a variety of cellular processes involved in cancer and non-cancer biology. OPCML is a member of this family and its inactivation is an important control point in oncogenesis and tumor growth. Here, we analyze RNA-Seq expression ratios in ovarian cancers from The Cancer Genome Atlas (TCGA) (189 subjects at Stage III) to identify genes that exhibit a cooperative survival impact (via Kaplan–Meier survival curves) with OPCML expression. Using enrichment analyses, we reconstruct functional pathway impacts revealing interactions of OPCML, and then validate these in independent cohorts of ovarian cancer. These results emphasize the role of OPCML’s regulation of receptor tyrosine kinase (RTK) signaling pathways (PI3K/AKT and MEK/ERK) while identifying three new potential RTK transcriptomic linkages to KIT, TEK, and ROS1 in ovarian cancer. We show that other known extracellular signaling receptor ligands are also transcriptionally linked to OPCML. Several key genes were validated in GEO datasets, including KIT and TEK. Considering the range of OPCML impacts evident in our analyses on both external membrane interactions and cytosolic signal transduction, we expand the understanding of OPCML’s broad cellular influences, demonstrating a multi-functional, pleiotropic, tumor suppressor, in keeping with prior published studies of OPCML function. Full article