Chemotherapy remains the primary treatment for advanced lung squamous cell carcinoma (LUSC); however, its severe toxic side effects significantly limit therapeutic efficacy. There is an urgent clinical need to integrate molecular targeting with chemotherapy to enhance treatment outcomes. Consequently, this study developed a co-loaded albumin-based nanodelivery system (NLB/PTX-NPs) for targeted delivery of nilotinib alongside the chemotherapeutic agent paclitaxel. We systematically evaluated its in vitro and in vivo anti-tumor activity, safety, and underlying molecular mechanisms. NLB/PTX-NPs were synthesized via the solvent displacement method, followed by characterization of their physicochemical properties, drug-loading performance, and biosafety. Using NCI-H520 cells as a model, the in vitro efficacy and molecular mechanisms were evaluated through cellular uptake studies, cytotoxicity assessments, in vitro cellular experiments, and Western Blot assays. Additionally, subcutaneous tumor and lung metastasis models were established in nude mice to evaluate in vivo targeted distribution, as well as anti-tumor and anti-metastatic activities. NLB/PTX-NPs exhibited a uniform spherical morphology, demonstrating excellent dispersibility, stability, and biosafety. In vitro experiments revealed that the nanoparticles significantly enhanced cellular uptake and inhibited the proliferation, migration, and invasion of NCI-H520 cells. Western blot analysis confirmed their ability to regulate the expression of proteins associated with apoptosis and epithelial-mesenchymal transition (EMT). Furthermore, in vivo experiments indicated that the nanoparticles significantly accumulated in tumor tissues, synergistically inhibiting tumor growth (P < 0.001) and lung metastasis (P < 0.05) through the downregulation of NF-κB and IKBα phosphorylation levels, as well as a reduction in the Ki67 index, without any apparent systemic toxicity. This study successfully developed NLB/PTX-NPs, achieving effective co-loading of dual drugs, efficient enrichment, and synergistic delivery at tumor sites. The system demonstrated promising preclinical anti-tumor and anti-metastatic effects in the NCI-H520 models by synergistically inhibiting the NF-κB pathway, thereby providing a novel strategy for the treatment of lung squamous cell carcinoma.

Parkinson's disease (PD) affects 11.77 million people worldwide, projected to reach 17.27 million by 2035. Current dopamine replacement therapies provide symptomatic relief but lack disease-modifying effects. Drug repurposing offers advantages: reduced development time (3-12 vs 10-17 years) and costs ($40-80 million vs $1-3 billion). To examine the pathophysiological connections between cancer and PD and evaluate the therapeutic potential of repurposing anticancer drugs through shared molecular mechanisms. Analysis of shared pathways, including mitochondrial dysfunction, ubiquitin-proteasome dysregulation, protein aggregation, neurotrophic factors, apoptotic genes, Dual Tyrosine Kinase Inhibition, microRNAs, and inflammation. Examination of repurposed anticancer agents in preclinical and clinical PD studies. Mitochondria-targeted metformin analogues showed 1000-fold increased potency in MitoPark models, although Mito-Q failed in human trials. Ixazomib enhances α-synuclein clearance via autophagy in preclinical models. Nilotinib showed poor CNS penetration (< 0.3% in CSF), resulting in worsening motor outcomes. Relatlimab, trehalose, and lapatinib demonstrated preclinical benefits through inhibition of α-synuclein spread, mTOR-independent autophagy, and multi-pathway neuroprotection, respectively. The AZA-PD Phase 2 trial (azathioprine) demonstrated a favourable safety and tolerability profile and offered valuable insights into peripheral immune modulation in early PD, though it did not meet its primary endpoint of slowing disease progression. Key barriers include poor CNS penetration, narrow therapeutic windows (70% neuronal loss at diagnosis), differential safety requirements, and timing-dependent efficacy necessitating early intervention. Mechanistic convergence provides a rationale for repurposing drugs; however, clinical success requires addressing the unique challenges of neurodegeneration. Future approaches should focus on precision medicine, innovative delivery systems, and multi-target interventions rather than direct therapeutic translation.

Background: Evidence regarding long-term outcomes among offspring following maternal or paternal exposure to BCR::ABL1 tyrosine kinase inhibitors (TKIs) is limited. We described pregnancy outcomes and offspring health through adolescence and early adulthood in a single-centre cohort of patients with chronic myeloid leukemia (CML). Methods: This retrospective, descriptive cohort study included patients with chronic-phase CML who experienced a pregnancy, or whose partner experienced a pregnancy, in association with TKI exposure and for whom longitudinal offspring follow-up was available. Long-term offspring outcomes were ascertained from detailed obstetric and pediatric medical records supplemented by parental reports. Fourteen patients (nine women and five men) contributed 21 pregnancy events and 23 live-born offspring, including two twin pregnancies in the paternal-exposure group. Results: In the maternal-exposure group, median gestational age at delivery was 38.0 weeks (range, 35-40), and four of 15 deliveries were preterm. In the paternal-exposure group, median gestational age was 39.0 weeks (range, 38-41), with no preterm deliveries. Median offspring follow-up was 252 months (range, 212-295), extending through adolescence and into early adulthood. One offspring had a primum atrial septal defect that was surgically corrected. No additional clinically documented major abnormalities in growth or developmental progress were identified during available follow-up. Given the small cohort, these observations were interpreted descriptively and were not considered evidence of equivalence with population-level rates. Conclusions: This small retrospective cohort provides unusually long observational follow-up of offspring after selected maternal or paternal TKI exposures. The findings are clinically informative but cannot establish reproductive safety or exclude rare adverse outcomes. Larger multicentre registries using standardized long-term developmental, neurocognitive, and endocrine assessments are needed.

Chronic myeloid leukemia (CML) is a clonal disorder of myeloid lineage. Our study was done to compare the three risk groups and evaluate utility and applicability of the ELTS scoring system in predicting survival of CML in chronic phase(CP) on treatment with nilotinib in a resource limited setting. A cross sectional study was conducted at National Institute of Blood Diseases and Bone marrow transplantation, Karachi, Pakistan from January 2015 to December 2022. A total of 204 diagnosed CML patients were included. Risk stratification was done based on the Sokal, EUTOS and ELTS scores. A total of 204 patients were enrolled in the study. Out of total, 130 (64%) were males. The median age was 37(ranging 15-77 years). The median follow-up duration was 40 months and median spleen size was 5.6 (ranging, 1.6-14 cm). On the basis of ELTS score, 86 (42%) patients were stratified as low, intermediate 91 (45%), and 27 (13%) patients were high-risk group. Patients stratified as high-risk according to ELTS scoring had a substantial lower MMR accomplishment. Moreover, the 12 months MMR accomplishment rates were 50 (39%) in low, 55 (43%)(p = 0.03). ELTS and EUTOS scoring system was also able to anticipate the DMR accomplishment (p = < 0.001). Our study implied that the new ELTS score can be used to predict prognosis in CML patients in CP treated with upfront nilotinib specifically in terms of molecular response and must be incorporated at disease baseline to predict disease prognosis and choice of tyrosine kinase inhibitor (TKI).

The third-generation tyrosine kinase inhibitor (TKI) ponatinib has demonstrated efficacy in patients with chronic phase chronic myeloid leukemia (CML-CP). However, limited data were reported for the use of ponatinib as a second-line treatment in real world evidence. This observational, multicenter, retrospective study included patients aged ≥ 16 years with CML-CP who received ponatinib as second-line therapy between September 2016 and October 2023 at Yokohama City University Medical Center and Fujisawa City Hospital. The median age at the time of data collection was 53 (range, 20-79) years. The median duration of TKI treatment was 15 (range, 1-85) months. The TKIs administered as first-line treatment were as follows: bosutinib in eight patients (50%), dasatinib in six patients (38%), and nilotinib in two patients (13%). Reasons for switching to ponatinib included intolerance (in five patients, 31%) and resistance (in 11 patients, 69%). The median ponatinib exposure was 637 (range, 49-1384) days, with a median follow-up of 1,052 (range, 411-1,732) days. Among the patients, 13 (81%) achieved or maintained major molecular response. Five patients (31%) discontinued ponatinib. Ponatinib demonstrated high efficacy in treating CML-CP resistant or intolerant to second-generation TKIs.

The introduction and refinement of tyrosine kinase inhibitors (TKIs) over the past 25 years have resulted in dramatic improvements in life expectancy in individuals with chronic myeloid leukemia (CML). There are now multiple effective and well-tolerated TKIs available, and because most patients will be receiving TKIs for their lifetime, quality-of-life (QoL) considerations are an increasing concern. Patients with CML receiving TKIs have worse QoL than the general population, but TKIs have a generally less negative impact on QoL factors than previously available treatments for CML. Commonly used TKIs (imatinib, nilotinib, dasatinib, bosutinib, ponatinib, asciminib, and olverembatinib) all have positive and negative impacts on QoL, each of which can be impacted by patient preference and priorities, as well as line of therapy. The inclusion of patient-reported QoL outcomes in clinical trials will be vital to helping physicians understand the patient experience of CML and thereby improve disease management.

TGF-beta-activated kinase 1 (TAK1) is a critical regulator of inflammatory and oncogenic signaling pathways and represents a promising therapeutic target for diseases ranging from chronic inflammation to cancer. However, existing therapies targeting downstream mediators often face limitations such as drug resistance and inconsistent efficacy. Here, we report on drug repurposing to discover FDA-approved compounds that can suppress TAK1 activity. Molecular docking of 3500 drugs from the DrugBank database was performed, followed by drug profiling, biological activity analysis, and 500-nanosecond molecular dynamics (MD) simulations via a multi-step computational protocol. The systematic screening identified a few hits where two drugs, nilotinib and dabrafenib, showed appreciable binding affinity to the ATP-binding site of TAK1 and showed appropriate drug profiles. Stable interaction analyses indicated consistent engagement of catalytic residues and structural motifs essential for ATP binding and subsequent TAK1 function. MD simulations further indicated stable TAK1-ligand complexes for both nilotinib and dabrafenib, with persistent hydrogen-bonding interactions and maintenance of protein compactness throughout the simulations. These findings support the repositioning of nilotinib and dabrafenib as potential TAK1-targeting compounds toward therapeutic development against inflammation-driven pathologies and cancer. Experimentally validating these insights at the level of cells, tissues, organs, and body systems is necessary to translate computational insights into practical use for therapeutic development.

Microglia are the resident immune cells of the brain and serve as key regulators of innate immune responses within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that plays a central role in innate immunity, and its excessive activation contributes to the pathogenesis of neurodegenerative diseases. Nilotinib, a second-generation tyrosine kinase inhibitor, has recently attracted attention due to its neuroprotective and immunomodulatory properties in the CNS. In the present study, we investigated the effects of nilotinib on NLRP3 inflammasome activation, GSDMD/NINJ1-mediated pyroptosis, NF-κB signaling, BAG3-dependent aggrephagy, and ESCRT-III-mediated plasma membrane repair in LPS plus ATP-induced murine N9 microglial cells. Our findings demonstrated that nilotinib significantly attenuated NLRP3 inflammasome activation, as evidenced by reduced NLRP3 expression, decreased caspase-1 activation, and suppressed secretion of proinflammatory cytokines IL-1β and IL-18 through modulation of the IκBα/NF-κB signaling axis. Furthermore, nilotinib markedly inhibited pyroptotic cell death by reducing GSDMD-N and NINJ1 expression, thereby preserving membrane integrity. In parallel, nilotinib enhanced BAG3-dependent selective autophagy and increased LC3B expression, suggesting activation of aggrephagy pathways involved in the clearance of inflammasome-associated components. Notably, nilotinib also restored VPS4A expression, indicating activation of ESCRT-III-mediated plasma membrane repair mechanisms. Collectively, our results reveal that nilotinib exerts a multi-layered regulatory effect on microglial inflammatory responses by suppressing inflammasome activation and pyroptosis while promoting autophagy-dependent clearance and membrane repair pathways. These findings highlight a novel integrative mechanism linking autophagy, pyroptosis, and membrane repair in the neuroprotective actions of nilotinib.