Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line therapy for advanced, EGFR-mutated nonsmall cell lung cancer (NSCLC). However, their benefit is limited in patients who have co-existing tumor suppressor gene (TSG) mutations, highlighting a need for intensified strategies to improve outcomes. ACROSS2 (ClinicalTrials.gov identifier NCT04500717) is the first prospective, multicenter, randomized phase 3 study to compare the third-generation EGFR-TKI aumolertinib in combination with carboplatin-pemetrexed versus aumolertinib monotherapy in patients who had NSCLC with EGFR mutations and concomitant TSG mutations. In total, 126 patients were enrolled and randomly assigned to either combination therapy (n = 62) or monotherapy (n = 64). The primary end point was median progression-free survival (PFS). At a median follow-up of 25.3 months, combination therapy significantly prolonged median PFS compared with monotherapy (19.78 vs 16.53 months; hazard ratio, 0.58; 95% confidence interval, 0.34-0.97). Landmark PFS rates at 12, 18, and 24 months were 78.7% versus 65.3%, 67.2% versus 40.8%, and 41.0% versus 29.9%, respectively. Subgroup analyses demonstrated a clear PFS benefit in patients who had co-existing tumor protein p53 (TP53) mutations. Grade 3 or greater adverse events occurred in 25.9% of patients who received combination therapy versus 17.2% of those who received monotherapy; no drug-related deaths were observed. Overall survival data were immature (data maturity, 4%). The ACROSS2 trial provides the first prospective evidence supporting a genotype-directed, chemotherapy-targeted intensification approach favoring aumolertinib plus carboplatin-pemetrexed for this molecularly defined population.
Background: Muscle atrophy, a debilitating condition prevalent in diabetes and extended periods of immobilization, lacks robust therapeutic strategies. This investigation examines ginsenoside Rg1's therapeutic potential in counteracting muscle atrophy under hyperglycemic conditions and in experimental models of immobilization and dietary protein restriction. Methods: C2C12 murine myoblasts were cultured under variable glucose concentrations and treated with or without Rg1. Multiple cellular parameters were evaluated, including cell viability, apoptotic indices, cell cycle distribution, and protein synthesis rates. The activation status of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling cascade and expression of atrophy-related markers were quantified using qRT-PCR and Western blot analyses. In parallel animal studies, rats were subjected to either immobilization or protein restriction protocols, with or without Rg1 administration. Muscle function, mass, and relevant biomarkers were evaluated. Results: Hyperglycemic conditions significantly compromised C2C12 myoblast viability, triggered apoptotic pathways, and disrupted normal cell cycle progression. Rg1 administration effectively attenuated these detrimental effects through enhanced AKT/mTOR pathway activation, upregulation of Myogenin (MyoG) expression, and suppression of atrophy-associated markers. In the rat models, Rg1 supplementation significantly ameliorated muscle deterioration, maintaining muscle mass, contractile force, and exercise tolerance, while simultaneously modulating atrophy signaling pathways and attenuating inflammatory responses. The protective effects of Rg1 were abrogated after the co-treatment with an AKT inhibitor. Conclusion: Ginsenoside Rg1 exhibits significant protective properties against muscle atrophy under hyperglycemic conditions and in experimental models of immobilization and protein restriction, primarily mediated through activation of the AKT/mTOR signaling pathway. These findings establish Rg1 as a promising therapeutic candidate for the treatment of muscle atrophy.
A critical need exists for advanced methods to monitor fluoroquinolones in food products. This work presents a sensitive fluorescence strategy for ofloxacin (OFL) detection in honey utilizing NH2-MIL-101(Cr), a chromium-based metal-organic framework synthesized hydrothermally. The framework exhibits intrinsic peroxidase (POD)-like activity, catalyzing H2O2-mediated oxidation of o-phenylenediamine (OPD) to yield the fluorescent product 2,3-diaminophenazine (DAP). The catalytic activity was notably quenched by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), which scavenges essential reactive oxygen species. Introduction of OFL, however, restores the fluorescence signal via the n → π* charge-transfer (CT) interaction with DDQ, decreasing its effective concentration. This recovery demonstrates a positive correlation with OFL levels. The assay shows a linear response from 25 to 600 μg/kg, a detection limit of 7.36 μg/kg, and recoveries of 81.5%-105.3% in spiked honey samples, with high selectivity against potential interferents. This study provides a novel approach for antibiotic residue analysis and underscores the utility of MOF-based nanozymes in food safety monitoring.
Cerebral infarction is one of the most common ischemic cerebrovascular diseases that can lead to neurological deficits. Remimazolam (RE) is a sedative agent that has been shown to improve neurological disorders. However, the underlying molecular mechanism of RE for the treatment of cerebral infarction remains to be further explored. Oxygen-glucose deprivation/reperfusion (OGD/R) cell model and middle cerebral artery occlusion (MCAO) rat model were constructed. Cell proliferation, apoptosis, and inflammation were evaluated using CCK8 assay, EdU assay, flow cytometry, and ELISA. Ferroptosis-related markers were assessed by commercial kits. The expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4) and tripartite motif-containing 67 (TRIM67) was examined by qRT-PCR or western blot. The interaction between TRIM67 and ACSL4 was confirmed by Co-IP assay. Cerebral injury in MCAO rat model was assessed by histological staining and neurological score. RE treatment enhanced proliferation, repressed apoptosis, inflammation and ferroptosis in OGD/R-induced SK-N-SH cells. RE decreased ACSL4 protein expression, and ACSL4 overexpression could reverse the anti-apoptosis, anti-inflammation and anti-ferroptosis roles of RE in OGD/R-induced SK-N-SH cells. TRIM67 reduced ACSL4 expression by increasing its ubiquitination and degradation. TRIM67 alleviated OGD/R-induced neuronal injury by downregulating ACSL4. RE enhanced TRIM67 protein expression, and TRIM67 knockdown also reversed the neuroprotective effect of RE. Also, RE relieved cerebral injury in the MCAO rat model via promoting TRIM67 expression to repress ACSL4. RE alleviated OGD/R-induced apoptosis, inflammation and ferroptosis through promoting TRIM67-mediated degradation of ACSL4, which provided a possible path for additional research in the therapies of cerebral infarction.
Diabetic nephropathy (DN), the most prevalent microvascular complication of diabetes, affects 20–40
