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The prognosis of non-small cell lung cancer (NSCLC) is poor, particularly for patients with metastatic disease. Numerous efforts have been made to improve the prognosis of these patients; however, only a small number of studies have explored the occurrence rate and prognostic value of different patterns of distant metastasis (DM) in NSCLC systematically. To investigate these, information from patients diagnosed with NSCLC between 2010 and 2014 was collected from the Surveillance, Epidemiology and End Results database. Survival rate comparisons were performed using Kaplan-Meier analysis and log-rank tests. A Cox proportional hazard model was established to determine factors associated with improved overall survival (OS) and cancer-specific survival (CSS). The present study revealed that the most common site of single metastasis occurrence was bone, and the least common was the liver for NSCLC. As for multi-site metastases, the most common two-site metastasis involved bone and lung, and the most common three-site metastasis involved bone, liver and lung. As for NSCLC subtypes, large cell carcinoma (LCC) exhibited more specific metastatic features. The most common single metastatic site was the brain for patients with LCC, and the most common two-site metastatic combination was bone and liver. Patients with isolated liver metastasis exhibited the worst OS and CSS among patients with single metastasis. Furthermore, for patients with multi-site metastases, metastases involving the liver were associated with the worst OS and CSS among various combinations. To the best of our knowledge, the present study is the first to investigate the occurrence rate and prognostic value of different metastatic patterns of site-specific DM for NSCLC using a large population-based dataset. The findings of the present study may have vital implications for classifying patients with advanced NSCLC, thus laying a foundation for individualized precise treatment.

Erlotinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Overcoming erlotinib resistance is crucial to improve the survival of advanced non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. It is also an important clinical problem that urgently needs a solution. In this study, we explored strategies to overcome erlotinib resistance from the perspective of energy metabolism. SIRT6 is a histone deacetylase. Here, we found that high expression of SIRT6 is associated with poor prognosis of lung adenocarcinoma, especially in EGFR-mutated NSCLC patients. The next cell experiment found that SIRT6 expression increased in erlotinib-resistant cells, and SIRT6 expression was negatively correlated with the sensitivity of NSCLC to erlotinib. Inhibition of SIRT6 promoted erlotinib-induced apoptosis in erlotinib-resistant cells, and glycolysis in drug-resistant cells was also inhibited. Functional studies have shown that SIRT6 increases glycolysis through the HIF-1α/HK2 signaling axis in drug-resistant cells and inhibits the sensitivity of NSCLC cells to erlotinib. In addition, the HIF-1α blocker PX478-2HCL attenuated the glycolysis and erlotinib resistance induced by SIRT6. More importantly, we confirmed the antitumor effect of SIRT6 inhibition combined with erlotinib in NSCLC-bearing mice. Our findings indicate that the cancer metabolic pathway regulated by SIRT6 may be a new target for attenuating NSCLC erlotinib resistance and has potential as a biomarker or therapeutic target to improve outcomes in NSCLC patients.

Objectives Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) has significant therapeutic efficacy in non‐small‐cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long‐term efficacy of EGFR‐TKI. Our study aimed to investigate the role of ras‐associated binding protein 25 (Rab25) in mediating EGFR‐TKI resistance in NSCLC. Materials and Methods Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell‐counting kit‐8 and flow cytometry. The interaction between Rab25 and β1 integrin was confirmed by co‐immunoprecipitation. Results Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with β1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane‐β1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/β‐catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR‐TKI treatment in NSCLC patients. Conclusions Rab25 mediates erlotinib resistance by activating the β1 integrin/AKT/β‐catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR‐TKI.

Objective Vitamin D plays a critical role in the prevention and management of osteoporosis. However, there is an ongoing debate regarding the most effective vitamin D supplementation strategies for maintaining optimal bone mineral density (BMD) levels in adults. This study sought to establish the correlation between serum 25-hydroxyvitamin D [25(OH)D] levels and total BMD in a substantial population sample. Methods Data from the National Health and Nutrition Examination Survey (NHANES) for the 2011–2018 cycles, encompassing 11,375 adult participants, were analyzed. The primary variables of interest were serum 25(OH)D levels and BMD. A multivariable logistic regression model was utilized to account for relevant variables associated with these correlations. Results A U-shaped relationship between serum 25(OH)D levels and BMD was observed. In males, a significant positive association was identified for 25(OH)D levels below 84.8 nmol/L ( p  < 0.0001), while levels above this threshold showed no significant correlation ( p  = 0.3377). In females, those with 25(OH)D levels below 31.4 nmol/L exhibited a significant positive association with BMD ( p  = 0.0010), but this association weakened and became marginally significant above this threshold ( p  = 0.0650). Conclusions For adult males, the optimal serum 25(OH)D level is 84.8 nmol/L, beyond which higher levels do not lead to increased BMD. A deficiency threshold for adult females should be above 31.4 nmol/L, as lower 25(OH)D levels are not conducive to BMD. These findings underscore the importance of maintaining appropriate vitamin D levels for bone health in both genders.

Background Traditional neuromodulation strategies show promise in enhancing cognitive abilities in bipolar disorder (BD) but remain suboptimal. This study introduces a novel multimodal neurostimulation (MNS) protocol to improve therapeutic outcomes. Methods The novel MNS protocol used individualized diffusion tensor imaging (DTI) data to identify fiber tracts between the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex. The highest structural connectivity point is selected as the individualized stimulation site, which is then targeted using a combination of optimized transcranial alternating current stimulation (tACS) and robot-assisted navigated repetitive transcranial magnetic stimulation (rTMS). A double-blind randomized controlled trial was conducted to investigate the clinical efficacy of this innovative neuromodulation approach on cognitive abilities in stable-phase BD patients. One hundred BD patients were randomly assigned to four groups: group A (active tACS-active rTMS (MNS protocol)), group B (sham tACS-active rTMS), group C (active tACS-sham rTMS), and group D (sham tACS-sham rTMS). Participants underwent 15 sessions over 3 weeks. Cognitive assessments (THINC integrated tool) were conducted at baseline (week 0) and post-treatment (week 3). Results Sixty-six participants completed all 15 sessions. Group A (MNS protocol) showed superior improvements in Spotter CRT, TMT, and DSST scores compared to other groups at week 3. Only group A exhibited significant activation in the left frontal region post-MNS intervention. The novel MNS protocol was well tolerated, with no significant side effects observed. Conclusions The study indicates that DTI-guided multimodal neurostimulation mode significantly improves cognitive impairments and is safe for stable-phase BD patients. Trial registration ClinicalTrials.gov identifier: NCT05964777.