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Abstract Background Lung cancer is a leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) comprises 85% of cases with rising incidence among never-smokers (NS). This study seeks to compare clinical, imaging, pathology, and outcomes between NS and ever-smokers (S) NSCLC patients to identify significant differences if any. Methods Retrospective cohort study of 155 NSCLC patients (88 S and 67 NS). The main predictor was smoking. Clinical, imaging, and pathology findings were evaluated at initial biopsy for staging. The primary outcome was all-cause mortality, and the secondary outcome was 12-month progression-free survival. Results Imaging: NS and S had similar nodule size (0.81), calcification (> 0.99), and invasion of adjacent structures (> 0.99) (p values). NS slightly trended to more commonly involve the RLL vs S the RUL (p = 0.11). NS had higher numbers of extrathoracic metastases at initial biopsy for staging (p = 0.055). Pathology: NS more commonly had adenocarcinoma compared to S, who had equal numbers of adenocarcinoma and squamous cell carcinoma (p = 0.001). Rates of lymphovascular and pleural invasion were similar (p = 0.84 and 0.28). Initial staging: NS were more often initially diagnosed with stage IV disease (p = 0.046), positive nodal disease (p = 0.002), and metastatic disease (p = 0.004). Outcomes: S had a non-significant trend toward worse 12-month progression-free survival (rate ratio = 1.31, p = 0.31; HR = 1.33, p = 0.28). NS and S had similar 1-year all-cause mortality (HR = 1.06, p = 0.90). S had nearly double the risk of all-cause mortality in 5 years (HR = 1.73, p = 0.056) and 10 years (HR = 1.77, p = 0.02). Median survival was 6.6 years for NS and 3.9 years for S, with NS surviving 2.7 years longer on average (p = 0.045). Conclusions CT nodule features were similar in NS and S. NS more often had metastatic adenopathy, distant metastases, and stage IV disease at initial biopsy. Despite similar 12-month progression-free survival and 1-year all-cause mortality, S had nearly double the risk of mortality in the first 5 and 10 years post-diagnosis. Trial registration Retrospectively registered.

Abstract Background Lung cancer is a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) comprising 85% of cases. Due to the lack of early clinical signs, metastasis often occurs before diagnosis, impacting treatment and prognosis. Cardiovascular disease (CVD) is a common comorbidity in lung cancer patients, with shared risk factors exacerbating outcomes. Methods This study investigates the association between coronary artery calcium (CAC) scores, major adverse cardiovascular events (MACE), and survival outcomes in NSCLC patients, utilizing positron emission tomography-computed tomography (PET-CT) for CAC scoring. A retrospective cohort study of 154 NSCLC patients (mean age 66.3 years, 52% women) at the University of Utah (2005–2022) was conducted. Baseline PET-CT or CT imaging was used to quantify CAC scores, categorized into five risk levels. Cox proportional hazards and logistic regression analyses assessed the impact of CAC scores on survival and cardiovascular events, adjusting for confounders such as age, gender, and smoking status. Results Higher CAC scores were significantly associated with increased MACE, acute myocardial infarction (MI), and poorer overall survival. The severe risk CAC score group had significantly lower survival (p = 0.022). Logistic regression revealed a strong association between higher CAC scores and MI incidence (moderate: OR = 13.8, severe: OR = 21.2) and MACE (severe: OR = 10.2). Smoking history was a significant predictor of overall survival (p = 0.006). Conclusion CAC scoring via PET-CT provides valuable prognostic insights in NSCLC patients, highlighting the need for integrated cardiovascular risk management in this population. Further research and advanced technologies like machine learning could enhance CAC scoring application in clinical practice. Trial registration Retrospectively registered.

Abstract Background TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 expression and formation of C-terminal TDP-43 fragmentation and accumulation in the cytoplasm. Recent studies have shown that TDP-43 can accumulate in RNA stress granules (SGs) in response to cell stresses and this could be associated with subsequent formation of TDP-43 ubiquinated protein aggregates. However, the initial mechanisms controlling endogenous TDP-43 accumulation in SGs during chronic disease are not understood. In this study we investigated the mechanism of TDP-43 processing and accumulation in SGs in SH-SY5Y neuronal-like cells exposed to chronic oxidative stress. Cell cultures were treated overnight with the mitochondrial inhibitor paraquat and examined for TDP-43 and SG processing. Results We found that mild stress induced by paraquat led to formation of TDP-43 and HuR-positive SGs, a proportion of which were ubiquitinated. The co-localization of TDP-43 with SGs could be fully prevented by inhibition of c-Jun N-terminal kinase (JNK). JNK inhibition did not prevent formation of HuR-positive SGs and did not prevent diffuse TDP-43 accumulation in the cytosol. In contrast, ERK or p38 inhibition prevented formation of both TDP-43 and HuR-positive SGs. JNK inhibition also inhibited TDP-43 SG localization in cells acutely treated with sodium arsenite and reduced the number of aggregates per cell in cultures transfected with C-terminal TDP-43 162-414 and 219-414 constructs. Conclusions Our studies are the first to demonstrate a critical role for kinase control of TDP-43 accumulation in SGs and may have important implications for development of treatments for FTD and ALS, targeting cell signal pathway control of TDP-43 aggregation.