Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy.

Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrial-targeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.

Risk factors and prognostic factors for pulmonary large cell neuroendocrine carcinoma with brain metastasis.

BACKGROUND: As the studies regarding the brain metastasis (BM) of pulmonary large cell neuroendocrine carcinoma (LCNEC) are insufficient, the present research aims to describe the risk factors and prognostic factors that are related to cancer-specific survival (CSS) for LCNEC patients with BM. METHODS: The data of LCNEC patients between January 2010 and October 2018 were obtained from the SEER database. Binary logistic regression analyses were utilized to screen the possible risk factors related to BM. Prognostic factors for LCNEC patients with BM were indentified by Cox regression analyses. Moreover, a nomogram was established to predict the 6-, 12-, and 18-month CSS rates. The concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves were utilized to assess the discrimination and reliability of the model. Clinical decision curves (DCAs) were used to evaluate the clinical benefits and utility of our model. RESULTS: Totally, 1875 patients were enrolled, with 294 (15.7%) of them having BM at diagnosis. Multivariate logistic regression analyses revealed that patients with age < 65 (odds ratio, OR = 1.564) and N2 staging (OR = 1.775) had a greater chance of developing BM. Age (≥ 65 vs. < 65: hazard ratio, HR = 1.409), T staging (T1 vs. T0: HR = 4.580; T2 vs. T0: HR = 6.008; T3 vs. T0: HR = 7.065; T4 vs. T0: HR = 6.821), N staging (N2 vs. N0: HR = 1.592; N3 vs. N0: HR = 1.654), liver metastasis (HR = 1.410), primary site surgery (HR = 0.581) and chemotherapy (HR = 0.452) were independent prognostic factors for LCNEC patients with BM. A nomogram prediction model was constructed by incorporating these factors. Using the C-index, calibration curves, ROC curves, and DCAs, we found that the clinical prediction model performed well. CONCLUSION: We described the risk factors and prognostic factors that were associated with CSS for LCNEC patients with BM. The related nomogram was established and validated to help clinicians formulate more rational and effective treatment strategies.

A new hybrid anchoring balloon for direct peroral cholangioscopy using an ultraslim upper endoscope.

BACKGROUND AND AIM: Large impacted or residual invisible common bile duct (CBD) stones after mechanical lithotripsy are challenging. We aimed to evaluate the feasibility and success rate of a new hybrid anchoring balloon-guided direct peroral cholangioscopy (POC) for these conditions using an ultraslim endoscope. METHODS: Sixty-five patients with large or residual invisible CBD stones for direct POC from July 2012 to July 2016 were identified, including six cases in whom an additional interventional procedure was required. There were altogether 55 cases undergoing a procedure with our new device, with a 0.021-inch guidewire tied to a balloon catheter at its distal end in this single-center retrospective study. Technical success, procedure time, diagnostic and therapeutic efficacy of direct POC, and procedure-related complications were studied. RESULTS: The hybrid anchoring balloon-guided direct POC was successful in 51/55 (92.7%) procedures, including 18 cases in whom the conventional wire-guided method failed within 25 min. Mean time for technical success by our method was 12.4 ± 3.4 min. In total, of the 43 cases with previous removal of CBD stones, seven (16.3%) were found to have residual stones ≥4 mm, excluding three cases in whom direct POC failed. In another 25 cases for difficult stones, 24 lithotripsies were carried out, resulting in 23 complete fragmentations. No significant procedure-related complications were observed. CONCLUSION: The new hybrid anchoring balloon device performs well in facilitating direct POC using an ultraslim endoscope for evaluation and extraction of residual or large impacted CBD stones.