Mediating role of accelerated aging in the association between depression and mortality risk: findings from NHANES.

OBJECTIVE: To investigate the association between depression, accelerated biological aging, and mortality risk, and to assess whether accelerated aging mediates the relationship between major depression and mortality risk. METHODS: A prospective cohort of 12,761 participants aged 20 years or older from the 2005-2010 cycle of the National Health and Nutrition Examination Survey (NHANES) was analyzed. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9), with scores of ≥ 10 indicating major depression. Accelerated biological aging was measured using phenotypic age acceleration (PhenoAgeAccel). Multivariable linear regression models and subgroup analyses were used to examine the association between depression and accelerated aging, while weighted multivariable Cox proportional hazards regression models and subgroup analyses assessed the impact of major depression on mortality risk. Mediation analysis was performed to assess whether PhenoAgeAccel mediated the relationship between major depression and mortality outcomes. RESULTS: Among the 12,761 adults, the weighted mean age was 46.6 years, with 48.8% being male, and 6.9% experiencing major depression. The results showed a positive association between major depression and PhenoAgeAccel (ß: 0.61, 95% CI: 0.06-1.16). Over a median follow-up duration of 11.3 years (interquartile range: 9.9-13.1), major depression was associated with increased all-cause mortality (HR: 1.35, 95% CI: 1.13-1.62) and cardiovascular mortality (HR: 1.73, 95% CI: 1.18-2.54). However, the relationship with cancer mortality was not statistically significant after full adjustment for confounding factors. The mediation analysis further revealed that PhenoAgeAccel accounted for 10.32% and 5.12% of the associations between major depression and all-cause mortality, and cardiovascular mortality, respectively. CONCLUSION: Depression is associated with accelerated aging and contributes to increased all-cause and cardiovascular mortality. Accelerated aging partially mediates the association between major depression and mortality risk. Our findings highlight the urgent need to incorporate mental health care into public health strategies to delay population aging and reduce mortality risk.

Maternal exposure to ambient ozone and fetal conotruncal heart defects in China: A multicenter cohort study.

BACKGROUND: The relationships between maternal genetic and environmental exposure and conotruncal heart defects (CTDs) have been extensively investigated. Nevertheless, there is limited knowledge regarding the impact of ozone (O3) on the risk of CTDs. OBJECTIVE: To explore the correlation between maternal exposure to O3 and CTDs in China. METHODS: Pregnant women who underwent fetal echocardiography at Beijing Anzhen Hospital between January 2013 and December 2021 were enrolled. Their sociodemographic characteristics and lifestyle information, along with fetal data, were systematically collected. Fetal echocardiography was used to detect CTDs. Maternal exposure to ambient O3 during the embryonic period, the first trimester, the three months preceding the last menstrual period, and the perinatal period was estimated using residential addresses or hospital addresses associated with prenatal visits. The concentration of O3 was divided by quartiles, with the first quartile serving as a reference. Adjusted logistic regression models were employed to examine the associations between every 10 µg/m3 increase or quartile increase in ambient O3 exposure and CTDs. RESULTS: Among 24,278 subjects, 1069 exhibited fetuses with CTDs. Maternal exposure to ambient O3 during three pregnancy periods was associated with increased CTD risk. The adjusted odds ratio (OR) and 95% confidence interval (CI) were 1.271 (1.189-1.360) per 10 µg/m3 increase in O3 during the perinatal period. For each quartile of O3, the risk increased with increasing exposure concentration, particularly during the perinatal period (OR = 2.206 for quartile 2, 2.367 for quartile 3, and 3.378 for quartile 4, all P<0.05). CONCLUSIONS: Elevated maternal exposure to O3 during pregnancy, particularly in the perinatal period, is linked to an increased risk of fetal CTDs. Further longitudinal analyses are needed to validate these results.

Assessing Differences in Lymph Node Metastasis Based Upon Sex in Early Non-Small Cell Lung Cancer.

BACKGROUNDS: Whether sex has any impact on the risk of lymph node (LN) metastasis (LNM) in patients with early-stage non-small cell lung cancer (NSCLC) remains controversial. Therefore, we aimed to objectively compared the risk of LNM between female and male patients with early-stage NSCLC so as to figure out whether sex-different extent of surgery may be justified for treating these patients. METHODS: We retrospectively collected clinical data of patients undergoing lobectomy or segmentectomy with systematic hilar and mediastinal LN dissection for clinical stage IA peripheral NSCLC from June 2014 to April 2019. Both multivariate logistic regression analysis and propensity score-matched(PSM) analysis were applied to compare the risk of LNM between female and male patients. RESULTS: We finally included a total of 660 patients for analysis. In the analysis of unmatched cohorts, there was no significant different rate of LNM (12.4% Vs 13.9%, P=0.556), hilar/intrapulmonary LNM (8.4% Vs 10.7%, P=0.318) and mediastinal LNM(7.9% Vs 7.5%, P=0.851) between female and male patients. In the multivariate analysis, sex was not found to be an independent predictor of LN in these patients. Moreover, in the analysis of well-matched cohorts generated by PSM analysis, there was still no significant different rate of LNM (13.8% Vs 13.4%, P=0.892), hilar/intrapulmonary LNM (9.1% Vs 11.2%, P=0.442) and mediastinal LNM (9.1% Vs 6.5%, P=0.289) between female and male patients. CONCLUSIONS: Sex was not an independent predictor of LNM in early-stage NSCLC and there is no sufficient evidence justifying for sex-different extent of surgical resection for these patients.

Video-Assisted Thoracoscopic Sleeve Lobectomy for Centrally Located Non-small Cell Lung Cancer: A Meta-analysis.

BACKGROUND: Whether video-assisted thoracoscopic surgery (VATS) sleeve lobectomy could be an alternative to traditional thoracotomy sleeve lobectomy in treating centrally located non-small cell lung cancer (NSCLC) remains unclear. Therefore, we conducted the first meta-analysis to compare the effects of VATS sleeve lobectomy with thoracotomy sleeve lobectomy. METHODS: We systematically searched relevant studies from Pubmed, Embase, and Web of Science on May 12, 2020. Data for analysis included short-term outcomes (blood loss, lymph node dissected, operation time, hospital stay, complications) and long-term outcomes (3-year overall survival (OS) and progression-free survival (PFS) rates). We calculated the weighted mean differences (WMDs) for continuous data and risk ratio (RR) for pooling categorical data. RESULTS: We finally included 5 retrospective cohort study consisting of 436 patients. VATS sleeve lobectomy yielded significantly less blood loss (WMD = -37.83; 95% confidence intervals (CIs) = [-58.56, -17.11]; P < 0.001) than thoracotomy sleeve lobectomy and comparable total number of dissected lymph node to thoracotomy sleeve lobectomy (WMD = - 0.07; 95%CI = [-1.14, 0.99]; P = 0.89). However, VATS sleeve lobectomy consumed significantly more operation time than thoracotomy sleeve lobectomy (WMD = 49.00; 95%CI = [14.67, 83.34]; P = 0.005). VATS sleeve lobectomy yielded significantly less postoperative hospital stay time than thoracotomy sleeve lobectomy (WMD = -1.68; 95%CI = [-2.98, -0.39]; P = 0.011) and comparable postoperative complication rate to thoracotomy sleeve lobectomy (RR = 0.84; 95%CI = [0.49, 1.44]; P = 0.52). Moreover, VATS sleeve lobectomy yielded comparable 3-year OS (RR = 1.08; 95%CI = [0.95, 1.22]; P = 0.23) and PFS (RR = 1.15; 95%CI = [0.96, 1.37]; P = 0.13) rates to thoracotomy sleeve lobectomy. No significant heterogeneities were observed. CONCLUSIONS: VATS sleeve lobectomy yielded less surgical trauma than thoracotomy sleeve lobectomy and improved postoperative recovery without compromising oncological prognosis. Even though VATS sleeve lobectomy may consume more operation time, it could be recommended as an alternative to thoracotomy sleeve lobectomy for treating centrally located NSCLC in carefully selected cases.

Empagliflozin alleviates ethanol-induced cardiomyocyte injury through inhibition of mitochondrial apoptosis via a SIRT1/PTEN/Akt pathway.

Ethanol-induced myocardial injury involves multiple pathophysiological processes including apoptosis. Empagliflozin (EMPA), is a novel hypoglycaemic drug which possesses multiple pharmacologically relevant protective effects, including anti-apoptotic, anti-inflammatory and antioxidant effects. However, whether EMPA treatment has a protective effect on ethanol-induced myocardial injury has not been assessed, to the best of our knowledge. Therefore, the aim of this study was to determine the effect of EMPA treatment on ethanol-induced myocardial injury and the underlying mechanism. An ethanol-induced myocardial injury model was established by culturing H9c2 cells treated with 200 mmol/L ethanol for 24 hours, and additional groups of ethanol treated cells were also treated with EMPA with or without SIRT1 inhibitors prior to ethanol treatment. Cell viability and apoptosis were assessed using a CCK-8 assay and flow cytometry, respectively. The expression of apoptosis-related proteins was assessed using western blotting. The results showed that EMPA pretreatment resulted in increased cell viability and a decrease in LDH activity. Moreover, EMPA pretreatment significantly reduced apoptosis of cardiomyocytes, and reduced the expression of cleaved caspase 3. Furthermore, EMPA increased the expression of SIRT1, increased the phosphorylation levels of Akt, and reduced the expression of PTEN. EMPA also reduced ethanol-induced mitochondrial apoptosis, increasing the Bcl-2/Bax ratio and the mitochondrial membrane potential. However, the cardioprotective effects of EMPA were abrogated when cells were pretreated with a SIRT1 inhibitor. In conclusion, EMPA can alleviate ethanol-induced myocardial injury by inhibiting mitochondrial apoptosis via the SIRT1/PTEN/Akt pathway. Therefore, EMPA may be a novel target for treatment of ethanol-induced myocardial injury.

Tanshinone IIA alleviates acute ethanol-induced myocardial apoptosis mainly through inhibiting the expression of PDCD4 and activating the PI3K/Akt pathway.

Myocardial apoptosis contributes to acute ethanol-induced cardiac injury. Improving immoderate apoptosis has become the potential therapeutic strategy for acute ethanol-induced heart damage. Previous studies reported that Tanshinone IIA (Tan IIA), a key ingredient extracted from Salvia miltiorrhiza Bunge, performed an anti-apoptotic role against acute ethanol-related cell damage. In this study, we investigated whether Tan IIA protected the acute ethanol-induced cardiac damage in vivo and in vitro. C57BL/6 mice were treated with acute ethanol and then treated with Tan IIA. The results showed that Tan IIA significantly improved heart function and blocked myocardial apoptosis. Acute ethanol exposure induced H9C2 cells apoptosis. Treatment with Tan IIA abrogated acute ethanol-induced H9C2 cells apoptosis. Mechanistically, Tan IIA inhibited apoptosis by downregulating the programmed cell death protein 4 (PDCD4) expression and activating the phosphoinositide 3-kinase (PI3K)/Akt pathway. Furthermore, PDCD4 overexpression abrogated Tan IIA-mediated anti-apoptotic role and activation on the PI3K/Akt pathway. Interestingly, the PI3K inhibitor (LY294002) application significantly attenuated the main protective effects of Tan IIA. In conclusion, Tan IIA improves acute ethanol-induced myocardial apoptosis mainly through regulating the PDCD4 expression and activating the PI3K/Akt signaling pathway. We provide evidence that Tan IIA is a new treatment approach for acute ethanol-induced heart damage.

Lobe-Specific Lymph Node Dissection for Clinical Early-Stage (cIA) Peripheral Non-small Cell Lung Cancer Patients: What and How?

OBJECTIVE: We investigated the possible lobe-specific lymph node (LN) metastasis pattern of early-stage peripheral non-small cell lung cancers (NSCLC) and define the extent of lobe-specific LN dissection for them. METHODS: We retrospectively collected clinical data of patients undergoing lobectomy or segmentectomy with systematic lymphadenectomy for clinical T1N0M0 peripheral NSCLC from January 2015 to December 2018. The LN metastasis pattern was analyzed by tumor lobe location. RESULTS: A total of 590 patients were included for analysis. The mean number of total dissected LNs was 12.3 ± 5.8 and 8.2 ± 4.1 for total dissected mediastinal LNs. The rate of mediastinal LN metastasis was 9.5%. For cases of upper lobe tumor and lower lobe tumor, 8.8% and 6.0% of them respectively metastasized to the upper LN zone (P = 0.274). However, upper lobe tumors hardly metastasized to the subcarinal (0.3%) and lower (0.3%) LN zones while for lower lobe tumors, the rate of LN metastasis was 10.2% and 5.4% respectively (both P < 0.001). However, all cases (100%) metastasizing from lower lobes to the upper LN zone had a tumor size of 2-3 cm, whereas cases with a tumor size ≤ 2 cm had no metastasis (0%). None of the tumors in the right middle lobe metastasized to the lower LN zone (0%). CONCLUSIONS: A lobe-specific LN metastasis pattern was observed in clinical stage IA peripheral NSCLC. For tumors in upper lobes (≤ 3 cm), there may be no need to dissect lower mediastinal LNs and for tumors in lower lobes (≤ 2 cm), dissecting upper mediastinal LNs may not be required.

Surgical Consideration Based on Lymph Nodes Spread Patterns in Patients with Peripheral Right Middle Non-small Cell Lung Cancer 3 cm or Less.

BACKGROUND: The optimal extent of lung resection and lymph nodes dissection for peripheral early-stage right middle non-small cell lung cancer (NSCLC) still remains controversial. In this study, we analyzed the patterns of lymph nodes metastasis (LNM) of patients with peripheral right middle NSCLC ≤ 3 cm, aiming to provide evidences for surgical choice for early-stage peripheral right middle lobe NSCLC. METHODS: We retrospectively investigated the clinical and pathological data of patients diagnosed with peripheral right middle lobe NSCLC ≤ 3 cm between January 2015 and December 2019. The LNM patterns were analyzed by tumor size. RESULTS: A total of 60 patients were included for analysis. The tumor size was preoperatively divided as follows: ≤ 1 cm (13 patients); > 1 cm but ≤ 2 cm (36 patients); > 2 cm but ≤ 3 cm (11 patients). Fifty-four patients were categorized as N0 group, 1 patient as N1 group, and 5 patients as N2 group. In the upper zone, 3 patients were found to have LNM. In the subcarinal zone, another 3 patients had LNM. But the lymph nodes of all these patients were negative in the lower zone. In station 10, 1 patient (1.67%) was found to have LNM, while in station 11-13, 2 patients (3.33%) were found to have LNM. CONCLUSION: For the right middle lobe peripheral NSCLC ≤ 1 cm, sublobar resection with lymph node sampling may be a feasible treatment. For cancers > 1 cm but ≤ 2 cm, lobectomy with lobe-specific lymph node dissection (especially station 2R and 4R) may be a preferred choice. For tumors > 2 cm but ≤ 3 cm, lobectomy with systematic lymph node dissection may still be the standard of care.

Diabetes mellitus and survival of esophageal cancer patients after esophagectomy: a systematic review and meta-analysis.

Diabetes mellitus (DM) is one of the most common comorbidities in esophageal cancer patients who undergo esophagectomy. It is well established that DM has an unfavorable impact on short-term outcomes of patients with surgically treated esophageal cancer; however, whether DM has any impact on long-term survival of these patients remains unclear. We performed the first meta-analysis to investigate the impact of DM on survival of surgically treated esophageal cancer patients. We searched the following databases systematically to retrieve relevant studies on January 2, 2019: PubMed, Embase, and Web of Science. The main outcome data consisting of 3- and 5-year overall survival (OS) rates and hazard ratios (HRs) of OS were extracted to compare survival between patients with and without DM. We finally included for meta-analysis a total of eight cohort studies involving 5,044 esophageal cancer patients who underwent esophagectomy. We found no significant difference between 3-year (risk ratio [RR] = 0.94, 95% CI: 0.73-1.21; P = 0.65) and 5-year (RR = 0.92, 95% CI: 0.80-1.08; P = 0.31) OS rates between patients with and without DM after esophagectomy. Moreover, DM was not found to be an independent predictor of OS for these patients (HR = 1.10, 95% CI: 0.65-1.84; P = 0.72). Our study suggests that DM appears to have no significant impact on long-term survival of esophageal cancer patients who undergo esophagectomy. To improve the prognosis of these patients, it may be more important to control glycemic level in patients with DM who undergo esophagectomy. However, further high-quality studies with appropriate adjustment for confounding factors are needed to verify this conclusion.

NO66 overexpression rescues ethanol-induced cell apoptosis in human AC16 cardiomyocytes by suppressing PTEN and activating the PI3K/Akt signaling.

Previously, Nucleolar protein 66 (NO66) was reported to be closely associated with alcohol exposure-induced injury. However, the role of NO66 in alcohol-induced cytotoxicity remains unclear. In this study, we explored the potential effect and mechanism of NO66 on ethanol-induced apoptosis in human AC16 cardiomyocytes. The AC16 cell lines with NO66 and phosphatase and tensin homolog (PTEN) overexpression were constructed. Cell counting kit-8 (CCK-8), lactate dehydrogenase (LDH) assay, Annexin V-FITC/PI staining, and flow cytometry were used to evaluate the cell viability, membrane damage, and apoptosis, respectively. Quantitative real-time PCR (qRT-PCR) and western blot analysis were applied to measure mRNA and protein expression. The results showed that acute ethanol exposure markedly augmented cytotoxicity and reduced NO66 level in AC16 cardiomyocytes. Overexpression of NO66 partially reversed ethanol-induced apoptosis. NO66 upregulation reversed the decrease in phosphorylation of protein kinase B (Akt) and B-cell lymphoma-2/Bcl-2-associated x (Bcl-2/Bax) ratio and the increase in PTEN, p53, and caspase-3 activity induced by ethanol treatment. Meanwhile, the application of PI3K inhibitor (LY294002) and PTEN overexpression attenuated the inhibition efficiency of NO66 on cell apoptosis. In addition, PTEN overexpression weakened the effect of NO66 on PI3K/Akt activation, without affecting the level of NO66. Our data suggested that NO66 overexpression might play an anti-apoptotic role in ethanol-induced cell injury via reducing PTEN and upregulating the PI3K/Akt pathway.

[Three Dimensional Measurement of the Space Distance Between the Hilum and Clinical Stage T 1 Non-small Cell Lung Cancer and Its Relationship with Lymph Node Metastasis].

OBJECTIVE: The aim of this study was to develop a novel method to quantitatively define the tumor location of clinical stage T 1 (cT 1) non-small cell lung cancer (NSCLC) and to evaluate its impact on lymph node metastasis in a large cohort group. METHODS: We developed a novel method to transform the datum of 2D CT scans to 3D datum and to quantitatively measure the distance between the tumor and hilum through the Pythagorean theorem. Multiple logistic regression analysis was applied to identify the risk factors associated with lymph node metastasis. RESULTS: A total of 399 patients (166 male and 233 female) with cT 1 NSCLC were enrolled in this study. The mean age was (57.48±10.88) yr., the mean distance between tumor and hilum was (5.44±1.96) cm, and the mean tumor diameter was (1.77±0.65) cm. Patients were divided into lymph node positive group (N + group) and lymph node negative group (N － group). By multiple logistic regression analysis, we identified 4 risk variables associated with lymph node metastasis. Gender (odds ratio ( OR)=2.118， P=0.022), distance between tumor and hilum ( OR=0.843， P=0.040), differentiation (moderate vs. high， OR=15.547， P=0.008；poor vs. high， OR=70.749， P=0.000), and cancer embolus ( OR=24.769， P=0.004) were independent risk variables associated with lymph node metastasis. CONCLUSION: Distance between tumor and hilum was identified as an independent risk factor associated with lymph node metastasis in cT 1 NSCLC.

Lung Adenocarcinoma has a Higher Risk of Lymph Node Metastasis than Squamous Cell Carcinoma: A Propensity Score-Matched Analysis.

BACKGROUND: Controversy still exists in which subtype of non-small-cell lung cancer [squamous cell carcinoma (SCC) or adenocarcinoma] is more likely to have lymph node (LN) metastasis. The aim of this study is to compare the pattern of LN metastasis in two cohorts of matched patients surgically treated for SCC or adenocarcinoma. METHODS: A retrospective analysis of patients undergoing lobectomy or segmentectomy with systematic lymphadenectomy without preoperative treatment for lung SCC or adenocarcinoma was conducted in this study. Data for analysis consisted of age, gender, tumor size, lobe-specific tumor location, tumor location (peripheral or central), and pathologic findings. We conducted the propensity score-matched (PSM) analysis to eliminate potential bias effects of possible confounding factors. RESULTS: From January 2015 to December 2016 in our department, we finally included a total of 387 patients (including 63 patients with SCC and 324 patients with adenocarcinoma) for analysis. For the unmatched cohort, there was no sufficient evidence of significantly different number of positive LNs (P = 0.90) and rate of LN metastasis (P = 0.23) between SCC patients and adenocarcinoma patients. However, potential confounding factors, for example gender, tumor size, tumor location, tumor differentiation, and total number of dissected LNs, were significantly different between patients with SCC and those with adenocarcinoma. In the analysis of matched cohort after PSM analysis, those above confounding factors were comparable between the two groups. However, patients with adenocarcinoma had significantly more mean positive LNs (2.2 and 0.7; P = 0.008) and a higher rate of LN metastasis (53% and 29%; P = 0.016) than those with SCC. CONCLUSIONS: Lung adenocarcinoma had a higher risk of LN metastasis than SCC, suggesting that different therapeutic modalities may be indicated for the two different subtypes of lung cancer.

Preoperative sarcopenia is a predictor of poor prognosis of esophageal cancer after esophagectomy: a comprehensive systematic review and meta-analysis.

The impact of preoperative sarcopenia on long-term survival of esophageal cancer patients after esophagectomy remains unclear. We conducted an updated meta-analysis focusing on current topic comprehensively. We systematically searched relevant studies investigating the impact of preoperative sarcopenia on survival of patients with surgically treated esophageal cancer in PubMed, Embase, and Web of Science up to July 20, 2018. Data of 3-year and 5-year overall survival (OS) rates as well as hazard ratio (HR) of OS and disease-free survival (DFS) were collected for analysis by using the STATA 12.0 package. Finally, a total of 11 cohort studies consisting of 1520 patients (795 sarcopenic patients and 725 nonsarcopenic patients) were included for analysis. Our meta-analysis showed that patients with sarcopenia had a significantly lower 3-year (51.6% vs. 65.4%, P < 0.001) and 5-year OS rate (41.2% vs. 52.2%, P = 0.018) than those without sarcopenia. Sarcopenia was found to be an independent predictor of poor OS (HR = 1.58; 95% confidence interval (CI) = [1.35, 1.85]; P < 0.001) and DFS (HR = 1.46; 95% CI = [1.12, 1.90]; P = 0.005) in esophageal cancer patients after esophagectomy. No obvious heterogeneities or publication bias were observed during analysis. Therefore, patients with sarcopenia had a significantly worse prognosis than those without after surgical resection of esophageal cancer. Preoperative sarcopenia is an independent unfavorable prognostic factor for esophageal cancer patients after esophagectomy. However, high-quality studies with appropriate adjustments for confounding factors are needed to confirm our conclusions.

The Role of Surgery in Treating Resectable Limited Disease of Esophageal Neuroendocrine Carcinoma.

BACKGROUND: Esophageal neuroendocrine carcinoma (NEC) is a rare malignant tumor. The role of surgery in resectable limited disease of esophageal NEC remains unclear. How to select a specific group of limited disease of esophageal NEC who might benefit from surgery remains to be answered. METHODS: Patients undergoing esophagectomy for resectable limited disease of esophageal NEC in our department from January 2007 to June 2015 were analyzed. TNM staging system was applied to describe those patients, and according to their different long-term prognosis after surgery, those patients were subgrouped into surgery response limited disease (SRLD) group and surgery non-response limited disease (SNRLD) group. Both univariate and multivariate analyses were applied to identify potential prognostic factors. RESULTS: A total of 72 patients with resectable limited disease of esophageal NEC were identified for analysis. The median survival time of those patients was 21.5 months. There was no significant survival differences among stage I, stage IIA, and stage IIB patients, but all these patients had significantly longer survival than stage III patients. Therefore, stage I, stage IIA, and stage IIB patients were aggregated together as SRLD group, and stage III patients were aggregated as SNRLD group. SRLD patients obtained significantly longer survival than SNRLD patients in both univariate analysis and multivariate analysis. Moreover, adjuvant therapy could significantly benefit SRLD patients (P = 0.004) but could not benefit SNRLD patients (P = 0.136). CONCLUSIONS: Different responses to surgery existed in resectable limited disease of esophageal NEC indicating the need of further subgrouping for those patients. The resectable limited disease of esophageal NEC could be further subgrouped into SRLD group and SNRLD group according to the TNM staging system.