Nomogram predicting overall survival of stage IIIB non-small-cell lung cancer patients based on the SEER database.

PURPOSE: We aimed to evaluate the prognostic value of stage IIIB non-small-cell (NSCLC) lung cancer patients and to construct a nomogram to effectively predict their overall survival (OS). METHODS: In total, 4323 patients with stage IIIB NSCLC diagnosed between 1975 and 2018 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Multiple prognostic factors were combined to construct a nomogram for predicting OS of patients with stage IIIB NSCLC. The discrimination and calibration of the nomogram were evaluated by C-indexes and calibration curves. The nomogram was evaluated for predictive ability using receiver operating characteristic (ROC) curves, decision curve analysis curve (DCA), and clinical impact curve (CIC). RESULTS: The nomogram was built on data of 4323 patients with stage IIIB NSCLC and consisted of the following prognostic factors: age, race, sex, primary labeled, pathology, T stage, whether to receive surgery, whether to receive radiotherapy, and whether to receive chemotherapy. The C-index in the training and validation sets for the nomogram was 0.672 (95% CI: 0.661-0.683) and 0.675 (95% CI: 0.656-0.694), respectively. According to scores of the nomogram, patients in the complete set, validation set, and training set were classified into two risk groups, low risk and high risk. CONCLUSIONS: We developed the first validated nomogram to estimate the OS of patients with stage IIIB NSCLC. The nomogram was based on nine prognostic factors and provided an individualized risk estimate of 3-year and 5-year OS survival in patients with stage IIIB NSCLC.

Sodium selenite inhibits proliferation of lung cancer cells by inhibiting NF-κB nuclear translocation and down-regulating PDK1 expression which is a key enzyme in energy metabolism expression.

As a trace element that maintains homeostasis in human body, selenium has significant anti-tumor activity. However, its exact molecular mechanism remains to be elucidated. Sodium selenite (SSe) is the most widely-distributed inorganic selenium in nature. In this study, we selected SSe as the research object to explore its anti-tumor mechanism in lung cancer. In vitro experiment showed that SSe could inhibit the activation of NF-κB signaling pathway, knowing that NF-κB is an important intracellular nuclear transcription factor that regulates the expression of pyruvate dehydrogenase kinase 1 (PDK1), a key energy metabolism switch affecting the survival status of the whole cell.At the same time, Bay11-7082(NF-κB signaling pathway inhibitors) and SSe resulted in phosphorylation of p65 and IκBα, decreased expression of PDK1 and Bcl-2,and increased expression of Bax in lung cancer cells. Our further study demonstrated that the reduction of PDK1 activity inhibited lactate secretion, reduced mitochondrial membrane potential, caused the release of Cytochrome C (Cyto C), activated mitochondrial respiration, and promoted the apoptosis of lung cancer cells. The in vivo experiment revealed that SSe inhibited the activation of NF-κB signaling pathway, decreased the expression of PDK1, and induced lung cancer cell proliferation and apoptosis. All these findings indicated that SSe promoted lung cancer cell apoptosis by inhibiting the activation of NF-κB signaling pathway, down-regulating PDK1 and activating mitochondrial apoptosis pathway.

The association between ethylene oxide exposure and asthma risk: a population-based study.

Ethylene oxide (EO) is a reactive epoxide. However, the association between EO exposure and the risk of developing asthma in humans is unknown. The aim of this study was to investigate the relationship between EO exposure and the risk of developing asthma in the general US population. In this cross-sectional study, data of 2542 patients from the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2016 were obtained and analyzed. Hemoglobin adducts of EO (HbEO) level be used as the main factor for predicting EO exposure. The association between the level of EO exposure and the risk of developing asthma was evaluated with logistic regression models and dose-response analysis curves of restricted cubic spline function. Mediation analysis and linear regression analysis were utilized to evaluate the association between EO exposure and inflammation indicators. According to the quartiles of HbEO level, the patients were divided into four groups. The results indicated that an increased HbEO level was associated with a higher risk of asthma onset. Compared with the lowest quartile, the odds ratio (OR) with the 95% confidence interval (CI) for the highest quartile was 1.960 (95% CI: 1.348-2.849, P = 0.003). After being adjusted for numerous potential confounders, the OR of quartile 4 relative to quartile 1 was 1.991 (95% CI: 1.359-2.916, P = 0.001). Consistent results were also obtained in most subgroup analyses and dose-response analysis curves. In addition, EO levels were positively correlated with the inflammatory indicators (P = 0.006 for WBC, P = 0.015 for lymphocyte, and P = 0.015 for neutrophil). This study revealed a positive correlation between the level of EO exposure and the risk of asthma in a representative US population. In addition, inflammatory response may prove to be a potential biological mechanism underlying EO-induced asthma.

Research Progress and Hotspot Evolution Analysis of Landscape Microclimate: Visual Analysis Based on CNKI and WOS.

With the increasing requirements of healthy habitat environments, landscape microclimates have been widely concerned. To comprehensively grasp the development history and research status of the landscape microclimates in China and other countries, CiteSpace software was used to comparatively analyze and visually present the literature related to landscape microclimates in CNKI and WOS databases for the past 20 years. The results show that: (1) The number of publications on landscape microclimate research shows an increasing trend in China and other countries, and the number of publications increased significantly after 2016. Although the number of publications by Chinese scholars is less than that of foreign scholars, they have developed rapidly in recent years, and their international influence has increased significantly. (2) A positive exchange has been formed among international scholars, and the number of collaborative studies has been increasing. China's microclimate research has formed relatively stable teams that have conducted numerous studies in the fields of urban communities, street greening, and plant communities, respectively. Although the links between research teams and institutions in China and other countries are relatively close, they still need to be further strengthened. (3) In the past decade, the theoretical system of landscape microclimates has been improved, and the research themes have become more concentrated, but it still has remained close to the early basic research. (4) Future research will remain centered on "mitigating the urban heat island effect" and "optimizing human heat perception". New topics such as "biodiversity", "carbon cycle", and "climate change" have been added. In conclusion, the research needs to continue to explore the evaluation system of microclimates and verify the evaluation index of outdoor thermal comfort for human thermal adaptation in different regions. The standards and systems of human habitat adapted to different regional characteristics should be formed.

Mitochondria dysfunction in CD8+ T cells as an important contributing factor for cancer development and a potential target for cancer treatment: a review.

CD8+ T cells play a central role in anti-tumor immunity. Naïve CD8+ T cells are active upon tumor antigen stimulation, and then differentiate into functional cells and migrate towards the tumor sites. Activated CD8+ T cells can directly destroy tumor cells by releasing perforin and granzymes and inducing apoptosis mediated by the death ligand/death receptor. They also secrete cytokines to regulate the immune system against tumor cells. Mitochondria are the central hub of metabolism and signaling, required for polarization, and migration of CD8+ T cells. Many studies have demonstrated that mitochondrial dysfunction impairs the anti-tumor activity of CD8+ T cells through various pathways. Mitochondrial energy metabolism maladjustment will cause a cellular energy crisis in CD8+ T cells. Abnormally high levels of mitochondrial reactive oxygen species will damage the integrity and architecture of biofilms of CD8+ T cells. Disordered mitochondrial dynamics will affect the mitochondrial number and localization within cells, further affecting the function of CD8+ T cells. Increased mitochondria-mediated intrinsic apoptosis will decrease the lifespan and quantity of CD8+ T cells. Excessively low mitochondrial membrane potential will cause the release of cytochrome c and apoptosis of CD8+ T cells, while excessively high will exacerbate oxidative stress. Dysregulation of mitochondrial Ca2+ signaling will affect various physiological pathways in CD8+ T cells. To some extent, mitochondrial abnormality in CD8+ T cells contributes to cancer development. So far, targeting mitochondrial energy metabolism, mitochondrial dynamics, mitochondria-mediated cell apoptosis, and other mitochondrial physiological processes to rebuild the anti-tumor function of CD8+ T cells has proved effective in some cancer models. Thus, mitochondria in CD8+ T cells may be a potential and powerful target for cancer treatment in the future.

Amygdalin Induced Mitochondria-Mediated Apoptosis of Lung Cancer Cells via Regulating NF[Formula: see text]B-1/NF[Formula: see text]B Signaling Cascade in Vitro and in Vivo.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Amygdalin, a natural compound commonly distributed in plants of the Rosaceae species, owns anticancer activity, less side effects, wide source, and relatively low price. Although the apoptosis is a central process activated by amygdalin in cancer cells, the underlying molecular mechanisms through which amygdalin induces the apoptosis of lung cancer cells remain poorly understood. In this research work, amygdalin could suppress the proliferation of lung cancer A549 and PC9 cells by CCK8 assay. Amygdalin significantly promoted the apoptosis of lung cancer A549 and PC9 cells stained with Annexin V-FITC/PI by flow cytometry assay. Furthermore, amygdalin dose-dependently decreased the mitochondrial membrane potential (MMP) with JC-1 dye by flow cytometry. To investigate the underlying molecular mechanisms through which amygdalin induced mitochondria-mediated apoptosis of cancer cells, the differentially-expressed genes with a fold change >2.0 and p < 0.05 were acquired from the cDNA microarray analysis. The results of qRT-PCR further confirmed that the differentially-expressed level of the NF[Formula: see text]B-1 gene was most obviously enhanced in lung cancer cells treated with amygdalin. The results of immunofluorescence staining, Western blotting and siRNA knockdown indicated that amygdalin induced mitochondria-mediated apoptosis of lung cancer cells via enhancing the expression of NF[Formula: see text]B-1 and inactivating NF[Formula: see text]B signaling cascade and further changing the expressions of proteins (Bax, Bcl-2, cytochrome C, caspase 9, caspase 3 and PARP) related to apoptosis, which were further checked by in vivo study of the lung cancer cell xenograft mice model accompanying with immunohistochemical staining and TUNEL staining. Our results indicated that amygdalin might be a potential activator of NF[Formula: see text]B-1, which sheds more light on the molecular mechanism of anticancer effects of amygdalin. These results highlighted amygdalin as a potential therapeutic anticancer agent, which warrants its development as a therapy for lung cancer.

Ejiao ameliorates lipopolysaccharide-induced pulmonary inflammation via inhibition of NFκB regulating NLRP3 inflammasome and mitochondrial ROS.

There is no effective treatment for acute lung injury (ALI) at present. Some studies have reported the anti-inflammatory effect of Ejiao, but no study has addressed the underlying action mechanism. In this study, the CCK8 assay displayed Ejiao had a protective effect against LPS-elicited inflammatory lung epithelial Beas 2B cells (LILEB 2B cells). Beas 2B cells treated with LPS and Ejiao were challenged with NFκB inhibitor Bay11-7082 and ROS scavenger N-acetyl cysteine (NAC) alone and in combination. The results of qRT-PCR, Western blotting and fluorescence labeling experiments using Bay11-7082 and NAC demonstrated Ejiao could significantly decrease the expression of p-p65 and p-IκBα in NFκB signaling pathway and its downstream NLRP3, ASC, Caspase-1 and IL-1ß related to pyroptosis of LILEB 2B cells. Moreover, Ejiao reduced the production of mitochondrial ROS and reversed the change of mitochondrial membrane potential of LILEB 2B cells. Then, HE staining demonstrated Ejiao had a protective effect against the LPS-elicited ALI mouse model (LAMM). Ejiao also dramatically decreased the cell amount and the overall protein concentration of bronchoalveolar lavage fluid in LAMM. Immunohistochemical staining showed Ejiao remarkably reduced the expression of p-p65 and p-IκBα in NFκB signaling pathway and its downstream NLRP3, ASC, Caspase-1 and IL-1ß. The ELISA of IL-1ß revealed Ejiao could dose-dependably decrease the concentration of IL-1ß in lung tissues, serum and BALF of LAMM. Finally, fluorescence labeling demonstrated Ejiao significantly reduced the mitochondrial ROS generation in the lung tissue of LAMM. This finding may afford a novel strategy for the precaution and therapy of ALI.

Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development.

Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .

Melatonin inhibits lung cancer development by reversing the Warburg effect via stimulating the SIRT3/PDH axis.

Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation, and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial functions and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function, among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9, and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels, and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ in the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity with stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.