Glucose Transporter 1-Mediated Transcytosis of Glucosamine-Labeled Liposomal Ceramide Targets Hypoxia Niches and Cancer Stem Cells to Enhance Therapeutic Efficacy.

Tumour hypoxia plays an important role in modulating tumorigenesis, angiogenesis, invasion, immunosuppression, resistance to treatment, and even maintenance of the stemness of cancer stem cells (CSCs). Moreover, the targeting and treatment of hypoxic cancer cells and CSCs to reduce the influence of tumor hypoxia on cancer therapy remains an imperative clinical problem that needs to be addressed. Since cancer cells upregulate the expression of glucose transporter 1 (GLUT1) through the Warburg effect, we considered the possibility of GLUT1-mediated transcytosis in cancer cells and developed a tumor hypoxia-targeting nanomedicine. Our experimental results indicate that glucosamine-labeled liposomal ceramide can be efficiently transported between cancer cells by GLUT1 transporters and substantially accumulated in the hypoxic area in in vitro CSC spheroids and in vivo tumor xenografts. We also verified the effects of exogenous ceramide on tumor hypoxia, including important bioactivities such as upregulation of p53 and retinoblastoma protein (RB), downregulation of hypoxia-inducible factor-1 alpha (HIF-1α) expression, disruption of the OCT4-SOX2 network of stemness, and inhibition of CD47 and PD-L1 expression. To achieve an ideal therapeutic outcome, we combined treatment of glucosamine-labeled liposomal ceramide with paclitaxel and carboplatin, and we found an excellent synergistic effect, with tumor clearance being noted in three-fourths of the mice. Overall, our findings provide a potential therapeutic strategy for the treatment of cancer.

Anxiety Is a Mediator between Heart Rate Variability and Quality of Life in Chronic Obstructive Pulmonary Disease.

Autonomic nervous system (ANS) dysregulation is an important pathophysiological mechanism in patients with chronic obstructive pulmonary disease (COPD). Heart rate variability (HRV) is a common index for ANS, and HRV has been used to explore the association between ANS and clinical illnesses. This study aimed to explore the group differences in HRV, depression, anxiety, and quality of life between participants with COPD and healthy controls (HC group), and whether emotion plays a mediating role between HRV and quality of life in participants with COPD. A total of ninety-six participants with COPD and 59 participants in the HC group completed the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and Saint George's Respiratory Questionnaire (SGRQ). Assessment of spirometry pulmonary function and five minute lead II electrocardiography (ECG) were also performed under the resting baseline. The COPD group had higher depression scores (F = 4.10, p = 0.008), and a lower quality of life (F = 14.44, p < 0.001) and HRV indices (such as standard deviation of RR intervals (F = 5.49, p < 0.05) and low frequency (F = 3.03, p < 0.05)) compared to the HC group. Sympathetic activation was positively correlated with depression (r = 0.312, p < 0.01), anxiety (r = 0.420, p < 0.001), and poor quality of life (r = 0.467, p < 0.001) in the COPD group. After controlling for age and sex, anxiety (ß = 0.585, p < 0.001) and sympathetic activation (ß = 0.231, p < 0.05) positively predicted poor quality of life, and lung function (ß = −0.251, p < 0.01) negatively predicted poor quality of life. Therefore, anxiety is a mediator between sympathetic activation and quality of life. Emotional and HRV screening should be applied to COPD patients in clinical practice, and emotional management or HRV biofeedback training can be used to improve anxiety and HRV for future studies.

Meta-Analysis of the Association between Asbestos Exposure and Esophageal Cancer.

BACKGROUND: We conducted a meta-analysis to quantitatively assess the association between asbestos exposure and esophageal cancer. METHODS: We systematically collected articles from three electronic databases and calculated the pooled standardized mortality rate (SMR) from the meta-analysis. Subgroup analysis according to the type of asbestos exposure, follow-up years, sample size, industry classification, sex, and high-dose exposure was conducted. RESULTS: From 242 studies, 34 cohort studies were included in our meta-analysis. Pooled SMR was positively associated with asbestos exposure and esophageal cancer (pooled SMR = 1.28; 95% confidence interval (CI) 1.19-1.38, p < 0.00001). In the subgroup analysis, (1) chrysolite, (2) four groups with follow-up over ten years, (3) the textile industry and shipyard, (4) both male and female, and (5) eight studies on highest asbestos exposure, all the subgroups showed significantly increased pooled SMRs. CONCLUSION: Asbestos exposure was significantly and positively associated with esophageal cancer, especially chrysolite. Considering the long latency period, we suggest that patients should be followed up for cancer, including esophageal cancer, for over ten years.

The Impact of the Synergistic Effect of Temperature and Air Pollutants on Chronic Lung Diseases in Subtropical Taiwan.

Previous studies have suggested an association between air pollution and lung disease. However, few studies have explored the relationship between chronic lung diseases classified by lung function and environmental parameters. This study aimed to comprehensively investigate the relationship between chronic lung diseases, air pollution, meteorological factors, and anthropometric indices. We conducted a cross-sectional study using the Taiwan Biobank and the Taiwan Air Quality Monitoring Database. A total of 2889 participants were included. We found a V/U-shaped relationship between temperature and air pollutants, with significant effects at both high and low temperatures. In addition, at lower temperatures (<24.6 °C), air pollutants including carbon monoxide (CO) (adjusted OR (aOR):1.78/Log 1 ppb, 95% CI 0.98-3.25; aOR:5.35/Log 1 ppb, 95% CI 2.88-9.94), nitrogen monoxide (NO) (aOR:1.05/ppm, 95% CI 1.01-1.09; aOR:1.11/ppm, 95% CI 1.07-1.15), nitrogen oxides (NOx) (aOR:1.02/ppm, 95% CI 1.00-1.05; aOR:1.06/ppm, 95% CI 1.04-1.08), and sulfur dioxide (SO2) (aOR:1.29/ppm, 95% CI 1.01-1.65; aOR:1.77/ppm, 95% CI 1.36-2.30) were associated with restrictive and mixed lung diseases, respectively. Exposure to CO, NO, NO2, NOx and SO2 significantly affected obstructive and mixed lung disease in southern Taiwan. In conclusion, temperature and air pollution should be considered together when evaluating the impact on chronic lung diseases.

Early phago-/endosomal escape of platinum drugs via ROS-responsive micelles for dual cancer chemo/immunotherapy.

Recent studies have indicated that cancer treatment based on immunotherapy alone is not viable. Combined treatment with other strategies is required to achieve the expected therapeutic effect. Reactive oxygen species (ROS) play an important role in regulating cancer cells and the tumor microenvironment, even in immune cells. However, rigorous regulation of the ROS level within the entire tumor tissue is difficult, limiting the application of ROS in cancer therapy. Therefore, we design an early phago-/endosome-escaping micelle that can release platinum-based drugs into the cytoplasm of macrophages and cancer cells, thereby enhancing the ROS levels of the entire tumor tissue; inducing apoptosis of cancer cells, down-regulation of CD47 expression of cancer cells, polarization of M1 macrophages, and phagocytosis of cancer cells by M1 macrophages; and achieving the dual effect of chemotherapy and macrophage-mediated immunotherapy.

Promotion of mitochondrial biogenesis via the regulation of PARIS and PGC-1α by parkin as a mechanism of neuroprotection by carnosic acid.

BACKGROUND: Impairment of mitochondrial biogenesis is associated with the pathological progression of Parkinson's disease (PD). Parkin-interacting substrate (PARIS) can be ubiquitinated by parkin and prevents the repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α). PURPOSE: This study investigated whether the neuroprotective mechanism of carnosic acid (CA) from rosemary is mediated via the regulation of PARIS and PGC-1α by parkin. METHODS: The Western blotting and RT-PCR were used to determine protein and mRNA, respectively. To investigate the protein-protein interaction of between PARIS and ubiquitin, the immunoprecipitation assay (IP assay) was utilized. Silencing of endogenous parkin or PGC-1α was performed by using transient transfection of small interfering RNA (siRNA). RESULTS: SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) increased PARIS protein, decreased PGC-1α protein, and reduced protein and mRNA of mitochondrial biogenesis-related genes. CA pretreatment reversed the effects of 6-OHDA. By IP assay, the interaction of PARIS with ubiquitin protein caused by CA was stronger than that caused by 6-OHDA. Moreover, knockdown of parkin attenuated the ability of CA to reverse the 6-OHDA-induced increase in PARIS and decrease in PGC-1α expression. PGC-1α siRNA was used to investigate how CA influenced the effect of 6-OHDA on the modulation of mitochondrial biogenesis and apoptosis. In the presence of PGC-1α siRNA, CA could no longer significantly reverse the reduction of mitochondrial biogenesis or the induction of cleavage of apoptotic-related proteins by 6-OHDA. CONCLUSION: The cytoprotective of CA is related to the enhancement of mitochondrial biogenesis by inhibiting PARIS and inducing PGC-1α by parkin. The activation of PGC-1α-mediated mitochondrial biogenesis by CA prevents the degeneration of dopaminergic neurons, CA may have therapeutic application in PD.

Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib.

OBJECTIVES: Gefitinib is currently used as a first-line therapy in patients of advanced non-small cell lung cancer (NSCLC) with susceptible epidermal growth factor receptor (EGFR) mutations. However, treatment outcomes of these patients vary. This study was conducted to evaluate the impact of specific metastatic sites on treatment outcomes of patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving first-line gefitinib, focusing on the impact of liver metastasis. MATERIALS AND METHODS: Between October 2009 and April 2014, patients of stage IV lung adenocarcinoma harboring EGFR mutation in exon 19 or 21, who received first-line gefitinib treatment, were enrolled in two hospitals and followed until December 22, 2014. The impacts of various clinical features, including sex, age, smoking history, performance status, EGFR mutation site, metastatic sites, etc., on progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: A total of 148 patients were eligible for analysis. Patients with liver metastasis on initial diagnosis (n=19) had shorter PFS and OS than those without liver metastasis did (median of PFS, 6.7 vs. 11.2 months, p<0.0001; median of OS, 9.2 vs. 17.5 months, p<0.0001). Multivariable Cox regression analysis showed liver metastasis was an independent poor prognostic factor for PFS (HR=2.939 [95% CI: 1.729-4.997], p<0.0001) and OS (HR=3.300 [95% CI: 1.708-6.373], p=0.0004). CONCLUSION: Liver metastasis predicts poorer PFS and OS in stage IV lung adenocarcinoma patients with susceptible gene mutations receiving first-line gefitinib. Further study is warranted to elucidate the underlying mechanisms and find treatment modalities to improve prognosis of these patients.