Lung-specific exosomes for doxorubicin delivery in lung adenocarcinoma therapy.

Doxorubicin (DOX) could be utilized to treat lung adenocarcinoma (LUAD), while dose-limiting cardiotoxicity limits its clinical utilization. MDA-MB-231 cell-derived exosomes show lung-specific organotropism features. In this study, we aimed to explore the potential of MDA-MB-231 cell-derived exosomes in DOX specific delivery to the lung. MDA-MB-231 cell-derived exosomes were coincubated with to construct for the doxorubicin delivery system (D-EXO). Exosomes labeled with fluorescein isothiocyanate were incubated with A549 cells or 293T cells, and the engulf and the mean intensity of the fluorescence were detected with immunofluorescence and flow cytometry assay. Cell viability was detected with cell counting kit-8 (CCK-8), and cell migration was determined by scratch test. The protein expression was detected by Western blot assay. A549 cell line-derived xenograft mouse model was constructed to examine the treatment effect of D-EXO. MDA-MB-231 cell-derived exosomes could be specially taken up by A549 cells with diminished cell viability but not engulfed by 293T cells. D-EXO inhibited A549 cell migration, and upregulated the protein expression of caspase 3 and cleaved caspase 3 expression, while did not show any inhibition on 293T cells. In vivo orthotopic xenotransplantation model indicated that D-EXO inhibited tumor growth characterized by diminished tumor weight and improved survival rate. No significant change in body weight was observed after the D-EXO treatment. In conclusion, D-EXO proposed in this study could be utilized to treat LUAD with lung-specific delivery effects to improve the survival rate.

Longitudinal analysis of quality of life in primary lung cancer patients with chlamydia pneumoniae infection: a time-to-deterioration model.

BACKGROUND: Chlamydia pneumoniae (Cpn) IgG and IgA has been strongly linked to lung cancer, but its impact on patients' quality of life remains unclear. Our objective was to investigate the relationship between pre-treatment Cpn IgG and IgA and time to deterioration (TTD) of the HRQoL in patients with primary lung cancer. METHODS: A prospective hospital-based study was conducted from June 2017 to December 2018, enrolling 82 patients with primary lung cancer admitted to the First Affiliated Hospital of Fujian Medical University for questionnaire surveys. Cpn IgG and IgA was detected by microimmunofluorescence method. HRQoL was assessed at baseline and during follow-up using the EORTC Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13). HRQoL scores were calculated using the QoLR package, and TTD events were determined (minimum clinically significant difference = 5 points). Cox regression analysis was used to evaluate the effect of Cpn IgG and IgA on HRQoL. RESULTS: We investigated the relationship between Cpn IgG and IgA and quality of life in patients with primary lung cancer. The study was found that 75.61% of cases were Cpn IgG + and 45.12% were Cpn IgA + . Cpn IgA + IgG + was 41.46%. For EORTC QLQ-C30, Physical function (PF) and Pain (PA) TTD events on the functional scale and Symptom scale were the most common during follow-up. After adjusting for gender and smoking status, Pre-treatment Cpn IgA + was found to signifcantly delay TTD of Physical functioning(HR = 0.539, 95% CI: 0.291-0.996, P = 0.048). In addition, Cpn IgG + before treatment significantly delayed TTD in Emotional functioning (HR = 0.310, 95% CI: 0.115-0.836, P = 0.021). For EORTC QLQ-LC13, deterioration of dyspnea (LC-DY) was the most common event. However, Cpn IgG and IgA before treatment had no effect on the TTD of EORTC QLQ-LC13 items. CONCLUSIONS: According to EORTC QLQ-C30 and EORTC QLQ-LC13, Cpn IgA delayed TTD in Physical functioning and Cpn IgG delayed TTD in Emotional functioning.

SiO2/hyaluronic acid nanoparticles carry CaO2, DOX and p53 plasmid to effectively achieve ion interference/chemical/gene multimodal therapy of lung cancer.

Monotherapy of lung cancer shows limited therapeutic effects due to its poorly targeted enrichment and low bioavailability. Using nanomaterials as carriers to form drug delivery systems has become a popular method to improve the targeting of anticancer drug therapy and patients' safety. However, the uniformity of the loaded drugs and the unsatisfactory effects are still the bottleneck in this field up to now. This study aims to construct a novel nanocomposite carrying 3 different types of anticancer drugs to enhance treatment efficacy. Herein, mesoporous silica (MSN) with high loading rate was constructed by dilute sulfuric acid thermal etching as the framework. Hyaluronic acid (HA) was loaded with CaO2, p53 and DOX to construct nanoparticle complexes-SiO2@CaO2@DOX@P53-HA. First, MSN was proved to be a porous sorbent with a mesoporous structure through BET analysis. The images obtained from the uptake experiment clearly show the gradual enrichment of the DOX and Ca2+ within the target cell. For in vitro experiments, the pro-apoptotic effects of SiO2@CaO2@DOX@P53-HA significantly increased compared to that of the single-agent group at different time points. Furthermore, in the tumor-bearing mouse experiment, the tumor volume was remarkably inhibited in the SiO2@CaO2@DOX@P53-HA group compared to that in the single-agent group. By observing the pathological sections of the euthanized mice, it is obvious that the tissues of the mice treated with the nanoparticles were more intact. Based on these beneficial results, it is believed that multimodal therapy is a meaningful treatment strategy for lung cancer.

Upregulation of ITGB6 in primary palmar hyperhidrosis.

BACKGROUND: The regulatory effect of integrin ß6 (ITGB6) on sweat gland cells in primary palmar hyperhidrosis (PPH) remains unclear. OBJECTIVES: This study investigated the involvement of ITGB6 in the pathogenesis of PPH. MATERIAL AND METHODS: Sweat gland tissues were collected from PPH patients and healthy volunteers. The expression levels of ITGB6 in sweat gland tissues were detected with quantitative polymerase chain reaction (qPCR), western blot and immunohistochemical staining. Sweat gland cells were extracted from PPH patients, and identified with immunofluorescence staining of CEA and CK7. The expression of aquaporin 5 (AQP5) and Na-K-Cl cotransporter 1 (NKCC1) in primary sweat gland cells that overexpress ITGB6 were also detected. Through a series of bioinformatic methods, differentially expressed genes in sweat gland tissues were examined and validated via comparing PPH samples and controls. The key proteins and biological functions enriched in PPH were determined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. RESULTS: The ITGB6 was upregulated in sweat gland tissues of PPH patients compared to that of healthy volunteers. The CEA and CK7 were positively expressed in sweat gland cells extracted from PPH patients. The overexpression of ITGB6 upregulated AQP5 and NKCC1 protein expression in the sweat gland cells of PPH patients. A total of 562 differentially expressed mRNAs were identified using high-throughput sequencing (394 upregulated, 168 downregulated), which were mainly active in the chemokine and Wnt signaling pathways. After verification with qPCR and western blot, the overexpression of ITGB6 significantly upregulated CXCL3, CXCL5, CXCL10, and CXCL11, and downregulated Wnt2 mRNA and protein expression in sweat gland cells. CONCLUSIONS: The ITGB6 is upregulated in PPH patients. It may be involved in the pathogenesis of PPH by upregulating AQP5, NKCC1, CXCL3, CXCL5, CXCL10, and CXCL11, and downregulating Wnt2 expression in sweat glands.

Knockdown of deoxythymidylate kinase suppresses progression and epithelial-mesenchymal-transition of lung adenocarcinoma via STAT3 signaling.

Current research has shown that inhibiting deoxythymidylate kinase (DTYMK) can significantly reduce development of lung cancer without liver kinase B1. However, its underlying regulatory mechanism is still unclear. We therefore aimed to investigate whether DTYMK inhibitors could suppress lung adenocarcinoma (LUAD) progression. In this study, human tissues, A549 cells, and xenograft tumors were used to explore the regulation and mechanism of DTYMK on LUAD cell proliferation and migration. Meanwhile, YMU1 (a DTYMK inhibitor) was applied to A549 cells and xenograft tumors to investigate its potential as a drug for LUAD. DTYMK was overexpressed in LUAD tissues and correlated with tumor stage. Knockdown of DTYMK suppressed cell viability, migration, and invasion. In addition, the activation of signal transducers and activators of transcription 3 (STAT3) was repressed upon DTYMK inhibition. YMU1 showed the same effect as DTYMK knockdown in vivo and in vitro. DTYMK plays an important role in progression of LUAD through the STAT3 signaling pathway. YMU1 may have the potential to inhibit the development of LUAD.NEW & NOTEWORTHY DTYMK plays an important role in progression of LUAD through the STAT3 signaling pathway. YMU1 may serve as a novel drug to suppress the development of LUAD.

Transareolar uniportal thoracoscopic extended thymectomy for patients with myasthenia gravis.

Background: Transareolar uniportal thoracoscopic extended thymectomy (TUTET) has not been previously reported. We attempted to assess the feasibility and safety of TUTET for male myasthenia gravis (MG) patients. Patients and methods: From February 2013 to February 2020, 46 men with MG underwent TUTET. All patients were followed up for 12-84 months postoperatively by clinic visits or telephone/e-mail interviews. Results: All surgeries were completed successfully, with an average operation time of 72.6 min. The mean length of transareolar uniportal incision was 3.0 ± 0.4 cm, and the mean postoperative cosmetic score was 3.1 ± 0.5 at discharge. Three months postoperatively, no patients had an apparent surgical scar on the chest wall or complained of postoperative pain. Substantial amelioration of the disease was achieved in a short period, and several benefits were clear. At the 1-year follow-up, all patients showed a good cosmetic effect and high satisfaction. Conclusions: TUTET is an effective and safe way for men with MG. The uniportal incision is hidden in the areola with sound cosmetic effects. We believe that TUTET is an acceptable procedure for extended thymectomy.

Antagonist of Chrna1 prevents the pathogenesis of primary focal hyperhidrosis.

BACKGROUND: Primary focal hyperhidrosis (PFH) is an autonomic neurological disease in which exocrine glands are oversecreted due to autonomic dysfunction of the sympathetic nervous system. Chrna1 promotes the pathogenesis of PFH. We aimed to check if downregulating of Chrna1 by cisatracurium could alleviate the symptoms of PFH. METHODS: The effect of cisatracurium in a hyperhidrosis mice model induced by pilocarpine hydrochloride was monitored for sweat gland secretion, and ultrastructural sweat secretory granules in sweat glands were analyzed. Meanwhile, markers of hyperhidrosis were checked, and release of Bdnf and Nrg1 from sympathetic ganglia axon was tested. Furthermore, the mechanism of cisatracurium function was evaluated in vitro using HEK293 expressing Chrna1. Finally, the effect of cisatracurium was determined in the hyperhidrosis mice model with overexpression or downregulation of Chrna1. RESULTS: In hyperhidrosis mice, pretreatment with cisatracurium effectively inhibited sweat secretion, along with fewer particle secretion in sweat glands. The molecular markers of hyperhidrosis (Aqp5 and Cacna1c) were inhibited by cisatracurium, acetylcholine (Ach) level in serum was found decreased. Neurotrophic factors (Bdnf and Nrg1) secreted by sympathetic axon activation were also inhibited. At last, it was confirmed that cisatracurium could not alter the gene or protein expression level of Chrna1, but could block the ion channel. Overexpression of Chrna1 abolished the effect of cisatracurium on hyperhidrosis, while cisatracurium could not function more in siChrna1-treated mice. CONCLUSION: Our results suggested that pretreatment of cisatracurium could alleviate hyperhidrosis in mice, probably through blocking the ion channel function of Chrna1.

LncRNA NRON negatively regulates cisplatin-induced cell apoptosis via downregulating miR-31 in esophageal squamous cell carcinomas.

LncRNA non-coding repressor of NFAT (NRON) can promote bladder cancer and suppress liver cancer, while its role in esophageal squamous cell carcinoma (ESCC) is unknown. We analyzed its involvement in ESCC. NRON and miR-31 expression in plasma before and after cisplatin treatment was detected using RT-qPCR. The correlation between NRON and miR-31 was analyzed by linear regression. Expression of NRON and miR-31 in ESCC cells was also analyzed using RT-qPCR. Overexpression of NRON and miR-31 was achieved in ESCC cells to explore their interaction. Cell apoptosis induced by cisplatin was studied using cell apoptosis assay. NRON was highly expressed in ESCC and further upregulated after cisplatin treatment. MiR-31 was downregulated in ESCC and inversely correlated with NRON. In ESCC cells, NRON overexpression decreased miR-31 expression, while miR-31 failed to alter NRON expression. Cisplatin treatment promoted NRON expression and inhibited miR-31 expression. Under cisplatin treatment, cell apoptosis was inhibited after NRON overexpression and increased after miR-31 overexpression. Moreover, NRON inhibited the effect of miR-31 on cell apoptosis. NRON might promote the development of cisplatin resistance via downregulating miR-31 in ESCC.