Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death worldwide. It is urgent to develop new drugs to improve the prognosis of ESCC patients. Here, we found benzydamine, a locally acting non-steroidal anti-inflammatory drug, had potent cytotoxic effect on ESCC cells. Benzydamine could suppress ESCC proliferation in vivo and in vitro. In terms of mechanism, CDK2 was identified as a target of benzydamine by molecular docking, pull-down assay and in vitro kinase assay. Specifically, benzydamine inhibited the growth of ESCC cells by inhibiting CDK2 activity and affecting downstream phosphorylation of MCM2, c-Myc and Rb, resulting in cell cycle arrest. Our study illustrates that benzydamine inhibits the growth of ESCC cells by downregulating the CDK2 pathway.
Humans ; Benzydamine ; Esophageal Neoplasms/drug therapy* ; Esophageal Squamous Cell Carcinoma/drug therapy* ; Molecular Docking Simulation ; Phosphorylation ; Cell Proliferation ; Cell Line, Tumor ; Apoptosis ; Cyclin-Dependent Kinase 2

Deficiency of natural killer (NK) cells shows a significant impact on tumor progression and failure of immunotherapy. It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment. Unfortunately, mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors, thus declining antitumor efficiency. Herein, we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15 (IL-15). The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction, which provides a new methodology to trigger aggregation. It shows self-adaptive size-enlargement upon acidity, thus improving drug retention in tumor to over 120 h. The diameter of agglomerates is increased and drug release is effectively promoted following reduced pH values. The nanoparticles activate both NK cell and CD8⁺ T cell immunity in vivo. It significantly suppresses CT26 tumor in immune-deficient BALB/c mice, and the efficiency is further improved in immunocompetent mice, indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity. The approach reported here provides an innovative strategy to improve drug retention in tumors, which will enhance cancer immunotherapy by boosting NK cells.

BACKGROUND: Metastasis is the main cause of tumor-associated death and mainly responsible for treatment failure of breast cancer. Autophagy accelerates tumor metastasis. In our work, we aimed to investigate the possibility of microRNAs (miRNAs) which participate in the regulation of autophagy to inhibit tumor metastasis. METHODS: MiRNA array and comprehensive analysis were performed to identify miRNAs which participated in the regulation of autophagy to inhibit tumor metastasis. The expression levels of miR-3653 in breast cancer tissues and cells were detected by quantitative real-time polymerase chain reaction. In vivo and in vitro assays were conducted to determine the function of miR-3653. The target genes of miR-3653 were detected by a dual luciferase reporter activity assay and Western blot. The relationship between miR-3653 and epithelial-mesenchymal transition (EMT) was assessed by Western blot. Student's t -test was used to analyze the difference between any two groups, and the difference among multiple groups was analyzed with one-way analysis of variance and a Bonferroni post hoc test. RESULTS: miR-3653 was downregulated in breast cancer cells with high metastatic ability, and high expression of miR-3653 blocked autophagic flux in breast cancer cells. Clinically, low expression of miR-3653 in breast cancer tissues (0.054 ± 0.013 vs . 0.131 ± 0.028, t  = 2.475, P  = 0.014) was positively correlated with lymph node metastasis (0.015 ± 0.004 vs . 0.078 ± 0.020, t  = 2.319, P  = 0.023) and poor prognosis ( P  < 0.001). miR-3653 ameliorated the malignant phenotypes of breast cancer cells, including proliferation, migration (MDA-MB-231: 0.353 ± 0.013 vs . 1.000 ± 0.038, t  = 16.290, P  < 0.001; MDA-MB-468: 0.200 ± 0.014 vs . 1.000 ± 0.043, t  = 17.530, P  < 0.001), invasion (MDA-MB-231: 0.723 ± 0.056 vs . 1.000 ± 0.035, t  = 4.223, P  = 0.013; MDA-MB-468: 0.222 ± 0.016 vs . 1.000 ± 0.019, t  = 31.050, P  < 0.001), and colony formation (MDA-MB-231: 0.472 ± 0.022 vs . 1.000 ± 0.022, t  = 16.620, P  < 0.001; MDA-MB-468: 0.650 ± 0.040 vs . 1.000 ± 0.098, t  = 3.297, P  = 0.030). The autophagy-associated genes autophagy-related gene 12 ( ATG12 ) and activating molecule in beclin 1-regulated autophagy protein 1 ( AMBRA1 ) are target genes of miR-3653. Further studies showed that miR-3653 inhibited EMT by targeting ATG12 and AMBRA1 . CONCLUSIONS Our findings suggested that miR-3653 inhibits the autophagy process by targeting ATG12 and AMBRA1 , thereby inhibiting EMT, and provided a new idea and target for the metastasis of breast cancer.
Cell Line, Tumor ; Epithelial-Mesenchymal Transition/genetics* ; MicroRNAs/metabolism* ; Autophagy/genetics* ; Genes, Regulator ; Gene Expression Regulation, Neoplastic/genetics* ; Cell Proliferation/genetics* ; Cell Movement/genetics* ; Neoplasms/genetics*

Intrauterine adhesion (IUA) is caused by damage of the basal layer of endometrium, which leads to fibrosis of the endometrium and the formation of adhesion, resulting in partial or complete occlusion of the uterine cavity, abnormal menstruation, infertility or recurrent miscarriage. The prevalence of IUA in women has been increasing in recent years, and the high recurrence rate of moderate to severe IUA makes IUA treatment more challenging. Iatrogenic endometrial injury is the main cause of IUA. However, the incidence of IUA and the severity of IUA vary among patients who have received similar uterine operations, suggesting that there may be other synergistic factors in the development of IUA. There is a certain correlation between the pathogenesis and the microbiota of the gential tract. In many IUA patients, it has been observed that the probiotics such as Lactobacillus in the vagina is significant reduced, and the pathogenic bacteria such as Gardnerella and Prevotella are excessive growth. The reproductive tract microbiota can be involved in the development and progression of IUA via impacting immune function and metabolism.
Humans ; Female

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.

Lung cancer is one of the most common malignant tumors. Globally, the incidence and mortality of lung cancer are very high and on the rise. In recent years, immune checkpoint inhibitors (ICIs) have a significant survival advantage in treating advanced NSCLC. However, for NSCLC patients with positive driver genes, ICIs are not effective. But some tumor suppressor genes have varying degrees of impact on immunotherapy through mutations or deletions. Among them, serine/threonine kinase 11 (STK11) gene mutations are closely related to PD-1/PD-L1 ICIs. Studies have found that STK11 mutations are related to reduced immune cell infiltration, low PD-L1 expression and poor response to PD-L1 inhibition. This article reviews the research progress of the correlation between STK11 gene mutation and immunotherapy on NSCLC.

While treating cancer, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) still faces inevitable drug resistance. Investigations into the mechanisms which foster resistance to EGFR-TKI has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKI, and is a standard-of-care predictive biomarker used in therapeutic stratification. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR-TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR-TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and first-generation EGFR-TKI in randomized clinical trials. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR-TKIs, and envisions future directions in translational and clinical research.

Introduction: Alveolar rhabdomyosarcoma (RMS) usually occurs in adolescents and young adults, and most frequently arises in the extremities. Case Report: We present a rare case of metastatic alveolar RMS from a nasal primary to cervical lymph nodes (LNs) in an elderly patient, diagnosed on the fine-needle aspiration (FNA) biopsy. Smears showed malignant round cells featuring focal rhabdoid appearance, with rhabdomyoblastic differentiation further supported by immunocytochemical stains. Diagnosis of alveolar RMS was confirmed by fluorescence in situ hybridization (FISH) identifying FOXO1 gene involvement with dual colour break-apart probes at locus 13q14. Discussion: The differential diagnosis for a small round blue cell tumour in the elderly generally includes metastatic small cell carcinoma, lymphoma, malignant melanoma, RMS, desmoplastic small round cell tumour and Ewing’s sarcoma/primitive neuroectodermal tumour. Subtle morphological analysis and expression pattern of immunostaining for skeletal muscle differentiation led to the diagnosis of RMS. Cytogenetic testing on the FOXO1 gene rearrangement helps definite subtyping of alveolar RMS.

Objective:To explore the effect of high-flow airway humidification on aspiration and residues in cases of dysphagia after a tracheotomy.Methods:Seventeen persons with dysphagia after a tracheotomy were asked to swallow 5ml of a thick liquid when their tracheal cannula was either connected to a high-flow airway humidification system or blocked, or the cuff was empty or full. Endoscopic evaluation was then used to grade the residue and aspiration in the different conditions.Results:There were significant differences in the residuals grading and aspiration among the four conditions. The average penetration-aspiration scale grade was significantly lower when the subject was connected to high-flow airway humidification than in the other three conditions. The grade of residuals was also significantly lower.Conclusion:High-flow airway humidification can effectively improve the swallowing of persons with dysphagia after a tracheotomy.

Objective: To understand the homosexual behavior and related factors among married MSM in Mianyang city. Methods: Between January and October in 2017, a snowball sampling method was adopted to carry out cross-sectional survey through questionnaires plus HIV testing among those MSM in Mianyang city. Logistic regression model was used to analyze homosexual behaviors and related factors among married MSM under study. Statistical analysis was used by EpiData 3.1 and SPSS 19.0 software. Results: A total of 234 MSM participated in this survey. The overall rate of homosexual behavior in these married MSM appeared as 94.9% (222/234). Rate of having anal sex behavior was 94.4% (221/234) in the past 6 months, with rate of condom use as 57.9% (128/221). HIV positive rate was 8.1% (18/222). As for the motives for homosexual behavior after marriage, 87.8% (195/222) were driven by feelings of love, 12.2% (27/222) due to 'releasing pressure’. Proportion of male sex partners would include occasional sex partners (62.2%, 138/222), stable male sex partners (26.1%, 58/222) and stable boyfriends (11.7%, 26/222). Factors from logistic regression analysis showed that homosexual behaviors were related to the factors including education level of senior high school or above vs. education level of junior middle school or below (OR=3.65, 95%CI: 1.33-9.98); local residency over one year vs. the ones having local residency less than one year (OR=23.28, 95%CI:1.67-324.89); having 10 or more friends in the MSM community vs. having below 10 friends in MSM community (OR=4.15, 95%CI: 1.28-13.43); without sex pleasure with spouse vs. having sex pleasure with spouse (OR=3.25, 95%CI: 1.22-8.62); having 2 or more anal sex partners in the past 6 months vs. having less than 2 anal sex partners in the past 6 months (OR=0.28,95%CI: 0.09-0.81). Conclusions The rate of homosexual behavior and HIV positive rate were high among MSM in Mianyang city. Homosexual behaviors after marriage were influenced by multiple factors among MSM. The motives of homosexual behavior after marriage were driven by feelings of love, the related factors were education level of senior high school or above, local residency over one year, having 10 or more friends in the MSM community and without sex pleasure with spouse. As for the motives of these behaviors was caused by releasing pressure, the related factors was having more than 2 anal sex partners.