ObjectiveTo develop a new polycystic ovary syndrome (PCOS) rat model suitable for exercise intervention.MethodThirty six rats were randomly divided into three experimental groups: PCOS rats with high-fat diet (PF, n = 24), PCOS rats with ordinary diet (PO, n = 6), and control rats with ordinary diet (CO, n = 6). Two kinds of PCOS rat model were made by adjustment diet structure and testosterone injection for 28 days. After a successful animal model, PF model rats were randomly assigned to three groups: exercise with a continuation of high-fat diet (PF-EF, n = 6), sedentary with a continuation of high-fat diet (PF-SF, n = 6), exercise with an ordinary diet (PF-EO, n = 6). Fasting blood glucose (FBG) and insulin (FINS), estrogen (E2), progesterone (P), and testosterone (T) in serum were determined by RIA, and ovarian morphology was evaluated by Image-Pro plus 6.0.ResultsBody weight, Lee index, FINS increased significantly in PF rat model. Serum levels of E2 and T were significantly higher in PF and PO than in CO. Ovary organ index and ovarian areas were significant lower in PF than in CO. After intervention for 2 weeks, the levels of 1 h postprandial blood glucose (PBG1), 2 h postprandial blood glucose (PBG2), FINS and the serum levels of T decreased significantly in PF-EF rats and PF-EO rats. The ratio of FBG/FINS was significant higher in PF-EO rats than in PF-SF rats. Ovarian morphology showed that the numbers of preantral follicles and atretic follicles decreased significantly, and the numbers of antral follicles and corpora lutea increased significantly in the rats of PF-EF and PF-EO.ConclusionBy combination of high-fat diet and testosterone injection, the obese PCOS rat model is conformable with the lifestyle habits of fatty foods and insufficient exercise, and has metabolic and reproductive characteristics of human PCOS. This model can be applied to study exercise intervention.

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Background. Recent research has established the existence of epigenetic modulation of the immune response. The possible involvement of RNA-n6-methyladenosine (m6A) alteration in tumor microenvironment (TME) cell invasion, on the other hand, is unknown. Methods. Based on 23 m6A regulators, we examined the alteration patterns of m6A in 629 LUAD tissues and comprehensively connected these modification patterns with TME cell invasion characteristics. The m6A score was calculated, and the m6A modification pattern of a single tumor was quantified using principal component analysis. Then, we further verified the expression of m6A related enzymes and the role hub gene (NOL10) closely related to survival in lung cancer cell lines. Results. Three separate m6A alteration modes have been discovered. TME cell invasion characteristics in the three modes were very similar to the three immunological phenotypes of tumors: immunological rejection, immunological inflammation, and immunological desert. We show that assessing the m6A modification pattern in a single tumor may help predict tumor inflammatory stage, subtype, TME interstitial activity, and prognosis. TME phenotypic inflammation is indicated by a high m6A score, which is characterized by elevated mutation load and immunological activation. The low m6A subtype showed matrix activation and ineffective immune infiltration, indicating that the TME phenotype of noninflammation and immunological rejection had a poor survival probability. Increased neoantigen burden was also linked to a high m6A score. Patients with a higher m6A score saw substantial therapeutic and clinical improvements. And reducing hub gene NOL10 expression substantially inhibited lung cancer cell growth and migration. Conclusions. This research shows that m6A alteration is critical in the creation of TME variety and complexity. The analysis of a single tumor’s m6A alteration pattern will aid in improving our knowledge of TME invasion features and guiding more effective immunotherapy tactics.

Osteosarcoma is a quickly developing, malignant cancer of the bone, which is associated with a bad prognosis. In osteosarcoma, hypoxia promotes the malignant phenotype, which results in a cascade of immunosuppressive processes, poor prognosis, and a high risk of metastasis. Nonetheless, additional methodologies for the study of hyperoxia in the tumor microenvironment also need more analysis. We obtained 88 children patients with osteosarcoma from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and 53 children patients with RNA sequence and clinicopathological data from the Gene Expression Omnibus (GEO). We developed a four-gene signature related to hypoxia to reflect the immune microenvironment in osteosarcoma that predicts survival. A high-risk score indicated a poor prognosis and immunosuppressive microenvironment. The presence of the four-gene signature related to hypoxia was correlated with clinical and molecular features and was an important prognostic predictor for pediatric osteosarcoma patients. In summary, we established and validated a four-gene signature related to hypoxia to forecast recovery and presented an independent prognostic predictor representing overall immune response strength within the osteosarcoma microenvironment.

Hyperandrogenism and hyperinsulinemia are major clinical features in women with polycystic ovary syndrome (PCOS). We hypothesized that serum insulin levels reduced by exercise could relieve hyperandrogenism and ameliorate polycystic ovarian morphology. Wistar female rats with 21-day-old were randomly divided into three groups: PCOS exercise (P-Ex), PCOS sedentary (P-Sed), and control sedentary (C-Sed). The rats with PCOS were induced by injection with testosterone propionate continuously. The exercise program was to swim with 120 min/d for two weeks. Fasting blood glucose (FBG) and insulin (FINS), estrogen (E (2)), progesterone (P), and testosterone (T) in serum were determined by RIA, and ovarian morphology was evaluated by Image-Pro Plus 6.0. The levels of FINS, E (2), and T in serum were significantly lower in P-Ex than in P-Sed. The ratios of FBG/FINS in P-Ex significantly increased in comparison with P-Sed. The levels of serum sex hormones in P-Ex were similar to C-Sed. There were no differences in blood glucose and serum progesterone among three groups. Ovarian morphology showed that the numbers of preantral follicles and atretic follicles significantly decreased, and the numbers of antral follicles and corpora lutea significantly increased in P-Ex compared with P-Sed. The changes of ovarian morphology in P-Ex were similar to C-Sed. These results demonstrated that short-term exercise training can improve insulin sensibility, decrease serum androgen levels, and recover normal ovarian morphology. The exercise training is the basic therapeutic means for PCOS.

BackgroundUveal melanoma(UVM) is the most common intraocular malignancy and has a poor prognosis. The clinical significance of necroptosis(NCPS) in UVM is unclear.MethodsWe first identified necroptosis genes in UVM by single-cell analysis of the GSE139829 dataset from the GEO database and weighted co-expression network analysis of TCGA data. COX regression and Lasso regression were used to construct the prognostic model. Then survival analysis, immune microenvironment analysis, and mutation analysis were carried out. Finally, cell experiments were performed to verify the role of ITPA in UVM.ResultBy necroptosis-related prognostic model, UVM patients in both TCGA and GEO cohorts could be classified as high-NCPS and low-NCPS groups, with significant differences in survival time between the two groups (P<0.001). Besides, the high-NCPS group had higher levels of immune checkpoint-related gene expression, suggesting that they might be more likely to benefit from immunotherapy. The cell experiments confirmed the role of ITPA, the most significant gene in the model, in UVM. After ITPA was knocked down, the activity, proliferation, and invasion ability of the MuM-2B cell line were significantly reduced.ConclusionOur study can provide a reference for the diagnosis and treatment of patients with UVM.

CD137 ligand (CD137L), a member of the tumor necrosis factor superfamily, is expressed on antigen-presenting cells and also on various tumor cells. Crosslinking of CD137L transmits signals that evoke different cellular responses in a variety of tumor cells. This study was designed to investigate signaling pathways activated by CD137L and its physiologic role in the progression of NSCLC. We investigated the expression of CD137L in tissues from 102 cases of human non-small cell lung cancer (NSCLC) using immunohistochemistry and analyzed the correlation with clinicopathological features using Fisher's exact test and overall survival using Kaplan-Meier curves and the log-rank test. The effect of CD137L reverse signaling induced by recombinant human CD137-Fc protein on NSCLC cell lines was assessed using proliferation and apoptosis assays, flow cytometry and Western blotting. Positive CD137L expression was observed in 53/102 (52.0%) of the NSCLC samples and correlated with early TNM stage (P = 0.046), well-differentiated tumors (P = 0.009) and better overall survival (P = 0.004). Moreover, induction of CD137L reverse signaling using CD137-Fc inhibited proliferation and induced apoptosis and cell cycle arrest in H1650 cells, which express high levels of CD137L; CD137L reverse signaling had no significant effects in PC9 cells, which express low levels of CD137L. In addition, CD137L reverse signaling-induced apoptosis occurred via activation of the intrinsic pathway and depended on phosphorylation of JNK. This study demonstrates a hitherto unrecognized role for CD137L reverse signaling in the development of NSCLC and indicates that CD137L has potential as a novel therapeutic target in NSCLC.

Background5α-reductase activity might be important during the development of polycystic ovary syndrome (PCOS). However, the changes of 5α-reductase activity in PCOS subjects and the relationship between 5α-reductase activity and body mass index (BMI), insulin resistance (IR) remain largely unknown.MethodsWe performed a meta-analysis to examine 5α-reductase activity in women with PCOS; exploratory subgroup analyses were also performed.ResultsFive articles (with 356 cases and 236 controls) reporting 5α-reductase activity in patients with PCOS were selected for the meta-analysis. We observed significantly higher ratios of 5αTHF/THF (5α-reduced tetrahydrocortisol to 5β-reduced tetrahydrocortisol) and An/Et (androsteroneto/etiocholanolone) levels, which were used to assess 5α-reductase activity, among the patients with PCOS, [standardized mean differences (SMD) =0.43, 95%confidence intervals (95%CI) =0.25–0.61, P < 0.00001; SMD = 0.86, 95% CI = 0.29–1.44, P = 0.003]. We observed significant heterogeneity between studies for An/Et (I2 = 89% and P < 0.00001). According to the group analysis, women with PCOS exhibited increased 5α-reductase activity which was significantly associated with homeostasis model assessment of insulin resistance (HOMA-IR) regardless of obesity.Conclusions5α-reductase activity was enhanced in women with PCOS. Increased 5α-reductase activity in patients with PCOS was related to IR.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-017-0242-9) contains supplementary material, which is available to authorized users.