Characterizing the critical role of metabolism in osteosarcoma based on establishing novel molecular subtypes.

OBJECTIVE: Osteosarcoma is the third most frequently diagnosed cancer among adolescents. Immunotherapy is an effective curative treatment for metastatic osteosarcoma patients. This study aimed to further reveal the significance of metabolism in tumor progression, and to categorize molecular subtypes for guiding personalized therapy. MATERIALS AND METHODS: Univariate Cox regression analysis was performed to screen metabolism-related genes associated with osteosarcoma prognosis. A molecular subtyping system was developed by unsupervised consensus clustering. Survival analysis and functional analysis were used to evaluate the performance of subtyping and characterize the TME of subtypes. Stepwise Akaike information criterion (stepAIC) was employed to optimize the prognostic model. RESULTS: C1 and C2 subtypes showed distinct prognosis, with more favorable survival in C2 subtype. C2 subtype presented a higher immune infiltration and active anti-tumor response. Notably, C2 subtype was predicted to have better immune response to immune checkpoint blockade. In addition, a 5-gene prognostic signature with robust ability to classify patients into high-risk and low-risk groups was developed. CONCLUSIONS: The study revealed the critical role of metabolism in tumorigenesis by comparing the features between the two subtypes. Oncogenic pathways including epithelial mesenchymal transition (EMT), glycolysis and hypoxia may be closely involved in the correlation with metabolism. Importantly, we developed a novel subtyping system and a 5-gene signature with high potential to be applied in clinical practice.

LncRNA DANCR aggravates the progression of ovarian cancer by downregulating UPF1.

OBJECTIVE: To uncover the role of long non-coding RNA (lncRNA) DANCR in aggravating the progression of ovarian cancer (OC) by downregulating UPF1 level. PATIENTS AND METHODS: DANCR level in OC tissues and matched adjacent normal ones was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Its expression level in OC patients with different tumor node metastasis (TNM) staging and either with metastasis, or not, was examined as well. Receiver operating characteristic (ROC) curves were introduced for assessing the prognostic value of DANCR in OC. Subsequently, regulatory effects of DANCR on proliferative and migratory abilities of HO8910 and HEY cells were evaluated. Subcellular distribution of DANCR in OC cells was analyzed. Furthermore, the interaction between DANCR and UPF1 was explored by RNA immunoprecipitation (RIP) and Pearson correlation analysis. Finally, rescue experiments were conducted to clarify the role of DANCR/UPF1 axis in the progression of OC. RESULTS: DANCR was upregulated in OC tissues and cell lines. Its level was higher in OC patients with worse tumor stage and accompanied by metastatic loci. DANCR exerted the potential to serve as a prognostic marker for OC. Overexpression of DANCR accelerated HO8910 and HEY cells to proliferate and migrate. UPF1 was found to be downregulated in OC tissues and negatively correlated to DANCR. DANCR was mainly distributed in the cytoplasm and interacted with UPF1. Overexpression of UPF1 in OC cells partially reversed the promotive effect of DANCR on proliferative and migratory rates. CONCLUSIONS: LncRNA DANCR accelerates the proliferative and migratory abilities of OC cells through negatively regulating UPF1 level, thus aggravating the progression of OC.

P2X3 receptor-mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD-like stress in the dorsal root ganglia of rats.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) often share co-morbidity with chronic pain conditions. Recent studies suggest a role of P2X3 receptors and ATP signaling in pain conditions. However, the underlying mechanisms of visceral hyperalgesia following exposure to PTSD-like stress conditions remain unclarified. METHODS: The behavior and hormones relevant for PTSD were studied. Visceromotor responses (VMR) and the abdominal withdrawal reflexes (AWR) to colorectal distention (CRD) were recorded to determine P2X3-receptor-mediated alteration of hyperalgesia following single-prolonged stress (SPS) exposure. Immunofluorescence, Western blotting, and patch-clamp were used. KEY RESULTS: The escape latency, adrenocorticotropic hormone and cortisol were increased on days 7-14. Visceromotor responses and AWR was reduced at day 1 in SPS rats but increased to higher levels than in controls after exposure to day 7. Intrathecal administration of the P2X3-receptor antagonist TNP-ATP abolished the CRD response. Based on immunofluorescence and Western blotting analysis, SPS-treated rats exhibited reduced P2X3 expression in dorsal root ganglia (DRG) after day 1 compared with controls. P2X3 expression in DRG was enhanced on day 7 after SPS and the increase of the P2X3 expression was maintained on day 14 and 21 compared with controls. The P2X3-receptor agonist α,ß-me ATP (10 µM) induced a fast desensitizing inward current in DRG neurons of both control and SPS-treated rats. The average peak current densities in SPS-treated group were increased 3.6-fold. TNP-ATP (100 nM) markedly blocked all fast α,ß-me ATP-induced inward currents in the DRG neurons both in control and SPS-treated rats. CONCLUSIONS & INFERENCES: The data indicate an important role of P2X3 signaling in visceral hyperalgesia following PTSD-like stress.

SOX4 is a potential prognostic factor in human cancers: a systematic review and meta-analysis

Objective. The aim of the this study was to analyze the status of sex-determining region Y-related high-mobility group box 4 (SOX4) expression in varied human cancers and its correlation with overall survival in patients with human cancers. Methods. To observe initially the expression status of SOX4 in twenty kinds of human cancers at protein database (The Human Protein Atlas). We systematically and carefully searched the studies from electronic databases and seriously identified according to eligibility criteria. The correlation between SOX4 expression and overall survival in human cancers was evaluated through Review Manager. Results. We found that SOX4 expression was significantly positive in most types of human cancer tissues, and the positive rate of SOX4 expression was about 78 % in overall cancer tissues. Furthermore, a total of 10 studies which included 1348 cancer patients were included in the final analysis. Meta-analysis showed that SOX4 overexpression was correlated with a poor overall survival and the pooled hazard ratio (HR), and corresponding 95 % confidence interval (CI) was 1.67 (95 % CI 1.01-2.78). From subgroup analyses, we present evidence that SOX4 overexpression was an unfavorable prognostic factor for colorectal cancer patients’ recurrence-free survival and gastric cancer patients’ overall survival, and the pooled HRs (95 % CI) were 1.73 (95 % CI 1.04-2.88) and 3.74 (95 % CI 1.04-13.45), respectively. Conclusions. In summary, SOX4 is a potential prognostic biomarker in human cancers (AU)

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Human skin fibroblast telomeres are shortened after ultraviolet irradiation.

OBJECTIVE: Telomere length was used as a biomarker of cell senescence to explore the role of telomere shortening in photoageing induced by ultraviolet A (UVA) light. METHODS: Real-time polymerase chain reaction was used to determine telomere length in cultured human fibroblasts of different generations and after exposure to UVA at doses up to 10 000 mJ/cm(2). Twoway analysis of variance was used to determine whether passaging or UVA was the main factor contributing to telomere shortening. RESULTS: In nonirradiated cells, telomere length was inversely related to cell generation number. In fibroblasts exposed to UVA at a dose of 1000 or 10 000 mJ/cm(2), telomere length was significantly shorter than that of nonirradiated controls and was negatively related to UVA dose. CONCLUSIONS: Telomere length and subsequent cell viability may be affected by UVA irradiation. DNA damage caused by UVA irradiation may initiate the photoageing process and telomeres may be a useful new target for attempts to prevent photoageing.