Identification of Prognostic Alternative Splicing Signature in Breast Carcinoma

BackgroundIncreasing evidence indicated a close relationship between aberrant splicing variants and carcinoma, whereas comprehensive analysis of prognostic alternative splicing (AS) profiling in breast cancer (BRCA) is lacking and largely unknown.MethodsRNA-seq data and corresponding clinical information of BRCA patients were obtained and integrated from The Cancer Genome Atlas (TCGA). Then SpliceSeq software was used to assess seven AS types and calculate the Percent Spliced In (PSI) value. Univariate followed by stepwise multivariate Cox regression analyses identified survival associated AS events and constructed the AS signature, which were further sent for enrichment analysis, respectively. Besides, the splicing correlation network was constructed. Additionally, nomogram incorporating AS signature and clinicopathological characteristics was developed and its efficacy was evaluated with respect to discrimination, calibration and clinical utility.ResultsA total of 45,421 AS events were detected, among which 3071 events were found associated with overall survival (OS) after strict filtering. Parent genes of these prognostic events were involved in BRCA-related processes including NF-kappaB and HIF-1 signaling pathway. Besides, the final prognostic signature built with 20 AS events performed well with an area under the curve (AUC) of receiver operating characteristic (ROC) curve up to 0.957 for 5 years. And gene set enrichment analysis (GSEA) also confirmed the candidate 20 AS events contributed to progression of BRCA. Moreover, the nomogram that incorporated 20-AS-event-based classifier, age, pathological stage and Her-2 status showed good calibration and moderate discrimination, with C-index of 0.883 (95% CI, 0.844–0.921). Decision curve analysis (DCA) confirmed more benefit was added to survival prediction with our nomogram, especially in 5 or 8 years with threshold probability up to 80%. Finally, splicing correlation network revealed an obvious regulatory pattern of prognostic splicing factors (SF) in BRCA.ConclusionThis study provided a systematic portrait of survival-associated AS events involved in BRCA and further presented a AS-clinicopathological nomogram, which could be conveniently used to assist the individualized prediction of long-term survival probability for BRCA patients. And a series of bioinformatic analysis provided a promising perspective for further uncovering the underlying mechanisms of AS events and validating therapeutic targets for BRCA

Observation of PeV Gamma Rays from the Monogem Ring with the Tibet Air Shower Array

We searched for steady PeV gamma-ray emission from the Monogem ring region with the Tibet air shower array from 1997 February to 2004 October. No evidence for statistically significant gamma-ray signals was found in a region 111\degr $\leq$ R.A. $<$ 114\degr, 12\fdg5 $\leq$ decl. $<$ 15\fdg5 in the Monogem ring where the MAKET-ANI experiment recently claimed a positive detection of PeV high-energy cosmic radiation, although our flux sensitivity is approximately 10 times better than MAKET-ANI's. We set the most stringent integral flux upper limit at a 99% confidence level of 4.0 $\times$ 10$^{-12}$ cm$^{-2}$ s$^{-1}$ sr$^{-1}$ above 1 PeV on diffuse gamma rays extended in the 3$^{\circ}$ $\times$ 3$^{\circ}$ region.Comment: 13 pages 3figures, 1 tabl

An Updated Search of Steady TeV γ−\gamma-Ray Point Sources in Northern Hemisphere Using the Tibet Air Shower Array

Using the data taken from Tibet II High Density (HD) Array (1997 February-1999 September) and Tibet-III array (1999 November-2005 November), our previous northern sky survey for TeV $\gamma-$ray point sources has now been updated by a factor of 2.8 improved statistics. From $0.0^{\circ}$ to $60.0^{\circ}$ in declination (Dec) range, no new TeV $\gamma-$ray point sources with sufficiently high significance were identified while the well-known Crab Nebula and Mrk421 remain to be the brightest TeV $\gamma-$ray sources within the field of view of the Tibet air shower array. Based on the currently available data and at the 90% confidence level (C.L.), the flux upper limits for different power law index assumption are re-derived, which are approximately improved by 1.7 times as compared with our previous reported limits.Comment: This paper has been accepted by hepn

Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors

Co-delivery of anti-cancer drugs is promising to improve the efficacy of cancer treatment. This study was aiming to investigate the potential of concurrent delivery of resveratrol (RES) and docetaxel (DTX) via polymeric nanocarriers to treat breast cancer. To this end, methoxyl poly(ethylene glycol)-poly(d,l-lactide) copolymer (mPEG-PDLA) was prepared and characterized using FTIR and 1H NMR, and their molecular weights were determined by GPC. Isobologram analysis and combination index calculation were performed to find the optimal ratio between RES and DTX to against human breast adenocarcinoma cell line (MCF-7 cells). Subsequently, RES and DTX were loaded in the mPEG-PDLA micelles simultaneously, and the morphology, particle size distribution, in vitro release, pharmacokinetic profiles, as well as cytotoxicity to the MCF-7 cells were characterized. IC50 of RES and DTX in MCF-7 cells were determined to be 23.0 µg/ml and 10.4 µg/ml, respectively, while a lower IC50 of 4.8 µg/ml of the combination of RES and DTX was obtained. The combination of RES and DTX at a ratio of 1:1 (w/w) generated stronger synergistic effect than other ratios in the MCF-7 cells. RES and DTX loaded mPEG-PDLA micelles exhibited prolonged release profiles, and enhanced cytotoxicity in vitro against MCF-7 cells. The AUC(0→t) of DTX and RES in mPEG-PDLA micelles after i.v. administration to rats were 3.0-fold and 1.6-fold higher than that of i.v. injections of the individual drugs. These findings indicated that the co-delivery of RES and DTX using mPEG-PDLA micelles could have better treatment of tumors. Keywords: Resveratrol, Docetaxel, Methoxyl poly(ethylene glycol)-poly(d,l-lactide) copolymer (mPEG-PDLA), Micelles, Drug resistance tumo

Tumor Necrosis Factor-α Induced Protein 8 Polymorphism and Risk of Non-Hodgkin’s Lymphoma in a Chinese Population: A Case-Control Study

BACKGROUND: Non-Hodgkin's lymphoma (NHL) has been reported to be associated with autoimmune and pro-inflammatory response, and genetic polymorphisms of candidate genes involved in autoimmune and pro-inflammatory response may influence the susceptibility to NHL. To evaluate the role of such genetic variations in risk of NHL, we conducted a case-control study of 514 NHL patients and 557 cancer-free controls in a Chinese population. METHOD: We used the Taqman assay to genotype six potentially functional single nucleotide polymorphisms (SNPs) in six previously reported inflammation and immune-related genes (TNF rs1799964T>C, LTA rs1800683G>A, IL-10 rs1800872T>G, LEP rs2167270G>A, LEPR rs1327118C>G, TNFAIP8 rs1045241C>T). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). RESULTS: We observed a significantly increased risk of NHL associated with the TNFAIP8 rs1045241C>T polymorphism (adjusted OR = 3.03; 95% CI = 1.68-5.45 for TT vs. CC and adjusted OR = 2.03; 95% CI = 1.53-2.69 for CT/TT vs. CC). The risk associated with the T allele was more evident in subgroups of 40-60 year-old, non-smokers or light-smokers (less than 25 pack-years), and subjects with normal weight or overweight. Risk for both B and T cell non-Hodgkin's lymphoma was elevated for CT/TT genotypes (adjusted OR = 1.95, 95% CI = 1.41-2.70 for B cell NHL and adjusted OR = 2.22, 95% CI = 1.49-3.30 for T cell NHL), particularly for DLBCL (adjusted OR = 2.01, 95%CI = 1.41-2.85) and FL (adjusted OR = 2.53, 95% CI = 1.17-5.45). These risks were not observed for variant genotypes of other five SNPs compared with their common homozygous genotypes. CONCLUSIONS: The polymorphism of TNFAIP8 rs1045241C>T may contribute to NHL susceptibility in a Chinese population. Further large-scale and well-designed studies are needed to confirm these results