Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 50 end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Potential Tumor Suppressor NESG1 as an Unfavorable Prognosis Factor in Nasopharyngeal Carcinoma

BACKGROUND:Recently we identified nasopharyngeal epithelium specific protein 1 (NESG1) as a potential tumor suppressor in nasopharyngeal carcinoma (NPC). The purpose of this study is to investigate the involvement of NESG1 in tumor progression and prognosis of human NPC. METHODOLOGY/PRINCIPAL FINDINGS:NESG1 protein expression in NPC was examined. Survival analysis was performed using Kaplan-Meier method. The effect of NESG1 on cell proliferation, migration, and invasion were also investigated. RESULTS:NESG1 expression was downregulated in atypical hyperplasia and NPC samples compared to normal and squamous nasopharynx tissues. Reduced protein expression was negatively associated with the status of NPC progression. Patients with lower NESG1 expression had a shorter overall survival and disease-free time than did patients with higher NESG1 expression. Multivariate analysis suggested NESG1 expression as an independent prognostic indicator for NPC patient survival. Proliferation, migration, and invasion ability were significantly increased in cell lines following lentiviral-mediated shRNA suppression of NESG1 expression. Microarray analysis indicated that NESG1 participated in multiple pathways, including MAPK signaling and cell cycle regulation. Finally, DNA methylation microarray examination revealed a lack of hypermethylation at the NESG1 promoter, suggesting other mechanisms are involved in suppressing NESG1 expression in NPC. CONCLUSION:Our studies are the first to demonstrate that decreased NESG1 expression is an unfavorable prognostic factor for NPC

The Anti-Breast Cancer Activity of Dihydroartemisinin-5-methylisatin Hybrids Tethered via Different Carbon Spacers

Sixteen dihydroartemisinin-5-methylisatin hybrids 6a–c and 7a–m tethered via different carbon spacers were assessed for their antiproliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR and MDA-MB-231/ADR breast cancer cell lines as well as cytotoxicity towards MCF-10A cells to investigate the influence of the length of carbon spacers on the activity. The preliminary results illustrated that the length of the carbon spacer was the main parameter which affected the activity, and hybrids tethered via the two-carbon linker showed the highest activity. Amongst the synthesized hybrids, the representative hybrid 7a (IC50: 15.3–20.1 µM) not only demonstrated profound activity against both drug-sensitive and drug-resistant breast cancer cell lines, but also possessed excellent safety and selectivity profile. Collectivity, hybrid 7a was a promising candidate for the treatment of both drug-sensitive and drug-resistant breast cancers and worthy of further preclinical evaluations

Systematic Chemical Analysis Approach Reveals Superior Antioxidant Capacity via the Synergistic Effect of Flavonoid Compounds in Red Vegetative Tissues

The flavonoid system comprises an abundance of compounds with multiple functions; however, their potential synergism in antioxidant function remains unclear. We established an approach using ever-red (RL) and ever-green leaves (GL) of crabapple cultivars during their development to determine interrelationships among flavonoid compounds. RL scored significantly better than GL in terms of the type, composition, and diversity of flavonoids than GL. Principal component analysis predicted flavonoids in RL to have positive interaction effects, and the total antioxidant capacity was significantly higher than the sum of antioxidant capacities of the individual compounds. This synergy was verified by the high antioxidant capacity in rat serum after feeding on red leaves. Our findings suggest that the synergistic effect is a result of the high transcription levels regulated by McMYBs in RL. In summary, individual flavonoids cooperate in a flavonoid system, thus producing a synergistic antioxidant effect, and the approach used herein can provide insights into the roles of flavonoids and other compounds in future studies

Fingerprinting Indoor Positioning Method Based on Kernel Ridge Regression with Feature Reduction

An important goal of indoor positioning systems is to improve positioning accuracy as well as reduce power consumption. In this paper, we propose an indoor positioning method based on the received signal strength (RSS) fingerprint. The proposed method used a certain criterion to select fixed access points (FPs) in an offline phase instead of an online phase for location estimation. Principal component analysis (PCA) was applied to reduce the features of the RSS measurements but retain the most information possible for establishing the positioning model. Then, a kernel-based ridge regression method was used to obtain the nonlinear relationship between the principal components of the RSS measures and the position of the target. We thoroughly investigated the performance of the proposed method in realistic wireless local area network (WLAN) and wireless sensor network (WSN) indoor environments and made comparisons with recently developed methods. The experimental results indicated that the proposed method was less dependent on the density of the reference points and had higher positioning accuracy than the commonly used positioning methods, and it adapts to different application environments