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BRCA1-BARD1 heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks. Dysfunction of the BRCA1 pathway enhances the therapeutic efficiency of poly-(ADP-ribose) polymerase inhibitors (PARPi) in cancers, but the molecular mechanisms underlying this sensitization to PARPi are not fully understood. Here, we show that cancer cell sensitivity to PARPi is promoted by the ring between ring fingers (RBR) protein RNF19A. We demonstrate that RNF19A suppresses HR by ubiquitinating BARD1, which leads to dissociation of BRCA1-BARD1 complex and exposure of a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in the export of BARD1 to the cytoplasm. We provide evidence that high RNF19A expression in breast cancer compromises HR and increases sensitivity to PARPi. We propose that RNF19A modulates the cancer cell response to PARPi by negatively regulating the BRCA1-BARD1 complex and inhibiting HR-mediated DNA repair., BRCA1 dysfunction sensitizes cancer cells to PARP inhibitors (PARPi) but the underlying mechanism is unclear. Here, the authors identify RNF19A as a determinant of PARPi sensitivity, showing that RNF19A ubiquitinates BARD1, negatively regulates the BRCA1-BARD1 complex, and inhibits homologous recombination.

Purpose: The study of Willis covered stent implantation on life-threatening hemorrhage from Radiation Internal Carotid Blowout Syndrome (RICBS) in patients with Nasopharyngeal Cancer (NPC) was evaluated in our hospital. Materials and Methods: Five NPC patients (3 male and 2 female patients) received Willis covered stent implantation from April 2011 to March 2017, in which radiation induced hemorrhage occurred in Internal Carotid Artery (ICA) was included in this study. The median age in the patient cohort was 56 (47-63). All patients were previously treated with radiotherapy (4 received IMRT and 1receivedheavy-ion RT). The median time was four years before the ICA ruptures after irradiation. The RICBS involved the C2 segment of the ICA in three patients and C3 in two patients. Results: All five patients’ ICA bleeding stopped immediately after the operation of Willis covered stent implantation. Follow-up mean time is 10 months. One patient died of suffocation (nasal hematorrhea) 2 weeks after the operation, in which the skull base is involved from recurrent lesions and associated dysphagia. One patient had rehaemorrhagia a week after the operation. One patient died of other accident 15 months after the operation. No adverse effects such as stroke and ischemia were found in all five patients during the follow-up period. Conclusion: The Willis covered stent implantation can immediately stop the bleeding caused by RICBS to save lives immediately. It is an effective and practical method to treat RICBS in NPC patients or other head and neck cancers patients, especially for the radiation-induced vascular events

Radiation-induced heart disease (RIHD) leads to myocardial dysfunction and metabolic abnormalities in patients treated with thoracic irradiation which restricts the long-term survival benefits of radiotherapy. There is no specific or effective manner of intervention currently available. Asparaginyl endopeptidase (AEP) plays a pivotal role in the maintenance of cellular functions through regulating proteolytic cleavage as peptidase enzyme. We aimed to investigate the role of unique cardiac AEP in cardiac function by modulating key signaling elements in the myocardium. The murine heart was exposed to a single dose of 14 Gy radiation. Cellular signaling and apoptosis was analyzed in human and rat cardiomyocytes treated with various doses of radiation, we observed expression of AEP was increased by immunohistochemical staining in murine heart exposed to radiation. The AEP production along with its increased level of mRNA expression was associated with increased doses of radiation (0, 2, 5, 10 Gy) in cardiomyocytes. The myocardial cells transfected with AEP overexpression showed overall cellular viability enhancement, DNA damage inhibition, the foci formation of γ-H2AX suppressed and DNA repair enhancement significantly after radiation exposure. Small interfering RNA-mediated AEP knockdown was with reduced cardiomyocyte viability, elevated apoptotic rate, increased γ-H2AX foci formation and inhibited DNA repair as well after irradiation. After radiation exposure of 10 Gy, the expression of AEP increased in P53 overexpressing cardiomyocytes and decreased in the P53 knockdown cells, indicates that radiation-induced expression of AEP might be regulated by P53. Moreover, treatments with either AEP overexpression or knockdown showed enhanced NRF2 activity in the nuclear or suppressed NRF2 expression in the cytoplasm of myocardial cells after irradiation, respectively, defined a possible regulatory effect of AEP associated with diminished NRF2 translocation and activation by radiation exposure, including impair myocardium and myocardial apoptosis. These findings suggest that increased levels of AEP in failing myocardium after irradiation is mediated by P53 and regulate a novel pathway that involves NRF2 activation. AEP is essential for maintaining cellular redox homeostasis of cardiac function.

Multiple studies have highlighted the importance of long noncoding RNAs in tumorigenesis. However, the molecular mechanisms underlying the role of lncRNAs in breast cancer are not well understood. Recently, the lncRNA HOXC-AS3 has drawn significant attention due to its regulatory effects on the tumorigenesis of human cancers. However, the potential molecular mechanisms whereby it mediates breast cancer progression remain unknown. Based on public breast cancer expression data and using bioinformatics methods, we discovered significantly upregulated expression levels of HOXC-AS3 in diseased tissues. We verified this result in breast cancer samples and found that the expression of HOXC-AS3 was well correlated with the prognosis of breast cancer. In vitro and in vivo experimental evidence suggests that HOXC-AS3 has the potential to regulate tumorigenesis. Further, mechanistic studies demonstrated the potential of HOXC-AS3 in the transcriptional activation of TK1 via its binding to YBX1. Furthermore, the silencing of TK1 reversed HOXC-AS3-mediated increase in breast cancer cell growth and migration. In conclusion, these results indicated the potential value of HOXC-AS as a prognostic biological marker for breast cancer, and possibly, as a therapeutic target.

Cardiac toxicity is one of the major advese effect associated with thoracic irradiation. Breast cancer patients with human epidermal factor receptor-2 (Her-2) overexpression could be indicated for both radiation and anti-Her2 target therapy. We aimed to investigate the early detection of radiation and Trastuzumab (TRZ) induced acute cardiotoxicity in mice. In the present study, the heart of animal was subjected to irradiation (IR, 14 Gy/1 Fx), TRZ was intraperitonealy (i.p.) administrated to mice in 2 weeks (6 fractions). The IR plus TRZ group received heart IR after TRZ. We found that body weight of mouse in treatment groups reduced significantly as compared with that of mouse in control group (P