Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the development of resistance limits clinical efficacy. Mutations in the BRCA Cterminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1-mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1-mutant tumors acquire anticancer therapy resistance.homologous recombination | cancer therapy T he breast cancer 1, early onset (BRCA1) gene is commonly mutated in hereditary breast and ovarian cancers. The BRCA1 protein has multiple domains that mediate protein interactions; BRCA1 gene mutations may produce truncated proteins that lose the ability to interact with associated proteins. Additionally, mutations in the BRCA C-terminal (BRCT) domain of BRCA1 create protein folding defects that result in protease-mediated degradation (1-3).Cells that contain dysfunctional BRCA1 proteins are hypersensitive to DNA damaging agents (4). In particular, BRCA1-deficient cell lines are exquisitely sensitive to poly(ADP-ribose) polymerase (PARP) inhibition (5). Despite initial responses of BRCA1-mutant cancers to PARP inhibitor treatment (6), acquired resistance universally develops. Resistance may result from secondary mutations in the BRCA1 gene that restore the reading frame and produce a functional BRCA1 protein (7,8). In Brca1-mutated mouse mammary tumors, activation of p-glycoprotein or loss of p53 binding protein 1 (53BP1) expression resulting from truncating TP53BP1 mutations confers PARP inhibitor resistance (9). Loss of 53BP1 in BRCA1-deficient cells provides the Cterminal binding protein interacting protein (CtIP) with unrestricted access to DNA breaks, facilitating DNA end resection, an early step in homologous recombination (HR) (9-11).Following BRCA1-CtIP-mediated activation of DNA end resection, eventual BRCA2-mediated assembly of the RAD51 recombinase in nucleoprotein filaments is a critical step in HR. A role for BRCA1 in RAD51 loading and the mechanisms by which it participates have not been fully clarified. Of note, in PARP in...

The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease.

BackgroundThe effects of intermittent, high dose vitamin D treatment in older adults have not been documented. We conducted a meta-analysis to provide a quantitative assessment of the efficiency of intermittent, high dose vitamin D treatment on falls, fractures, and mortality among older adults.MethodsElectronic databases were searched for randomized controlled trials (RCTs) on high dose, intermittent vitamin D supplementation among older adults. Two researchers independently screened the literature according to specified inclusive and exclusive criteria to extract the data. Meta-analysis was performed by using Review Manager 5.1.0 software.ResultsNine trials were included in this meta-analysis. High dose, intermittent vitamin D therapy did not decrease all-cause mortality among older adults. The risk ratio (95% CI) was 1.04 (0.91–1.17). No benefit was seen in fracture or fall prevention. The risk ratio for hip fractures (95% CI) was 1.17 (0.97–1.41) while for non-vertebral fractures (95% CI) it was 1.06 (0.91–1.22), and the risk ratio for falls (95% CI) was 1.02 (0.96–1.08). Results remained robust after sensitivity analysis.ConclusionSupplementation of intermittent, high dose vitamin D may not be effective in preventing overall mortality, fractures, or falls among older adults. The route of administration of vitamin D supplements may well change the physiological effects.

The goal of this study was to evaluate real-time volumetric and dosimetric changes of the parotid gland so as to determine replanning criteria and timing for parotid protection-based adaptive radiation therapy in nasopharyngeal carcinoma. Fifty NPC patients were treated with helical tomotherapy; volumetric and dosimetric (D mean, V 1, and D 50) changes of the parotid gland at the 1st, 6th, 11th, 16th, 21st, 26th, 31st, and 33rd fractions were evaluated. The clinical parameters affecting these changes were studied by analyses of variance methods for repeated measures. Factors influencing the actual parotid dose were analyzed by a multivariate logistic regression model. The cut-off values predicting parotid overdose were developed from receiver operating characteristic curves and judged by combining them with a diagnostic test consistency check. The median absolute value and percentage of parotid volume reduction were 19.51 cm3 and 35%, respectively. The interweekly parotid volume varied significantly (p < 0.05). The parotid D mean, V 1, and D 50 increased by 22.13%, 39.42%, and 48.45%, respectively. The actual parotid dose increased by an average of 11.38% at the end of radiation therapy. Initial parotid volume, initial parotid D mean, and weight loss rate are valuable indicators for parotid protection-based replanning.