Coordinated regulation of mitochondrial topoisomerase IB with mitochondrial nuclear encoded genes and MYC

Mitochondrial DNA (mtDNA) is entirely dependent on nuclear genes for its transcription and replication. One of these genes is TOP1MT, which encodes the mitochondrial DNA topoisomerase IB, involved in mtDNA relaxation. To elucidate TOP1MT regulation, we performed genome-wide profiling across the 60-cell line panel (the NCI-60) of the National Cancer Institute Developmental Therapeutics Program. We show that TOP1MT mRNA expression varies widely across these cell lines with the highest levels in leukemia (HL-60, K-562) and melanoma (SK-MEL-28), intermediate levels in breast (MDA-MB-231), ovarian (OVCAR) and colon (HCT-116, HCT-15, KM-12), and lowest levels in renal (ACHN, A498), prostate (PC-3, DU-145) and central nervous system cell lines (SF-539, SF-268, SF-295). Genome-wide analyses show that TOP1MT expression is significantly correlated with the other mitochondrial nuclear-encoded genes including the mitochondrial nucleoid genes, and demonstrate an overall co-regulation of the mitochondrial nuclear-encoded genes. We also find very high correlation between the expression of TOP1MT and the proto-oncogene MYC (c-myc). TOP1MT contains E-boxes (c-myc binding sites) and TOP1MT transcription follows MYC up- and down-regulation by MYC promoter activation and siRNA against MYC. Our finding implicates MYC as a novel regulator of TOP1MT and confirms its role as a master regulator of MNEGs and mitochondrial nucleoids

Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS)

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody–associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21–1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57–3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22–26 vs. 22–27) and fewer with reduced GC (median, 23; IQR, 20–25) versus standard GC (median, 26; IQR, 25–28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality.publishedVersio

Sprint start training, progressive resistance training and the ability to accelerate to maximum velocity

The purpose of this study was to investigate the effect progressive resistance training has on the ability to accelerate to maximum velocity from an orthodox sprint start position. 32 subjects were randomly assigned to one of four treatment groups: Group I (Control, n = 9), Group II (Progressive Resistance Training, n = 8), Group III (Sprint Start Training, n = 10), Group IV (Combination Progressive Resistance and Sprint Start Training, n = 5). Groups II and IV met three times a week for six weeks to weight train using the Universal Machine and barbells. The subjects involved in orthodox sprint start training met three times per week and accelerated a distance of 50 meters for each trial. Each subject performed a total of 20 trials per session. Testing for the sprint performances occurred at the pre and post tests (first and seventh week). Acceleration and velocity maintenance time in running 50 meters was recorded, with times taken at 5, 10, 15, 20, 30, 40, and 50 meter intervals. The subjects were tested one week after the training had ceased (seventh week) to allow them to recover from the fatiguing effects of training. The Nissen Leg Dynamometer Test for leg extension strength was administered at the end of the third and seventh weeks. The remainder of the tests, Margaria Power Test, Hamstring strength test and Running Machine Test, were administered three times during the experimental period: during the first week, at the end of the third week and at the end of the seventh week. Analysis of variance yielded no significant difference between the various treatment conditions in sprinting, power and strength performance. No one treatment group improved more than the other. However, there was a significant trials effect in sprint, power and strength performance, for the four treatment groups, showing that there was a significant change in performance by all four treatment groups over the trial period. The results of this study tend to support those researchers who found no significant improvement in sprinting performance with the use of supplementary program of progressive resistance training. However, the conflict between the conclusions of this study, and other similar studies that found a significant relationship between progressive resistance training and sprinting performance, indicate that there is a great deal yet to be learned about this relationship. Experiments that deal with the application of more specific types of strength training to the art of sprinting, and experiments that investigate the mechanism limiting the rate of leg movement are needed.Education, Faculty ofCurriculum and Pedagogy (EDCP), Department ofGraduat