Hyperoxia Causes Mitochondrial Fragmentation in Pulmonary Endothelial Cells by Increasing Expression of Pro-Fission Proteins

Objective—We explored mechanisms that alter mitochondrial structure and function in pulmonary endothelial cells (PEC) function after hyperoxia. Approach and Results—Mitochondrial structures of PECs exposed to hyperoxia or normoxia were visualized and mitochondrial fragmentation quantified. Expression of pro-fission or fusion proteins or autophagy-related proteins were assessed by Western blot. Mitochondrial oxidative state was determined using mito-roGFP. Tetramethylrhodamine methyl ester estimated mitochondrial polarization in treatment groups. The role of mitochondrially derived reactive oxygen species in mt-fragmentation was investigated with mito-TEMPOL and mitochondrial DNA (mtDNA) damage studied by using ENDO III (mt-tat-endonuclease III), a protein that repairs mDNA damage. Drp-1 (dynamin-related protein 1) was overexpressed or silenced to test the role of this protein in cell survival or transwell resistance. Hyperoxia increased fragmentation of PEC mitochondria in a time-dependent manner through 48 hours of exposure. Hyperoxic PECs exhibited increased phosphorylation of Drp-1 (serine 616), decreases in Mfn1 (mitofusion protein 1), but increases in OPA-1 (optic atrophy 1). Pro-autophagy proteins p62 (LC3 adapter–binding protein SQSTM1/p62), PINK-1 (PTEN-induced putative kinase 1), and LC3B (microtubule-associated protein 1A/1B-light chain 3) were increased. Returning cells to normoxia for 24 hours reversed the increased mt-fragmentation and changes in expression of pro-fission proteins. Hyperoxia-induced changes in mitochondrial structure or cell survival were mitigated by antioxidants mito-TEMPOL, Drp-1 silencing, or inhibition or protection by the mitochondrial endonuclease ENDO III. Hyperoxia induced oxidation and mitochondrial depolarization and impaired transwell resistance. Decrease in resistance was mitigated by mito-TEMPOL or ENDO III and reproduced by overexpression of Drp-1. Conclusions—Because hyperoxia evoked mt-fragmentation, cell survival and transwell resistance are prevented by ENDO III and mito-TEMPOL and Drp-1 silencing, and these data link hyperoxia-induced mt-DNA damage, Drp-1 expression, mt-fragmentation, and PEC dysfunction

Hormonal content and potency of oral contraceptives and breast cancer risk among young women

A small study of women with early-onset breast cancer published in 1983 initially sparked the debate about combination oral contraceptives and breast cancer by suggesting that a woman's risk of breast cancer increased if she used oral contraceptives early in life, particularly pills with high progestin potency (Pike et al, 1983). Evidence from a multitude of case–control and cohort studies conducted in the 1980s and early 1990s subsequently found a modest (approximately 20–40%) but consistent excess in breast cancer risk associated with recent oral contraceptive use among women younger than 45 years of age (Collaborative Group on Hormonal Factors in Breast Cancer, 1996a). Whether this excess risk is ubiquitous for all pill types or attributable to specific oral contraceptive preparations is considerably less well studied

Reproductive outcomes in male childhood cancer survivors: a linked cancer-birth registry analysis

OBJECTIVE: Compare the risk of reproductive and infant outcomes between male childhood cancer survivors and a population-based comparison group. DESIGN: Retrospective cohort study. SETTING: 4 U.S. regions. PARTICIPANTS: Cancer registries identified males <20 years old diagnosed with cancer 1973-2000. Linked birth certificates identified first subsequent live offspring (n=470). Comparison subjects were identified from remaining birth certificates, frequency-matched on year and age at fatherhood, and race/ethnicity (n=4150). MAIN EXPOSURE: Cancer diagnosis prior to age 20. OUTCOME MEASURES: Pregnancy and infant outcomes identified from birth certificates. RESULTS: Compared with infants born to unaffected males, offspring of cancer survivors had a borderline risk of birth weight <2500 g (RR 1.43, 95% CI 0.99-2.05), with risk associated most strongly with younger age of cancer diagnosis and exposure to any chemotherapy (RR 1.96, 95% CI 1.22-3.17) or radiotherapy (RR 1.95, 95% CI 1.14-3.35). However, they were not at risk of being born prematurely, small for gestational age, having malformations or an altered male:female sex ratio. Overall, female partners of male survivors were not more likely to have maternal complications recorded on birth records versus the comparison group. However, preeclampsia was associated with some cancers, especially central nervous system tumors (RR 3.36, 95% CI 1.63-6.90). CONCLUSIONS: Most pregnancies resulting in live births among partners of male childhood cancer survivors were not at significantly greater risk of complications versus comparison subjects. The possibility of a paternal component affected by prior cancer history influencing predisposition towards some adverse perinatal outcomes merits further investigation

Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis

Objective: To compare birth outcomes among childhood and adolescent female cancer survivors who subsequently bear children, relative to those of women without cancer history. Design: Retrospective cohort study. Setting: 4 U.S. regions. Participants: Cancer registries identified girls <20 years, diagnosed with cancer 1973-2000. Linked birth records identified first live births after diagnosis (n=1898). Comparison subjects were selected from birth records (n=14278). Cervical/genital tract cancer cases were analyzed separately. Main Exposure: Cancer diagnosis <20 years. Outcome Measures: Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, delivery method; maternal diabetes, anemia, preeclampsia. Results: Childhood cancer survivors’ infants were more likely to be preterm (relative risk [RR] 1.54, 95% CI 1.30-1.83) and weigh <2500 g (RR 1.31, 95% CI 1.10-1.57). For cervical/genital cancer patients’ offspring, estimates were 1.33 (95% CI 1.13, 1.56), and 1.29 (95% CI 1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR 4.92, 95% CI 1.60-15.13), and anemia was more common among brain tumor survivors (RR 3.05, 95% CI 1.16-7.98) and childhood cancer survivors with initial treatment of chemotherapy only (RR 2.45, 95% CI 1.16-5.17). Conclusions: Infants of female childhood and adolescent cancer patients were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest close monitoring is warranted. Increased diabetes and anemia among sub-groups have not been reported, suggesting areas for study

Frequency of CHEK2 mutations in a population based, case–control study of breast cancer in young women

INTRODUCTION: The cell-cycle checkpoint kinase (CHEK)2 protein truncating mutation 1100delC has been associated with increased risk for breast or prostate cancer. Multiple studies have found an elevated frequency of the 1100delC variant in specific stratifications of breast cancer patients with a family history of the disease, including BRCA1/BRCA2 negative families and families with a history of bilateral disease or male breast cancer. However, the 1100delC mutation has only been investigated in a few population-based studies and none from North America. METHODS: We report here on the frequency of three CHEK2 variants that alter protein function – 1100delC, R145W, and I175T – in 506 cases and 459 controls from a population based, case–control study of breast cancer conducted in young women from western Washington. RESULTS: There was a suggestive enrichment in the 1100delC variant in the cases (1.2%) as compared with the controls (0.4%), but this was based on small numbers of carriers and the differences were not statistically significant. The 1100delC variant was more frequent in cases with a first-degree family history of breast cancer (4.3%; P = 0.02) and slightly enriched in cases with a family history of ovarian cancer (4.4%; P = 0.09). CONCLUSION: The CHEK2 variants are rare in the western Washington population and, based on accumulated evidence across studies, are unlikely to be major breast cancer susceptibility genes. Thus, screening for the 1100delC variant may have limited usefulness in breast cancer prevention programs in the USA

Praktijkervaringen met waterberging en natuur in een beekdal : achtergrondrapport : Beerze

Hoofddoel van het pilotprogramma is waterbeheerders, terreinbeherende instanties en provincies te ondersteunen in hun activiteiten een koppeling tot stand te brengen tussen waterberging en - buffering en natuurbehoud en -ontwikkeling. Eén van de geselecteerde pilots uit het pilotprogramma ligt langs de Beerze. De Beerze is representatief voor de huidige situatie in veel Brabantse beekdalen: er is sprake van een waterkwantiteitsprobleem, en (tijdelijke) berging van het beekwater in natuurgebieden stuit op problemen, vooral vanwege de (eutrofe) waterkwaliteit. Tegelijkertijd speelt verdroging van natuurgebieden een rol. De pilot Beerze ligt in het traject Logtse Baan - Logtse Velden - Smalbroeken. De onderzoeksperiode van deze pilot besloeg 2004 tot medio 200

Analysis of Radiation Doses from Operation of Postulated Commercial Spent Fuel Transportation Systems

This report contains a system study of estimated radiation doses to the public and workers resulting from the transport of spent fuel from commercial nuclear power reactors to a geologic repository. The report contains a detailed breakdown of activities and a description of time/distance/dose-rate estimates for each activity within the system. Collective doses are estimated for each of the major activities at the reactor site, in transit, and at the repository receiving facility. Annual individual doses to the maximally exposed individuals or groups of individuals are also estimated. A total of 17 alternatives and subalternatives to the postulated reference transportation system are identified, conceptualized, and their dose-reduction potentials and costs estimated. Resulting ratios of ..delta..cost/..delta..collective system dose for each alternative relative to the postulated reference transportation system are given. Most of the alternatives evaluated are estimated to provide both cost and dose reductions. Major reductions in transportation system dose and cost are estimated to result from using higher-capacity rail and truck casks, and particularly when replacing legalweight truck casks with ''advanced design'' overweight truck casks. The greatest annual dose reduction to the highest exposed individual workers (i.e., at the repository) is estimated to be achieved by using remote handling equipment for the cask handling operations at the repository. Additional shielding is also effective in reducing doses to both radiation workers at the reactor and repository and to transport workers. 69 refs., 36 figs., 156 tabs