Finite Element Methods for Elliptic Distributed Optimal Control Problems with Pointwise State Constraints

Finite element methods for a model elliptic distributed optimal control problem with pointwise state constraints are considered from the perspective of fourth order boundary value problems

Incidence, mortality and survival patterns of prostate cancer among residents in Singapore from 1968 to 2002

<p>Abstract</p> <p>Background</p> <p>From 1968 to 2002, Singapore experienced an almost four-fold increase in prostate cancer incidence. This paper examines the incidence, mortality and survival patterns for prostate cancer among all residents in Singapore from 1968 to 2002.</p> <p>Methods</p> <p>This is a retrospective population-based cohort study including all prostate cancer cases aged over 20 (n = 3613) reported to the Singapore Cancer Registry from 1968 to 2002. Age-standardized incidence, mortality rates and 5-year Relative Survival Ratios (RSRs) were obtained for each 5-year period. Follow-up was ascertained by matching with the National Death Register until 2002. A weighted linear regression was performed on the log-transformed age-standardized incidence and mortality rates over period.</p> <p>Results</p> <p>The percentage increase in the age-standardized incidence rate per year was 5.0%, 5.6%, 4.0% and 1.9% for all residents, Chinese, Malays and Indians respectively. The percentage increase in age-standardized mortality rate per year was 5.7%, 6.0%, 6.6% and 2.5% for all residents, Chinese, Malays and Indians respectively. When all Singapore residents were considered, the RSRs for prostate cancer were fairly constant across the study period with slight improvement from 1995 onwards among the Chinese.</p> <p>Conclusion</p> <p>Ethnic differences in prostate cancer incidence, mortality and survival patterns were observed. There has been a substantial improvement in RSRs since the 1990s for the Chinese.</p

Impact of uncertainties in exposure assessment on estimates of thyroid cancer risk among Ukrainian children and adolescents exposed from the chernobyl accident

The 1986 accident at the Chernobyl nuclear power plant remains the most serious nuclear accident in history, and excess thyroid cancers, particularly among those exposed to releases of iodine-131 remain the best-documented sequelae. Failure to take dose-measurement error into account can lead to bias in assessments of dose-response slope. Although risks in the Ukrainian-US thyroid screening study have been previously evaluated, errors in dose assessments have not been addressed hitherto. Dose-response patterns were examined in a thyroid screening prevalence cohort of 13,127 persons aged <18 at the time of the accident who were resident in the most radioactively contaminated regions of Ukraine. We extended earlier analyses in this cohort by adjusting for dose error in the recently developed TD-10 dosimetry. Three methods of statistical correction, via two types of regression calibration, and Monte Carlo maximum-likelihood, were applied to the doses that can be derived from the ratio of thyroid activity to thyroid mass. The two components that make up this ratio have different types of error, Berkson error for thyroid mass and classical error for thyroid activity. The first regression-calibration method yielded estimates of excess odds ratio of 5.78 Gy-1 (95% CI 1.92, 27.04), about 7% higher than estimates unadjusted for dose error. The second regression-calibration method gave an excess odds ratio of 4.78 Gy-1 (95% CI 1.64, 19.69), about 11% lower than unadjusted analysis. The Monte Carlo maximum-likelihood method produced an excess odds ratio of 4.93 Gy-1 (95% CI 1.67, 19.90), about 8% lower than unadjusted analysis. There are borderline-significant (p= 0.101-0.112) indications of downward curvature in the dose response, allowing for which nearly doubled the low-dose linear coefficient. In conclusion, dose-error adjustment has comparatively modest effects on regression parameters, a consequence of the relatively small errors, of a mixture of Berkson and classical form, associated with thyroid dose assessment

Treatment of stage I seminoma: is it time to change your practice?

At the plenary session of the 2008 annual meeting of the American Society of Clinical Oncology, updated results were presented from a large randomized phase III trial comparing adjuvant radiation therapy (RT) and one cycle of Carboplatin for the adjuvant treatment of Stage I seminoma. Results of this Medical Research Council (MRC) trial led its investigators to conclude that one cycle of carboplatin was equivalent in safety and efficacy and less toxic than RT. In this editorial, the trial's design, statistics, toxicity, and length of follow-up are discussed within the context of historical treatments of this disease. With a 1.3% increase in relapse rate (5.3% with carboplatin vs. 4.0% with radiation), a 3% or greater increase in relapse rate could not be excluded, the primary endpoint of the study. A decrease in second testicular germ cell tumors was observed, but was equivalent to the increase in relapse rate. Acute toxicity was generally less with carboplatin. However, the extent of late toxicity, including late second neoplasms, cannot be evaluated because of the short median follow-up. Carboplatin is not yet a standard of care. Surveillance-based strategies, including risk-adapted policies that limit RT to patients with the greatest likelihood of relapse remain prudent at this time

Radiation-induced malignancies following radiotherapy for breast cancer

With advances in diagnosis and treatment, breast cancer is becoming an increasingly survivable disease resulting in a large population of long-term survivors. Factors affecting the quality of life of such patients include the consequences of breast cancer treatment, which may have involved radiotherapy. In this study, we compare the incidence of second primary cancers in women who received breast radiotherapy with that in those who did not (non-radiotherapy). All women studied received surgery for their first breast cancer. Second cancers of the lung, colon, oesophagus and thyroid gland, malignant melanomas, myeloid leukaemias and second primary breast cancers were studied. Comparing radiotherapy and non-radiotherapy cohorts, elevated relative risks (RR) were observed for lung cancer at 10-14 years and 15 or more (15+) years after initial breast cancer diagnosis (RR 1.62, 95% confidence interval [CI] 1.05-2.54 and RR 1.49, 95% CI 1.05-2.14, respectively), and for myeloid leukaemia at 1-5 years (RR 2.99, 95% CI 1.13-9.33), for second breast cancer at 5-10 years (RR 1.34, 95% CI 1.10-1.63) and 15+ years (RR 1.26, 95% CI 1.00-1.59) and oesophageal cancer at 15+ years (RR 2.19, 95% CI 1.10-4.62)

Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident

BACKGROUND: Previous studies showed an increased risk of thyroid cancer among children and adolescents exposed to radioactive iodines released after the Chornobyl (Chernobyl) accident, but the effects of screening, iodine deficiency, age at exposure and other factors on the dose-response are poorly understood. METHODS: We screened 11 970 individuals in Belarus aged 18 years or younger at the time of the accident who had estimated (131)I thyroid doses based on individual thyroid activity measurements and dosimetric data from questionnaires. The excess odds ratio per gray (EOR/Gy) was modelled using linear and linear-exponential functions. RESULTS: For thyroid doses \u3c5 \u3eGy, the dose-response was linear (n=85; EOR/Gy=2.15, 95% confidence interval: 0.81-5.47), but at higher doses the excess risk fell. The EOR/Gy was significantly increased among those with prior or screening-detected diffuse goiter, and larger for men than women, and for persons exposed before age 5 than those exposed between 5 and 18 years, although not statistically significant. A somewhat higher EOR/Gy was estimated for validated pre-screening cases. CONCLUSION: 10-15 years after the Chornobyl accident, thyroid cancer risk was significantly increased among individuals exposed to fallout as children or adolescents, but the risk appeared to be lower than in other Chornobyl studies and studies of childhood external irradiation

The C. elegans H3K27 Demethylase UTX-1 Is Essential for Normal Development, Independent of Its Enzymatic Activity

Epigenetic modifications influence gene expression and provide a unique mechanism for fine-tuning cellular differentiation and development in multicellular organisms. Here we report on the biological functions of UTX-1, the Caenorhabditis elegans homologue of mammalian UTX, a histone demethylase specific for H3K27me2/3. We demonstrate that utx-1 is an essential gene that is required for correct embryonic and postembryonic development. Consistent with its homology to UTX, UTX-1 regulates global levels of H3K27me2/3 in C. elegans. Surprisingly, we found that the catalytic activity is not required for the developmental function of this protein. Biochemical analysis identified UTX-1 as a component of a complex that includes SET-16(MLL), and genetic analysis indicates that the defects associated with loss of UTX-1 are likely mediated by compromised SET-16/UTX-1 complex activity. Taken together, these results demonstrate that UTX-1 is required for many aspects of nematode development; but, unexpectedly, this function is independent of its enzymatic activity

A Two-Gene Balance Regulates Salmonella Typhimurium Tolerance in the Nematode Caenorhabditis elegans

Lysozymes are antimicrobial enzymes that perform a critical role in resisting infection in a wide-range of eukaryotes. However, using the nematode Caenorhabditis elegans as a model host we now demonstrate that deletion of the protist type lysozyme LYS-7 renders animals susceptible to killing by the fatal fungal human pathogen Cryptococcus neoformans, but, remarkably, enhances tolerance to the enteric bacteria Salmonella Typhimurium. This trade-off in immunological susceptibility in C. elegans is further mediated by the reciprocal activity of lys-7 and the tyrosine kinase abl-1. Together this implies a greater complexity in C. elegans innate immune function than previously thought

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Physiological IRE-1-XBP-1 and PEK-1 Signaling in Caenorhabditis elegans Larval Development and Immunity

Endoplasmic reticulum (ER) stress activates the Unfolded Protein Response, a compensatory signaling response that is mediated by the IRE-1, PERK/PEK-1, and ATF-6 pathways in metazoans. Genetic studies have implicated roles for UPR signaling in animal development and disease, but the function of the UPR under physiological conditions, in the absence of chemical agents administered to induce ER stress, is not well understood. Here, we show that in Caenorhabditis elegans XBP-1 deficiency results in constitutive ER stress, reflected by increased basal levels of IRE-1 and PEK-1 activity under physiological conditions. We define a dynamic, temperature-dependent requirement for XBP-1 and PEK-1 activities that increases with immune activation and at elevated physiological temperatures in C. elegans. Our data suggest that the negative feedback loops involving the activation of IRE-1-XBP-1 and PEK-1 pathways serve essential roles, not only at the extremes of ER stress, but also in the maintenance of ER homeostasis under physiological conditions.National Institutes of Health (U.S.) (grant R01-GM084477