Optimizing Performance of Continuous-Time Stochastic Systems using Timeout Synthesis

We consider parametric version of fixed-delay continuous-time Markov chains (or equivalently deterministic and stochastic Petri nets, DSPN) where fixed-delay transitions are specified by parameters, rather than concrete values. Our goal is to synthesize values of these parameters that, for a given cost function, minimise expected total cost incurred before reaching a given set of target states. We show that under mild assumptions, optimal values of parameters can be effectively approximated using translation to a Markov decision process (MDP) whose actions correspond to discretized values of these parameters

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G2 assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (P<0.001). Using the 90th percentile of the G2 scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P=0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (⩽50 years, 1.32 breaks per cell, 38%) and in the non- and light smoking patient group (⩽10 pack-years, 1.28 breaks per cell, 46%). In conclusion, enhanced chromosomal radiosensitivity is a marker of genetic predisposition to head and neck cancer, and the genetic contribution is highest for oral cavity and pharynx cancer patients and for early onset and non- and light smoking patients

Validation of the use of Actigraph GT3X accelerometers to estimate energy expenditure in full time manual wheel chair users with Spinal Cord Injury

Study design: Cross-sectional validation study. Objectives: The goals of this study were to validate the use of accelerometers by means of multiple linear models (MLMs) to estimate the O2 consumption (VO2) in paraplegic persons and to determine the best placement for accelerometers on the human body. Setting: Non-hospitalized paraplegics’ community. Methods: Twenty participants (age=40.03 years, weight=75.8 kg and height=1.76 m) completed sedentary, propulsion and housework activities for 10 min each. A portable gas analyzer was used to record VO2. Additionally, four accelerometers (placed on the non-dominant chest, non-dominant waist and both wrists) were used to collect second-by-second acceleration signals. Minute-by-minute VO2 (ml kg−1 min−1) collected from minutes 4 to 7 was used as the dependent variable. Thirty-six features extracted from the acceleration signals were used as independent variables. These variables were, for each axis including the resultant vector, the percentiles 10th, 25th, 50th, 75th and 90th; the autocorrelation with lag of 1 s and three variables extracted from wavelet analysis. The independent variables that were determined to be statistically significant using the forward stepwise method were subsequently analyzed using MLMs. Results: The model obtained for the non-dominant wrist was the most accurate (VO2=4.0558−0.0318Y25+0.0107Y90+0.0051YND2−0.0061ZND2+0.0357VR50) with an r-value of 0.86 and a root mean square error of 2.23 ml kg−1 min−1. Conclusions: The use of MLMs is appropriate to estimate VO2 by accelerometer data in paraplegic persons. The model obtained to the non-dominant wrist accelerometer (best placement) data improves the previous models for this population.LM Garcia-Raffi and EA Sanchez-Perez gratefully acknowledge the support of the Ministerio de Economia y Competitividad under project #MTM2012-36740-c02-02. X Garcia-Masso is a Vali + D researcher in training with support from the Generalitat Valenciana.Garcia Masso, X.; Serra Añó, P.; García Raffi, LM.; Sánchez Pérez, EA.; Lopez Pascual, J.; González, L. (2013). Validation of the use of Actigraph GT3X accelerometers to estimate energy expenditure in full time manual wheel chair users with Spinal Cord Injury. Spinal Cord. 51(12):898-903. https://doi.org/10.1038/sc.2013.85S8989035112Van den Berg-Emons RJ, Bussmann JB, Haisma JA, Sluis TA, van der Woude LH, Bergen MP et al. A prospective study on physical activity levels after spinal cord injury during inpatient rehabilitation and the year after discharge. Arch Phys Med Rehabil 2008; 89: 2094–2101.Jacobs PL, Nash MS . Exercise recommendations for individuals with spinal cord injury. Sports Med 2004; 34: 727–751.Erikssen G . Physical fitness and changes in mortality: the survival of the fittest. Sports Med 2001; 31: 571–576.Warburton DER, Nicol CW, Bredin SSD . Health benefits of physical activity: the evidence. CMAJ 2006; 174: 801–809.Haennel RG, Lemire F . Physical activity to prevent cardiovascular disease. How much is enough? Can Fam Physician 2002; 48: 65–71.Manns PJ, Chad KE . Determining the relation between quality of life, handicap, fitness, and physical activity for persons with spinal cord injury. Arch Phys Med Rehabil 1999; 80: 1566–1571.Hetz SP, Latimer AE, Buchholz AC, Martin Ginis KA . Increased participation in activities of daily living is associated with lower cholesterol levels in people with spinal cord injury. Arch Phys Med Rehabil 2009; 90: 1755–1759.Buchholz AC, Martin Ginis KA, Bray SR, Craven BC, Hicks AL, Hayes KC et al. Greater daily leisure time physical activity is associated with lower chronic disease risk in adults with spinal cord injury. Appl Physiol Nutr Metab 2009; 34: 640–647.Slater D, Meade MA . Participation in recreation and sports for persons with spinal cord injury: review and recommendations. Neurorehabilitation 2004; 19: 121–129.Valanou EM, Bamia C, Trichopoulou A . Methodology of physical-activity and energy-expenditure assessment: a review. J Public Health 2006; 14: 58–65.Liu S, Gao RX, Freedson PS . Computational methods for estimating energy expenditure in human physical activities. Med Sci Sports Exerc 2012; 44: 2138–2146.Troiano RP, Berrigan D, Dodd KW, Mâsse LC, Tilert T, McDowell M . Physical activity in the United States measured by accelerometer. Med Sci Sports Exerc 2008; 40: 181–188.Riddoch CJ, Bo Andersen L, Wedderkopp N, Harro M, Klasson-Heggebø L, Sardinha LB et al. Physical activity levels and patterns of 9- and 15-yr-old European children. Med Sci Sports Exerc 2004; 36: 86–92.Hiremath SV, Ding D . Evaluation of activity monitors in manual wheelchair users with paraplegia. J Spinal Cord Med 2011; 34: 110–117.Hiremath SV, Ding D . Evaluation of activity monitors to estimate energy expenditure in manual wheelchair users. Conf Proc IEEE Eng Med Biol Soc 2009; 2009: 835–838.Washburn R, Copay A . Assessing physical activity during wheelchair pushing: validity of a portable accelerometer. Adapt Phys Activ Q 1999; 16: 290–299.Hiremath SV, Ding D . Regression equations for RT3 activity monitors to estimate energy expenditure in manual wheelchair users. Conf Proc IEEE Eng Med Biol Soc 2011; 2011: 7348–7351.Hiremath SV, Ding D, Farringdon J, Cooper RA . Predicting energy expenditure of manual wheelchair users with spinal cord injury using a multisensor-based activity monitor. Arch Phys Med Rehabil 2012; 93: 1937–1943.Bassett DR Jr, Ainsworth BE, Swartz AM, Strath SJ, O’Brien WL, King GA . Validity of four motion sensors in measuring moderate intensity physical activity. Med Sci Sports Exerc 2000; 32: S471–S480.Motl RW, Sosnoff JJ, Dlugonski D, Suh Y, Goldman M . Does a waist-worn accelerometer capture intra- and inter-person variation in walking behavior among persons with multiple sclerosis? Med Eng Phys 2010; 32: 1224–1228.Van Remoortel H, Raste Y, Louvaris Z, Giavedoni S, Burtin C, Langer D et al. Validity of six activity monitors in chronic obstructive pulmonary disease: a comparison with indirect calorimetry. PLoS One 2012; 7: e39198.Macfarlane DJ . Automated metabolic gas analysis systems: a review. Sports Med 2001; 31: 841–861.Staudenmayer J, Pober D, Crouter S, Bassett D, Freedson P . An artificial neural network to estimate physical activity energy expenditure and identify physical activity type from an accelerometer. J Appl Physiol 2009; 107: 1300–1307.Daubechies I . Ten Lectures on Wavelets. SIAM, Philadelphia. 1999.Debnat I . Wavelets and Signal Processing. Birkhauser, Boston. 2003.Collins EG, Gater D, Kiratli J, Butler J, Hanson K, Langbein WE . Energy cost of physical activities in persons with spinal cord injury. Med Sci Sports Exerc 2010; 42: 691–700.Lee M, Zhu W, Hedrick B, Fernhall B . Determining metabolic equivalent values of physical activities for persons with paraplegia. Disabil Rehabil 2010; 32: 336–343.Crouter SE, Clowers KG, Bassett DR Jr . A novel method for using accelerometer data to predict energy expenditure. J Appl Physiol 2006; 100: 1324–1331

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Evaluation of the efficacy and safety of olanzapine as an adjunctive treatment for anorexia nervosa in adolescent females: a randomized, double-blind, placebo-controlled trial

<p>Abstract</p> <p>Background</p> <p>Anorexia Nervosa (AN) is a serious, debilitating condition that causes significant physical, emotional, and functional impairment. The condition is characterized by destructive weight loss behaviours and a refusal to maintain body weight at or above a minimally normal weight for age and height. AN often develops in adolescence and is a predominantly female disorder. Treatment for AN typically involves medical, nutritional and psychological interventions. Pharmacotherapy is also often used; however, the literature on the effectiveness of these drugs in a pediatric population is very limited. Olanzapine, which is an 'atypical' antipsychotic, is becoming more widespread in the treatment of AN. Olanzapine is hypothesized to facilitate weight gain, while decreasing levels of agitation and decreasing resistance to treatment in young women with AN. This randomized, double-blind placebo-controlled trial seeks to examine the effectiveness and safety of olanzapine in female youth with AN.</p> <p>Methods/Design</p> <p>Adolescent females between the ages of 12 and 17 diagnosed with AN (either restricting or binge/purge type) or Eating Disorder Not Otherwise Specified with a Body Mass Index of less than or equal to 17.5, will be offered inclusion in the study. Patients will be randomly assigned to receive either olanzapine or placebo. Patients assigned to receive olanzapine will start at a low dose of 1.25 mg/day for three days, followed by 2.5 mg/day for four days, 5 mg/day for one week, then 7.5 mg/day (the target dose chosen) for 10 weeks. After 10 weeks at 7.5 mg the medication will be tapered and discontinued over a period of two weeks. The effectiveness of olanzapine versus placebo will be determined by investigating the change from baseline on measures of eating attitudes and behaviors, depression and anxiety, and change in Body Mass Index at week 12, and after a follow-up period at week 40. It is anticipated that 67 participants will be recruited over two years to complete enrollment.</p> <p>Discussion</p> <p>Randomized controlled trials designed to measure the safety and effectiveness of olanzapine in comparison to placebo are desperately needed, particularly in the adolescent population.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN23032339</p

Ptc6 is required for proper rapamycin-induced down-regulation of the genes coding for ribosomal and rRNA processing proteins in S. cerevisiae

Ptc6 is one of the seven components (Ptc1-Ptc7) of the protein phosphatase 2C family in the yeast Saccharomyces cerevisiae. In contrast to other type 2C phosphatases, the cellular role of this isoform is poorly understood. We present here a comprehensive characterization of this gene product. Cells lacking Ptc6 are sensitive to zinc ions, and somewhat tolerant to cell-wall damaging agents and to Li+. Ptc6 mutants are sensitive to rapamycin, albeit to lesser extent than ptc1 cells. This phenotype is not rescued by overexpression of PTC1 and mutation of ptc6 does not reproduce the characteristic geneti

Differential responses to doxorubicin-induced phosphorylation and activation of Akt in human breast cancer cells

INTRODUCTION: We have shown previously that overexpression of constitutively active Akt or activation of Akt caused by constitutively active Ras or human epidermal growth factor receptor-2 (HER2) confers on breast cancer cells resistance to chemotherapy or radiotherapy. As an expanded study we here report differential responses in terms of phosphorylation and activation of Akt as a result of treatment with doxorubicin in a panel of breast cancer cell lines. METHODS: The levels of Akt phosphorylation and activity were measured by Western blot analysis with an anti-Ser473-phosphorylated Akt antibody and by in vitro Akt kinase assay using glycogen synthase kinase-3 as a substrate. RESULTS: Within 24 hours after exposure to doxorubicin, MCF7, MDA468 and T47D cells showed a drug-dose-dependent increase in the levels of phosphorylated Akt; in contrast, SKBR3 and MDA231 cells showed a decrease in the levels of phosphorylated Akt, and minimal or no changes were detected in MDA361, MDA157 and BT474 cells. The doxorubicin-induced Akt phosphorylation was correlated with increased kinase activity and was dependent on phosphoinositide 3-kinase (PI3-K). An increased baseline level of Akt was also found in MCF7 cells treated with ionizing radiation. The cellular responses to doxorubicin-induced Akt phosphorylation were potentiated after the expression of Akt upstream activators including HER2, HER3 and focal adhesion kinase. CONCLUSION: Taken together with our recent published results showing that constitutive Akt mediates resistance to chemotherapy or radiotherapy, our present data suggest that the doxorubicin-induced phosphorylation and activation of Akt might reflect a cellular defensive mechanism of cancer cells to overcome doxorubicin-induced cytotoxic effects, which further supports the current efforts of targeting PI3-K/Akt for enhancing the therapeutic responses of breast cancer cells to chemotherapy and radiotherapy

Chemotherapy Synergizes with Radioimmunotherapy Targeting La Autoantigen in Tumors

To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 (90Y)-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment. Methodology/Principal Findings: Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB®, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-​tetraacetic acid (DOTA), and then radiolabeled with 90Y. Mice bearing established subcutaneous tumors were treated with 90Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2) model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of 90Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants. Conclusions/Significance: We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4-targeted ionizing radiation induces additional cycles of tumor cell death, which further augments DAB4 binding to produce a tumor-lethal ‘genotoxic chain reaction’. Clinically, this approach may be useful as consolidation treatment after a drug-induced cell death among (small-volume) metastatic deposits, the commonest cause of cancer death. This article is part II of a two-part series providing proof-of-concept for the diagnostic and therapeutic use of the DAB4 clone of the La-specific monoclonal antibody, APOMAB®.Fares Al-Ejeh, Jocelyn M. Darby and Michael P. Brow