Genome-Wide Effects of Long-Term Divergent Selection

To understand the genetic mechanisms leading to phenotypic differentiation, it is important to identify genomic regions under selection. We scanned the genome of two chicken lines from a single trait selection experiment, where 50 generations of selection have resulted in a 9-fold difference in body weight. Analyses of nearly 60,000 SNP markers showed that the effects of selection on the genome are dramatic. The lines were fixed for alternative alleles in more than 50 regions as a result of selection. Another 10 regions displayed strong evidence for ongoing differentiation during the last 10 generations. Many more regions across the genome showed large differences in allele frequency between the lines, indicating that the phenotypic evolution in the lines in 50 generations is the result of an exploitation of standing genetic variation at 100s of loci across the genome

Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age ∼13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m−2/150 mg m−2 day−1, 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1–7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin–temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m−2 cisplatin and 150 mg m−2 × 5 temozolomide in heavily treated, and 200 mg m−2 × 5 temozolomide in less-heavily pretreated children

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer. © 1999 Cancer Research Campaig

Using Classical Population Genetics Tools with Heterochroneous Data: Time Matters!

BACKGROUND:New polymorphism datasets from heterochroneous data have arisen thanks to recent advances in experimental and microbial molecular evolution, and the sequencing of ancient DNA (aDNA). However, classical tools for population genetics analyses do not take into account heterochrony between subsets, despite potential bias on neutrality and population structure tests. Here, we characterize the extent of such possible biases using serial coalescent simulations. METHODOLOGY/PRINCIPAL FINDINGS:We first use a coalescent framework to generate datasets assuming no or different levels of heterochrony and contrast most classical population genetic statistics. We show that even weak levels of heterochrony ( approximately 10% of the average depth of a standard population tree) affect the distribution of polymorphism substantially, leading to overestimate the level of polymorphism theta, to star like trees, with an excess of rare mutations and a deficit of linkage disequilibrium, which are the hallmark of e.g. population expansion (possibly after a drastic bottleneck). Substantial departures of the tests are detected in the opposite direction for more heterochroneous and equilibrated datasets, with balanced trees mimicking in particular population contraction, balancing selection, and population differentiation. We therefore introduce simple corrections to classical estimators of polymorphism and of the genetic distance between populations, in order to remove heterochrony-driven bias. Finally, we show that these effects do occur on real aDNA datasets, taking advantage of the currently available sequence data for Cave Bears (Ursus spelaeus), for which large mtDNA haplotypes have been reported over a substantial time period (22-130 thousand years ago (KYA)). CONCLUSIONS/SIGNIFICANCE:Considering serial sampling changed the conclusion of several tests, indicating that neglecting heterochrony could provide significant support for false past history of populations and inappropriate conservation decisions. We therefore argue for systematically considering heterochroneous models when analyzing heterochroneous samples covering a large time scale

Status of the astrid gas power conversion system option

International audienceWithin the framework of the French 600 MWe Advanced Sodium Technological Reactor for Industrial Demonstration project, two options of Power Conversion System (PCS) were studied during the conceptual design phase (2010-2015)- the use of a classical Rankine water-steam cycle, similar to the solution implemented in France in Phenix and Superphenix , but with the goal of greatly reducing the probability of occurrence and limiting the potential consequences of a sodium-water reaction; chosen as the reference for the ASTRID Plant Model during the conceptual design phase due its high level of maturity,- the use of a Brayton gas cycle which has never been implemented in a Sodium Fast Reactor. Its application is mainly justified by safety and public acceptance considerations in inherently eliminating the sodium-water and sodium-water-air reaction risk existing with a Rankine cycle.The ASTRID conceptual design phase period allowed to greatly increase the maturity level of a standalone Gas Power Conversion System option. It has been thus decided to lay during the 2016-2017 phase the ASTRID Gas PCS integration studies at the same level as that achieved by ASTRID Water based PCS at the end of 2015. The 2016-2017 period, in which the Gas PCS has been integrated in the overall layout of the reactor, has allowed to better specify the technical and economic implications of the selection of gas PCS taking into account all the aspects of the integration of such an option. A well-documented comparison between the two systems is therefore facilitated.This paper resumes progress in the integration of the Gas Power Conversion System in the ASTRID Reactor Plant Model. It describes the main characteristics defined particularly on the Balance of Plant (BOP), the turbomachinery, the Sodium Gas Heat Exchangers (SGHE) as well as expected performances, operability and safety analysis

Progress in the ASTRID Gas Power Conversion System development

International audienceWithin the framework of the French 600 MWe Advanced Sodium Technological Reactor for Industrial Demonstration project (ASTRID), two options of Power Conversion System (PCS) were studied during the conceptual design phase (2010-2015)- the use of a classical Rankine water-steam cycle, similar to the solution implemented in France in Phenix and Superphenix, but with the goal of greatly reducing the probability of occurrence and limiting the potential consequences of a sodium-water reaction; chosen as the reference for the ASTRID Plant Model during the conceptual design phase due its high level of maturity,- an alternative approach using a Brayton gas cycle which has never been implemented in any Sodium Fast Reactor. Its application is mainly justified by safety and acceptance considerations in inherently eliminating the sodium-water and sodium-water-air reaction risk existing with a Rankine cycle.The ASTRID conceptual design phase period allowed to greatly increase the maturity level of a standalone Gas Power Conversion System option. Thus, it has been decided to lay during the 2016-2017 phase the ASTRID Gas PCS integration studies at the same level as that achieved by the ASTRID water-steam based PCS at the end of 2015. The 2016-2017 period, in which the Gas PCS is integrated in the overall layout of the reactor, will allow to better specify the technical and economic implications of the selection of the Gas PCS taking into account all the aspects of the integration of such an option. A well-documented comparison between the two systems will be therefore facilitated.This paper resumes progress in the integration of the Gas Power Conversion System in the Astrid Reactor Plant Model. It describes the characteristics of main systems particularly the turbomachinery, the Heat Exchangers (Sodium/Gas, Gas/Gas and Gas/Water) and the Gas Inventory Management System

Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta-Analysis

Purpose To assess the prognostic role of clinical parameters and histology in early childhood medulloblastoma. Patients and Methods Clinical and histologic data from 270 children younger than age 5 years diagnosed with medulloblastoma between March 1987 and July 2004 and treated within prospective trials of five national study groups were centrally analyzed. Results Two hundred sixty children with medulloblastoma and specified histologic subtype were eligible for analysis (median age, 1.89 years; median follow-up, 8.0 years). Rates for 8-year event-free survival (EFS) and overall survival (OS) were 55% and 76%, respectively, in 108 children with desmoplastic/nodular medulloblastoma (DNMB) or medulloblastoma with extensive nodularity (MBEN); 27% and 42%, respectively, in 145 children with classic medulloblastoma (CMB); and 14% and 14%, respectively, in seven children with large-cell/anaplastic (LC/A) medulloblastoma (P < .001). Histology (DNMB/MBEN: hazard ratio [HR], 0.44; 95% CI, 0.31 to 0.64; LC/A medulloblastoma: HR, 2.27; 95% CI, 0.95 to 5.54; P < .001 compared with CMB), incomplete resection and metastases (M0R1: HR, 1.86; 95% CI, 1.29 to 2.80; M+ : HR, 2.28; 95% CI, 1.50 to 3.46; P < .001 compared with M0R0), and national group were independent prognostic factors for EFS, and OS. The HRs for OS ranged from 0.14 for localized M0 and DNMB/MBEN to 13.67 for metastatic LC/A medulloblastoma in different national groups. Conclusion Our results confirm the high frequency of desmoplastic variants of medulloblastomas in early childhood and histopathology as a strong independent prognostic factor. A controlled de-escalation of treatment may be appropriate for young children with DNMB and MBEN in future clinical trials. J Clin Oncol 28:4961-4968. (C) 2010 by American Society of Clinical Oncolog