Human small cell lung cancer NYH cells resistant to the bisdioxopiperazine ICRF-187 exhibit a functional dominant Tyr165Ser mutation in the Walker A ATP binding site of topoisomerase IIα

AbstractBisdioxopiperazine anti-cancer agents are catalytic inhibitors of topoisomerase II which by unknown means lock the enzyme in a closed clamp form and inhibit its ATPase activity. In order to demarcate a putative pharmacophore, we here describe a novel Tyr165Ser mutation in the enzyme’s Walker A ATP binding site leading to specific bisdioxopiperazine resistance when transformed into a temperature-conditional yeast system. The Tyr165Ser mutation differed from a previously described Arg162Gln by being heterozygous and by purified Tyr165Ser enzyme being drug-resistant in a kinetoplast DNA decatenation enzymatic assay. This suggested dominant nature of Tyr165Ser was supported by co-transformation studies in yeast of plasmids carrying wild type and mutant genes. These results enable a model of the bisdioxopiperazine pharmacophore using the proposed asymmetric ATP hydrolysis of the enzyme

Operational river discharge forecasting in poorly gauged basins: the Kavango River Basin case study

Operational probabilistic forecasts of river discharge are essential for effective water resources management. Many studies have addressed this topic using different approaches ranging from purely statistical black-box approaches to physically based and distributed modeling schemes employing data assimilation techniques. However, few studies have attempted to develop operational probabilistic forecasting approaches for large and poorly gauged river basins. The objective of this study is to develop open-source software tools to support hydrologic forecasting and integrated water resources management in Africa. We present an operational probabilistic forecasting approach which uses public-domain climate forcing data and a hydrologic–hydrodynamic model which is entirely based on open-source software. Data assimilation techniques are used to inform the forecasts with the latest available observations. Forecasts are produced in real time for lead times of 0–7 days. The operational probabilistic forecasts are evaluated using a selection of performance statistics and indicators and the performance is compared to persistence and climatology benchmarks. The forecasting system delivers useful forecasts for the Kavango River, which are reliable and sharp. Results indicate that the value of the forecasts is greatest for intermediate lead times between 4 and 7 days

Operational river discharge forecasting in poorly gauged basins: the Kavango River basin case study

Operational probabilistic forecasts of river discharge are essential for effective water resources management. Many studies have addressed this topic using different approaches ranging from purely statistical black-box approaches to physically based and distributed modeling schemes employing data assimilation techniques. However, few studies have attempted to develop operational probabilistic forecasting approaches for large and poorly gauged river basins. The objective of this study is to develop open-source software tools to support hydrologic forecasting and integrated water resources management in Africa. We present an operational probabilistic forecasting approach which uses public-domain climate forcing data and a hydrologic–hydrodynamic model which is entirely based on open-source software. Data assimilation techniques are used to inform the forecasts with the latest available observations. Forecasts are produced in real time for lead times of 0–7 days. The operational probabilistic forecasts are evaluated using a selection of performance statistics and indicators and the performance is compared to persistence and climatology benchmarks. The forecasting system delivers useful forecasts for the Kavango River, which are reliable and sharp. Results indicate that the value of the forecasts is greatest for intermediate lead times between 4 and 7 days

Perceived barriers to career progression in the headache field : A global web-based cross-sectional survey

It is well recognized that underrepresented and minoritized groups do not have the same career opportunities. However, there are limited data on the range and specifics of potential barriers that withhold people in headache medicine and science from reaching their full potential. Moreover, people from different geographical regions often perceive different challenges. We aimed to identify world-wide perceived career barriers and possibilities for promoting equality amongst professionals in the headache fields. A cross-sectional online survey was conducted among professionals in the field of headache globally. The questions of the survey were aimed at assessing perceived career barriers in four domains: professional recognition, opportunities in scientific societies, clinical practice, and salary and compensation. Perceived mentorship was also assessed. In total 580 responders completed the survey (55.3% women). Gender was the most important perceived barrier in almost all domains. Additionally, country of birth emerged as an important barrier to participation in international scientific societies. Career barriers varied across world regions. It is essential that longstanding and ongoing disparities by gender and country of origin for professionals in the headache field are globally acknowledged and addressed in areas of recruitment, retention, opportunities, mentor- and sponsorships, and advancemen

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homeostatic contexts. They also suggest an epithelial contribution to Ret loss-of-function disorders such as Hirschsprung disease.Peer reviewe

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management