Adaptation of sea turtles to climate warming: Will phenological responses be sufficient to counteract changes in reproductive output?

Sea turtles are vulnerable to climate change since their reproductive output is influenced by incubating temperatures, with warmer temperatures causing lower hatching success and increased feminization of embryos. Their ability to cope with projected increases in ambient temperatures will depend on their capacity to adapt to shifts in climatic regimes. Here, we assessed the extent to which phenological shifts could mitigate impacts from increases in ambient temperatures (from 1.5 to 3°C in air temperatures and from 1.4 to 2.3°C in sea surface temperatures by 2100 at our sites) on four species of sea turtles, under a "middle of the road" scenario (SSP2-4.5). Sand temperatures at sea turtle nesting sites are projected to increase from 0.58 to 4.17°C by 2100 and expected shifts in nesting of 26-43 days earlier will not be sufficient to maintain current incubation temperatures at 7 (29%) of our sites, hatching success rates at 10 (42%) of our sites, with current trends in hatchling sex ratio being able to be maintained at half of the sites. We also calculated the phenological shifts that would be required (both backward for an earlier shift in nesting and forward for a later shift) to keep up with present-day incubation temperatures, hatching success rates, and sex ratios. The required shifts backward in nesting for incubation temperatures ranged from -20 to -191 days, whereas the required shifts forward ranged from +54 to +180 days. However, for half of the sites, no matter the shift the median incubation temperature will always be warmer than the 75th percentile of current ranges. Given that phenological shifts will not be able to ameliorate predicted changes in temperature, hatching success and sex ratio at most sites, turtles may need to use other adaptive responses and/or there is the need to enhance sea turtle resilience to climate warming.

Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Bayesian sample size determination for diagnostic accuracy studies.

The development of a new diagnostic test ideally follows a sequence of stages which, among other aims, evaluate technical performance. This includes an analytical validity study, a diagnostic accuracy study, and an interventional clinical utility study. In this article, we propose a novel Bayesian approach to sample size determination for the diagnostic accuracy study, which takes advantage of information available from the analytical validity stage. We utilize assurance to calculate the required sample size based on the target width of a posterior probability interval and can choose to use or disregard the data from the analytical validity study when subsequently inferring measures of test accuracy. Sensitivity analyses are performed to assess the robustness of the proposed sample size to the choice of prior, and prior-data conflict is evaluated by comparing the data to the prior predictive distributions. We illustrate the proposed approach using a motivating real-life application involving a diagnostic test for ventilator associated pneumonia. Finally, we compare the properties of the approach against commonly used alternatives. The results show that, when suitable prior information is available, the assurance-based approach can reduce the required sample size when compared to alternative approaches.

Generalisations of a Bayesian decision-theoretic randomisation procedure and the impact of delayed responses.

The design of sequential experiments and, in particular, randomised controlled trials involves a trade-off between operational characteristics such as statistical power, estimation bias and patient benefit. The family of randomisation procedures referred to as Constrained Randomised Dynamic Programming (CRDP), which is set in the Bayesian decision-theoretic framework, can be used to balance these competing objectives. A generalisation and novel interpretation of CRDP is proposed to highlight its inherent flexibility to adapt to a variety of practicalities and align with individual trial objectives. CRDP, as with most response-adaptive randomisation procedures, hinges on the limiting assumption of patient responses being available before allocation of the next patient. This forms one of the greatest barriers to their implementation in practice which, despite being an important research question, has not received a thorough treatment. Therefore, motivated by the existing gap between the theory of response-adaptive randomisation (which is abundant with proposed methods in the immediate response setting) and clinical practice (in which responses are typically delayed), the performance of CRDP in the presence of fixed and random delays is evaluated. Simulation results show that CRDP continues to offer patient benefit gains over alternative procedures and is relatively robust to delayed responses. To compensate for a fixed delay, a method which adjusts the time horizon used in the optimisation objective is proposed and its performance illustrated.

Selective Ion Acceleration by Intense Radiation Pressure.

We report on the selective acceleration of carbon ions during the interaction of ultrashort, circularly polarized and contrast-enhanced laser pulses, at a peak intensity of 5.5×10^{20} W/cm^{2}, with ultrathin carbon foils. Under optimized conditions, energies per nucleon of the bulk carbon ions reached significantly higher values than the energies of contaminant protons (33 MeV/nucleon vs 18 MeV), unlike what is typically observed in laser-foil acceleration experiments. Experimental data, and supporting simulations, emphasize different dominant acceleration mechanisms for the two ion species and highlight an (intensity dependent) optimum thickness for radiation pressure acceleration; it is suggested that the preceding laser energy reaching the target before the main pulse arrives plays a key role in a preferential acceleration of the heavier ion species.

Atopic dermatitis in the elderly: a review of clinical and pathophysiological hallmarks.

BACKGROUND: Atopic dermatitis (AD) is a multifactorial and complex disease, characterized by an impaired skin barrier function and abnormal immune response. Many elderly patients present with pruritus and xerosis to dermatology, allergy and primary care clinics, and there is a lack of information available to clinicians regarding the proper diagnosis and management of these patients. Although the elderly are described as having a distinct presentation of AD and important comorbidities, most investigations and clinical care guidelines pertaining to AD do not include patients aged 60 years and older as a separate group from younger adults. OBJECTIVES: To summarize current information on pathophysiology, diagnosis and management of AD in the elderly population and identify areas of insufficient information to be explored in future investigations. METHODS: We carried out a systematic review of published literature, which assessed changes in the skin barrier and immune function with ageing and current information available for physicians to use in the diagnosis and treatment of AD in elderly patients. RESULTS: Many age-related changes overlap with key hallmarks observed in AD, most notably a decline in skin barrier function, dysregulation of the innate immune system, and skewing of adaptive immunity to a type-2 T helper cell response, in addition to increased Staphylococcus aureus infection. CONCLUSIONS: While general physiological alterations with ageing overlap with key features of AD, a research gap exists regarding specific ageing-related changes in AD disease development. More knowledge about AD in the elderly is needed to establish firm diagnostic and treatment methodologies. What's already known about this topic? Atopic dermatitis (AD) is a common inflammatory skin disease that causes significant burden worldwide. Recently, elderly patients have been considered a subgroup of patients with distinct AD manifestation. Limited studies have characterized the clinical presentation and role of IgE-mediated allergy in elderly patients with AD. What does this study add? This review offers a summary of age-related skin and immune alterations that correspond to pathogenic changes noted in patients with AD. The role of itch, environmental factors and skin microbiota in AD disease presentation in ageing patients is explored.

A response-adaptive randomization procedure for multi-armed clinical trials with normally distributed outcomes.

We propose a novel response-adaptive randomization procedure for multi-armed trials with continuous outcomes that are assumed to be normally distributed. Our proposed rule is non-myopic, and oriented toward a patient benefit objective, yet maintains computational feasibility. We derive our response-adaptive algorithm based on the Gittins index for the multi-armed bandit problem, as a modification of the method first introduced in Villar et al. (Biometrics, 71, pp. 969-978). The resulting procedure can be implemented under the assumption of both known or unknown variance. We illustrate the proposed procedure by simulations in the context of phase II cancer trials. Our results show that, in a multi-armed setting, there are efficiency and patient benefit gains of using a response-adaptive allocation procedure with a continuous endpoint instead of a binary one. These gains persist even if an anticipated low rate of missing data due to deaths, dropouts, or complete responses is imputed online through a procedure first introduced in this paper. Additionally, we discuss how there are response-adaptive designs that outperform the traditional equal randomized design both in terms of efficiency and patient benefit measures in the multi-armed trial context.

Influence of temperature on prevalence of health and welfare conditions in pigs: time-series analysis of pig abattoir inspection data in England and Wales.

The prevalence of many diseases in pigs displays seasonal distributions. Despite growing concerns about the impacts of climate change, we do not yet have a good understanding of the role that weather factors play in explaining such seasonal patterns. In this study, national and county-level aggregated abattoir inspection data were assessed for England and Wales during 2010-2015. Seasonally-adjusted relationships were characterised between weekly ambient maximum temperature and the prevalence of both respiratory conditions and tail biting detected at slaughter. The prevalence of respiratory conditions showed cyclical annual patterns with peaks in the summer months and troughs in the winter months each year. However, there were no obvious associations with either high or low temperatures. The prevalence of tail biting generally increased as temperatures decreased, but associations were not supported by statistical evidence: across all counties there was a relative risk of 1.028 (95% CI 0.776-1.363) for every 1 °C fall in temperature. Whilst the seasonal patterns observed in this study are similar to those reported in previous studies, the lack of statistical evidence for an explicit association with ambient temperature may possibly be explained by the lack of information on date of disease onset. There is also the possibility that other time-varying factors not investigated here may be driving some of the seasonal patterns.

An optically multiplexed single-shot time-resolved probe of laser-plasma dynamics.

We introduce a new approach to temporally resolve ultrafast micron-scale processes via the use of a multi-channel optical probe. We demonstrate that this technique enables highly precise time-resolved, two-dimensional spatial imaging of intense laser pulse propagation dynamics, plasma formation and laser beam filamentation within a single pulse over four distinct time frames. The design, development and optimization of the optical probe system is presented, as are representative experimental results from the first implementation of the multi-channel probe with a high-power laser pulse interaction with a helium gas jet target.

Innovative playgrounds: use, physical activity, and implications for health.

OBJECTIVES: The aim of the study is to assess the use and levels of moderate-to-vigorous physical activity (MVPA) occurring in innovative playgrounds in London vs. traditional playgrounds in the US in neighborhoods with a similar population density. STUDY DESIGN: This is a cross-sectional observational study. METHODS: We selected a sample of London playgrounds based on their innovative design. One group of eight playgrounds was matched to the US playgrounds by size and population density; a second group of very large London playgrounds was matched only by population density. Playground use and person-hours of MVPA were measured using direct observation at similar times of the day and days of the week in all locations. RESULTS: The number of playground visit hours was 58% higher in London than in the US (394 vs 249). The matched London playgrounds had 37.8% more children and 129% more adults who were, respectively, engaging in 90% and 116% more MVPA. While the London playgrounds were nearly 8.5 times larger than the US ones, they attracted a total of 5.8 times more visitors (1399 vs 243, P < .0001), and this included 10 times as many adults (679 vs. 66, P < .0001) and 7.5 times more seniors (23 vs. 3). The London playgrounds included more amenities targeting adults. CONCLUSIONS: The design of an innovative playground was associated with the amount of MVPA in similar-sized playgrounds, but the size of the playground was more strongly associated with the number of visitors. It is as important to design playgrounds for adults as it is for children to increase visit hours.

Longitudinal study on the occurrence in pigs of colistin-resistant Escherichia coli carrying mcr-1 following the cessation of use of colistin.

AIMS: In 2015, colistin-resistant Escherichia coli and Salmonella with the mcr-1 gene were isolated from a pig farm in Great Britain. Pigs were subsequently monitored over a ~20-month period for the occurrence of mcr-1-mediated colistin resistance and the risk of mcr-1 E. coli entering the food chain was assessed. METHODS AND RESULTS: Pig faeces and slurry were cultured for colistin-resistant E. coli and Salmonella, tested for the mcr-1 gene by PCR and selected isolates were further analysed. Seventy-eight per cent of faecal samples (n = 275) from pigs yielded mcr-1 E. coli after selective culture, but in positive samples only 0·2-1·3% of the total E. coli carried mcr-1. Twenty months after the initial sampling, faecal samples (n = 59) were negative for E. coli carrying mcr-1. CONCLUSIONS: The risk to public health from porcine E. coli carrying mcr-1 was assessed as very low. Twenty months after cessation of colistin use, E. coli carrying mcr-1 was not detected in pig faeces on a farm where it was previously present. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggest that cessation of colistin use may help over time to reduce or possibly eliminate mcr-1 E. coli on pig farms where it occurs.

Costs of fragility hip fractures globally: a systematic review and meta-regression analysis.

Purpose This study was conducted in order to systematically review the costs of hip fractures globally and identify drivers of differences in costs. Methods A systematic review was conducted to identify studies reporting patient level fragility hip fracture costs between 1990 and 2015. We extracted data on the participants and costs from these studies. Cost data concerning the index hospitalisation were pooled, and a meta-regression was used to examine its potential drivers. We also pooled data on the first-year costs following hip fracture and considered healthcare, social care as well as other cost categories if reported by studies. Results One hundred and thirteen studies reported costs of hip fracture based on patient level data. Patients developing complications as well as patients enrolled in intervention arms of comparative studies were found to have significantly higher costs compared to the controls. The pooled estimate of the cost for the index hospitalisation was $10,075. Health and social care costs at 12 months were $43,669 with inpatient costs being their major driver. Meta-regression analysis identified age, gender and geographic region as being significantly associated with the differences in costs for the index hospitalisation. Conclusion Hip fracture poses a significant economic burden and variation exists in their costs across different regions. We found that there was a considerable variation across studies in terms of study design, methodology, follow-up period, costs considered and results reported that highlights the need for more standardisation in this area of research.

Comparing hospital and telephone follow-up for patients treated for stage-I endometrial cancer (ENDCAT trial): a randomised, multicentre, non-inferiority trial.

OBJECTIVE: To evaluate the effectiveness of nurse-led telephone follow-up (TFU) for patients with stage-I endometrial cancer. DESIGN: Multicentre, randomised, non-inferiority trial. SETTING: Five centres in the North West of England. SAMPLE: A cohort of 259 women treated for stage-I endometrial cancer attending hospital outpatient clinics for routine follow-up. METHODS: Participants were randomly allocated to receive traditional hospital based follow-up (HFU) or nurse-led TFU. MAIN OUTCOME MEASURES: Primary outcomes were psychological morbidity (State Trait Anxiety Inventory, STAI-S) and patient satisfaction with the information provided. Secondary outcomes included patient satisfaction with service, quality of life, and time to detection of recurrence. RESULTS: The STAI-S scores post-randomisation were similar between groups [mean (SD): TFU 33.0 (11.0); HFU 35.5 (13.0)]. The estimated between-group difference in STAI-S was 0.7 (95% confidence interval, 95% CI -1.9 to 3.3); the confidence interval lies above the non-inferiority limit (-3.5), indicating the non-inferiority of TFU. There was no significant difference between groups in reported satisfaction with information (odds ratio, OR 0.9; 95% CI 0.4-2.1; P = 0.83). Women in the HFU group were more likely to report being kept waiting for their appointment (P = 0.001), that they did not need any information (P = 0.003), and were less likely to report that the nurse knew about their particular case and situation (P = 0.005). CONCLUSIONS: The TFU provides an effective alternative to HFU for patients with stage-I endometrial cancer, with no reported physical or psychological detriment. Patient satisfaction with information was high, with similar levels between groups. TWEETABLE ABSTRACT: ENDCAT trial shows effectiveness of nurse-led telephone follow-up for patients with stage-I endometrial cancer.

Deprivation and healthy food access, cost and availability: a cross-sectional study.

BACKGROUND: Food access, cost and availability have been identified as determinants of dietary choice. It has been suggested that these are socio-economically patterned; however, the evidence is inconclusive. The present study investigated whether differences exist with respect to healthy food access, cost and availability between areas of contrasting deprivation. METHODS: An ecological, cross-sectional study was conducted in two of the most and two of the least deprived wards in Plymouth. Food retail outlets (FROs) (n = 38) were identified and mapped using Geographic Information Systems to assess 'physical access', by foot, to food retail provision. Healthy food basket (HFB) surveys were conducted (n = 32) to compare the cost and availability of 28 healthy food items between the more and less deprived areas. RESULTS: Areas of poor access to food retail provision were identified in both study areas, with a higher number of households in the more-deprived areas being affected than in the less-deprived areas, after accounting for car ownership levels. Median [IQR] HFB availability was lower in more-deprived than the less-deprived areas (48%, [39-71%] vs. 75%, [68-82%]; P=0.003), and in convenience stores than supermarkets (54%, [43-72%] vs. 78%, [72-96%]; P=0.001). Descriptive summaries revealed negligible differences in total median HFB cost between the more-deprived and less-deprived areas (£55.97 versus £55.94) and a larger cost difference between convenience stores and supermarkets (£62.39 versus £44.25). CONCLUSIONS: Differences were found with respect to healthy food access, cost and availability in areas of contrasting deprivation. These appeared to be related to FRO type rather than deprivation alone.

A Bayesian adaptive design for clinical trials in rare diseases.

Development of treatments for rare diseases is challenging due to the limited number of patients available for participation. Learning about treatment effectiveness with a view to treat patients in the larger outside population, as in the traditional fixed randomised design, may not be a plausible goal. An alternative goal is to treat the patients within the trial as effectively as possible. Using the framework of finite-horizon Markov decision processes and dynamic programming (DP), a novel randomised response-adaptive design is proposed which maximises the total number of patient successes in the trial and penalises if a minimum number of patients are not recruited to each treatment arm. Several performance measures of the proposed design are evaluated and compared to alternative designs through extensive simulation studies using a recently published trial as motivation. For simplicity, a two-armed trial with binary endpoints and immediate responses is considered. Simulation results for the proposed design show that: (i) the percentage of patients allocated to the superior arm is much higher than in the traditional fixed randomised design; (ii) relative to the optimal DP design, the power is largely improved upon and (iii) it exhibits only a very small bias and mean squared error of the treatment effect estimator. Furthermore, this design is fully randomised which is an advantage from a practical point of view because it protects the trial against various sources of bias. As such, the proposed design addresses some of the key issues that have been suggested as preventing so-called bandit models from being implemented in clinical practice.

Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study.

BACKGROUND: Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, 'liquid biopsies' such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). PATIENTS AND METHODS: CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. RESULTS: The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which ∼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. CONCLUSIONS: This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM(+)) does not preclude CDX generation, highlighting epithelial to mesenchymal transition and the functional importance of mesenchymal CTCs in dissemination of this disease.

A prevalence study of Salmonella spp., Yersinia spp., Toxoplasma gondii and porcine reproductive and respiratory syndrome virus in UK pigs at slaughter.

An abattoir-based study was undertaken between January and May 2013 to estimate the prevalence of Salmonella spp. and Yersinia spp. carriage and seroprevalence of antibodies to Toxoplasma gondii and porcine reproductive and respiratory syndrome virus (PRRSv) in UK pigs at slaughter. In total, 626 pigs were sampled at 14 abattoirs that together process 80% of the annual UK pig slaughter throughput. Sampling was weighted by abattoir throughput and sampling dates and pig carcasses were randomly selected. Rectal swabs, blood samples, carcass swabs and the whole caecum, tonsils, heart and tongue were collected. Salmonella spp. was isolated from 30·5% [95% confidence interval (CI) 26·5-34·6] of caecal content samples but only 9·6% (95% CI 7·3-11·9) of carcass swabs, which was significantly lower than in a UK survey in 2006-2007. S. Typhimurium and S. 4,[5],12:i:- were the most commonly isolated serovars, followed by S. Derby and S. Bovismorbificans. The prevalence of Yersinia enterocolitica carriage in tonsils was 28·7% (95% CI 24·8-32·7) whereas carcass contamination was much lower at 1·8% (95% CI 0·7-2·8). The seroprevalence of antibodies to Toxoplasma gondii and PRRSv was 7·4% (95% CI 5·3-9·5) and 58·3% (95% CI 53·1-63·4), respectively. This study provides a comparison to previous abattoir-based prevalence surveys for Salmonella and Yersinia, and the first UK-wide seroprevalence estimates for antibodies to Toxoplasma and PRRSv in pigs at slaughter.

Rapid Identification of Resistance Loci Effective Against Puccinia graminis f. sp. tritici Race TTKSK in 33 Spring Wheat Landraces.

Wheat breeders worldwide are seeking new sources of resistance to Puccinia graminis f. sp. tritici race TTKSK. To prioritize field-resistant landraces for follow-up genetic studies to test for the presence of new resistance genes, seedling response to P. graminis f. sp. tritici race TTKSK, molecular markers linked to specific Sr genes, segregation ratios among progeny from crosses, and bulked segregant analyses (BSA) were used. In total, 33 spring wheat landraces with seedling resistance to P. graminis f. sp. tritici race TTKSK were crossed to a susceptible genotype, LMPG-6. The segregation ratios of stem rust reactions in F2 seedlings fit a single dominant gene model in 31 populations and progeny from two crosses gave ambiguous results. Using the 90K wheat single-nucleotide polymorphism genotyping platform, BSA showed that the seedling resistance in 29 accessions is probably controlled by loci on chromosome 2BL. For the three remaining accessions, BSA revealed that the seedling resistance is most likely controlled by previously unreported genes. For confirmation, two populations were advanced to the F2:3 and screened against P. graminis f. sp. tritici race TTKSK. Segregation of the F2:3 families fit a 1:2:1 ratio for a single dominant gene. Using the F2:3 families, BSA located the TTKSK locus on chromosome 6DS to the same location as Sr42.

Mapping resistance to the Ug99 race group of the stem rust pathogen in a spring wheat landrace.

KEY MESSAGE: A new gene for Ug99 resistance from wheat landrace PI 374670 was detected on the long arm of chromosome 7A. Wheat landrace PI 374670 has seedling and field resistance to stem rust caused by Puccinia graminis f. sp tritici Eriks. & E. Henn (Pgt) race TTKSK. To elucidate the inheritance of resistance, 216 BC1F2 families, 192 double haploid (DH) lines, and 185 recombinant inbred lines (RILs) were developed by crossing PI 374670 and the susceptible line LMPG-6. The parents and progeny were evaluated for seedling resistance to Pgt races TTKSK, MCCFC, and TPMKC. The DH lines were tested in field stem rust nurseries in Kenya and Ethiopia. The DH lines were genotyped with the 90K wheat iSelect SNP genotyping platform. Goodness-of-fit tests indicated that a single dominant gene in PI 374670 conditioned seedling resistance to the three Pgt races. The seedling resistance locus mapped to the long arm of chromosome 7A and this result was verified in the RIL population screened with the flanking SNP markers using KASP assays. In the same region, a major QTL for field resistance was detected in a 7.7 cM interval and explained 34-54 and 29-36% of the variation in Kenya and Ethiopia, respectively. Results from tests with specific Pgt races and the csIH81 marker showed that the resistance was not due to Sr22. Thus, a new stem rust resistance gene or allele, either closely linked or allelic to Sr15, is responsible for the seedling and field resistance of PI 374670 to Ug99.

Characterisations of human prostate stem cells reveal deficiency in class I UGT enzymes as a novel mechanism for castration-resistant prostate cancer.

BACKGROUND: Evidence increasingly supports that prostate cancer is initiated by the malignant transformation of stem cells (SCs). Furthermore, many SC-signalling pathways are shown to be shared in prostate cancer. Therefore, we planned transcriptome characterisation of adult prostate SCs as a strategy to consider new targets for cancer treatment. METHODS: Intuitive pathway analysis was used for putative target discovery in 12 matched selections of human prostate SCs, transiently amplifying cells and terminally differentiated cells. These were pooled into three groups according to the stage of differentiation for mRNA microarray analysis. Targets identified were validated using uncultured primary tissue (n=12), functional models of prostate cancer and a tissue microarray consisting of benign (n=42) and malignant prostate (n=223). RESULTS: A deficiency in class 1 UDP glucuronosyltransferase (UGT) enzymes (UGT1A) was identified in prostate SCs, which are involved in androgen catabolism. Class 1 UGT enzyme expression was also downregulated in cancer SCs and during progression to metastatic castration-resistant prostate cancer (CRPC). Reduction of UGT1A expression in vitro was seen to improve cell survival and increase androgen receptor (AR) activity, as shown by upregulation of prostate-specific antigen expression. INTERPRETATION: Inactivation of intracellular androgen catabolism represents a novel mechanism to maintain AR activity during CRPC.