Survival rates of captive-bred Asian Houbara Chlamydotis macqueenii in a hunted migratory population

Asian Houbara Chlamydotis macqueenii numbers are declining owing to unsustainable levels of hunting and poaching, with the main conservation response being population reinforcement through the release of captive-bred birds. We assessed the contribution of captive breeding to the species’ conservation by examining the fates of 65 captive-bred birds fitted with satellite transmitters and released during spring (March–May) and autumn (August) into breeding habitat in Uzbekistan. Of the released birds, 58.5% survived to October, the month favoured by Emirati hunters in Uzbekistan, but only 10.8% of those released survived the winter to return as sub-adults next spring. To mitigate and compensate the loss of wild adults to hunting, the number of released birds needs to be an order of magnitude higher than hunting quotas (with a release of between 1640-1920 required for a hypothetical quota of 200), indicating that releases may be costly and do not remove the need for a biologically determined sustainable hunting quota

Patient access to complex chronic disease records on the internet

Background: Access to medical records on the Internet has been reported to be acceptable and popular with patients, although most published evaluations have been of primary care or office-based practice. We tested the feasibility and acceptability of making unscreened results and data from a complex chronic disease pathway (renal medicine) available to patients over the Internet in a project involving more than half of renal units in the UK. Methods: Content and presentation of the Renal PatientView (RPV) system was developed with patient groups. It was designed to receive information from multiple local information systems and to require minimal extra work in units. After piloting in 4 centres in 2005 it was made available more widely. Opinions were sought from both patients who enrolled and from those who did not in a paper survey, and from staff in an electronic survey. Anonymous data on enrolments and usage were extracted from the webserver. Results: By mid 2011 over 17,000 patients from 47 of the 75 renal units in the UK had registered. Users had a wide age range (<10 to >90 yrs) but were younger and had more years of education than non-users. They were enthusiastic about the concept, found it easy to use, and 80% felt it gave them a better understanding of their disease. The most common reason for not enrolling was being unaware of the system. A minority of patients had security concerns, and these were reduced after enrolling. Staff responses were also strongly positive. They reported that it aided patient concordance and disease management, and increased the quality of consultations with a neutral effect on consultation length. Neither patient nor staff responses suggested that RPV led to an overall increase in patient anxiety or to an increased burden on renal units beyond the time required to enrol each patient. Conclusions: Patient Internet access to secondary care records concerning a complex chronic disease is feasible and popular, providing an increased sense of empowerment and understanding, with no serious identified negative consequences. Security concerns were present but rarely prevented participation. These are powerful reasons to make this type of access more widely available

Improving the cost-effectiveness of photographic screening for diabetic macular oedema: a prospective, multi-centre, UK study

Background/aims: Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. Methods: Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. Results: 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England’s scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland’s had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30 000 per quality adjusted life years (QALY) gained, Scotland’s scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England’s scheme, but was not cost effective, at the study’s operating point, compared with Scotland’s. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. Conclusions: Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies

Fundamental Science Investigations to Develop a 6-MV Laser Triggered Gas Switch for ZR: First Annual Report.

In October 2005, an intensive three-year Laser Triggered Gas Switch (LTGS) development program was initiated to investigate and solve observed performance and reliability issues with the LTGS for ZR. The approach taken has been one of mission-focused research: to revisit and reassess the design, to establish a fundamental understanding of LTGS operation and failure modes, and to test evolving operational hypotheses. This effort is aimed toward deploying an initial switch for ZR in 2007, on supporting rolling upgrades to ZR as the technology can be developed, and to prepare with scientific understanding for the even higher voltage switches anticipated needed for future high-yield accelerators. The ZR LTGS was identified as a potential area of concern quite early, but since initial assessments performed on a simplified Switch Test Bed (STB) at 5 MV showed 300-shot lifetimes on multiple switch builds, this component was judged acceptable. When the Z{sub 20} engineering module was brought online in October 2003 frequent flashovers of the plastic switch envelope were observed at the increased stresses required to compensate for the programmatically increased ZR load inductance. As of October 2006, there have been 1423 Z{sub 20} shots assessing a variety of LTGS designs. Numerous incremental and fundamental switch design modifications have been investigated. As we continue to investigate the LTGS, the basic science of plastic surface tracking, laser triggering, cascade breakdown, and optics degradation remain high-priority mission-focused research topics. Significant progress has been made and, while the switch does not yet achieve design requirements, we are on the path to develop successively better switches for rolling upgrade improvements to ZR. This report summarizes the work performed in FY 2006 by the large team. A high-level summary is followed by detailed individual topical reports

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Lung adenocarcinoma promotion by air pollutants

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Scottish compact baseline review

Includes bibliographical referencesAvailable from British Library Document Supply Centre- DSC:m03/31740 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo