Indigenous organic-oxidized fluid interactions in the Tissint Mars meteorite

Part of this work was supported by UK Space Agency Grant ST/N000560/1 and by internal funding by Tufts University and the School of Earth and Environmental Sciences at the University of St Andrews.The observed fall and rapid recovery of the Tissint Mars meteorite has provided minimally contaminated samples of the Martian surface. We report analyses of Tissint for organic compounds by pyrolysis-gas chromatography-mass spectrometry and for soluble salts by ion chromatography. Pyrolysis-gas chromatography-mass spectrometry analysis shows the presence of organic compounds similar to those in the Mars EETA79001 and Nakhla meteorites. The organic profile is dominated by aromatic hydrocarbons, including oxygen and nitrogen-containing aromatics, and sulfur-containing species including thiophenes. The soluble salts in Tissint are dominated by sulfate and various oxidation states of chlorine, including perchlorate. The organic compounds and salts in the soils from the Tissint recovery strewn field differ significantly from those found in Tissint suggesting minimal terrestrial contamination. Our results support the hypothesis that the soluble inorganic components of Tissint are most likely a result of indigenous fluid inclusion, thus providing a glimpse into the composition of early Martian fluids.Publisher PDFPeer reviewe

Telephone based self-management support by 'lay health workers' and 'peer support workers' to prevent and manage vascular diseases: a systematic review and meta-analysis

Background: Improved prevention and management of vascular disease is a global priority. Non-health care professionals (such as, ‘lay health workers’ and ‘peer support workers’) are increasingly being used to offer telephone support alongside that offered by conventional services, to reach disadvantaged populations and to provide more efficient delivery of care. However, questions remain over the impact of such interventions, particularly on a wider range of vascular related conditions (such as, chronic kidney disease), and it is unclear how different types of telephone support impact on outcome. This study assessed the evidence on the effectiveness and cost-effectiveness of telephone self-management interventions led by ‘lay health workers’ and ‘peer support workers’ for patients with vascular disease and long-term conditions associated with vascular disease. Methods: Systematic review of randomised controlled trials. Three electronic databases were searched. Two authors independently extracted data according to the Cochrane risk of bias tool. Random effects meta-analysis was used to pool outcome measures. Results: Ten studies were included, primarily based in community settings in the United States; with participants who had diabetes; and used ‘peer support workers’ that shared characteristics with patients. The included studies were generally rated at risk of bias, as many methodological criteria were rated as ‘unclear’ because of a lack of information. Overall, peer telephone support was associated with small but significant improvements in self-management behaviour (SMD = 0.19, 95% CI 0.05 to 0.33, I2 = 20.4%) and significant reductions in HbA1c level (SMD = -0.26, 95% CI −0.41 to −0.11, I2 = 47.6%). There was no significant effect on mental health quality of life (SMD = 0.03, 95% CI −0.12 to 0.18, I2 = 0%). Data on health care utilisation were very limited and no studies reported cost effectiveness analyses. Conclusions: Positive effects were found for telephone self-management interventions via ‘lay workers’ and ‘peer support workers’ for patients on diabetes control and self-management outcomes, but the overall evidence base was limited in scope and quality. Well designed trials assessing non-healthcare professional delivered telephone support for the prevention and management of vascular disease are needed to identify the content of effective components on health outcomes, and to assess cost effectiveness, to determine if such interventions are potentially useful alternatives to professionally delivered care

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

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

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

Wordplay in Shakespeare's Hamlet and the Accusation of Derrida's “Logical Phallusies”

That “Derrida's writing borders on being unreadable” has been maintained by several academics, journalists and students. This essay considers this reaction to Jacques Derrida's writing in relation to a broader history of wordplay and puns. Using Shakespeare's Hamlet as a starting point followed by the infamous letter to The Times that accused Derrida of “logical phallusies”, it argues that if Derrida's writing does border on being unreadable, then, this is the condition of all writing. The essay suggests that rather than suppressing the spectres of Derrida in Shakespeare studies, we should welcome back the aspects of his work that help us to “read and write in the space or heritage of Shakespeare”