Magnetoluminescence

Pulsar Wind Nebulae, Blazars, Gamma Ray Bursts and Magnetars all contain regions where the electromagnetic energy density greatly exceeds the plasma energy density. These sources exhibit dramatic flaring activity where the electromagnetic energy distributed over large volumes, appears to be converted efficiently into high energy particles and gamma-rays. We call this general process magnetoluminescence. Global requirements on the underlying, extreme particle acceleration processes are described and the likely importance of relativistic beaming in enhancing the observed radiation from a flare is emphasized. Recent research on fluid descriptions of unstable electromagnetic configurations are summarized and progress on the associated kinetic simulations that are needed to account for the acceleration and radiation is discussed. Future observational, simulation and experimental opportunities are briefly summarized.Comment: To appear in "Jets and Winds in Pulsar Wind Nebulae, Gamma-ray Bursts and Blazars: Physics of Extreme Energy Release" of the Space Science Reviews serie

Atomic X-ray Spectroscopy of Accreting Black Holes

Current astrophysical research suggests that the most persistently luminous objects in the Universe are powered by the flow of matter through accretion disks onto black holes. Accretion disk systems are observed to emit copious radiation across the electromagnetic spectrum, each energy band providing access to rather distinct regimes of physical conditions and geometric scale. X-ray emission probes the innermost regions of the accretion disk, where relativistic effects prevail. While this has been known for decades, it also has been acknowledged that inferring physical conditions in the relativistic regime from the behavior of the X-ray continuum is problematic and not satisfactorily constraining. With the discovery in the 1990s of iron X-ray lines bearing signatures of relativistic distortion came the hope that such emission would more firmly constrain models of disk accretion near black holes, as well as provide observational criteria by which to test general relativity in the strong field limit. Here we provide an introduction to this phenomenon. While the presentation is intended to be primarily tutorial in nature, we aim also to acquaint the reader with trends in current research. To achieve these ends, we present the basic applications of general relativity that pertain to X-ray spectroscopic observations of black hole accretion disk systems, focusing on the Schwarzschild and Kerr solutions to the Einstein field equations. To this we add treatments of the fundamental concepts associated with the theoretical and modeling aspects of accretion disks, as well as relevant topics from observational and theoretical X-ray spectroscopy.Comment: 63 pages, 21 figures, Einstein Centennial Review Article, Canadian Journal of Physics, in pres

High-time Resolution Astrophysics and Pulsars

The discovery of pulsars in 1968 heralded an era where the temporal characteristics of detectors had to be reassessed. Up to this point detector integration times would normally be measured in minutes rather seconds and definitely not on sub-second time scales. At the start of the 21st century pulsar observations are still pushing the limits of detector telescope capabilities. Flux variations on times scales less than 1 nsec have been observed during giant radio pulses. Pulsar studies over the next 10 to 20 years will require instruments with time resolutions down to microseconds and below, high-quantum quantum efficiency, reasonable energy resolution and sensitive to circular and linear polarisation of stochastic signals. This chapter is review of temporally resolved optical observations of pulsars. It concludes with estimates of the observability of pulsars with both existing telescopes and into the ELT era.Comment: Review; 21 pages, 5 figures, 86 references. Book chapter to appear in: D.Phelan, O.Ryan & A.Shearer, eds.: High Time Resolution Astrophysics (Astrophysics and Space Science Library, Springer, 2007). The original publication will be available at http://www.springerlink.co

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

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and ‘tumor spread through air spaces’ were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk

The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution

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

Lung cancer is the leading cause of cancer-associated mortality worldwide1. 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