75 research outputs found
On the Two Species Asymmetric Exclusion Process with Semi-Permeable Boundaries
We investigate the structure of the nonequilibrium stationary state (NESS) of
a system of first and second class particles, as well as vacancies (holes), on
L sites of a one-dimensional lattice in contact with first class particle
reservoirs at the boundary sites; these particles can enter at site 1, when it
is vacant, with rate alpha, and exit from site L with rate beta. Second class
particles can neither enter nor leave the system, so the boundaries are
semi-permeable. The internal dynamics are described by the usual totally
asymmetric exclusion process (TASEP) with second class particles. An exact
solution of the NESS was found by Arita. Here we describe two consequences of
the fact that the flux of second class particles is zero. First, there exist
(pinned and unpinned) fat shocks which determine the general structure of the
phase diagram and of the local measures; the latter describe the microscopic
structure of the system at different macroscopic points (in the limit L going
to infinity in terms of superpositions of extremal measures of the infinite
system. Second, the distribution of second class particles is given by an
equilibrium ensemble in fixed volume, or equivalently but more simply by a
pressure ensemble, in which the pair potential between neighboring particles
grows logarithmically with distance. We also point out an unexpected feature in
the microscopic structure of the NESS for finite L: if there are n second class
particles in the system then the distribution of first class particles
(respectively holes) on the first (respectively last) n sites is exchangeable.Comment: 28 pages, 4 figures. Changed title and introduction for clarity,
added reference
First-principles study of nucleation, growth, and interface structure of Fe/GaAs
We use density-functional theory to describe the initial stages of Fe film
growth on GaAs(001), focusing on the interplay between chemistry and magnetism
at the interface. Four features appear to be generic: (1) At submonolayer
coverages, a strong chemical interaction between Fe and substrate atoms leads
to substitutional adsorption and intermixing. (2) For films of several
monolayers and more, atomically abrupt interfaces are energetically favored.
(3) For Fe films over a range of thicknesses, both Ga- and As-adlayers
dramatically reduce the formation energies of the films, suggesting a
surfactant-like action. (4) During the first few monolayers of growth, Ga or As
atoms are likely to be liberated from the interface and diffuse to the Fe film
surface. Magnetism plays an important auxiliary role for these processes, even
in the dilute limit of atomic adsorption. Most of the films exhibit
ferromagnetic order even at half-monolayer coverage, while certain
adlayer-capped films show a slight preference for antiferromagnetic order.Comment: 11 two-column pages, 12 figures, to appear in Phys. Rev.
Observation of hard scattering in photoproduction events with a large rapidity gap at HERA
Events with a large rapidity gap and total transverse energy greater than 5
GeV have been observed in quasi-real photoproduction at HERA with the ZEUS
detector. The distribution of these events as a function of the
centre of mass energy is consistent with diffractive scattering. For total
transverse energies above 12 GeV, the hadronic final states show predominantly
a two-jet structure with each jet having a transverse energy greater than 4
GeV. For the two-jet events, little energy flow is found outside the jets. This
observation is consistent with the hard scattering of a quasi-real photon with
a colourless object in the proton.Comment: 19 pages, latex, 4 figures appended as uuencoded fil
Conhecimento popular sobre plantas medicinais em comunidades rurais de mata atlântica - Itacaré, BA, Brasil
Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020
We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe
Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy
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
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 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
The evolution of non-small cell lung cancer metastases in TRACERx
Metastatic disease is responsible for the majority of cancer-related deaths1. 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
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