Deregulation of transcription factors (TFs) is an important driver of tumorigenesis, but non-invasive assays for assessing transcription factor activity are lacking. Here we develop and validate a ...minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyze whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a bioinformatics pipeline developed by us that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observe patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of detection of early-stage colorectal carcinomas. Our approach for mapping tumor-specific transcription factor binding in vivo based on blood samples makes a key part of the noncoding genome amenable to clinical analysis.
Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyse 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 ...plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP and SHQ1) and driver amplifications (AR and MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5-52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumour genome, most consistent with subclonal diversification of the tumour. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression.
Abstract
Debates concerning digital automation are mostly focused on the question of the availability of jobs in the short and long term. To counteract the possible negative effects of automation, it ...is often suggested that those at risk of technological unemployment should have access to retraining and reskilling opportunities. What is often missing in these debates are implications that all of this may have for individual autonomy understood as the ability to make and develop long-term plans. In this paper, I argue that if digital automation becomes rapid, it will significantly undermine the legitimate expectation of stability and consequently, the ability to make and pursue long-term plans in the sphere of work. I focus on what is often taken to be one of the main long-term plans, i.e. the choice of profession, and I argue that this choice may be undermined by the pressure to continuously acquire new skills while at the same time facing a diminishing range of professions that one can choose from. Given that the choice of profession is significant for not-work related spheres of life, its undermining can greatly affect individual autonomy in these other spheres too. I argue that such undermining of individual planning agency constitutes a distinctive form of harm that necessitates a proactive institutional response.
Whole‐genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the ...translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA from minute volumes of blood in PDX mice. We developed a xenograft Tumour Fraction (xTF) metric using shallow WGS of dried blood spots (DBS), and demonstrate its application to quantify disease burden, monitor treatment response and predict disease outcome in a preclinical study of PDX mice. Further, we show how our DBS‐based ctDNA assay can be used to detect gene‐specific copy number changes and examine the copy number landscape over time. Use of sequential DBS ctDNA assays could transform future trial designs in both mice and patients by enabling increased sampling and molecular monitoring.
Synopsis
A novel approach is developed for longitudinal monitoring of tumour burden in patient‐derived xenograft (PDX) models using dried blood spots from minute volumes of blood.
Circulating tumour DNA (ctDNA) can be detected in minute volumes of blood (~ 50 µl) collected as dried blood spots (DBS) from the tail vein in PDX mice.
The xenograft Tumour Fraction (xTF) is calculated using species‐specific alignment of reads obtained from shallow whole‐genome sequencing of DBS samples.
The xTF metric allows accurate monitoring of disease progression over time.
The xTF rate of change during the first 30 days of treatment is predictive of disease outcome in PDX mice.
A novel approach is developed for longitudinal monitoring of tumour burden in patient‐derived xenograft (PDX) models using dried blood spots from minute volumes of blood.
How much should we sacrifice for the sake of others? While some argue in favour of significant sacrifices, others contend that morality cannot demand too much from individuals. Recently, the debate ...has taken a new turn by focusing on moral demands under non-ideal conditions in which the essential interests of many people are set back. Under such conditions, in some views, moral theories must require extreme moral demands as anything less is incompatible with equal consideration of everyone’s interests. The insistence on the extremeness of moral demands, however, presupposes a simplistic account of non-ideal conditions as characterized mainly by the non-compliance of many individuals. Non-ideal conditions are also characterized by institutional non-compliance, whereby institutions often do not do what they ought to do. Institutional non-compliance is significant as it increases the size of moral demands significantly, thereby exacerbating the conflict between these demands and the self-interest of individuals subjected to these institutions. I argue that individuals have a meta-interest in not experiencing such internal conflicts as these can undermine their affirmation of self-respect. Meta-interest can be advanced by adopting the promotion of just institutions as an ultimate aim, as such institutions lessen the conflict and, accordingly, enable us to live more harmonious lives. Moreover, the promotion of just institutions allows us to affirm our sense of self-respect under non-ideal conditions too. Because the promotion of just institutions is in our self-interest, this is not an extreme but a moderate moral demand.
Background: Focal amplification of fibroblast growth factor receptor 1 (FGFR1) defines a subgroup of breast cancers with poor prognosis and high risk of recurrence. We sought to demonstrate the ...potential of circulating cell-free DNA (cfDNA) analysis to evaluate FGFR1 copy numbers from a cohort of 100 metastatic breast cancer (mBC) patients. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were screened for FGFR1 amplification by FISH, and positive cases were confirmed with a microarray platform (OncoscanTM). Subsequently, cfDNA was evaluated by two approaches, i.e., mFAST-SeqS and shallow whole-genome sequencing (sWGS), to estimate the circulating tumor DNA (ctDNA) allele fraction (AF) and to evaluate the FGFR1 status. Results: Tissue-based analyses identified FGFR1 amplifications in 20/100 tumors. All cases with a ctDNA AF above 3% (n = 12) showed concordance for FGFR1 status between tissue and cfDNA. In one case, we were able to detect a high-level FGFR1 amplification, although the ctDNA AF was below 1%. Furthermore, high levels of ctDNA indicated an association with unfavorable prognosis based on overall survival. Conclusions: Screening for FGFR1 amplification in ctDNA might represent a viable strategy to identify patients eligible for treatment by FGFR inhibition, and mBC ctDNA levels might be used for the evaluation of prognosis in clinical drug trials.
We present a workflow to aid the discovery of new dyes for the role of a photosensitive unit in the dye-sensitized photo-electrochemical cells (DS-PECs). New structures are generated in a fully ...automated way using the Compound Attachment Tool (CAT) introduced in this work. These structures are characterized with efficient approximate density functional theory (DFT) methods, and molecules with favorable optical properties are suggested for possible further use in DS-PECs. As around 2500 structures are generated in this work, and as we aim for still larger volumes of compounds to screen in subsequent applications, we have assessed the reliability of low-cost screening methods and show that simplified time-dependent density functional theory (sTDDFT) provides a satisfying accuracy/cost ratio. From the dyes considered, we propose a set that can be suitable for panchromatic sensitization of the photoelectrode in DS-PECs to further increase DS-PEC efficiency.
We addressed a significant unknown feature of circulating tumor DNA (ctDNA), i.e., how ctDNA levels change during chemotherapy, by serially monitoring ctDNA in patients with colorectal cancer during ...the 48-h application of FOLFOX. Surprisingly, we did not observe a spike in ctDNA as a sign of a responsive tumor, but instead ctDNA levels initially decreased and remained low in patients with stable disease or partial response. Our observations reveal further insights into cell destruction during chemotherapy with important implications for the management of patients.
Sustainable solutions for hydrogen production, such as dye-sensitized photoelectrochemical cells (DS-PEC), rely on the fundamental properties of its components whose modularity allows for their ...separate investigation. In this work, we design and execute a high-throughput scheme to tune the ground state oxidation potential (GSOP) of perylene-type dyes by functionalizing them with different ligands. This allows us to identify promising candidates which can then be used to improve the cell's efficiency. First, we investigate the accuracy of different theoretical approaches by benchmarking them against experimentally determined GSOPs. We test different methods to calculate the vertical oxidation potential, including
GW
with different levels of self-consistency, Kohn-Sham (KS) orbital energies and total energy differences. We find that there is little difference in the performance of these methods. However, we show that it is crucial to take into account solvent effects as well as the structural relaxation of the dye after oxidation. Other thermodynamic contributions are negligible. Based on this benchmark, we decide on an optimal strategy, balancing computational cost and accuracy, to screen more than 1000 dyes and identify promising candidates which could be used to construct more robust DS-PECs.
The alignment of the GSOP, calculated with the adiabatic approach for large number of dyes, with the limitations of a hypothetical system - the CB edge of TiO
2
semiconductor and highest oxidation potential of Ru-based WOC.
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