Academic literature on the topic 'Cosmic Epsilon'

e13050 Background: DNA polymerase epsilon and polymerase delta encoded by the POLE and POLD1 gene are the major components participating in DNA replication, which both carry a proofreading (exonuclease) domain allowing error correction during replication. In case of POLE/POLD1 mutation, a deficient DNA repair activity results in a hypermutated phenotype of cancer, which would be a promising biomarker for immune checkpoint inhibitors (ICPIs). However, the prevalence of POLE and POLD1 in Chinese patients (pts) with solid tumors remained unknown. Methods: Targeted panel sequencing of 450 cancer genes were performed on FFPE tissues and matched blood samples obtained from 6313 Chinese pts with 23 different types of solid tumors. In our cohort, 41% were female pts with a median age of 56-year-old (range: 1-91), while 59% were male with a median age of 59-year-old (range: 1-96). The major cancer types were NSCLC (29%), HCC (11%), CRC (11%), gastric cancer (GC, 7%), soft tissure sarcoma (6%), pancreatic cancer (5%), intrahepatic cholangiocarcinoma (5%), and others. Somatic genomic alterations (sGAs) including single base substitutions, short and long insertions/deletions (indels), copy number alterations (CNA), rearrangements, TMB and MSI status were assessed by NGS. Results: Clinical relevant genomic alterations (CRGAs) were defined as known loss-of-function mutations, truncations, mutations on splicing sites and confirmed somatic mutations in COSMIC. CRGAs of POLE and POLD1 accounted for 2.1% and 1.3% of Chinese solid tumors respectively. Tumors with highest frequency of POLE CRGAs in Chinese cohort were endometrial cancer (8.3%), urothelial cancer (4.8%), CRC (4.3%), GC (3.2%), breast cancer (2.9%), cancer of unknown primary (CUP, 2.5%), ovarian cancer (2.1%) and NSCLC (2.0%), which tumors with highest frequency of POLD1 CRGAs were endometrial cancer (8.3%), urothelial cancer (4.8%), GC (3.0%), CRC (2.8%), SCLC (2.1%), HCC (1.9%), cervical cancer (1.6%), CUP (1.2%) and pancreatic cancer (1.2%). In addition, 1.6% and 1.2% of Chinese solid tumors harbored variants of unknown significance of POLE and POLD1, respectively. Conclusions: For the first time, our study reported prevalence of somatic mutations of POLE and POLD1 in large samples of Chinese population. Comparing with large cohort study of western population (ESMO 2017, 1170P), more CRGAs of POLE were identified in Chinese solid tumors (2.1% vs. 0.6%, p < 0.0001) indicating ethnic differences of ICPIs potential candidates between Chinese and western populations.

Abstract Background DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly recognized in ovarian cancer (OC) of endometrioid type. POLE-driven cases possess an abundance of TCT > TAT and TCG > TTG somatic mutations characterized by mutational signature 10 from the Catalog of Somatic Mutations in Cancer (COSMIC). By quantifying the contribution of COSMIC mutational signature 10 in RNA sequencing (RNA-seq) we set out to identify POLE-driven tumors in a set of unselected Mayo Clinic OC. Methods Mutational profiles were calculated using expressed single-nucleotide variants (eSNV) in the Mayo Clinic OC tumors (n = 195), The Cancer Genome Atlas (TCGA) OC tumors (n = 419), and the Genotype-Tissue Expression (GTEx) normal ovarian tissues (n = 84). Non-negative Matrix Factorization (NMF) of the mutational profiles inferred the contribution per sample of four distinct mutational signatures, one of which corresponds to COSMIC mutational signature 10. Results In the Mayo Clinic OC cohort we identified six tumors with a predicted contribution from COSMIC mutational signature 10 of over five mutations per megabase. These six cases harbored known POLE hotspot mutations (P286R, S297F, V411L, and A456P) and were of endometrioid histotype (P = 5e−04). These six tumors had an early onset (average age of patients at onset, 48.33 years) when compared to non-POLE endometrioid OC cohort (average age at onset, 60.13 years; P = .008). Samples from TCGA and GTEx had a low COSMIC signature 10 contribution (median 0.16 mutations per megabase; maximum 1.78 mutations per megabase) and carried no POLE hotspot mutations. Conclusions From the largest cohort of RNA-seq from endometrioid OC to date (n = 53), we identified six hypermutated samples likely driven by POLE (frequency, 11%). Our result suggests the clinical need to screen for POLE driver mutations in endometrioid OC, which can guide enrollment in immunotherapy clinical trials.

AbstractWe present a detailed investigation of the Rastall gravity extension of the standard $$\Lambda $$ Λ CDM model. We review the model for two simultaneous modifications of different nature in the Friedmann equation due to the Rastall gravity: the new contributions of the material (actual) sources (considered as effective source) and the altered evolution of the material sources. We discuss the role/behavior of these modifications with regard to some low redshift tensions, including the so-called $$H_0$$ H 0 tension, prevailing within the standard $$\Lambda $$ Λ CDM. We constrain the model at the level of linear perturbations, and obtain the first constraints through a robust and accurate analysis using the latest full Planck cosmic microwave background (CMB) data, with and without including baryon acoustic oscillations (BAO) data. We find that the Rastall parameter $$\epsilon $$ ϵ (null for general relativity) is consistent with zero at 68% CL (with a tendency towards positive values, $$-0.0001< \epsilon < 0.0007$$ - 0.0001 < ϵ < 0.0007 (CMB+BAO) at 68% CL), which in turn implies no significant statistical evidence for deviation from general relativity, and also a precision of $$\mathcal {O}(10^{-4})$$ O ( 10 - 4 ) for the coefficient $$-1/2$$ - 1 / 2 of the term $$g_{\mu \nu }R$$ g μ ν R in the Einstein field equations of general relativity (guaranteeing the local energy-momentum conservation). We explore the consequences led by the Rastall gravity on the cosmological parameters in the light of the observational analyses. It turns out that the effective source, with a present-day density parameter $$\Omega _\mathrm{X0}=-0.0010\pm 0.0013$$ Ω X 0 = - 0.0010 ± 0.0013 (CMB+BAO, 68% CL), dynamically screens the usual vacuum energy at high redshifts, but this mechanism barely works due to the opposition by the altered evolution of cold dark matter. Consequently, two simultaneous modifications of different nature in the Friedmann equation by the Rastall gravity act against each other, and do not help to considerably relax the low redshift tensions, including the so-called $$H_0$$ H 0 tension. Our results may offer a guide for the research community that studies the Rastall gravity in various aspects of gravitation and cosmology.

Reconstructions of the primordial power spectrum (PPS) of curvature perturbations from cosmic microwave background anisotropies and large-scale structure data suggest that the usually assumed power-law PPS has localised features (up to \sim 10\%∼10% in amplitude), although of only marginal significance in the framework of \LambdaΛCDM cosmology. On the other hand if the cosmology is taken to be Einstein-de Sitter, larger features in the PPS (up to \sim 20\%∼20% in amplitude) are required to accurately fit the observed acoustic peaks. Within the context of single clock inflation, we show that any given reconstruction of the PPS can be mapped on to functional parameters of the underlying effective theory of the adiabatic mode within a 2nd-order formalism, provided the best fit fractional change of the PPS, \Delta{P}_{R}/{P}_{R}ΔPR/PR is such that (\Delta{P}_{R}/{P}_{R})^3(ΔPR/PR)3 falls within the 1\,\sigma1σ confidence interval of the reconstruction for features induced by variations of either the sound speed c_\mathrm{s}cs or the slow-roll parameter \epsilonϵ. Although there is a degeneracy amongst these functional parameters (and the models that project onto them), we can identify simple representative inflationary models that yield such features in the PPS. Thus we provide a dictionary (more accurately, a thesaurus) to go from observational data, via the reconstructed PPS, to models that reproduce them to per cent level precision.

This chapter examines Nigel Walmsley's space odyssey in In the Ocean of Night and Across the Sea of Suns, which span the dates from 1999 to 2061. By the end of the first novel, Nigel has discovered a cosmic struggle between machine intelligence and organic life that will soon engulf Earth. Through several contacts with alien artifacts and entities that had come to Earth in both prehistoric and recent times, he predicts the coming of the machines. In Across the Sea of Suns, Nigel does battle with the machines with the help of organic life forms he finds on the moon of a planet in distant Epsilon Eridani. In the process, he reaffirms what he had earlier discovered on Earth: that, in the evolutionary sense, the boundary between machine and organism is not clear cut. The stamp of Arthur C. Clarke's Space Odyssey is clearly on both In the Ocean of Night and Across the Sea of Suns. The chapter analyzes the two novels in order to understand how Gregory Benford launched his space epic.