Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle ...of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment.
Plasma DNA 128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS).
Plasma tumor DNA detection was associated with shorter OS hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001 and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients.
Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.
•The rolling B-allele method applied to a clinical assay allows detection of plasma tumor DNA independent of mutation calls.•Patients with TP53, RB1 or PTEN alterations persisting after one cycle of treatment have the worst outcomes.•Conversion of alterations after one cycle is associated with similar outcomes as patients negative before treatment.•Plasma AR gain pre-treatment persists at progression while AR point mutations appear de novo in ∼16%.
ABSTRACT
Time-delay cosmography can be used to infer the Hubble parameter H0 by measuring the relative time delays between multiple images of gravitationally lensed quasars. A few of such systems ...have already been used to measure H0: Their time delays were determined from the light curves of the multiple images obtained by regular, years long, monitoring campaigns. Such campaigns can hardly be performed by any telescope: many facilities are often oversubscribed with a large amount of observational requests to fulfill. While the ideal systems for time-delay measurements are lensed quasars whose images are well resolved by the instruments, several lensed quasars have a small angular separation between the multiple images, and would appear as a single, unresolved, image to a large number of telescopes featuring poor angular resolutions or located in not privileged geographical sites. Methods allowing to infer the time delay also from unresolved light curves would boost the potential of such telescopes and greatly increase the available statistics for H0 measurements. This work presents a study of unresolved lensed quasar systems to estimate the time delay using a deep learning-based approach that exploits the capabilities of one-dimensional convolutional neural networks. Experiments on state-of-the-art simulations of unresolved light curves show the potential of the proposed method and pave the way for future applications in time-delay cosmography.
We study the dynamics of a
supersymmetric SU(
N
) gauge theory with fundamental or adjoint matter in presence of a non trivial Ω-background along a two dimensional plane. The prepotential and chiral ...correlators of the gauge theory can be obtained, via a saddle point analysis, from an equation which can be viewed as a non commutative version of the “standard” Seiberg and Witten curve.
During an infection the immune system produces pathogen-specific antibodies. These antibody repertoires become specific to the history of infections and represent a rich source of diagnostic markers. ...However, the specificities of these antibodies are mostly unknown. Here, using high-density peptide arrays we examined the human antibody repertoires of Chagas disease patients. Chagas disease is a neglected disease caused by Trypanosoma cruzi, a protozoan parasite that evades immune mediated elimination and mounts long-lasting chronic infections. We describe a proteome-wide search for antigens, characterised their linear epitopes, and show their reactivity on 71 individuals from diverse human populations. Using single-residue mutagenesis we revealed the core functional residues for 232 of these epitopes. Finally, we show the diagnostic performance of identified antigens on challenging samples. These datasets enable the study of the Chagas antibody repertoire at an unprecedented depth and granularity, while also providing a rich source of serological biomarkers.
Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase ...I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients.
Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months’ exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics’ GmbH).
Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months.
The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide.
NCT01171898.
We present high-precision photometry of two transit events of the extrasolar planetary system WASP-5, obtained with the Danish 1.54-m telescope at European Southern Obseratory La Silla. In order to ...minimize both random and flat-fielding errors, we defocused the telescope so its point spread function approximated an annulus of diameter 40 pixel (16 arcsec). Data reduction was undertaken using standard aperture photometry plus an algorithm for optimally combining the ensemble of comparison stars. The resulting light curves have point-to-point scatters of 0.50 mmag for the first transit and 0.59 mmag for the second. We construct detailed signal-to-noise ratio calculations for defocused photometry, and apply them to our observations. We model the light curves with the jktebop code and combine the results with tabulated predictions from theoretical stellar evolutionary models to derive the physical properties of the WASP-5 system. We find that the planet has a mass of Mb= 1.637 ± 0.075 ± 0.033 MJup, a radius of Rb= 1.171 ± 0.056 ± 0.012 R Jup, a large surface gravity of gb= 29.6 ± 2.8 m s−2 and a density of ρb= 1.02 ± 0.14 ± 0.01 ρJup (statistical and systematic uncertainties). The planet's high equilibrium temperature of Teq= 1732 ± 80 K makes it a good candidate for detecting secondary eclipses.
Availability of highly parallelized immunoassays has renewed interest in the discovery of serology biomarkers for infectious diseases. Protein and peptide microarrays now provide a rapid, ...high-throughput platform for immunological testing and validation of potential antigens and B-cell epitopes. However, there is still a need for tools to prioritize and select relevant probes when designing these arrays. In this work we describe a computational method called APRANK (Antigenic Protein and Peptide Ranker) which integrates multiple molecular features to prioritize potentially antigenic proteins and peptides in a given pathogen proteome. These features include subcellular localization, presence of repetitive motifs, natively disordered regions, secondary structure, transmembrane spans and predicted interaction with the immune system. We trained and tested this method with a number of bacteria and protozoa causing human diseases:
(Lyme disease),
(Brucellosis),
(Q fever),
(Gastroenteritis),
(Tularemia),
(Leishmaniasis),
(Leptospirosis),
(Leprae),
(Tuberculosis),
(Malaria),
(Periodontal disease),
(Bacteremia),
(Group A Streptococcal infections),
(Toxoplasmosis) and
(Chagas Disease). We have evaluated this integrative method using non-parametric ROC-curves and made an unbiased validation using
as an independent data set. We found that APRANK is successful in predicting antigenicity for all pathogen species tested, facilitating the production of antigen-enriched protein subsets. We make APRANK available to facilitate the identification of novel diagnostic antigens in infectious diseases.
Trypanosoma cruzi, the agent of Chagas disease, displays a highly structured population, with multiple strains that can be grouped into 6-7 evolutionary lineages showing variable eco-epidemiological ...traits and likely also distinct disease-associated features. Previous works have shown that antibody responses to 'isoforms' of the polymorphic parasite antigen TSSA enable robust and sensitive identification of the infecting strain with near lineage-level resolution. To optimize the serotyping performance of this molecule, we herein used a combination of immunosignaturing approaches based on peptide microarrays and serum samples from Chagas disease patients to establish a deep linear B-cell epitope profiling of TSSA.
Our assays revealed variations in the seroprevalence of TSSA isoforms among Chagas disease populations from different settings, hence strongly supporting the differential distribution of parasite lineages in domestic cycles across the Americas. Alanine scanning mutagenesis and the use of peptides of different lengths allowed us to identify key residues involved in antibody pairing and the presence of three discrete B-cell linear epitopes in TSSAII, the isoform with highest seroprevalence in human infections. Comprehensive screening of parasite genomic repositories led to the discovery of 9 novel T. cruzi TSSA variants and one TSSA sequence from the phylogenetically related bat parasite T. cruzi marinkellei. Further residue permutation analyses enabled the identification of diagnostically relevant or non-relevant substitutions among TSSA natural polymorphisms. Interestingly, T. cruzi marinkellei TSSA displayed specific serorecognition by one chronic Chagas disease patient from Colombia, which warrant further investigations on the diagnostic impact of such atypical TSSA.
Overall, our findings shed new light into TSSA evolution, epitope landscape and modes of recognition by Chagas disease patients; and have practical implications for the design and/or evaluation of T. cruzi serotyping strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The 1-dimensional reaction-diffusion-convection code TOMATOR-1D describes plasma production by RF waves inside a tokamak using the Braginskii continuity and heat balance equations. The model ...simulates self-consistent radial density and temperature profiles for magnetised plasma mixtures of hydrogen and helium. The model reproduces the density profiles of X2 electron cyclotron resonance heating (ECRH) plasmas on TCV and proposes a Bohm-like poloidal magnetic field dependent scaling for anomalous diffusion and a convection scaling that results from drifts in the toroidal magnetic field configuration. A relation is proposed between the anomalous diffusion and the outward convection in toroidal plasmas. It is found that the EC absorption efficiency decreases at higher power, which is understood from the acceleration of electrons beyond the optimal energy for the electron impact ionisation of helium. A dramatic increase of the absorption efficiency is seen at intermediate vertical magnetic field values of Bz=0.25%−0.5%BT which results in the highest density plasmas. Losses along the field lines in the vertical direction become dominant at higher fields which effectively reduces the plasma density in these discharges. To arrive at predictive capabilities towards ECRH plasmas on JT-60SA and ITER, the proposed scalings, subsuming dependencies on the torus major radius and the toroidal field strength, need to be validated in a multi-machine study.
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