118 research outputs found
Predictive Genomic Biomarkers of Hormonal Therapy Versus Chemotherapy Benefit in Metastatic Castration-resistant Prostate Cancer
Drug development; Predictive biomarkers; Prostate cancerDesarrollo de fármacos; Biomarcadores predictivos; Cáncer de próstataDesenvolupament de fàrmacs; Biomarcadors predictius; Càncer de pròstataBackground
Biomarkers predicting second-generation novel hormonal therapy (NHT) benefit relative to taxanes are critical for optimized treatment decisions for metastatic castration-resistant prostate cancer (mCRPC) patients. These associations have not been reported simultaneously for common mCRPC genomic biomarkers.
Objective
To evaluate predictive associations of common genomic aberrations in mCRPC using an established comprehensive genomic profiling (CGP) system.
Design, setting, and participants
A retrospective cohort study used data from a deidentified US-based clinicogenomic database comprising patients treated in routine clinical practice between 2011 and 2020, evaluated with Foundation Medicine CGP in tissue biopsies obtained around the time of treatment decision. The main cohort included 180 NHT and 179 taxane lines of therapy (LOTs) from 308 unique patients. The sequential cohort comprised a subset of the main cohort NHT LOTs immediately followed by taxane from 55 unique patients.
Outcome measurements and statistical analysis
Prostate-specific antigen (PSA) response, time to next treatment (TTNT), and overall survival (OS) were assessed. Main cohort analyses were adjusted for known treatment assignment biases via inverse probability of treatment weighting (IPTW) in treatment interaction models.
Results and limitations
In the main cohort, patients with AR amplification (ARamp) or PTEN aberrations (PTENalt) had worse relative PSA response on NHT versus taxanes compared with patients without. Patients with ARamp, PTENalt, or RB1 aberrations (RB1alt) also had worse relative TTNT and OS on NHT but not on taxanes. In multivariable models for TTNT and OS adjusted via IPTW, ARamp, PTENalt, and RB1alt were shown as poor prognostic factors overall and demonstrated significant treatment interactions, indicating reduced hazards of therapy switch and death on taxanes versus NHT. Consistent associations favoring increased benefit from subsequent taxane despite prior NHT treatment line were observed only for ARamp in the sequential cohort, in which very few patients had RB1alt for assessment.
Conclusions
ARamp status is a candidate biomarker to predict poor effectiveness of NHT relative to taxanes in mCRPC in scenarios where both options are considered
FAPRI 1999 U.S. Agricultural Outlook
Crop Production/Industries, Livestock Production/Industries,
Cluster M Mycobacteriophages Bongo, PegLeg, and Rey with Unusually Large Repertoires of tRNA Isotopes
Genomic analysis of a large set of phages infecting the common hostMycobacterium smegmatis mc2155 shows that they span considerable genetic diversity. There are more than 20 distinct types that lack nucleotide similarity with each other, and there is considerable diversity within most of the groups. Three newly isolated temperate mycobacteriophages, Bongo, PegLeg, and Rey, constitute a new group (cluster M), with the closely related phages Bongo and PegLeg forming subcluster M1 and the more distantly related Rey forming subcluster M2. The cluster M mycobacteriophages have siphoviral morphologies with unusually long tails, are homoimmune, and have larger than average genomes (80.2 to 83.7 kbp). They exhibit a variety of features not previously described in other mycobacteriophages, including noncanonical genome architectures and several unusual sets of conserved repeated sequences suggesting novel regulatory systems for both transcription and translation. In addition to containing transfer-messenger RNA and RtcB-like RNA ligase genes, their genomes encode 21 to 24 tRNA genes encompassing complete or nearly complete sets of isotypes. We predict that these tRNAs are used in late lytic growth, likely compensating for the degradation or inadequacy of host tRNAs. They may represent a complete set of tRNAs necessary for late lytic growth, especially when taken together with the apparent lack of codons in the same late genes that correspond to tRNAs that the genomes of the phages do not obviously encode
Ten Misconceptions from the History of Analysis and Their Debunking
The widespread idea that infinitesimals were "eliminated" by the "great
triumvirate" of Cantor, Dedekind, and Weierstrass is refuted by an
uninterrupted chain of work on infinitesimal-enriched number systems. The
elimination claim is an oversimplification created by triumvirate followers,
who tend to view the history of analysis as a pre-ordained march toward the
radiant future of Weierstrassian epsilontics. In the present text, we document
distortions of the history of analysis stemming from the triumvirate ideology
of ontological minimalism, which identified the continuum with a single number
system. Such anachronistic distortions characterize the received interpretation
of Stevin, Leibniz, d'Alembert, Cauchy, and others.Comment: 46 pages, 4 figures; Foundations of Science (2012). arXiv admin note:
text overlap with arXiv:1108.2885 and arXiv:1110.545
The Precision nEDM Measurement with UltraCold Neutrons at TRIUMF
The TRIUMF Ultra-Cold Advanced Neutron (TUCAN) collaboration aims at a
precision neutron electric dipole moment (nEDM) measurement with an uncertainty
of , which is an order-of-magnitude better than
the current nEDM upper limit and enables us to test Supersymmetry. To achieve
this precision, we are developing a new high-intensity ultracold neutron (UCN)
source using super-thermal UCN production in superfluid helium (He-II) and a
nEDM spectrometer. The current development status of them is reported in this
article.Comment: Proceedings of the 24th International Spin Symposium (SPIN 2021),
18-22 October 2021, Matsue, Japa
Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling–informed personalized monitoring assay
IntroductionCirculating tumor DNA (ctDNA) detection postoperatively may identify patients with urothelial cancer at a high risk of relapse. Pragmatic tools building off clinical tumor next-generation sequencing (NGS) platforms could have the potential to increase assay accessibility.MethodsWe evaluated the widely available Foundation Medicine comprehensive genomic profiling (CGP) platform as a source of variants for tracking of ctDNA when analyzing residual samples from IMvigor010 (ClinicalTrials.gov identifier NCT02450331), a randomized adjuvant study comparing atezolizumab with observation after bladder cancer surgery. Current methods often involve germline sampling, which is not always feasible or practical. Rather than performing white blood cell sequencing to filter germline and clonal hematopoiesis (CH) variants, we applied a bioinformatic approach to select tumor (non-germline/CH) variants for molecular residual disease detection. Tissue-informed personalized multiplex polymerase chain reaction–NGS assay was used to detect ctDNA postsurgically (Natera).ResultsAcross 396 analyzed patients, prevalence of potentially actionable alterations was comparable with the expected prevalence in advanced disease (13% FGFR2/3, 20% PIK3CA, 13% ERBB2, and 37% with elevated tumor mutational burden ≥10 mutations/megabase). In the observation arm, 66 of the 184 (36%) ctDNA-positive patients had shorter disease-free survival [DFS; hazard ratio (HR) = 5.77; 95% confidence interval (CI), 3.84–8.67; P < 0.0001] and overall survival (OS; HR = 5.81; 95% CI, 3.41–9.91; P < 0.0001) compared with ctDNA-negative patients. ctDNA-positive patients had improved DFS and OS with atezolizumab compared with those in observation (DFS HR = 0.56; 95% CI, 0.38–0.83; P = 0.003; OS HR = 0.66; 95% CI, 0.42–1.05). Clinical sensitivity and specificity for detection of postsurgical recurrence were 58% (60/103) and 93% (75/81), respectively.ConclusionWe present a personalized ctDNA monitoring assay utilizing tissue-based FoundationOne® CDx CGP, which is a pragmatic and potentially clinically scalable method that can detect low levels of residual ctDNA in patients with resected, muscle-invasive bladder cancer without germline sampling
Searching for continuous Gravitational Waves in the second data release of the International Pulsar Timing Array
The International Pulsar Timing Array 2nd data release is the combination of
datasets from worldwide collaborations. In this study, we search for continuous
waves: gravitational wave signals produced by individual supermassive black
hole binaries in the local universe. We consider binaries on circular orbits
and neglect the evolution of orbital frequency over the observational span. We
find no evidence for such signals and set sky averaged 95% upper limits on
their amplitude h 95 . The most sensitive frequency is 10nHz with h 95 = 9.1
10-15 . We achieved the best upper limit to date at low and high frequencies of
the PTA band thanks to improved effective cadence of observations. In our
analysis, we have taken into account the recently discovered common red noise
process, which has an impact at low frequencies. We also find that the peculiar
noise features present in some pulsars data must be taken into account to
reduce the false alarm. We show that using custom noise models is essential in
searching for continuous gravitational wave signals and setting the upper
limit
Comparing Recent Pulsar Timing Array Results on the Nanohertz Stochastic Gravitational-wave Background
The Australian, Chinese, European, Indian, and North American pulsar timing array (PTA) collaborations recently reported, at varying levels, evidence for the presence of a nanohertz gravitational-wave background (GWB). Given that each PTA made different choices in modeling their data, we perform a comparison of the GWB and individual pulsar noise parameters across the results reported from the PTAs that constitute the International Pulsar Timing Array (IPTA). We show that despite making different modeling choices, there is no significant difference in the GWB parameters that are measured by the different PTAs, agreeing within 1σ. The pulsar noise parameters are also consistent between different PTAs for the majority of the pulsars included in these analyses. We bridge the differences in modeling choices by adopting a standardized noise model for all pulsars and PTAs, finding that under this model there is a reduction in the tension in the pulsar noise parameters. As part of this reanalysis, we "extended" each PTA's data set by adding extra pulsars that were not timed by that PTA. Under these extensions, we find better constraints on the GWB amplitude and a higher signal-to-noise ratio for the Hellings–Downs correlations. These extensions serve as a prelude to the benefits offered by a full combination of data across all pulsars in the IPTA, i.e., the IPTA's Data Release 3, which will involve not just adding in additional pulsars but also including data from all three PTAs where any given pulsar is timed by more than a single PTA
Comparing recent PTA results on the nanohertz stochastic gravitational wave background
The Australian, Chinese, European, Indian, and North American pulsar timing
array (PTA) collaborations recently reported, at varying levels, evidence for
the presence of a nanohertz gravitational wave background (GWB). Given that
each PTA made different choices in modeling their data, we perform a comparison
of the GWB and individual pulsar noise parameters across the results reported
from the PTAs that constitute the International Pulsar Timing Array (IPTA). We
show that despite making different modeling choices, there is no significant
difference in the GWB parameters that are measured by the different PTAs,
agreeing within . The pulsar noise parameters are also consistent
between different PTAs for the majority of the pulsars included in these
analyses. We bridge the differences in modeling choices by adopting a
standardized noise model for all pulsars and PTAs, finding that under this
model there is a reduction in the tension in the pulsar noise parameters. As
part of this reanalysis, we "extended" each PTA's data set by adding extra
pulsars that were not timed by that PTA. Under these extensions, we find better
constraints on the GWB amplitude and a higher signal-to-noise ratio for the
Hellings and Downs correlations. These extensions serve as a prelude to the
benefits offered by a full combination of data across all pulsars in the IPTA,
i.e., the IPTA's Data Release 3, which will involve not just adding in
additional pulsars, but also including data from all three PTAs where any given
pulsar is timed by more than as single PTA.Comment: 21 pages, 9 figures, submitted to Ap
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
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