198 research outputs found
Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial
The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. (“GUIDED”), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian “GAPP-MDD” RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477)
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing
molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin
Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context
Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts
Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas
Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN
Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images
Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images
of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL
maps are derived through computational staining using a convolutional neural network trained to
classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and
correlation with overall survival. TIL map structural patterns were grouped using standard
histopathological parameters. These patterns are enriched in particular T cell subpopulations
derived from molecular measures. TIL densities and spatial structure were differentially enriched
among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial
infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic
patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for
the TCGA image archives with insights into the tumor-immune microenvironment
Expression of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain
<p>Abstract</p> <p>Background</p> <p>Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia, a malignancy characterized by uncontrolled proliferation of virally-infected CD4+ T-cells. Hypercalcemia and bone lesions due to osteoclast-mediated bone resorption are frequently associated with more aggressive forms of the disease. The HTLV-1 provirus contains a unique antisense gene that expresses HTLV-1 basic leucine zipper (bZIP) factor (HBZ). HBZ is localized to the nucleus where it regulates levels of transcription by binding to certain cellular transcriptional regulators. Among its protein targets, HBZ forms a stable complex with the homologous cellular coactivators, p300 and CBP, which is modulated through two N-terminal LXXLL motifs in the viral protein and the conserved KIX domain in the coactivators.</p> <p>Results</p> <p>To determine the effects of these interactions on transcription, we performed a preliminary microarray analysis, comparing levels of gene expression in cells with wild-type HBZ versus cells with HBZ mutated in its LXXLL motifs. <it>DKK1</it>, which encodes the secreted Wnt signaling inhibitor, Dickkopf-1 (Dkk1), was confirmed to be transcriptionally activated by HBZ, but not its mutant. Dkk1 plays a major role in the development of bone lesions caused by multiple myeloma. In parallel with the initial findings, activation of Dkk1 expression by HBZ was abrogated by siRNA-mediated knockdown of p300/CBP or by a truncated form of p300 containing the KIX domain. Among HTLV-1-infected T-cell lines tested, the detection of Dkk1 mRNA partially correlated with a threshold level of HBZ mRNA. In addition, an uninfected and an HTLV-1-infected T-cell line transfected with an HBZ expression vector exhibited <it>de novo </it>and increased DKK1 transcription, respectively. In contrast to HBZ, The HTLV-1 Tax protein repressed Dkk1 expression.</p> <p>Conclusions</p> <p>These data indicate that HBZ activates Dkk1 expression through its interaction with p300/CBP. However, this effect is limited in HTLV-1-infected T-cell lines, which in part, may be due to suppression of Dkk1 expression by Tax. Consequently, the ability of HBZ to regulate expression of Dkk1 and possibly other cellular genes may only be significant during late stages of ATL, when Tax expression is repressed.</p
Early Release Science of the Exoplanet WASP-39b with JWST NIRSpec G395H
Measuring the abundances of carbon and oxygen in exoplanet atmospheres is
considered a crucial avenue for unlocking the formation and evolution of
exoplanetary systems. Access to an exoplanet's chemical inventory requires
high-precision observations, often inferred from individual molecular
detections with low-resolution space-based and high-resolution ground-based
facilities. Here we report the medium-resolution (R600) transmission
spectrum of an exoplanet atmosphere between 3-5 m covering multiple
absorption features for the Saturn-mass exoplanet WASP-39b, obtained with JWST
NIRSpec G395H. Our observations achieve 1.46x photon precision, providing an
average transit depth uncertainty of 221 ppm per spectroscopic bin, and present
minimal impacts from systematic effects. We detect significant absorption from
CO (28.5) and HO (21.5), and identify SO as the
source of absorption at 4.1 m (4.8). Best-fit atmospheric models
range between 3 and 10x solar metallicity, with sub-solar to solar C/O ratios.
These results, including the detection of SO, underscore the importance of
characterising the chemistry in exoplanet atmospheres, and showcase NIRSpec
G395H as an excellent mode for time series observations over this critical
wavelength range.Comment: 44 pages, 11 figures, 3 tables. Resubmitted after revision to Natur
Early Release Science of the exoplanet WASP-39b with JWST NIRISS
Transmission spectroscopy provides insight into the atmospheric properties
and consequently the formation history, physics, and chemistry of transiting
exoplanets. However, obtaining precise inferences of atmospheric properties
from transmission spectra requires simultaneously measuring the strength and
shape of multiple spectral absorption features from a wide range of chemical
species. This has been challenging given the precision and wavelength coverage
of previous observatories. Here, we present the transmission spectrum of the
Saturn-mass exoplanet WASP-39b obtained using the SOSS mode of the NIRISS
instrument on the JWST. This spectrum spans m in wavelength and
reveals multiple water absorption bands, the potassium resonance doublet, as
well as signatures of clouds. The precision and broad wavelength coverage of
NIRISS-SOSS allows us to break model degeneracies between cloud properties and
the atmospheric composition of WASP-39b, favoring a heavy element enhancement
("metallicity") of the solar value, a sub-solar
carbon-to-oxygen (C/O) ratio, and a solar-to-super-solar potassium-to-oxygen
(K/O) ratio. The observations are best explained by wavelength-dependent,
non-gray clouds with inhomogeneous coverage of the planet's terminator.Comment: 48 pages, 12 figures, 2 tables. Under review at Natur
A broadband thermal emission spectrum of the ultra-hot Jupiter WASP-18b
Close-in giant exoplanets with temperatures greater than 2,000 K (''ultra-hot
Jupiters'') have been the subject of extensive efforts to determine their
atmospheric properties using thermal emission measurements from the Hubble and
Spitzer Space Telescopes. However, previous studies have yielded inconsistent
results because the small sizes of the spectral features and the limited
information content of the data resulted in high sensitivity to the varying
assumptions made in the treatment of instrument systematics and the atmospheric
retrieval analysis. Here we present a dayside thermal emission spectrum of the
ultra-hot Jupiter WASP-18b obtained with the NIRISS instrument on JWST. The
data span 0.85 to 2.85 m in wavelength at an average resolving power of
400 and exhibit minimal systematics. The spectrum shows three water emission
features (at 6 confidence) and evidence for optical opacity,
possibly due to H, TiO, and VO (combined significance of 3.8).
Models that fit the data require a thermal inversion, molecular dissociation as
predicted by chemical equilibrium, a solar heavy element abundance
(''metallicity'', M/H = 1.03 solar), and a
carbon-to-oxygen (C/O) ratio less than unity. The data also yield a dayside
brightness temperature map, which shows a peak in temperature near the
sub-stellar point that decreases steeply and symmetrically with longitude
toward the terminators.Comment: JWST ERS bright star observations. Uploaded to inform JWST Cycle 2
proposals. Manuscript under review. 50 pages, 14 figures, 2 table
Early Release Science of the exoplanet WASP-39b with JWST NIRCam
Measuring the metallicity and carbon-to-oxygen (C/O) ratio in exoplanet
atmospheres is a fundamental step towards constraining the dominant chemical
processes at work and, if in equilibrium, revealing planet formation histories.
Transmission spectroscopy provides the necessary means by constraining the
abundances of oxygen- and carbon-bearing species; however, this requires broad
wavelength coverage, moderate spectral resolution, and high precision that,
together, are not achievable with previous observatories. Now that JWST has
commenced science operations, we are able to observe exoplanets at previously
uncharted wavelengths and spectral resolutions. Here we report time-series
observations of the transiting exoplanet WASP-39b using JWST's Near InfraRed
Camera (NIRCam). The long-wavelength spectroscopic and short-wavelength
photometric light curves span 2.0 - 4.0 m, exhibit minimal systematics,
and reveal well-defined molecular absorption features in the planet's spectrum.
Specifically, we detect gaseous HO in the atmosphere and place an upper
limit on the abundance of CH. The otherwise prominent CO feature at 2.8
m is largely masked by HO. The best-fit chemical equilibrium models
favour an atmospheric metallicity of 1-100 solar (i.e., an enrichment
of elements heavier than helium relative to the Sun) and a sub-stellar
carbon-to-oxygen (C/O) ratio. The inferred high metallicity and low C/O ratio
may indicate significant accretion of solid materials during planet formation
or disequilibrium processes in the upper atmosphere.Comment: 35 pages, 13 figures, 3 tables, Nature, accepte
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