344 research outputs found
Regulation of episialin/MUC1 expression in breast carcinomas: a complex interplay between stimulatory and inhibitory factors
Reliability of panel-based mutational signatures for immune-checkpoint-inhibition efficacy prediction in non-small cell lung cancer
OBJECTIVES: Mutational signatures (MS) are gaining traction for deriving therapeutic insights for immune checkpoint inhibition (ICI). We asked if MS attributions from comprehensive targeted sequencing assays are reliable enough for predicting ICI efficacy in non-small cell lung cancer (NSCLC).METHODS: Somatic mutations of m = 126 patients were assayed using panel-based sequencing of 523 cancer-related genes. In silico simulations of MS attributions for various panels were performed on a separate dataset of m = 101 whole genome sequenced patients. Non-synonymous mutations were deconvoluted using COSMIC v3.3 signatures and used to test a previously published machine learning classifier.RESULTS: The ICI efficacy predictor performed poorly with an accuracy of 0.51 -0.09 +0.09, average precision of 0.52 -0.11 +0.11, and an area under the receiver operating characteristic curve of 0.50 -0.09 +0.10. Theoretical arguments, experimental data, and in silico simulations pointed to false negative rates (FNR) related to panel size. A secondary effect was observed, where deconvolution of small ensembles of point mutations lead to reconstruction errors and misattributions. CONCLUSION: MS attributions from current targeted panel sequencing are not reliable enough to predict ICI efficacy. We suggest that, for downstream classification tasks in NSCLC, signature attributions be based on whole exome or genome sequencing instead.</p
Automation and validation of micronucleus detection in the 3D EpiDerm⢠human reconstructed skin assay and correl
Recent restrictions on the testing of cosmetic ingredients in animals have resulted in the need to test the genotoxic potential of chemicals exclusively in vitro prior to licensing. However, as current in vitro tests produce some misleading positive results, sole reliance on such tests could prevent some chemicals with safe or beneficial exposure levels from being marketed. The 3D human reconstructed skin micronucleus (RSMN) assay is a promising new in vitro approach designed to assess genotoxicity of dermally applied compounds. The assay utilises a highly differentiated in vitro model of the human epidermis. For the first time, we have applied automated micronucleus detection to this assay using MetaSystems Metafer Slide Scanning Platform (Metafer), demonstrating concordance with manual scoring. The RSMN assay's fixation protocol was found to be compatible with the Metafer, providing a considerably shorter alternative to the recommended Metafer protocol. Lowest observed genotoxic effect levels (LOGELs) were observed for mitomycin-C at 4.8 Îźg/ ml and methyl methanesulfonate (MMS) at 1750 Îźg/ml when applied topically to the skin surface. In-medium dosing with MMS produced a LOGEL of 20 Îźg/ml, which was very similar to the topical LOGEL when considering the total mass of MMS added. Comparisons between 3D medium and 2D LOGELs resulted in a 7-fold difference in total mass of MMS applied to each system, suggesting a protective function of the 3D microarchitecture. Interestingly, hydrogen peroxide (H2O 2), a positive clastogen in 2D systems, tested negative in this assay. A non-genotoxic carcinogen, methyl carbamate, produced negative results, as expected. We also demonstrated expression of the DNA repair protein N-methylpurine-DNA glycosylase in EpiDermâ˘. Our preliminary validation here demonstrates that the RSMN assay may be a valuable followup to the current in vitro test battery, and together with its automation, could contribute to minimising unnecessary in vivo tests by reducing in vitro misleading positives. Š The Author 2014
Evidence for tidal interaction and a supergiant HI shell in the Local Group dwarf galaxy NGC 6822
We present a wide-field, high spatial and velocity resolution map of the
entire extended HI distribution of the Local Group dwarf galaxy NGC 6822. The
observations were obtained with the Australia Telescope Compact Array in
mosaicing mode. The interstellar medium of NGC 6822 is shaped by the presence
of numerous H{\sc i} holes and shells, including a supergiant shell, and the
effects of tidal interaction, in the form of a tidal arm and an infalling or
interacting HI complex. The HI shell is situated outside the optical galaxy and
occupies roughly a quarter of the area of the main HI disk. It measures 2.0
times 1.4 kpc, making it one of the largest supergiant HI shells ever found.
The giant hole shows no signs of expansion and no obvious creation mechanism is
evident from our data. If star formation was the cause, an energy equivalent of
\~100 supernovae (10^53 erg) is needed to create the hole. We derive an upper
limit for the age of order 100 Myr. The presence of a possible tidal arm
indicates that NGC 6822 may recently have undergone some interaction. An HI
complex located in the north-west of the galaxy may be the interaction partner.
We argue that it is likely that these features were created about 100 Myr ago
in an event that also enhanced the star formation rateComment: Accepted for publication in Astrophysical Journal Letters (needs
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Outcomes in Dutch DPP6 risk haplotype for familial idiopathic ventricular fibrillation:a focused update
Background: The genetic risk haplotype DPP6 has been linked to familial idiopathic ventricular fibrillation (IVF), but the associated long-term outcomes are unknown. Methods: DPP6 risk haplotype-positive family members (DPP6 cases) and their risk haplotype-negative relatives (DPP6 controls) were included. Clinical follow-up data were collected through March 2023. Implantable cardioverter-defibrillator (ICD) indication was divided in primary or secondary prevention. Cumulative survival and event rates were calculated. Results: We included 327 DPP6 cases and 315 DPP6 controls. Median follow-up time was 9 years (interquartile range: 4â12). Of the DPP6 cases, 129 (39%) reached the composite endpoint of appropriate ICD shock, sudden cardiac arrest or death, at a median age of 45 years (range: 15â97). Median overall survival was 83 years and 87 years for DPP6 cases and DPP6 controls, respectively (pâŻ< 0.001). In DPP6 cases, median overall survival was shorter for males (74 years) than females (85 years) (pâŻ< 0.001). Of the DPP6 cases, 97 (30%) died, at a median age of 50 years. With a prophylactic ICD implantation advise based on risk haplotype, sex and age, 137 (42%) of DPP6 cases received an ICD, for primary prevention (nâŻ= 109) or secondary prevention (nâŻ= 28). In the primary prevention subgroup, 10 patients experienced a total of 34 appropriate ICD shocks, and there were no deaths during follow-up. DPP6 cases with a secondary prevention ICD experienced a total of 231 appropriate ICD shocks.Conclusion: Patients with the DPP6 risk haplotype, particularly males, are at an increased risk of IVF and sudden cardiac death. Using a risk stratification approach based on risk haplotype, sex and age, a substantial proportion of patients with a primary prevention ICD experienced appropriate ICD shocks, showing the benefit of prophylactic ICD implantation with this strategy.</p
Rotation Curves of Spiral Galaxies
Rotation curves of spiral galaxies are the major tool for determining the
distribution of mass in spiral galaxies. They provide fundamental information
for understanding the dynamics, evolution and formation of spiral galaxies. We
describe various methods to derive rotation curves, and review the results
obtained. We discuss the basic characteristics of observed rotation curves in
relation to various galaxy properties, such as Hubble type, structure,
activity, and environment.Comment: 40 pages, 6 gif figures; Ann. Rev. Astron. Astrophys. Vol. 39, p.137,
200
Galaxy Populations and Evolution in Clusters IV: Deep HI Observations of Dwarf Ellipticals in the Virgo Cluster
We present in this paper the deepest Arecibo HI observations of Virgo cluster
dwarf ellipticals (dEs) taken to date. Based on this data we argue that a
significant fraction of Virgo cluster dEs recently underwent evolution. Our new
observations consist of HI 21-cm line observations for 22 classified dE
galaxies with optical radial velocities consistent with membership in the Virgo
cluster. Cluster members VCC 390 and VCC 1713 are detected with HI masses M(HI)
= 6*10^7 M_solar and 8*10^7 M_solar, respectively, while M(HI) in the remaining
20 dE galaxies have upper limits as low as 5*10^5 M_solar. We combine our
results with those for 27 other Virgo cluster dEs with HI observations in the
literature, 7 of which have HI detection claims. New optical images from the
WIYN telescope of 5 of these HI-detected dEs, along with archival data, suggest
that seven of the claimed detections are real, yielding a ~ 15% detection rate.
These HI-detected classified dEs are preferentially located near the periphery
of the Virgo cluster. Three Virgo dEs have observed HI velocity widths > 200
km/s, possibly indicating the presence of a large dark matter content, or
transient extended HI. We discuss the possible origins of these objects and
argue that they originate from field galaxies accreted onto high angular
momentum orbits by Virgo in the last few Gyr. As a result these galaxies are
slowly transformed within the cluster by gradual gas stripping processes,
associated truncation of star formation, and passive fading of stellar
populations. Low-mass early-type cluster galaxies are therefore currently being
produced as the product of cluster environmental effects. We utilize our
results to estimate the recent (past 1-3 Gyr) average mass accretion rate into
the Virgo cluster, finding dM/dt ~ 50 M_solar/year.Comment: Accepted to ApJ, 21 page
Interventricular Differences in βâAdrenergic Responses in the Canine Heart: Role of Phosphodiesterases
Background
RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in βâadrenergic (βâAR) responsiveness is unknown. In this study, we examine whether βâAR response and signaling differ in right (RV) versus left (LV) ventricles.
Methods and Results
Sarcomere shortening, Ca2+ transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes. Intracellular [cAMP] and PKA activity were measured by live cell imaging using FRETâbased sensors. Isoproterenol increased sarcomere shortening â10âfold and Ca2+âtransient amplitude â2âfold in LV midmyocytes (LVMs) versus â25âfold and â3âfold in RVMs. FRET imaging using targeted Epac2camps sensors revealed no change in subsarcolemmal [cAMP], but a 2âfold higher βâAR stimulation of cytoplasmic [cAMP] in RVMs versus LVMs. Accordingly, βâAR regulation of ICa,L and IKs were similar between LVMs and RVMs, whereas cytoplasmic PKA activity was increased in RVMs. Both PDE3 and PDE4 contributed to the βâAR regulation of cytoplasmic [cAMP], and the difference between LVMs and RVMs was abolished by PDE3 inhibition and attenuated by PDE4 inhibition. Finally LV and RV intracavitary pressures were recorded in anesthetized beagle dogs. A bolus injection of isoproterenol increased RV dP/dtmaxâ5âfold versus 3âfold in LV.
Conclusion
Canine RV and LV differ in their βâAR response due to intrinsic differences in myocyte βâAR downstream signaling. Enhanced βâAR responsiveness of the RV results from higher cAMP elevation in the cytoplasm, due to a decreased degradation by PDE3 and PDE4 in the RV compared to the LV
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