Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants ...associated with ACT in patients treated for childhood cancer.
We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands.
We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT.
We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.
ABSTRACT
We explore the fundamental relations governing the radial and vertical velocity dispersions of stars in the Milky Way, from combined studies of complementary surveys including GALAH, LAMOST, ...APOGEE, the NASA Kepler and K2 missions, and Gaia DR2. We find that different stellar samples, even though they target different tracer populations and employ a variety of age estimation techniques, follow the same set of fundamental relations. We provide the clearest evidence to date that, in addition to the well-known dependence on stellar age, the velocity dispersions of stars depend on orbital angular momentum Lz, metallicity, and height above the plane |z|, and are well described by a multiplicatively separable functional form. The dispersions have a power-law dependence on age with exponents of 0.441 ± 0.007 and 0.251 ± 0.006 for σz and σR, respectively, and the power law is valid even for the oldest stars. For the solar neighbourhood stars, the apparent break in the power law for older stars, as seen in previous studies, is due to the anticorrelation of Lz with age. The dispersions decrease with increasing Lz until we reach the Sun’s orbital angular momentum, after which σz increases (implying flaring in the outer disc) while σR flattens. For a given age, the dispersions increase with decreasing metallicity, suggesting that the dispersions increase with birth radius. The dispersions also increase linearly with |z|. The same set of relations that work in the solar neighbourhood also work for stars between 3 < R/kpc < 20. Finally, the high-α/Fe stars follow the same relations as the low-α/Fe stars.
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD
+
)-dependent lysine deacetylase that regulates longevity and enhances mitochondrial metabolism. Both activation and inhibition of SIRT1 ...were previously shown to ameliorate neuropathological mechanisms in Huntington’s disease (HD), a neurodegenerative disease that selectively affects the striatum and cortex and is commonly linked to mitochondrial dysfunction. Thus, in this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models, namely striatal and cortical neurons isolated from YAC128 transgenic mice embryos, HD human lymphoblasts, and an in vivo HD model. HD cell models displayed a deregulation in mitochondrial membrane potential and respiration, implicating a decline in mitochondrial function. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD
+
levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.
Huntington's disease is a fatal neurodegenerative disorder that is caused by CAG-CAA repeat expansion, encoding polyglutamine, in the huntingtin (HTT) gene. Current age-of-clinical-onset prediction ...models for Huntington's disease are based on polyglutamine length and explain only a proportion of the variability in age of onset observed between patients. These length-based assays do not interrogate the underlying genetic variation, because known genetic variants in this region do not alter the protein coding sequence. Given that individuals with identical repeat lengths can present with Huntington's disease decades apart, the search for genetic modifiers of clinical age of onset has become an active area of research.
Results from three independent genetic studies of Huntington's disease have shown that glutamine-encoding CAA variants that interrupt DNA CAG repeat tracts, but do not alter polyglutamine length or polyglutamine homogeneity, are associated with substantial differences in age of onset of Huntington's disease in carriers. A variant that results in the loss of CAA interruption is associated with early onset and is particularly relevant to individuals that carry alleles in the reduced penetrance range (ie, CAG 36–39). Approximately a third of clinically manifesting carriers of reduced penetrance alleles, defined by current diagnostics, carry this variant. Somatic repeat instability, modified by interrupted CAG tracts, is the most probable cause mediating this effect. This relationship is supported by genome-wide screens for disease modifiers, which have revealed the importance of DNA-repair genes in Huntington's disease (ie, FAN1, LIG1, MLH1, MSH3, PMS1, and PMS2).
Focus needs to be placed on refining our understanding of the effect of the loss-of-interruption and duplication-of-interruption variants and other interrupting sequence variants on age of onset, and assessing their effect in disease-relevant brain tissues, as well as in diverse population groups, such as individuals from Africa and Asia. Diagnostic tests should be augmented or updated, since current tests do not assess the underlying DNA sequence variation, especially when assessing individuals that carry alleles in the reduced penetrance range. Future studies should explore somatic repeat instability and DNA repair as new therapeutic targets to modify age of onset in Huntington's disease and in other repeat-mediated disorders. Disease-modifying therapies could potentially be developed by therapeutically targeting these processes. Promising approaches include therapeutically targeting the expanded repeat or directly perturbing key DNA-repair genes (eg, with antisense oligonucleotides or small molecules). Targeting the CAG repeat directly with naphthyridine-azaquinolone, a compound that induces contractions, and altering the expression of MSH3, represent two viable therapeutic strategies. However, as a first step, the capability of such novel therapeutic approaches to delay clinical onset in animal models should be assessed.
Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration ...resulting in motor dysfunction, cognitive decline, and psychiatric disturbances. Currently, there is no disease altering treatment, and symptomatic therapy has limited benefit. The pathogenesis of HD is complicated and multiple pathways are compromised. Addressing the problem at its genetic root by suppressing mutant huntingtin expression is a promising therapeutic strategy for HD. We have developed and evaluated antisense oligonucleotides (ASOs) targeting single nucleotide polymorphisms that are significantly enriched on HD alleles (HD-SNPs). We describe our structure-activity relationship studies for ASO design and find that adjusting the SNP position within the gap, chemical modifications of the wings, and shortening the unmodified gap are critical for potent, specific, and well tolerated silencing of mutant huntingtin. Finally, we show that using two distinct ASO drugs targeting the two allelic variants of an HD-SNP could provide a therapeutic option for all persons with HD; allele-specifically for roughly half, and non-specifically for the remainder.
Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it ...remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate-type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.
ABSTRACT Using a sample of 69,919 red giants from the SDSS-III/APOGEE Data Release 12, we measure the distribution of stars in the /Fe versus Fe/H plane and the metallicity distribution functions ...(MDFs) across an unprecedented volume of the Milky Way disk, with radius 3 < R < 15 kpc and height kpc. Stars in the inner disk (R < 5 kpc) lie along a single track in /Fe versus Fe/H, starting with -enhanced, metal-poor stars and ending at /Fe ∼ 0 and Fe/H ∼ +0.4. At larger radii we find two distinct sequences in /Fe versus Fe/H space, with a roughly solar- sequence that spans a decade in metallicity and a high- sequence that merges with the low- sequence at super-solar Fe/H. The location of the high- sequence is nearly constant across the disk; however, there are very few high- stars at R > 11 kpc. The peak of the midplane MDF shifts to lower metallicity at larger R, reflecting the Galactic metallicity gradient. Most strikingly, the shape of the midplane MDF changes systematically with radius, from a negatively skewed distribution at 3 < R < 7 kpc, to a roughly Gaussian distribution at the solar annulus, to a positively skewed shape in the outer Galaxy. For stars with kpc or /Fe > 0.18, the MDF shows little dependence on R. The positive skewness of the outer-disk MDF may be a signature of radial migration; we show that blurring of stellar populations by orbital eccentricities is not enough to explain the reversal of MDF shape, but a simple model of radial migration can do so.
The GALAH Survey: second data release Buder, Sven; Asplund, Martin; Duong, Ly ...
Monthly notices of the Royal Astronomical Society,
08/2018, Letnik:
478, Številka:
4
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
The Galactic Archaeology with HERMES (GALAH) survey is a large-scale stellar spectroscopic survey of the Milky Way, designed to deliver complementary chemical information to a large number ...of stars covered by the Gaia mission. We present the GALAH second public data release (GALAH DR2) containing 342 682 stars. For these stars, the GALAH collaboration provides stellar parameters and abundances for up to 23 elements to the community. Here we present the target selection, observation, data reduction, and detailed explanation of how the spectra were analysed to estimate stellar parameters and element abundances. For the stellar analysis, we have used a multistep approach. We use the physics-driven spectrum synthesis of Spectroscopy Made Easy (SME) to derive stellar labels (Teff, log g, Fe/H, X/Fe, vmic, vsin i, $A_{K_S}$) for a representative training set of stars. This information is then propagated to the whole sample with the data-driven method of The Cannon. Special care has been exercised in the spectral synthesis to only consider spectral lines that have reliable atomic input data and are little affected by blending lines. Departures from local thermodynamic equilibrium (LTE) are considered for several key elements, including Li, O, Na, Mg, Al, Si, and Fe, using 1D marcs stellar atmosphere models. Validation tests including repeat observations, Gaia benchmark stars, open and globular clusters, and K2 asteroseismic targets lend confidence to our methods and results. Combining the GALAH DR2 catalogue with the kinematic information from Gaia will enable a wide range of Galactic Archaeology studies, with unprecedented detail, dimensionality, and scope.
Abstract
The measurement of the structure of stellar populations in the Milky Way disc places fundamental constraints on models of galaxy formation and evolution. Previously, the disc's structure has ...been studied in terms of populations defined geometrically and/or chemically, but a decomposition based on stellar ages provides a more direct connection to the history of the disc, and stronger constraint on theory. Here, we use positions, abundances and ages for 31 244 red giant branch stars from the Sloan Digital Sky Survey (SDSS)-APOGEE survey, spanning 3 < R
gc < 15 kpc, to dissect the disc into mono-age and mono-Fe/H populations at low and high
$\mathrm{ \alpha \mathrm{/Fe}}$
. For each population, with Δage < 2 Gyr and ΔFe/H < 0.1 dex, we measure the structure and surface-mass density contribution. We find that low
$\mathrm{ \alpha \mathrm{/Fe}}$
mono-age populations are fit well by a broken exponential, which increases to a peak radius and decreases thereafter. We show that this profile becomes broader with age, interpreted here as a new signal of disc heating and radial migration. High
$\mathrm{ \alpha \mathrm{/Fe}}$
populations are well fit as single exponentials within the radial range considered, with an average scalelength of 1.9 ± 0.1 kpc. We find that the relative contribution of high to low
$\mathrm{ \alpha \mathrm{/Fe}}$
populations at R
0 is
$f_\Sigma = 18\hbox{ per cent} \pm 5\hbox{ per cent}$
; high
$\mathrm{ \alpha \mathrm{/Fe}}$
contributes most of the mass at old ages, and low
$\mathrm{ \alpha \mathrm{/Fe}}$
at young ages. The low and high
$\mathrm{ \alpha \mathrm{/Fe}}$
populations overlap in age at intermediate Fe/H, although both contribute mass at R
0 across the full range of Fe/H. The mass-weighted scaleheight hZ
distribution is a smoothly declining exponential function. High
$\mathrm{ \alpha \mathrm{/Fe}}$
populations are thicker than low
$\mathrm{ \alpha \mathrm{/Fe}}$
, and the average hZ
increases steadily with age, between 200 and 600 pc.
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