89 research outputs found
Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease
AbstractEmerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20âmg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20âmg/kg/week or 40âmg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (nâ=â4), infantile-onset (nâ=â9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy
The impact of FADS genetic variants on Ï6 polyunsaturated fatty acid metabolism in African Americans
<p>Abstract</p> <p>Background</p> <p>Arachidonic acid (AA) is a long-chain omega-6 polyunsaturated fatty acid (PUFA) synthesized from the precursor dihomo-gamma-linolenic acid (DGLA) that plays a vital role in immunity and inflammation. Variants in the Fatty Acid Desaturase (<it>FADS</it>) family of genes on chromosome 11q have been shown to play a role in PUFA metabolism in populations of European and Asian ancestry; no work has been done in populations of African ancestry to date.</p> <p>Results</p> <p>In this study, we report that African Americans have significantly higher circulating levels of plasma AA (p = 1.35 Ă 10<sup>-48</sup>) and lower DGLA levels (p = 9.80 Ă 10<sup>-11</sup>) than European Americans. Tests for association in N = 329 individuals across 80 nucleotide polymorphisms (SNPs) in the Fatty Acid Desaturase (<it>FADS</it>) locus revealed significant association with AA, DGLA and the AA/DGLA ratio, a measure of enzymatic efficiency, in both racial groups (peak signal p = 2.85 Ă 10<sup>-16 </sup>in African Americans, 2.68 Ă 10<sup>-23 </sup>in European Americans). Ancestry-related differences were observed at an upstream marker previously associated with AA levels (rs174537), wherein, 79-82% of African Americans carry two copies of the G allele compared to only 42-45% of European Americans. Importantly, the allelic effect of the G allele, which is associated with <it>enhanced </it>conversion of DGLA to AA, on enzymatic efficiency was similar in both groups.</p> <p>Conclusions</p> <p>We conclude that the impact of <it>FADS </it>genetic variants on PUFA metabolism, specifically AA levels, is likely more pronounced in African Americans due to the larger proportion of individuals carrying the genotype associated with increased FADS1 enzymatic conversion of DGLA to AA.</p
Genetic modifiers of CHEK2*1100delC-associated breast cancer risk
Purpose: CHEK2*1100delC is a founder variant in European populations that confers a two-to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). Methods: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. Results: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.212.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. Conclusion: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Peer reviewe
Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications
Introduction: Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. Methods: In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. Results: We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels. Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions: We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation
The NANOGrav 15 yr Data Set: Search for Transverse Polarization Modes in the Gravitational-wave Background
Recently we found compelling evidence for a gravitational-wave background with Hellings and Downs (HD) correlations in our 15 yr data set. These correlations describe gravitational waves as predicted by general relativity, which has two transverse polarization modes. However, more general metric theories of gravity can have additional polarization modes, which produce different interpulsar correlations. In this work, we search the NANOGrav 15 yr data set for evidence of a gravitational-wave background with quadrupolar HD and scalar-transverse (ST) correlations. We find that HD correlations are the best fit to the data and no significant evidence in favor of ST correlations. While Bayes factors show strong evidence for a correlated signal, the data does not strongly prefer either correlation signature, with Bayes factors âŒ2 when comparing HD to ST correlations, and âŒ1 for HD plus ST correlations to HD correlations alone. However, when modeled alongside HD correlations, the amplitude and spectral index posteriors for ST correlations are uninformative, with the HD process accounting for the vast majority of the total signal. Using the optimal statistic, a frequentist technique that focuses on the pulsar-pair cross-correlations, we find median signal-to-noise ratios of 5.0 for HD and 4.6 for ST correlations when fit for separately, and median signal-to-noise ratios of 3.5 for HD and 3.0 for ST correlations when fit for simultaneously. While the signal-to-noise ratios for each of the correlations are comparable, the estimated amplitude and spectral index for HD are a significantly better fit to the total signal, in agreement with our Bayesian analysis
The NANOGrav 15-year data set: Search for Transverse Polarization Modes in the Gravitational-Wave Background
Recently we found compelling evidence for a gravitational wave background
with Hellings and Downs (HD) correlations in our 15-year data set. These
correlations describe gravitational waves as predicted by general relativity,
which has two transverse polarization modes. However, more general metric
theories of gravity can have additional polarization modes which produce
different interpulsar correlations. In this work we search the NANOGrav 15-year
data set for evidence of a gravitational wave background with quadrupolar
Hellings and Downs (HD) and Scalar Transverse (ST) correlations. We find that
HD correlations are the best fit to the data, and no significant evidence in
favor of ST correlations. While Bayes factors show strong evidence for a
correlated signal, the data does not strongly prefer either correlation
signature, with Bayes factors when comparing HD to ST correlations,
and for HD plus ST correlations to HD correlations alone. However,
when modeled alongside HD correlations, the amplitude and spectral index
posteriors for ST correlations are uninformative, with the HD process
accounting for the vast majority of the total signal. Using the optimal
statistic, a frequentist technique that focuses on the pulsar-pair
cross-correlations, we find median signal-to-noise-ratios of 5.0 for HD and 4.6
for ST correlations when fit for separately, and median signal-to-noise-ratios
of 3.5 for HD and 3.0 for ST correlations when fit for simultaneously. While
the signal-to-noise-ratios for each of the correlations are comparable, the
estimated amplitude and spectral index for HD are a significantly better fit to
the total signal, in agreement with our Bayesian analysis.Comment: 11 pages, 5 figure
The NANOGrav 15-year Data Set: Bayesian Limits on Gravitational Waves from Individual Supermassive Black Hole Binaries
Evidence for a low-frequency stochastic gravitational wave background has
recently been reported based on analyses of pulsar timing array data. The most
likely source of such a background is a population of supermassive black hole
binaries, the loudest of which may be individually detected in these datasets.
Here we present the search for individual supermassive black hole binaries in
the NANOGrav 15-year dataset. We introduce several new techniques, which
enhance the efficiency and modeling accuracy of the analysis. The search
uncovered weak evidence for two candidate signals, one with a
gravitational-wave frequency of 4 nHz, and another at 170 nHz. The
significance of the low-frequency candidate was greatly diminished when
Hellings-Downs correlations were included in the background model. The
high-frequency candidate was discounted due to the lack of a plausible host
galaxy, the unlikely astrophysical prior odds of finding such a source, and
since most of its support comes from a single pulsar with a commensurate binary
period. Finding no compelling evidence for signals from individual binary
systems, we place upper limits on the strain amplitude of gravitational waves
emitted by such systems.Comment: 23 pages, 13 figures, 2 tables. Accepted for publication in
Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set
and the Gravitational Wave Background. For questions or comments, please
email [email protected]
The NANOGrav 15-year Data Set: Evidence for a Gravitational-Wave Background
We report multiple lines of evidence for a stochastic signal that is
correlated among 67 pulsars from the 15-year pulsar-timing data set collected
by the North American Nanohertz Observatory for Gravitational Waves. The
correlations follow the Hellings-Downs pattern expected for a stochastic
gravitational-wave background. The presence of such a gravitational-wave
background with a power-law-spectrum is favored over a model with only
independent pulsar noises with a Bayes factor in excess of , and this
same model is favored over an uncorrelated common power-law-spectrum model with
Bayes factors of 200-1000, depending on spectral modeling choices. We have
built a statistical background distribution for these latter Bayes factors
using a method that removes inter-pulsar correlations from our data set,
finding (approx. ) for the observed Bayes factors in the
null no-correlation scenario. A frequentist test statistic built directly as a
weighted sum of inter-pulsar correlations yields (approx. ). Assuming a fiducial
characteristic-strain spectrum, as appropriate for an ensemble of binary
supermassive black-hole inspirals, the strain amplitude is (median + 90% credible interval) at a reference frequency of
1/(1 yr). The inferred gravitational-wave background amplitude and spectrum are
consistent with astrophysical expectations for a signal from a population of
supermassive black-hole binaries, although more exotic cosmological and
astrophysical sources cannot be excluded. The observation of Hellings-Downs
correlations points to the gravitational-wave origin of this signal.Comment: 30 pages, 18 figures. Published in Astrophysical Journal Letters as
part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave
Background. For questions or comments, please email [email protected]
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