80 research outputs found
Extramural venous invasion is a potential imaging predictive biomarker of neoadjuvant treatment in rectal cancer
BACKGROUND: Extramural venous invasion (EMVI) is a poor prognostic factor in rectal cancer and identified on magnetic resonance imaging (MRI) (mrEMVI). The clinical relevance of improvement in mrEMVI following neoadjuvant therapy is unknown. This study aimed to demonstrate that regression of mrEMVI following neoadjuvant chemoradiotherapy (CRT) results in improved outcomes and mrEMVI can be used as an imaging biomarker METHODS: Retrospective analysis of prospectively collected data was conducted examining the staging and post-treatment MRIs of patients who had presented with EMVI-positive rectal cancer. All patients had undergone neoadjuvant CRT and curative surgery. Changes in mrEMVI were graded with a new MRI-based TRG scale–mr-vTRG; and related to disease-free survival (DFS). The study fulfilled Reporting Recommendations for Tumour Marker Prognostic Studies criteria for biomarkers. RESULTS: Sixty-two patients were included. Thirty-five patients showed more than 50% fibrosis of mrEMVI (mr-vTRG 1-3); 3-year DFS 87.8% and 9% recurrence. Twenty-seven patients showed less than 50% fibrosis (mr-vTRG 4-5); 3-year DFS 45.8% with 44% recurrence – P<0.0001. On multivariate Cox-regression, only mr-vTRG 4-5 increased risk of disease recurrence – HR=5.748. CONCLUSION: Patients in whom there has been a significant response of EMVI to CRT show improved DFS. Those patients with poor response should be considered for intensive treatment. As an imaging biomarker in rectal cancer, mrEMVI can be used
Planet Populations as a Function of Stellar Properties
Exoplanets around different types of stars provide a window into the diverse
environments in which planets form. This chapter describes the observed
relations between exoplanet populations and stellar properties and how they
connect to planet formation in protoplanetary disks. Giant planets occur more
frequently around more metal-rich and more massive stars. These findings
support the core accretion theory of planet formation, in which the cores of
giant planets form more rapidly in more metal-rich and more massive
protoplanetary disks. Smaller planets, those with sizes roughly between Earth
and Neptune, exhibit different scaling relations with stellar properties. These
planets are found around stars with a wide range of metallicities and occur
more frequently around lower mass stars. This indicates that planet formation
takes place in a wide range of environments, yet it is not clear why planets
form more efficiently around low mass stars. Going forward, exoplanet surveys
targeting M dwarfs will characterize the exoplanet population around the lowest
mass stars. In combination with ongoing stellar characterization, this will
help us understand the formation of planets in a large range of environments.Comment: Accepted for Publication in the Handbook of Exoplanet
Lattice Boltzmann simulations of soft matter systems
This article concerns numerical simulations of the dynamics of particles
immersed in a continuum solvent. As prototypical systems, we consider colloidal
dispersions of spherical particles and solutions of uncharged polymers. After a
brief explanation of the concept of hydrodynamic interactions, we give a
general overview over the various simulation methods that have been developed
to cope with the resulting computational problems. We then focus on the
approach we have developed, which couples a system of particles to a lattice
Boltzmann model representing the solvent degrees of freedom. The standard D3Q19
lattice Boltzmann model is derived and explained in depth, followed by a
detailed discussion of complementary methods for the coupling of solvent and
solute. Colloidal dispersions are best described in terms of extended particles
with appropriate boundary conditions at the surfaces, while particles with
internal degrees of freedom are easier to simulate as an arrangement of mass
points with frictional coupling to the solvent. In both cases, particular care
has been taken to simulate thermal fluctuations in a consistent way. The
usefulness of this methodology is illustrated by studies from our own research,
where the dynamics of colloidal and polymeric systems has been investigated in
both equilibrium and nonequilibrium situations.Comment: Review article, submitted to Advances in Polymer Science. 16 figures,
76 page
Systematic review of the relationship between family history and lung cancer risk
We performed a systematic review of 28 case–control, 17 cohort and seven twin studies of the relationship between family history and risk of lung cancer and a meta-analysis of risk estimates. Data from both case–control and cohort studies show a significantly increased lung cancer risk associated with having an affected relative. Risk appears to be greater in relatives of cases diagnosed at a young age and in those with multiple affected family members. Increased lung cancer risk was observed in association with an affected spouse and twin studies, while limited, favour shared environmental exposures. The limitations of the currently published epidemiological studies to infer genetic susceptibility are discussed
Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation
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Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
Background:
Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (
BMPR2
) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (
EIF2AK4
) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.
Methods:
Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in
BMPR2
and biallelic
EIF2AK4
variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and
sorting intolerant from tolerant
predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.
Results:
Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in
BMPR2
were identified in 130 patients (14.8%). Biallelic mutations in
EIF2AK4
were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic
EIF2AK4
mutations. These patients had a reduced transfer coefficient for carbon monoxide (K
co
; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without
EIF2AK4
mutations. However, radiological assessment alone could not accurately identify biallelic
EIF2AK4
mutation carriers. Patients with PAH with biallelic
EIF2AK4
mutations had a shorter survival.
Conclusions:
Biallelic
EIF2AK4
mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K
co
and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
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Reconstruction of sediment-transport pathways on a modern microtidal coast by a new grain-size trend analysis method
A new method for granulometric-parameter-based reconstruction of sediment-transport pathways is proposed and is termed P-GSTA (grain-size trend analysis using principal component analysis) herein. The main advantage of this method is its applicability to depositional environments involving mixed transport processes, for instance, fluvial, tidal, and wave-influenced environments. In the P-GSTA method, a linear function with all significant granulometric parameters that are summed with different weighting factors was used to infer sediment-transport direction (sediment flux pattern); the previous grain-size trend analysis (GSTA) methods considered only three parameters (mean grain size, sorting, and skewness) with equal weighting. This study chose six parameters (namely, median grain size, coefficient of variation, skewness, kurtosis, and mud and gravel log-ratios) for calculation. First, the zero values of mud and gravel fractions are replaced, and their log-ratios are defined. Then, all values are standardized. Thereafter, principal component analysis (PCA) is conducted to determine the weighting factor of each granulometric parameter. Each principal component is then interpreted, and the function best representing a sediment flux pattern is chosen from these components. Trend vectors are calculated, solely on the basis of a map interpolated from the scores of the chosen principal component, as the two-dimensional gradient of this value. The P-GSTA method proposed in this study was applied to a modern microtidal coast (tidal sand flat along the Kushida River Delta, central Japan). Sediment-transport pathways reconstructed by this method were consistent with observed sediment-transport patterns determined by field experiments using tracer sediments and geomorphologic observation; the results of the previous GSTA method were inconsistent with the observations. The proposed method also revealed additional minor depositional processes on the sand flat, namely, the deposition of fluvial-channel lags and muddy particles. Thus, this study demonstrates that the proposed P-GSTA method is a potentially powerful tool to reconstruct sediment-transport patterns even under mixed transport processes, where the estimation of the sediment-transport function is difficult
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