169 research outputs found
Collapse of a semiflexible polymer in poor solvent
We investigate the dynamics and the pathways of the collapse of a single,
semiflexible polymer in a poor solvent via 3-D Brownian Dynamics simulations.
Earlier work indicates that the condensation of semiflexible polymers
generically proceeds via a cascade through metastable racquet-shaped,
long-lived intermediates towards the stable torus state. We investigate the
rate of decay of uncollapsed states, analyze the preferential pathways of
condensation, and describe likelihood and lifespan of the different metastable
states. The simulation are performed with a bead-stiff spring model with
excluded volume interaction and exponentially decaying attractive potential.
The semiflexible chain collapse is studied as functions of the three relevant
length scales of the phenomenon, i.e., the total chain length , the
persistence length and the condensation length , where is a measure of the attractive potential per unit
length. Two dimensionless ratios, and , suffice to describe
the decay rate of uncollapsed states, which appears to scale as . The condensation sequence is described in terms of the time series
of the well separated energy levels associated with each metastable collapsed
state. The collapsed states are described quantitatively through the spatial
correlation of tangent vectors along the chain. We also compare the results
obtained with a locally inextensible bead-rod chain and with a phantom
bead-spring model. Finally, we show preliminary results on the effects of
steady shear flow on the kinetics of collapse.Comment: 9 pages, 8 figure
Homogeneous nucleation of quark-gluon plasma, finite size effects and long-lived metastable objects
The general formalism of homogeneous nucleation theory is applied to study
the hadronization pattern of the ultra-relativistic quark-gluon plasma (QGP)
undergoing a first order phase transition. A coalescence model is proposed to
describe the evolution dynamics of hadronic clusters produced in the nucleation
process. The size distribution of the nucleated clusters is important for the
description of the plasma conversion. The model is most sensitive to the
initial conditions of the QGP thermalization, time evolution of the energy
density, and the interfacial energy of the plasma-hadronic matter interface.
The rapidly expanding QGP is first supercooled by about . Then it reheats again up to the critical temperature T_c. Finally it
breaks up into hadronic clusters and small droplets of plasma. This fast
dynamics occurs within the first . The finite size effects and
fluctuations near the critical temperature are studied. It is shown that a drop
of longitudinally expanding QGP of the transverse radius below 4.5 fm can
display a long-lived metastability. However, both in the rapid and in the
delayed hadronization scenario, the bulk pion yield is emitted by sources as
large as 3-4.5 fm. This may be detected experimentally both by a HBT
interferometry signal and by the analysis of the rapidity distributions of
particles in narrow p_T-intervals at small p_T on an event-by-event basis.Comment: 29 pages, incl. 12 figures and 1 table; to be published in Phys. Rev.
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types
Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours
BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting
their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD),
safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers.
METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected
tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD.
RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study
1280.2, 64 patients (part I: 10–3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred;
the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab
showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at
≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal
carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic
Regression Modeling (BLRM) confirmed the RBD.
CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM.
Xentuzumab showed preliminary anti-tumour activity
Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.
Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy
Associations of autozygosity with a broad range of human phenotypes
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe
Measurement of prompt ψ(2S) production cross sections in proton–lead and proton–proton collisions at √SNN = 5.02 TeV
Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group
BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus
Identification of type 2 diabetes loci in 433,540 East Asian individuals
Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes—NKX6-3 and ANK1—in different tissues4–6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways
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