282 research outputs found
A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma
Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options
Effect of Composition Changes on the Structural Relaxation of a Binary Mixture
Within the mode-coupling theory for idealized glass transitions, we study the
evolution of structural relaxation in binary mixtures of hard spheres with size
ratios of the two components varying between 0.5 and 1.0. We find two
scenarios for the glassy dynamics. For small size disparity, the mixing yields
a slight extension of the glass regime. For larger size disparity, a
plasticization effect is obtained, leading to a stabilization of the liquid due
to mixing. For all , a decrease of the elastic moduli at the transition
due to mixing is predicted. A stiffening of the glass structure is found as is
reflected by the increase of the Debye-Waller factors at the transition points.
The critical amplitudes for density fluctuations at small and intermediate wave
vectors decrease upon mixing, and thus the universal formulas for the
relaxation near the plateau values describe a slowing down of the dynamics upon
mixing for the first step of the two-step relaxation scenario. The results
explain the qualitative features of mixing effects reported by Williams and van
Megen [Phys. Rev. E \textbf{64}, 041502 (2001)] for dynamical light-scattering
measurements on binary mixtures of hard-sphere-like colloids with size ratio
Shrinking a large dataset to identify variables associated with increased risk of Plasmodium falciparum infection in Western Kenya
Large datasets are often not amenable to analysis using traditional single-step approaches. Here, our general objective was to apply imputation techniques, principal component analysis (PCA), elastic net and generalized linear models to a large dataset in a systematic approach to extract the most meaningful predictors for a health outcome. We extracted predictors for Plasmodium falciparum infection, from a large covariate dataset while facing limited numbers of observations, using data from the People, Animals, and their Zoonoses (PAZ) project to demonstrate these techniques: data collected from 415 homesteads in western Kenya, contained over 1500 variables that describe the health, environment, and social factors of the humans, livestock, and the homesteads in which they reside. The wide, sparse dataset was simplified to 42 predictors of P. falciparum malaria infection and wealth rankings were produced for all homesteads. The 42 predictors make biological sense and are supported by previous studies. This systematic data-mining approach we used would make many large datasets more manageable and informative for decision-making processes and health policy prioritization
Observation of Orbitally Excited B_s Mesons
We report the first observation of two narrow resonances consistent with
states of orbitally excited (L=1) B_s mesons using 1 fb^{-1} of ppbar
collisions at sqrt{s} = 1.96 TeV collected with the CDF II detector at the
Fermilab Tevatron. We use two-body decays into K^- and B^+ mesons reconstructed
as B^+ \to J/\psi K^+, J/\psi \to \mu^+ \mu^- or B^+ \to \bar{D}^0 \pi^+,
\bar{D}^0 \to K^+ \pi^-. We deduce the masses of the two states to be m(B_{s1})
= 5829.4 +- 0.7 MeV/c^2 and m(B_{s2}^*) = 5839.7 +- 0.7 MeV/c^2.Comment: Version accepted and published by Phys. Rev. Let
Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set
We report a measurement of the bottom-strange meson mixing phase \beta_s
using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays
in which the quark-flavor content of the bottom-strange meson is identified at
production. This measurement uses the full data set of proton-antiproton
collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment
at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity.
We report confidence regions in the two-dimensional space of \beta_s and the
B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2,
-1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in
agreement with the standard model expectation. Assuming the standard model
value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +-
0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +-
0.009 (syst) ps, which are consistent and competitive with determinations by
other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012
Global Search for New Physics with 2.0/fb at CDF
Data collected in Run II of the Fermilab Tevatron are searched for
indications of new electroweak-scale physics. Rather than focusing on
particular new physics scenarios, CDF data are analyzed for discrepancies with
the standard model prediction. A model-independent approach (Vista) considers
gross features of the data, and is sensitive to new large cross-section
physics. Further sensitivity to new physics is provided by two additional
algorithms: a Bump Hunter searches invariant mass distributions for "bumps"
that could indicate resonant production of new particles; and the Sleuth
procedure scans for data excesses at large summed transverse momentum. This
combined global search for new physics in 2.0/fb of ppbar collisions at
sqrt(s)=1.96 TeV reveals no indication of physics beyond the standard model.Comment: 8 pages, 7 figures. Final version which appeared in Physical Review D
Rapid Communication
Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV
The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8 TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum
Saethre-Chotzen syndrome : cranofacial anomalies caused by genetic changes in the TWIST gene
In this thesis, one of the most frequently occurring and most variable craniosynostosis
syndromes was investigated; Saethre-Chotzen syndrome. Craniosynostosis is the premature
obliteration of cranial sutures in the developing embryo. It can also occur in the first few
months of life. Saethre-Chotzen syndrome is, besides craniosynostosis, characterized by
specific facial and limb abnormalities, of which the most frequently reported are ptosis,
prominent crus helicis, cutaneous syndactyly of digit 2 and 3 on both hands and feet, and
broad halluces. Saethre-Chotzen syndrome has been linked to the TWIST gene on
chromosome 7p21.1. Mutations in and variably sized deletions of this gene can be found in
patients with clinical features of Saethre-Chotzen syndrome. The latter, TWIST deletions,
often also include part of the surrounding chromosome 7p and are reported to be associated
with mental retardation. In Saethre-Chotzen patients, in whom neither a mutation nor a
deletion of TWIST had been found, the FGFR3 P250R mutation was in some cases detected.
This mutation has specifically been linked to Muenke syndrome that is characterized by unior
bicoronal synostosis and slight facial dysmorphology. However, a Saethre-Chotzen like
phenotype can also result from this mutation.
Because of the possible overlap of Saethre-Chotzen with Muenke syndrome, these syndromes
were studied in order to provide clinical criteria that discriminate between the two (chapter 4).
Many phenotypic features occur in both syndromes. In addition, although unicoronal
synostosis occurs slightly more frequently in Muenke syndrome, unicoronal and bicoronal
synostosis are seen in both syndromes. The discrimination between Saethre-Chotzen and
Muenke is often not made easily and the associated genes, TWIST and FGFR3, respectively,
are simultaneously tested for pathogenic m
Search for long-lived doubly charged Higgs bosons in p(p)over-bar collisions at root s=1.96 TeV
We present a search for long-lived doubly charged Higgs bosons (H+/-+/-), with signatures of high ionization energy loss and muonlike penetration. We use 292 pb(-1) of data collected in p (p) over bar collisions at root s=1.96 TeV by the CDF II detector at the Fermilab Tevatron. Observing no evidence of long-lived doubly charged particle production, we exclude H-L(+/-+/-) and H-R(+/-+/-) bosons with masses below 133 GeV/c(2) and 109 GeV/c(2), respectively. In the degenerate case we exclude H+/-+/- mass below 146 GeV/c(2). All limits are quoted at the 95% confidence level
Measurement of the ttbar Production Cross Section in ppbar collisions at sqrt s = 1.96 TeV in the All Hadronic Decay Mode
We report a measurement of the ttbar production cross section using the
CDF-II detector at the Fermilab Tevatron. The analysis is performed using 311
pb-1 of ppbar collisions at sqrt(s)=1.96 TeV. The data consist of events
selected with six or more hadronic jets with additional kinematic requirements.
At least one of these jets must be identified as a b-quark jet by the
reconstruction of a secondary vertex. The cross section is measured to be
sigma(tbart)=7.5+-2.1(stat.)+3.3-2.2(syst.)+0.5-0.4(lumi.) pb, which is
consistent with the standard model prediction.Comment: By CDF collaboratio
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