4,185 research outputs found
Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenibresistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. © 2017 American Association for Cancer Research
Inferring condition-specific transcription factor function from DNA binding and gene expression data
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Inferring condition-specific transcription factor function from DNA binding and gene expression data
Numerous genomic and proteomic datasets are permitting the elucidation of transcriptional regulatory networks in the yeast Saccharomyces cerevisiae. However, predicting the condition dependence of regulatory network interactions has been challenging, because most proteinâDNA interactions identified in vivo are from assays performed in one or a few cellular states. Here, we present a novel method to predict the condition-specific functions of S. cerevisiae transcription factors (TFs) by integrating 1327 microarray gene expression data sets and either comprehensive TF binding site data from protein binding microarrays (PBMs) or in silico motif data. Importantly, our method does not impose arbitrary thresholds for calling target regions âbound' or genes âdifferentially expressed', but rather allows all the information derived from a TF binding or gene expression experiment to be considered. We show that this method can identify environmental, physical, and genetic interactions, as well as distinct sets of genes that might be activated or repressed by a single TF under particular conditions. This approach can be used to suggest conditions for directed in vivo experimentation and to predict TF function
Massive Lepton Pairs as a Prompt Photon Surrogate
We discuss the transverse momentum distribution for the production of massive
lepton-pairs in hadron reactions at fixed target and collider energies within
the context of next-to-leading order perturbative quantum chromodynamics. For
values of the transverse momentum greater than the pair mass , , we show that the differential cross section is dominated by subprocesses
initiated by incident gluons. Massive lepton-pair differential cross sections
are an advantageous source of constraints on the gluon density, free from the
experimental and theoretical complications of photon isolation that beset
studies of prompt photon production. We compare calculations with data and
provide predictions for the differential cross section as a function of
in proton-antiproton reactions at center-of-mass energies of 1.8 TeV, and in
proton-nucleon reactions at fixed target and LHC energies.Comment: 36 pages, RevTeX, including 16 ps files of figures; minor changes in
wording; one reference added. Version to appear in Phys Rev
Thickness Estimation of Epitaxial Graphene on SiC using Attenuation of Substrate Raman Intensity
A simple, non-invasive method using Raman spectroscopy for the estimation of
the thickness of graphene layers grown epitaxially on silicon carbide (SiC) is
presented, enabling simultaneous determination of thickness, grain size and
disorder using the spectra. The attenuation of the substrate Raman signal due
to the graphene overlayer is found to be dependent on the graphene film
thickness deduced from X-ray photoelectron spectroscopy and transmission
electron microscopy of the surfaces. We explain this dependence using an
absorbing overlayer model. This method can be used for mapping graphene
thickness over a region and is capable of estimating thickness of multilayer
graphene films beyond that possible by XPS and Auger electron spectroscopy
(AES).Comment: 14 pages, 9 figure
Bilateral phrenic nerve block to reduce hazardous respiratory drive in a mechanically ventilated patient with COVID-19âA case report
Key Clinical Message
Forced inspiration during mechanical ventilation risks selfâinflicted lung injury. However, controlling it with sedation or paralysis may cause polyneuropathy and myopathy. We tested bilateral phrenic nerve paralysis with local anesthetic in a patient, showing reduced inspiratory force. This offers an alternative to drugâinduced muscle paralysis.Mechanical ventilation, although a lifeâsaving measure, can also pose a risk of causing lung injury known as âventilatorâinduced lung injuryâ or VILI. Patients undergoing mechanical ventilation sometimes exhibit heightened inspiratory efforts, wherein the negative pressure generated by the respiratory muscles adds to the positive pressure generated by the ventilator. This combination of high pressures can lead to a syndrome similar to VILI, referred to as âpatient selfâinflicted lung injuryâ or PâSILI. Prevention of PâSILI requires the administration of deep sedation and muscle paralysis to the patients, but both these measures can have undesired effects on their health. In this case report, we demonstrate the effect of a bilateral phrenic nerve block aiming to reduce excessive inspiratory respiratory efforts in a patient suffering from COVIDâ19 pneumonitis
Risk Factors for Major Early Adverse Events Related to Cardiac Catheterization in Children and Young Adults With Pulmonary Hypertension: An Analysis of Data From the IMPACT (Improving Adult and Congenital Treatment) Registry.
BACKGROUND: Cardiac catheterization is the gold standard for assessment and follow-up of patients with pulmonary hypertension (PH). To date, there are limited data about the factors that influence the risk of catastrophic adverse events after catheterization in this population.
METHODS AND RESULTS: A retrospective multicenter cohort study was performed to measure risk of catastrophic adverse outcomes after catheterization in children and young adults with PH and identify risk factors for these outcomes. All catheterizations in children and young adults, aged 0 to 21 years, with PH at hospitals submitting data to the IMPACT (Improving Adult and Congenital Treatment) registry between January 1, 2011, and December 31, 2015, were studied. Using mixed-effects multivariable regression, we assessed the association between prespecified subject-, procedure-, and center-level covariates and the risk of death, cardiac arrest, or mechanical circulatory support during or after cardiac catheterization. A total of 8111 procedures performed in 7729 subjects at 77 centers were studied. The observed risk of the composite outcome was 1.4%, and the risk of death before discharge was 5.2%. Catheterization in prematurely born neonates and nonpremature infants was associated with increased risk of catastrophic adverse event, as was precatheterization treatment with inotropes and lower systemic arterial saturation. Secondary analyses demonstrated the following: (1) increasing volumes of catheterization in patients with PH were associated with reduced risk of composite outcome (odds ratio, 0.8 per 10 procedures;
CONCLUSIONS: Young patients with PH are a high-risk population for diagnostic and interventional cardiac catheterization. Hospital experience with PH is associated with reduced risk, independent of total catheterization case volume
Atmospheric Neutrinos
The results of experiments on atmospheric neutrinos are summarized, with the
important exception of Superkamiokande. The main emphasis is given to the
Soudan-2 and MACRO experiments. Both experiments observe atmospheric neutrino
anomalies in agreement with nu_mu-->> nu_tau oscillations with maximum mixing.
The nu_mu-->> nu_sterile oscillation is disfavored by the MACRO experiment.Comment: To be published in the proceedings of TAUP99 Conference College de
France - Paris 6-10 September 1999 11 pages 12 figure
Strong Coupling Constant from the Photon Structure Function
We extract the value of the strong coupling constant alpha_s from a
single-parameter pointlike fit to the photon structure function F_2^gamma at
large x and Q^2 and from a first five-parameter full (pointlike and hadronic)
fit to the complete F_2^gamma data set taken at PETRA, TRISTAN, and LEP. In
next-to-leading order and the MSbar renormalization and factorization schemes,
we obtain alpha_s(m_Z)=0.1183 +/- 0.0050(exp.)^+0.0029_-0.0028(theor.)
[pointlike] and alpha_s(m_Z)=0.1198 +/- 0.0028(exp.)^+0.0034_-0.0046(theor.)
[pointlike and hadronic]. We demonstrate that the data taken at LEP have
reduced the experimental error by about a factor of two, so that a competitive
determination of alpha_s from F_2^gamma is now possible.Comment: 11 pages, 2 tables, 2 figures. Version accepted for publication by
Phys. Rev. Let
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