2,046 research outputs found
The diastereoselective Meth-Cohn epoxidation of camphor-derived vinyl sulfones
Some camphor-derived vinyl sulfones bearing oxygen functionality at the allylic position have been synthesized and their nucleophilic epoxidation reactions under Meth-Cohn conditions have been explored. The γ-oxygenated camphor-derived vinyl sulfones underwent mildly diastereoselective nucleophilic epoxidation reactions, affording the derived sulfonyloxiranes in up to 5.8:1 dr. The observed diastereoselectivities were sensitive to the reaction conditions employed. In contrast, no stereoselectivity was observed in the nucleophilic epoxidation of the corresponding γ-oxygenated isobornyl vinyl sulfone. A tentative mechanism has been proposed to explain the origins of the diastereoselectivit
Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease
Molecular Dynamics Simulations
A tutorial introduction to the technique of Molecular Dynamics (MD) is given,
and some characteristic examples of applications are described. The purpose and
scope of these simulations and the relation to other simulation methods is
discussed, and the basic MD algorithms are described. The sampling of intensive
variables (temperature T, pressure p) in runs carried out in the microcanonical
(NVE) ensemble (N= particle number, V = volume, E = energy) is discussed, as
well as the realization of other ensembles (e.g. the NVT ensemble). For a
typical application example, molten SiO2, the estimation of various transport
coefficients (self-diffusion constants, viscosity, thermal conductivity) is
discussed. As an example of Non-Equilibrium Molecular Dynamics (NEMD), a study
of a glass-forming polymer melt under shear is mentioned.Comment: 38 pages, 11 figures, to appear in J. Phys.: Condens. Matte
An Early & Comprehensive Millimeter and Centimeter Wave and X-ray Study of Supernova 2011dh: A Non-Equipartition Blastwave Expanding into A Massive Stellar Wind
Only a handful of supernovae (SNe) have been studied in multi-wavelength from
radio to X-rays, starting a few days after explosion. The early detection and
classification of the nearby type IIb SN2011dh/PTF11eon in M51 provides a
unique opportunity to conduct such observations. We present detailed data
obtained at the youngest phase ever of a core-collapse supernova (days 3 to 12
after explosion) in the radio, millimeter and X-rays; when combined with
optical data, this allows us to explore the early evolution of the SN blast
wave and its surroundings. Our analysis shows that the expanding supernova
shockwave does not exhibit equipartition (e_e/e_B ~ 1000), and is expanding
into circumstellar material that is consistent with a density profile falling
like R^-2. Within modeling uncertainties we find an average velocity of the
fast parts of the ejecta of 15,000 +/- 1800 km/s, contrary to previous
analysis. This velocity places SN 2011dh in an intermediate blast-wave regime
between the previously defined compact and extended SN IIb subtypes. Our
results highlight the importance of early (~ 1 day) high-frequency observations
of future events. Moreover, we show the importance of combined radio/X-ray
observations for determining the microphysics ratio e_e/e_B.Comment: 9 pages, 5 figures, submitted to Ap
Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer.
Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib\u27s efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (\u3e 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib
The Fifth Data Release of the Sloan Digital Sky Survey
This paper describes the Fifth Data Release (DR5) of the Sloan Digital Sky
Survey (SDSS). DR5 includes all survey quality data taken through June 2005 and
represents the completion of the SDSS-I project (whose successor, SDSS-II will
continue through mid-2008). It includes five-band photometric data for 217
million objects selected over 8000 square degrees, and 1,048,960 spectra of
galaxies, quasars, and stars selected from 5713 square degrees of that imaging
data. These numbers represent a roughly 20% increment over those of the Fourth
Data Release; all the data from previous data releases are included in the
present release. In addition to "standard" SDSS observations, DR5 includes
repeat scans of the southern equatorial stripe, imaging scans across M31 and
the core of the Perseus cluster of galaxies, and the first spectroscopic data
from SEGUE, a survey to explore the kinematics and chemical evolution of the
Galaxy. The catalog database incorporates several new features, including
photometric redshifts of galaxies, tables of matched objects in overlap regions
of the imaging survey, and tools that allow precise computations of survey
geometry for statistical investigations.Comment: ApJ Supp, in press, October 2007. This paper describes DR5. The SDSS
Sixth Data Release (DR6) is now public, available from http://www.sdss.or
The Seventh Data Release of the Sloan Digital Sky Survey
This paper describes the Seventh Data Release of the Sloan Digital Sky Survey
(SDSS), marking the completion of the original goals of the SDSS and the end of
the phase known as SDSS-II. It includes 11663 deg^2 of imaging data, with most
of the roughly 2000 deg^2 increment over the previous data release lying in
regions of low Galactic latitude. The catalog contains five-band photometry for
357 million distinct objects. The survey also includes repeat photometry over
250 deg^2 along the Celestial Equator in the Southern Galactic Cap. A
coaddition of these data goes roughly two magnitudes fainter than the main
survey. The spectroscopy is now complete over a contiguous area of 7500 deg^2
in the Northern Galactic Cap, closing the gap that was present in previous data
releases. There are over 1.6 million spectra in total, including 930,000
galaxies, 120,000 quasars, and 460,000 stars. The data release includes
improved stellar photometry at low Galactic latitude. The astrometry has all
been recalibrated with the second version of the USNO CCD Astrograph Catalog
(UCAC-2), reducing the rms statistical errors at the bright end to 45
milli-arcseconds per coordinate. A systematic error in bright galaxy photometr
is less severe than previously reported for the majority of galaxies. Finally,
we describe a series of improvements to the spectroscopic reductions, including
better flat-fielding and improved wavelength calibration at the blue end,
better processing of objects with extremely strong narrow emission lines, and
an improved determination of stellar metallicities. (Abridged)Comment: 20 pages, 10 embedded figures. Accepted to ApJS after minor
correction
Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cance
Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies
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