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Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer.
BackgroundPancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer.MethodsWe characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo.ResultsNT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine.ConclusionsFavorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease
Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids.
A unified strategy for enantioselective total synthesis of all stereoisomers of the 2+2 family of quadrigemine alkaloids is reported. In this approach, two enantioselective intramolecular Heck reactions are carried out at the same time on precursors fashioned in four steps from either meso- or (+)-chimonanthine to form the two critical quaternary carbons of the peripheral cyclotryptamine rings of these products. Useful levels of catalyst control are realized in either desymmetrizing a meso precursor or controlling diastereoselectivity in elaborating C2-symmetic intermediates. None of the synthetic quadrigemines are identical with alkaloids isolated previously and referred to as quadrigemines A and E. In addition, we report improvements in our previous total syntheses of (+)- or (-)-quadrigemine C that shortened the synthetic sequence to 10 steps and provided these products in 2.2% overall yield from tryptamine
CSM Testbed Development and Large-Scale Structural Applications
A research activity called Computational Structural Mechanics (CSM) conducted at the NASA Langley Research Center is described. This activity is developing advanced structural analysis and computational methods that exploit high-performance computers. Methods are developed in the framework of the CSM Testbed software system and applied to representative complex structural analysis problems from the aerospace industry. An overview of the CSM Testbed methods development environment is presented and some new numerical methods developed on a CRAY-2 are described. Selected application studies performed on the NAS CRAY-2 are also summarized
Physics on the edge: contour dynamics, waves and solitons in the quantum Hall effect
We present a theoretical study of the excitations on the edge of a
two-dimensional electron system in a perpendicular magnetic field in terms of a
contour dynamics formalism. In particular, we focus on edge excitations in the
quantum Hall effect. Beyond the usual linear approximation, a non-linear
analysis of the shape deformations of an incompressible droplet yields soliton
solutions which correspond to shapes that propagate without distortion. A
perturbative analysis is used and the results are compared to analogous
systems, like vortex patches in ideal hydrodynamics. Under a local induction
approximation we find that the contour dynamics is described by a non-linear
partial differential equation for the curvature: the modified Korteweg-de Vries
equation.
PACS number(s): 73.40.Hm, 02.40.Ma, 03.40.Gc, 11.10.LmComment: 15 pages, 12 embedded figures, submitted to Phys. Rev.
Bone Density Screening and Re-screening in Postmenopausal Women and Older Men
Clinical practice guidelines universally recommend bone mineral density (BMD) screening to identify osteoporosis in women aged 65 years and older. Risk assessment is recommended to guide BMD screening in postmenopausal women under age 65. Insufficient data are available to inform standard ages to start and stop BMD screening in postmenopausal women. Based on longitudinal studies of incident osteoporosis and fracture in postmenopausal women, an initial BMD test should be ordered for all women aged 65, and the frequency of re-screening should be based on age and BMD T score (more frequent testing for older age and lower T score). Although clinical practice guidelines recommend BMD screening according to risk factors for fracture in postmenopausal women under age 65, no standard approach to risk assessment exists. Minimal evidence is available to guide osteoporosis screening in men, but some experts recommend initiation of BMD screening in men at age 70
Solitons on the edge of a two-dimensional electron system
We present a study of the excitations of the edge of a two-dimensional
electron droplet in a magnetic field in terms of a contour dynamics formalism.
We find that, beyond the usual linear approximation, the non-linear analysis
yields soliton solutions which correspond to uniformly rotating shapes. These
modes are found from a perturbative treatment of a non-linear eigenvalue
problem, and as solutions to a modified Korteweg-de Vries equation resulting
from a local induction approximation to the nonlocal contour dynamics. We
discuss applications to the edge modes in the quantum Hall effect.Comment: 4 pages, 2 eps figures (included); to appear in Phys. Rev. Letter
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