395 research outputs found
Actions for Vacuum Einstein's Equation with a Killing Symmetry
In a space-time with a Killing vector field which is either
everywhere timelike or everywhere spacelike, the collection of all trajectories
of gives a 3-dimension space . Besides the symmetry-reduced action
from that of Einstein-Hilbert, an alternative action of the fields on is
also proposed, which gives the same fields equations as those reduced from the
vacuum Einstein equation on .Comment: 8 pages, the difference between the action we proposed and the
symmetry-reduced action is clarifie
The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis
Background
The tumor microenvironment has complex effects in cancer pathophysiology that are not fully understood. Most cancer therapies are directed against malignant cells specifically, leaving pro-malignant signals from the microenvironment unaddressed. Defining specific mechanisms by which the tumor microenvironment contributes to breast cancer metastasis may lead to new therapeutic approaches against advanced breast cancer.
Methods
We use a novel method for manipulating three-dimensional mixed cell co-cultures, along with studies in mouse xenograft models of human breast cancer and a histologic study of human breast cancer samples, to investigate how breast cancer-associated fibroblasts affect the malignant behaviors of breast cancer cells.
Results
Altering fibroblast Tiam1 expression induces changes in invasion, migration, epithelial-mesenchymal transition, and cancer stem cell characteristics in associated breast cancer cells. These changes are both dependent on fibroblast secretion of osteopontin and also long-lasting even after cancer cell dissociation from the fibroblasts, indicating a novel Tiam1-osteopontin pathway in breast cancer-associated fibroblasts. Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis. Moreover, fibroblast expression patterns of Tiam1 and osteopontin in human breast cancers show converse changes correlating with invasion, supporting the hypothesis that this pathway in tumor-associated fibroblasts regulates breast cancer invasiveness in human disease and is thus clinically relevant.
Conclusions
These findings suggest a new therapeutic paradigm for preventing breast cancer metastasis. Pro-malignant signals from the tumor microenvironment with long-lasting effects on associated cancer cells may perpetuate the metastatic potential of developing cancers. Inhibition of these microenvironment signals represents a new therapeutic strategy against cancer metastasis that enables targeting of stromal cells with less genetic plasticity than associated cancer cells and opens new avenues for investigation of novel therapeutic targets and agents.National Institute of General Medical Sciences (U.S.) (GM074825
Intermediate filament–membrane attachments function synergistically with actin-dependent contacts to regulate intercellular adhesive strength
By tethering intermediate filaments (IFs) to sites of intercellular adhesion, desmosomes facilitate formation of a supercellular scaffold that imparts mechanical strength to a tissue. However, the role IF–membrane attachments play in strengthening adhesion has not been directly examined. To address this question, we generated Tet-On A431 cells inducibly expressing a desmoplakin (DP) mutant lacking the rod and IF-binding domains (DPNTP). DPNTP localized to the plasma membrane and led to dissociation of IFs from the junctional plaque, without altering total or cell surface distribution of adherens junction or desmosomal proteins. However, a specific decrease in the detergent-insoluble pool of desmoglein suggested a reduced association with the IF cytoskeleton. DPNTP-expressing cell aggregates in suspension or substrate-released cell sheets readily dissociated when subjected to mechanical stress whereas controls remained largely intact. Dissociation occurred without lactate dehydrogenase release, suggesting that loss of tissue integrity was due to reduced adhesion rather than increased cytolysis. JD-1 cells from a patient with a DP COOH-terminal truncation were also more weakly adherent compared with normal keratinocytes. When used in combination with DPNTP, latrunculin A, which disassembles actin filaments and disrupts adherens junctions, led to dissociation up to an order of magnitude greater than either treatment alone. These data provide direct in vitro evidence that IF–membrane attachments regulate adhesive strength and suggest furthermore that actin- and IF-based junctions act synergistically to strengthen adhesion
Recommended from our members
Efficient Derivation of Human Cardiac Precursors and Cardiomyocytes from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction
To date, the lack of a suitable human cardiac cell source has been the major setback in regenerating the human myocardium, either by cell-based transplantation or by cardiac tissue engineering. Cardiomyocytes become terminally-differentiated soon after birth and lose their ability to proliferate. There is no evidence that stem/progenitor cells derived from other sources, such as the bone marrow or the cord blood, are able to give rise to the contractile heart muscle cells following transplantation into the heart. The need to regenerate or repair the damaged heart muscle has not been met by adult stem cell therapy, either endogenous or via cell delivery. The genetically stable human embryonic stem cells (hESCs) have unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of large supplies of human somatic cells that are restricted to the lineage in need of repair and regeneration. Due to the prevalence of cardiovascular disease worldwide and acute shortage of donor organs, there is intense interest in developing hESC-based therapies as an alternative approach. However, how to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to a desired phenotype has been a major challenge for both developmental study and clinical translation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity (see a schematic in Fig. 1A). In addition, undefined foreign/animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic. To overcome these obstacles, we have resolved the elements of a defined culture system necessary and sufficient for sustaining the epiblast pluripotence of hESCs, serving as a platform for de novo derivation of clinically-suitable hESCs and effectively directing such hESCs uniformly towards clinically-relevant lineages by small molecules (see a schematic in Fig. 1B). After screening a variety of small molecules and growth factors, we found that such defined conditions rendered nicotinamide (NAM) sufficient to induce the specification of cardiomesoderm direct from pluripotent hESCs that further progressed to cardioblasts that generated human beating cardiomyocytes with high efficiency (Fig. 2). We defined conditions for induction of cardioblasts direct from pluripotent hESCs without an intervening multi-lineage embryoid body stage, enabling well-controlled efficient derivation of a large supply of human cardiac cells across the spectrum of developmental stages for cell-based therapeutics
GPU-based Fast Low-dose Cone Beam CT Reconstruction via Total Variation
Cone-beam CT (CBCT) has been widely used in image guided radiation therapy
(IGRT) to acquire updated volumetric anatomical information before treatment
fractions for accurate patient alignment purpose. However, the excessive x-ray
imaging dose from serial CBCT scans raises a clinical concern in most IGRT
procedures. The excessive imaging dose can be effectively reduced by reducing
the number of x-ray projections and/or lowering mAs levels in a CBCT scan. The
goal of this work is to develop a fast GPU-based algorithm to reconstruct high
quality CBCT images from undersampled and noisy projection data so as to lower
the imaging dose. The CBCT is reconstructed by minimizing an energy functional
consisting of a data fidelity term and a total variation regularization term.
We developed a GPU-friendly version of the forward-backward splitting algorithm
to solve this model. A multi-grid technique is also employed. We test our CBCT
reconstruction algorithm on a digital NCAT phantom and a head-and-neck patient
case. The performance under low mAs is also validated using a physical Catphan
phantom and a head-and-neck Rando phantom. It is found that 40 x-ray
projections are sufficient to reconstruct CBCT images with satisfactory quality
for IGRT patient alignment purpose. Phantom experiments indicated that CBCT
images can be successfully reconstructed with our algorithm under as low as 0.1
mAs/projection level. Comparing with currently widely used full-fan
head-and-neck scanning protocol of about 360 projections with 0.4
mAs/projection, it is estimated that an overall 36 times dose reduction has
been achieved with our algorithm. Moreover, the reconstruction time is about
130 sec on an NVIDIA Tesla C1060 GPU card, which is estimated ~100 times faster
than similar iterative reconstruction approaches.Comment: 20 pages, 10 figures, Paper was revised and more testing cases were
added
3D tumor localization through real-time volumetric x-ray imaging for lung cancer radiotherapy
Recently we have developed an algorithm for reconstructing volumetric images
and extracting 3D tumor motion information from a single x-ray projection. We
have demonstrated its feasibility using a digital respiratory phantom with
regular breathing patterns. In this work, we present a detailed description and
a comprehensive evaluation of the improved algorithm. The algorithm was
improved by incorporating respiratory motion prediction. The accuracy and
efficiency were then evaluated on 1) a digital respiratory phantom, 2) a
physical respiratory phantom, and 3) five lung cancer patients. These
evaluation cases include both regular and irregular breathing patterns that are
different from the training dataset. For the digital respiratory phantom with
regular and irregular breathing, the average 3D tumor localization error is
less than 1 mm. On an NVIDIA Tesla C1060 GPU card, the average computation time
for 3D tumor localization from each projection ranges between 0.19 and 0.26
seconds, for both regular and irregular breathing, which is about a 10%
improvement over previously reported results. For the physical respiratory
phantom, an average tumor localization error below 1 mm was achieved with an
average computation time of 0.13 and 0.16 seconds on the same GPU card, for
regular and irregular breathing, respectively. For the five lung cancer
patients, the average tumor localization error is below 2 mm in both the axial
and tangential directions. The average computation time on the same GPU card
ranges between 0.26 and 0.34 seconds
Efficient Derivation of Human Neuronal Progenitors and Neurons from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction
There is a large unfulfilled need for a clinically-suitable human neuronal cell source for repair or regeneration of the damaged central nervous system (CNS) structure and circuitry in today's healthcare industry. Cell-based therapies hold great promise to restore the lost nerve tissue and function for CNS disorders. However, cell therapies based on CNS-derived neural stem cells have encountered supply restriction and difficulty to use in the clinical setting due to their limited expansion ability in culture and failing plasticity after extensive passaging1-3. Despite some beneficial outcomes, the CNS-derived human neural stem cells (hNSCs) appear to exert their therapeutic effects primarily by their non-neuronal progenies through producing trophic and neuroprotective molecules to rescue the endogenous cells1-3. Alternatively, pluripotent human embryonic stem cells (hESCs) proffer cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types in the developing CNS for regeneration1,4-7. However, how to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to a desired phenotype has been a major challenge for both developmental study and clinical translation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity7-10. In addition, undefined foreign/animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic11-13. To overcome these obstacles, we have resolved the elements of a defined culture system necessary and sufficient for sustaining the epiblast pluripotence of hESCs, serving as a platform for de novo derivation of clinically-suitable hESCs and effectively directing such hESCs uniformly towards clinically-relevant lineages by small molecules14 (please see a schematic in Fig. 1). Retinoic acid (RA) does not induce neuronal differentiation of undifferentiated hESCs maintained on feeders1, 14. And unlike mouse ESCs, treating hESC-differentiated embryoid bodies (EBs) only slightly increases the low yield of neurons1, 14, 15. However, after screening a variety of small molecules and growth factors, we found that such defined conditions rendered retinoic acid (RA) sufficient to induce the specification of neuroectoderm direct from pluripotent hESCs that further progressed to neuroblasts that generated human neuronal progenitors and neurons in the developing CNS with high efficiency (Fig. 2). We defined conditions for induction of neuroblasts direct from pluripotent hESCs without an intervening multi-lineage embryoid body stage, enabling well-controlled efficient derivation of a large supply of human neuronal cells across the spectrum of developmental stages for cell-based therapeutics
Laughlin liquid - Wigner solid transition at high density in wide quantum wells
Assuming that the phase transition between the Wigner solid and the Laughlin
liquid is first-order, we compare ground-state energies to find features of the
phase diagram at fixed . Rather than use the Coulomb interaction, we
calculate the effective interaction in a square quantum well, and fit the
results to a model interaction with length parameter roughly
proportional to the width of the well. We find a transition to the Wigner solid
phase at high density in very wide wells, driven by the softening of the
interaction at short distances, as well as the more well-known transition to
the Wigner solid at low density, driven by Landau-level mixing.Comment: RevTeX 3.0, 3 Postscript figures appended in uuencoded forma
Engineering Superfluidity in Electron-Hole Double Layers
We show that band-structure effects are likely to prevent superfluidity in
semiconductor electron-hole double-layer systems. We suggest the possibility
that superfluidity could be realized by the application of uniaxial pressure
perpendicular to the electron and hole layers.Comment: 4 pages, includes 3 figure
Excitonic condensation in a symmetric electron-hole bilayer
Using Diffusion Monte Carlo simulations we have investigated the ground state
of a symmetric electron-hole bilayer and determined its phase diagram at T=0.
We find clear evidence of an excitonic condensate, whose stability however is
affected by in-layer electronic correlation. This stabilizes the electron-hole
plasma at large values of the density or inter-layer distance, and the Wigner
crystal at low density and large distance. We have also estimated pair
correlation functions and low order density matrices, to give a microscopic
characterization of correlations, as well as to try and estimate the condensate
fraction.Comment: 4 pages, 3 figures, 2 table
- …