532 research outputs found
Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B
BACKGROUND: Self-complementary adeno-associated virus (scAAV) vectors have become a desirable vector for therapeutic gene transfer due to their ability to produce greater levels of transgene than single-stranded AAV (ssAAV). However, recent reports have suggested that scAAV vectors are more immunogenic than ssAAV. In this study, we investigated the effects of a self-complementary genome during gene therapy with a therapeutic protein, human factor IX (hF.IX). METHODS: Hemophilia B mice were injected intramuscularly with ss or scAAV1 vectors expressing hF.IX. The outcome of gene transfer was assessed, including transgene expression as well as antibody and CD8(+) T cell responses to hF.IX. RESULTS: Self-complementary AAV1 vectors induced similar antibody responses (which eliminated systemic hF.IX expression) but stronger CD8(+) T cell responses to hF.IX relative to ssAAV1 in mice with F9 gene deletion. As a result, hF.IX-expressing muscle fibers were effectively eliminated in scAAV-treated mice. In contrast, mice with F9 nonsense mutation (late stop codon) lacked antibody or T cell responses, thus showing long-term expression regardless of the vector genome. CONCLUSIONS: The nature of the AAV genome can impact the CD8(+) T cell response to the therapeutic transgene product. In mice with endogenous hF.IX expression, however, this enhanced immunogenicity did not break tolerance to hF.IX, suggesting that the underlying mutation is a more important risk factor for transgene-specific immunity than the molecular form of the AAV genome
Charged Dilatonic AdS Black Branes in Arbitrary Dimensions
We study electromagnetically charged dilatonic black brane solutions in
arbitrary dimensions with flat transverse spaces, that are asymptotically AdS.
This class of solutions includes spacetimes which possess a bulk region where
the metric is approximately invariant under Lifshitz scalings. Given fixed
asymptotic boundary conditions, we analyze how the behavior of the bulk up to
the horizon varies with the charges and derive the extremality conditions for
these spacetimes.Comment: References update
New Insights into Properties of Large-N Holographic Thermal QCD at Finite Gauge Coupling at (the Non-Conformal/Next-to) Leading Order in N
In the context of [1]'s string theoretic dual of large-N thermal QCD-like
theories at finite gauge/string coupling (as part of the `MQGP' limit of [2]),
we discuss the following. First, up to LO in N, using the results of [3], we
show that the local T^3 of [2] is the T^2-invariant sLag of [3] in a resolved
conifold. This, together with the results of [4], shows that for a
(predominantly resolved or deformed) resolved warped deformed conifold, the
local T^3 of [2] in the MQGP limit, is the T^2-invariant sLag of [3] justifying
the construction of the delocalized SYZ type IIA mirror of the type IIB
background of [1]. Then, using the prescription of [5], we obtain the
temperature dependence of the thermal (and electrical) conductivity working up
to leading order in N (the number of D3-branes), and upon comparison with [6]
show that the results mimic a 1+1-dimensional Luttinger liquid with impurities.
Further, including sub-leading non-conformal terms in the metric determined by
M (the number of fractional D-branes = the number of colors = 3 in the IR after
the end of a Seiberg duality cascade), by looking at respectively the scalar,
vector and tensor modes of metric perturbations and using [7]'s prescription of
constructing appropriate gauge-invariant perturbations, we obtain respectively
the speed of sound, the diffusion constant and the shear viscosity \eta (and
\eta/s) including the non-conformal O((g_s M^2) (g_s N_f)/N<<1)-corrections,
N_f being the number of flavor D7-branes.Comment: 1+75 pages, LaTeX; Some corrections in Tc-related calculations,
results unchange
MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.
BACKGROUND: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. METHODS: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. RESULTS: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. CONCLUSION: These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis
Effective Holographic Theories for low-temperature condensed matter systems
The IR dynamics of effective holographic theories capturing the interplay
between charge density and the leading relevant scalar operator at strong
coupling are analyzed. Such theories are parameterized by two real exponents
that control the IR dynamics. By studying the thermodynamics,
spectra and conductivities of several classes of charged dilatonic black hole
solutions that include the charge density back reaction fully, the landscape of
such theories in view of condensed matter applications is characterized.
Several regions of the plane can be excluded as the extremal
solutions have unacceptable singularities. The classical solutions have
generically zero entropy at zero temperature, except when where
the entropy at extremality is finite. The general scaling of DC resistivity
with temperature at low temperature, and AC conductivity at low frequency and
temperature across the whole plane, is found. There is a
codimension-one region where the DC resistivity is linear in the temperature.
For massive carriers, it is shown that when the scalar operator is not the
dilaton, the DC resistivity scales as the heat capacity (and entropy) for
planar (3d) systems. Regions are identified where the theory at finite density
is a Mott-like insulator at T=0. We also find that at low enough temperatures
the entropy due to the charge carriers is generically larger than at zero
charge density.Comment: (v3): Added discussion on the UV completion of the solutions, and on
extremal spectra in the charged case. Expanded discusion on insulating
extremal solutions. Many other refinements and corrections. 126 pages. 48
figure
Optimisation of the conditions for stripping voltammetric analysis at liquid-liquid interfaces supported at micropore arrays: a computational simulation
Micropore membranes have been used to form arrays of micro interfaces between immiscible electroly tesolutions (ÎĽITIES) as a basis for the sensing of non-redoxactiveions. Implementation of stripping voltammetry as asensing method at these arrays of ÎĽITIES was applied recently to detect drugs and biomolecules at low concentrations. The present study uses computational simulation to investigate the optimum conditions for stripping voltammetricsensing at the ÎĽITIES array. In this scenario, thediffusion of ions in both the aqueous and the organic phasescontributes to the sensing response. The influence of the preconcentration time, the micropore aspect ratio, the location of the micro interface within the pore, the ratio of the diffusion coefficients of the analyte ion in the organic and aqueous phases, and the pore wall angle were investigated. The simulations reveal that the accessibility of the microinterfaces during the preconcentration period should not be hampered by a recessed interface and that diffusional transport in the phase where the analyte ions are preconcentrated should be minimized. This will ensure that the ions are accumulated within the micropores close to the interface and thus be readily available for back transferduring the stripping process. On the basis of the results, an optimal combination of the examined parameters is proposed,which together improve the stripping voltammetric signal and provide an improvement in the detection limit
Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer
Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies
Analysis of the usage of continence pads and help-seeking behavior of women with stress urinary incontinence in Poland
Stochastic Gravity: Theory and Applications
Whereas semiclassical gravity is based on the semiclassical Einstein equation
with sources given by the expectation value of the stress-energy tensor of
quantum fields, stochastic semiclassical gravity is based on the
Einstein-Langevin equation, which has in addition sources due to the noise
kernel. In the first part, we describe the fundamentals of this new theory via
two approaches: the axiomatic and the functional. In the second part, we
describe three applications of stochastic gravity theory. First, we consider
metric perturbations in a Minkowski spacetime, compute the two-point
correlation functions of these perturbations and prove that Minkowski spacetime
is a stable solution of semiclassical gravity. Second, we discuss structure
formation from the stochastic gravity viewpoint. Third, we discuss the
backreaction of Hawking radiation in the gravitational background of a black
hole and describe the metric fluctuations near the event horizon of an
evaporating black holeComment: 100 pages, no figures; an update of the 2003 review in Living Reviews
in Relativity gr-qc/0307032 ; it includes new sections on the Validity of
Semiclassical Gravity, the Stability of Minkowski Spacetime, and the Metric
Fluctuations of an Evaporating Black Hol
Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue.
E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments
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