805 research outputs found
Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas
BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or cold, with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.
METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10
RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes.
CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically cold tumors to hot. (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.)
Response to radiation in renal medullary carcinoma
Renal medullary carcinoma (RMC) is a rare and highly aggressive malignancy arising from the renal medulla and found mostly in patients with sickle cell trait. RMC usually presents with widely metastatic disease. We describe a young man diagnosed with metastatic RMC who sustained a complete response to systemic chemotherapy but developed brain metastases with leptomeningeal involvement and subsequently had a partial response to brain irradiation. The use of radiation in the management of RMC is reviewed. Due to the apparent propensity for RMC to spread to the central nervous system, prophylactic treatment such as craniospinal irradiation should be considered along with chemotherapy in patients with metastatic RMC to potentially improve the progression-free interval
Relativistic Stellar Pulsations With Near-Zone Boundary Conditions
A new method is presented here for evaluating approximately the pulsation
modes of relativistic stellar models. This approximation relies on the fact
that gravitational radiation influences these modes only on timescales that are
much longer than the basic hydrodynamic timescale of the system. This makes it
possible to impose the boundary conditions on the gravitational potentials at
the surface of the star rather than in the asymptotic wave zone of the
gravitational field. This approximation is tested here by predicting the
frequencies of the outgoing non-radial hydrodynamic modes of non-rotating
stars. The real parts of the frequencies are determined with an accuracy that
is better than our knowledge of the exact frequencies (about 0.01%) except in
the most relativistic models where it decreases to about 0.1%. The imaginary
parts of the frequencies are determined with an accuracy of approximately M/R,
where M is the mass and R is the radius of the star in question.Comment: 10 pages (REVTeX 3.1), 5 figs., 1 table, fixed minor typos, published
in Phys. Rev. D 56, 2118 (1997
Topology and Signature Changes in Braneworlds
It has been believed that topology and signature change of the universe can
only happen accompanied by singularities, in classical, or instantons, in
quantum, gravity. In this note, we point out however that in the braneworld
context, such an event can be understood as a classical, smooth event. We
supply some explicit examples of such cases, starting from the
Dirac-Born-Infeld action. Topology change of the brane universe can be realised
by allowing self-intersecting branes. Signature change in a braneworld is made
possible in an everywhere Lorentzian bulk spacetime. In our examples, the
boundary of the signature change is a curvature singularity from the brane
point of view, but nevertheless that event can be described in a completely
smooth manner from the bulk point of view.Comment: 26 pages, 8 figures, references and comments are added, minor
revisions and a number of additional footnotes added, error corrected, minor
corrections, to appear in Class. Quant. Gra
Second-order rotational effects on the r-modes of neutron stars
Techniques are developed here for evaluating the r-modes of rotating neutron
stars through second order in the angular velocity of the star. Second-order
corrections to the frequencies and eigenfunctions for these modes are evaluated
for neutron star models. The second-order eigenfunctions for these modes are
determined here by solving an unusual inhomogeneous hyperbolic boundary-value
problem. The numerical techniques developed to solve this unusual problem are
somewhat non-standard and may well be of interest beyond the particular
application here. The bulk-viscosity coupling to the r-modes, which appears
first at second order, is evaluated. The bulk-viscosity timescales are found
here to be longer than previous estimates for normal neutron stars, but shorter
than previous estimates for strange stars. These new timescales do not
substantially affect the current picture of the gravitational radiation driven
instability of the r-modes either for neutron stars or for strange stars.Comment: 13 pages, 5 figures, revte
A robust system for RNA interference in the chicken using a modified microRNA operon
AbstractRNA interference (RNAi) provides an effective method to silence gene expression and investigate gene function. However, RNAi tools for the chicken embryo have largely been adapted from vectors designed for mammalian cells. Here we present plasmid and retroviral RNAi vectors specifically designed for optimal gene silencing in chicken cells. The vectors use a chicken U6 promoter to express RNAs modelled on microRNA30, which are embedded within chicken microRNA operon sequences to ensure optimal Drosha and Dicer processing of transcripts. The chicken U6 promoter works significantly better than promoters of mammalian origin and in combination with a microRNA operon expression cassette (MOEC), achieves up to 90% silencing of target genes. By using a MOEC, we show that it is also possible to simultaneously silence two genes with a single vector. The vectors express either RFP or GFP markers, allowing simple in vivo tracking of vector delivery. Using these plasmids, we demonstrate effective silencing of Pax3, Pax6, Nkx2.1, Nkx2.2, Notch1 and Shh in discrete regions of the chicken embryonic nervous system. The efficiency and ease of use of this RNAi system paves the way for large-scale genetic screens in the chicken embryo
Stability of Black Holes and Black Branes
We establish a new criterion for the dynamical stability of black holes in spacetime dimensions in general relativity with respect to axisymmetric
perturbations: Dynamical stability is equivalent to the positivity of the
canonical energy, \E, on a subspace, , of linearized solutions
that have vanishing linearized ADM mass, momentum, and angular momentum at
infinity and satisfy certain gauge conditions at the horizon. This is shown by
proving that---apart from pure gauge perturbations and perturbations towards
other stationary black holes---\E is nondegenerate on and that,
for axisymmetric perturbations, \E has positive flux properties at both
infinity and the horizon. We further show that \E is related to the second
order variations of mass, angular momentum, and horizon area by \E = \delta^2
M - \sum_A \Omega_A \delta^2 J_A - \frac{\kappa}{8\pi} \delta^2 A, thereby
establishing a close connection between dynamical stability and thermodynamic
stability. Thermodynamic instability of a family of black holes need not imply
dynamical instability because the perturbations towards other members of the
family will not, in general, have vanishing linearized ADM mass and/or angular
momentum. However, we prove that for any black brane corresponding to a
thermodynamically unstable black hole, sufficiently long wavelength
perturbations can be found with \E < 0 and vanishing linearized ADM
quantities. Thus, all black branes corresponding to thermodynmically unstable
black holes are dynamically unstable, as conjectured by Gubser and Mitra. We
also prove that positivity of \E on is equivalent to the
satisfaction of a "local Penrose inequality," thus showing that satisfaction of
this local Penrose inequality is necessary and sufficient for dynamical
stability.Comment: 54 pages, Latex, 2 figures, v2: Anzatz for momentum in proof of
Gubser-Mitra conjecture corrected; factor of 2 in symplectic form corrected;
several typos in formulas corrected; v3: revised argument concerning horizon
gauge condition on p. 10; typos corrected and several minor changes;
reference added; v4: formula (86) for \E corrected, footnote adde
Generalized Weyl Solutions
It was shown by Weyl that the general static axisymmetric solution of the
vacuum Einstein equations in four dimensions is given in terms of a single
axisymmetric solution of the Laplace equation in three-dimensional flat space.
Weyl's construction is generalized here to arbitrary dimension . The
general solution of the D-dimensional vacuum Einstein equations that admits D-2
orthogonal commuting non-null Killing vector fields is given either in terms of
D-3 independent axisymmetric solutions of Laplace's equation in
three-dimensional flat space or by D-4 independent solutions of Laplace's
equation in two-dimensional flat space. Explicit examples of new solutions are
given. These include a five-dimensional asymptotically flat ``black ring'' with
an event horizon of topology S^1 x S^2 held in equilibrium by a conical
singularity in the form of a disc.Comment: 50 pages, 10 figures; v2: minor improvement
Just how long can you live in a black hole and what can be done about it?
We study the problem of how long a journey within a black hole can last.
Based on our observations, we make two conjectures. First, for observers that
have entered a black hole from an asymptotic region, we conjecture that the
length of their journey within is bounded by a multiple of the future
asymptotic ``size'' of the black hole, provided the spacetime is globally
hyperbolic and satisfies the dominant-energy and non-negative-pressures
conditions. Second, for spacetimes with Cauchy surfaces (or an
appropriate generalization thereof) and satisfying the dominant energy and
non-negative-pressures conditions, we conjecture that the length of a journey
anywhere within a black hole is again bounded, although here the bound requires
a knowledge of the initial data for the gravitational field on a Cauchy
surface. We prove these conjectures in the spherically symmetric case. We also
prove that there is an upper bound on the lifetimes of observers lying ``deep
within'' a black hole, provided the spacetime satisfies the
timelike-convergence condition and possesses a maximal Cauchy surface. Further,
we investigate whether one can increase the lifetime of an observer that has
entered a black hole, e.g., by throwing additional matter into the hole.
Lastly, in an appendix, we prove that the surface area of the event horizon
of a black hole in a spherically symmetric spacetime with ADM mass
is always bounded by , provided
that future null infinity is complete and the spacetime is globally hyperbolic
and satisfies the dominant-energy condition.Comment: 20 pages, REVTeX 3.0, 6 figures included, self-unpackin
Expression of Regulatory Platelet MicroRNAs in Patients with Sickle Cell Disease
Background: Increased platelet activation in sickle cell disease (SCD) contributes to a state of hypercoagulability and confers a risk of thromboembolic complications. The role for post-transcriptional regulation of the platelet transcriptome by microRNAs (miRNAs) in SCD has not been previously explored. This is the first study to determine whether platelets from SCD exhibit an altered miRNA expression profile. Methods and Findings: We analyzed the expression of miRNAs isolated from platelets from a primary cohort (SCD = 19, controls = 10) and a validation cohort (SCD = 7, controls = 7) by hybridizing to the Agilent miRNA microarrays. A dramatic difference in miRNA expression profiles between patients and controls was noted in both cohorts separately. A total of 40 differentially expressed platelet miRNAs were identified as common in both cohorts (p-value 0.05, fold change>2) with 24 miRNAs downregulated. Interestingly, 14 of the 24 downregulated miRNAs were members of three families - miR-329, miR-376 and miR-154 - which localized to the epigenetically regulated, maternally imprinted chromosome 14q32 region. We validated the downregulated miRNAs, miR-376a and miR-409-3p, and an upregulated miR-1225-3p using qRT-PCR. Over-expression of the miR-1225-3p in the Meg01 cells was followed by mRNA expression profiling to identify mRNA targets. This resulted in significant transcriptional repression of 1605 transcripts. A combinatorial approach using Meg01 mRNA expression profiles following miR-1225-3p overexpression, a computational prediction analysis of miRNA target sequences and a previously published set of differentially expressed platelet transcripts from SCD patients, identified three novel platelet mRNA targets: PBXIP1, PLAGL2 and PHF20L1. Conclusions: We have identified significant differences in functionally active platelet miRNAs in patients with SCD as compared to controls. These data provide an important inventory of differentially expressed miRNAs in SCD patients and an experimental framework for future studies of miRNAs as regulators of biological pathways in platelets. © 2013 Jain et al
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