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 $D \geq 4$ 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, $\mathcal T$, 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 $\mathcal T$ 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 $\mathcal T$ 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 $D\ge 4$. 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

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

Pathologies in Asymptotically Lifshitz Spacetimes

There has been significant interest in the last several years in studying possible gravitational duals, known as Lifshitz spacetimes, to anisotropically scaling field theories by adding matter to distort the asymptotics of an AdS spacetime. We point out that putative ground state for the most heavily studied example of such a spacetime, that with a flat spatial section, suffers from a naked singularity and further point out this singularity is not resolvable by any known stringy effect. We review the reasons one might worry that asymptotically Lifshitz spacetimes are unstable and employ the initial data problem to study the stability of such systems. Rather surprisingly this question, and even the initial value problem itself, for these spacetimes turns out to generically not be well-posed. A generic normalizable state will evolve in such a way to violate Lifshitz asymptotics in finite time. Conversely, enforcing the desired asymptotics at all times puts strong restrictions not just on the metric and fields in the asymptotic region but in the deep interior as well. Generically, even perturbations of the matter field of compact support are not compatible with the desired asymptotics.Comment: 36 pages, 1 figure, v2: Enhanced discussion of singularity, including relationship to Gubser's conjecture and singularity in RG flow solution, plus minor clarification