The safety and effectiveness of chenodeoxycholic acid treatment in patients withcerebrotendinous xanthomatosis:two retrospective cohort studies.

Objective: To evaluate the safety and effectiveness of chenodeoxycholic acid (CDCA) treatment in patients with cerebrotendinous xanthomatosis (CTX). Methods: Two retrospective cohort studies were conducted in CTX patients who underwent CDCA treatment: one in the Netherlands (NL; CDCA-STUK-15-001) and one in Italy (IT; CDCA-STRCH-CR-14-001). Eligible patients were aged 2–75 years, had been diagnosed with CTX, and were treated with CDCA orally for ≥1 year. The impact of CDCA treatment on biochemical markers (including serum cholestanol levels) and disease signs and symptoms were assessed, in addition to the safety and tolerability of CDCA treatment. Results: A total of 35 patients were screened in the NL study and were diagnosed with CTX at 25.6 (± 13.7 SD) years on average. These patients were treated with CDCA and followed up for a median of 9.00 (range: 0.4–26.3) years. In addition, 28 patients were enrolled in the IT study and were diagnosed at 35.0 (± 11.4 SD) years on average (median duration of CDCA treatment: 5.75 [range: 0.0–25.0] years). Signs and symptoms of disease resolved, improved, or remained stable in many patients, with concomitant improvements in biochemical marker levels (serum cholestanol, p < 0.001; 7α-hydroxy-4-cholesten-3-one, p < 0.001 [IT study]). Conclusions: The outcomes of these retrospective cohort studies indicate that CDCA is effective in the long-term treatment of CTX, with an acceptable safety profile. © 2019, The Author(s)

The Mystery of the Asymptotic Quasinormal Modes of Gauss-Bonnet Black Holes

We analyze the quasinormal modes of $D$-dimensional Schwarzschild black holes with the Gauss-Bonnet correction in the large damping limit and show that standard analytic techniques cannot be applied in a straightforward manner to the case of infinite damping. However, by using a combination of analytic and numeric techniques we are able to calculate the quasinormal mode frequencies in a range where the damping is large but finite. We show that for this damping region the famous $\ln(3)$ appears in the real part of the quasinormal mode frequency. In our calculations, the Gauss-Bonnet coupling, $\alpha$, is taken to be much smaller than the parameter $\mu$, which is related to the black hole mass.Comment: 12 pages and 5 figure

Generation Of Virus-Specific Cytotoxic T Lymphocytes (CTLS) Resistant to the Immunosuppressive Drug Tacrolimus (FK506)

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Enhancing Chimeric Antigen Receptor T-Cell Efficacy in Solid Tumors

Chimeric antigen receptor (CAR) T-cell therapy has been acclaimed as a revolution in cancer treatment following the impressive results in hematologic malignancies. Unfortunately, in patients with solid tumors, objectives responses to CAR T cells are still anecdotal, and important issues are driven by on-target but off-tumor activity of CAR T cells and by the extremely complex biology of solid tumors. Here, we will review the recent attempts to challenge the therapeutic impediments to CAR T-cell therapy in solid tumors. We will focus on the most promising strategies of antigen targeting to improve tumor specificity and address the tumor heterogeneity, efforts to circumvent the physical barriers of the tumor architecture such as subverted tumor vasculature, impediments of CAR T-cell trafficking and immune suppressive microenvironment

Higher-Derivative Corrected Black Holes: Perturbative Stability and Absorption Cross-Section in Heterotic String Theory

This work addresses spherically symmetric, static black holes in higher-derivative stringy gravity. We focus on the curvature-squared correction to the Einstein-Hilbert action, present in both heterotic and bosonic string theory. The string theory low-energy effective action necessarily describes both a graviton and a dilaton, and we concentrate on the Callan-Myers-Perry solution in d-dimensions, describing stringy corrections to the Schwarzschild geometry. We develop the perturbation theory for the higher-derivative corrected action, along the guidelines of the Ishibashi-Kodama framework, focusing on tensor type gravitational perturbations. The potential obtained allows us to address the perturbative stability of the black hole solution, where we prove stability in any dimension. The equation describing gravitational perturbations to the Callan-Myers-Perry geometry also allows for a study of greybody factors and quasinormal frequencies. We address gravitational scattering at low frequencies, computing corrections arising from the curvature-squared term in the stringy action. We find that the absorption cross-section receives \alpha' corrections, even though it is still proportional to the area of the black hole event-horizon. We also suggest an expression for the absorption cross-section which could be valid to all orders in \alpha'.Comment: JHEP3.cls, 29 pages; v2: added refs, minor corrections and additions; v3: added more refs, more minor corrections and addition

Naked Singularity in a Modified Gravity Theory

The cosmological constant induced by quantum fluctuation of the graviton on a given background is considered as a tool for building a spectrum of different geometries. In particular, we apply the method to the Schwarzschild background with positive and negative mass parameter. In this way, we put on the same level of comparison the related naked singularity (-M) and the positive mass wormhole. We discuss how to extract information in the context of a f(R) theory. We use the Wheeler-De Witt equation as a basic equation to perform such an analysis regarded as a Sturm-Liouville problem . The application of the same procedure used for the ordinary theory, namely f(R)=R, reveals that to this approximation level, it is not possible to classify the Schwarzschild and its naked partner into a geometry spectrum.Comment: 8 Pages. Contribution given to DICE 2008. To appear in the proceeding

Is there life inside black holes?

Bound inside rotating or charged black holes, there are stable periodic planetary orbits, which neither come out nor terminate at the central singularity. Stable periodic orbits inside black holes exist even for photons. These bound orbits may be defined as orbits of the third kind, following the Chandrasekhar classification of particle orbits in the black hole gravitational field. The existence domain for the third kind orbits is rather spacious, and thus there is place for life inside supermassive black holes in the galactic nuclei. Interiors of the supermassive black holes may be inhabited by civilizations, being invisible from the outside. In principle, one can get information from the interiors of black holes by observing their white hole counterparts.Comment: 11 pages, 5 figures; references adde

Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15

Purpose: A delay in encountering the cognate antigen while in the circulation, and the suboptimal costimulation received at the tumor site are key reasons for the limited activity of chimeric antigen receptor–redirected T cells (CAR-T) in solid tumors. We have explored the benefits of incorporating the IL15 cytokine within the CAR cassette to provide both a survival signal before antigen encounter, and an additional cytokine signaling at the tumor site using a neuroblastoma tumor model. Experimental Design: We optimized the construct for the CAR specific for the NB-antigen GD2 without (GD2.CAR) or with IL15 (GD2.CAR.15). We then compared the expansion, phenotype, and antitumor activity of T cells transduced with these constructs against an array of neuroblastoma cell lines in vitro and in vivo using a xenogeneic metastatic model of neuroblastoma. Results: We observed that optimized GD2.CAR.15-Ts have reduced expression of the PD-1 receptor, are enriched in stem cell–like cells, and have superior antitumor activity upon repetitive tumor exposures in vitro and in vivo as compared with GD2.CAR-Ts. Tumor rechallenge experiments in vivo further highlighted the role of IL15 in promoting enhanced CAR-T antitumor activity and survival, both in the peripheral blood and tissues. Finally, the inclusion of the inducible caspase-9 gene (iC9) safety switch warranted effective on demand elimination of the engineered GD2. CAR.15-Ts. Conclusions: Our results guide new therapeutic options for GD2.CAR-Ts in patients with neuroblastoma, and CAR-T development for a broad range of solid tumors

Massive binary black holes in galactic nuclei and their path to coalescence

Massive binary black holes form at the centre of galaxies that experience a merger episode. They are expected to coalesce into a larger black hole, following the emission of gravitational waves. Coalescing massive binary black holes are among the loudest sources of gravitational waves in the Universe, and the detection of these events is at the frontier of contemporary astrophysics. Understanding the black hole binary formation path and dynamics in galaxy mergers is therefore mandatory. A key question poses: during a merger, will the black holes descend over time on closer orbits, form a Keplerian binary and coalesce shortly after? Here we review progress on the fate of black holes in both major and minor mergers of galaxies, either gas-free or gas-rich, in smooth and clumpy circum-nuclear discs after a galactic merger, and in circum-binary discs present on the smallest scales inside the relic nucleus.Comment: Accepted for publication in Space Science Reviews. To appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher

Supermassive Black Hole Binaries: The Search Continues

Gravitationally bound supermassive black hole binaries (SBHBs) are thought to be a natural product of galactic mergers and growth of the large scale structure in the universe. They however remain observationally elusive, thus raising a question about characteristic observational signatures associated with these systems. In this conference proceeding I discuss current theoretical understanding and latest advances and prospects in observational searches for SBHBs.Comment: 17 pages, 4 figures. To appear in the Proceedings of 2014 Sant Cugat Forum on Astrophysics. Astrophysics and Space Science Proceedings, ed. C.Sopuerta (Berlin: Springer-Verlag