Current and future treatment strategies for rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, and can be subcategorized histologically and/or based on PAX-FOXO1 fusion gene status. Over the last four decades, there have been no significant improvements in clinical outcomes for advanced and metastatic RMS patients, underscoring a need for new treatment options for these groups. Despite significant advancements in our understanding of the genomic landscape and underlying biological mechanisms governing RMS that have informed the identification of novel therapeutic targets, development of these therapies in clinical trials has lagged far behind. In this review, we summarize the current frontline multi-modality therapy for RMS according to pediatric protocols, highlight emerging targeted therapies and immunotherapies identified by preclinical studies, and discuss early clinical trial data and the implications they hold for future clinical development

Addressing the controversial origin of the marble source used in the Phoenician anthropoid sarcophagi of Gadir (Cadiz, Spain)

Dating from the fifth century bce, two Phoenician anthropoid sarcophagi, a male and a female, found in Gadir (Cadiz, Spain), are so far the most ancient marble sculptures found in the Iberian Peninsula. The identification of the source of the marble used to produce them has been a subject of controversy for several decades and has recently resurfaced when it was published that they were made by Phoenician artisans using Iberian marble from Macael. This identification is not only unreasonable from an archaeological point of view but also unsupported by any analytical data. On the contrary, as the sarcophagi belong to an Eastern Mediterranean Sidonian production, their raw material is most likely to be Greek-Minor Asian in origin. In order to shed a light on this dispute and objectively resolve the provenance of the marble, a multi-method analytical approach was carried out. Optical microscopy, cathodoluminescence analyses, and C and O stable isotopes clarify the provenance of the marble, confirming that both singular sarcophagi were carved in a Cycladic marble, in accordance with their Sidonian style

Emulsion Chamber with Big Radiation Length for Detecting Neutrino Oscillations

A conceptual scheme of a hybrid-emulsion spectrometer for investigating various channels of neutrino oscillations is proposed. The design emphasizes detection of $\tau$ leptons by detached vertices, reliable identification of electrons, and good spectrometry for all charged particles and photons. A distributed target is formed by layers of low-Z material, emulsion-plastic-emulsion sheets, and air gaps in which $\tau$ decays are detected. The tracks of charged secondaries, including electrons, are momentum-analyzed by curvature in magnetic field using hits in successive thin layers of emulsion. The $\tau$ leptons are efficiently detected in all major decay channels, including \xedec. Performance of a model spectrometer, that contains 3 tons of nuclear emulsion and 20 tons of passive material, is estimated for different experimental environments. When irradiated by the $\nu_\mu$ beam of a proton accelerator over a medium baseline of $\sim 1$ km/GeV, the spectrometer will efficiently detect either the \omutau and \omue transitions in the mass-difference region of $\Delta m^2 \sim 1$ eV$^2$, as suggested by the results of LSND. When exposed to the neutrino beam of a muon storage ring over a long baseline of $\sim$ 10-20 km/GeV, the model detector will efficiently probe the entire pattern of neutrino oscillations in the region $\Delta m^2 \sim 10^{-2}-10^{-3}$ eV$^2$, as suggested by the data on atmospheric neutrinos.Comment: 34 pages, 8 figure

A layer stripping approach for monitoring resistivity variations using surface magnetotelluric responses

The resolution of surface-acquired magnetotelluric data is typically not sufficiently high enough in monitoring surveys to detect and quantify small resistivity variations produced within an anomalous structure at a given depth within the subsurface. To address this deficiency we present an approach, called "layer stripping", based on the analytical solution of the one-dimensional magnetotelluric problem to enhance the sensitivity of surface magnetotelluric responses to such subtle subsurface temporal variations in resistivity within e.g. reservoirs. Given a well-known geoelectrical baseline model of a reservoir site, the layer stripping approach aims to remove the effect of the upper, unchanging structures in order to simulate the time-varying magnetotelluric responses at depth. This methodology is suggested for monitoring all kinds of reservoirs, e.g. hydrocarbons, gas, geothermal, compress air storage, etc., but here we focus on CO2 geological storage. We study one-dimensional and three-dimensional resistivity variations in the reservoir layer and the feasibility of the method is appraised by evaluating the error of the approach and defining different detectability parameters. The geoelectrical baseline model of the Hontomín site (Spain) for CO2 geological storage in a deep saline aquifer is taken as our exemplar for studying the validity of the 1D assumption in a real scenario. We conclude that layer stripping could help detect resistivity variations and locate them in the space, showing potential to also sense unforeseen resistivity variations at all depths. The proposed approach constitutes an innovative contribution to take greater advantage of surface magnetotelluric data and to use the method as a cost-effective permanent monitoring technique in suitable geoelectrical scenarios

Tau Lepton Mixing with Charginos and its Effects on Chargino Searches at e+e- Colliders

In bilinear R-Parity violating models where a term \epsilon_3L_3H_2 is introduced in the superpotential, the tau lepton can mix with charginos. We show that this mixing is fully compatible with LEP1 precision measurements of the Z\tau\tau and W\tau\nu_\tau couplings even for large values of \epsilon_3 and of the induced vacuum expectation value v_3 of the tau-sneutrino. The single production of charginos at e+e- colliders is possible in this case and we present numerical values of the cross-section at LEP1, LEP2 and an NLC. We find maximum values of 10 pb at LEP1 and 1 fb at NLC, while the corresponding values at LEP2 are too small to observe.Comment: 16 pages (including 7 figures), LaTex, uses axodraw.sty (included

Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS

[EN] The human genome is constantly attacked by endogenous and exogenous agents (ultraviolet light, xenobiotics, reactive oxygen species), which can induce chemical transformations leading to DNA lesions. To combat DNA damage, cells have developed several repair mechanisms; however, if the repair is defective, DNA lesions lead to permanent mutations. Single-cell gel electrophoresis (COMET assay) is a sensitive and well-established technique for quantifying DNA damage in individual cells. Nevertheless, this tool lacks relationship with mutagenesis. Therefore, to identify errors that give rise to mutations it would be convenient to test an alternative known procedure, such as next generation sequencing (NGS). Thus, the present work aims to evaluate the photomutagenicity of neuroleptic drug chlorpromazine (CPZ), and its N-demethylated metabolites using COMET assay and to test NGS as an alternative method to assess photomutagenesis. In this context, upon exposure to UVA radiation, COMET assay reveals CPZ-photosensitized DNA damage partially repaired by cells. Conversely with this result, metabolites demethylchlorpromazine (DMCPZ) and didemethylchlorpromazine (DDMCPZ) promote extensive DNA-photodamage, hardly repaired under the same conditions. Parallel assessment of mutagenesis by NGS is consistent with these results with minor discrepancies for DDMCPZ. To our knowledge, this is the first example demonstrating the utility of NGS for evaluating drug-induced photomutagenicity.This study was funded by the Carlos III Institute (ISCIII) of Health (Grants: PI15/00303, PI18/00540, PI16/01877, CPII16/00052, the Thematic Networks and Co-operative Research Centres: ARADyAL RD16/0006/0004 and RD16/0006/0030), IB16170, GR18145 from Junta de Extremadura, Spain, co-funded by European Regional Development Fund and Generalitat Valenciana Prometeo/2017/075. We would also like to thank M. Dolores Coloma for technical assistance in the preliminary experiments.Agúndez, JA.; García-Martín, E.; Garcia-Lainez, G.; Miranda Alonso, MÁ.; Andreu Ros, MI. (2020). Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS. Scientific Reports. 10(1):1-6. https://doi.org/10.1038/s41598-020-63651-yS16101Bjelland, S. & Seeberg, E. Mutagenicity, toxicity and repair of DNA base damage induced by oxidation. Mutat. Res. 531, 37–80 (2003).Friedberg, E. C. A brief history of the DNA repair field. Cell Res. 18, 3–7 (2008).Cadet, J. & Wagner, J. R. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb. Perspect. Biol. 5, (2013).Bauer, N. C., Corbett, A. H. & Doetsch, P. W. The current state of eukaryotic DNA base damage and repair. Nucleic Acids Res. 43, 10083–10101 (2015).Cadet, J. & Davies, K. J. A. Oxidative DNA damage & repair: An introduction. Free Radic. Biol. Med. 107, 2–12 (2017).Sancar, A., Lindsey-Boltz, L. A., Unsal-Kaçmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004).Roos, W. P., Thomas, A. D. & Kaina, B. DNA damage and the balance between survival and death in cancer biology. Nat. Rev. Cancer 16, 20–33 (2016).Møller, P. Assessment of reference values for DNA damage detected by the comet assay in human blood cell DNA. Mutat. Res. 612, 84–104 (2006).Azqueta, A. & Collins, A. R. The essential comet assay: a comprehensive guide to measuring DNA damage and repair. Arch. Toxicol. 87, 949–968 (2013).Collins, A. R. et al. Controlling variation in the comet assay. Front. Genet. 5, 359 (2014).Møller, P. The comet assay: ready for 30 more years. Mutagenesis 33, 1–7 (2018).Shendure, J. & Ji, H. Next-generation DNA sequencing. Nat. Biotechnol. 26, 1135–1145 (2008).Metzker, M. L. Sequencing technologies—the next generation. Nat. Rev. Genet. 11, 31 (2010).Gawad, C., Koh, W. & Quake, S. R. Single-cell genome sequencing: current state of the science. Nat. Rev. Genet. 17, 175–188 (2016).Schwarz, U. I., Gulilat, M. & Kim, R. B. The Role of Next-Generation Sequencing in Pharmacogenetics and Pharmacogenomics. Cold Spring Harb. Perspect. Med. 9, (2019).Epstein, J. H., Brunsting, L. A., Petersen, M. C. & Schwarz, B. E. A study of photosensitivity occurring with chlorpromazine therapy. J. Invest. Dermatol. 28, 329–338 (1957).Kochevar, I. E., Chung, F. L. & Jeffrey, A. M. Photoaddition of chlorpromazine to DNA. Chem. Biol. Interact. 51, 273–284 (1984).Palumbo, F. et al. Enhanced photo(geno)toxicity of demethylated chlorpromazine metabolites. Toxicol. Appl. Pharmacol. 313, 131–137 (2016).Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995)

Solitons in nonlocal nonlinear media: exact results

We investigate the propagation of one-dimensional bright and dark spatial solitons in a nonlocal Kerr-like media, in which the nonlocality is of general form. We find an exact analytical solution to the nonlinear propagation equation in the case of weak nonlocality. We study the properties of these solitons and show their stability.Comment: 9 figures, submitted to Phys. Rev.

Modulational instability in nonlocal nonlinear Kerr media

We study modulational instability (MI) of plane waves in nonlocal nonlinear Kerr media. For a focusing nonlinearity we show that, although the nonlocality tends to suppress MI, it can never remove it completely, irrespectively of the particular profile of the nonlocal response function. For a defocusing nonlinearity the stability properties depend sensitively on the response function profile: for a smooth profile (e.g., a Gaussian) plane waves are always stable, but MI may occur for a rectangular response. We also find that the reduced model for a weak nonlocality predicts MI in defocusing media for arbitrary response profiles, as long as the intensity exceeds a certain critical value. However, it appears that this regime of MI is beyond the validity of the reduced model, if it is to represent the weakly nonlocal limit of a general nonlocal nonlinearity, as in optics and the theory of Bose-Einstein condensates.Comment: 8 pages, submitted to Phys. Rev.

Patient Perspective on the Management of Cancer Pain in Spain

Pain in cancer is often underdiagnosed and undertreated. Breakthrough pain, in particular, severely impacts the quality of life of patients. In this study, we evaluated management and care of pain in Spain from the patient perspective by assessing the experience of 275 patients who had suffered breakthrough pain. Although most patients had suffered moderate-to-severe pain in the last 24 hours, pain relief was achieved in the majority of cases. The body areas with a higher pain intensity was felt varied based on primary cancer. Adherence to treatment was subpar, and patients were moderately concerned about addiction to treatment and adverse events. Doctors did not assess pain in every visit and there is room for improvement in its classification. Education strategies directed toward patients and health care personnel are needed to improve pain assessment, follow-up, and compliance. These could guide shared decision-making and improve communication about cancer pain to improve its care