Evaluation in a Cytokine Storm Model in Vivo of the Safety and Efficacy of Intravenous Administration of PRS CK STORM (Standardized Conditioned Medium Obtained by Coculture of Monocytes and Mesenchymal Stromal Cells)

Our research group has been developing a series of biological drugs produced by cocul-ture techniques with M2-polarized macrophages with different primary tissue cells and/or mesen-chymal stromal cells (MSC), generally from fat, to produce anti-inflammatory and anti-fibrotic ef-fects, avoiding the overexpression of pro-inflammatory cytokines by the innate immune system at a given time. One of these products is the drug PRS CK STORM, a medium conditioned by allogenic M2-polarized macrophages, from coculture, with those macrophages M2 with MSC from fat, whose composition, in vitro safety, and efficacy we studied. In the present work, we publish the results obtained in terms of safety (pharmacodynamics and pharmacokinetics) and efficacy of the intravenous application of this biological drug in a murine model of cytokine storm associated with severe infectious processes, including those associated with COVID-19. The results demonstrate the safety and high efficacy of PRS CK STORM as an intravenous drug to prevent and treat the cytokine storm associated with infectious processes, including COVID-19

Cytokine profile and anti-inflammatory activity of a standardized conditioned medium obtained by coculture of monocytes and mesenchymal stromal cells (PRS CK STORM)

Intercellular communication between monocytes/macrophages and cells involved in tissue regeneration, such as mesenchymal stromal cells (MSCs) and primary tissue cells, is essential for tissue regeneration and recovery of homeostasis. Typically, in the final phase of the inflammation-resolving process, this intercellular communication drives an anti-inflammatory immunomodulatory response. To obtain a safe and effective treatment to counteract the cytokine storm associated with a disproportionate immune response to severe infections, including that associated with COVID-19, by means of naturally balanced immunomodulation, our group has standardized the production under GMP-like conditions of a secretome by coculture of macrophages and MSCs. To characterize this proteome, we determined the expression of molecules related to cellular immune response and tissue regeneration, as well as its possible toxicity and anti-inflammatory potency. The results show a specific molecular pattern of interaction between the two cell types studied, with an anti-inflammatory and regenerative profile. In addition, the secretome is not toxic by itself on human PBMC or on THP-1 monocytes and prevents lipopolysaccharide (LPS)-induced growth effects on those cell types. Finally, PRS CK STORM prevents LPS-induced TNF-A and IL-1B secretion from PBMC and from THP-1 cells at the same level as hydrocortisone, demonstrating its anti-inflammatory potency. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Underdiagnosis and prognosis of chronic obstructive pulmonary disease after percutaneous coronary intervention: a prospective study

Background: Retrospective studies based on clinical data and without spirometric confirmation suggest a poorer prognosis of patients with ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) following percutaneous coronary intervention (PCI). The impact of undiagnosed COPD in these patients is unknown. We aimed to evaluate the prognostic impact of COPD – previously or newly diagnosed – in patients with IHD treated with PCI. Methods: Patients with IHD confirmed by PCI were consecutively included. After PCI they underwent forced spirometry and evaluation for cardiovascular risk factors. All-cause mortality, new cardiovascular events, and their combined endpoint were analyzed. Results: A total of 133 patients (78%) male, with a mean (SD) age of 63 (10.12) years were included. Of these, 33 (24.8%) met the spirometric criteria for COPD, of whom 81.8% were undiagnosed. IHD patients with COPD were older, had more coronary vessels affected, and a greater history of previous myocardial infarction. Median follow-up was 934 days (interquartile range [25%–75%]: 546–1,160). COPD patients had greater mortality (P=0.008; hazard ratio [HR]: 8.85; 95% confidence interval [CI]: 1.76–44.47) and number of cardiovascular events (P=0.024; HR: 1.87; 95% CI: 1.04–3.33), even those without a previous diagnosis of COPD (P=0.01; HR: 1.78; 95% CI: 1.12–2.83). These differences remained after adjustment for sex, age, number of coronary vessels affected, and previous myocardial infarction (P=0.025; HR: 1.83; 95% CI: 1.08–3.1)The CATEPOC study was supported in part by Menarini Spai

Validation of a new In Vitro Sun Protection Factor (SPF) method to include a wide range of sunscreen product emulsion types

In 2017, Cosmetics Europe performed a double-blinded ring test of 24 emulsion-type sunscreen products, across 3 in vivo test laboratories and 3 in vitro test laboratories, using a new candidate in vitro SPF test method. Based on the results of this work, an article was published showing how data derived from a new lead candidate method conform to new International Standards (ISO) acceptance criteria for alternative SPF test methods (Any alternative method should consider the matrix effect and if required, specify the matrix applicability of the method; Criterion 1a: Systematic differences between methods should be negligible: 95% of all individual results of an alternative method are within the range of ±2× reproducibility standard deviation of the in vivo method, that is overall bias must be below 0.5× reproducibility standard deviation of the in vivo method; Criterion 1b: Measurement uncertainty of an alternative method should be below the measurement uncertainty of the in vivo method. Candidate method predicted values must fall within the full 'funnel' (SPF 6-50+) limits proposed by Cosmetics Europe (derived from the same minimum test design, that is using the ISO24444 Method to measure at least 24 products across at least 3 laboratories using at least 5 test subjects/laboratory, in a blinded fashion).). Of the 24 sunscreen products tested, the majority of emulsions were of the oil-in-water (O/W) type, whereas only one was water-in-oil (W/O) and there were no products with a mineral-only sun filter system. In order to confirm the scope of this method, therefore, a new study was conducted that included 73 W/O (12 mineral + organic, 44 mineral only and 17 organic only) and 3 O/W mineral-only, emulsion-type sunscreen products (a total of 76 new sunscreen products). When combined with the previous 24 products (tested in 3 different laboratories), this yielded a new data set comprising a total of 100 emulsion-type sunscreen products, with SPF values ranging from 6 to 50+ (with a total of 148 data points). These products were tested using the double-plate in vitro SPF test method and compared with the ISO TC217/WG7 acceptance criteria for alternative SPF test methods. Over 95% of paired in vitro: in vivo SPF values lay within the upper and lower limits of the ISO acceptance criteria funnel, with no bias. This new in vitro SPF test method, therefore, meets the minimum requirements for an alternative SPF test method to ISO24444:2010, for emulsion-type sunscreen products (which make up the majority of marketed sunscreen products)

Spectra of supernovae in the nebular phase

When supernovae enter the nebular phase after a few months, they reveal spectral fingerprints of their deep interiors, glowing by radioactivity produced in the explosion. We are given a unique opportunity to see what an exploded star looks like inside. The line profiles and luminosities encode information about physical conditions, explosive and hydrostatic nucleosynthesis, and ejecta morphology, which link to the progenitor properties and the explosion mechanism. Here, the fundamental properties of spectral formation of supernovae in the nebular phase are reviewed. The formalism between ejecta morphology and line profile shapes is derived, including effects of scattering and absorption. Line luminosity expressions are derived in various physical limits, with examples of applications from the literature. The physical processes at work in the supernova ejecta, including gamma-ray deposition, non-thermal electron degradation, ionization and excitation, and radiative transfer are described and linked to the computation and application of advanced spectral models. Some of the results derived so far from nebular-phase supernova analysis are discussed.Comment: Book chapter for 'Handbook of Supernovae,' edited by Alsabti and Murdin, Springer. 51 pages, 14 figure

The Iron Discrepancy in Elliptical Galaxies after ASCA

We present estimates for the iron content of the stellar and diffused components of elliptical galaxies, as derived respectively from integrated optical spectra and from ASCA X-ray observations. A macroscopic discrepancy emerges between the expected iron abundances in the hot interstellar medium (ISM) and what is indicated by the X-ray observations, especially when allowance is made for the current iron enrichment by Type Ia supernovae. This strong discrepancy, that in some extreme instances may be as large as a factor of $\sim 20$, calls into question our current understanding of supernova enrichment and chemical evolution of galaxies. We discuss several astrophysical implications of the inferred low iron abundances in the ISM, including the chemical evolution of galaxies and cluster of galaxies, the evolution of gas flows in ellipticals, and the heating of the intracluster medium. Some of the consequences appear hard to accept, and in the attempt to avoid some of these difficulties we explore ways of hiding or diluting iron in the ISM of ellipticals. None of these possibilities appears astrophysically plausible, and we alternatively rise the question of the reliability of iron-L line diagonostic tools. Various thin plasma emission models are shown to give iron abundances that may differ significantly, especially at low temperatures (kT \lsim 1 keV). From a collection of ASCA and other X-ray observatory data, it is shown that current thin plasma codes tend to give very low iron abundances when the temperature of the objects is below $\sim 1$ keV. We conclude that -- besides rethinking the chemical evolution of galaxies -- one should also consider the possibility that existing thin plasma models may incorporate inaccurate atomic physics for the ions responsible for the iron-L complex.Comment: 39 pages, TeX file, 5 figures, Accepted for publication in the Ap

The imprint of a symbiotic binary progenitor on the properties of Kepler's supernova remnant

We present a model for the Type Ia supernova remnant (SNR) of SN 1604, also known as Kepler's SNR. We find that its main features can be explained by a progenitor model of a symbiotic binary consisting of a white dwarf and an AGB donor star with an initial mass of 4-5 M_sun. The slow, nitrogen rich wind emanating from the donor star has partially been accreted by the white dwarf, but has also created a circumstellar bubble. Based on observational evidence, we assume that the system moves with a velocity of 250 km/s. Due to the systemic motion the interaction between the wind and the interstellar medium has resulted in the formation of a bow shock, which can explain the presence of a one-sided, nitrogen rich shell. We present two-dimensional hydrodynamical simulations of both the shell formation and the SNR evolution. The SNR simulations show good agreement with the observed kinematic and morphological properties of Kepler's SNR. Specifically, the model reproduces the observed expansion parameters (m=V/(R/t)) of m=0.35 in the north and m=0.6 in the south of Kepler's SNR. We discuss the variations among our hydrodynamical simulations in light of the observations, and show that part of the blast wave may have traversed through the one-sided shell completely. The simulations suggest a distance to Kepler's SNR of 6 kpc, or otherwise require that SN 1604 was a sub-energetic Type Ia explosion. Finally, we discuss the possible implications of our model for Type Ia supernovae and their remnants in general.Comment: 13 pages, 9 figures. Submitted to A&

Restframe I-band Hubble diagram for type Ia supernovae up to redshift z ~0.5

We present a novel technique for fitting restframe I-band light curves on a data set of 42 Type Ia supernovae (SNe Ia). Using the result of the fit, we construct a Hubble diagram with 26 SNe from the subset at 0.01< z<0.1. Adding two SNe at z~0.5 yields results consistent with a flat Lambda-dominated``concordance universe'' ($\Omega_M,\Omega_\Lambda$)=(0.25,0.75). For one of these, SN 2000fr, new near infrared data are presented. The high redshift supernova NIR data are also used to test for systematic effects in the use of SNe Ia as distance estimators. A flat, Lambda=0, universe where the faintness of supernovae at z~0.5 is due to grey dust homogeneously distributed in the intergalactic medium is disfavoured based on the high-z Hubble diagram using this small data-set. However, the uncertainties are large and no firm conclusion may be drawn. We explore the possibility of setting limits on intergalactic dust based on B-I and B-V colour measurements, and conclude that about 20 well measured SNe are needed to give statistically significant results. We also show that the high redshift restframe I-band data points are better fit by light curve templates that show a prominent second peak, suggesting that they are not intrinsically underluminous.Comment: Accepted for publication in A&A (01/04/2005

Los métodos alternativos en el estudio de la seguridad de cosméticos

El Reglamento 1223/2009 establece las normas que deben cumplir todos los productos cosméticos comercializados en Europa, con objeto de velar por el funcionamiento del mercado interior y lograr un elevado nivel de protección de la salud humana garantizando el uso de métodos alternativos que no impliquen la utilización de animales. El Laboratorio Europeo de Referencia para las Alternativas a la Experimentación con Animales (EURL-EURL- ECVAM) es el laboratorio de referencia en Europa encargado de validar los métodos alternativos. Posteriormente pueden ser homologados por la Organización de Cooperación y Desarrollo Económico (OCDE). Por otro lado, el Comité Científico de Seguridad de los Consumidores (SCCS) asesora a la Comisión sobre todos los temas relacionados con la seguridad de los cosméticos. En esta revisión se detalla una relación de métodos alternativos necesarios para evaluar la seguridad de los ingredientes cosméticos así como los métodos usados y sus limitaciones