Conceptual design of the beryllium rotating target for the ESS-Bilbao facility

The ESS-Bilbao facility, hosted by the University of the Basque Country (UPV/EHU), envisages the operation of a high-current proton accelerator delivering beams with energies up to 50 MeV. The time-averaged proton current will be 2.25 mA, delivered by 1.5 ms proton pulses with a repetition rate of 20 Hz. This beam will feed a neutron source based upon the Be (p,n) reaction, which will enable the provision of relevant neutron experimentation capabilities. The neutron source baseline concept consists in a rotating beryllium target cooled by water. The target structure will comprise a rotatable disk made of 6061-T6 aluminium alloy holding 20 beryllium plates. Heat dissipation from the target relies upon a distribution of coolant-flow channels. The practical implementation of such a concept is here described with emphasis put on the beryllium plates thermo-mechanical optimization, the chosen coolant distribution system as well as the mechanical behavior of the assembly

Neutronic design for ESS-Bilbao neutron source

The European Spallation Source-Bilbao (ESS-Bilbao) project plans to build an accelerator facility compliant with the ESS-AB requirements which will be able to drive several experimental stations for research purposes involving intense proton beams with currents up to 75 mA, 50 MeV of final energy, 1.5 ms of pulse length and up to 50 Hz repetition rate. The accelerator will also drive a compact neutron source which will provide useful neutron beams to carry out experiments on moderator optimization, neutron optics devices and general neutron instrumentation as well as preparation work for experiments to be carried out by neutron beam users at the large facilities

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

Millions of individuals worldwide suffer from impaired vision, a condition with multiple origins that often impinge upon the light sensing cells of the retina, the photoreceptors, affecting their integrity. The molecular components contributing to this integrity are however not yet fully understood. Here we have asked whether Secreted Frizzled Related Protein 1 (SFRP1) may be one of such factors. SFRP1 has a context-dependent function as modulator of Wnt signalling or of the proteolytic activity of A Disintegrin And Metalloproteases (ADAM) 10, a main regulator of neural cell-cell communication. We report that in Sfrp1^{-/-} mice, the outer limiting membrane (OLM) is discontinuous and the photoreceptors disorganized and more prone to light-induced damage. Sfrp1 loss significantly enhances the effect of the Rpe6^{Leu450Leu} genetic variant -present in the mouse genetic background- which confers sensitivity to light-induced stress. These alterations worsen with age, affect visual function and are associated to an increased proteolysis of Protocadherin 21 (PCDH21), localized at the photoreceptor outer segment, and N-cadherin, an OLM component. We thus propose that SFRP1 contributes to photoreceptor fitness with a mechanism that involves the maintenance of OLM integrity. These conclusions are discussed in view of the broader implication of SFRP1 in neurodegeneration and aging

The use of fluoroproline in MUC1 antigen enables efficient detection of antibodies in patients with prostate cancer

A structure-based design of a new gene22ration tumor-associated glycopeptides with improved affinity against two anti-MUC1 antibodies is described. These unique antigens feature a fluorinated proline residue, such as a (4S)-4-fluoro-L-proline or 4,4-difluoroproline, at the most immunogenic domain. Binding assays using bio-layer interferometry reveal 3-fold to 10-fold affinity improvement with respect to the natural (glyco)peptides. According to X-ray crystallography and MD simulations, the fluorinated residues stabilize the antigen-antibody complex by enhancing key CH/ interactions. Interestingly, a notable improvement in detection of cancer-associated anti-MUC1 antibodies from serum of patients with prostate cancer is achieved with the non-natural antigens, which proves that these derivatives can be considered better diagnostic tools than the natural antigen for this type of cancer.We thank the Ministerio de Economía y Competitividad (projects CTQ2015-67727-R, UNLR13-4E-1931, CTQ2013-44367-C2-2-P, CTQ2015-64597-C2-1P, and BFU2016-75633-P). I. A. B. thanks the Asociación Española Contra el Cancer en La Rioja for a grant. I. S. A. and G. J. L. B. thank FCT Portugal (PhD studentship and FCT Investigator, respectively) and the EPSRC for funding. G. J. L. B. holds a Royal Society URF and an ERC StG (TagIt). F.C. and G. J. L. B thank the EU (Marie-Sklodowska Curie ITN, Protein Conjugates). R.H-G. thanks Agencia Aragonesa para la Investigación y Desarrollo (ARAID) and the Diputación General de Aragón (DGA, B89) for financial support. The research leading to these results has also received funding from the FP7 (2007-2013) under BioStruct-X (grant agreement N°283570 and BIOSTRUCTX_5186). We thank synchrotron radiation source DIAMOND (Oxford) and beamline I04 (number of experiment mx10121-19). Hokkaido University group acknowledges to JSPS KAKENHI Grant Number 25220206 and JSPS Wakate B KAKENHI Grant Number 24710242. We also thank CESGA (Santiago de Compostela) for computer support

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

Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER1) node-negative breast cancer

Este artículo ha sido publicado en Annals of Oncology. Esta versión tiene Licencia Creative Commons CC-BY.This study examined the impact of the Recurrence Score (RS) in Spanish breast cancer patients and explored the associations between clinicopathological markers and likelihood of change in treatment recommendations. Patients and methods: Enrollment was offered consecutively to eligible women with estrogen receptor-positive; human epidermal growth factor receptor 2-negative, node-negative breast cancer. Oncologists recorded treatment recommendation and confidence in it before and after knowing the patient’s RS. Results: Treatment recommendation changed in 32% of 107 patients enrolled: in 21% from chemohormonal (CHT) to hormonal therapy (HT) and in 11% from HT to CHT. RS was associated with the likelihood of change from HT to CHT (P < 0.001) and from CHT to HT (P < 0.001). Confidence of oncologists in treatment recommendations increased for 60% of cases. Higher tumor grade (P = 0.007) and a high proliferative index (Ki-67) (P = 0.023) were significantly associated with a greater chance of changing from HT to CHT, while positive progesterone receptor status (P = 0.002) with a greater probability of changing from CHT to HT. Conclusions: Results from the first prospective European study are consistent with published experience and use of the RS as proposed in European clinical practice guidelines and provide evidence on how Oncotype DX and clinicopathological factors are complementary and patient selection may be improved.This work was supported in part by Plan Nacional de Investigacio´ n Cientı´fica, Desarrollo e Innovacio´ n Tecnolo´ gica (I + D + I), iniciativa Ingenio 2010, programa Consolider and Instituto de Salud Carlos III (ISCIII)/FEDER (RD06/0020/0109, RD06/0020/0080, RD06/002/002); PN de I + D + I 2008-20011, and ISCIII/FEDER—Subdireccio´n General de Evaluacio´n y Fomento de la Investigacio´n (PS09/01285, PS09/01700, PS09/ 01296 FIS PI04417, FIS PI082031, CIT-090000-2008-010,); DIUE Generalitat de Catalunya

Therapeutic effect of all-trans-retinoic acid (at-RA) on an autoimmune nephritis experimental model: role of the VLA-4 integrin

BACKGROUND: Mercuric chloride (HgCl(2)) induces an autoimmune nephritis in the Brown Norway (BN) rats characterized by anti-glomerular basement membrane antibodies (anti-GBM Ab) deposition, proteinuria and a severe interstitial nephritis, all evident at day 13 of the disease. We assessed the effects of all-trans retinoic acid (at-RA) in this experimental model. At-RA is a vitamin A metabolite which has shown beneficial effects on several nephropathies, even though no clear targets for at-RA were provided. METHODS: We separated animals in four different experimental groups (HgCl(2), HgCl(2)+at-RA, at-RA and vehicle). From each animal we collected, at days 0 and 13, numerous biological samples: urine, to measure proteinuria by colorimetry; blood to determine VLA-4 expression by flow citometry; renal tissue to study the expression of VCAM-1 by Western blot, the presence of cellular infiltrates by immunohistochemistry, the IgG deposition by immunofluorescence, and the cytokines expression by RT-PCR. Additionally, adhesion assays to VCAM-1 were performed using K562 α4 transfectant cells. ANOVA tests were used for statistical significance estimation. RESULTS: We found that at-RA significantly decreased the serum levels of anti-GBM and consequently its deposition along the glomerular membrane. At-RA markedly reduced proteinuria as well as the number of cellular infiltrates in the renal interstitium, the levels of TNF-α and IL-1β cytokines and VCAM-1 expression in renal tissue. Moreover, we reported here for the first time in an in vivo model that at-RA reduced, to basal levels, the expression of VLA-4 (α4β1) integrin induced by mercury on peripheral blood leukocytes (PBLs). In addition, using K562 α4 stable transfectant cells, we found that at-RA inhibited VLA-4 dependent cell adhesion to VCAM-1. CONCLUSION: Here we demonstrate a therapeutic effect of at-RA on an autoimmune experimental nephritis model in rats. We report a significant reduction of the VLA-4 integrin expression on PBLs as well as the inhibition of the VLA4/VCAM1-dependent leukocyte adhesion by at-RA treatment. Thereby we point out the VLA-4 integrin as a target for at-RA in vivo

Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study

Background: The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19. Methods: We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero (2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis. Findings: 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16-0·55; p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26-0·57; p<0·0001, compared with the VIR-N1-Storm group). Interpretation: The presence of a so-called viral storm is associated with increased all-cause death in patients admitted to the intensive care unit with severe COVID-19. Preventing this viral storm could help to reduce poor outcomes. Viral storm could be an enrichment marker for treatment with antivirals or purification devices to remove viral components from the blood.This work was supported by grants from the Instituto de Salud Carlos III (FONDO-COVID19, COV20/00110, CIBERES, 06/06/0028; AT), Proyectos de Investigación en Salud (PI19/00590; JFB-M), Miguel Servet (CP20/00041; DdG-C), Sara Borrell (CD018/0123; APT), and Predoctorales de Formación en Investigación en Salud (FI20/00278; AdF). We also received funds from Programa de Donaciones Estar Preparados, UNESPA (Madrid, Spain), and from the Canadian Institutes of Health Research (CIHR OV2–170357; DJK and JFB-M), Research Nova Scotia, Li-Ka Shing Foundation (DJK), and finally by a Research Grant 2020 from ESCMID (APT). COV20/00110, PI19/00590, CP20/00041, CD018/0123, FI20/00278 were co-funded by European Regional Development Fund and European Social Fund (A way to make Europe, and Investing in your future). We thank the IRB-Lleida Biobank 119 (B.0000682) and Plataforma Biobancos PT17/0015/0027 in Lleida, the Hospital Clinic Barcelona (HCB)-IDIBAPS biobank in Barcelona, and the National DNA Bank and the Hospital Universitario de Salamanca biobank (both in Salamanca) for their logistical support with sample processing and storage. We are indebted to the Fundació Glòria Soler for its contribution and support to the COVIDBANK of HCBIDIBAPS Biobank. This work was not supported by any pharmaceutical company or other agency.S