RhoE is required for contact inhibition and negatively regulates tumor initiation and progression

RhoE is a small GTPase involved in the regulation of actin cytoskeleton dynamics, cell cycle and apoptosis. The role of RhoE in cancer is currently controversial, with reports of both oncogenic and tumor-suppressive functions for RhoE. Using RhoE-deficient mice, we show here that the absence of RhoE blunts contact-inhibition of growth by inhibiting p27 Kip1 nuclear translocation and cooperates in oncogenic transformation of mouse primary fibroblasts. Heterozygous RhoE +/gt mice are more susceptible to chemically induced skin tumors and RhoE knock-down results in increased metastatic potential of cancer cells. These results indicate that RhoE plays a role in suppressing tumor initiation and progression

A pre-correlation RFI mitigation algorithm for L-band interferometric radiometers

Radio Frequency Interference (RFI) is a major concern for both real and synthetic aperture radiometers. After the lessons learnt from SMOS, ESA is preparing the next generation of L-band interferometric radiometers with RFI mitigation integrated into the cross-correlators. This work presents a preliminary design and results of a pre-correlation RFI mitigation algorithm tailored for interferometric radiometers. The results show that the correlation error introduced by the RFI is reduced on average to the half, with peaks of 20 dB of mitigation.Peer ReviewedPostprint (author's final draft

Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1

Background Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of unknown aetiology and poor prognosis, characterized by altered tissue repair and fibrosis. The extracellular matrix (ECM) is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in IPF lungs. Methods ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), categorized as chronic (cHP) and subacute (saHP), and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate tenascin-C (TNC) synthesis. Results A total of 20 ECM proteins were upregulated and 6 proteins downregulated in IPF. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs (IPF and cHP) compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from IPF patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and α-sma was induced by TGF-β1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased α-sma mRNA. Conclusions The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung fibrosis. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing

RFI detection and mitigation for advanced correlators in interferometric radiometers

This work presents the first RFI detection and mitigation algorithm for the interferometric radiometers that will be implemented in its correlator unit. The algorithm operates in the time and frequency domains, applying polarimetric and statistical tests in both domains, and exhibiting a tunable and arbitrary low probability of false alarm. It is scalable to a configurable number of receivers, and it is optimized in terms of quantization bits and the implementation of the cross-correlations in the time or frequency domains for hardware resource saving. New features of this algorithm are the computation of the Stokes parameters per frequency bin in the Short-Time Fourier Transform and a new parameter called Polarimetric Kurtosis. If RFI is detected in one domain or in both, it is removed using the calculated blanking masks. The optimum algorithm parameters are computed, such as length of the FFTs, the threshold selection for a given probability of false alarm, and the selection of the blanking masks. Last, an important result refers to the application of Parseval’s theorem for the computation of the cross-correlations in the frequency domain, instead of in the time domain, which is more efficient and leads to smaller errors even when using moderate quantization levels. The algorithm has been developed in the framework of the ESA’s technology preparation for a potential L-band radiometer mission beyond SMOS. However, it is also applicable to (polarimetric) real aperture radiometers, and its performance would improve if more than one bit is used in the signal quantization.This research was funded by ESA, grant number ITT AO9359, by project SPOT: Sensing with Pioneering Opportunistic Techniques grant RTI2018-099008-B-C21/AEI/10.13039/501100011033, and the grant for recruitment of early stage research staff of the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) Generalitat de Catalunya, Spain (FISDUR2020/105).Peer ReviewedPostprint (published version

Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. We present the generation and characterization of five distinct MPNST orthoxenograft models for preclinical testing and personalized medicine. Four of the models are patient-derived tumor xenografts (PDTX), two independent MPNSTs from the same NF1 patient and two from different sporadic patients. The fifth model is an orthoxenograft derived from an NF1-related MPNST cell line. All MPNST orthoxenografts were generated by tumor implantation, or cell line injection, next to the sciatic nerve of nude mice, and were perpetuated by 7-10 mouse-to-mouse passages. The models reliably recapitulate the histopathological properties of their parental primary tumors. They also mimic distal dissemination properties in mice. Human stroma was rapidly lost after MPNST engraftment and replaced by murine stroma, which facilitated genomic tumor characterization. Compatible with an origin in a catastrophic event and subsequent genome stabilization, MPNST contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Mutational frequency and type of somatic point mutations were highly variable among the different MPNSTs modeled, but very consistent when comparing primary tumors with matched orthoxenografts generated. Unsupervised cluster analysis and principal component analysis (PCA) using an MPNST expression signature of ~1,000 genes grouped together all primary tumor-orthoxenograft pairs. Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines. Following standardization and extensive characterization and validation, the orthoxenograft models were used for initial preclinical drug testing. Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth. The development of genomically well-characterized preclinical models for MPNST allowed the evaluation of novel therapeutic strategies for personalized medicine

Colecciones ex situ de planta viva para la conservación de la planta amenazada Silene hifacensis, Rouy ex Willk (Caryophyllaceae)

The establishment of seed orchards has allowed obtaining a great deal of germoplasm of Silene hifacensis, an endangered endemic Ibero-Balearic species. In four years, 3.958.531 seeds have been collected in our four seed orchards from a total of 570 plants/year per average, including all genetic variability from natural populations of this species in Alicante province (Illot of Mona, the Pessebret, Cova de les Cendres, Morro de Toix)

Left atrial geometry and outcome of atrial fibrillation ablation: results from the multicentre LAGO-AF study

Aims: Left atrial (LA) remodelling is a key determinant of atrial fibrillation (AF) ablation outcome. Optimal methods to assess this process are scarce. LA sphericity is a shape-based parameter shown to be independently associated to procedural success. In a multicentre study, we aimed to test the feasibility of assessing LA sphericity and evaluate its capability to predict procedural outcomes. Methods and results: This study included consecutive patients undergoing first AF ablation during 2013. A 3D model of the LA chamber, excluding pulmonary veins and LA appendage, was used to quantify LA volume (LAV) and LA sphericity (≥82.1% was considered spherical LA). In total, 243 patients were included across 9 centres (71% men, aged 56 ± 10 years, 44% with hypertension and 76% CHA2DS2-VASc ≤ 1). Most patients had paroxysmal AF (66%) and underwent radiofrequency ablation (60%). Mean LA diameter (LAD), LAV, and LA sphericity were 42 ± 6 mm, 100 ± 33 mL, and 82.6 ± 3.5%, respectively. Adjusted Cox models identified paroxysmal AF [hazard ratio (HR 0.54, P = 0.032)] and LA sphericity (HR 1.87, P = 0.035) as independent predictors for AF recurrence. A combined clinical-imaging score [Left Atrial Geometry and Outcome (LAGO)] including five items (AF phenotype, structural heart disease, CHA2DS2-VASc ≤ 1, LAD, and LA sphericity) classified patients at low (≤2 points) and high risk (≥3 points) of procedural failure (35% vs. 82% recurrence at 3-year follow-up, respectively; HR 3.10, P < 0.001). Conclusion: In this multicentre, real-life cohort, LA sphericity and AF phenotype were the strongest predictors of AF ablation outcome after adjustment for covariates. The LAGO score was easy to implement, identified high risk of procedural failure, and could help select optimal candidates. Clinical Trial Registration Information: NCT02373982 (http://clinicaltrials.gov/ct2/show/NCT02373982)

Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. We present the generation and characterization of five distinct MPNST orthoxenograft models for preclinical testing and personalized medicine. Four of the models are patient-derived tumor xenografts (PDTX), two independent MPNSTs from the same NF1 patient and two from different sporadic patients. The fifth model is an orthoxenograft derived from an NF1-related MPNST cell line. All MPNST orthoxenografts were generated by tumor implantation, or cell line injection, next to the sciatic nerve of nude mice, and were perpetuated by 7-10 mouse-to-mouse passages. The models reliably recapitulate the histopathological properties of their parental primary tumors. They also mimic distal dissemination properties in mice. Human stroma was rapidly lost after MPNST engraftment and replaced by murine stroma, which facilitated genomic tumor characterization. Compatible with an origin in a catastrophic event and subsequent genome stabilization, MPNST contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Mutational frequency and type of somatic point mutations were highly variable among the different MPNSTs modeled, but very consistent when comparing primary tumors with matched orthoxenografts generated. Unsupervised cluster analysis and principal component analysis (PCA) using an MPNST expression signature of ~1,000 genes grouped together all primary tumor-orthoxenograft pairs. Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines. Following standardization and extensive characterization and validation, the orthoxenograft models were used for initial preclinical drug testing. Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth. The development of genomically well-characterized preclinical models for MPNST allowed the evaluation of novel therapeutic strategies for personalized medicine

Previous SARS-CoV-2 Infection Increases B.1.1.7 Cross-Neutralization by Vaccinated Individuals

Altres ajuts: This work was partially funded by Grifols, the Departament de Salut of the Generalitat de Catalunya (grant SLD016 to J.B. and Grant SLD015 to J.C.), and the crowdfunding initiatives #joemcorono, BonPreu/Esclat and Correos.With the spread of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a need to assess the protection conferred by both previous infections and current vaccination. Here we tested the neutralizing activity of infected and/or vaccinated individuals against pseudoviruses expressing the spike of the original SARS-CoV-2 isolate Wuhan-Hu-1 (WH1), the D614G mutant and the B.1.1.7 variant. Our data show that parameters of natural infection (time from infection and nature of the infecting variant) determined cross-neutralization. Uninfected vaccinees showed a small reduction in neutralization against the B.1.1.7 variant compared to both the WH1 strain and the D614G mutant. Interestingly, upon vaccination, previously infected individuals developed more robust neutralizing responses against B.1.1.7, suggesting that vaccines can boost the neutralization breadth conferred by natural infection