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Maria de la Visitación - portugalska zakonnica, bohaterka anonimowego hiszpańskiego manuskryptu ze zbiorów tzw. „kolekcji berlińskiej” Biblioteki Jagiellońskiej Artykuł nawiązuje do postaci portugalskiej zakonnicy Marii de la Visitación (1551-ok. 1603), która zyskała rozgłos wśród współczesnych dzięki pseudomistycznym doświadczeniom. Obok wymiaru religijnego, historia zakonnicy wpisuje się także w klimat napięć politycznych między Hiszpanią i Portugalią w początkowym okresie Unii Iberyjskiej (1580-1640), kiedy to oba sąsiadujące ze sobą królestwa połączono pod wspólnym berłem hiszpańskiego monarchy Filipa II. Artykuł powstał w oparciu o anonimowy rękopis hiszpański należący do tzw. kolekcji berlińskiej, pochodzącej z dawnej Pruskiej Biblioteki Państwowej w Berlinie (Preussische Staatsbibliothek zu Berlin), zdeponowanej obecnie w Bibliotece Jagiellońskiej w Krakowie.

This research was supported by Asociacion Espanola de LAM; The LAM Foundation Seed Grant 2019; Carlos III Institute of Health grants PI18/01029, PI21/01306 and ICI19/00047 (co-funded by European Regional Development Fund (ERDF), "A way to build Europe"); Ministry of Economy and Competitivity grant SAF2017-88457-R; the Generalitat de Catalunya SGR 2017-449 and 2017-529; PERIS PFI-Salut SLT017-20-000076; and the CERCA Program to IDIBELL and Institut Germans Trias i Pujol. X. Farre is supported by the VEIS project (001-P-001647, ERDF Operational Programme of Catalonia 2014-2020; co-funded by ERDF, "A way to build Europe"). Funding information for this article has been deposited with the Crossref Funder Registry., Introduction Lymphangioleiomyomatosis (LAM) is a rare low-grade metastasising disease characterised by cystic lung destruction. The genetic basis of LAM remains incompletely determined, and the disease cell-of-origin is uncertain. We analysed the possibility of a shared genetic basis between LAM and cancer, and LAM and pulmonary function. Methods The results of genome-wide association studies of LAM, 17 cancer types and spirometry measures (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio and peak expiratory flow (PEF)) were analysed for genetic correlations, shared genetic variants and causality. Genomic and transcriptomic data were examined, and immunodetection assays were performed to evaluate pleiotropic genes. Results There were no significant overall genetic correlations between LAM and cancer, but LAM correlated negatively with FVC and PEF, and a trend in the same direction was observed for FEV1. 22 shared genetic variants were uncovered between LAM and pulmonary function, while seven shared variants were identified between LAM and cancer. The LAM-pulmonary function shared genetics identified four pleiotropic genes previously recognised in LAM single-cell transcriptomes: ADAM12, BNC2, NR2F2 and SP5. We had previously associated NR2F2 variants with LAM, and we identified its functional partner NR3C1 as another pleotropic factor. NR3C1 expression was confirmed in LAM lung lesions. Another candidate pleiotropic factor, CNTN2, was found more abundant in plasma of LAM patients than that of healthy women. Conclusions This study suggests the existence of a common genetic aetiology between LAM and pulmonary function., Asociacion Espanola de LAM, LAM Foundation Seed Grant 2019, Instituto de Salud Carlos III PI18/01029 PI21/01306 ICI19/00047, European Regional Development Fund (ERDF), "A way to build Europe", Ministry of Economy and Competitivity SAF2017-88457-R, Generalitat de Catalunya, General Electric SGR 2017-449 2017-529, PERIS PFI-Salut SLT017-20-000076, CERCA Program, VEIS project 001-P-001647, ERDF, "A way to build Europe" ERDF Operational Programme of Catalonia 2014-2020

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., Andre Franke and David Ellinghaus were supported by a grant from the German Federal Ministry of Education and Research (01KI20197), Andre Franke, David Ellinghaus and Frauke Degenhardt were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). David Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". This project was supported by a Covid-19 grant from the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197). Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by a MIUR grant to the Department of Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program / Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa")., Beatriz Cortes is supported by national grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”). Additional data included in this study was obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià and Sara Marsal were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). Antonio Julià was also supported the by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán and Douglas Maya Miles are supported by the “Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health (CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from Research Council of Norway grant no 312780 during the conduct of the study. Dr. Solligård: reports grants from Research Council of Norway grant no 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF)., Oliver A. Cornely is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping was performed by the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. Kerstin U. Ludwig is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf are supported by the German Center for Infection Research (DZIF). Thorsen Brenner, Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).

Human pigmentation has largely been associated with different disease prevalence among populations, but most of these studies are observational and inconclusive. Known to be genetically determined, pigmentary traits have largely been studied by Genome-Wide Association Study (GWAS), mostly in Caucasian ancestry cohorts from North Europe, identifying robustly, several loci involved in many of the pigmentary traits. Here, we conduct a detailed analysis by GWAS and Polygenic Risk Score (PRS) of 13 pigmentary-related traits in a South European cohort of Caucasian ancestry (n = 20,000). We observed fair phototype strongly associated with non-melanoma skin cancer and other dermatoses and confirmed by PRS-approach the shared genetic basis with skin and eye diseases, such as melanoma (OR = 0.95), non-melanoma skin cancer (OR = 0.93), basal cell carcinoma (OR = 0.97) and darker phototype with vitiligo (OR = 1.02), cataracts (OR = 1.04). Detailed genetic analyses revealed 37 risk loci associated with 10 out of 13 analyzed traits, and 16 genes significantly associated with at least two pigmentary traits. Some of them have been widely reported, such as MC1R, HERC2, OCA2, TYR, TYRP1, SLC45A2, and some novel candidate genes C1QTNF3, LINC02876, and C1QTNF3-AMACR have not been reported in the GWAS Catalog, with regulatory potential. These results highlight the importance of the assess phototype as a genetic proxy of skin functionality and disease when evaluating open mixed populations.

Background: Different approaches for treatment de-escalation are being investigated; however, the current ongoing phase III adjuvant trials with CDK4/6 inhibitors are not addressing the question if these drugs can replace multi-agent chemotherapy in high-risk early breast cancer. Here, we present the primary results of the CORALLEEN phase 2 trial, which evaluates the efficacy of ribociclib plus endocrine therapy (ET) as neoadjuvant treatment in patients with high-risk Luminal B disease. Methods: CORALLEEN is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable hormone receptor-positive (HR+)/HER2-negative breast cancer, Luminal B by Prosigna®. Other eligibility criteria include stage I-III operable breast cancer and ECOG 0-1. Patients were randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy (CT): 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel (80 mg/m2) during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens were collected for molecular characterization and evaluation of response. The primary endpoint is the rate of PAM50 Risk of Relapse (ROR)-low disease at surgery in each arm. PAM50 ROR score integrates gene expression data, tumor size, and nodal status to define a low-risk group in the adjuvant setting (i.e. >90% distant relapse-free survival at 10 years). ROR-low was defined using the standard cutpoints as Citation Format: Joaquín Gavilá, Cristina Saura, Tomás Pascual, Cristina Hernando, Montserrat Muñoz, Laia Paré, Blanca González Farré, Pedro Fernandez, Patricia Galván, Xavier González Farré, Mafalda Oliveira, Miguel Gil Gil, Miriam Arumi, Neus Ferrer Tur, Alvaro Montaño, Yan Izarzugaza, Antonio Llombart Cussac, Raquel Bratos, Santiago González, Eduardo Martínez, Sergio Hoyos, Beatriz Rojas, Juan Antonio Virizuela, Vanesa Ortega, Rafael López, Pamela Céliz, Eva Ciruelos, Patricia Villagrasa, Aleix Prat. Primary results of SOLTI-1402/CORALLEEN phase 2 trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: An open-label, multicenter, two-arm, randomized study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS2-06.

Background: CDK4/6 inhibitors increase tumor immunogenicity in preclinical models of breast cancer and several trials combining CDK4/6 inhibitors and anti-PD1/PDL1 therapies are underway. However, immune response data in tumor samples from patients (pts) treated with CDK4/6 inhibitors are scarce. Here, we present exploratory results of the CORALLEEN trial, which evaluated the efficacy of ribociclib and endocrine therapy in patients with high-risk Luminal B disease (Gavilá et al. submitted to SABCS 2019). Methods: CORALLEEN is a randomized exploratory study in postmenopausal women with operable stage I-III breast cancer, hormone receptor positive (HR+)/HER2-negative and Luminal B by Prosigna®. Pts were randomized 1:1 to receive either 6 cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (R+L) or chemotherapy (CHT): 4 cycles of AC followed by 12 doses of weekly paclitaxel. The primary endpoint is the rate of PAM50 Risk of Relapse (ROR)-low disease at surgery in each arm. Baseline and surgical specimens were also collected for stromal tumor infiltrating lymphocyte (TIL) determination and gene expression analysis. Expression of 770 genes and 31 biological signatures were determined using the Breast360TM panel (nCounter). In order to identify genes whose expression correlated with TIL, a significance of microarrays (SAM) quantitative analysis was used with a false discovery rate (FDR) Citation Format: Nuria Chic, Blanca González Farré, Laia Paré, Tomás Pascual, Cristina Saura, Cristina Hernando, Montserrat Muñoz, Pedro Fernandez, Patricia Galván, Xavier González Farré, Mafalda Oliveira, Miguel Gil Gil, Pamela Céliz, Eva Ciruelos, Patricia Villagrasa, Joaquín Gavilá, Aleix Prat. Immune response following neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: A correlative analysis of the SOLTI-1402 CORALLEEN phase 2 randomized trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-01.

Adam Zagajewski ma ugruntowaną pozycję w hiszpańskim systemie literackim. Być może jest on najbardziej cenionym twórcą spośród zagranicznych poetów. Jego twórczość stanowi przedmiot odniesienia hiszpańskich poetów, reprezentujących różne pokolenia i kierunki. Artykuł przedstawia mechanizmy, które umożliwiały polskiemu poecie zajęcie centralnej pozycji w nowym systemie, analizuje tło i przebieg tego specyficznego transferu literackiego. Dynamic of Transfer, Displacement in Motion. Polish Poetry on the Way to Spain Adam Zagajewski is an established figure within the Spanish literary system. He might be the most admired author amongst foreign poets. His oeuvre is a reference point for Spanish poets from various generations and representing diverse literary movements. This article explores the mechanisms, which allowed the Polish poet to claim a central position in the new system and analyses the background as well as the course of this particular literary transfer.

The enormous mammal’s lifespan variation is the result of each species’ adaptations to their own biological trade-offs and ecological conditions. Comparative genomics have demonstrated that genomic factors underlying both, species lifespans and longevity of individuals, are in part shared across the tree of life. Here, we compared protein-coding regions across the mammalian phylogeny to detect individual amino acid (AA) changes shared by the most long-lived mammals and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 AA in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (P = 0.003). These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by genome-wide association studies. Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human genome-wide association studies. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan., This work was supported by AEI-PGC2018-101927-BI00 (FEDER/UE), the Spanish National Institute of Bioinformatics of the Instituto de Salud Carlos III (PT17/0009/0020), FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo), “Unidad de Excelencia María de Maeztu,” funded by the AEI (CEX2018-000792-M) and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880)., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2018-000792-M).

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression models, we present a catalogue of 35,431,441 variants, including 89,178 SVs (≥50bp), 30,325,064 SNVs and 5,017,199 indels, across 785 Illumina high coverage (30X) whole-genomes from the Iberian GCAT Cohort, containing 3.52M SNVs, 606,336 indels and 6,393 SVs in median per individual. The haplotype panel is able to impute up to 14,360,728 SNVs/indels and 23,179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.

Long and Zhang1 present empirical and conceptual objections to our results2. Concerning data, they observe that a single disease provides nearly all the support for mutation accumulation (MA). On a more theoretical note, they find no evidence for a putative prediction of antagonistic pleiotropy (AP): that at ‘each’ antagonistic pleiotropic single nucleotide polymorphism (SNP), the risk allele frequencies (RAFs) should be lower for early-onset rather than late-onset diseases., This work was supported by Ministerio de Ciencia e Innovación, Spain (with project grants BFU2015-68649-P, BFU2016-77961-P and PGC2018-101927-B-I00, MINECO/AEI/FEDER, UE), the Spanish National Institute of Bioinformatics (PT17/0009/0020), Direcció General de Recerca, Generalitat de Catalunya (2017SGR702, 2017SGR880) and the “Unidad de Excelencia María de Maeztu”, funded by the MINECO (ref: MDM-2014-0370).

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Mammals vary 100-fold in their maximum lifespan. This enormous variation is the result of the adaptations of each species to their own biological trade-offs and ecological conditions. Comparative genomics studies have demonstrated that the genomic factors underlying the lifespans of species and the longevity of individuals are shared across the tree of life. Here, we set out to compare protein-coding regions across the mammalian phylogeny, aiming to detect individual amino acid changes shared by the most long-lived mammal species and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 amino acid changes in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (p=0.003). The detected genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 amino acids, located in 996 different genes, showed a significant association with maximum lifespan in a phylogenetically controlled test. Interestingly, most of the detected amino acids positions do not vary in extant human populations (>81.2%) or have allele frequencies below 1% (99.78%), Consequently, almost none could have been detected by Genome-Wide Association Studies (GWAS). Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected by chance, successfully demonstrating for the first time that comparative genomics can be used to enhance the interpretation of human GWAS. Finally, we show that the human longevity-associated proteins coded by the detected genes are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap—pleiotropy—between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder., This work was supported by Ministerio de Ciencia e Innovación, Spain, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) with project grants BFU2016-77961-P and PGC2018-101927-B-I00 to EB and AN, respectively, by the Spanish National Institute of Bioinformatics (PT17/0009/0020 to AN), the Direcció General de Recerca, the Generalitat de Catalunya (2017SGR444 to EV, 2017SGR702 to EB and 2017SGR880 to AN) and the “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M).

The publisher Edicions del Mall made the first attempt to translate the most important poets of the 20th century into Catalan language, and suffered a clear setback, as this happened after 35 years of dictatorship in which Catalan literature was not allowed to be published officially. The publisher tried to recover normality within the literary tradition. In this context, they published the translation of an author of Lemberg, who had emigrated to Palestine and who writes in Hebrew, David Rokeah. The editor was Eduard Feliu, a prestigious translator of Hebrew and also of English and who had already translated to poets such as W.H. Auden in that same collection.The relevance already acquired by the publisher and by the translator at the time of publishing Rokeah facilitates the reception of this unknown author by the general public. The way in which the publisher is presented, as well as the para-texts, the translator’s work and the use of specific language for translation indicate that we are dealing with a case of literary translation in which the invisibility not only of the translator is fictitious, since the translated text must respond to a more literary-social action and must have a specific role within the new literary system.

Cranial sutures are growth and stress diffusion sites that connect the bones protecting the brain. The closure of cranial suture is a key feature of mammalian late development and evolution, which can also lead to head malformations when it occurs prematurely (craniosynostosis). To unveil the phenotypic and genetic causes of suture closure in evolution, we examined 48 mammalian species searching for (i) causal links between suture patency, brain size, and diet using phylogenetic path analysis; and (ii) instances of genome-phenome convergence amino acid substitutions. Here we show that brain size and the anteroposterior order of ossification of the skull are the two main causes of sutures patency in evolution. We also identified three novel candidate genes for suture closure in evolution (HRNR, KIAA1549, and TTN), which have never been reported in clinical studies of craniosynostosis. Our results suggest that different genetic pathways underlie cranial suture closure in evolution and disease.

[Abstract] The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However, copy number differences among rhesus macaques and between the human and macaque genomes, as well as the relevance of this diversity to research involving this nonhuman primate, remain understudied. Here we present a high-resolution map of sequence copy number for the rhesus macaque genome constructed from a dataset of 198 individuals. Our results show that about one-eighth of the rhesus macaque reference genome is composed of recently duplicated regions, either copy number variable regions or fixed duplications. Comparison with human genomic copy number maps based on previously published data shows that, despite overall similarities in the genome-wide distribution of these regions, there are specific differences at the chromosome level. Some of these create differences in the copy number profile between human disease genes and their rhesus macaque orthologs. Our results highlight the importance of addressing the number of copies of target genes in the design of experiments and cautions against human-centered assumptions in research conducted with model organisms. Overall, we present a genome-wide copy number map from a large sample of rhesus macaque individuals representing an important novel contribution concerning the evolution of copy number in primate genomes., [Author summary] One commonly used model organism in biomedical research is a species of Old World monkey, the rhesus macaque (Macaca mulatta). When translating biomedical research findings from rhesus macaques to humans, knowledge about the genetic differences between these two species is fundamental. In this study, we focus on copy number variation, which happens as a consequence of large duplication and deletion events in the genome, and which often has been overlooked. Copy number variation is a type of genetic variation which consists of one individual having more copies of a particular genomic region than another individual. We have performed an extensive evaluation of the copy number variants and fixed duplications among the genomes of 198 rhesus macaques and have generated a copy number map of high resolution for this species. We find that the overall pattern of within-species variation is similar to that in humans. However, when comparing specific duplicated regions between rhesus macaques and humans, we do find differences that could potentially have functional consequences. We have identified genes associated with human disease that have different copy number profiles between these two species, and therefore, we suggest avoiding human-centered assumptions in biomedical research conducted with model organisms., This work was supported in part by NIH grants R24-OD011173 to J.R., UM1-HG008898 to R.A.H., AGAUR (FI – DGR 2015) to M.B.-V., BFU2017-86471-P (MINECO/FEDER, UE), Howard Hughes International Early Career, Obra Social "La Caixa" and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880) to T.M.B. D.J. is supported by Juan de la Cierva fellowship (FJCI-2016-29558) from MICINN. In addition, we wish to acknowledge NIH grant R24-OD010962 to J. Capitanio which supported the development of the Biobehavioral Assessment resource and associated DNA samples from California NPRC rhesus macaques. We also acknowledge NIH grant support to specific National Primate Research Centers: California NPRC (OD011107) and Oregon NPRC (OD011092 and OD021324).

[EN] We introduce a version of the epistasis test in FaST-LMM for clusters of multithreaded processors. This new software maintains the sensitivity of the original FaST-LMM while delivering acceleration that is close to linear on 12-16 nodes of two recent platforms, with respect to improved implementation of FaST-LMM presented in an earlier work. This efficiency is attained through several enhancements on the original single-node version of FaST-LMM, together with the development of a message passing interface (MPI)-based version that ensures a balanced distribution of the workload as well as a multigraphics processing unit (GPU) module that can exploit the presence of multiple GPUs per node., The researchers from the Universitat Jaume I were supported by projects TIN2014-53495-R and TIN2017-82972-R of the MINECO and FEDER.

[Motivation] Association studies based on SNP arrays and Next Generation Sequencing technologies have enabled the discovery of thousands of genetic loci related to human diseases. Nevertheless, their biological interpretation is still elusive, and their medical applications limited. Recently, various tools have been developed to help bridging the gap between genomes and phenomes. To our knowledge, however none of these tools allows users to retrieve the phenotype-wide list of genetic variants that may be linked to a given disease or to visually explore the joint genetic architecture of different pathologies., [Results] We present the Genome-Phenome Explorer (GePhEx), a web-tool easing the visual exploration of phenotypic relationships supported by genetic evidences. GePhEx is primarily based on the thorough analysis of linkage disequilibrium between disease-associated variants and also considers relationships based on genes, pathways or drug-targets, leveraging on publicly available variant-disease associations to detect potential relationships between diseases. We demonstrate that GePhEx does retrieve well-known relationships as well as novel ones, and that, thus, it might help shedding light on the patho-physiological mechanisms underlying complex diseases. To this end, we investigate the potential relationship between schizophrenia and lung cancer, first detected using GePhEx and provide further evidence supporting a functional link between them., This work was supported by Ministerio de Economía y Competitividad (MINECO): BFU2015-68649-P (MINECO/FEDER, UE), and by the Agencia Estatal de investigación: AEI-PGC2018-101927-B-I00 (FEDER/UE), by Direcció General de Recerca, Generalitat de Catalunya (2017SGR880) and by the Spanish National Institute of Bioinformatics (PT17/0009/0020), the REEM (RD16/00150017) of the Instituto de Salud Carlos III. This research has also received funding from the European Union's Horizon 2020 research and innovation programme 2014–2020 under Grant Agreement N°. 634143 (MedBioinformatics).

Background The combination of trastuzumab, pertuzumab (HP) and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2-positive (HER2+) advanced breast cancer (BC). PIK3CA mutations can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mutation (mut) had a shorter PFS. The AKT inhibitor ipatasertib (IPAT) blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. We hypothesize that ipatasertib + HP is safe and can be beneficial in patients with PIK3CAmut HER2+ BC. Trial design This is an open-label, single arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP (+/- endocrine therapy [ET]) in patients with PIK3CA mut HER2+ BC. Key inclusion criteria include the presence of locally advanced/unresectable or metastatic HER2+ BC with a PIK3CA mut (detected in tissue or plasma ctDNA); candidates to receive maintenance HP (+/- ET) after taxane discontinuation in first line setting for a reason different to progressive disease; male and female (pre and postmenopausal status); adequate performance status (ECOG 0-1); and adequate bone marrow, cardiac and hepatic function. Key exclusion criteria include: active or progressive brain metastases; diabetes mellitus requiring insulin, and prior exposure to an AKT inhibitor. The primary endpoint is to define the maximum tolerated dose (MTD) and the recommended phase 2 dose of the combination. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose-limiting toxicity (DLT) during the first 28 days of treatment. Grade ≥3 diarrhea for more than 72 hours or Grade ≥2 diarrhea for more than 5 days are considered DLTs amongst others. Secondary endpoints include objective response rate, duration of response, clinical benefit rate and PFS. Exploratory objectives include identification of molecular biomarkers of response to treatment both in ctDNA (Amplicon-seq) and tumor tissue (Breast Cancer 360 panel), as well as to characterize the pharmacokinetics of study drugs. Given the low risk for overlapping toxicities, full doses of IPAT (400mg orally once daily D1-21 q28d) and standard dose HP will be used in the first cohort. Dose reductions of IPAT (300mg and 200mg) are allowed if the full dose exceeds MTD. Loperamide is given as prophylaxis for diarrhea. In HR-positive tumors, ET may be started after the DLT period. Approximately 25 evaluable patients in a given dose level will be required to assess the safety of the combination of IPAT plus HP. Patients are currently being screened for PIK3CA mutations at 7 sites in Spain. The first patient was enrolled in March 2020 and the recruitment is ongoing. This study is sponsored by SOLTI and financially supported by Roche. For further information on this trial, visit ClinicalTrials.gov (NCT04253561) Citation Format: Mafalda Oliveira, Patricia Villagrasa, Eva Ciruelos, Joaquín Gavilá, Alexandra Cortegoso, Fernando Henao, Estela Vega, Javier S. Bofill, Vanesa Quiroga, Laura García-Estevez, Serafín Morales, Pablo Tolosa, Pamela Céliz, Xavier Gonzalez Farré, Cristina Saura. Solti-1507 A phase ib study of ipatasertib and anti-her2 therapy in her2-positive advanced breast cancer with pik3ca mutation (ipather) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-35-01.

Epstein-Barr virus (EBV), human herpes virus 4, has been classically associated with infectious mononucleosis, multiple sclerosis and several types of cancers. Many of these diseases show marked geographical differences in prevalence, which points to underlying genetic and/or environmental factors. Those factors may include a different susceptibility to EBV infection and viral copy number among human populations. Since EBV is commonly used to transform B-cells into lymphoblastoid cell lines (LCLs) we hypothesize that differences in EBV copy number among individual LCLs may reflect differential susceptibility to EBV infection. To test this hypothesis, we retrieved whole-genome sequenced EBV-mapping reads from 1,753 LCL samples derived from 19 populations worldwide that were sequenced within the context of the 1000 Genomes Project. An in silico methodology was developed to estimate the number of EBV copy number in LCLs and validated these estimations by real-time PCR. After experimentally confirming that EBV relative copy number remains stable over cell passages, we performed a genome wide association analysis (GWAS) to try detecting genetic variants of the host that may be associated with EBV copy number. Our GWAS has yielded several genomic regions suggestively associated with the number of EBV genomes per cell in LCLs, unraveling promising candidate genes such as CAND1, a known inhibitor of EBV replication. While this GWAS does not unequivocally establish the degree to which genetic makeup of individuals determine viral levels within their derived LCLs, for which a larger sample size will be needed, it potentially highlighted human genes affecting EBV-related processes, which constitute interesting candidates to follow up in the context of EBV related pathologies.

Aging is a complex process affecting different species and individuals in different ways. Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity. Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity. Here, we examine the relationship between genomic variation and maximum lifespan across primate species. We used two different approaches. First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage. Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms. The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders. We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging. A second approach was focused on changes in rates of protein evolution across the primate phylogeny. Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits. These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes. Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity. This work was supported by Ministerio de Ciencia e Innovación, Spain (BFU2012-38236 and BFU2015-68649-P (MINECO/FEDER, UE) to AN), by Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866 to A.N., and 2014BP-B00157 to G.M.), by the Spanish National Institute of Bioinfomatics of the Instituto de Salud Carlos III (PT13/0001/0026), by “Unidad de Excelencia María de Maeztu”, funded by the MINECO (ref: MDM-2014-0370), and by FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo)

La valoración económica de los usos recreativos de los espacios naturales es relativamente reciente en España. La utilización del método del Coste de Viaje (MCV), como herramienta para acometer dicha valoración, ha resultado fértil en la literatura científica reciente tanto en lo que hace referencia a su variante individual como zonal. Este artículo llevará a cabo de manera inicial y novedosa la valoración económica del parque natural del Delta del Ebro a través de la variante zonal para el período 1999-2007. Los resultados obtenidos ponen de manifiesto un aumento en el valor de casi un 60%, pasando de los 4.1 millones de euros en 1999 hasta los 6.5 millones en 2007. Por otra parte, el salto en el valor en el 2005 podría atribuirse a la promoción del parque asociada a la derogación del Plan Hidrológico nacional.

Mieth, Bettina et al., The standard approach to the analysis of genome-wide association studies (GWAS) is based on testing each position in the genome individually for statistical significance of its association with the phenotype under investigation. To improve the analysis of GWAS, we propose a combination of machine learning and statistical testing that takes correlation structures within the set of SNPs under investigation in a mathematically well-controlled manner into account. The novel two-step algorithm, COMBI, first trains a support vector machine to determine a subset of candidate SNPs and then performs hypothesis tests for these SNPs together with an adequate threshold correction. Applying COMBI to data from a WTCCC study (2007) and measuring performance as replication by independent GWAS published within the 2008–2015 period, we show that our method outperforms ordinary raw p-value thresholding as well as other state-of-the-art methods. COMBI presents higher power and precision than the examined alternatives while yielding fewer false (i.e. non-replicated) and more true (i.e. replicated) discoveries when its results are validated on later GWAS studies. More than 80% of the discoveries made by COMBI upon WTCCC data have been validated by independent studies. Implementations of the COMBI method are available as a part of the GWASpi toolbox 2.0., EF acknowledges support from the advanced ERC grant (ERC-2011-AdG 295642-FEP) on the Foundation of Economic Preferences. MK, BM, and KRM were supported by the German National Science Foundation (DFG) under the grants MU 987/6-1 and RA 1894/1-1. TD and DS were supported by the German National Science Foundation (DFG) under the grants DI 1723/3-1 und SCHU 2828/2-1. GB and TS acknowledge support of the German National Science Foundation (DFG) under the research group grant FOR 1735. MK, DT, KRM, and GB acknowledge financial support by the FP7-ICT Programme of the European Community, under the PASCAL2 Network of Excellence. MK acknowledges a postdoctoral fellowship by the German Research Foundation (DFG), award KL 2698/2-1, and from the Federal Ministry of Science and Education (BMBF) awards 031L0023A and 031B0187B. AN acknowledges support from the Spanish Multiple Sclerosis Network (REEM), of the Instituto de Salud Carlos III (RD12/0032/0011), the Spanish National Institute for Bioinformatics (PT13/0001/0026) the Spanish Government Grant BFU2012-38236 and from FEDER. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 634143 (MedBioinformatics). MK and KRM were financially supported by the Ministry of Education, Science, and Technology, through the National Research Foundation of Korea under Grant R31-10008 (MK, KRM) and BK21 (KRM).

PTOV1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. The PTOV1 protein consists of two novel protein domains arranged in tandem, without significant similarities to known protein motifs. By immunohistochemical analysis, we have found that PTOV1 is overexpressed in 71% of 38 prostate carcinomas and in 80% of samples with prostate intraepithelial neoplasia. High levels of PTOV1 in tumors correlated significantly with proliferative index, as assessed by Ki67 immunoreactivity, and associated with a nuclear localization of the protein, suggesting a functional relationship between PTOV1 overexpression, proliferative status, and nuclear localization. In quiescent cultured prostate tumor cells, PTOV1 localized to the cytoplasm, being excluded from nuclei. After serum stimulation, PTOV1 partially translocated to the nucleus at the beginning of the S phase. At the end of mitosis, PTOV1 exited the nucleus. Transient transfection of chimeric green fluorescent protein-PTOV1 forced the entry of cells into the S phase of the cell cycle, as shown by double fluorescent imaging for green fluorescent protein and for Ki67, and also by flow cytometry. This was accompanied by greatly increased levels of cyclin D1 protein in the transfected cells. These observations suggest that overexpression of PTOV1 can contribute to the proliferative status of prostate tumor cells and thus to their biological behavior.

Background: Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment. Methods: Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples. Results: 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. Conclusions: Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy., The Long-HER study was supported by an unrestricted grant from Roche. AGP (CA12/00258) and RLV (CA12/00264) are supported by Instituto de Salud Carlos III, Spain. The funders had no role in study design, data analysis, decision to publish, or preparation of the manuscript.

OBJECTIVES: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-β treatment in patients with multiple sclerosis (MS). METHODS: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-β responders (n = 416) and nonresponders (n = 414) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-β response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-β responders and 274 nonresponders). RESULTS: Seven single nucleotide polymorphisms (SNPs) were selected from the screening phase for further validation: rs832032 (GABRR3; p = 0.0006), rs6597 (STUB1; p = 0.019), rs3747517 (IFIH1; p = 0.010), rs2277302 (PELI3; p = 0.017), rs10958713 (IKBKB; p = 0.003), rs2834202 (IFNAR1; p = 0.030), and rs4422395 (CXCL1; p = 0.017). None of these SNPs were significantly associated with IFN-β response when genotyped in an independent cohort of patients. Combined analysis of these SNPs in all patients with MS (N = 1,385) revealed 2 polymorphisms associated with IFN-β response: rs2277302 (PELI3; p = 0.008) and rs832032 (GABRR3; p = 0.006). CONCLUSIONS: These findings do not support an association between polymorphisms located in genes related to the type I IFN or TLR pathways or genes encoding neurotransmitter receptors and the clinical response to IFN-β. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted. SM is early stage researcher of the FP7 (2007-2013) Marie Curie Initial Training Network "UEPHA*MS" (2008-2012; Grant Agreement Number 212877). Spanish Ministry of Economy and Competitiveness, SAF/ 2012-34670, MS research, 2013-2015. Ministerio de Economía y Competitividad (MINECO) Convocatoria Proyectos de Investigación 2012 (Madrid, Spain); Funciones intracelulares de tipo-no-citoquina de las subunidades de la familia IL-12; SAF2012-32118. Dirección General de Investigación Científica y Técnica - DGICYT. Spanish Government (BFU2012-38236).

En este trabajo se lleva a cabo un análisis de la concentración temporal de la demanda turística en las provincias españolas para el período 1999-2012. El análisis se realiza a partir del uso de diferentes índices sumario, que recogen diferentes sensibilidades de las medidas en relación a la distribución temporal de la actividad, y de los datos de pernoctaciones hoteleras ofrecidos por el INE. El trabajo realiza un análisis descriptivo de la concentración provincial, de su evolución temporal y, finalmente aborda el grado de correlación entre la concentración y diferentes vectores explicativos potenciales.

To assess the prognostic value of p27 protein expression in clinically localised prostate cancer with respect to biochemical recurrence after radical prostatectomy.Fifty-two patients (median age 63 years) with prostate cancer were treated by radical prostatectomy in an 18-month period. Data recorded: preoperative PSA level, histopathological Gleason grade, pathological stage and status of surgical margins. p27 expression was evaluated in this group of tumors by immunohistochemistry (positivity was defined asor = 30% positive cells). Biochemical relapse (BR) was defined by a serum PSA levelor = 0.3 ng/ml.Twenty-two out of 47 patients (47%) with available follow-up showed a low p27 protein expression. p27 expression did not correlate with pathological stage, Gleason score, serum PSA levels or the status of the surgical margins. Patients presented with BR during the follow-up (risk of BR (RBR) at 36 months: 40%). Patients with low p27 expression showed a higher RBR than the others (RBR 36-month 59% vs. 18%, respectively; p = 0.02). In a multivariate analysis, only p27 along with stage maintained the predictive value for biochemical relapse.p27 expression is a promising prognostic factor in prostate cancer, since it has proved to be a predictor of biochemical relapse.

Cathepsins B and S (CatB, CatS) are lysosomal cysteine proteases which, among other functions, appear to play a role in cancer progression in different tumor models due to their matrix-degrading properties. To investigate their possible involvement in the development of prostate carcinoma, we immunohistochemically analyzed CatB and CatS in 38 primary human prostatic adenocarcinomas, as well as concomitant high-grade prostatic intra-epithelial neoplasia, nodular hyperplasia and normal tissue. CatB expression was observed in 28 (74%) and CatS in 32 (84%) carcinomas, being concomitant in 24 cases (63%). High-grade intra-epithelial neoplasia expressed CatB in 20/23 cases (87%), and a similar result was obtained for CatS, with expression of both coinciding in 18 cases (78%). In non-neoplastic tissue, strong expression of both proteases was observed in macrophages, inflamed glands and transitional metaplasia, whereas atrophic glands and basal cells of normal glands displayed intense CatB positivity. We conclude that CatB and CatS are often expressed together in neoplastic prostatic cells from pre-invasive to invasive and clinically detectable stages, suggesting a putative role in local invasion, though other functions cannot be ruled out.

Studies of autopsies indicate that atherosclerosis begins in childhood and is related to risk factors for coronary heart disease in the same way as for adult atherosclerosis.1 In Spain, despite risk factors for coronary heart disease being common, incidence of myocardial infarction and related mortality rates are among the lowest in the world.2 3 This paradox may be explained in two ways. One theory proposes that there is a time lag between increased consumption of animal fat and raised serum cholesterol concentrations, which have occurred more recently in Mediterranean populations than in other Western countries, and the expected increase in rates of coronary heart disease.4 An alternative explanation is that Mediterranean countries share behavioural and socioeconomic factors that prevent or delay atherogenesis.5 If this is true, the arteries of young Spaniards should be free from atheroma. We studied autopsies to evaluate the prevalence and severity of atherosclerosis in several arterial beds of young trauma victims from Barcelona. We report the results of left coronary artery evaluation. At …