iTETRIS Platform Architecture for the Integration of Cooperative Traffic and Wireless Simulations

The use of cooperative wireless communications can support driving through dynamic exchange of Vehicle-to-Vehicle (V2V) and Vehicle-to-Infrastructure (V2I) messages. Traffic applications based on such systems will be able to generate a safer, faster, cheaper and cleaner way for people and goods to move. In this context, the iTERIS project aims at providing the framework to combine traffic mobility and wireless communication simulations for large scale testing of traffic management solutions based on cooperative systems. This paper addresses the description and explanation of the implementation choices taken to build a modular and interoperable architecture integrating heterogeneous traffic and wireless simulators, and application algorithms supporting traffic management strategies. The functions of an “in-between” control system for managing correct simulation executions over the platform are presented. The inter-block interaction procedures identified to ensure optimum data transfer for simulation efficiency are also introduced

A protocol for a new methodological model for work-related shoulder complex injuries:From diagnosis to rehabilitation

Incluye 4 ficheros de datosBackground: Work-related injuries of the shoulder complex represent a challenge for clinicians because of the large variety of clinical entities involved and the broad anatomic structures that can be affected. Furthermore, commonly performed orthopedic tests have demonstrated limited accuracy for diagnosing the injury despite considerable research efforts. The aim of this study protocol is therefore to describe a comprehensive approach integrating both a clinical- and functional status-based pathology and an adapted rehabilitation prescription. Methods/Design: A longitudinal cohort study will be performed at the Department of Rehabilitation and Medical Assistance of a mutual insurance society for work-related injury management in Spain (Mutua Navarra, Pamplona, Navarra Spain). Patients will be attended by an occupational physician who specializes in work-related injuries and is part of the project team that will systematically visit all the participants. After the medical diagnosis and any requested supplementary evaluations (i.e., radiological examinations), the patients will be referred to the rehabilitation service. Before the physiotherapeutic rehabilitation program is initiated, the patients will undergo a comprehensive functional screening at the biomechanics laboratory. Using a decision-making scheme, the identified functional deficits will be used to customize the individual rehabilitation plan. Discussion: The proposed objective criteria-based shoulder diagnosis and rehabilitation model could be a new effective strategy for minimizing the time required to regain functional capacity and recover from symptoms among patients with work-related shoulder injuries

Implication of m6A mRNA Methylation in Susceptibility to Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that develops due to the interaction between genetic and environmental factors. More than 160 loci have been associated with IBD, but the functional implication of many of the associated genes remains unclear. N6-Methyladenosine (m6A) is the most abundant internal modification in mRNA. m6A methylation regulates many aspects of mRNA metabolism, playing important roles in the development of several pathologies. Interestingly, SNPs located near or within m6A motifs have been proposed as possible contributors to disease pathogenesis. We hypothesized that certain IBD-associated SNPs could regulate the function of genes involved in IBD development via m6A-dependent mechanisms. We used online available GWAS, m6A and transcriptome data to find differentially expressed genes that harbored m6A-SNPs associated with IBD. Our analysis resulted in five candidate genes corresponding to two of the major IBD subtypes: UBE2L3 and SLC22A4 for Crohn’s Disease and TCF19, C6orf47 and SNAPC4 for Ulcerative Colitis. Further analysis using in silico predictions and co-expression analyses in combination with in vitro functional studies showed that our candidate genes seem to be regulated by m6A-dependent mechanisms. These findings provide the first indication of the implication of RNA methylation events in IBD pathogenesis.This work was supported by Spanish Ministry of Science, Innovation and Universities (grant PGC2018-097573-A-I00) to A.C.-R. I.S. was funded by research project grant 2015111068 of the Basque Department of Health and a Research Grant from the European Foundation for the Study of Diabetes. M.S.-d. and I.G.-M. are predoctoral fellows funded by grants from the University of Basque Country and A.O.-G. is a predoctoral fellow funded by Basque Department of Education, Universities and Research

Postnatal exposure to mercury and neuropsychological development among preschooler children

The objective of this study was to describe the postnatal exposure to Hg and to evaluate its association with neuropsychological development among preschool children. The study population are 4–5 years old children (n = 1252) participant in the Spanish INMA Project. Total Hg was measured in cord blood and in hair samples taken at 4 years of age (2008–2012). Neuropsychological development was assessed using the McCarthy Scales of Children’s Abilities (MSCA). Information on covariates and possible confounders was obtained by questionnaires during pregnancy and childhood. Generalized additive and linear regression models were built in order to assess the relationship between MSCA scores and Hg exposure. We also evaluated the magnitude of the possible bias generated from measurement error in seafood intake estimate from questionnaire and Hg determination. The geometric mean of hair Hg was 0.98 μg/g [95% confidence interval (CI) 0.94, 1.03]. In the regression analysis, the association between Hg and the MSCA scores was positive for all the scales and statistically significant for the verbal (β = 0.89; 95%CI 0.38, 1.39), memory (β = 0.42; 95%CI 0.09, 0.76) and general cognitive scales (β = 1.35; 95%CI 0.45, 2.25). However, these associations were clearly attenuated when we adjusted by the children’s fish intake variables or when took into account theoretical scenarios of low precision in fish intake and Hg measurements. Hg levels in this Spanish population were high in comparison with other European countries; however, we did not observe adverse effects on child neuropsychological development associated with this postnatal exposure to Hg

Identification of Androgen Receptor Metabolic Correlome Reveals the Repression of Ceramide Kinase by Androgens

Prostate cancer (PCa) is one of the most prevalent cancers in men. Androgen receptor signaling plays a major role in this disease, and androgen deprivation therapy is a common therapeutic strategy in recurrent disease. Sphingolipid metabolism plays a central role in cell death, survival, and therapy resistance in cancer. Ceramide kinase (CERK) catalyzes the phosphorylation of ceramide to ceramide 1-phosphate, which regulates various cellular functions including cell growth and migration. Here we show that activated androgen receptor (AR) is a repressor of CERK expression. We undertook a bioinformatics strategy using PCa transcriptomics datasets to ascertain the metabolic alterations associated with AR activity. CERK was among the most prominent negatively correlated genes in our analysis. Interestingly, we demonstrated through various experimental approaches that activated AR reduces the mRNA expression of CERK: (i) expression of CERK is predominant in cell lines with low or negative AR activity; (ii) AR agonist and antagonist repress and induce CERK mRNA expression, respectively; (iii) orchiectomy in wildtype mice or mice with PCa (harboring prostate-specific Pten deletion) results in elevated Cerk mRNA levels in prostate tissue. Mechanistically, we found that AR represses CERK through interaction with its regulatory elements and that the transcriptional repressor EZH2 contributes to this process. In summary, we identify a repressive mode of AR that influences the expression of CERK in PCa.A.G.-M. is funded by the MINECO (SAF2016-79695-R) and the department of education (IKERTALDE IT1106-16). V.T. is funded by Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (BIO15/CA/052), the AECC J.P. Bizkaia and the Basque Department of Health (2016111109) and the MINECO RTI2018-097267-B-I00. The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the department of education (IKERTALDE IT1106-16) and health (RIS3), the MICINN (PID2019-108787RB-I00 (FEDER/EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks RED2018-102769-T), the AECC (GCTRA18006CARR), La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/ and the European Research Council (Consolidator Grant 819242). CIBERONC was co-funded with FEDER funds and funded by ISCIII

Lrf suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion

Lrf has been previously described as a powerful proto-oncogene. Here we surprisingly demonstrate that Lrf plays a critical oncosuppressive role in the prostate. Prostate specific inactivation of Lrf leads to a dramatic acceleration of Pten-loss-driven prostate tumorigenesis through a bypass of Pten-loss-induced senescence (PICS). We show that LRF physically interacts with and functionally antagonizes SOX9 transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long non-coding RNA precursor for an Rb-targeting miRNA. Inactivation of Lrf in vivo leads to Rb down-regulation, PICS bypass and invasive prostate cancer. Importantly, we found that LRF is genetically lost, as well as down-regulated at both the mRNA and protein levels in a subset of human advanced prostate cancers. Thus, we identify LRF as a context-dependent cancer gene that can act as an oncogene in some contexts but also displays oncosuppressive-like activity in Pten−/− tumors

Angiocrine polyamine production regulates adiposity.

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid β-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism.We thank members of the Endothelial Pathobiology and Microenvironment Group for helpful discussions. We thank the CERCA Program/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. The research leading to these results has received funding from la Fundación BBVA (Ayuda Fundacion BBVA a Equipos de Investigación Científica 2019, PR19BIOMET0061) and from SAF2017-82072-ERC from Ministerio de Ciencia, Innovación y Universidades (MCIU) (Spain). The laboratory of M.G. is also supported by the research grants SAF2017-89116R-P (FEDER/EU) co-funded by European Regional Developmental Fund (ERDF), a Way to Build Europe and PID2020-116184RB-I00 from MCEI; by the Catalan Government through the project 2017-SGR; PTEN Research Foundation (BRR-17-001); La Caixa Foundation (HR19-00120 and HR21-00046); by la Asociación Española contra el Cancer-Grupos Traslacionales (GCTRA18006CARR, also to A.C.); European Foundation for the Study of Diabetes/Lilly research grant, also to M.C.); and by the People Programme (Marie Curie Actions; grant agreement 317250) of the European Union’s Seventh Framework Programme FP7/2007-2013 and the Marie Skłodowska-Curie (grant agreement 675392) of the European Union’s Horizon 2020 research. The laboratory of A.C. is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and the department of education (IKERTALDE IT1106-16), the MCIU (PID2019-108787RB-I00 (FEDER/ EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT), La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17, the Vencer el Cancer foundation and the European Research Council (ERC) (consolidator grant 819242). CIBERONC was co-funded with FEDER funds and funded by Instituto de Salud Carlos III (ISCIII). The laboratory of M.C. is supported by the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya (M.C.). The laboratory of D.S. is supported by research grants from MINECO (SAF2017- 83813-C3-1-R, also to L.H., cofounded by the ERDF), CIBEROBN (CB06/03/0001), Government of Catalonia (2017SGR278) and Fundació La Marató de TV3 (201627- 30). The laboratory of R.N. is supported by FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (RTI2018-099413-B-I00 and and RED2018-102379-T), Xunta de Galicia (2016-PG057 and 2020-PG015), ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 810331), Fundación BBVA, Fundacion Atresmedia and CIBEROBN, which is an initiative of the ISCIII of Spain, which is supported by FEDER funds. The laboratory of J.A.V. is supported by research grants from MICINN (RTI2018-099250-B100) and by La Caixa Foundation (ID 100010434, LCF/PR/HR17/52150009). P.M.G.-R. is supported by ISCIII grant PI15/00701 cofinanced by the ERDF, A Way to Build Europe. Personal support was from Marie Curie ITN Actions (E.M.), Juan de la Cierva (IJCI-2015-23455, P.V.), CONICYT fellowship from Chile (S.Z.), Vetenskapsradet (Swedish Research Council, 2018-06591, L.G.) and NCI K99/R00 Pathway to Independence Award (K99CA245122, P. Castel).S

Cancer immunotherapy in special challenging populations: recommendations of the Advisory Committee of Spanish Melanoma Group (GEM)

Cancer immunotherapy based on the use of antibodies targeting the so-called checkpoint inhibitors, such as programmed cell death-1 receptor, its ligand, or CTLA-4, has shown durable clinical benefit and survival improvement in melanoma and other tumors. However, there are some special situations that could be a challenge for clinical management. Persons with chronic infections, such as HIV-1 or viral hepatitis, latent tuberculosis, or a history of solid organ transplantation, could be candidates for cancer immunotherapy, but their management requires a multidisciplinary approach. The Spanish Melanoma Group (GEM) panel in collaboration with experts in virology and immunology from different centers in Spain reviewed the literature and developed evidence-based guidelines for cancer immunotherapy management in patients with chronic infections and immunosuppression. These are the first clinical guidelines for cancer immunotherapy treatment in special challenging populations. Cancer immunotherapy in chronically infected or immunosuppressed patients is feasible but needs a multidisciplinary approach in order to decrease the risk of complications related to the coexistent comorbidities

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70-75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.info:eu-repo/semantics/publishedVersio

Frequency and Characteristics of familial melanoma in Spain: the FAM-GEM-1 Study.

Familial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain. PATIENTS AND METHODS: An observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments. RESULTS: In all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups. CONCLUSIONS: Similar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior