Effectiveness of Mediterranean Diet Implementation in Dry Eye Parameters: A Study of PREDIMED-PLUS Trial

This study was cofounded by grants from the Spanish Ministry of Science-Instituto de Salud Carlos III (PI17/00764) and FEDER funds. The authors wish to thank Ingrid de Ruiter, MBChB, Ph.D., for English language support.The purpose of this study is to evaluate the effect of a Mediterranean diet supplemented with extra virgin olive oil and nuts on dry eye parameters. The participants in this study were randomized into one of the two interventional arms: (1) a standard intervention group, a Mediterranean diet supplemented with extra virgin olive oil and nuts; and (2) an intensive intervention group, based on a hypocaloric Mediterranean diet and an intensive lifestyle program with physical activity and weight-loss goals. In both groups, common dry eye tests were conducted at baseline and after six months: the Ocular Surface Disease Index (OSDI), the Dry Eye Scoring System (DESS), tear break-up time (TBUT), the Schirmer’s test, and the Oxford staining grade. Sixty-seven eyes were examined. After six months, dry eye parameters improved in both groups; differences between groups were favorable for the intensive intervention group. The implementation of a Mediterranean diet pattern was beneficial for the selected patients with dry eye, and could be beneficial for patients with dry eye in general. Behavioral support for diet adherence and the promotion of healthy lifestyles (exercise) and weight loss (calorie restriction) have an added positive effect.Instituto de Salud Carlos III Spanish Government PI17/00764European Union (EU

The multifaceted roles of gasdermins in cancer biology and oncologic therapies

The involvement of the Gasdermin (GSDM) protein family in cancer and other pathologies is one of the hottest topics in biomedical research. There are six GSDMs in humans (GSDMA, B, C, D, GSDME/DFNA5 and PJVK/DFNB59) and, except PJVK, they can trigger cell death mostly by pyroptosis (a form of lytic and pro-inflammatory cell death) but also other mechanisms. The exact role of GSDMs in cancer is intricate, since depending on the biological context, these proteins have diverse cell-death dependent and independent functions, exhibit either pro-tumor or anti-tumor functions, and promote either sensitization or resistance to oncologic treatments. In this review we provide a comprehensive overview on the multifaceted roles of the GSDMs in cancer, and we critically discuss the possibilities of exploiting GSDM functions as determinants of anti-cancer treatment and as novel therapeutic targets, with special emphasis on innovative GSDM-directed nano-therapies. Finally, we discuss the issues to be resolved before GSDM-mediated oncologic therapies became a reality at the clinical levelThis study was supported by the Ministerio de Ciencia e Innovaci´on (PID2019-104644RB-I00 -GMB-), the Instituto de Salud Carlos III (CIBERONC, CB16/12/00295 –GMB-; partly supported by FEDER funds) and by the Fundaci´on Científica de la AECC (FC_AECC PROYE19036MOR -GMB-

Depth of maximum of air-shower profiles at the Pierre Auger Observatory. I. Measurements at energies above 10(17.8) eV

The successful installation, commissioning, and operation of the Pierre Auger Observatory would not have been possible without the strong commitment and effort from the technical and administrative staff in Malargue. We are very grateful to the following agencies and organizations for financial support: Comision Nacional de Energia Atomica, Fundacion Antorchas, Gobierno De La Provincia de Mendoza, Municipalidad de Malargue, NDM Holdings and Valle Las Lenas, in gratitude for their continuing cooperation over land access, Argentina; the Australian Research Council; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundacao de Amparo a Pesquisa do Estado de Rio de Janeiro (FAPERJ), Sao Paulo Research Foundation (FAPESP) Grants No. 2010/07359-6, No. 1999/05404-3, Ministerio de Ciencia e Tecnologia (MCT), Brazil; MSMT-CR LG13007, 7AMB14AR005, CZ.1.05/2.1.00/03.0058 and the Czech Science Foundation Grant No. 14-17501S, Czech Republic; Centre de Calcul IN2P3/CNRS, Centre National de la Recherche Scientifique (CNRS), Conseil Regional Ile-de-France, Departement Physique Nucleaire et Corpusculaire (PNC-IN2P3/CNRS), Departement Sciences de l'Univers (SDU-INSU/CNRS), Institut Lagrange de Paris, ILP LABEX ANR-10-LABX-63, within the Investissements d'Avenir Programme ANR-11-IDEX-0004-02, France; Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Finanzministerium Baden-Wurttemberg, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), Ministerium fur Wissenschaft und Forschung, Nordrhein Westfalen, Ministerium fur Wissenschaft, Forschung und Kunst, Baden-Wurttemberg, Germany; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Gran Sasso Center for Astroparticle Physics (CFA), CETEMPS Center of Excellence, Italy; Consejo Nacional de Ciencia y Tecnologia (CONACYT), Mexico; Ministerie van Onderwijs, Cultuur en Wetenschap, Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), Stichting voor Fundamenteel Onderzoek der Materie (FOM), Netherlands; National Centre for Research and Development, Grants No. ERA-NET-ASPERA/01/11 and No. ERA-NET-ASPERA/02/11, National Science Centre, Grants No. 2013/08/M/ST9/00322, No. 2013/08/M/ST9/00728 and No. HARMONIA 5 - 2013/10/M/ST9/00062, Poland; Portuguese national funds and FEDER funds within COMPETE - Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia, Portugal; Romanian Authority for Scientific Research ANCS, CNDI-UEFISCDI partnership projects nr. 20/2012 and nr. 194/2012, project nr. 1/ASPERA2/2012 ERA-NET, PN-II-RU-PD-2011-3-0145-17, and PN-II-RU-PD-2011-3-0062, the Minister of National Education, Programme for research - Space Technology and Advanced Research - STAR, project no. 83/2013, Romania; Slovenian Research Agency, Slovenia; Comunidad de Madrid, FEDER funds, Ministerio de Educacion y Ciencia, Xunta de Galicia, European Community 7th Framework Program, Grant No. FP7-PEOPLE-2012-IEF-328826, Spain; Science and Technology Facilities Council, U.K.; Department of Energy, Contracts No. DE-AC02-07CH11359, No. DE-FR02-04ER41300, No. DE-FG02-99ER41107 and No. DE-SC0011689, National Science Foundation, Grant No. 0450696, The Grainger Foundation, USA; NAFOSTED, Vietnam; Marie Curie-IRSES/EPLANET, European Particle Physics Latin American Network, European Union 7th Framework Program, Grant No. PIRSES-2009-GA-246806; and UNESCO.We report a study of the distributions of the depth of maximum, Xmax, of extensive air-shower profiles with energies above 1017.8  eV as observed with the fluorescence telescopes of the Pierre Auger Observatory. The analysis method for selecting a data sample with minimal sampling bias is described in detail as well as the experimental cross-checks and systematic uncertainties. Furthermore, we discuss the detector acceptance and the resolution of the Xmax measurement and provide parametrizations thereof as a function of energy. The energy dependence of the mean and standard deviation of the Xmax distributions are compared to air-shower simulations for different nuclear primaries and interpreted in terms of the mean and variance of the logarithmic mass distribution at the top of the atmosphere.Comision Nacional de Energia AtomicaFundacion AntorchasGobierno De La Provincia de MendozaMunicipalidad de MalargueNDM HoldingsValle Las LenasAustralian Research CouncilNational Council for Scientific and Technological Development (CNPq)Ciencia Tecnologia e Inovacao (FINEP)Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2010/07359-6 1999/05404-3Ministerio de Ciencia e Tecnologia (MCT), BrazilGrant Agency of the Czech Republic Czech Republic Government 14-17501SCentre National de la Recherche Scientifique (CNRS)Region Ile-de-FranceDepartement Sciences de l'Univers (SDU-INSU/CNRS)Institut Lagrange de ParisFrench National Research Agency (ANR) ANR-10-LABX-63 ANR-11-IDEX-0004-02Federal Ministry of Education & Research (BMBF)German Research Foundation (DFG)Finanzministerium Baden-WurttembergHelmholtz AssociationMinisterium fur Wissenschaft und ForschungNordrhein WestfalenMinisterium fur WissenschaftForschung und KunstBaden-Wurttemberg, GermanyIstituto Nazionale di Fisica Nucleare (INFN)Ministry of Education, Universities and Research (MIUR)Gran Sasso Center for Astroparticle Physics (CFA)CETEMPS Center of Excellence, ItalyConsejo Nacional de Ciencia y Tecnologia (CONACyT)Ministerie van Onderwijs, Cultuur en WetenschapNetherlands Organization for Scientific Research (NWO)FOM (The Netherlands) Netherlands GovernmentNational Centre for Research and Development ERA-NET-ASPERA/01/11 ERA-NET-ASPERA/02/11National Science Centre, Poland 2013/08/M/ST9/00322 2013/08/M/ST9/00728 HARMONIA 5 - 2013/10/M/ST9/00062Portuguese national funds within COMPETE - Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia, PortugalFEDER funds within COMPETE - Programa Operacional Factores de Competitividade through Fundacao para a Ciencia e a Tecnologia, PortugalRomanian Authority for Scientific Research ANCSCNDI-UEFISCDI 20/2012 194/2012 1/ASPERA2/2012 ERA-NET PN-II-RU-PD-2011-3-0145-17 PN-II-RU-PD-2011-3-0062Minister of National Education, Programme for research - Space Technology and Advanced Research - STAR, Romania 83/2013Slovenian Research Agency - SloveniaComunidad de Madrid Instituto de Salud Carlos IIIEuropean Union (EU)Spanish GovernmentXunta de GaliciaEuropean Community 7th Framework Program, Spain FP7-PEOPLE-2012-IEF-328826Science & Technology Facilities Council (STFC)United States Department of Energy (DOE) DE-AC02-07CH11359 DE-FR02-04ER41300 DE-FG02-99ER41107 DE-SC0011689National Science Foundation (NSF) 0450696Grainger Foundation, USANational Foundation for Science & Technology Development (NAFOSTED)European Union (EU) PIRSES-2009-GA-246806UNESCOMSMT-CR LG130077AMB14AR005CZ.1.05/2.1.00/03.005

Undercarboxylated Osteocalcin: A Promising Target for Early Diagnosis of Cardiovascular and Glycemic Disorders in Patients with Metabolic Syndrome: A Pilot Study

Lifestyle changes are causing an exponential increase in the prevalence of obesity and metabolic syndrome (MetS) worldwide. The most frequent complications of these are the development of diabetes (T2D) and cardiovascular disease (CVD). Accurate tools are needed to classify the cardiovascular risk (CVR) in the MetS population. In recent years, numerous biomarkers of bone metabolism have been associated with CVR. The aim of this study was to determine the levels of undercarboxylated osteocalcin (ucOC) in a cohort of patients with MetS and to analyse its association with MetS parameters and CVR as well as with T2D prevalence. A longitudinal study was conducted in which a MetS population was followed for one year. Weight change, adherence to the Mediterranean diet (MedDiet), ucOC levels, MetS parameters and CVR were analysed and CVR was calculated using different scores. Our results showed a decrease of CVR associated with a better adherence to the MetDiet resulting in higher HDL-C and ucOC levels though the improvement of MetS risk factors. This bone protein appeared as a potential biomarker to classify CVR in the MetS population, especially for MetS patients without prevalent T2D. Furthermore, ucOC serum levels could be good predictors of T2D prevalence.Instituto de Salud Carlos III European Commission PI18-00803 PI21/01069 PI18-01235 FI19/00118 CD20/00022European CommissionJunta de Andalucia CD20/00022 PI-0268-2019 RH-0069202

Adecuación Nutricional y Adherencia a la Dieta Mediterránea y su Asociación con Hábitos de Vida de Estudiantes de Medicina: Un Estudio Transversal Descriptivo

Introducción. A pesar de que la etapa universitaria es crucial para la adquisición de hábitos de vida que pueden repercutir en el estado de salud, se ha evidenciado una alimentación inadecuada en esta población. Objetivos. (1) Estudiar el nivel de adecuación a las recomendaciones de ingesta alimentarias en estudiantes de medicina, (2) determinar la adhesión a la Dieta Mediterránea (Diet Med) y (3) determinar las variables asociadas con el cumplimiento de las recomendaciones dietéticas. Metodología. Estudio descriptivo transversal. Se analizó la ingesta dietética de 225 estudiantes de medicina mediante un cuestionario de frecuencia de alimentos. Se calculó la ingesta de nutrientes mediante la utilización de tablas de composición de alimentos y el porcentaje de cumplimiento de micronutrientes (RDI para población adulta española). Se determinó la adhesión a la Diet Med y el riesgo cardiovascular. Se realizaron modelos regresión logística múltiple con objeto de determinar las variables asociadas con la adecuación nutricional. Resultados. Los estudiantes de medicina muestran una baja adhesión a la Diet Med así como una baja frecuencia del cumplimiento de las RDI de vitamina A, D y calcio. El cumplimiento con las recomendaciones se asoció positivamente con variables como el sexo femenino y la Diet Med en el caso de las recomendaciones de vitamina A, mientras que un mayor IMC y sedentarismo se asociaron negativamente con las de vitamina D. Conclusiones. Los hábitos alimentarios de los estudiantes de medicina pueden considerarse poco saludables, por lo que deben priorizarse intervenciones educativas y conductuales para mejorar el estilo de vida de esta población.  Financiación. B.R.-G. is a Postdoctoral Investigator funded by the Junta de Andalucía (ref. RH-0069-2021)

Bacterial density rather than diversity correlates with hatching success across different avian species

We thank Rosario Millán for technical assistance; Liesbeth de Neve, María Roldán, Juan Rodríguez-Ruiz, Deseada Parejo, Magdalena Ruiz-Rodríguez and Carlos Navarro for sampling nests of some species. We also thank the efforts and comments of two anonymous reviewers that have greatly improved the manuscript. Bird and egg manipulations were performed under the authorization of Junta de Andalucía - Consejería de Medio Ambiente (permit No. SGYB-AFR-CMM, February 19th 2007).Bacterial communities within avian nests are considered an important determinant of egg viability, potentially selecting for traits that confer embryos with protection against trans-shell infection. A high bacterial density on the eggshell increases hatching failure, whether this effect could be due to changes in bacterial community or just a general increase in bacterial density. We explored this idea using intra- and interspecific comparisons of the relationship between hatching success and eggshell bacteria characterized by culture and molecular techniques (fingerprinting and high-throughput sequencing). We collected information for 152 nests belonging to 17 bird species. Hatching failures occurred more frequently in nests with higher density of aerobic mesophilic bacteria on their eggshells. Bacterial community was also related to hatching success, but only when minority bacterial operational taxonomic units were considered. These findings support the hypothesis that bacterial density is a selective agent of embryo viability, and hence a proxy of hatching failure only within species. Although different avian species hold different bacterial densities or assemblages on their eggs, the association between bacteria and hatching success was similar for different species. This result suggests that interspecific differences in antibacterial defenses are responsible for keeping the hatching success at similar levels in different species.Funding was provided by Ministerio de Educación y Ciencia and European founds (FEDER) [CGL2007-61251, CGL2010-19233-C03- 01, CGL2010-19233-C03-03]. JMPS was funded by Ministerio de Educación and Consejería de Innovación, Ciencia y Empresa under International Excellence Campus Program, University of Granada (CEI Granada 2009). RK was supported in part by the Howard Hughes Medical Institute. The Earth Microbiome Project was supported in part by the John Templeton Foundation and the W.M. Keck Foundation

IgE-reactivity pattern of tomato seed and peel nonspecific lipid-transfer proteins after in vitro gastrointestinal digestion

The influence of gastrointestinal digestion on the immunological properties of three different nonspecific lipid-transfer proteins (nsLTPs) described in tomato fruit has been assessed using an in vitro system mimicking the stomach and intestine digestion conditions. Tomato peel/pulp nsLTP, Sola l 3, was degraded after digestion, although the immunoglobulin E (IgE) recognition of intact protein and a 10 kDa band were still observed after 30 min of duodenal digestion in the presence of phosphatidylcholine. The tomato seed nsLTP, Sola l 7, showed a higher stability than the other seed allergen, Sola l 6, during digestion. Sola l 7 showed an IgE immunoreactive 6.5 kDa band in immunoblotting analysis, retaining up to 7% of its IgE-binding capacity in inhibition ELISA test after 60 min of duodenal digestion and keeping intact its ability to activate basophils after digestion. These results suggest that the tomato seed allergen Sola l 7 might be considered as an important allergen in the induction of allergic responses to tomato due to its high stability against gastrointestinal digestion.This work was supported by grants SAF2017-86483-R from the Ministerio de Economía y Competitividad and PI13/00928 Instituto de Salud Carlos III (ISCIII), ISCIII cofounded by Fondo Europeo de Desarrollo Regional – FEDER for the Thematic Networks and Co-operative Research Centres; RIRAAF RD16/0006/0024 and ARADyAL (RD16/0006/0001; RD16/0006/0013; RD16/0006/0014); and EAACI Exchange Research Fellowship 2016. The authors would like to thank the excellent technical support of Sara Abián. S.B. was supported by a Juan de la Cierva Incorporación contract from the Spanish Ministerio de Ciencia, Innovación y Universidades.Peer reviewe

Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation

Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome. The online version contains supplementary material available at 10.1186/s13046-022-02497-w

Incidence and Prognosis of Colorectal Cancer After Heart Transplantation: Data From the Spanish Post-Heart Transplant Tumor Registry

In this observational and multicenter study, that included all patients who underwent a heart transplantation (HT) in Spain from 1984 to 2018, we analyzed the incidence, management, and prognosis of colorectal cancer (CRC) after HT. Of 6,244 patients with a HT and a median follow-up of 8.8 years since the procedure, 116 CRC cases (11.5% of noncutaneous solid cancers other than lymphoma registered) were diagnosed, mainly adenocarcinomas, after a mean of 9.3 years post-HT. The incidence of CRC increased with age at HT from 56.6 per 100,000 person-years among under 45 year olds to 436.4 per 100,000 person-years among over 64 year olds. The incidence rates for age-at-diagnosis groups were significantly greater than those estimated for the general Spanish population. Curative surgery, performed for 62 of 74 operable tumors, increased the probability of patient survival since a diagnosis of CRC, from 31.6% to 75.7% at 2 years, and from 15.8% to 48.6% at 5 years, compared to patients with inoperable tumors. Our results suggest that the incidence of CRC among HT patients is greater than in the general population, increasing with age at HT

Multiplex RNA-based detection of clinically relevant MET alterations in advanced non-small cell lung cancer

We studied MET alterations in 474 advanced non-small-cell lung cancer (NSCLC) patients by nCounter, an RNA-based technique. We identified 3% with MET Δex14 mRNA and 3.5% with very-high MET mRNA expression, a surrogate of MET amplification. MET alterations identified by nCounter correlated with clinical benefit from MET inhibitors. Quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies. MET inhibitors have shown activity in non-small-cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (METΔex14). However, patient stratification is imperfect, and thus, response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with MET Δex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally coexist with other drivers. For MET Δex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very-high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies