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Lamin A, a product of the LMNA gene, is an essential nuclear envelope component in most differentiated cells. Mutations in LMNA have been linked to premature aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS). HGPS is caused by progerin, an aberrant form of lamin A that leads to premature death, typically from the complications of atherosclerotic disease. A key characteristic of HGPS is a severe loss of vascular smooth muscle cells (VSMCs) in the arteries. Various mouse models of HGPS have been created, but few of them feature VSMC depletion and none develops atherosclerosis, the death-causing symptom of the disease in humans. We recently generated a mouse model that recapitulates most features of HGPS, including VSMC loss and accelerated atherosclerosis. Furthermore, by generating cell-type-specific HGPS mouse models, we have demonstrated a central role of VSMC loss in progerin-induced atherosclerosis and premature death. M.R.H. is supported by a ‘Juan de la Cierva’ postdoctoral fellowship (FJCI-2017-33299) from the Spanish Ministerio de Ciencia, Innovación yUniversidades (MCIU). Work in V.A.’s laboratory is supported by grants from the Spanish Instituto de Salud Carlos III (AC16/00091 and AC17/00067) and MCIU (SAF2016-79490-R), with co-funding from the Fondo Europeo de Desarrollo Regional (FEDER, ‘Una manera de hacer Europa’), the Progeria Research Foundation (Established Investigator Award 2014-52), and the Fundació Marató TV3 (122/C/2015). The CNIC is supported by theMCIU and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505); Instituto de Salud Carlos III [AC16/00091 and AC17/00067]; MCIU [SAF2016-79490-R]; MCIU [FJCI2017-33299]; MCIU [SEV-2015-0505]; Progeria Research Foundation [2014-52]. Sí

The work was supported in part by research grants from Instituto de Salud Carlos III, Ministry of Health, Government of Spain - cofunded by FEDER (FIS PI13/00020, FIS PI17/00088, and CIBER de Epidemiologia y Salud Publica CIBERESP) ; the Hospital del Mar Medical Research Institute (IMIM) , Barcelona; the Government of Catalonia (2014 SGR 1012, 2017 SGR 439) ; Fundacio La Marato de TV3 (20132910) ; and the CRUE-Santander Fondo Supera Covid19 (15072020) . UB was supported by the Office of the Director of the National Institutes of Health under award number DP5OD26429. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Background: Few cities in the world biomonitor changes in human levels of persistent organic pollutants (POPs) through periodic health surveys representative of the general population. Objectives: To analyze changes in serum concentrations of POPs in Barcelona from 2006 to 2016, and to analyze socio-demographic correlates of concentrations of 62 POPs in 2016. Methods: Participants in the Barcelona Health Surveys of 2006 and 2016 (N = 231 and 240, respectively) were interviewed face-to-face, gave blood, and underwent a physical exam. POPs were analyzed by gas chromatography mass spectrometry. Results: Concentrations of all nine most prevalent compounds decreased markedly during the 10-years . Reductions occurred in almost all sex, age and BMI subgroups. For most organochlorine compounds the reduction was larger in women than men (for HCB, & minus;77% and & minus; 62%, respectively). For beta-HCH, PCBs, naphthalene and phenanthrene the decrease was larger in the younger groups. Large reductions in concentrations of PCBs and DDE were observed in individuals with normal weight but not in individuals with obesity. Conclusions: While concentrations of most POPs are decreasing in Barcelona, significant sociodemographic differences in such reductions warrant strengthening public and private policies towards groups making slower progress. A relevant component of the success in the current decreasing is a reduction of differences (convergence) by gender., Instituto de Salud Carlos III, Ministry of Health, Government of Spain - FEDER FIS PI13/00020 FIS PI17/00088, Instituto de Salud Carlos III, Ministry of Health, Government of Spain - FEDER (CIBER de Epidemiologia y Salud Publica CIBERESP), Hospital del Mar Medical Research Institute (IMIM) , Barcelona, Generalitat de Catalunya 2014 SGR 1012 2017 SGR 439, Fundacio La Marato de TV3 20132910, CRUE-Santander Fondo Supera Covid19 15072020, United States Department of Health & Human Services National Institutes of Health (NIH) - USA DP5OD26429

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma.Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its role in mammals. CIC is inactivated in a variety of human tumors and has been implicated recently in the promotion of lung metastases. Here, we describe a mouse model in which we inactivated Cic by selectively disabling its DNA-binding activity, a mutation that causes derepression of its target genes. Germline Cic inactivation causes perinatal lethality due to lung differentiation defects. However, its systemic inactivation in adult mice induces T-cell acute lymphoblastic lymphoma (T-ALL), a tumor type known to carry CIC mutations, albeit with low incidence. Cic inactivation in mice induces T-ALL by a mechanism involving derepression of its well-known target, Etv4. Importantly, human T-ALL also relies on ETV4 expression for maintaining its oncogenic phenotype. Moreover, Cic inactivation renders T-ALL insensitive to MEK inhibitors in both mouse and human cell lines. Finally, we show that Ras-induced mouse T-ALL as well as human T-ALL carrying mutations in the RAS/MAPK pathway display a genetic signature indicative of Cic inactivation. These observations illustrate that CIC inactivation plays a key role in this human malignancy, This work was supported by grants from the Fundació La Marató de TV3 (20131730/1) to G.J. and M.B., and the European Research Council (ERC-AG/ 250297-RAS AHEAD), the EU-Framework Programme (HEALTH-F2-2010-259770/LUNGTARGET and HEALTH-2010- 260791/EUROCANPLATFORM), the Spanish Ministry of Economy and Competitiveness (SAF2014-59864-R), the Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE), and the Asociación Española contra el Cáncer (AECC) (GC16173694BARB) to M.B. M.B. is the recipient of an Endowed Chair from the AXA Research Fund. L.S.-C. was supported by a fellowship from the Programa de Formación de Personal Investigator (FPI) of the Spanish Ministry of Economy and Competitiveness.

Background Although frailty has been associated with increased risks for hospitalization and mortality in chronic heart failure, the precise average effect remains uncertain. We performed a systematic review and meta‐analysis to summarize the hazards for mortality and incident hospitalization in patients with heart failure and frailty compared with those without frailty and explored the heterogeneity underlying the effect size estimates. Methods and Results MEDLINE , EMBASE, and Cochrane databases were queried for articles published between January 1966 and March 2018. Predefined selection criteria were used. Hazard ratios ( HRs ) were pooled for meta‐analyses, and where odds ratios were used previously, original data were recalculated for HR . Overlapping data were consolidated, and only unique data points were used. Study quality and bias were assessed. Eight studies were included for mortality (2645 patients), and 6 studies were included for incident hospitalization (2541 patients) during a median follow‐up of 1.82 and 1.12 years, respectively. Frailty was significantly associated with an increased hazard for mortality ( HR , 1.54; 95% confidence interval, 1.34–1.75; P HR , 1.56; 95% confidence interval, 1.36–1.78; P HR , 1.80; 95% confidence interval, 1.41–2.28; P HR , 1.57; 95% confidence interval, 1.30–1.89; P 2 =0%), and high quality of studies was verified by the Newcastle‐Ottawa scale. Conclusions Overall, the presence of frailty in chronic heart failure is associated with an increased hazard for death and hospitalization by ≈1.5‐fold.

Background: Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, accelerated aging and atherosclerosis, and die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part, because of the lack of appropriate animal models. Methods: We generated an atherosclerosis-prone model of HGPS by crossing apolipoprotein E–deficient ( Apoe –/– ) mice with Lmna G609G/G609G mice ubiquitously expressing progerin. To induce progerin expression specifically in macrophages or vascular smooth muscle cells (VSMCs), we crossed Apoe –/– Lmna LCS/LCS mice with LysMCre and SM22αCre mice, respectively. Progerin expression was evaluated by polymerase chain reaction and immunofluorescence. Cardiovascular alterations were determined by immunofluorescence and histology in male mice fed normal chow or a high-fat diet. In vivo low-density lipoprotein retention was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein. Cardiac electric defects were evaluated by electrocardiography. Results: Apoe –/– Lmna G609G/G609G mice with ubiquitous progerin expression exhibited a premature aging phenotype that included failure to thrive and shortened survival. In addition, high-fat diet–fed Apoe –/– Lmna G609G/G609G mice developed a severe vascular pathology, including medial VSMC loss and lipid retention, adventitial fibrosis, and accelerated atherosclerosis, thus resembling most aspects of cardiovascular disease observed in patients with HGPS. The same vascular alterations were also observed in Apoe –/– Lmna LCS/LCS SM22αCre mice expressing progerin specifically in VSMCs, but not in Apoe –/– Lmna LCS/LCS LysMCre mice with macrophage-specific progerin expression. Moreover, Apoe –/– Lmna LCS/LCS SM22αCre mice had a shortened lifespan despite the lack of any overt aging phenotype. Aortas of ubiquitously and VSMC-specific progerin-expressing mice exhibited increased retention of fluorescently labeled human low-density lipoprotein, and atheromata in both models showed vulnerable plaque features. Immunohistopathological examination indicated that Apoe –/– Lmna LCS/LCS SM22αCre mice, unlike Apoe –/– Lmna G609G/G609G mice, die of atherosclerosis-related causes. Conclusions: We have generated the first mouse model of progerin-induced atherosclerosis acceleration, and demonstrate that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan. Our results identify progerin-induced VSMC death as a major factor triggering atherosclerosis and premature death in HGPS.

The transcriptional repressor Capicua (CIC) has emerged as an important rheostat of cell growth regulated by RAS/MAPK signaling. Cic was originally discovered inDrosophila, where it was shown to be inactivated by MAPK signaling downstream of the RTKs Torso and EGFR, which results in signal-dependent responses that are required for normal cell fate specification, proliferation and survival of developing and adult tissues. CIC is highly conserved in mammals, where it is also negatively regulated by MAPK signaling. Here, we review the roles of CIC during mammalian development, tissue homeostasis, tumor formation and therapy resistance. Available data indicate that CIC is involved in multiple biological processes, including lung development, liver homeostasis, autoimmunity and neurobehavioral processes. Moreover, CIC has been shown to be involved in tumor development as a tumor suppressor, both in human as well as in mouse models. Finally, several lines of evidence implicate CIC as a determinant of sensitivity to EGFR and MAPK pathway inhibitors, suggesting that CIC may play a broader role in human cancer than originally anticipated, This work has been supported by grants from the Fundaci o La Marat ode TV3 (20131730/1) to G.J. and M.B., from the European Research Council (ERC-AG/250297-RAS AHEAD and ERC-AG/695566-THERACAN), the Autonomous Community of Madrid (S2011/BDM-2470/ONCOCYCLE) and the Foundation of the Asociaci on Espa ~ nola contra el C ancer (AECC) (GC16173694BARB) to M.B, and the Spanish Ministry of Economy and Competitiveness (SAF2014-59864-R to M.B. and BFU2014-52863-P to G.J.). M.B. is the recipient of an Endowed Chair from the AXA Research Fund. L.S.C. has been supported by a fellowship from the Programa de Formación de Personal Investigator (FPI) of the Spanish Ministry of Economy and Competitiveness.

During vertebrate cardiac development NOTCH signaling activity in the endocardium is essential for the crosstalk between endocardium and myocardium that initiates ventricular trabeculation and valve primordium formation. This crosstalk leads later to the maturation and compaction of the ventricular chambers and the morphogenesis of the cardiac valves, and its alteration may lead to disease. Although endocardial NOTCH signaling has been shown to be crucial for heart development, its physiological role in the myocardium has not been clearly established. Here we have used mouse genetics to evaluate the role of NOTCH in myocardial development. We have inactivated the unique and ubiquitous NOTCH effector RBPJ in early cardiomyocytes progenitors, and examined its consequences in cardiac development and function. Our results show that mice with Tnnt2-Cre-mediated myocardial-specific deletion of Rbpj develop to term, with homozygous mutant animals showing normal expression of cardiac development markers, and normal adult heart function. Similar observations have been obtained after Notch1 deletion with Tnnt2-Cre. We have also deleted Rbpj in both myocardial and endocardial progenitor cells, using the Nkx2.5-Cre driver, resulting in ventricular septal defect (VSD), double outlet right ventricle (DORV), and bicuspid aortic valve (BAV), due to NOTCH signaling abrogation in the endocardium of cardiac valves. Our data demonstrate that NOTCH-RBPJ inactivation in the myocardium does not affect heart development or adult cardiac function. This study was funded by grants SAF2016-78370-R, CB16/11/00399 (CIBER CV) and RD16/0011/0021 (TERCEL) from the the Spanish Ministry of Science, Innovation and Universities (MCIU) and grants from the Fundacion BBVA (Ref.: BIO14_298) and Fundacion La Marato (Ref.: 20153431) to JLDLP. AS-J holds a FPU fellowship from the Ministerio de Educacion, Cultura y Deporte of Spain. JG-B is funded by the Programa de Atraccion de Talento of the Comunidad de Madrid (2016T1/BMD1540). The cost of this publication was supported in part with FEDER funds. The CNIC (https://www.cnic.es/en) is supported by the MEIC and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

The microvasculature continuously adapts in response to pathophysiological conditions to meet tissue demands. Quantitative assessment of the dynamic changes in the coronary microvasculature is therefore crucial in enhancing our knowledge regarding the impact of cardiovascular diseases in tissue perfusion and in developing efficient angiotherapies. Using confocal microscopy and thick tissue sections, we developed a 3D fully automated pipeline that allows to precisely reconstruct the microvasculature and to extract parameters that quantify all its major features, its relation to smooth muscle actin positive cells and capillary diffusion regions. The novel pipeline was applied in the analysis of the coronary microvasculature from healthy tissue and tissue at various stages after myocardial infarction (MI) in the pig model, whose coronary vasculature closely resembles that of human tissue. We unravelled alterations in the microvasculature, particularly structural changes and angioadaptation in the aftermath of MI. In addition, we evaluated the extracted knowledge's potential for the prediction of pathophysiological conditions in tissue, using different classification schemes. The high accuracy achieved in this respect, demonstrates the ability of our approach not only to quantify and identify pathology-related changes of microvascular beds, but also to predict complex and dynamic microvascular patterns. The authors would like to thank Angel Colmenar for staining tissues for four of the subjects. The authors would also like to express their gratitude to Carlos Galan Arriola for providing us with the tissue from infarcted pigs at 45 days post MI along with the characteristics of the corresponding subjects and MRI-based estimations of blood flow. The research leading to these results has received funding from the People Programme (Marie Curie Action) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant Agreement 608027. This work was also supported by grants from the Spanish Ministry of Economy and Competitiveness SAF2014-52050-R to A.G.A., TEC2015-66978-R to A.S. and SAF2013-49663-EXP to B.I., from the Institute of Health Carlos III and the European Regional Development Fund (ERDF/FEDER) PI13/01979 to B.I., from La Marato TV3 Foundation to A.G.A., and from NIH grant R01HL101200 to A.P. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

Reperfusion alters post-myocardial infarction (MI) healing; however, very few systematic studies report the early molecular changes following ischemia/reperfusion (I/R). Alterations in the remote myocardium have also been neglected, disregarding its contribution to post-MI heart failure (HF) development. This study characterizes protein dynamics and contractile abnormalities in the ischemic and remote myocardium during one week after MI. Closed-chest 40 min I/R was performed in 20 pigs sacrificed at 120 min, 24 hours, 4days, and 7days after reperfusion (n = 5 per group). Myocardial contractility was followed up by cardiac magnetic resonance (CMR) and tissue samples were analyzed by multiplexed quantitative proteomics. At early reperfusion (120 min), the ischemic area showed a coordinated upregulation of inflammatory processes, whereas interstitial proteins, angiogenesis and cardio-renal signaling processes increased at later reperfusion (day 4 and 7). Remote myocardium showed decreased contractility at 120 min- and 24 h-CMR accompanied by transient alterations in contractile and mitochondrial proteins. Subsequent recovery of regional contractility was associated with edema formation on CMR and increases in inflammation and wound healing proteins on post-MI day 7. Our results establish for the first time the altered protein signatures in the ischemic and remote myocardium early after I/R and might have implications for new therapeutic targets to improve early post-MI remodeling. This study was supported by competitive grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (BIO2015-67580-P) through the Carlos III Institute of Health-Fondo de Investigación Sanitaria (PI13/01979 and PRB2 (IPT13/0001 - ISCIII-SGEFI/FEDER, ProteoRed)), the Fondo Europeo de Desarrollo Regional (FEDER, RD: SAF2013-49663EXP), the Fundación La Marato TV3 and in part by the FP7-PEOPLE-2013-ITN Next generation training in cardiovascular research and innovation-Cardionext. Borja Ibanez and Jesús Vázquez are supported by the Red de Investigación Cardiovascular (RIC) of the Spanish Ministry of Health (RD 12/0042/0054 and RD12/0042/0056). Rodrigo Fernández-Jiménez is a recipient of non-overlapping grants from the Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (Rio Hortega fellowship); and the Fundació Jesús Serra, the Fundación Interhospitalaria de Investigación Cardiovascular (FIC), and the CNIC (FICNIC Fellowship). Jaume Agüero, Aleksandra Binek, and Navratan Bagwan are FP7-PEOPLE-2013-ITN-Cardionext fellows. This work has been co-funded by FEDER funds. This study forms part of a Master Research Agreement (MRA) between CNIC and Philips Healthcare. The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015–0505). Sí

The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury Fil: Romero, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Holubiec, Mariana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Tornatore, Tamara Logica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina Fil: Rivière, Stéphanie. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina Fil: Hanschmann, Eva Maria. Heinrich Heine University; Argentina Fil: Kölliker Frers, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina Fil: Tau, Julia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología; Argentina Fil: Blanco, Eduardo. Universidad de Lleida; España Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Rodríguez de Fonseca, Fernando. Universidad de Málaga; España Fil: Lillig, Christopher Horst. Heinrich Heine University; Alemania Fil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina. Universidad de Chile; Chile. Universidad Argentina "John F. Kennedy"; Argentina

Sepsis still constitutes an unmet clinical need, which could benefit from novel adjunctive strategies to conventional antibiotic therapy. The soluble form of the scavenger-like human CD6 lymphocyte receptor (shCD6) binds to key pathogenic components from Gram-positive and -negative bacteria and shows time- and dose-dependent efficacy in mouse models of monobacterial sepsis. The objective of the present work was to demonstrate the effectiveness of infusing mouse and human sCD6 by different systemic routes, either alone or as adjunctive therapy to gold standard antibiotics, in a lethal model of polymicrobial sepsis. To this end, C57BL/6 mice undergoing high-grade septic shock induced by cecal ligation and puncture (CLP; ≥90% lethality) were infused via the intraperitoneal (i.p.) or intravenous (i.v.) route with shCD6 at different doses and time points, either alone or in combination with imipenem/cilastatin (I/C) at a dose of 33 mg/kg of body weight every 8 h. Significantly reduced mortality and proinflammatory cytokine levels were observed by i.p. infusion of a single shCD6 dose (1.25 mg/kg) 1 h pre- or post-CLP. When using the i.v. route, mice survival was significantly extended by starting shCD6 infusion at later time points post-CLP (up to 6 h after CLP). Significant adjunctive effects on mouse survival were observed by i.p. or i.v. infusion of shCD6 in combination with i.p. I/C post-CLP. Similar results were obtained in mice expressing high sustained levels (5 to 10 μg/ml) of mouse sCD6 in serum by means of transduction with hepatotropic adeno-associated virus (AAV). Taken together, the data support the conserved antibacterial effects of human and mouse sCD6 and their use as adjunctive therapy in experimental models of complex and severe polymicrobial sepsis., This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (Plan Nacional de I+D+i, SAF2013-46151-R), Instituto de Salud Carlos III (ISCIII)-cofinanced by European Development Regional Fund “A way to achieve Europe” ERDF (Spanish Network for Research in Infectious Diseases, REIPI, RD12/0015/0018), and Fundació La Marató TV3 (201319-30-31). F.A. is recipient of a Sara Borrell fellowship (CD15/00016) from ISCIII.

Peritoneal dialysis (PD) is a form of renal replacement therapy whose repeated use can alter dialytic function through induction of epithelial-mesenchymal transition (EMT) and fibrosis, eventually leading to PD discontinuation. The peritoneum from Cav1(-/-) mice showed increased EMT, thickness, and fibrosis. Exposure of Cav1(-/-) mice to PD fluids further increased peritoneal membrane thickness, altered permeability, and increased the number of FSP-1/cytokeratin-positive cells invading the sub-mesothelial stroma. High-throughput quantitative proteomics revealed increased abundance of collagens, FN, and laminin, as well as proteins related to TGF-beta activity in matrices derived from Cav1(-/-) cells. Lack of Cav1 was associated with hyperactivation of a MEK-ERK1/2-Snail-1 pathway that regulated the Smad2-3/Smad1-5-8 balance. Pharmacological blockade of MEK rescued E-cadherin and ZO-1 inter-cellular junction localization, reduced fibrosis, and restored peritoneal function in Cav1(-/-) mice. Moreover, treatment of human PD-patient-derived MCs with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induced re-acquisition of epithelial features. This study demonstrates a pivotal role of Cav1 in the balance of epithelial versus mesenchymal state and suggests targets for the prevention of fibrosis during PD. We thank Dr. Kurzchalia, Dr. Pol, and Dr. Lisanti for providing us MEFs from WT and Cav1-/- mice. We thank Dr. Valeria Caiolfa, head of CNIC Microscopy unit, and Elvira Arza and Antonio Manuel Santos Beneit for technical assistance. We thank Cecilia Battistelli and Marta Loureiro Lopez por technical assistance in molecular biology and proteomics, respectively. This work was supported by grants from the MINECO (Spanish Ministry of Economy and Competitivity) to MADP (SAF2008-02100, SAF2011-25047 and CONSOLIDER CSD2009-00016) and to MLC (SAF2010-21249 and SAF2013-47611R), and from Fundacio la Marato TV3 (674/C/2013) to MADP. Raffaele Strippoli was supported by a Rio Hortega Contract (Instituto de Salud Carlos III). Ignacio Benedicto was recipient of a CIBERehd fellowship (Spanish Ministry of Health and Consumer Affairs). Susana Minguet was supported by the Ramon y Cajal program (Spanish Ministry of Science and Innovation). Simon Bartlett (CNIC) provided editorial assistance. The CNIC is supported by MINECO and the Pro-CNIC Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí