San Raffaele Cimena, Italy
San Raffaele Cimena, Italy

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PubMed | Karolinska Institutet, University of Bristol, Oxford Genetics, University of Maryland Baltimore County and 76 more.
Type: Journal Article | Journal: Nature genetics | Year: 2016

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

PubMed | University of Turku, Key Laboratory of Metabolism and Molecular Medicine, Finnish Institute of Occupational Health, St George's, University of London and 43 more.
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2016

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified -Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 10

PubMed | London School of Hygiene and Tropical Medicine, King Abdulaziz University, University of Western States, McGill University and 16 more.
Type: | Journal: Nature communications | Year: 2015

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 10(-11)). All common variants explain 20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

PubMed | University of Texas Southwestern Medical Center, Yale University, San Raffaele Research Institute, Michigan State University and Biomedical University of Rome
Type: | Journal: Molecular cancer therapeutics | Year: 2016

Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and-4, the receptors for Clostridium Perfringens Enterotoxin (CPE), are overexpressed in over 70% of these tumors. Here we synthesized and characterized poly(lactic-co-glycolic-acid) (PLGA) nanoparticles (NP) modified with the carboxi-terminal binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapy-resistant ovarian cancer cells. As a therapeutic payload we generated a plasmid encoding for the Diphteria Toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells. Flow cytometry and immunofluorescence demonstrated that c-CPE-NPs encapsulating the CMV GFP plasmid (CMV GFP c-CPE-NP) were significantly more efficient than control NP modified with a scrambled peptide (CMV GFP scr-NP) in transfecting primary chemotherapy-resistant ovarian tumor cell lines in vitro (p=0.03). Importantly, c-CPE-NPs encapsulating the p16 DT-A vector (p16 DT-A c-CPE-NP) were significantly more effective than control p16 DT-A scr-NP in inducing ovarian cancer cell death in vitro (% cytotoxicity: mean STDV = 32.9 0.15 and 7.45 7.93, respectively, p=0.03). In vivo bio-distribution studies demonstrated efficient transfection of tumor cells within 12 hours after intraperitoneal (IP) injection of CMV GFP c-CPE-NP in mice harboring chemotherapy-resistant ovarian cancer xenografts. Finally, multiple IP injections of p16 DT-A c-CPE-NP resulted in a significant inhibition of tumor growth compared to control NP in chemotherapy-resistant tumor-bearing mice (p=0.041). p16 DT-A c-CPE-NP may represent a novel dual-targeting therapeutic approach for the selective delivery of gene therapy to chemotherapy-resistant ovarian cancer cells.

Martinelli N.,University of Verona | Traglia M.,San Raffaele Research Institute | Campostrini N.,University of Verona | Biino G.,San Raffaele Research Institute | And 13 more authors.
PLoS ONE | Year: 2012

The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS. © 2012 Martinelli et al.

Celona B.,University of Milan | Weiner A.,Hebrew University of Jerusalem | Di Felice F.,University of Rome La Sapienza | Mancuso F.M.,IFOM IEO Campus | And 16 more authors.
PLoS Biology | Year: 2011

The basic unit of genome packaging is the nucleosome, and nucleosomes have long been proposed to restrict DNA accessibility both to damage and to transcription. Nucleosome number in cells was considered fixed, but recently aging yeast and mammalian cells were shown to contain fewer nucleosomes. We show here that mammalian cells lacking High Mobility Group Box 1 protein (HMGB1) contain a reduced amount of core, linker, and variant histones, and a correspondingly reduced number of nucleosomes, possibly because HMGB1 facilitates nucleosome assembly. Yeast nhp6 mutants lacking Nhp6a and -b proteins, which are related to HMGB1, also have a reduced amount of histones and fewer nucleosomes. Nucleosome limitation in both mammalian and yeast cells increases the sensitivity of DNA to damage, increases transcription globally, and affects the relative expression of about 10% of genes. In yeast nhp6 cells the loss of more than one nucleosome in four does not affect the location of nucleosomes and their spacing, but nucleosomal occupancy. The decrease in nucleosomal occupancy is non-uniform and can be modelled assuming that different nucleosomal sites compete for available histones. Sites with a high propensity to occupation are almost always packaged into nucleosomes both in wild type and nucleosome-depleted cells; nucleosomes on sites with low propensity to occupation are disproportionately lost in nucleosome-depleted cells. We suggest that variation in nucleosome number, by affecting nucleosomal occupancy both genomewide and gene-specifically, constitutes a novel layer of epigenetic regulation. © 2011 Celona et al.

Karnavas T.,Chromatin | Pintonello L.,San Raffaele Research Institute | Agresti A.,Chromatin | Bianchi M.E.,Chromatin
Frontiers in Physiology | Year: 2014

Mouse embryonic stem cells (ESCs) are pluripotent mammalian cells derived from the inner cell mass (ICM) of mouse blastocysts, which give rise to all three embryonic germ layers both in vivo and in vitro. Mouse ESCs have a distinct epigenetic landscape and a more decondensed chromatin compared to differentiated cells. Numerous studies have shown that distinct histone modifications in ESCs serve as hallmarks of pluripotency. However, so far it is still unknown whether the total histone content (as opposed to histone modifications) remains the same in cells of different developmental stage and differentiation capacity. In this work we show that total histone content differs between pluripotent and differentiated cells. In vitro spontaneous differentiation from ESCs to Embryoid Bodies (EBs) and directed differentiation towards neuronal and endodermal cells entails an increase in histone content. Primary MEFs also contain more histones than ESCs. We suggest that the difference in histone content is an additional hallmark of pluripotency, in addition to and besides histone modifications. © 2014 Karnavas, Pintonello, Agresti and Bianchi.

PubMed | University of Rome La Sapienza, San Raffaele Research Institute and Instituto Superiore Of Sanita
Type: | Journal: Pathogens and global health | Year: 2017

The emergence of novel strains of influenza A viruses with hemagglutinins (HAs) that are antigenically distinct from those circulating in humans, and thus have pandemic potential, pose concerns and call for the development of more broadly protective influenza vaccines. In the present study, modified vaccinia virus Ankara (MVA) encoding internal influenza antigens were evaluated for their immunogenicity and ability to protect HLA-A2.1 transgenic (AAD) mice from infection with influenza viruses.MVAs expressing NP (MVA-NP), M1 (MVA-M1) or polymerase PB1 (MVA-PB1) of A/California/4/09 (CA/09) virus were generated and used to immunize AAD mice. Antibodies and CD8+T cell responses were assessed by ELISA and ELISPOT, respectively, and challenge experiments were performed by infecting vaccinated mice with CA/09 virus.CD8+T cells specific to immunodominant and subdominant epitopes on the internal influenza proteins were elicited by MVA-based vectors in AAD mice, whereas influenza-specific antibodies were detected only in MVA-NP-immunized mice. Both M1- and NP-based MVA vaccines, regardless of whether they were applied individually or in combination, conferred protection against lethal influenza virus challenge.Our data further emphasize the promising potential of MVA vector expressing internal antigens toward the development of a universal influenza vaccine.

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