Fondazione IRCCS CaGranda Ospedale Maggiore Policlinico

Milano, Italy

Fondazione IRCCS CaGranda Ospedale Maggiore Policlinico

Milano, Italy

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Nunes J.M.,University of Geneva | Buhler S.,University of Geneva | Roessli D.,University of Geneva | Sanchez-Mazas A.,University of Geneva | And 33 more authors.
Tissue Antigens | Year: 2014

In this review, we present for the first time an integrated version of the Gene[rate] computer tools which have been developed during the last 5 years to analyse human leukocyte antigen (HLA) data in human populations, as well as the results of their application to a large dataset of 145 HLA-typed population samples from Europe and its two neighbouring areas, North Africa and West Asia, now forming part of the Gene[va] database. All these computer tools and genetic data are, from now, publicly available through a newly designed bioinformatics platform, HLA-net, here presented as a main achievement of the HLA-NET scientific programme. The Gene[rate] pipeline offers user-friendly computer tools to estimate allele and haplotype frequencies, to test Hardy-Weinberg equilibrium (HWE), selective neutrality and linkage disequilibrium, to recode HLA data, to convert file formats, to display population frequencies of chosen alleles and haplotypes in selected geographic regions, and to perform genetic comparisons among chosen sets of population samples, including new data provided by the user. Both numerical and graphical outputs are generated, the latter being highly explicit and of publication quality. All these analyses can be performed on the pipeline after scrupulous validation of the population sample's characterisation and HLA typing reporting according to HLA-NET recommendations. The Gene[va] database offers direct access to the HLA-A, -B, -C, -DQA1, -DQB1, -DRB1 and -DPB1 frequencies and summary statistics of 145 population samples having successfully passed these HLA-NET 'filters', and representing three European subregions (South-East, North-East and Central-West Europe) and two neighbouring areas (North Africa, as far as Sudan, and West Asia, as far as South India). The analysis of these data, summarized in this review, shows a substantial genetic variation at the regional level in this continental area. These results have main implications for population genetics, transplantation and epidemiological studies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 83 5 May 2014 10.1111/tan.12356 Review article Review article © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Riccio M.E.,University of Geneva | Buhler S.,University of Geneva | Nunes J.M.,University of Geneva | Vangenot C.,University of Geneva | And 38 more authors.
International Journal of Immunogenetics | Year: 2013

We present here the results of the Analysis of HLA Population Data (AHPD) project of the 16th International HLA and Immunogenetics Workshop (16IHIW) held in Liverpool in May-June 2012. Thanks to the collaboration of 25 laboratories from 18 different countries, HLA genotypic data for 59 new population samples (either well-defined populations or donor registry samples) were gathered and 55 were analysed statistically following HLA-NET recommendations. The new data included, among others, large sets of well-defined populations from north-east Europe and West Asia, as well as many donor registry data from European countries. The Gene[rate] computer tools were combined to create a Gene[rate] computer pipeline to automatically (i) estimate allele frequencies by an expectation-maximization algorithm accommodating ambiguities, (ii) estimate heterozygosity, (iii) test for Hardy-Weinberg equilibrium (HWE), (iv) test for selective neutrality, (v) generate frequency graphs and summary statistics for each sample at each locus and (vi) plot multidimensional scaling (MDS) analyses comparing the new samples with previous IHIW data. Intrapopulation analyses show that HWE is rarely rejected, while neutrality tests often indicate a significant excess of heterozygotes compared with neutral expectations. The comparison of the 16IHIW AHPD data with data collected during previous workshops (12th-15th) shows that geography is an excellent predictor of HLA genetic differentiations for HLA-A, -B and -DRB1 loci but not for HLA-DQ, whose patterns are probably more influenced by natural selection. In Europe, HLA genetic variation clearly follows a north to south-east axis despite a low level of differentiation between European, North African and West Asian populations. Pacific populations are genetically close to Austronesian-speaking South-East Asian and Taiwanese populations, in agreement with current theories on the peopling of Oceania. Thanks to this project, HLA genetic variation is more clearly defined worldwide and better interpreted in relation to human peopling history and HLA molecular evolution. © 2012 Blackwell Publishing Ltd.


Pieri L.,University of Florence | Bonadonna P.,Allergy Unit | Elena C.,University of Pavia | Papayannidis C.,University of Bologna | And 31 more authors.
American Journal of Hematology | Year: 2016

Systemic mastocytosis is a rare heterogeneous myeloproliferative neoplasm characterized by abnormal proliferation and activation of mast cells. We describe a large multicentre series of 460 adult patients with systemic mastocytosis, with a diagnosis based on WHO 2008 criteria, in a “real-life” setting of ten Italian centers with dedicated multidisciplinary programs. We included indolent forms with (n = 255) and without (n = 165) skin lesions, smouldering (n = 20), aggressive (n = 28), associated with other hematological diseases mastocytosis (n = 21) and mast cell leukemia (n = 1). This series was uniquely characterized by a substantial proportion of patients with low burden of neoplastic mast cells; notably, 38% of cases were diagnosed using only minor diagnostic criteria according to WHO 2008 classification, underlying the feasibility of early diagnosis where all diagnostic approaches are made available. This has particular clinical relevance for prevention of anaphylaxis manifestations, that were typically associated with indolent forms. In multivariate analysis, the most important features associated with shortened overall survival were disease subtype and age at diagnosis >60 years. Disease progression was correlated with mastocytosis subtype and thrombocytopenia. As many as 32% of patients with aggressive mastocytosis suffered from early evolution into acute leukemia. Overall, this study provides novel information about diagnostic approaches and current presentation of patients with SM and underlines the importance of networks and specialized centers to facilitate early diagnosis and prevent disease-associated manifestations. Am. J. Hematol. 91:692–699, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.


Fundaro C.,Luigi Sacco Hospital | Galli A.,Luigi Sacco Hospital | Paglia S.,Ospedale Maggiore Niguarda | Colombo S.,Ospedale Maggiore Niguarda | And 4 more authors.
Emergency Medicine Journal | Year: 2012

Background: Current guidelines do not provide definitive indications about the treatment in emergency departments (ED) of patients with recent-onset atrial fibrillation (AF). Methods: A multicentre observational study involving four general hospitals of the same metropolitan area was conducted. All consecutive adult patients admitted to the ED with recent symptoms of AF (<48 h duration) and discharged home were considered. Patients who underwent ED early cardioversion were enrolled in group A. Patients managed with ventricular rate control were enrolled in group B. Results: On the 24 h Holter recordings at 1-week follow-up, stable sinus rhythm was detected in 46/58 (79.3%; 95% CI 68.9 to 89.7) patients in group A and 8/33 (24.2%; 95% CI 9.6 to 38.9) patients in group B (p<0.01). Conclusion: According to the study results, rhythm at the time of ED discharge is a poor indicator of the short-term evolution of AF.


Longhi L.,University of Milan | Orsini F.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | De Blasio D.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | De Blasio D.,University of Chieti Pescara | And 6 more authors.
Critical Care Medicine | Year: 2014

Objective: Mannose-binding lectin protein is the activator of the lectin complement pathway. Goals were 1) to investigate mannose-binding lectin expression after human and experimental traumatic brain injury induced by controlled cortical impact and 2) to evaluate whether mannose-binding lectin deletion is associated with reduced sequelae after controlled cortical impact. Design: Translational research, combining a human/experimental observational study and a prospective experimental study. Setting: University hospital/research laboratory. PATIENTS AND Subjects: Brain-injured patients, C57Bl/6 mice, and mannose-binding lectin-A and mannose-binding lectin-C double-knockout (-/-) mice. Interventions: Using anti-human mannose-binding lectin antibody, we evaluated mannose-binding lectin expression in tissue samples from six patients who underwent surgery for a cerebral contusion. Immunohistochemistry was also performed on tissues obtained from mice at 30 minutes; 6, 12, 24, 48, and 96 hours; and 1 week after controlled cortical impact using anti-mouse mannose-binding lectin-A and mannose-binding lectin-C antibodies. We evaluated the effects of mannose-binding lectin deletion in wild-type and mannose-binding lectin-A and mannose-binding lectin-C double-knockout mice. Functional outcome was evaluated using the neuroscore and beam walk tests for 4 weeks postinjury (n = 11). Histological injury was evaluated by comparing neuronal cell counts in the cortex adjacent to the contusion (n = 11). Measurements and main results: Following human traumatic brain injury, we observed mannose-binding lectin-positive immunostaining in the injured cortex as early as few hours and up to 5 days postinjury. Similarly in mice, we observed mannose-binding lectin-C-positive immunoreactivity in the injured cortex beginning 30 minutes and persisting up to 1 week postinjury. The extent of mannose-binding lectin-A expression was lower when compared with that of mannose-binding lectin-C. We observed attenuated sensorimotor deficits in mannose-binding lectin (-/-) mice compared with wild-type mice at 2-4 weeks postinjury. Furthermore, we observed reduced cortical cell loss at 5 weeks postinjury in mannose-binding lectin (-/-) mice compared with wild-type mice. Conclusions: Mannose-binding lectin expression was documented after traumatic brain injury. The reduced sequelae associated with mannose-binding lectin absence suggest that mannose-binding lectin modulation might be a potential target after traumatic brain injury. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Russo M.V.,Fondazione IRCCS CaGranda Ospedale Maggiore Policlinico | Russo M.V.,University of Milan | Faversani A.,Fondazione IRCCS CaGranda Ospedale Maggiore Policlinico | Gatti S.,The Surgical Center | And 10 more authors.
Frontiers in Oncology | Year: 2015

Introduction Lung cancer remains the leading cause of tumor-related deaths, despite advances in the understanding of the disease pathogenesis and in its clinical treatment. It is crucial to develop novel technologies to discover disease biomarkers and predict individual therapy response. Materials and Methods We established 48 Patients-Derived Tumor Xenografts (PDTXs) implanted in the subrenal capsule of immunodeficient mice using thin, precision-cut tumor tissue slices, derived from 5 patients affected by Non Small Cell Lung Cancer. Twenty-six tissue slices were immediately processed and implanted at sample recovery (dPDTX), whereas the remaining sections were cultured on specific organotypic supports at 37°C and 5% CO2 for 24h before grafting (cPDTX). At sacrifice, xenografts tissue morphology, proliferation (Ki67) and histotype markers were analyzed. Oncogenic miRNAs profiles were assessed in PDTXs, human tumors and serum from one patient. Results Xenografts retained the original cancer features and there were no differences between dPDTXs and cPDTXs. Squamous Cell Carcinoma (SCC) xenografts showed a higher engraftment rate than Adenocarcinoma (AC) derived tumors. At basal time, Ki67 levels were higher in SCCs than in ACs, and the expression levels of genes associated to a stem cell-like phenotype were also more expressed in SCC samples. The analysis of oncogenic miRNAs showed that circulating miR- 19b, -21 and -210 levels were correlated with higher Ki67 expression in xenografts. Conclusion Our study implemented the PDTX model with thin, precision-cut tumor slices from small tumors, which could be useful for clinical applications and predictive purposes. The different engraftment success is likely determined by tumor histotype, high proliferation index and the expression of genes essential for cancer stem cells maintenance. Our PDTXs model could be a valid tool to expand primary tumors for the discovery of new biomarkers and explore therapeutic options. © 2015 Russo, Faversani, Gatti, Ricca, Del gobbo, Ferrero, Palleschi, Vaira and Bosari.


Magnoni S.,University of Milan | Tedesco C.,University of Milan | Carbonara M.,University of Milan | Pluderi M.,Fondazione IRCCS CaGranda Ospedale Maggiore Policlinico | And 2 more authors.
Critical Care Medicine | Year: 2012

Objective: To clarify the dynamics of glucose delivery to the brain and the effects of changes in blood glucose after severe traumatic brain injury. Design: Retrospective analysis of a prospective observational cohort study. Setting: Neurosurgical intensive care unit of a university hospital. Patients: Seventeen patients with acute traumatic brain injury monitored with cerebral and subcutaneous microdialysis. Interventions: None. Measurements and Main Results: For continuous, accurate systemic monitoring, glucose was measured in the interstitial space of subcutaneous adipose tissue using microdialysis, and 39 specific episodes of spontaneous rises in glucose were identified. During these episodes, there was a significant positive linear relationship between systemic glucose levels and brain glucose concentrations measured by microdialysis (p < .0001). The basal lactate/pyruvate ratio, with a threshold of 25, was adopted to distinguish between disturbed and presumably preserved cerebral oxidative metabolism. Using normal vs. elevated lactate/pyruvate ratio as variable factor, the relationship between brain and systemic glucose during the episodes could be described by two significantly distinct parallel lines (p = .0001), which indicates a strong additive effect of subcutaneous glucose and lactate/pyruvate ratio in determining brain glucose. The line describing the relationship under disturbed metabolic conditions was lower than in presumably intact metabolic conditions, with a significant difference of 0.648 ± 0.192 mM (p = .002). This let us to accurately predict that in this situation systemic glucose concentrations in the lower range of normality would result in critical brain glucose levels. Conclusions: The linear relationship between systemic and brain glucose in healthy subjects is preserved in traumatic brain-injured patients. As a consequence, in brain tissue where oxidative metabolism is disturbed, brain glucose concentrations might possibly drop below the critical threshold of 0.8 mM to 1.0 mM when there is a reduction in systemic glucose toward the lower limits of the "normal" range. © 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Vercellini P.,University of Milan | Bracco B.,University of Milan | Mosconi P.,Mario Negri Institute for Pharmacological Research | Roberto A.,Mario Negri Institute for Pharmacological Research | And 3 more authors.
Fertility and Sterility | Year: 2016

Objective To assess the proportion of patients satisfied with their treatment before and after a systematic change from norethindrone acetate to dienogest as the first-line progestin for symptomatic endometriosis. Design Before and after study. Setting Academic department. Patient(s) The last 90 new consecutive endometriosis patients in whom norethindrone acetate was used, and the first 90 new consecutive endometriosis patients in whom dienogest was used. Intervention(s) Norethindrone acetate at the oral dose of 2.5 mg once a day until June 6, 2013, then dienogest at the oral dose of 2 mg once a day thereafter. Main Outcome Measure(s) Degree of satisfaction with treatment after 6 months of progestin therapy and assessment of any variations in pain symptoms, psychological status, sexual function, or health-related quality of life associated with the introduction of dienogest. Result(s) The proportion of satisfied plus very satisfied women after 6 months of treatment was 71% in the "before" period (norethindrone acetate) and 72% in the "after" period (dienogest). The implementation of dienogest was not associated with statistically significant ameliorations in overall pain relief, psychological status, sexual functioning, or health-related quality of life. Treatment was well tolerated by 58% of norethindrone acetate users compared with 80% of dienogest users. After dienogest implementation, the absolute risk reduction in the occurrence of any side effect was 13.9% (95% confidence interval, 0.8%-28.6%). Conclusion(s) Considering the large difference in the cost of the two drugs, dienogest should be suggested selectively in women who do not tolerate norethindrone acetate. © 2016 American Society for Reproductive Medicine.

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