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2. Tissue fluidification promotes a cGAS–STING cytosolic DNA response in invasive breast cancer

Author

Frittoli E., Palamidessi A., Iannelli F., Zanardi F., Villa S., Barzaghi L., Abdo H., Cancila V., Beznoussenko G. V., Della Chiara G., Pagani M., Malinverno C., Bhattacharya D., Pisati F., Yu W., Galimberti V., Bonizzi G., Martini E., Mironov A. A., Gioia U., Ascione F., Li Q., Havas K., Magni S., Lavagnino Z., Pennacchio F. A., Maiuri P., Caponi S., Mattarelli M., Martino S., d'Adda di Fagagna F., Rossi C., Lucioni M., Tancredi R., Pedrazzoli P., Vecchione A., Petrini C., Ferrari F., Lanzuolo C., Bertalot G., Nader G., Foiani M., Piel M., Cerbino R., Giavazzi F., Tripodo C., Scita G., Frittoli, E., Palamidessi, A., Iannelli, F., Zanardi, F., Villa, S., Barzaghi, L., Abdo, H., Cancila, V., Beznoussenko, G. V., Della Chiara, G., Pagani, M., Malinverno, C., Bhattacharya, D., Pisati, F., Yu, W., Galimberti, V., Bonizzi, G., Martini, E., Mironov, A. A., Gioia, U., Ascione, F., Li, Q., Havas, K., Magni, S., Lavagnino, Z., Pennacchio, F. A., Maiuri, P., Caponi, S., Mattarelli, M., Martino, S., d'Adda di Fagagna, F., Rossi, C., Lucioni, M., Tancredi, R., Pedrazzoli, P., Vecchione, A., Petrini, C., Ferrari, F., Lanzuolo, C., Bertalot, G., Nader, G., Foiani, M., Piel, M., Cerbino, R., Giavazzi, F., Tripodo, C., and Scita, G.

Abstract

The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.

Published
2023

3. Author Correction: Tissue fluidification promotes a cGAS–STING cytosolic DNA response in invasive breast cancer (Nature Materials, (2022), 10.1038/s41563-022-01431-x)

Author

Frittoli E., Palamidessi A., Iannelli F., Zanardi F., Villa S., Barzaghi L., Abdo H., Cancila V., Beznoussenko G. V., Della Chiara G., Pagani M., Malinverno C., Bhattacharya D., Pisati F., Yu W., Galimberti V., Bonizzi G., Martini E., Mironov A. A., Gioia U., Ascione F., Li Q., Havas K., Magni S., Lavagnino Z., Pennacchio F. A., Maiuri P., Caponi S., Mattarelli M., Martino S., d'Adda di Fagagna F., Rossi C., Lucioni M., Tancredi R., Pedrazzoli P., Vecchione A., Petrini C., Ferrari F., Lanzuolo C., Bertalot G., Nader G., Foiani M., Piel M., Cerbino R., Giavazzi F., Tripodo C., Scita G., Frittoli E., Palamidessi A., Iannelli F., Zanardi F., Villa S., Barzaghi L., Abdo H., Cancila V., Beznoussenko G.V., Della Chiara G., Pagani M., Malinverno C., Bhattacharya D., Pisati F., Yu W., Galimberti V., Bonizzi G., Martini E., Mironov A.A., Gioia U., Ascione F., Li Q., Havas K., Magni S., Lavagnino Z., Pennacchio F.A., Maiuri P., Caponi S., Mattarelli M., Martino S., d'Adda di Fagagna F., Rossi C., Lucioni M., Tancredi R., Pedrazzoli P., Vecchione A., Petrini C., Ferrari F., Lanzuolo C., Bertalot G., Nader G., Foiani M., Piel M., Cerbino R., Giavazzi F., Tripodo C., and Scita G.

Subjects
c-gas, Settore MED/05 - Patologia Clinica, Settore MED/08 - Anatomia Patologica
Abstract

In the version of this article initially published, the first name of Flora Ascione was listed as “Floriana”; the error has been corrected in the HTML and PDF versions of the article.

Published
2023

6. Transcriptome signatures from discordant sibling pairs reveal changes in peripheral blood immune cell composition in Autism Spectrum Disorder

Author

Filosi, Michele, Kam-Thong, Tony, Essioux, Laurent, Muglia, Pierandrea, Trabetti, Elisabetta, Spooren, Will, Müller-Myshok, Bertram, Domenici, EnricoAlibrio G, Anchisi L, Andruccioli M, Benvenuto A, Battistella PA, Boscaini F, Bravaccio C, Ceppi E, Cosentino D, Curatolo P, Da Ros L, Bernardina BD, De Giacomo A, Di Vita G, Domenici E, Elia M, Gitti F, Grittani S, Lamanna AL, Mani E, Manzi B, Margari L, Masi G, Molteni M, Muglia P, Nardocci F, Pascotto A, Parmeggiani A, Pignatti PF, Piroddi T, Prandini P, Ratti E, Rizzini P, Russo S, Scifo R, Tancredi R, Tiberti A, Trabetti E, Zoccante L, Zuddas A., Michele Filosi , Tony Kam-Thong , Laurent Essioux , Pierandrea Muglia , Elisabetta Trabetti , Will Spooren , Bertram Müller-Myshok , Italian Autism Network, Enrico Domenici, Antonia Parmeggiani, Filosi, Michele, Kam-Thong, Tony, Essioux, Laurent, Muglia, Pierandrea, Trabetti, Elisabetta, Spooren, Will, Müller-Myshok, Bertram, Domenici, Enricoalibrio, G, Anchisi, L, Andruccioli, M, Benvenuto, A, Battistella, Pa, Boscaini, F, Bravaccio, C, Ceppi, E, Cosentino, D, Curatolo, P, Da Ros, L, Bernardina, Bd, De Giacomo, A, Di Vita, G, Domenici, E, Elia, M, Gitti, F, Grittani, S, Lamanna, Al, Mani, E, Manzi, B, Margari, L, Masi, G, Molteni, M, Muglia, P, Nardocci, F, Pascotto, A, Parmeggiani, A, Pignatti, Pf, Piroddi, T, Prandini, P, Ratti, E, Rizzini, P, Russo, S, Scifo, R, Tancredi, R, Tiberti, A, Trabetti, E, Zoccante, L, and Zuddas, A.

Subjects
0301 basic medicine, Autism Spectrum Disorder, autism spectrum disorders, Biology, Molecular neuroscience, Peripheral blood mononuclear cell, Article, lcsh:RC321-571, Transcriptome, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, transcriptomic signatures, mental disorders, medicine, Humans, Allele, Sibling, Autistic Disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Genetics, Autism, genetics, neuroscience, Blood Cells, Siblings, medicine.disease, Gene expression profiling, Psychiatry and Mental health, 030104 developmental biology, Asperger syndrome, Autism spectrum disorder, Autism, 030217 neurology & neurosurgery, Biomarkers
Abstract

Notwithstanding several research efforts in the past years, robust and replicable molecular signatures for autism spectrum disorders from peripheral blood remain elusive. The available literature on blood transcriptome in ASD suggests that through accurate experimental design it is possible to extract important information on the disease pathophysiology at the peripheral level. Here we exploit the availability of a resource for molecular biomarkers in ASD, the Italian Autism Network (ITAN) collection, for the investigation of transcriptomic signatures in ASD based on a discordant sibling pair design. Whole blood samples from 75 discordant sibling pairs selected from the ITAN network where submitted to RNASeq analysis and data analyzed by complementary approaches. Overall, differences in gene expression between affected and unaffected siblings were small. In order to assess the contribution of differences in the relative proportion of blood cells between discordant siblings, we have applied two different cell deconvolution algorithms, showing that the observed molecular signatures mainly reflect changes in peripheral blood immune cell composition, in particular NK cells. The results obtained by the cell deconvolution approach are supported by the analysis performed by WGCNA. Our report describes the largest differential gene expression profiling in peripheral blood of ASD subjects and controls conducted by RNASeq. The observed signatures are consistent with the hypothesis of immune alterations in autism and an increased risk of developing autism in subjects exposed to prenatal infections or stress. Our study also points to a potential role of NMUR1, HMGB3, and PTPRN2 in ASD.

Published
2020

9. THE RESILIENCE OF ONCOLOGISTS DURING THE EARLY TIME OF THE COVID-19 PANDEMIC

Author

Lasagna, A., primary, Secondino, S., additional, Agustoni, F., additional, Monaco, T., additional, Imarisio, I., additional, Pagani, A., additional, Rizzo, G., additional, Tancredi, R. J., additional, Pozzi, E., additional, Ferraris, E., additional, Chiellino, S., additional, Gandini, C., additional, Ferrari, A., additional, Brugnatelli, S. G., additional, and Pedrazzoli, P., additional

Published
2021
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10. 925TiP The efficacy of immunonutrition in improving tolerance to chemoradiotherapy in patients with head and neck cancer, receiving nutritional counseling: Study protocol of a randomized, open-label, parallel group, bicentric pilot study

Author

Tancredi, R., primary, Cereda, E., additional, Klersy, C., additional, Nardi, M.T., additional, Masi, S., additional, Crotti, S., additional, Caissutti, V., additional, Brovia, C., additional, Bonzano, E., additional, Comoli, P., additional, Catenacci, L., additional, Imarisio, I., additional, Bossi, P., additional, Ghi, M.G., additional, Pedrazzoli, P., additional, and Caccialanza, R., additional

Published
2021
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11. Introduction and methods of the evidence-based guidelines for the diagnosis and management of autism spectrum disorder by the Italian National Institute of Health

Author

Morgano, G. P., Fulceri, F., Nardocci, F., Barbui, C., Ostuzzi, G., Papola, D., Fatta, L. M., Fauci, A. J., Coclite, D., Napoletano, A., De Crescenzo, F., D'Alo, G. L., Amato, L., Cinquini, M., Iannone, P., Schunemann, H. J., Scattoni, M. L., Arduino, M., Bellosio, C., Biasci, S., Buono, S., Cappa, C., Cordo, C., Di Tommaso, E., Duff, C. M., Felici, C., Massagli, A., Molteni, M., Reali, L., Tancredi, R., Valeri, G., Venturini, L., Zuddas, A., Andreoli, M., Bergamin, C., Bertelli, M., Catania, D., Cavagnola, R., Cirrincione, P., Corti, S., Crognale, M., Faggioli, R., Giogoli, A. M., Grittani, S., Keller, R., Pace, P., Politi, P., Starace, F., Valenti, M., Balduzzi, S., Basile, M., Cruciani, F., D'Amico, R., Davoli, M., Lorenzo, M. G., Minozzi, S., Mitrova, Z., Moschetti, I., Pistotti, V., Saulle, R., and Vecchi, S.

Subjects
Adult, Male, Evidence-based practice, Adolescent, Autism Spectrum Disorder, Psychological intervention, Guideline, Recommendations, lcsh:Computer applications to medicine. Medical informatics, 03 medical and health sciences, 0302 clinical medicine, Diagnosis, medicine, Humans, 030212 general & internal medicine, Patient Reported Outcome Measures, Autism Spectrum disorder, GRADE approach, Healthcare decision, Italian National Institute of health, Italian national guidelines system, Treatment, Grading (education), Child, Medical education, Evidence-Based Medicine, Research, Public Health, Environmental and Occupational Health, Conflict of interest, Stakeholder, Italy, Quality of Life, Practice Guidelines as Topic, General Medicine, Evidence-based medicine, medicine.disease, Autism spectrum disorder, ComputingMilieux_COMPUTERSANDSOCIETY, lcsh:R858-859.7, Psychology, 030217 neurology & neurosurgery
Abstract

Background Autism Spectrum Disorder (ASD) is a neuro-developmental disorder that affects communication and behavior with a prevalence of approximately 1% worldwide. Health outcomes of interventions for ASD are largely Participant Reported Outcomes (PROs). Specific guidelines can help support the best care for people with ASD to optimize these health outcomes but they have to adhere to standards for their development to be trustworthy. Objective The goal of this article is to describe the new methodological standards of the Italian National Institute of Health and novel aspects of this guideline development process. This article will serve as a reference standard for future guideline development in the Italian setting. Methods We applied the new standards of the Italian National Institute of Health to the two guidelines on diagnosis and management of children/adolescents and adults with ASD, with a focus on the scoping, panel composition, management of conflict of interest, generation and prioritization of research questions, early stakeholders’ involvement, and PROs. Recommendations are based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision frameworks. Results Following a public application process, the ISS established two multidisciplinary panels including people with ASD and/or their caregivers. Seventy-nine research questions were identified as potentially relevant for the guideline on children and adolescents with ASD and 31 for the one on adults with ASD. Questions deemed to have the highest priority were selected for inclusion in the guidelines. Other stakeholders valued their early involvement in the process which will largely focus on PROs. The panels then successfully piloted the development of recommendations using the methodological standards and process set by the ISS with a focus on PROs. Conclusions In this article, we describe the development of practice guidelines that focus on PROs for the diagnosis and management of ASD based on novel methods for question prioritization and stakeholder involvement. The recommendations allow for the adoption or adaptation to international settings.

Published
2020

12. Neoadjuvant chemotherapy followed by fast-track cytoreductive surgery plus short-course hyperthermic intraperitoneal chemotherapy (HIPEC) in advanced ovarian cancer: preliminary results of a promising all-in-one approach

Author

Batista TP, Carneiro VCG, Tancredi R, Teles ALB, Badiglian-Filho L, and Leão CS

Subjects
Surgical Procedures, Drug Therapy, Induced, Intraperitoneal, Hyperthermia, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Operative, lcsh:RC254-282, Peritoneal Neoplasms, Injections
Abstract

Thales Paulo Batista,1,2 Vandré Cabral G Carneiro,1,3 Rodrigo Tancredi,4,5 Ana Ligia Bezerra Teles,6 Levon Badiglian-Filho,7 Cristiano Souza Leão8 1Department of Surgery/Oncology, IMIP – Instituto de Medicina Integral Professor Fernando Figueira, 2Department of Surgery, UFPE – Universidade Federal de Pernambuco, 3Department of Gynecology, HCP – Hospital de Câncer de Pernambuco, 4Department of Clinical Oncology, IMIP – Instituto de Medicina Integral Professor Fernando Figueira, 5Department of Clinical Oncology, HCP – Hospital de Câncer de Pernambuco, 6Department of Anaesthesiology, IMIP – Instituto de Medicina Integral Professor Fernando Figueira, Recife, 7Department of Gynecology, AC Camargo Cancer Center, Sao Paulo, 8Department of Surgery, IMIP – Instituto de Medicina Integral Professor Fernando Figueira, Recife, Brazil Purpose: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered a promising treatment option for advanced or recurrent ovarian cancer, but there is no clear evidence based on randomized controlled trials to advocate this approach as a standard therapy. In this study, we aim to present the early outcomes and insights after an interim analysis of a pioneering clinical trial in Brazil.Methods: This study was a cross-sectional analysis of early data from our ongoing clinical trial – an open-label, double-center, single-arm trial on the safety and efficacy of using HIPEC for advanced ovarian cancer (ClinicalTrials.gov: NCT02249013). A fast-track recovery strategy was also applied to improve patient outcomes.Results: Nine patients with stage IIIB (n=1) or IIIC (n=8) epithelial malignancies were enrolled until February 2017. The median (range) serum CA125 level at diagnosis was 692 (223.7–6550) U/mL. The median number of preoperative cycles of intravenous (i.v.) chemotherapy was 3 (2–4), resulting in peritoneal cancer index scores of 9 (3–18) at the time of HIPEC. Time of restarting i.v. chemotherapy was 37 (33–50) days with all patients completing 6 cycles as planned. The median operation time was 395 (235–760) minutes, the length of hospital stay was 4 (3–10) days, and all the patients left the ICU on the morning after the procedure. Two patients experienced no postoperative complications, whereas 91% of the complications were minor G1/G2 events. Preliminary assessment also suggested no impairment of the patient’s quality of life.Conclusion: Our comprehensive protocol might represent a promising all-in-one approach for advanced ovarian cancer. The patient recruitment for this trial is ongoing. Keywords: hyperthermia, peritoneal neoplasms, peritoneal surface malignancy, peritoneal carcinomatosis, ovarianneoplasms

Published
2017

13. The Italian autism network (ITAN): a resource for molecular genetics and biomarker investigations

Author

Muglia, P., Filosi, M., Ros, Da, Kam-Thong, T., Nardocci, F., Trabetti, E., Ratti, E., Rizzini, P., Zuddas, A., Bernardina, B. D., Domenici, Enrico, Alibrio, G., Anchisi, L., Andruccioli, M., Benvenuto, A., Battistella, P. A., Boscaini, F., Bravaccio, C., Ceppi, E., Cosentino, D., Curatolo, P., De Giacomo, A., Di Vita, G., Elia, M., Gitti, F., Grittani, S., Lamanna, A. L., Mani, E., Manzi, B., Margari, L., Masi, G., Molteni, M., Pascotto, A., Parmeggiani, A., Pignatti, P. F., Piroddi, T., Prandini, P., Russo, S., Scifo, R., Tancredi, R., Tiberti, A., Zoccante, L., Pierandrea Muglia, Michele Filosi, Lucio Da Ros, Tony Kam-Thong, Franco Nardocci, Elisabetta Trabetti, Emiliangelo Ratti, Paolo Rizzini, Alessandro Zuddas, Bernardo Dalla Bernardina, Enrico Domenici,..Antonia Parmeggiani, Muglia, Pierandrea, Filosi, Michele, Da Ros, Lucio, Kam-Thong, Tony, Nardocci, Franco, Trabetti, Elisabetta, Ratti, Emiliangelo, Rizzini, Paolo, Zuddas, Alessandro, Bernardina, Bernardo Dalla, Domenici, Enrico, Alibrio, Giovanni, Anchisi, Laura, Andruccioli, Milena, Benvenuto, Arianna, Battistella, Pier Antonio, Boscaini, Flavio, Bravaccio, Carmela, Ceppi, Elisa, Cosentino, Diego, Curatolo, Paolo, De Giacomo, Andrea, Di Vita, Giuseppa, Elia, Massimo, Gitti, Filippo, Grittani, Serenella, Lamanna, Anna Linda, Mani, Elisa, Manzi, Barbara, Margari, Lucia, Masi, Gabriele, Molteni, Massimo, Pascotto, Antonio, Parmeggiani, Antonia, Pignatti, Pier Franco, Piroddi, Tiziana, Prandini, Paola, Russo, Sebastiano, Scifo, Renato, Tancredi, Raffaella, Tiberti, Alessandra, and Zoccante, Leonardo

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Adolescent, lcsh:RC435-571, Autism Spectrum Disorder, Medical Records, Autism Spectrum disorders, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Genetic, Language assessment, lcsh:Psychiatry, medicine, Pervasive developmental disorder, Child and adolescent psychiatry, Genetics, Humans, Biorepository, Asperger Syndrome, Child, Biomarkers, Wechsler Intelligence Scale for Children, Biological Specimen Banks, business.industry, Leiter International Performance Scale, Medical record, Autism Spectrum disorders, Biomarkers, Biorepository, Genetics, Biomarker, medicine.disease, Settore MED/39 - Neuropsichiatria Infantile, Psychiatry and Mental health, 030104 developmental biology, Databases as Topic, Italy, Psychiatry and Mental Health, Child Development Disorders, Pervasive, Child, Preschool, Autism, Health Resources, Female, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

BackgroundA substantial genetic component accounts for Autism Spectrum Disorders (ASD) aetiology, with some rare and common genetic risk factors recently identified. Large collections of DNAs from thoroughly characterized ASD families are an essential step to confirm genetic risk factors, identify new variants and investigate genotype-phenotype correlations. The Italian Autism Network aimed at constituting a clinical database and a biorepository of samples derived from ASD subjects and first-degree relatives extensively and consistently characterized by child psychiatry centers in Italy.MethodsThe study was approved by the ethical committee of the University of Verona, the coordinating site, and by the local ethical committees of each recruiting site. Certified staff was specifically trained at each site for the overall study conduct, for clinical protocol administration and handling of biological material. A centralized database was developed to collect clinical assessment and medical records from each recruiting site. Children were eligible for recruitment based on the following inclusion criteria: age 4–18 years, at least one parent or legal guardian giving voluntary written consent, meeting DSM-IV criteria for Autistic Disorder or Asperger’s Disorder or Pervasive Developmental Disorder NOS. Affected individuals were assessed by full psychiatric, neurological and physical examination, evaluation with ADI-R and ADOS scales, cognitive assessment with Wechsler Intelligence Scale for Children or Preschool and Primary, Leiter International Performance Scale or Griffiths Mental Developmental Scale. Additional evaluations included language assessment, the Krug Asperger’s Disorder Index, and instrumental examination such as EEG and structural MRI. DNA, RNA and plasma were collected from eligible individuals and relatives. A central laboratory was established to host the biorepository, perform DNA and RNA extraction and lymphocytes immortalisation. DiscussionThe study has led to an extensive collection of biological samples associated with standardised clinical assessments from a network of expert clinicians and psychologists. Eighteen sites have received ADI/ADOS training, thirteen of which have been actively recruiting. The clinical database currently includes information on 812 individuals from 249 families, and the biorepository has samples for 98% of the subjects. This effort has generated a highly valuable resource for conducting clinical and genetic research of ASD, amenable to further expansion.

Published
2018

16. 92 Non-inferiority prospective randomized controlled trial on simple hysterectomy versus radical hysterectomy in early stage cervical cancer. An interim analyzis of lesser trial

Author

Carneiro, V, primary, Paulo Batista, T, additional, Rodrigues de Andrade Neto, M, additional, Vieira Barros, A, additional, Licio Rocha Bezerra, A, additional, de Olanda Lima Dornelas Camara, L, additional, Moreira Ramalho, N, additional, Angelica Lucena, M, additional, Fontão, D, additional, Tancredi, R, additional, César Silva Júnior, T, additional, and Baiocchi, G, additional

Published
2019
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17. Importance of a hereditary cancer program in brazilian northeast

Author

Carneiro, V., primary, Ramalho, N., additional, de Oliveira Ferreira, C., additional, de Araújo Mariz, C., additional, Fonseca, H., additional, Terjo Salgado, M. Ramos, additional, Rodrigues de Andrade Neto, M., additional, Angelica de Lucena, M., additional, Telles de Oliveria Lima, J., additional, Amorim de Araújo Lima Santos, C., additional, Rameri ALexandre Silva de Azevedo, C., additional, Tancredi, R., additional, Batista, T. Paulo, additional, de Lima Ferreira Filho, D., additional, José de Matos e Silva, M., additional, and Costa, I., additional

Published
2019
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19. Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection

Author

Sykes NH, Wilson N, Volpi EV, Sousa I, Pagnamenta AT, Tancredi R, Battaglia A, Bailey AJ, Monaco AP, International Molecular Genetic Study of Autism Consortium, TOMA, CLAUDIO, MAESTRINI, ELENA, Sykes NH, Toma C, Wilson N, Volpi EV, Sousa I, Pagnamenta AT, Tancredi R, Battaglia A, Maestrini E, Bailey AJ, Monaco AP, and International Molecular Genetic Study of Autism Consortium (IMGSAC).

Subjects
Proband, gene copy number, Male, Candidate gene, Genotype, 22q13.3, Nerve Tissue Proteins, Biology, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, synapse, mental disorders, Genetics, medicine, SNP, Humans, Heritability of autism, Genetic Predisposition to Disease, Copy-number variation, Autistic Disorder, SHANK3, Genetics (clinical), In Situ Hybridization, Fluorescence, 030304 developmental biology, Genetic association, Chromosome Aberrations, 0303 health sciences, Models, Genetic, Genetic Variation, medicine.disease, association analysis, Developmental disorder, Italy, Synapses, Disease Progression, Autism, Female, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

SHANK3 is located on chromosome 22q13.3 and encodes a scaffold protein that is found in excitatory synapses opposite the pre-synaptic active zone. SHANK3 is a binding partner of neuroligins, some of whose genes contain mutations in a small subset of individuals with autism. In individuals with autism spectrum disorders (ASDs), several studies have found SHANK3 to be disrupted by deletions ranging from hundreds of kilobases to megabases, suggesting that 1% of individuals with ASDs may have these chromosomal aberrations. To further analyse the involvement of SHANK3 in ASD, we screened the International Molecular Genetic Study of Autism Consortium (IMGSAC) multiplex family sample, 330 families, for SNP association and copy number variants (CNVs) in SHANK3. A collection of 76 IMGSAC Italian probands from singleton families was also examined by multiplex ligation-dependent probe amplification for CNVs. No CNVs or SNP associations were found within the sample set, although sequencing of the gene was not performed. Our data suggest that SHANK3 deletions may be limited to lower functioning individuals with autism.

Published
2009

21. VEGF-induced intracellular Ca2+oscillations are down-regulated and do not stimulate angiogenesis in breast cancer-derived endothelial colony forming cells

Author

Lodola, F, Laforenza, U, Cattaneo, F, Ruffinatti, F, Poletto, V, Massa, M, Tancredi, R, Zuccolo, E, Khdar, D, Riccardi, A, Biggiogera, M, Rosti, V, Guerra, G, Moccia, F, Lodola, Francesco, Laforenza, Umberto, Cattaneo, Fabio, Ruffinatti, Federico Alessandro, Poletto, Valentina, Massa, Margherita, Tancredi, Richard, Zuccolo, Estella, Khdar, Dlzar Alì, Riccardi, Alberto, Biggiogera, Marco, Rosti, Vittorio, Guerra, Germano, Moccia, Francesco, RICCARDI, ALBERTO, Lodola, F, Laforenza, U, Cattaneo, F, Ruffinatti, F, Poletto, V, Massa, M, Tancredi, R, Zuccolo, E, Khdar, D, Riccardi, A, Biggiogera, M, Rosti, V, Guerra, G, Moccia, F, Lodola, Francesco, Laforenza, Umberto, Cattaneo, Fabio, Ruffinatti, Federico Alessandro, Poletto, Valentina, Massa, Margherita, Tancredi, Richard, Zuccolo, Estella, Khdar, Dlzar Alì, Riccardi, Alberto, Biggiogera, Marco, Rosti, Vittorio, Guerra, Germano, Moccia, Francesco, and RICCARDI, ALBERTO

Abstract

Endothelial colony forming cells (ECFCs) represent a population of truly endothelial precursors that promote the angiogenic switch in solid tumors, such as breast cancer (BC). The intracellular Ca2+ toolkit, which drives the pro-angiogenic response to VEGF, is remodelled in tumor-associated ECFCs such that they are seemingly insensitive to this growth factor. This feature could underlie the relative failure of anti-VEGF therapies in cancer patients. Herein, we investigated whether and how VEGF uses Ca2+ signalling to control angiogenesis in BC-derived ECFCs (BCECFCs). Although VEGFR-2 was normally expressed, VEGF failed to induce proliferation and in vitro tubulogenesis in BC-ECFCs. Likewise, VEGF did not trigger robust Ca2+ oscillations in these cells. Similar to normal cells, VEGF-induced intracellular Ca2+ oscillations were triggered by inositol-1,4,5-trisphosphate-dependent Ca2+ release from the endoplasmic reticulum (ER) and maintained by store-operated Ca2+ entry (SOCE). However, InsP3-dependent Ca2+ release was significantly lower in BC-ECFCs due to the down-regulation of ER Ca2+ levels, while there was no remarkable difference in the amplitude, pharmacological profile and molecular composition of SOCE. Thus, the attenuation of the pro-angiogenic Ca2+ response to VEGF was seemingly due to the reduction in ER Ca2+ concentration, which prevents VEGF from triggering robust intracellular Ca2+ oscillations. However, the pharmacological inhibition of SOCE prevented BC-ECFC proliferation and in vitro tubulogenesis. These findings demonstrate for the first time that BC-ECFCs are insensitive to VEGF, which might explain at cellular and molecular levels the failure of anti-VEGF therapies in BC patients, and hint at SOCE as a novel molecular target for this disease.

Published
2017

22. Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

Author

Romano, M., Della Porta, M. G., Galli, A., Panini, N., Licandro, S. A., Bello, E., Craparotta, I., Rosti, V., Bonetti, E., Tancredi, R., Rossi, M., Mannarino, L., Marchini, S., Porcu, L., Galmarini, C. M., Zambelli, A., Zecca, M., Locatelli, Franco, Cazzola, M., Biondi, A., Rambaldi, A., Allavena, P., Erba, E., D'Incalci, M., Locatelli F. (ORCID:0000-0002-7976-3654), Romano, M., Della Porta, M. G., Galli, A., Panini, N., Licandro, S. A., Bello, E., Craparotta, I., Rosti, V., Bonetti, E., Tancredi, R., Rossi, M., Mannarino, L., Marchini, S., Porcu, L., Galmarini, C. M., Zambelli, A., Zecca, M., Locatelli, Franco, Cazzola, M., Biondi, A., Rambaldi, A., Allavena, P., Erba, E., D'Incalci, M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. Methods: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. Results: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. Conclusions: Trabectedin could be good candidate for clinical studies in JMML/CMML patients.

Published
2017

23. Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms

Author

Romano, M, della Porta, M, Gallì, A, Panini, N, Licandro, S, Bello, E, Craparotta, I, Rosti, V, Bonetti, E, Tancredi, R, Rossi, M, Mannarino, L, Marchini, S, Porcu, L, Galmarini, C, Zambelli, A, Zecca, M, Locatelli, F, Cazzola, M, Biondi, A, Rambaldi, A, Allavena, P, Erba, E, D'Incalci, M, ROSSI, MARIANNA, BIONDI, ANDREA, D'Incalci, M., Romano, M, della Porta, M, Gallì, A, Panini, N, Licandro, S, Bello, E, Craparotta, I, Rosti, V, Bonetti, E, Tancredi, R, Rossi, M, Mannarino, L, Marchini, S, Porcu, L, Galmarini, C, Zambelli, A, Zecca, M, Locatelli, F, Cazzola, M, Biondi, A, Rambaldi, A, Allavena, P, Erba, E, D'Incalci, M, ROSSI, MARIANNA, BIONDI, ANDREA, and D'Incalci, M.

Abstract

Background: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. Methods: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. Results: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. Conclusions: Trabectedin could be good candidate for clinical studies in JMML/CMML patients.

Published
2017

26. AMPLIAMENTO GALLERIA COMUNALE ARTE MODERNA E CONTEMPORANEA

Author

GHIO, FRANCESCO RICCARDO, TANCREDI R., Ghio, FRANCESCO RICCARDO, and Tancredi, R.

Subjects
MACRO
Abstract

Documentazione storica, rilievi, programma concorsuale, documentazione degli esiti e dei lavori della giuria del concorso che ha portato alla realizzazione del MACRO Museo Arte Contemporanea di Roma

Published
2001

28. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Author

Casey, J.P. Magalhaes, T. Conroy, J.M. Regan, R. Shah, N. Anney, R. Shields, D.C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bolton, P.F. Bourgeron, T. Brennan, S. Cali, P. Correia, C. Corsello, C. Coutanche, M. Dawson, G. De Jonge, M. Delorme, R. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Foley, S. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Green, J. Guter, S.J. Hakonarson, H. Holt, R. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Lamb, J.A. Leboyer, M. Couteur, A.L. Leventhal, B.L. Lord, C. Lund, S.C. Maestrini, E. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Miller, J. Minopoli, F. Mirza, G.K. Munson, J. Nelson, S.F. Nygren, G. Oliveira, G. Pagnamenta, A.T. Papanikolaou, K. Parr, J.R. Parrini, B. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Ragoussis, J. Roge, B. Rutter, M.L. Sequeira, A.F. Soorya, L. Sousa, I. Sykes, N. Stoppioni, V. Tancredi, R. Tauber, M. Thompson, A.P. Thomson, S. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Vorstman, J.A.S. Wallace, S. Wang, K. Wassink, T.H. White, K. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Geschwind, D.H. Haines, J.L. Hallmayer, J. Monaco, A.P. Nurnberger Jr., J.I. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vieland, V.J. Wijsman, E.M. Green, A. Gill, M. Gallagher, L. Vicente, A. Ennis, S.

Subjects
mental disorders
Abstract

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data. © The Author(s) 2011.

Published
2012

29. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author

Anney, R.J., Kenny, E.M., O'Dushlaine, C., Parkhomenka, E., Buxbaum, J.D., Sutcliffe, J., Gill, M., Gallagher, L., Bailey, A.J., Fernandez, B.A., Szatmari, P., Nurnberger Jr, J.I., McDougle, C.J., Posey, D.J., Lord, C., Corsello, C., Hus, V., Kolevzon, A., Soorya, L., Parkhomenko, E., Scherer, S.W., Leventhal, B.L., Dawson, G., Vieland, V.J., Hakonarson, H., Glessner, J.T., Kim, C., Wang, K., Schellenberg, G.D., Devlin, B., Klei, L., Patterson, A., Minshew, N., Sutcliffe, J.S., Haines, J.L., Lund, S.C., Thomson, S., Yaspan, B.L., Coon, H., Miller, J., McMahon, W.M., Munson, J., Marshall, C.R., Estes, A., Wijsman, EM., The Autism Genome Project, Pinto, D., Vincent, J.B., Fombonne, E., Betancur, C., Delorme, R., Leboyer, M., Bourgeron, T., Mantoulan, C., Roge, B., Tauber, M., Freitag, C.M., Poustka, F., Duketis, E., Klauck, S.M., Poustka, A., Papanikolaou, K., Tsiantis, J., Anney, R., Bolshakova, N., Brennan, S., Hughes, G., McGrath, J., Merikangas, A., Ennis, S., Green, A., Casey, J.P., Conroy, J.M., Regan, R., Shah, N., Maestrini, E., Bacchelli, E., Minopoli, F., Stoppioni, V., Battaglia, A., Igliozzi, R., Parrini, B., Tancredi, R., Oliveira, G., Almeida, J., Duque, F., Vicente, A.M., Correia, C., Magalhaes, T.R., Gillberg, C., Nygren, G., Jonge, M.D., Van Engeland, H., Vorstman, J.A., Wittemeyer, K., Baird, G., Bolton, P.F, Rutter, M.L., Green, J., Lamb, J.A., Pickles, A., Parr, J.R., Couteur, A.L., Berney, T., McConachie, H., Wallace, S., Coutanche, M., Foley, S., White, K., Monaco, A.P., Holt, R., Farrar, P., Pagnamenta, A.T., Mirza, G.K., Ragoussis, J., Sousa, I., Sykes, N., Wing, K., Hallmayer, J., Cantor, R.M., Nelson, S.F., Geschwind, D.H., Abrahams, B.S., Volkmar, F., Pericak-Vance, M.A., Cuccaro, M.L., Gilbert, J., Cook, E.H., Guter, S.J., and Jacob, S.

Subjects
Pathway analysis, Autism, Perturbações do Desenvolvimento Infantil e Saúde Mental, Gene ontology, Genome-wide association analysis, Family-based association test
Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.

Published
2011

33. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author

Anney, R.J.L. Kenny, E.M. O'Dushlaine, C. Yaspan, B.L. Parkhomenka, E. Buxbaum, J.D. Sutcliffe, J. Gill, M. Gallagher, L. Bailey, A.J. Fernandez, B.A. Szatmari, P. Scherer, S.W. Patterson, A. Marshall, C.R. Pinto, D. Vincent, J.B. Fombonne, E. Betancur, C. Delorme, R. Leboyer, M. Bourgeron, T. Mantoulan, C. Roge, B. Tauber, M. Freitag, C.M. Poustka, F. Duketis, E. Klauck, S.M. Poustka, A. Papanikolaou, K. Tsiantis, J. Bolshakova, N. Brennan, S. Hughes, G. McGrath, J. Merikangas, A. Ennis, S. Green, A. Casey, J.P. Conroy, J.M. Regan, R. Shah, N. Maestrini, E. Bacchelli, E. Minopoli, F. Stoppioni, V. Battaglia, A. Igliozzi, R. Parrini, B. Tancredi, R. Oliveira, G. Almeida, J. Duque, F. Vicente, A. Correia, C. Magalhaes, T.R. Gillberg, C. Nygren, G. De Jonge, M. Van Engeland, H. Vorstman, J.A.S. Wittemeyer, K. Baird, G. Bolton, P.F. Rutter, M.L. Green, J. Lamb, J.A. Pickles, A. Parr, J.R. Le Couteur, A. Berney, T. McConachie, H. Wallace, S. Coutanche, M. Foley, S. White, K. Monaco, A.P. Holt, R. Farrar, P. Pagnamenta, A.T. Mirza, G.K. Ragoussis, J. Sousa, I. Sykes, N. Wing, K. Hallmayer, J. Cantor, R.M. Nelson, S.F. Geschwind, D.H. Abrahams, B.S. Volkmar, F. Pericak-Vance, M.A. Cuccaro, M.L. Gilbert, J. Cook, E.H. Guter, S.J. Jacob, S. Nurnberger, J.I., Jr. McDougle, C.J. Posey, D.J. Lord, C. Corsello, C. Hus, V. Kolevzon, A. Soorya, L. Parkhomenko, E. Leventhal, B.L. Dawson, G. Vieland, V.J. Hakonarson, H. Glessner, J.T. Kim, C. Wang, K. Schellenberg, G.D. Devlin, B. Klei, L. Minshew, N. Sutcliffe, J.S. Haines, J.L. Lund, S.C. Thomson, S. Coon, H. Miller, J. McMahon, W.M. Munson, J. Estes, A. Wijsman, E.M. Autism Genome Project

Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings. © 2011 Macmillan Publishers Limited All rights reserved.

Published
2011

35. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Devlin, B. Ennis, S. Hallmayer, J.

Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 3 10-28. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10-28 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. © The Author 2010. Published by Oxford University Press. All rights reserved.

Published
2010

36. Functional impact of global rare copy number variation in autism spectrum disorders

Author

Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.

Subjects
mental disorders
Abstract

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (

Published
2010

38. 48 Trabectedin and lurbinectedin are effective against leukemic cells derived from patients affected by chronic and juvenile myelomonocytic leukemia

Author

Romano, M., primary, Gallì, A., additional, Panini, N., additional, Paracchini, L., additional, Beltrame, L., additional, Bello, E., additional, Licandro, S.A., additional, Cattrini, C., additional, Tancredi, R., additional, Marchini, S., additional, Rosti, V., additional, Zecca, M., additional, Porta, M. Della, additional, Zambelli, A., additional, Galmarini, C.M., additional, Erba, E., additional, and D'Incalci, M., additional

Published
2014
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46. Remodelling of the Ca2+ signalling machinery in endothelial progenitor cells isolated from breast cancer patients

Author

Moccia, F, Lodola, F, Dragoni, S, Cattaneo, F, Tancredi, R, Bottino, C, Laforenza, U, Guerra, G, Zambelli, A, Rosti, V, DELLA PORTA, M, Tanzi, F, MOCCIA, FRANCESCO, LODOLA, FRANCESCO, DRAGONI, SILVIA, Cattaneo, Fabio, Tancredi, Rinchard, BOTTINO, CINZIA, LAFORENZA, UMBERTO, Guerra, Germano, Zambelli, Alberto, Rosti, Vittorio, DELLA PORTA, MATTEO GIOVANNI, TANZI, FRANCO, Moccia, F, Lodola, F, Dragoni, S, Cattaneo, F, Tancredi, R, Bottino, C, Laforenza, U, Guerra, G, Zambelli, A, Rosti, V, DELLA PORTA, M, Tanzi, F, MOCCIA, FRANCESCO, LODOLA, FRANCESCO, DRAGONI, SILVIA, Cattaneo, Fabio, Tancredi, Rinchard, BOTTINO, CINZIA, LAFORENZA, UMBERTO, Guerra, Germano, Zambelli, Alberto, Rosti, Vittorio, DELLA PORTA, MATTEO GIOVANNI, and TANZI, FRANCO

Published
2013

49. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author

Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., Vorstman, J., Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., and Vorstman, J.

Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm < 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

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