78 results on '"Berardino Porfirio"'
Search Results
2. Normal tension glaucoma in CSF-shunted normal pressure hydrocephalus patients. An extended follow-up
- Author
-
Pasquale Gallina, Alfonso Savastano, Matilde Buzzi, Lucia Angelini, Alba Miele, Stanislao Rizzo, Antonio Scollato, Saverio Caini, and Berardino Porfirio
- Subjects
Ophthalmology - Published
- 2022
3. A Multiple Sclerosis Patient Benefitting from CSF Flow Enhancement Had Imaging Signs of 'Glymphatic-Lymphatic System Disease.' Case Report
- Author
-
Antonio Scollato, Francesco Lolli, Giancarlo Lastrucci, Anna Repice, Giuseppe De Santis, Claudio Nicoletti, Berardino Porfirio, and Pasquale Gallina
- Abstract
Background The derangement of CSF circulation impacts the functions of glymphatic-lymphatic system (G-Ls), which regulates solute trafficking and immune surveillance in the CNS. The imaging features of dilated perivascular spaces imply the substantial impairment of the G-Ls and can be easily estimated It has been proposed that multiple sclerosis can be viewed as a disease involving a failure component and therapeutically could be targeted as such.Case presentationWe report the case of a female patient diagnosed with primary progressive multiple sclerosis, also presenting perivascular spaces dilatation, who transiently improved after CSF shunt diversions. ConclusionsThe G-Ls failure leads to dysregulation of waste molecule clearance in the brain and an altered CNS immune response, potentially in many diseases. The clinical improvement observed in our patient may relate to an increased clearance of inflammatory mediators following the G-Ls reestablishment obtained by CSF flow enhancement.
- Published
- 2021
4. Accuracy and safety of 1-day external lumbar drainage of CSF for shunt selection in patients with idiopathic normal pressure hydrocephalus
- Author
-
Pasquale Gallina, Antonio Scollato, Giancarlo Lastrucci, Nicola Di Lorenzo, Saverio Caini, and Berardino Porfirio
- Subjects
medicine.medical_specialty ,Nerve root ,business.industry ,Test sensitivity ,General Medicine ,Confidence interval ,Surgery ,Lumbar ,(Idiopathic) normal pressure hydrocephalus ,Medicine ,In patient ,Positive test ,business ,Complication - Abstract
OBJECTIVEThree to five days of external lumbar drainage (ELD) of CSF is a test for ventriculoperitoneal shunt (VPS) selection in idiopathic normal pressure hydrocephalus (iNPH). The accuracy and complication rates of a shorter (1-day) ELD procedure were analyzed.METHODSData of patients with iNPH who underwent 1-day ELD to be selected to undergo VPS placement with a programmable valve in the period from 2005 to 2015 were reviewed. Patients experiencing VPS complications, valve malfunctioning, or with less than 1 year of follow-up were excluded. The ability of 1-day ELD to predict VPS outcome at 1- and 12-month follow-up was assessed by calculating sensitivity, specificity, and positive and negative predictive values.RESULTSOf 93 patients who underwent 1-day ELD, 3 did not complete the procedure. Of the remaining 90 patients, 2 experienced transient nerve root irritation. Twenty-four patients had negative test outcomes and 66 had positive test outcomes. Nine negative-outcome patients had intraprocedural headache, which showed 37.5% sensitivity (95% confidence interval [CI] 19.5%–59.2%) and 100% specificity (95% CI 93.1%–100%) as predictors of negative 1-day ELD outcome. Sixty-eight patients (6 with negative and 62 with positive outcomes) underwent VPS insertion, which was successful in 0 and 58 patients, respectively, at 1-month follow-up. Test sensitivity and specificity in predicting surgical outcome at 1-month follow-up were 100% (95% CI 92.3%–100%) and 60% (95% CI 27.4%–86.3%), respectively, with 94.1% accuracy (95% CI 85.6–98.4%). Among the 1-day ELD–positive patients, 2 showed no clinical benefit at 12 months follow-up. Test sensitivity and specificity in predicting surgical outcome at 12-month follow-up was 100% (95% CI 92.5%–100%) and 75.0% (95% CI 35.6%–95.5%), respectively, with 97.1% (95% CI 89.8%–99.6%) accuracy.CONCLUSIONSOne-day ELD is a reliable tool in iNPH management, with low complication risk and short trial duration. The test is very consistent in predicting who will have a positive outcome with VPS placement, given the high chance of successful outcome at 1- and 12-month follow-up; negative-outcome patients have a high risk of unsuccessful surgery. Intraprocedural headache is prognostic of 1-day ELD negative outcome.
- Published
- 2019
5. Aqueductal CSF stroke volume measurements may drive management of shunted idiopathic normal pressure hydrocephalus patients
- Author
-
Pasquale Gallina, Berardino Porfirio, Saverio Caini, Giancarlo Lastrucci, Antonio Scollato, Nicola Di Lorenzo, and Lucia Angelini
- Subjects
Adult ,Male ,medicine.medical_specialty ,Science ,Diseases ,Article ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Risk groups ,Csf shunting ,Internal medicine ,Medicine ,Humans ,CSF shunting, normal pression hydrocephalus, aqueductal CSF stroke volume ,Multidisciplinary ,medicine.diagnostic_test ,business.industry ,Cerebral Aqueduct ,Magnetic resonance imaging ,Stroke Volume ,Odds ratio ,Stroke volume ,Middle Aged ,medicine.disease ,Hydrocephalus, Normal Pressure ,Hydrocephalus ,(Idiopathic) normal pressure hydrocephalus ,Cardiology ,Female ,Neurosurgery ,business ,030217 neurology & neurosurgery ,Neurological disorders - Abstract
CSF shunting with adjustable valve is the treatment of idiopathic normal pressure hydrocephalus. The opening pressure valve setting is left to the neurosurgeon’s experience. Aqueductal CSF stroke volume by phase-contrast magnetic resonance measures the CSF passing through the Sylvian aqueduct and it changes with intracranial hydrodynamics. We sought to identify a window of stroke volume differences associated with the best clinical outcome and lowest rate of complications. The records of 69 patients were reviewed. At every clinical check, stroke volume, opening pressure valve, clinical outcome, and CSF overdrainage were analyzed. The correlation between stroke volume differences and negative outcome was also analyzed. The median follow-up was 2.3 years (range 0.3–10.4 years). The odds of negative outcome between two consecutive checks significantly increased by 16% (95%CI 4–28%, p = 0.006). Taking the lowest risk group as reference, the odds ratio of negative outcome was 1.16 (95%CI 0.51–2.63, p = 0.726) for SV differences less than − 37.6 µL, while it was 1.96 (95%CI 0.97–3.98, p = 0.062) for stroke volume changes above + 23.1 µL. Maintaining stroke volume values within a definite range might help maximize clinical benefit and avoid the risk of CSF overdrainage.
- Published
- 2021
6. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants:Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
- Author
-
Christi J. van Asperen, Leigha Senter, Javier Benitez, Kenneth Offit, Marco Montagna, Irene L. Andrulis, Phuong L. Mai, Yen Y. Tan, Lidia Moserle, Sara Torres-Esquius, Trinidad Caldés, Orland Diez, Daniel R. Barnes, Åke Borg, Daniel Barrowdale, Joanne Ngeow, Siranoush Manoukian, Soo Hwang Teo, Maria A. Caligo, Inge Søkilde Pedersen, Jennifer T. Loud, Marta Santamariña, Amanda E. Toland, Anna Marie Mulligan, Irene Konstantopoulou, Antonis C. Antoniou, Paul A. James, Eitan Friedman, Barbara Wappenschmidt, Marc Tischkowitz, Laura Papi, Ana Osorio, Georgia Chenevix-Trench, Eva Machackova, Pedro Pinto, Keivan Majidzadeh-A, Bernardo Bonanni, Kristiina Aittomäki, Berardino Porfirio, Johanna Rantala, Valentina Silvestri, Bent Ejlertsen, Melissa C. Southey, Ramunas Janavicius, Elisabetta Landucci, Liene Nikitina-Zake, Lajos Géczi, Saundra S. Buys, Angela R. Solano, Sarah Colonna, Ana Vega, Fabienne Lesueur, Frans B. L. Hogervorst, Goska Leslie, David E. Goldgar, Peter J. Hulick, Rosa B. Barkardottir, Kristin K. Zorn, Elisa Alducci, Miguel de la Hoya, Fergus J. Couch, Laura Ottini, Anne-Marie Gerdes, Uffe Birk Jensen, Ute Hamann, Christoph Engel, Allison W. Kurian, Douglas F. Easton, Annabeth Høgh Petersen, Alessandra Viel, Linda Steele, Zoe Steinsnyder, Ava Kwong, Alicia Barroso, Eric Hahnen, Mads Thomassen, Maria Rossing, Rita K. Schmutzler, Wendy K. Chung, Angel Izquierdo, Barak Rosenzweig, Jeroen Vierstraete, Mark H. Greene, Lenka Foretova, Jeffrey N. Weitzel, Paolo Radice, Muhammad Usman Rashid, Katherine L. Nathanson, Lesley McGuffog, Ian G. Campbell, John L. Hopper, Laura Cortesi, Christian F. Singer, Sook-Yee Yoon, Lídia Feliubadaló, Bjarni A. Agnarsson, Susan M. Domchek, Vijai Joseph, Manuel R. Teixeira, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Jacques Simard, Yuan Chun Ding, Carlo Capalbo, Florentia Fostira, Greet Wieme, Mary Beth Terry, Kathleen Claes, Olufunmilayo I. Olopade, Pedro Pérez-Segura, Heli Nevanlinna, D. Gareth Evans, Edith Olah, Michael T. Parsons, Claudine Isaacs, Miquel Angel Pujana, Timothy R. Rebbeck, Gord Glendon, Susan L. Neuhausen, Judy Kirk, Sue K. Park, Esther M. John, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, University of Helsinki, HUS Gynecology and Obstetrics, Biosciences, and Department of Obstetrics and Gynecology
- Subjects
Male ,Cancer Research ,endocrine system diseases ,GUIDELINES ,0302 clinical medicine ,Neoplasms ,Medicine ,030212 general & internal medicine ,Prospective cohort study ,skin and connective tissue diseases ,GENE-ENVIRONMENT INTERACTION ,Original Investigation ,RISK ,Aged, 80 and over ,education.field_of_study ,BRCA1 Protein ,Middle Aged ,BRCA2 Protein/genetics ,3. Good health ,PROSTATE-CANCER ,Phenotype ,Oncology ,030220 oncology & carcinogenesis ,Male breast cancer ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,3122 Cancers ,MUTATION CARRIERS ,03 medical and health sciences ,Young Adult ,Breast cancer ,Internal medicine ,BREAST-CANCER ,Humans ,education ,Germ-Line Mutation ,Aged ,Retrospective Studies ,BRCA2 Protein ,business.industry ,Cancer ,Correction ,Retrospective cohort study ,Odds ratio ,medicine.disease ,BRCA1 Protein/genetics ,business ,Neoplasms/diagnosis - Abstract
Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P
- Published
- 2020
7. Early-onset malignant phyllodes breast tumor in a patient with germline pathogenic variants in NF1 and BRCA1 genes
- Author
-
Berardino Porfirio, Francesca Gensini, Maria Cristina Petrella, Paola Daniele, Lorenzo Orzalesi, Laura Papi, Valentina Pinna, Roberta Sestini, and Alessandro De Luca
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Heterozygote ,Neurofibromatosis 1 ,Offspring ,Genetic counseling ,Genes, BRCA1 ,Breast Neoplasms ,030105 genetics & heredity ,Germline ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Breast cancer ,Phyllodes Tumor ,Genes, Neurofibromatosis 1 ,Genetics ,medicine ,Humans ,Genetic Testing ,Neurofibromatosis ,skin and connective tissue diseases ,Gene ,Genetics (clinical) ,Germ-Line Mutation ,Mastectomy ,business.industry ,Chromosome ,medicine.disease ,Human genetics ,Pedigree ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Chromosomes, Human, Pair 17 - Abstract
We present a 24-year-old female patient affected by neurofibromatosis type 1 (NF1) who developed a malignant phyllodes tumor of the breast. The molecular studies showed that the patient carried a heterozygous inactivating deleterious variant in BRCA1 inherited from the father associated with a germline de novo pathogenic alteration in NF1; the tumor presented a biallelic inactivation of both genes. Therefore, tumor analyses helped to establish that the germline NF1 and BRCA1 variants were in cis on the paternal chromosome. This last information is important to provide adequate genetic counselling regarding the risk of recurrence in the offspring, as well as opportunity for early intervention. In conclusion, we present the first case of a malignant phyllodes tumor of the breast in patient carrying pathogenic variants in NF1 and BRCA1. Further studies will be necessary to understand if the phyllodes histotype represents a very rare component of NF1-associated breast cancer.
- Published
- 2020
8. iNPH as a '2-hit' Intracranial Hydrodynamic Derangement Disease
- Author
-
Pasquale Gallina, Francesco Lolli, and Berardino Porfirio
- Subjects
medicine.medical_specialty ,business.industry ,Disease ,medicine.disease ,Hydrocephalus, Normal Pressure ,Article ,Derangement ,Alzheimer Disease ,Internal medicine ,(Idiopathic) normal pressure hydrocephalus ,medicine ,Cardiology ,Hydrodynamics ,Molecular Medicine ,Dementia ,Humans ,Glymphatic system ,business ,Molecular Biology ,Glymphatic System - Abstract
~10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer’s disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and Aβ plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte Aquaporin-4 (AQP4). The glymphatic system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics.
- Published
- 2020
9. Evaluation of a Next-Generation Sequencing Assay for BRCA1 and BRCA2 Mutation Detection
- Author
-
Anna Laura Putignano, Francesca Gensini, Sharon Trujillo Saavedra, Gabriele Lorenzo Capone, Irene Paganini, Berardino Porfirio, Roberta Sestini, Irene De Rienzo, and Laura Papi
- Subjects
0301 basic medicine ,DNA Copy Number Variations ,Concordance ,Susceptibility gene ,Biology ,Polymorphism, Single Nucleotide ,DNA sequencing ,Pathology and Forensic Medicine ,03 medical and health sciences ,symbols.namesake ,Exon ,0302 clinical medicine ,BRCA2 Mutation ,Humans ,Multiplex ,Copy-number variation ,BRCA2 Protein ,Genetics ,Sanger sequencing ,BRCA1 Protein ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,Exons ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,symbols ,Molecular Medicine - Abstract
The efficiency of a novel targeted next-generation sequencing (NGS) test, the Devyser BRCA kit, for a comprehensive analysis of all 48 coding exons of the high-risk breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 has been assessed. The new assay intended to detect nucleotide substitutions, small deletions/insertions, and large deletions/duplications. To document the false-negative and false-positive rates of the NGS assay in the hands of end users, 48 samples with previously identified 444 small variants and seven gross rearrangements were analyzed, showing 100% concordance with gold standards. Furthermore, all other 43 variants (42 single-nucleotide variation or insertion/deletion variation and one copy number variation, whose significance is or may be of clinical value), which were called by the NGS assay in a prospectively analyzed 179-sample set, were confirmed by Sanger sequencing or multiplex ligation probe amplification, according to their nature. We conclude that the Devyser BRCA kit performed satisfactorily for use in a clinical laboratory.
- Published
- 2018
10. A novelPAX1null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency
- Author
-
Francesca Gensini, Gabriele Lorenzo Capone, Elisa Contini, Alessandro Barilaro, Berardino Porfirio, Anna Laura Putignano, Roberta Sestini, Irene Paganini, Laura Papi, Irene Giotti, and Annabella Marozza
- Subjects
0301 basic medicine ,Genetics ,Severe combined immunodeficiency ,Mutation ,Hearing loss ,media_common.quotation_subject ,Point mutation ,Nonsense ,Aplasia ,Biology ,medicine.disease ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Missense mutation ,medicine.symptom ,030217 neurology & neurosurgery ,Genetics (clinical) ,Exome sequencing ,media_common - Abstract
Otofaciocervical syndrome is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of otofaciocervical syndrome and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which two children, showing features of otofaciocervical syndrome, expired from severe combined immunodeficiency. To date, the co-occurrence of otofaciocervical syndrome and severe combined immunodeficiency has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the two affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for severe combined immunodeficiency. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where severe combined immunodeficiency might represent the main feature.
- Published
- 2017
11. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
- Author
-
Luigi Mori, Sara González, Elia Grau, Dieter Niederacher, Alexandra C. Kölbl, Ares Solanes, Cassandra B. Nichols, Marine Guillaud-Bataille, Ulrike Schoenwiese, Katherine L. Nathanson, Alfons Meindl, Ellen Honisch, Hans Ehrencrona, Ute Enders, Anke Waha, Trinidad Caldés, Inge Søkilde Pedersen, Ana Blanco, Emma Tudini, Conxi Lázaro, Paolo Radice, Torben A Kruse, María Concepción Alonso-Cerezo, Chantal Farra, Shan Wang-Gohrke, Wilko Weichert, Heli Nevanlinna, Setareh Moghadasi, Bernd Auber, Carla Bruzzone, Aliana Guerrieri-Gonzaga, Sabine Grill, Raymonda Varon, Nicolas Derive, Ana Vega, Nicolai Maass, Åke Borg, Cora M. Aalfs, Nadia Naldi, Silvia Iglesias, Kai Ren Ong, Encarna B. Gomez Garcia, Karl Hackmann, Emma R. Woodward, Norbert Arnold, David E. Goldgar, Bernard Peissel, Karolin Bucksch, Berardino Porfirio, Françoise Révillion, Angel Izquierdo, Isabell Witzel, Sebastian Wagner, Silke Zachariae, Elisa Alducci, Mads Thomassen, Jesús del Valle, Valentina Zampiga, Kerstin Rhiem, Lidia Moserle, Edenir Inêz Palmero, Maaike P.G. Vreeswijk, Christoph Mundhenke, Laura Papi, Alejandro Moles-Fernández, Paula Rofes, Ulrike Faust, Andrea Gehrig, Sandrine M. Caputo, Logan C. Walker, Fiona Lalloo, Ute Felbor, Joan Brunet, Henriette Roed Nielsen, Sean V. Tavtigian, Beatrice Bortesi, Thomas Hansen, Maria Grazia Tibiletti, Estela Carrasco, Lisa Wiesmüller, Viviana Gismondi, Sophie Krieger, Pedro Pérez-Segura, Esther Pohl-Rescigno, Emanuela Lucci-Cordisco, Barbara Wappenschmidt, Rui Manuel Reis, Gabriele Lorenzo Capone, Ileana Carnevali, Christi J. van Asperen, KCon Fab Investigators, Jochen Seggewiß, Rhiannon J. Walters, Irmgard Debatin, Susan M. Domchek, Marco Montagna, Francesca Gensini, Kristiina Aittomäki, Véronique Dutrannoy, Arcangela De Nicolo, Giulia Cagnoli, Elisa J. Cops, Henrique de Campos Reis Galvão, Giulia Cini, Barbara Riboli, Eva Tornero, Paul A. James, Judith Balmaña, Anne-Marie Gerdes, Heide Hellebrand, Miriam Fine, Mathias Stiller, Aldo Germani, Diana Eccles, Britta Blümcke, Dominique Stoppa-Lyonnet, Elena Leinert, Alexandra Lewis, Daniela Rivera, Verena Hübbel, Fergus J. Couch, Gunnar Schmidt, Katharina Keupp, Bernhard H. F. Weber, Tilman Heinrich, Mariarosaria Calvello, Michael Dean, Udo Jeschke, Vanessa Lattimore, Linda A.M. Janssen, Siranoush Manoukian, Eva Gross, Kelly J. Sullivan, Doris Steinemann, Susanne Ledig, Alessandra Viel, Christoph Engel, Ana Sánchez de Abajo, Nina Ditsch, Sandra Bonache, Maria A. Caligo, Katharina Pfeifer, Thomas Haaf, Christian Sutter, Eric Hahnen, Laura Matricardi, Marc Tischkowitz, Alex Teulé, Katherine M. Tucker, Jutta Giesecke, Silvia Tognazzo, Gemma Montalban, Carolina Gómez, Anders Kvist, Joanna Lim, Alison H. Trainer, Rachel Susman, Judit Horvath, Amanda B. Spurdle, Mirjam Larsen, Therese Törngren, Mónica Salinas, Nicholas Pachter, Rachel Austin, Nicola K. Poplawski, C Zeder-Göß, Juliane Ramser, Julia Ritter, Anne Sophie Vesper, Paola Concolino, D. Gareth Evans, Clemens R. Müller, Matilde Navarro, Sara Torres-Esquius, Claus R. Bartram, Laura Cortesi, Jacopo Azzollini, Marion Harris, Edward M. Clarke, Marion Kiechle, Lídia Feliubadaló, Almuth Caliebe, Karen N. Herold, Charlotte Kvist Lautrup, Anne S. Quante, Gardenia Vargas-Parra, Michael T. Parsons, Pietro Cavalli, Hongyan Li, Rodrigo Augusto Depieri Michelli, Irene Feroce, Achim Wöckel, Kerstin Wieland, Silke Kaulfuß, Soo Hwang Teo, Angela Velasco, Capucine Delnatte, Marta Pineda, Marion van Mackelenbergh, Eva Montes, Angela Toss, Rita K. Schmutzler, William D. Foulkes, Alvaro N.A. Monteiro, Jan Hauke, Monica Marabelli, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Esther Darder, Simona Agata, Amanda E. Toland, Bernardo Bonanni, Liliana Varesco, Orland Diez, Andreas Rump, Virginie Caux-Moncoutier, Gaetana Gambino, Markus Loeffler, Claude Houdayer, Elena Barbieri, Adrià López-Fernández, et. al., Universidade do Minho, QIMR Berghofer Medical Research Institute, Chinese Academy of Geological Sciences [Beijing] (CAGS), Ministry of Land and Resources (MLR), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Programa de Càncer Hereditari, Unitat de Diagnòstic Molecular, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Department of Clinical Genetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Helsinki University Central Hospital, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Università degli Studi di Milano [Milano] (UNIMI), Medical Oncology Department, Vall d'Hebron University Hospital [Barcelona], Institute of Human Genetics, Universität Heidelberg [Heidelberg], Fundación Pública Galega de Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica-USC, CIBER-ER, Division of Cancer Prevention and Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Genetic Counseling and Hereditary Cancer Programme, Catalan Institute of Oncology, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Institut Curie [Paris], Programa de Consell Genètic en Càncer, Institut Català d'Oncologia, Girona-IdIBGi, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Centre René Gauducheau, CRLCC René Gauducheau, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Ludwig-Maximilians-Universität München (LMU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetics, University of Southampton, Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Genomic Medicine, University of Manchester [Manchester], Department of Medical Genetics, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Obstetrics and Gynaecology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institüt für Humangenetik [Würzburg], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institute of Chemistry [Budapest], Faculty of Sciences [Budapest], Eötvös Loránd University (ELTE)-Eötvös Loránd University (ELTE), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universitaet, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Department of Oncology, Lund University [Lund]-Clinical Sciences, Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Institute for Medical Informatics, Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, University Medical Center Kiel, Department of Obstetrics and Gynecology, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Medical Genetics Unit, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Biochemistry, Section of Molecular Diagnostics, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Institute of Cell and Molecular Pathology, Medizinische Hochschule Hannover (MHH), University of California [Santa Cruz] (UCSC), University of California, Heidelberg University Hospital [Heidelberg], International Agency for Cancer Research (IACR), Programa de Consejo Genético en Cáncer, Instituto Catalán de Oncología-IDIBELL, L'Hospitalet, Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Hospitalet de Llobregat, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, CIBER de Enfermedades Raras (CIBERER), Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, University of Otago [Dunedin, Nouvelle-Zélande], Institute of Pathology, Department of Gynecology, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), King‘s College London, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Medicum, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, University Management, University of Helsinki, Università degli Studi di Milano = University of Milan (UNIMI), Universität Heidelberg [Heidelberg] = Heidelberg University, Department of Genetics and Pathology, Uppsala University, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Julius-Maximilians-Universität Würzburg (JMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Firenze = University of Florence (UniFI), Université de Lille-UNICANCER-Université de Lille-UNICANCER, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Universität Leipzig, University of Cologne, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
- Subjects
Male ,Multifactorial Inheritance ,BRCA1 ,BRCA2 ,classification ,clinical ,multifactorial ,quantitative ,uncertain significance ,variant ,Alternative Splicing ,BRCA1 Protein ,BRCA2 Protein ,Computational Biology ,Early Detection of Cancer ,Female ,Genetic Predisposition to Disease ,Humans ,Likelihood Functions ,Neoplasms ,Mutation, Missense ,Medicina Básica [Ciências Médicas] ,Settore MED/03 - GENETICA MEDICA ,GUIDELINES ,Genetic analysis ,CLINGEN ,SEQUENCE VARIANTS ,Missense mutation ,FUNCTIONAL ASSAYS ,Genetics (clinical) ,BRCA1, BRCA2, quantitative, clinical, classification, multifactorial, variant, uncertain significance ,0303 health sciences ,education.field_of_study ,030305 genetics & heredity ,1184 Genetics, developmental biology, physiology ,SPLICING ANALYSIS ,OVARIAN ,BRCA2 Protein/genetics ,3. Good health ,ddc ,Mutation (genetic algorithm) ,Ciências Médicas::Medicina Básica ,Medical genetics ,Special Articles ,medicine.medical_specialty ,Posterior probability ,Population ,Computational biology ,Biology ,INTEGRATED EVALUATION ,03 medical and health sciences ,Special Article ,medicine ,Genetics ,BREAST-CANCER ,Genetic variability ,ddc:610 ,education ,030304 developmental biology ,Tumors ,Science & Technology ,Proteins ,Computational Biology/methods ,RISKS ,Mutation ,BRCA1 Protein/genetics ,3111 Biomedicine ,Missense ,Proteïnes ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Genètica ,Neoplasms/diagnosis - Abstract
The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., Ohio State University Comprehensive Cancer Center Barretos Cancer Hospital. Grant Number: FINEP ‐ CT‐INFRA (02/2010) Breast Cancer Foundation of New Zealand Canadian Institutes of Health Research. Grant Number: PSR‐SIIRI‐701 Cancer Research UK. Grant Numbers: C8197/A16565, C5047/A8384, C1281/A12014, C12292/A11174, C1287/A10710, C1287/A10118, C1287/A16563, C5047/A10692, C5047/A15007 Department of Defence, USA. Grant Number: W81XWH‐10‐1‐0341 Helsinki University Hospital Research fund Scientific Foundation Asociación Española Contra el Cáncer Leiden University Medical Centre. Grant Number: Grant 30.925 Generalitat de Catalunya. Grant Numbers: PERIS_MedPerCan, URDCat, 2017SGR1282, 2017SGR496 Royal Society of New Zealand Cancer Council Victoria Netherlands Organization for Scientific Research (NWO). Grant Number: Grant 017.008.022 Breast Cancer Research Foundation Cancer Foundation of Western Australia EU H2020. Grant Number: 634935 Fundación Mutua Madrileña Seventh Framework Programme. Grant Numbers: 634935, 223175, 633784 Cancer Council South Australia Government of Galicia. Grant Number: Consolidation and structuring program: IN607B Cancer Council Tasmania Italian Association of Cancer Research. Grant Number: 15547 Queensland Cancer Fund AstraZeneca National Institute of Health (USA). Grant Numbers: 1U19 CA148065‐01, CA128978, CA192393, 1U19 CA148537, P50 CA1162091, CA116167, 1U19 CA148112 Newcastle University Dutch Cancer Society KWF. Grant Numbers: KWF/Pink Ribbon‐11704, UL2012‐5649 National Institute for Health Research. Grant Number: Manchester Biomedical Research centre (IS‐BRC‐1215 National Council of Technological and Scientific Development (CNPq) Instituto de Salud Carlos III. Grant Numbers: FIS PI15/00355, FIS PI13/01711, CIBERONC, FIS PI16/01218, PI16/00563 French National Institute of Cancer National Breast Cancer Foundation National Health and Medical Research Council. Grant Numbers: ID1061778, ID1104808 Carlos III National Health Centro de Investigación Biomédica en Red de Enferemdades Raras. Grant Number: ACCI 2016: ER17P1AC7112/2018 Cancer Council NSW Deutsche Krebshilfe. Grant Numbers: (#110837, #70111850 Fondazione Pisa. Grant Number: Grant “Clinical characterization of BRCA 1/2 Mis
- Published
- 2019
12. Glaucoma in patients with shunt-treated normal pressure hydrocephalus
- Author
-
Nicola Di Lorenzo, Pasquale Gallina, Eleonora Becattini, Antonio Scollato, Giulia Carreras, Berardino Porfirio, Stanislao Rizzo, Simone Orlandini, and Alfonso Savastano
- Subjects
Male ,Intracranial Pressure ,genetic structures ,CSF diversion ,ICP = intracranial pressure ,IOP = intraocular pressure ,NPH = normal pressure hydrocephalus ,NTG = normal tension glaucoma ,VP = ventriculoperitoneal ,intracranial hypotension ,normal pressure hydrocephalus ,normal tension glaucoma ,trans–lamina cribrosa gradient ,Glaucoma ,Ventriculoperitoneal Shunt ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Reference Values ,Risk Factors ,Normal pressure hydrocephalus ,Normal tension glaucoma ,Humans ,Medicine ,In patient ,Low Tension Glaucoma ,Intracranial Hypotension ,Intraocular Pressure ,Aged ,Intracranial pressure ,Aged, 80 and over ,business.industry ,Optic Nerve ,General Medicine ,medicine.disease ,Hydrocephalus, Normal Pressure ,eye diseases ,Anesthesia ,030221 ophthalmology & optometry ,Optic nerve ,Female ,sense organs ,business ,030217 neurology & neurosurgery ,Shunt (electrical) - Abstract
OBJECTIVEChanges in the pressure gradient between intraocular and intracranial compartments at the lamina cribrosa level are a possible explanation of normal tension glaucoma (NTG). Shunt-treated normal pressure hydrocephalus (NPH) is a model for testing whether the increase (time from disease onset to CSF shunt placement, i.e., “protection period”) and decrease (time from shunt placement to observation, i.e., “exposure period”) in intracranial pressure (ICP) are glaucoma protective or risk factors, respectively. The authors estimated the prevalence of NTG in patients with shunt-treated NPH and calculated the extent of optic nerve exposure to changes in the trans–lamina cribrosa gradient.METHODSData obtained in patients with NPH who had undergone ventriculoperitoneal (VP) shunt placement were analyzed. Patients with more than 6 months’ follow-up, no pathologies associated with ICP changes or CSF dynamics disturbances, and no surgical or valve-related complications were scheduled for ophthalmic evaluation.RESULTSNine of 22 patients had NTG, which is about a 40-fold increase in rate compared with the rate in the general elderly population without hydrocephalus (p < 0.001). The median protection period was 12.0 months in patients with NTG and 18.0 months in those without NTG (p = 0.033). The median ICP decrease multiplied by duration of exposure in months was 76.0 mm Hg × months in the NTG group and 24.1 mm Hg × months in the no-NTG group (p = 0.048). The patients’ median adjusted age (adjusted for “protection” and “exposure” times) was 85.1 years in the NTG group and 78.8 years in the no-NTG group (p = 0.001).CONCLUSIONSA crucial risk factor for development of NTG in patients with shunt-treated NPH is the duration of optic nerve exposure to the lowering of ICP. Patients with NPH who are candidates for CSF shunting should be informed of the risk of incurring glaucoma. Longitudinal studies could provide estimates of tolerated times for a given ICP decrease.
- Published
- 2018
13. Donor-Specific Anti-HLA Antibodies in Huntington's Disease Recipients of Human Fetal Striatal Grafts
- Author
-
Giovanni Rombolà, Benedetta Nacmias, Riccardo Saccardi, Letizia Lombardini, Anna Laura Putignano, Berardino Porfirio, Silvia Bagnoli, Pasquale Gallina, Gabriella B. Vannelli, E Ghelli, Benedetta Mazzanti, Nicola Di Lorenzo, Sandra Bucciantini, and Marco Paganini
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Biomedical Engineering ,lcsh:Medicine ,Disease ,Fetus ,Huntington's disease ,HLA Antigens ,Isoantibodies ,Humans ,Medicine ,Hla antibodies ,Transplantation ,biology ,business.industry ,lcsh:R ,Cell Biology ,Allografts ,medicine.disease ,Corpus Striatum ,Huntington Disease ,Human fetal ,Immunology ,biology.protein ,Female ,Antibody ,business ,Allotransplantation - Abstract
Fetal grafting in a human diseased brain was thought to be less immunogenic than other solid organ transplants, hence the minor impact on the efficacy of the transplant. How much prophylactic immune protection is required for neural allotransplantation is also debated. High-sensitive anti-HLA antibody screening in this field has never been reported. Sixteen patients with Huntington's disease underwent human fetal striatal transplantation in the frame of an open-label observational trial, which is being carried out at Florence University. All patients had both brain hemispheres grafted in two separate robotic-stereotactic procedures. The trial started in February 2006 with the first graft to the first patient (R1). R16 was given his second graft on March 2011. All patients received triple immunosuppressive treatment. Pre- and posttransplant sera were analyzed for the presence of anti-HLA antibodies using the multiplexed microsphere-based suspension array Luminex xMAP technology. Median follow-up was 38.5 months (range 13-85). Six patients developed anti-HLA antibodies, which turned out to be donor specific. Alloimmunization occurred in a time window of 0–49 months after the first neurosurgical procedure. The immunogenic determinants were non-self-epitopes from mismatched HLA antigens. These determinants were both public epitopes shared by two or more HLA molecules and private epitopes unique to individual HLA molecules. One patient had non-donor-specific anti-HLA antibodies in her pretransplant serum sample, possibly due to previous sensitization events. Although the clinical significance of donor-specific antibodies is far from being established, particularly in the setting of neuronal transplantation, these findings underline the need of careful pre- and posttransplant immunogenetic evaluation of patients with intracerebral grafts.
- Published
- 2015
14. Fibroblast growth factor and endothelin-1 receptors mediate the response of human striatal precursor cells to hypoxia
- Author
-
Erica Sarchielli, Gabriella B. Vannelli, Pasquale Gallina, Stefano Ambrosini, Annamaria Morelli, Berardino Porfirio, and Paolo Comeglio
- Subjects
Vascular Endothelial Growth Factor A ,Oxidoreductases Acting on CH-CH Group Donors ,medicine.medical_specialty ,Cell Survival ,Nerve Tissue Proteins ,Biology ,Fibroblast growth factor ,chemistry.chemical_compound ,Neural Stem Cells ,Neurotrophic factors ,Internal medicine ,medicine ,Humans ,RNA, Messenger ,Receptor, Fibroblast Growth Factor, Type 1 ,Receptor ,Cells, Cultured ,Cell Proliferation ,Fetal Stem Cells ,Dose-Response Relationship, Drug ,Endothelin-1 ,Cell growth ,General Neuroscience ,Fibroblast growth factor receptor 1 ,Cobalt ,Hypoxia-Inducible Factor 1, alpha Subunit ,Receptor, Endothelin A ,Receptor, Endothelin B ,Endothelin 1 ,Cell Hypoxia ,Corpus Striatum ,Cell biology ,Fibroblast Growth Factors ,Vascular endothelial growth factor ,Endocrinology ,chemistry ,Fibroblast Growth Factor 2 ,Endothelin receptor ,Central Nervous System Agents - Abstract
Fetal striatal transplantation has emerged as a new therapeutic strategy in Huntington's disease (HD). Hypoxia is one of the microenvironmental stress conditions to which fetal tissue is exposed as soon as it is isolated and transplanted into the diseased host brain. Mechanisms that support neuroblast survival and replenishment of damaged cells within the HD brain in the hypoxic condition have yet to be fully elucidated. This study is aimed at investigating the molecular pathways associated with the hypoxic condition in human fetal striatal neuroblasts (human striatal precursor (HSP) cells), using the hypoxia-mimetic agent cobalt chloride (CoCl2). We analyzed the effect of CoCl2 on HSP cell proliferation and on the expression of hypoxia-related proteins, such as hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Moreover, we evaluated fibroblast growth factor 2 (FGF2; 50ng/ml) and endothelin-1 (ET-1; 100nM) proliferative/survival effects in HSP cells in normoxic and hypoxic conditions. Dose-response experiments using increasing concentrations of CoCl2 (50-750μM) showed that the HSP cell growth was unaffected after 24h, while it increased at 48h, with the maximal effect observed at 400μM. In contrast, cell survival was impaired at 72h. Hypoxic conditions determined HIF-1α protein accumulation and increased gene and protein expression of VEGF, while FGF2 and ET-1 significantly stimulated HSP cell proliferation both in normoxic and hypoxic conditions, thus counteracting the apoptotic CoCl2 effect at 72h. The incubation with selective receptor (FGFR1, endothelin receptor A (ETA) and endothelin receptor B (ETB)) inhibitors abolished the FGF2 and ET-1 neuroprotective effect. In particular, ET-1 stimulated HSP cell survival through ETA in normoxic conditions and through ETB during hypoxia. Accordingly, ETA expression was down-regulated, while ETB expression was up-regulated by CoCl2 treatment. Overall, our results support the idea that HSP cells possess the machinery for their adaptation to hypoxic conditions and that neurotrophic factors, such as FGF2 and ET-1, may sustain neurogenesis and long-term survival through complex receptor-mediated mechanisms.
- Published
- 2015
15. Multifaceted roles of BDNF and FGF2 in human striatal primordium development. An in vitro study
- Author
-
Stefano Ambrosini, Berardino Porfirio, Erica Sarchielli, Pasquale Gallina, Ferdinando Paternostro, Mirca Marini, Annamaria Morelli, Alessandro Peri, Gabriella B. Vannelli, Emanuela Barletta, Pamela Pinzani, Lara Ballerini, Marco Paganini, and Benedetta Mazzanti
- Subjects
Population ,Nerve Tissue Proteins ,Biology ,Cell therapy ,Fetus ,Neural Stem Cells ,Developmental Neuroscience ,Antigens, CD ,Cell Movement ,Cell Plasticity ,Neurites ,Humans ,Antigens ,Progenitor cell ,education ,Cells, Cultured ,Cell Proliferation ,Neurons ,education.field_of_study ,Brain-Derived Neurotrophic Factor ,Neurogenesis ,O Antigens ,Cell Differentiation ,Corpus Striatum ,Neural stem cell ,Transplantation ,Gene Expression Regulation ,nervous system ,Neurology ,biology.protein ,Fibroblast Growth Factor 2 ,Proteoglycans ,Cell Adhesion Molecules ,Neuroglia ,Neuroscience ,Neurotrophin - Abstract
Grafting fetal striatal cells into the brain of Huntington's disease (HD) patients has raised certain expectations in the past decade as an effective cell-based-therapy for this devastating condition. We argue that the first requirement for successful transplantation is defining the window of plasticity for the striatum during development when the progenitor cells, isolated from their environment, are able to maintain regional-specific-identity and to respond appropriately to cues. The primary cell culture from human fetal striatal primordium described here consists of a mixed population of neural stem cells, neuronal-restricted progenitors and striatal neurons. These cells express trophic factors, such as BDNF and FGF2. We show that these neurotrophins maintain cell plasticity, inducing the expression of neuronal precursor markers and cell adhesion molecules, as well as promoting neurogenesis, migration and survival. We propose that BDNF and FGF2 play an important autocrine-paracrine role during early striatum development in vivo and that their release by fetal striatal grafts may be relevant in the setting of HD cell therapy.
- Published
- 2014
16. A Comment on 'Juvenile-onset Normal Tension Glaucoma From Chronic, Recurrent Low Cerebrospinal Fluid Pressure.' J Glaucoma. 2016;25: e738-e740
- Author
-
Simone Orlandini, Eleonora Becattini, Berardino Porfirio, Stanislao Rizzo, Alfonso Savastano, and Pasquale Gallina
- Subjects
Intraocular pressure ,medicine.medical_specialty ,business.industry ,Glaucoma ,medicine.disease ,Low Tension Glaucoma ,03 medical and health sciences ,Ophthalmology ,0302 clinical medicine ,Juvenile onset ,Normal pressure hydrocephalus ,Cerebrospinal Fluid Pressure ,Normal tension glaucoma ,030221 ophthalmology & optometry ,medicine ,Humans ,Cerebrospinal fluid pressure ,business ,030217 neurology & neurosurgery ,Intraocular Pressure - Published
- 2016
17. A Comment on the 'Progression of Normal-tension Glaucoma After Ventriculoperitoneal Shunt to Decrease Cerebrospinal Fluid Pressure'. J Glaucoma. 2016;25
- Author
-
Pasquale Gallina, Alfonso Savastano, Berardino Porfirio, Stanislao Rizzo, and Nicola Di Lorenzo
- Subjects
Ophthalmology ,medicine.medical_specialty ,business.industry ,Normal tension glaucoma ,Medicine ,Glaucoma ,Cerebrospinal fluid pressure ,business ,medicine.disease ,Surgery ,Shunt (medical) - Published
- 2016
18. A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria
- Author
-
Wendy J. Introne, Berardino Porfirio, Miriam Cordovana, Greta Gorelli, Roberta Sestini, Alessandro Mannoni, Jeanette L. Usher, William A. Gahl, and Thierry Vilboux
- Subjects
0301 basic medicine ,Genetics ,Ochronosis ,Biology ,medicine.disease ,Article ,Alkaptonuria ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,alkaptonuria, founder effect, population screening ,Genotyping ,030217 neurology & neurosurgery ,Founder effect ,Homogentisate 1,2-dioxygenase - Abstract
We sought to establish rapid and specific genotyping methods for G360R mutation and for seven tightly linked markers in the homogentisate dioxygenase gene to address the question of whether G360R is a mutational hot spot or the result of a founder effect, as it has been repeatedly found in alkaptonuric patients from a geographic isolate in Italy.For G360R and single nucleotide polymorphism genotyping, high-resolution melting analysis was performed. Microsatellites were analysed by multiplex PCR and capillary electrophoresis. To investigate the natural history of the G360R mutation, we genotyped markers in 52 controls and in 8 unrelated patients from the UK and USA, who also segregated the G360R mutation, and calculated its age using DMLE+2.3 software.A distinct G360R-bearing haplotype was identified in all patients of Caucasian descent. Estimated mutation age was 545 generations (95% credible set, 402-854), suggesting that G360R arose in an ancestor who lived 8,000-10,000 years BC. Archaeological, historical and demographic data support that a G360R carrier has settled the remote valley where present-day population might have a heterozygote frequency of at least 6%.Given the late health-threatening complications of alkaptonuria and a cure within reach, inhabitants of this isolate would benefit from screening and genetic counselling.
- Published
- 2016
19. Functional polymorphisms of the microsomal epoxide hydrolase gene: A reappraisal on a early-onset lung cancer patients series
- Author
-
Luca Messerini, Luca Novelli, Berardino Porfirio, Camilla E. Comin, Matteo Andreani, Clemente Crisci, Claudio Graziano, and Leonardo Politi
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,EPHX1 ,Polymorphism, Single Nucleotide ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Lung cancer ,Epoxide hydrolase ,Carcinogen ,Aged ,Aged, 80 and over ,Epoxide Hydrolases ,business.industry ,Respiratory disease ,Age Factors ,Cancer ,Middle Aged ,medicine.disease ,Exact test ,Microsomal epoxide hydrolase ,Immunology ,Female ,business - Abstract
Summary Microsomal epoxide hydrolase gene ( EPHX1 ) is polymorphic and encodes an enzyme involved in both the activation and detoxification of several tobacco carcinogens. Therefore, a contribution of EPHX1 enzymatic activity on lung cancer risk is possible. A genetic component of early-onset lung cancer has been suggested but variations in enzyme activity and polymorphisms in EPHX1 have seldom been studied in young patients with lung cancer. Primary lung cancer cases of both sexes and under age 45 at diagnosis were considered for this study. Controls fulfilled the following criteria: over 60 years old, smoking history of at least 40 years, no malignancies. Because of these criteria, they are referred to as super controls. The polymorphisms at exons 3 (Tyr113His) and 4 (His139Arg) as well as at the 5′-UTR-290T/G of the EPHX1 gene were genotyped by minisequencing. The association of these three polymorphisms with the development of early-onset lung cancer and the group of the super controls was evaluated by means of 2×2 tables using Yate's X 2 test or Fisher's exact test. Overall, data were obtained from 42 cases and 72 super controls. There was a significant association between early-onset lung cancer and the presence of the EPHX1 exon 4 variant (OR=3.33, 95% CI=1.50–7.41). This was confirmed at the phenotypic level when the data of both patients and super controls were stratified according to the predicted enzymatic activity ( X 2 for linear trend=7.23, p =0.007). This analysis of lung cancer in subjects under age 45 supports the hypothesis that EPHX1 polymorphisms may have a role in cancer susceptibility in this age group.
- Published
- 2009
20. The metabonomic signature of celiac disease
- Author
-
Leonardo Tenori, Claudio Luchinat, Stefano Nepi, Antonio Calabrò, Edoardo Saccenti, Daniela Renzi, Berardino Porfirio, Valeria De Carli, and Ivano Bertini
- Subjects
Adult ,Male ,Proteomics ,Magnetic Resonance Spectroscopy ,Proteomics methods ,Energy metabolism ,Disease ,Biology ,Biochemistry ,NMR spectroscopy ,HLA Antigens ,Humans ,Metabolomics ,Celiac disease ,Systems and Synthetic Biology ,Intestinal Mucosa ,Autoantibodies ,VLAG ,Gut microflora ,Potential impact ,Systeem en Synthetische Biologie ,Models, Statistical ,Support vector machines ,Case-control study ,General Chemistry ,Intestines ,Case-Control Studies ,Immunology ,Female - Abstract
Celiac disease (CD) is a multifactorial disorder involving genetic and environmental factors, thus, having great potential impact on metabolism. This study aims at defining the metabolic signature of CD through Nuclear Magnetic Resonance (NMR) of urine and serum samples of CD patients. Thirty-four CD patients at diagnosis and 34 healthy controls were examined by 1H NMR of their serum and urine. A CD patients' subgroup was also examined after a gluten-free diet (GFD). Projection to Latent Structures provided data reduction and clustering, and Support Vector Machines provided pattern recognition and classification. The classification accuracy of CD and healthy control groups was 79.7-83.4% for serum and 69.3% for urine. Sera of CD patients were characterized by lower levels (P < 0.01) of several metabolites such as amino acids, lipids, pyruvate and choline, and by higher levels of glucose and 3-hydroxybutyric acid, while urines showed altered levels (P < 0.05) of, among others, indoxyl sulfate, meta-[hydroxyphenyl]propionic acid and phenylacetylglycine. After 12 months of GFD, all but one of the patients were classified as healthy by the same statistical analysis. NMR thus reveals a characteristic metabolic signature of celiac disease. Altered serum levels of glucose and ketonic bodies suggest alterations of energy metabolism, while the urine data point to alterations of gut microbiota. Metabolomics may thus provide further hints on the biochemistry of the disease.
- Published
- 2009
21. Aβ Clearance, 'hub' of Multiple Deficiencies Leading to Alzheimer Disease
- Author
-
Pasquale Gallina, Nicola Di Lorenzo, Berardino Porfirio, Antonio Scollato, and R. Conti
- Subjects
Apolipoprotein E ,Opinion ,Aging ,Cognitive Neuroscience ,Tau protein ,Hyperphosphorylation ,Context (language use) ,lcsh:RC321-571 ,neuroinflammation ,mental disorders ,medicine ,Dementia ,neurovascular unit ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neuroinflammation ,apolipoprotein E ,biology ,Neurodegeneration ,Aβ clearance ,medicine.disease ,biology.protein ,Alzheimer disease ,Virchow–Robin spaces ,Alzheimer's disease ,Psychology ,Neuroscience - Abstract
The role of the amyloid cascade in the pathogenesis of Alzheimer’s disease (AD) is still the subject of passionate debates (Herrup, 2015; Musiek and Holtzman, 2015). According to quite a radical viewpoint (Herrup, 2015), the tendency to try to find a unifying etiopathogenetic pathway has so far hampered the understanding of such a complex disease. Thus, it would be better to reject the amyloid cascade hypothesis since it is neither necessary nor sufficient to drive the development and progression of AD. Herrup (2015) proposes, as food for thought, to relocate the amyloid cascade in a multifactorial context where it represents only one of a number of deficiencies contributing to degenerative escalation in the age-weakened brain (Herrup, 2015). From a more conservative perspective, the amyloid cascade is the necessary key initiator of a complex sequence of pathological changes, especially tau protein hyperphosphorylation, which mediates neurodegeneration (Musiek and Holtzman, 2015). However, owing to the lapse in time between the appearance of amyloid plaques and that of tau protein tangles, neuronal loss and dementia, as well as the absence of an obvious anatomical colocalization between the amyloidogenic process and neurodegeneration areas, the amyloid cascade hypothesis is not sufficient to explain AD pathology unless supported by a series of “wingmen” (Musiek and Holtzman, 2015).
- Published
- 2015
22. A commentary on 'Differentiation of pluripotent stem cells into striatal projection neurons: a pure MSN fate may not be sufficient'
- Author
-
Gabriella B. Vannelli, Annamaria Morelli, R. Conti, Pasquale Gallina, and Berardino Porfirio
- Subjects
embryonic stem cell striatal-committed progenitors ,Fetus ,General Commentary ,Cell ,Fetal tissue ,Huntington's disease ,striatal anlagen ,medicine.disease ,Neural stem cell ,Transplantation ,DARPP-32 neurons ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,medicine ,Stem cell ,fetal striatal transplantation ,Induced pluripotent stem cell ,Psychology ,Neuroscience - Abstract
Proof-of-concept has long been gained from both Huntington's disease (HD) animal models and pilot clinical trials that transplantation of fetal striatal tissue has the potential to offer a substitutive therapy to HD patients (Peschanski et al., 1995; Bachoud-Levi et al., 2006; Reuter et al., 2008; Paganini et al., 2014). Nonetheless, in the stem cell era, the body of knowledge so far obtained from fetal tissue as cell source may well be handed over to the clinical exploitation of neural stem cells (Tabar and Studer, 2014).
- Published
- 2015
23. Radiation-induced cutaneous carcinoma of the head and neck: is there an early role for p53 mutations?
- Author
-
Alessandro Franchi, Daniela Massi, Oreste Gallo, Marco Santucci, and Berardino Porfirio
- Subjects
Pathology ,medicine.medical_specialty ,Neoplasms, Radiation-Induced ,Skin Neoplasms ,MOUSE SKIN ,Tumor suppressor gene ,Dermatology ,Biology ,medicine.disease_cause ,Immunoenzyme Techniques ,BASAL-CELL ,medicine ,Humans ,Radiodermatitis ,Genetic Predisposition to Disease ,Polymorphism, Single-Stranded Conformational ,Microdissection ,Mutation ,IONIZING-RADIATION ,GAMMA-IRRADIATION ,CANCER ,DNA ,INDUCTION ,CARCINOGENESIS ,APOPTOSIS ,ADJACENT ,Base Sequence ,Transition (genetics) ,Epidermis (botany) ,Neoplasms, Second Primary ,DNA, Neoplasm ,Genes, p53 ,Head and Neck Neoplasms ,Immunohistochemistry ,Tumor Suppressor Protein p53 ,Carcinogenesis - Abstract
Summary Background. Little is known about the molecular mechanisms underlying ionizing radiation-induced carcinogenesis of the skin. Aims. To investigate the possible role of p53 in radiodermatitis and in the development of radiation-induced cutaneous carcinomas. Methods. The study group comprised six patients affected by cutaneous carcinomas arising in radiodermatitis (one squamous cell carcinoma and five basal cell carcinomas), and seven patients presenting only chronic radiodermatitis. Skin specimens were evaluated for p53 immunohistochemical expression. Using laser-assisted microdissection, areas with different p53 immunoreactivity were separately submitted to DNA isolation and p53 gene analysis. Results. In the majority of cases (9/12, 75%), p53 immunoreactivity was detected in radiation-damaged epidermis. In carcinomas p53 oncoprotein was expressed by several neoplastic cells in one case (16.7%%), or by nearly all neoplastic cells in four (66.7%). SSCP band shifts were detected in 9/25 samples (36%) microdissected from irradiated epidermis and in 3/6 (50%) carcinomas. DNA sequencing demonstrated two repeatedly found mutations: a G deletion at codon 244 and an AG transition at codon 205, as well as hallmarks of ultraviolet mutagenic action, including a CT transition occurring at a dipyrimidine site and a CCTT tandem double-base transition. Conclusion. Our data indicate that irradiation induces significant p53 alterations that may be relevant in the modification of epithelial maturation processes and may be responsible for the high risk for development of carcinomas in radiodermatitis.
- Published
- 2006
24. Lack of association between the HLA-DRB1 locus and post-streptococcal reactive arthritis and acute rheumatic fever in italian children
- Author
-
Berardino Porfirio, Teresa Giani, Giovanni Battista Calabri, Rolando Cimaz, Gabriele Simonini, and Fernanda Falcini
- Subjects
Male ,musculoskeletal diseases ,medicine.medical_specialty ,Adolescent ,Locus (genetics) ,Arthritis, Reactive ,Cohort Studies ,Rheumatology ,immune system diseases ,Streptococcal Infections ,Internal medicine ,Genotype ,medicine ,Humans ,Reactive arthritis ,Typing ,Allele ,Child ,skin and connective tissue diseases ,HLA-DRB1 ,business.industry ,Histocompatibility Testing ,HLA-DR Antigens ,medicine.disease ,Anesthesiology and Pain Medicine ,Italy ,Child, Preschool ,Acute Disease ,Immunology ,Rheumatic fever ,Female ,Rheumatic Fever ,business ,HLA-DRB1 Chains - Abstract
OBJECTIVE Post-streptococcal reactive arthritis (PSReA) may be a variant of acute rheumatic fever (ARF), but there still is debate on the relationship between the 2 entities. Possible associations with HLA class II antigens of PSReA (DRB1*01) and ARF (DRB1*16) were described previously in white Americans. To confirm these findings, we studied DRB1 alleles in a group of Italian children with PSReA and ARF. METHODS We performed low-resolution HLA-DRB1 typing by a sequence-specific primer polymerase chain reaction method in 33 children with PSReA and 25 children with ARF. We also compared the DRB1 genotypes of our patients with 200 normal subjects from the same geographic area and typed in the same laboratory with the same methods. RESULTS The allele distributions at the DRB1 locus observed in PSReA patients, ARF patients, and controls were not significantly different from each other (chi-square test with small numbers, P = .65). The positivity for each of the 13 HLA-DRB1 alleles was compared in disease groups (PSReA and ARF) and controls, and failed to show any significant association. Comparisons of the frequency of the DRB1*01 allele among PSReA, ARF, and controls did not show any statistical differences. No significant difference in the frequency of DRB1*16 was present between ARF vs the control group, between ARF vs PSReA, and in PSReA patients when compared with controls. CONCLUSIONS Our data do not confirm in Italian patients the previously reported associations of DRB1*01 and DRB1*16 with PSReA and ARF, respectively.
- Published
- 2004
25. Alkaptonuria, ochronosis, and ochronotic arthropathy
- Author
-
Lupo Andreotti, Sauro Lorenzini, Alessandro Mannoni, Massimo Giorgi, Berardino Porfirio, Enrico Selvi, Roberto Marcolongo, Paolo Airó, and Daniele Cammelli
- Subjects
Male ,medicine.medical_specialty ,Pathology ,DNA Mutational Analysis ,Arthritis ,Alkaptonuria ,Dioxygenases ,Rheumatology ,Internal medicine ,Arthropathy ,medicine ,Humans ,Pigmentation disorder ,Aged ,Homogentisate 1,2-dioxygenase ,Homogentisate 1,2-Dioxygenase ,Ochronosis ,business.industry ,Middle Aged ,medicine.disease ,Anesthesiology and Pain Medicine ,Aminoaciduria ,Mutation ,Oxygenases ,Female ,Joint Diseases ,business - Abstract
Objectives To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition. Methods We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers. Results Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane. Conclusions Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.
- Published
- 2004
26. Shared-epitope HLA-DRB1 alleles and sex ratio in Italian patients with rheumatoid arthritis
- Author
-
Berardino Porfirio, G. Bianucci, A. Palasciano, Giovanni Rombolà, S. Maddali Bongi, and Elisabetta Beneforti
- Subjects
Adult ,Male ,musculoskeletal diseases ,Immunogenetics ,Human leukocyte antigen ,Epitope ,Arthritis, Rheumatoid ,Epitopes ,Gene Frequency ,Rheumatology ,immune system diseases ,medicine ,Humans ,Genetic Predisposition to Disease ,Sex Ratio ,Typing ,Allele ,skin and connective tissue diseases ,HLA-DRB1 ,Allele frequency ,Aged ,Aged, 80 and over ,business.industry ,HLA-DR Antigens ,Middle Aged ,medicine.disease ,Italy ,Rheumatoid arthritis ,Immunology ,Female ,business ,HLA-DRB1 Chains - Abstract
Objective. – To investigate the association between the HLA-DRB1 alleles sharing the epitope (Q/R)(K/R)RAA and rheumatoid arthritis (RA) in a large sample of Italian patients ( N = 264) recruited from a single centre over the last 5 years. Methods. - Patients’ classification according to the ACR criteria. DNA typing of HLA-DRB1 alleles by conventional polymerase chain reaction sequence specific oligonucleotide probing techniques. Results. – Low-resolution DRB1 “generic” typing showed a significantly higher frequency of DR4+ RA patients as compared to normal controls. Both DR1 and DR10 specificities were over-represented in our patients, but neither reached the statistically significant P level of 0.05 after Bonferroni’s correction. However, direct search of Q(K/R)RAA epitopes, which are present in most DR4+ and DRl+ samples, demonstrated that these motifs were found at increased frequencies in RA patients. Stratification according to gender did not show differences in the proportion of disease-associated HLA alleles. Conclusions. – Our study confirms the association of HLA-DR4, and -DR1 alleles, and more generally speaking of the shared epitopes Q(K/R)RAA, with disease susceptibility in Italian patients.
- Published
- 2004
27. Tag SNPs of the ancestral haplotype 57.1 do not substitute HLA-B*57:01 typing for eligibility to abacavir treatment in the Italian population
- Author
-
Miryam Martinetti, Berardino Porfirio, Roberta Sestini, C. Badulli, Ilaria Sbarsi, Marta Baroncelli, and Cinzia Pizzochero
- Subjects
Pharmacology ,Genetics ,Haplotype ,HCP5 ,Single-nucleotide polymorphism ,Biology ,Dideoxynucleosides ,HLA-B ,Drug Hypersensitivity ,Major Histocompatibility Complex ,HLA-B Antigens ,Abacavir ,Genetic marker ,Pharmacogenomics ,medicine ,Humans ,Reverse Transcriptase Inhibitors ,Molecular Medicine ,Typing ,medicine.drug - Abstract
A letter in response to: Sanchez-Giron F, Villegas-Torres B, Jaramillo-Villafuerte K et al. Association of the genetic marker for abacavir hypersensitivity HLA-B*5701 with HCP5 rs2395029 in Mexican Mestizos. Pharmacogenomics 12(6), 809–814 (2011).
- Published
- 2012
28. Retrospective analysis of 77 patients with ovarian cancer undergoing genetic testing for BRCA1 and BRCA2 mutations
- Author
-
Laura Papi, K. Tavella, Enrico Mini, B. Fantechi, Gabriele Lorenzo Capone, Gianni Amunni, Francesca Gensini, Teresita Mazzei, Berardino Porfirio, A. Villanucci, V. Rossi, Laura Vannini, and Anna Laura Putignano
- Subjects
Oncology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Brca1 protein ,Hematology ,medicine.disease ,Internal medicine ,Mutation (genetic algorithm) ,medicine ,Cancer research ,business ,Ovarian cancer ,Brca1 gene ,Genetic testing - Published
- 2017
29. Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy
- Author
-
Richard Imrich, Shruthi K Bharadwaj, Hana Ayoob, Nicolas Sireau, Birgitta Olsson, G. Biolcati, Tom L. Blundell, Lakshminarayan R. Ranganath, Rangan Srinivasaraghavan, Anthony K Hall, Andrea Zatkova, Oliver Timmis, Kim Hanh Le Quan Sang, Fiammetta Sorge, Ludevit Kadasi, Charles Marques Lourenço, Caterina Aurizi, Mohammed Alsbou, Douglas E. V. Pires, Ronen Spiegel, Jan Radvanszky, Martina Nemethova, Kanakasabapathi Ramadevi, Annalisa Santucci, Robert Aquaron, Lia Milucci, Jozef Rovensky, Alessandro Mannoni, Berardino Porfirio, Silvia Sestini, Federica Genovese, David B. Ascher, James A. Gallagher, and Christa van Kan
- Subjects
0301 basic medicine ,Male ,Models, Molecular ,Genetics (clinical) ,Genetics ,Nitisinone ,Molecular Sequence Data ,Mutation, Missense ,Gene Expression ,Biology ,medicine.disease_cause ,Alkaptonuria ,Polymorphism, Single Nucleotide ,Bone and Bones ,Protein Structure, Secondary ,Article ,03 medical and health sciences ,Exon ,Genetic Heterogeneity ,Polymorphism (computer science) ,Catalytic Domain ,Databases, Genetic ,medicine ,Missense mutation ,Humans ,Gene ,Mutation ,Homogentisate 1,2-Dioxygenase ,Base Sequence ,Genetic heterogeneity ,Exons ,Sequence Analysis, DNA ,medicine.disease ,Introns ,Pedigree ,Bone Diseases, Metabolic ,030104 developmental biology ,Phenotype ,Italy ,Female ,medicine.drug - Abstract
Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650–85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.
- Published
- 2014
30. Large-sized Fetal Striatal Grafts in Huntington’s Disease Do Stop Growing. Long-term Monitoring in the Florence Experience
- Author
-
Pasquale Gallina, Gabriella B. Vannelli, Letizia Lombardini, Nicola Di Lorenzo, Berardino Porfirio, Stefano Diciotti, R. Conti, Andrea Ginestroni, Andrea Bianchi, Mario Mascalchi, and Marco Paganini
- Subjects
medicine.medical_specialty ,Fetus ,business.industry ,Grafting procedure ,Medicine (miscellaneous) ,Bioinformatics ,medicine.disease ,Surgery ,Transplantation ,surgical procedures, operative ,Huntington's disease ,Clinical Assessment ,Experimental therapy ,Long term monitoring ,Human fetal ,medicine ,business ,Neurological deficit - Abstract
Development of six large nodules of solid tissue after bilateral human fetal striatal transplantation in four Huntington's disease patients has raised concern about the safety of this experimental therapy in our setting. We investigated by serial MRI-based volumetric analysis the growth behaviour of such grafts. After 33-73 months from transplantation the size of five grafts was stable and one graft showed a mild decrease in size. Signs neither of intracranial hypertension nor of adjuctive focal neurological deficit have ever been observed. This supports long-term safety of the grafting procedure at our Institution.
- Published
- 2014
31. Re: Fast circulation of cerebrospinal fluid: an alternative perspective on the protective role of high intracranial pressure in ocular hypertension
- Author
-
Alfonso Savastano, Pasquale Gallina, Berardino Porfirio, and Stanislao Rizzo
- Subjects
Intracranial Pressure ,business.industry ,Perspective (graphical) ,Ocular hypertension ,medicine.disease ,03 medical and health sciences ,Ophthalmology ,0302 clinical medicine ,Circulation (fluid dynamics) ,Cerebrospinal fluid ,Anesthesia ,Normal tension glaucoma ,030221 ophthalmology & optometry ,medicine ,Humans ,Ocular Hypertension ,Glymphatic system ,business ,030217 neurology & neurosurgery ,Cerebrospinal Fluid ,Optometry ,Intracranial pressure - Abstract
EDITOR: We read with interest the paper by Wostyn and colleagues2016 on ‘Fast circulation of cerebrospinal fluid: an alternative perspective on the protective role of high intracranial pressure in ...
- Published
- 2016
32. Fetal striatal grafting slows motor and cognitive decline of Huntington's disease
- Author
-
Luca Massacesi, Berardino Porfirio, Silvia Pradella, Letizia Lombardini, Annibale Biggeri, Valentina Berti, Anna Maria Romoli, Marco Paganini, Claudia Mechi, Nicola Di Lorenzo, Mario Mascalchi, Riccardo Saccardi, Gabriella B. Vannelli, Sandra Bucciantini, E Ghelli, Dolores Catelan, and Pasquale Gallina
- Subjects
Fetal Tissue Transplantation ,Adult ,Male ,Pathology ,medicine.medical_specialty ,cell-based therapy ,Neuropsychological Tests ,chemistry.chemical_compound ,Iodobenzamide ,Neuroimaging ,Huntington's disease ,Functional neuroimaging ,Fluorodeoxyglucose F18 ,Internal medicine ,medicine ,Humans ,Brain Tissue Transplantation ,cell-based therapy, corpus striatum, fetal tissue transplantation ,Cognitive decline ,Cerebral Cortex ,medicine.diagnostic_test ,Iodobenzenes ,Receptors, Dopamine D2 ,Functional Neuroimaging ,Middle Aged ,medicine.disease ,Corpus Striatum ,Transplantation ,corpus striatum ,fetal tissue transplantation ,Psychiatry and Mental health ,Huntington Disease ,Treatment Outcome ,chemistry ,Positron emission tomography ,Positron-Emission Tomography ,Cardiology ,Surgery ,Female ,Neurology (clinical) ,Psychology ,Follow-Up Studies - Abstract
Objective To assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntington9s disease (HD). Methods We carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted patients. All patients were evaluated with the Unified HD Rating Scale (UHDRS) whose change in motor, cognitive, behavioural and functional capacity total scores were considered as outcome measures. Grafted patients also received morphological and molecular neuroimaging. Results Patients were followed-up from disease onset for a total of 309.3 person-years (minimum 5.3, median 11.2 years, maximum 21.6 years). UHDRS scores have been available since 2004 (median time of 5.7 years since onset, minimum zero, maximum 17.2 years). Median post-transplantation follow-up was 4.3 years, minimum 2.8, maximum 5.1 years. Adjusted post-transplantation motor score deterioration rate was reduced compared to the pretransplantation period, and to that of not-transplanted patients by 0.9 unit/years (95% CI 0.2 to 1.6). Cognitive score deterioration was reduced of 2.7 unit/years (95% CI 0.1 to 5.3). For grafted patients the 2-year post-transplantation [ 18 F]fluorodeoxyglucose positron emission tomography (PET) showed striatal/cortical metabolic increase compared to the presurgical evaluation; 4-year post-transplantation PET values were slightly decreased, but remained higher than preoperatively. [ 123 I]iodobenzamide single photon emission CT demonstrated an increase in striatal D2-receptor density during postgrafting follow-up. Conclusions Grafted patients experienced a milder clinical course with less pronounced motor/cognitive decline and associated brain metabolism improvement. Life-time follow-up may ultimately clarify whether transplantation permanently modifies the natural course of the disease, allowing longer sojourn time at less severe clinical stage, and improvement of overall survival.
- Published
- 2013
33. Alkaptonuria in Italy: polymorphic haplotype background, mutational profile, and description of four novel mutations in the homogentisate 1,2-dioxygenase gene
- Author
-
Claudio Graziano, Enrico Zammarchi, Amelia Morrone, Mannoni A, Berardino Porfirio, De Córdoba, De Bernabé Db, and Chiarelli I
- Subjects
Genetics ,Genetic heterogeneity ,Haplotype ,Biology ,medicine.disease ,Human genetics ,Alkaptonuria ,medicine ,Allelic heterogeneity ,Allele ,Letters to the Editor ,Gene ,Genetics (clinical) ,Homogentisate 1,2-dioxygenase - Abstract
Editor—Alkaptonuria (AKU, OMIM 203500) is a rare disorder caused by the deficiency of homogentisate 1,2 dioxygenase (HGO, EC 1.13.11.5).1 HGO catalyses the conversion of homogentisate (HGA) to maleylacetoacetate in the phenylalanine/tyrosine catabolic pathway.2 As a consequence, affected subjects excrete HGA in their urine, which becomes dark upon exposure to air. The medical interest in this condition stems from its association with ochronosis, or the deposition of a brownish pigment in connective tissues including cartilage, where its accumulation can produce a debilitating degenerative joint disease.3 AKU occupies a unique place in the history of human genetics because it was the first disorder to be described as a Mendelian recessive trait.4-6 Recent advances in the understanding of the molecular basis of AKU7-9 have verified that loss of function mutations in the HGO gene are responsible for the disease. A few mutations have been repeatedly detected in patients from different European countries. Since these mutations segregated with specific haplotypes, they should be considered to be old mutations that have spread throughout western Europe with migration. However, allelic heterogeneity is the main feature emerging from the above and other studies.7 9-12Most HGO mutations were found in just one family and did not involve CpG dinucleotides. Rather, a preferential occurrence in the CCC sequence motif and its inverted complement GGG has recently been reported.12 Furthermore, some AKU chromosomes escaped mutation detection within the HGO coding region, suggesting the existence of HGO alleles whose defect might be related to gene expression. To determine the extent of allelic heterogeneity in Italian patients, we started a systematic search of AKU families through announcements at relevant National Congresses. We present here the results leading to the identification of four novel mutations. Our data should facilitate future mutation screening …
- Published
- 2000
34. Epstein-Barr virus infection and P53 expression in HIV-related oral large B cell lymphoma
- Author
-
Gianna Baroni, Simonetta Di Lollo, Ilaria Chiarelli, Berardino Porfirio, A Papucci, Giuseppe Ficarra, and Anna Calzolari
- Subjects
Adult ,Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,DNA Mutational Analysis ,Gene Expression ,In situ hybridization ,Gene mutation ,medicine.disease_cause ,Virus ,Viral Matrix Proteins ,hemic and lymphatic diseases ,medicine ,Humans ,B-cell lymphoma ,Epstein–Barr virus infection ,Gene ,In Situ Hybridization ,Polymorphism, Single-Stranded Conformational ,Lymphoma, AIDS-Related ,business.industry ,Exons ,Middle Aged ,Genes, p53 ,medicine.disease ,Immunohistochemistry ,Epstein–Barr virus ,Virology ,Lymphoma ,Otorhinolaryngology ,DNA, Viral ,Cancer research ,Mouth Neoplasms ,Tumor Suppressor Protein p53 ,business - Abstract
Background. Head and neck non-Hodgkin's lymphomas in HIV positive patients are highly related with Epstein-Barr virus (EBV) infection. In general, viral agents can alter p53 protein levels by enhancing degradation of cellular p53 or by increasing its half-life by viral protein-p53 interaction. Moreover, it has been reported that modifications of p53 gene can modulate tumor cells' response to radio- and chemotherapy. Methods. To assess a possible role of EBV infection, p53 protein deregulation, and p53 gene alterations in exons 5 to 8, we have studied six cases of HIV-related primary oral large B-cell lymphoma. We used in situ hybridization (ISH) for EBV-DNA and EBV-encoded nuclear RNA-1 (EBER-1), immunohistochemistry (IHC) for EBV latent membrane protein -1 (LMP-1) and p53 proteins expression, and single strand conformational polymorphism (SSCP) analysis to screen p53 gene mutations in exons 5 to 8. Results. The EBV-DNA was present in all specimens, according to conventional DNA-ISH. No evidence for EBER-1 was found by ISH. The presence of EBV-DNA was correlated with the LMP-1 expression in all but one case. Moreover, p53 protein expression was negative in three cases and strongly positive in the others. However, mutational analysis of p53 gene in exons 5-8 showed no alteration. Conclusions. Our data may suggest that both EBV infection and LMP-1 expression may cause p53 loss of function even in the absence of p53 gene mutations, as assessed by SSCP. We speculate that the presence of EBV-infection and p53 protein deregulation may be responsible for radio- and chemotherapy resistance, by influencing apoptosis of cancer cells.
- Published
- 1999
35. Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy
- Author
-
Marina Pedemonte, Roberto Cusano, Martin Lammens, Michel Fardeau, Victor Dubowitz, Pirta Hilpelä, Avril Castagna-Sloane, Susan T. Iannaccone, Berardino Porfirio, Claudio Graziano, J. Andoni Urtizberea, Francesco Muntoni, Carlo Minetti, Katarina Pelin, Kati Donner, Carina Wallgren-Pettersson, Alan H. Beggs, Nigel G. Laing, Kathryn J. Swoboda, Caroline Sewry, Marco Seri, and Albert de la Chapelle
- Subjects
Genetic Linkage ,Muscle Proteins ,Genes, Recessive ,Gene mutation ,Biology ,Myopathies, Nemaline ,03 medical and health sciences ,Nebulin ,0302 clinical medicine ,Nemaline myopathy ,Genetic linkage ,Locus heterogeneity ,medicine ,Humans ,Tumor pathology ,Child ,Myopathy ,Genetics (clinical) ,030304 developmental biology ,Genetics ,0303 health sciences ,Neuromusculaire en neurometabole aandoeningen ,Genetic heterogeneity ,Chromosome Mapping ,Genetic Variation ,Infant ,Tumor pathologie ,medicine.disease ,Congenital myopathy ,Pedigree ,Neuromuscular and neurometabolic disorders ,Neurology ,Child, Preschool ,Chromosomes, Human, Pair 2 ,Pediatrics, Perinatology and Child Health ,biology.protein ,Neurology (clinical) ,Lod Score ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.
- Published
- 1999
36. Immunohistochemical vs Molecular Biology Methods:Complementary Techniques for Effective Screening of p53 Alterations in Head and Neck Cancer
- Author
-
Ilaria Chiarelli, Pier Luigi Mattiuz, Simonetta Bianchi, Luca Messerini, Anna Calzolari, Oreste Gallo, and Berardino Porfirio
- Subjects
Pathology ,medicine.medical_specialty ,Gene Expression ,Biology ,Polymerase Chain Reaction ,Frameshift mutation ,law.invention ,Immunoenzyme Techniques ,Exon ,law ,medicine ,Humans ,Gene ,Polymorphism, Single-Stranded Conformational ,Polymerase chain reaction ,Antibodies, Monoclonal ,Single-strand conformation polymorphism ,DNA, Neoplasm ,General Medicine ,Genes, p53 ,Epidermoid carcinoma ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Immunohistochemistry ,Tumor Suppressor Protein p53 ,Immunostaining - Abstract
The purpose of this study was to correlate p53 gene alterations and their expression in 85 head and neck squamous cell carcinomas. Genomic p53 was amplified with the polymerase chain reaction (PCR) from formalin-fixed, paraffin-embedded tissues. Exons 5 through 8 were screened for mutations by means of non-isotopic single-strand conformation polymorphism (SSCP) analysis. p53 expression was detected by means of immunohistochemistry (IHC) with the p53 monoclonal antibody DO-7. Twenty-three lesions (27%) showed both SSCP variants and DO-7 immunostaining, whereas 37 (44%) demonstrated both SSCP normal patterns and negative staining. Twenty-five lesions (29%) were discordant, including 12 IHC-positive (14%) and 13 SSCP-positive (15%) lesions. However, discordant IHC-negative, SSCP-positive lesions could have been easily interpreted after sequencing of the abnormal samples. Had these been screened with IHC only, all nonsense or frameshift p53 mutations would have been missed. IHC-positive, SSCP-negative lesions were interpreted in light of current models of p53 immunodetection. Had these been screened with SSCP or sequencing only, a sizeable number of tumors expressing p53 protein abnormalities would have been undetected. Therefore, simultaneous use of both methods increases the number of p53 abnormalities detected, and is warranted.
- Published
- 1997
37. Human striatum remodelling after neurotransplantation in Huntington's disease
- Author
-
E Ghelli, Erica Sarchielli, Mario Maggi, Marco Paganini, Annibale Biggeri, Gabriella B. Vannelli, Benedetta Mazzanti, Carmela Guido, Mirca Marini, Alessandro Peri, Nicola Di Lorenzo, Letizia Lombardini, Valentina Berti, Paolo Simonelli, Pasquale Gallina, Berardino Porfirio, and Annamaria Romoli
- Subjects
Adult ,Male ,Telencephalon ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Neuroimaging ,Striatum ,Severity of Illness Index ,Stereotaxic Techniques ,Huntington's disease ,Fetal Tissue Transplantation ,mental disorders ,medicine ,Humans ,Brain Tissue Transplantation ,Stereotactic neurosurgery ,Neuronal Plasticity ,Gene Expression Profiling ,Graft Survival ,Follow up studies ,Robotics ,medicine.disease ,Combined Modality Therapy ,Magnetic Resonance Imaging ,Corpus Striatum ,Huntington Disease ,Italy ,Positron-Emission Tomography ,Stereotaxic technique ,Surgery ,Graft survival ,Neurology (clinical) ,Psychology ,Cognition Disorders ,Neuroscience ,Central Nervous System Agents ,Follow-Up Studies - Abstract
Background: Restoration of functions in Huntington's disease (HD) by neurotransplantation stems from the formation of a striatum-like structure capable of establishing host connections as a result of grafted striatal neuroblast maturation. For the first time, we demonstrated some developmental steps accomplished by progenitor cells in the brain of an HD patient and analysed the molecular asset of the human primordium. Case Report: Surgery involved bilateral (two sessions) stereotactic, caudate-putaminal transplantation of whole ganglionic eminence fragments from single legally aborted fetuses. MRI showed that the tissue deposits of the left hemisphere grew and joined to constitute a single tissue mass that remodelled basal ganglia anatomy and remained stable in size over time. No evidence of graft growth was observed contralaterally. PET demonstrated increased striatal and stable cortical metabolism. Unified Huntington's Disease Rating Scale assessments demonstrated improvement of motor performances, which faded over the 36-month follow-up. Cognitive performance tended to decrease at a lower rate than before transplantation. Conclusion: The striatal primordium grew into the host brain and this process was associated with metabolic change and some clinical benefit. The study suggests the plasticity and reparative potential of un-manipulated primordium in an era where promising cell-based therapies are still in their infancy.
- Published
- 2013
38. High resolution melting analysis of deletion/insertion polymorphisms: A new method for the detection and quantification of mixed chimerism in allogeneic stem cell transplantation
- Author
-
Maurizio Dal Canto, Chiara Gerini, and Berardino Porfirio
- Subjects
Genotyping Techniques ,Coefficient of variation ,Single-nucleotide polymorphism ,Biology ,Polymerase Chain Reaction ,Sensitivity and Specificity ,High Resolution Melt ,INDEL Mutation ,Humans ,Transition Temperature ,Transplantation, Homologous ,In patient ,Molecular Biology ,Transplantation Chimera ,Mixed chimerism ,Polymorphism, Genetic ,Genome, Human ,Hematopoietic Stem Cell Transplantation ,Genetic Variation ,Cell Biology ,DNA ,Molecular biology ,Transplantation ,Deletion insertion ,Stem cell ,Microsatellite Repeats - Abstract
Increasing mixed chimerism after allogeneic stem cell transplantation has been associated with a high risk of relapse and probable graft failure in patient with hematological malignancies as well as non-malignant conditions. We evaluated a new method for chimerism detection, based on the quantitative High Resolution Melting Analysis (HRMA) of deletion/insertion polymorphisms (DIPs). The study consisted in the selection of a panel of DIPs, all generating genotype-specific melting curves, and in the use of samples containing opposite molecular species (homozygous INS/INS and DEL/DEL) mixed in different percentages to create a standard curve for each polymorphism. The detection of mixed chimerism with the HRMA attained a sensitivity of
- Published
- 2013
39. Sister Chromatid Exchanges in Cultured Amniocytes Exposed to Diagnostic Ultrasound in Vitro
- Author
-
Bruno Dallapiccola, Adriano Piffanelli, Corrado Cittanti, P. Colamussi, Berardino Porfirio, and Melchiore Giganti
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,Diagnostic ultrasound ,Ultrasonography, Prenatal ,Andrology ,Pregnancy ,medicine ,Humans ,Sister chromatids ,Ultrasonics ,Radiology, Nuclear Medicine and imaging ,Cells, Cultured ,Analysis of Variance ,Fetus ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,business.industry ,Cell Cycle ,General Medicine ,Amniotic Fluid ,In vitro ,Linear relationship ,Cell culture ,Amniocentesis ,Female ,Chromatid ,business ,Sister Chromatid Exchange - Abstract
An in vitro system has been set up to study the possible genetic effects of diagnostic ultrasound (US) on the developing fetus. Amniotic cells were cultured by the in situ technique. Well established clones were exposed to US for various lengths of time using a linear array transducer within a sound transparent apparatus. Cells were then grown in the presence of 5-bromo-2'-deoxyuridine and processed for scoring the number of sister chromatid exchanges (SCE) as the cytogenetic endpoint. There was no linear relationship between the SCE frequency and the duration of US exposure. Variance analysis showed that only interindividual variability was a significant component of total variation. Neither the main effect of treatment nor the interaction effect were statistically significant. The data suggest that US delivered from a diagnostic unit to actively growing cultured fetal cells in a system closely mimicking the conditions of US exposure during amniocentesis does not induce SCE.
- Published
- 1994
40. Expression of aphidicolin-induced fragile sites in lymphocytes of patients with breast cancer
- Author
-
Emilio Donti, Carmela Ardisia, Stephen Davis, Cristina Breschi, Berardino Porfirio, Venti G, M.Antonietta Colozza, and Maurizio Tonato
- Subjects
Aphidicolin ,Cancer Research ,Lymphocyte ,Chromosomal fragile site ,Mammary gland ,Biology ,medicine.disease ,Peripheral blood ,chemistry.chemical_compound ,medicine.anatomical_structure ,Breast cancer ,chemistry ,Immunology ,Gene expression ,Genetics ,Cancer research ,medicine ,Molecular Biology ,Metaphase - Abstract
The expression of fragile sites induced by aphidicolin (APC) was evaluated on metaphase chromosomes obtained from the peripheral blood lymphocytes of 26 women with breast cancer and 15 sex- and age-metched normal controls. Both the proportion of damaged cells (P
- Published
- 1993
41. The conundrum of HLA-DRB1*14:01/*14:54 and HLA-DRB3*02:01/*02:02 mismatches in unrelated hematopoietic SCT
- Author
-
Nicoletta Sacchi, Carlo Carcassi, Valeria Miotti, T Valentini, G. Carella, Benedetta Mazzi, Miryam Martinetti, Loretta Crespiatico, Berardino Porfirio, Annamaria Pasi, G. Mazzola, L. Mascaretti, Lucia Garbarino, Alberto Bosi, Katharina Fleischhauer, Roberto Crocchiolo, M Bontempelli, C. Tagliaferri, and C Vecchiato
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Biology ,Exon ,Young Adult ,immune system diseases ,Internal medicine ,medicine ,Humans ,Allele ,Child ,Gene ,HLA-DRB1 ,HLA-DRB3 ,Aged ,Transplantation ,Hematology ,Histocompatibility Testing ,Hematopoietic Stem Cell Transplantation ,Infant ,Middle Aged ,Histocompatibility ,Child, Preschool ,Immunology ,Female ,HLA-DRB3 Chains ,HLA-DRB1 Chains - Abstract
Uncertainty still exists on the role of polymorphisms outside the HLA-DRB1 binding site or inside the HLA-DRB3 binding groove in unrelated hematopoietic SCT (HSCT). The ideal model to solve the conundrum consists of the transplants mismatched for HLA-DRB1*14:01/*14:54 and/or for HLA-DRB3*02:01/*02:02. A task force was set up in Italy to recruit transplanted pairs defined as HLA-DRB1*14:01 before 2006, the year crucial for the proper definition of the HLA-DRB1*14:54 allele in molecular biology. Out of 2723 unrelated pairs, 189 transplanted in Italy from 1995 to 2006 were HLA-DRB1*14:01 positive; 103/189 pairs with good historical DNA were retyped for HLA-DRB1*14 and HLA-DRB3 at-high resolution level; 31/103 pairs had HLA-DRB1*14 and/or HLA-DRB3 mismatched; 99/103, having complete clinical data, underwent statistical analysis for OS, TRM, disease-free survival and acute and chronic GvHD. No significant involvement of HLA-DRB1*14:01/*14:54 or HLA-DRB3*02:01/*02:02 mismatches was found, either alone or combined. Our findings suggest that disparities at exon 3 of the HLA-DRB1 gene seem unlikely to influence the outcome after HSCT. The same may be envisaged for HLA-DRB3(*)02:01 and (*)02:02 alleles which, although differing in the Ag binding site, seem unable to modulate an appreciable immune response in an HSCT setting.
- Published
- 2010
42. Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington's disease patients after transplantation
- Author
-
Mario Mascalchi, Marco Paganini, Letizia Lombardini, Clara Crescioli, Pasquale Gallina, Mirca Marini, Riccardo Saccardi, Berardino Porfirio, Benedetta Bartolozzi, Sandra Bucciantini, Alberto Pupi, Davide Gadda, Maria Teresa De Cristofaro, Nicola Di Lorenzo, Francesca Salvianti, Claudia Mechi, Gabriella B. Vannelli, Serena Urbani, Erica Sarchielli, Anna Maria Romoli, Pamela Pinzani, Silvia Piacentini, and E Bertini
- Subjects
Nervous system ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Central nervous system ,Enzyme-Linked Immunosorbent Assay ,Nerve Tissue Proteins ,Striatum ,Severity of Illness Index ,Central nervous system disease ,Fetus ,Imaging, Three-Dimensional ,Developmental Neuroscience ,Neuroblast ,Huntington's disease ,Cell Movement ,Fluorodeoxyglucose F18 ,HLA Antigens ,medicine ,Humans ,Brain Tissue Transplantation ,RNA, Messenger ,Neurologic Examination ,Tomography, Emission-Computed, Single-Photon ,business.industry ,Receptors, Dopamine D2 ,Putamen ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Corpus Striatum ,Transplantation ,medicine.anatomical_structure ,Huntington Disease ,Neurology ,Gene Expression Regulation ,Female ,business ,Neuroscience ,Follow-Up Studies ,Protein Binding - Abstract
Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntington's disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.
- Published
- 2009
43. Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation
- Author
-
Irene Mancini, Maurizio Genuardi, R. Vivarelli, Laura Papi, Berardino Porfirio, Irene Paganini, Aldesia Provenzano, Costanza Bacci, and Roberta Sestini
- Subjects
Adult ,Male ,TYPE-2 NEUROFIBROMATOSIS ,Chromosomal Proteins, Non-Histone ,MOLECULAR ANALYSIS ,Biology ,Settore MED/03 - GENETICA MEDICA ,Meningioma ,Cellular and Molecular Neuroscience ,Exon ,Germline mutation ,otorhinolaryngologic diseases ,Genetics ,medicine ,Consensus sequence ,Humans ,SMARCB1 ,Schwannomatosis ,GERMLINE MUTATION ,INI1 MUTATION ,Genetics (clinical) ,Aged ,MALIGNANT RHABDOID TUMOR ,CENTRAL-NERVOUS-SYSTEM ,NEUROFIBROMATOSIS 2 ,PREDISPOSITION SYNDROME ,SUPPRESSOR GENE ,HSNF5/INI1 GENE ,SMARCB1 Protein ,Middle Aged ,medicine.disease ,Human genetics ,Pedigree ,DNA-Binding Proteins ,Phenotype ,Haplotypes ,Italy ,Mutation (genetic algorithm) ,Mutation ,Cancer research ,Female ,Neurilemmoma ,Microsatellite Repeats ,Transcription Factors - Abstract
Schwannomatosis (MIM 162091) is a condition predisposing to the development of central and peripheral schwannomas; most cases are sporadic without a clear family history but a few families with a clear autosomal dominant pattern of transmission have been described. Germline mutations in SMARCB1 are associated with schwannomatosis. We report a family with multiple schwannomas and meningiomas. A SMARCB1 germline mutation in exon 1 was identified. The mutation, c.92A>T (p.Glu31Val), occurs in a highly conserved amino acid in the SMARCB1 protein. In addition, in silico analysis demonstrated that the mutation disrupts the donor consensus sequence of exon 1. RNA studies verified the absence of mRNA transcribed by the mutant allele. This is the first report of a SMARCB1 germline mutation in a family with schwannomatosis characterized by the development of multiple meningiomas.
- Published
- 2009
44. Fatal hypertrophic cardiomyopathy and nemaline myopathy associated with ACTA1 K336E mutation
- Author
-
Adele D'Amico, Caroline Sewry, Steven B. Marston, Juan-Juan Feng, Nigel G. Laing, Enrico Bertini, Adam Jacques, Berardino Porfirio, Kristen J. Nowak, Renata Boldrini, Giuseppe Limongelli, Claudio Graziano, Stefania Petrini, Giuseppe Pacileo, Filippo M. Santorelli, D'Amico, A, Graziano, C, Pacileo, G, Petrini, S, Nowak, Kj, Boldrini, R, Jacques, A, Feng, Jj, Porfirio, B, Sewry, Ca, Santorelli, Fm, Limongelli, Giuseppe, Bertini, E, Laing, N, and Marston, Sb
- Subjects
Male ,Mutant ,DNA Mutational Analysis ,Muscle Fibers, Skeletal ,Cardiomyopathy ,Mutation, Missense ,Glutamic Acid ,macromolecular substances ,Myopathies, Nemaline ,Exon ,Nemaline myopathy ,Fatal Outcome ,medicine ,Cardiomyopathy, Hypertrophic, Familial ,Missense mutation ,Humans ,Actinin ,Genetic Predisposition to Disease ,Genetic Testing ,Muscle, Skeletal ,Genetics (clinical) ,Actin ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,Lysine ,Myocardium ,Hypertrophic cardiomyopathy ,medicine.disease ,Molecular biology ,Actins ,Neurology ,Amino Acid Substitution ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,business ,Muscle Contraction - Abstract
We report on a 2-year-old male child with both nemaline myopathy and hypertrophic cardiomyopathy (HCM). Sequencing of the ACTA1 gene showed a "de novo" missense heterozygous mutation a>g in exon 7 (Lys336Glu). Two-dimensional electrophoresis showed 28% mutant actin present in his muscle biopsy. Actin was isolated from the muscle biopsy and examined by in vitro motility assay. The sliding speed was 13+/-3% less than normal and the affinity of actin for the Z-line protein alpha-actinin was reduced 10 fold. This is the first report on a hypertrophic cardiomyopathy associated with nemaline myopathy and an ACTA1 mutation.
- Published
- 2006
45. α-actin gene mutations and polymorphisms in Italian patients with nemaline myopathy
- Author
-
Enrico Bertini, Claudio Graziano, Carlo Minetti, and Berardino Porfirio
- Subjects
Genetics ,Mutation ,Genetic heterogeneity ,Genetic counseling ,Haplotype ,General Medicine ,Biology ,Gene mutation ,medicine.disease ,Bioinformatics ,medicine.disease_cause ,Nemaline myopathy ,Genetic variation ,medicine ,Gene - Abstract
Nemaline myopathy is a rare neuromuscular disorder, showing striking clinical and genetic heterogeneity. Patients can show a spectrum of disease ranging from severe congenital to an adult-onset mild form. Disease-causing mutations have been reported in five genes encoding sarcomeric thin filament proteins, and inheritance can be either autosomal recessive or dominant. No phenotype-genotype correlation is apparent at the moment. alpha-actin gene mutations are responsible for about 20% of cases. We have collected 18 patients from 17 families. Our patients exhibit an overall marked clinical variability, but 10 out of 18 show typical features of nemaline myopathy (slowly progressive congenital form). We have identified disease-causing mutations in the alpha-actin gene in 5 out of 17 families, through direct sequencing of its whole coding sequence. One patient carried two mutations, thus we describe a total of 6 mutations, all arising de novo. We also describe some intronic polymorphisms which constitute two common alpha-actin gene haplotypes; we show that haplotype characterisation may have a strong impact in mutation detection due to preferential amplification of a chromosome in subjects carrying both haplotypes. Screening of the alpha-actin gene coding sequence may account for the identification of disease-causing mutations in 20-30% of nemaline myopathy patients. Since the chance to identify mutations is independent of the clinical picture, we suggest that it is appropriate to check for mutations in all patients. Demonstration of a de novo origin of the mutation is of great relevance for families seeking genetic counselling.
- Published
- 2004
46. Alpha-actin gene mutations and polymorphisms in Italian patients with nemaline myopathy
- Author
-
Claudio, Graziano, Enrico, Bertini, Carlo, Minetti, and Berardino, Porfirio
- Subjects
Polymorphism, Genetic ,Base Sequence ,Italy ,DNA Mutational Analysis ,Molecular Sequence Data ,Mutation ,Genetic Variation ,Humans ,Myopathies, Nemaline ,Actins - Abstract
Nemaline myopathy is a rare neuromuscular disorder, showing striking clinical and genetic heterogeneity. Patients can show a spectrum of disease ranging from severe congenital to an adult-onset mild form. Disease-causing mutations have been reported in five genes encoding sarcomeric thin filament proteins, and inheritance can be either autosomal recessive or dominant. No phenotype-genotype correlation is apparent at the moment. alpha-actin gene mutations are responsible for about 20% of cases. We have collected 18 patients from 17 families. Our patients exhibit an overall marked clinical variability, but 10 out of 18 show typical features of nemaline myopathy (slowly progressive congenital form). We have identified disease-causing mutations in the alpha-actin gene in 5 out of 17 families, through direct sequencing of its whole coding sequence. One patient carried two mutations, thus we describe a total of 6 mutations, all arising de novo. We also describe some intronic polymorphisms which constitute two common alpha-actin gene haplotypes; we show that haplotype characterisation may have a strong impact in mutation detection due to preferential amplification of a chromosome in subjects carrying both haplotypes. Screening of the alpha-actin gene coding sequence may account for the identification of disease-causing mutations in 20-30% of nemaline myopathy patients. Since the chance to identify mutations is independent of the clinical picture, we suggest that it is appropriate to check for mutations in all patients. Demonstration of a de novo origin of the mutation is of great relevance for families seeking genetic counselling.
- Published
- 2004
47. Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients
- Author
-
Luigi Ferrucci, Giuseppe Bianchi, Laura Soldati, Giuseppe Vezzoli, Cecilia Malentacchi, Berardino Porfirio, Cristiana Bianchin, Donatella Adamo, Annalisa Tanini, Alberto Falchetti, Francesco Franceschelli, Daniele Cusi, Annalisa Terranegra, Maria Luisa Brandi, Vezzoli, G, Tanini, A, Ferrucci, L, Soldati, L, Bianchin, C, Franceschelli, F, Malentacchi, C, Porfirio, B, Adamo, D, Terranegra, A, Falchetti, A, Cusi, D, Bianchi, G, and Brandi, Ml
- Subjects
Male ,medicine.medical_specialty ,Receptors, Cell Surface ,Single-nucleotide polymorphism ,Biology ,Excretion ,Kidney Calculi ,Exon ,Gene Frequency ,Reference Values ,Internal medicine ,medicine ,Humans ,Hypercalciuria ,Allele frequency ,Polymorphism, Genetic ,Haplotype ,General Medicine ,Middle Aged ,medicine.disease ,Urinary calcium ,Phenotype ,Endocrinology ,Haplotypes ,Nephrology ,Calcium ,Female ,Calcium-sensing receptor ,Receptors, Calcium-Sensing - Abstract
Calcium-sensing receptor (CaSR) is a plasma membrane protein that regulates tubular reabsorption of Ca. To establish its role in idiopathic hypercalciuria, the association of urinary Ca excretion with the polymorphisms of CASR gene has been studied in healthy subjects and in hypercalciuric and normocalciuric Ca stone formers. CASR exon 7 single nucleotide polymorphisms (SNP), G/T at codon 986, G/A at codon 990, and C/G at codon 1011, were evaluated by PCR amplification and direct sequencing in 97 normocalciuric stone formers, 134 hypercalciuric stone formers, and 101 normocalciuric healthy controls. Four haplotypes were defined on the basis of CASR gene SNP: haplotype 1 was characterized by the most frequent sequence; haplotypes 2, 3, or 4 by the presence of a single polymorphic variant at codon 986, 990, or 1011, respectively. The relative risk of hypercalciuria was calculated with multinomial logistic regression and was significantly increased only in individuals carrying haplotype 3 (Odds ratio, 13.0 [95% confidence interval, 1.7 to 99.4]). Accordingly, Ca excretion was higher in subjects bearing haplotype 3, whereas those bearing haplotype 2 showed a slight increase of plasma Ca concentration. Multiple regression analysis showed that haplotype 3 explained 4.1% of the total variance of Ca excretion and 12.6% of the variance explained by the variables considered in the study. In conclusion, CASR gene could be a component of the complex genetic background regulating Ca excretion. Arg990Gly polymorphism could facilitate activation of CaSR and increase Ca excretion and susceptibility to idiopathic hypercalciuria.
- Published
- 2002
48. Cumulative prognostic value of p53 mutations and bcl-2 protein expression in head-and-neck cancer treated by radiotherapy
- Author
-
Ilaria Chiarelli, Luca Bruschini, Corso Bocciolini, Oreste Gallo, Berardino Porfirio, and Vieri Boddi
- Subjects
Adult ,Male ,Cancer Research ,Time Factors ,Tumor suppressor gene ,Oncology ,medicine.medical_treatment ,Biology ,medicine.disease_cause ,Disease-Free Survival ,Biopsy ,medicine ,Carcinoma ,Humans ,Laryngeal Neoplasms ,Aged ,Aged, 80 and over ,Mutation ,medicine.diagnostic_test ,Head and neck cancer ,Cancer ,Middle Aged ,medicine.disease ,Genes, p53 ,Prognosis ,Immunohistochemistry ,Genes, bcl-2 ,Radiation therapy ,Survival Rate ,Epidermoid carcinoma ,Proto-Oncogene Proteins c-bcl-2 ,Head and Neck Neoplasms ,Multivariate Analysis ,Cancer research ,Carcinoma, Squamous Cell ,Female - Abstract
We investigated the prognostic significance of p53-gene mutation (exon 5–9) and bcl-2-protein expression in primary squamous-cell carcinoma of the head and neck (HNSCC) treated by curative radiotherapy (RT). Primary squamous-cell carcinomas for analysis were obtained from 85 consecutive head-and-neck-cancer patients, with complete follow-up data. We detected bcl-2 protein in 24% (20/85) of HNSCC studied; 38 (45%) of the 85 tumours had cells bearing p53 mutations. A strong association was observed between tobacco exposure and bcl-2-protein expression (p = 0.003), an association also evident in those patients who had a p53-mutated carcinoma (p = 0.049). Moreover, we found that most of the bcl-2-positive cancers (70%) were also mutated in the p53 gene (p = 0.010). In univariate and in multivariate analyses, the simultaneous detection of bcl-2 expression and a p53-gene mutation in a tumour biopsy specimen was associated with greater risk of locoregional failure (p = 0.002 and 0.001 respectively) and worse survival (p = 0.045 and 0.033) within 5 years in HNSCC patients treated by RT. The present study shows a cumulative prognostic value of simultaneous detection of bcl-2 over-expression and p53-gene aberration in some primary HNSCC treated with conventional RT, and provides further evidence for cross-talk between p53 and bcl-2, suggesting that these genes are important determinants of radiation-induced apoptosis, thereby modulating resistance to RT. Int. J. Cancer (Pred. Oncol.) 84:573–579, 1999. © 1999 Wiley-Liss, Inc.
- Published
- 1999
49. Genetic STRs variation in a large population from Tuscany (Italy)
- Author
-
Berardino Porfirio, Maurizio Genuardi, Anna Lucia Nutini, Ilaria Carboni, and Ugo Ricci
- Subjects
Forensic Genetics ,Male ,Large population ,Genetic Variation ,Population genetics ,DNA ,Pathology and Forensic Medicine ,Forensic science ,Geography ,Gene Frequency ,Italy ,Ethnicity ,Genetics ,Humans ,Microsatellite ,Female ,Allele frequency ,Alleles ,Microsatellite Repeats ,Demography - Abstract
Allele frequencies for 17 STRs, together with some parameters of forensic interest, were estimated in a sample of 835 unrelated individuals born in Tuscany, an Italian region. These data were compared with Italian, Chinese, Kosovo Albanian, Romanian and Tunisian populations, strongly represented in this area. No significant differences in single loci were detected, except for Chinese in comparison with all the other populations.
- Published
- 2007
50. A method for point mutation analysis that links SSCP and dye primer fluorescent sequencing
- Author
-
Giovanni Romeo, Iacopo Celli, Berardino Porfirio, Sara Volorio, Ilaria Chiarelli, Francesco Caroli, Massimo Zollo, Pier Luigi Mattiuz, and Marco Seri
- Subjects
Chromosomale lokalisatie van gendefecten en erfelijke risicofactoren met behulp van nieuwe, efficiente strategieën ,Biopsy ,Biology ,Polymerase Chain Reaction ,law.invention ,Exon ,law ,Humans ,Point Mutation ,Molecular Biology ,Gene ,Polymorphism, Single-Stranded Conformational ,Polymerase chain reaction ,DNA Primers ,Fluorescent Dyes ,Cloning ,Base Sequence ,Point mutation ,Genetic Variation ,Single-strand conformation polymorphism ,Exons ,Cell Biology ,Genes, p53 ,Fluorescence ,Molecular biology ,Localization of disease genes and genetic risk factors by new strategies ,Head and Neck Neoplasms ,Carcinoma, Squamous Cell ,Primer (molecular biology) - Abstract
A method is presented for mutation detection directly from single-strand conformational polymorphism (SSCP) variants. This approach is based on: (i) amplification of the exons to be analysed by SSCP using the forward primer with an eight-base tail to form a universal SSCP cassette; (ii) excision from the gel of the shifted silver-stained bands; (iii) reamplification of the eluted DNAs using, as the forward primer, a 26-base universal adaptor primer corresponding to the 18-base-21M13 sequence plus the eight nucleotides of the universal SSCP cassette; and (iv) direct sequencing of the purified products using the standard-21M13 fluorescent primer. This procedure presents several advantages including the avoidance of a cloning step which leads to significant time reduction, while maintaining comparable accuracy at relatively low costs. In conclusion, the presence of the universal SSCP cassette and subsequent reamplification with the same adaptor primer for direct sequencing makes the method universal for scanning and identification of gene alterations.
- Published
- 1998
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.