12 results on '"Benedicenti F"'
Search Results
2. OC.02.3: EFFICACY OF A DESIGNED KIT FOR THE DIAGNOSIS OF NONCELIAC GLUTEN SENSITIVITYAND GLUTEN-RELATED SYMPTOMS
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Elli, L., primary, Bascuñán, K.A., additional, Costantino, A., additional, Benedicenti, F., additional, Doneda, L., additional, Scricciolo, A., additional, Lombardo, V., additional, and Roncoroni, L., additional
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- 2024
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3. OC.01.6: COLD SNARE POLYPECTOMY IN THE MANAGEMENT OF DUODENAL ADENOMA IN FAMILIAL ADENOMATOUS POLYPOSIS
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Cavalcoli, F., primary, Magarotto, A., additional, Emanuele, R., additional, Rosa, R., additional, Borsotti, E., additional, Mancini, A., additional, Benedicenti, F., additional, Lauricella, S., additional, Vitellaro, M., additional, and Cantù, P., additional
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- 2024
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4. Combined use of antegrade double-balloon enteroscopy and electrohydraulic lithotripsy for bezoar retrieval in a patient with Crohn’s Disease
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Scaramella, L., additional, Benedicenti, F., additional, Pessarelli, T., additional, Tontini, G. E., additional, Nandi, N., additional, Vecchi, M., additional, and Elli, L., additional
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- 2024
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5. SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.
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Wood KA, Tong RS, Motta M, Cordeddu V, Scimone ER, Bush SJ, Maxwell DW, Giannoulatou E, Caputo V, Traversa A, Mancini C, Ferrero GB, Benedicenti F, Grammatico P, Melis D, Steindl K, Brunetti-Pierri N, Trevisson E, Wilkie AO, Lin AE, Cormier-Daire V, Twigg SR, Tartaglia M, and Goriely A
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- Humans, Male, Contracture genetics, Adult, Facies, Spermatozoa metabolism, Spermatozoa pathology, Cryptorchidism genetics, Growth Disorders genetics, Hand Deformities, Congenital genetics, Selection, Genetic, Alleles, Paternal Age, Testis pathology, Testis metabolism, Smad4 Protein genetics, Germ-Line Mutation, Intellectual Disability genetics
- Abstract
While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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6. Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.
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Mastromoro G, Santoro C, Motta M, Sorrentino U, Daniele P, Peduto C, Petrizzelli F, Tripodi M, Pinna V, Zanobio M, Rotundo G, Bellacchio E, Lepri F, Farina A, D'Asdia MC, Piceci-Sparascio F, Biagini T, Petracca A, Castori M, Melis D, Accadia M, Traficante G, Tarani L, Fontana P, Sirchia F, Paparella R, Currò A, Benedicenti F, Scala I, Dentici ML, Leoni C, Trevisan V, Cecconi A, Giustini S, Pizzuti A, Salviati L, Novelli A, Zampino G, Zenker M, Genuardi M, Digilio MC, Papi L, Perrotta S, Nigro V, Castellanos E, Mazza T, Trevisson E, Tartaglia M, Piluso G, and De Luca A
- Abstract
Purpose: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs)., Methods: A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing. Data on 125 individuals with heterozygous LZTR1 variants were collected for characterizing their clinical features and the associated molecular spectrum. In vitro functional assessment was performed on a representative panel of missense variants and small in-frame deletions., Results: Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated but occasionally associated with features recurring in RASopathies. In 2 families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating loss-of-function. These variants substantially overlapped with those occurring in schwannomatosis and recessive NS. Functional characterization showed accelerated protein degradation or mislocalization, and failure to downregulate mitogen-activated protein kinase signaling., Conclusion: Our findings expand the phenotypic variability associated with LZTR1 variants, which, in addition to conferring susceptibility to schwannomatosis and causing dominant and recessive NS, occur in individuals with isolated multiple CaLMs., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2024
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7. Natural history of adults with KBG syndrome: A physician-reported experience.
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Bayat A, Grimes H, de Boer E, Herlin MK, Dahl RS, Lund ICB, Bayat M, Bolund ACS, Gjerulfsen CE, Gregersen PA, Zilmer M, Juhl S, Cebula K, Rahikkala E, Maystadt I, Peron A, Vignoli A, Alfano RM, Stanzial F, Benedicenti F, Currò A, Luk HM, Jouret G, Zurita E, Heuft L, Schnabel F, Busche A, Veenstra-Knol HE, Tkemaladze T, Vrielynck P, Lederer D, Platzer K, Ockeloen CW, Goel H, and Low KJ
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- Humans, Adult, Male, Female, Middle Aged, Young Adult, Haploinsufficiency genetics, Seizures genetics, Seizures epidemiology, Physicians, Adolescent, Facies, Abnormalities, Multiple, Bone Diseases, Developmental, Tooth Abnormalities, Intellectual Disability genetics, Intellectual Disability epidemiology, Phenotype
- Abstract
Purpose: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS., Methods: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data., Results: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets., Conclusion: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2024
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8. Correction: Olfactory bulb anomalies in KBG syndrome mouse model and patients.
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Goodkey K, Wischmeijer A, Perrin L, Watson AES, Qureshi L, Cordelli DM, Toni F, Gnazzo M, Benedicenti F, Elmaleh-Berges M, Low KJ, and Voronova A
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- 2024
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9. Circulating hematopoietic stem/progenitor cell subsets contribute to human hematopoietic homeostasis.
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Quaranta P, Basso-Ricci L, Jofra Hernandez R, Pacini G, Naldini MM, Barcella M, Seffin L, Pais G, Spinozzi G, Benedicenti F, Pietrasanta C, Cheong JG, Ronchi A, Pugni L, Dionisio F, Monti I, Giannelli S, Darin S, Fraschetta F, Barera G, Ferrua F, Calbi V, Ometti M, Di Micco R, Mosca F, Josefowicz SZ, Montini E, Calabria A, Bernardo ME, Cicalese MP, Gentner B, Merelli I, Aiuti A, and Scala S
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- Animals, Humans, Mice, Single-Cell Analysis, Hematopoiesis, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Homeostasis
- Abstract
Abstract: In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPCs) are present in the peripheral blood, but their contribution to human hematopoiesis remain unsolved. By integrating advanced immunophenotyping, single-cell transcriptional and functional profiling, and integration site (IS) clonal tracking, we unveiled the biological properties and the transcriptional features of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPCs reduced in cell count over aging and are enriched for primitive, lymphoid, and erythroid subpopulations, showing preactivated transcriptional and functional state. Moreover, cHSPCs have low expression of multiple BM-retention molecules but maintain their homing potential after xenotransplantation. By generating a comprehensive human organ-resident HSPC data set based on single-cell RNA sequencing data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Notably, circulating multi-lymphoid progenitors are primed for seeding the thymus and actively contribute to T-cell production. Human clonal tracking data from patients receiving gene therapy (GT) also showed that cHSPCs connect distant BM niches and participate in steady-state hematopoietic production, with primitive cHSPCs having the highest recirculation capability to travel in and out of the BM. Finally, in case of hematopoietic impairment, cHSPCs composition reflects the BM-HSPC content and might represent a biomarker of the BM state for clinical and research purposes. Overall, our comprehensive work unveiled fundamental insights into the in vivo dynamics of human HSPC trafficking and its role in sustaining hematopoietic homeostasis. GT patients' clinical trials were registered at ClinicalTrials.gov (NCT01515462 and NCT03837483) and EudraCT (2009-017346-32 and 2018-003842-18)., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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10. A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.
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Cesana D, Cicalese MP, Calabria A, Merli P, Caruso R, Volpin M, Rudilosso L, Migliavacca M, Barzaghi F, Fossati C, Gazzo F, Pizzi S, Ciolfi A, Bruselles A, Tucci F, Spinozzi G, Pais G, Benedicenti F, Barcella M, Merelli I, Gallina P, Giannelli S, Dionisio F, Scala S, Casiraghi M, Strocchio L, Vinti L, Pacillo L, Draghi E, Cesana M, Riccardo S, Colantuono C, Six E, Cavazzana M, Carlucci F, Schmidt M, Cancrini C, Ciceri F, Vago L, Cacchiarelli D, Gentner B, Naldini L, Tartaglia M, Montini E, Locatelli F, and Aiuti A
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- Humans, Male, Retroviridae genetics, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Genetic Therapy methods, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Mas, Severe Combined Immunodeficiency therapy, Severe Combined Immunodeficiency genetics, Genetic Vectors genetics, Hematopoietic Stem Cell Transplantation, Agammaglobulinemia therapy, Agammaglobulinemia genetics
- Abstract
Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors., (© 2024. The Author(s).)
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- 2024
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11. Olfactory bulb anomalies in KBG syndrome mouse model and patients.
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Goodkey K, Wischmeijer A, Perrin L, Watson AES, Qureshi L, Cordelli DM, Toni F, Gnazzo M, Benedicenti F, Elmaleh-Bergès M, Low KJ, and Voronova A
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- Humans, Animals, Mice, Facies, Olfactory Bulb, Disease Models, Animal, Abnormalities, Multiple, Intellectual Disability, Tooth Abnormalities, Bone Diseases, Developmental
- Abstract
ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans., (© 2024. The Author(s).)
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- 2024
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12. Removal of innate immune barriers allows efficient transduction of quiescent human hematopoietic stem cells.
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Valeri E, Unali G, Piras F, Abou-Alezz M, Pais G, Benedicenti F, Lidonnici MR, Cuccovillo I, Castiglioni I, Arévalo S, Spinozzi G, Merelli I, Behrendt R, Oo A, Kim B, Landau NR, Ferrari G, Montini E, and Kajaste-Rudnitski A
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- Humans, Transduction, Genetic, Lentivirus genetics, Genetic Therapy methods, Immunity, Innate, Genetic Vectors genetics, Antigens, CD34, Hematopoietic Stem Cells, Hematopoietic Stem Cell Transplantation
- Abstract
Quiescent human hematopoietic stem cells (HSC) are ideal targets for gene therapy applications due to their preserved stemness and repopulation capacities; however, they have not been exploited extensively because of their resistance to genetic manipulation. We report here the development of a lentiviral transduction protocol that overcomes this resistance in long-term repopulating quiescent HSC, allowing their efficient genetic manipulation. Mechanistically, lentiviral vector transduction of quiescent HSC was found to be restricted at the level of vector entry and by limited pyrimidine pools. These restrictions were overcome by the combined addition of cyclosporin H (CsH) and deoxynucleosides (dNs) during lentiviral vector transduction. Clinically relevant transduction levels were paired with higher polyclonal engraftment of long-term repopulating HSC as compared with standard ex vivo cultured controls. These findings identify the cell-intrinsic barriers that restrict the transduction of quiescent HSC and provide a means to overcome them, paving the way for the genetic engineering of unstimulated HSC., Competing Interests: Declaration of interests E.V., G.U., F.P., and A.K.-R. are inventors on pending and issued patents on lentiviral gene transfer filed by the Telethon Foundation and the San Raffaele Scientific Institute., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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