40 results on '"Isidori, Federica"'
Search Results
2. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies
- Author
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Stegmann, Jil D., Kalanithy, Jeshurun C., Dworschak, Gabriel C., Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M., Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T., Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J., Klee, Eric W., Lanpher, Brendan C., Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R., Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L., Riley, Kacie, Klee, Victoria, Walsh, Laurence E., Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stoppe, Arzu, Stuurman, Kyra, van Slegtenhorst, Marjon, Barakat, Tahsin Stefan, Mulhern, Maureen S., Sands, Tristan T., Cytrynbaum, Cheryl, Weksberg, Rosanna, Isidori, Federica, Pippucci, Tommaso, Severi, Giulia, Montanari, Francesca, Kruer, Michael C., Bakhtiari, Somayeh, Darvish, Hossein, Reutter, Heiko, Hagelueken, Gregor, Geyer, Matthias, Woolf, Adrian S., Posey, Jennifer E., Lupski, James R., Odermatt, Benjamin, and Hilger, Alina C.
- Published
- 2024
- Full Text
- View/download PDF
3. Multimodal Access to Scientific Experiments Through the RIALE Platform - Main Steps of Bioinformatics Analysis
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Salis, Carole, Zedda, Davide, Isidori, Federica, Cusano, Roberto, Cabras, Francesco, Wilson, Marie Florence, Cau, Federico, Spano, Lucio Davide, Kacprzyk, Janusz, Series Editor, Pal, Nikhil R., Advisory Editor, Bello Perez, Rafael, Advisory Editor, Corchado, Emilio S., Advisory Editor, Hagras, Hani, Advisory Editor, Kóczy, László T., Advisory Editor, Kreinovich, Vladik, Advisory Editor, Lin, Chin-Teng, Advisory Editor, Lu, Jie, Advisory Editor, Melin, Patricia, Advisory Editor, Nedjah, Nadia, Advisory Editor, Nguyen, Ngoc Thanh, Advisory Editor, Wang, Jun, Advisory Editor, Auer, Michael E., editor, and Centea, Dan, editor
- Published
- 2021
- Full Text
- View/download PDF
4. ACTN1‐related thrombocytopenia: Homozygosity for an ACTN1 variant results in a more severe phenotype
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Zanchetta, Melania Eva, primary, Barozzi, Serena, additional, Isidori, Federica, additional, Marconi, Caterina, additional, Farinasso, Loredana, additional, Bottega, Roberta, additional, Savoia, Anna, additional, Pecci, Alessandro, additional, and Faleschini, Michela, additional
- Published
- 2024
- Full Text
- View/download PDF
5. miRNA–221 and miRNA–483–3p Dysregulation in Esophageal Adenocarcinoma
- Author
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Bozzarelli, Isotta, primary, Orsini, Arianna, additional, Isidori, Federica, additional, Mastracci, Luca, additional, Malvi, Deborah, additional, Lugaresi, Marialuisa, additional, Fittipaldi, Silvia, additional, Gozzellino, Livia, additional, Astolfi, Annalisa, additional, Räsänen, Jari, additional, D’Errico, Antonia, additional, Rosati, Riccardo, additional, Fiocca, Roberto, additional, Seri, Marco, additional, Krishnadath, Kausilia K., additional, Bonora, Elena, additional, and Mattioli, Sandro, additional
- Published
- 2024
- Full Text
- View/download PDF
6. A New Homozygous CACNB2 Mutation has Functional Relevance and Supports a Role for Calcium Channels in Autism Spectrum Disorder
- Author
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Graziano, Claudio, Despang, Patrick, Palombo, Flavia, Severi, Giulia, Posar, Annio, Cassio, Alessandra, Pippucci, Tommaso, Isidori, Federica, Matthes, Jan, and Bonora, Elena
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- 2021
- Full Text
- View/download PDF
7. miRNA-221 and miRNA-483-3p Dysregulation Correlated with Poor Survival in Esophageal Adenocarcinoma
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Bozzarelli, Isotta, primary, Isidori, Federica, additional, Orsini, Arianna, additional, Mastracci, Luca, additional, Malvi, Deborah, additional, Lugaresi, Marialuisa, additional, Fittipaldi, Silvia, additional, Soderstrom, Henna, additional, Räsänen, Jari, additional, D'Errico, Antonietta, additional, Tomezzoli, Anna, additional, Rosati, Riccardo, additional, Fiocca, Roberto, additional, Seri, Marco, additional, Krishnadath, Kausilia Krishnawatie, additional, Bonora, Elena, additional, and Mattioli, Sandro, additional
- Published
- 2023
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- View/download PDF
8. Resources and tools for rare disease variant interpretation
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Licata, Luana, primary, Via, Allegra, additional, Turina, Paola, additional, Babbi, Giulia, additional, Benevenuta, Silvia, additional, Carta, Claudio, additional, Casadio, Rita, additional, Cicconardi, Andrea, additional, Facchiano, Angelo, additional, Fariselli, Piero, additional, Giordano, Deborah, additional, Isidori, Federica, additional, Marabotti, Anna, additional, Martelli, Pier Luigi, additional, Pascarella, Stefano, additional, Pinelli, Michele, additional, Pippucci, Tommaso, additional, Russo, Roberta, additional, Savojardo, Castrense, additional, Scafuri, Bernardina, additional, Valeriani, Lucrezia, additional, and Capriotti, Emidio, additional
- Published
- 2023
- Full Text
- View/download PDF
9. Targeted Sequencing of Sorted Esophageal Adenocarcinoma Cells Unveils Known and Novel Mutations in the Separated Subpopulations
- Author
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Isidori, Federica, Bozzarelli, Isotta, Mastracci, Luca, Malvi, Deborah, Lugaresi, Marialuisa, Molinari, Chiara, Söderström, Henna, Räsänen, Jari, DʼErrico, Antonia, Fiocca, Roberto, Seri, Marco, Krishnadath, Kausilia K., Bonora, Elena, and Mattioli, Sandro
- Published
- 2020
- Full Text
- View/download PDF
10. COQ7defect causes prenatal onset of mitochondrial CoQ10deficiency with cardiomyopathy and gastrointestinal obstruction
- Author
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Pettenuzzo, Ilaria, Carli, Sara, Sánchez-Cuesta, Ana, Isidori, Federica, Montanari, Francesca, Grippa, Mina, Lanzoni, Giulia, Ambrosetti, Irene, Di Pisa, Veronica, Cordelli, Duccio Maria, Mondardini, Maria Cristina, Pippucci, Tommaso, Ragni, Luca, Cenacchi, Giovanna, Costa, Roberta, Lima, Mario, Capristo, Maria Antonietta, Tropeano, Concetta Valentina, Caporali, Leonardo, Carelli, Valerio, Brunelli, Elena, Maffei, Monica, Ahmed Sheikhmaye, Hodman, Fetta, Anna, Brea-Calvo, Gloria, and Garone, Caterina
- Abstract
COQ7pathogenetic variants cause primary CoQ10deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10supplementation. Here, we report novel compound heterozygous variants in the COQ7gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10levels, and reduced basal and maximal respiration in patients’ fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10(30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10deficiency due to COQ7gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.
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- 2024
- Full Text
- View/download PDF
11. Correlations between molecular alterations, histopathological characteristics, and poor prognosis in esophageal adenocarcinoma
- Author
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Orsini, Arianna, Mastracci, Luca, Bozzarelli, Isotta, Ferrari, Anna, Isidori, Federica, Fiocca, Roberto, Lugaresi, Marialuisa, D’Errico, Antonietta, Malvi, Deborah, Cataldi-Stagetti, Erica, Spaggiari, Paola, Tomezzoli, Anna, Albarello, Luca, Ristimäki, Ari, Bottiglieri, Luca, Krishnadath, Kausilia K., Rosati, Riccardo, Romario, Uberto Fumagalli, Manzoni, Giovanni De, Räsänen, Jari, Martinelli, Giovanni, Mattioli, Sandro, Bonora, Elena, Consortium, on behalf of the EACSGE Consortium on behalf of the EACSGE, EACSGE Consortium, and Arianna Orsini, Luca Mastracci, Isotta Bozzarelli, Anna Ferrari, Federica Isidori, Roberto Fiocca, Marialuisa Lugaresi, Antonietta D’Errico, Deborah Malvi, Erica Cataldi-Stagetti, Paola Spaggiari, Anna Tomezzoli, Luca Albarello, Ari Ristimäki, Luca Bottiglieri, Kausilia K. Krishnadath, Riccardo Rosati, Uberto Fumagalli Romario, Giovanni De Manzoni, Jari Räsänen, Giovanni Martinelli, Sandro Mattioli, Elena Bonora, EACSGE Consortium
- Subjects
Cancer Research ,HNF1alpha ,esophageal adenocarcinoma ,Oncology ,TP53 ,SMAD4 ,Human medicine - Abstract
Simple Summary The molecular heterogeneity of esophageal adenocarcinoma (EAC), a severe malignancy with increasing incidence and low survival rates, misperceives the underlying biology of tumor onset and development. However, advances in high-throughput next-generation sequencing (NGS) technologies have highlighted the potential role of somatic DNA sequence markers for new diagnostic techniques or constitute novel therapeutic targets. Thus, in order to identify a molecular and prognostic signature in EAC patients, we decided to integrate the sequencing of specimens from naive patients (not treated with chemo-radiotherapy) with histological classification, with the aim of identification of potential biomarkers, and patient stratification. Combining different approaches paves the way for early identification and the selection of better therapy. Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naive patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.
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- 2023
12. 490. CORRELATION BETWEEN HISTOLOGICAL AND MOLECULAR ALTERATIONS WITH POOR SURVIVAL IN ESOPHAGEAL ADENOCARCINOMA
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Bonora, Elena, primary, Mastracci, Luca, additional, Orsini, Arianna, additional, Bozzarelli, Isotta, additional, Isidori, Federica, additional, Tassi, Valentina, additional, Fiocca, Roberto, additional, Lugaresi, Marialuisa, additional, D'Errico, Antonietta, additional, Malvi, Deborah, additional, Spaggiari, Paola, additional, Tomezzoli, Anna, additional, Albarello, Luca, additional, Ristimäki, Ari, additional, Bottiglieri, Luca, additional, Krishnadath, Kausilia, additional, Rosati, Riccardo, additional, Romario, Uberto Fumagalli, additional, De Manzoni, Giovanni, additional, Räsänen, Jari, additional, and Mattioli, Sandro, additional
- Published
- 2022
- Full Text
- View/download PDF
13. Genomic profiles of primary and metastatic esophageal adenocarcinoma identified via digital sorting of pure cell populations: results from a case report
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Isidori, Federica, Malvi, Deborah, Fittipaldi, Silvia, Forcato, Claudio, Bozzarelli, Isotta, Sala, Claudia, Raulli, Giovanni, D'Errico, Antonia, Fiorentino, Michelangelo, Seri, Marco, Krishnadath, Kausilia K., Bonora, Elena, Mattioli, Sandro, Lugaresi, Maria Luisa, D'Errico, Antonietta, Castellani, Gastone, Fiocca, Roberto, Mastracci, Luca, Räsänen, Jari, Söderström, Henna, CCA - Imaging and biomarkers, Gastroenterology and Hepatology, AGEM - Re-generation and cancer of the digestive system, Isidori, Federica, Malvi, Deborah, Fittipaldi, Silvia, Forcato, Claudio, Bozzarelli, Isotta, Sala, Claudia, Raulli, Giovanni, D'Errico, Antonia, Fiorentino, Michelangelo, Seri, Marco, Krishnadath, Kausilia K., Bonora, Elena, Mattioli, Sandro, Lugaresi, Maria Luisa, Castellani, Gastone, Fiocca, Roberto, Mastracci, Luca, Räsänen, Jari, and Söderström, Henna
- Subjects
0301 basic medicine ,Cancer Research ,Esophageal Neoplasms ,Receptor, ErbB-2 ,Biopsy ,medicine.medical_treatment ,Case Report ,Somatic evolution in cancer ,Targeted therapy ,ErbB-2 ,0302 clinical medicine ,Surgical oncology ,Neoplasm Metastasis ,Stage (cooking) ,Esophageal Neoplasm ,Tumor ,medicine.diagnostic_test ,Single Nucleotide ,Genomics ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunohistochemistry ,Neoplasm Metastasi ,Oncology ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,Esophageal adenocarcinoma ,Human ,Receptor ,Stromal cell ,Polymorphism, Single Nucleotide ,lcsh:RC254-282 ,Clonal Evolution ,03 medical and health sciences ,Genetic ,Next generation sequencing ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,Polymorphism ,Neoplasm Staging ,Digital cell sorting, Esophageal adenocarcinoma, Next generation sequencing, Adenocarcinoma, Biomarkers, Tumor, Biopsy, Clonal Evolution, Esophageal Neoplasms, Female, Humans, Immunohistochemistry, Mutation, Neoplasm Metastasis, Neoplasm Staging, Polymorphism, Single Nucleotide, Receptor, ErbB-2, Genomics, Whole Genome Sequencing ,Whole Genome Sequencing ,business.industry ,Cancer ,medicine.disease ,Digital cell sorting ,030104 developmental biology ,Mutation ,Genomic ,Cancer research ,business ,Biomarkers - Abstract
Background We report on a female patient who underwent primary radical resection for a stage 2B Her-2-positive Barrett’s-type esophageal adenocarcinoma (EAC). Despite Her-2 targeted therapy, her disease recurred and required repeated metastectomies. Case presentation Digital cell sorting and targeted sequencing of cancer sub-clones from EAC and metastases revealed a completely mutated TP53, whereas the sorted stromal cells were wild-type. Her-2 amplification was significantly lower in the metastases when the patient became therapy-resistant. Conclusions The mechanism of therapy resistance illustrated by this case could only be detected through accurate analysis of tumor sub-populations. Investigating tumor sub-populations of recurrent disease is important for adjusting therapy in recurrent EAC. Electronic supplementary material The online version of this article (10.1186/s12885-018-4789-4) contains supplementary material, which is available to authorized users.
- Published
- 2018
14. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy
- Author
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Bonora, Elena, Chakrabarty, Sanjiban, Kellaris, Georgios, Tsutsumi, Makiko, Bianco, Francesca, Bergamini, Christian, Ullah, Farid, Isidori, Federica, Liparulo, Irene, Diquigiovanni, Chiara, Masin, Luca, Rizzardi, Nicola, Cratere, Mariapia Giuditta, Boschetti, Elisa, Papa, Valentina, Maresca, Alessandra, Cenacchi, Giovanna, Casadio, Rita, Martelli, Pierluigi, Matera, Ivana, Ceccherini, Isabella, Fato, Romana, Raiola, Giuseppe, Arrigo, Serena, Signa, Sara, Sementa, Angela Rita, Severino, Mariasavina, Striano, Pasquale, Fiorillo, Chiara, Goto, Tsuyoshi, Uchino, Shumpei, Oyazato, Yoshinobu, Nakamura, Hisayoshi, Mishra, Sushil K., Yeh, Yu Sheng, Kato, Takema, Nozu, Kandai, Tanboon, Jantima, Morioka, Ichiro, Nishino, Ichizo, Toda, Tatsushi, Goto, Yu Ichi, Ohtake, Akira, Kosaki, Kenjiro, Yamaguchi, Yoshiki, Nonaka, Ikuya, Iijima, Kazumoto, Mimaki, Masakazu, Kurahashi, Hiroki, Raams, Anja, Macinnes, Alyson, Alders, Mariel, Engelen, Marc, Linthorst, Gabor, De Koning, Tom, Den Dunnen, Wilfred, Dijkstra, Gerard, Van Spaendonck, Karin, Van Gent, Dik C., Aronica, Eleonora M., Picco, Paolo, Carelli, Valerio, Seri, Marco, Katsanis, Nicholas, Duijkers, Floor A.M., Taniguchi-Ikeda, Mariko, De Giorgio, Roberto, Bonora, Elena, Chakrabarty, Sanjiban, Kellaris, Georgios, Tsutsumi, Makiko, Bianco, Francesca, Bergamini, Christian, Ullah, Farid, Isidori, Federica, Liparulo, Irene, Diquigiovanni, Chiara, Masin, Luca, Rizzardi, Nicola, Cratere, Mariapia Giuditta, Boschetti, Elisa, Papa, Valentina, Maresca, Alessandra, Cenacchi, Giovanna, Casadio, Rita, Martelli, Pierluigi, Matera, Ivana, Ceccherini, Isabella, Fato, Romana, Raiola, Giuseppe, Arrigo, Serena, Signa, Sara, Sementa, Angela Rita, Severino, Mariasavina, Striano, Pasquale, Fiorillo, Chiara, Goto, Tsuyoshi, Uchino, Shumpei, Oyazato, Yoshinobu, Nakamura, Hisayoshi, Mishra, Sushil K., Yeh, Yu Sheng, Kato, Takema, Nozu, Kandai, Tanboon, Jantima, Morioka, Ichiro, Nishino, Ichizo, Toda, Tatsushi, Goto, Yu Ichi, Ohtake, Akira, Kosaki, Kenjiro, Yamaguchi, Yoshiki, Nonaka, Ikuya, Iijima, Kazumoto, Mimaki, Masakazu, Kurahashi, Hiroki, Raams, Anja, Macinnes, Alyson, Alders, Mariel, Engelen, Marc, Linthorst, Gabor, De Koning, Tom, Den Dunnen, Wilfred, Dijkstra, Gerard, Van Spaendonck, Karin, Van Gent, Dik C., Aronica, Eleonora M., Picco, Paolo, Carelli, Valerio, Seri, Marco, Katsanis, Nicholas, Duijkers, Floor A.M., Taniguchi-Ikeda, Mariko, and De Giorgio, Roberto
- Abstract
Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized
- Published
- 2021
15. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy
- Author
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Bonora, Elena, primary, Chakrabarty, Sanjiban, additional, Kellaris, Georgios, additional, Tsutsumi, Makiko, additional, Bianco, Francesca, additional, Bergamini, Christian, additional, Ullah, Farid, additional, Isidori, Federica, additional, Liparulo, Irene, additional, Diquigiovanni, Chiara, additional, Masin, Luca, additional, Rizzardi, Nicola, additional, Cratere, Mariapia Giuditta, additional, Boschetti, Elisa, additional, Papa, Valentina, additional, Maresca, Alessandra, additional, Cenacchi, Giovanna, additional, Casadio, Rita, additional, Martelli, Pierluigi, additional, Matera, Ivana, additional, Ceccherini, Isabella, additional, Fato, Romana, additional, Raiola, Giuseppe, additional, Arrigo, Serena, additional, Signa, Sara, additional, Sementa, Angela Rita, additional, Severino, Mariasavina, additional, Striano, Pasquale, additional, Fiorillo, Chiara, additional, Goto, Tsuyoshi, additional, Uchino, Shumpei, additional, Oyazato, Yoshinobu, additional, Nakamura, Hisayoshi, additional, Mishra, Sushil K, additional, Yeh, Yu-Sheng, additional, Kato, Takema, additional, Nozu, Kandai, additional, Tanboon, Jantima, additional, Morioka, Ichiro, additional, Nishino, Ichizo, additional, Toda, Tatsushi, additional, Goto, Yu-ichi, additional, Ohtake, Akira, additional, Kosaki, Kenjiro, additional, Yamaguchi, Yoshiki, additional, Nonaka, Ikuya, additional, Iijima, Kazumoto, additional, Mimaki, Masakazu, additional, Kurahashi, Hiroki, additional, Raams, Anja, additional, MacInnes, Alyson, additional, Alders, Mariel, additional, Engelen, Marc, additional, Linthorst, Gabor, additional, de Koning, Tom, additional, den Dunnen, Wilfred, additional, Dijkstra, Gerard, additional, van Spaendonck, Karin, additional, van Gent, Dik C, additional, Aronica, Eleonora M, additional, Picco, Paolo, additional, Carelli, Valerio, additional, Seri, Marco, additional, Katsanis, Nicholas, additional, Duijkers, Floor A M, additional, Taniguchi-Ikeda, Mariko, additional, and De Giorgio, Roberto, additional
- Published
- 2021
- Full Text
- View/download PDF
16. Addressing tumor heterogeneity in esophageal adenocarcinoma through different molecular approaches
- Author
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Isidori, Federica and Daddi, Niccolò
- Subjects
MED/21 Chirurgia toracica - Abstract
Several studies have shown epidemiologic, clinical, immune-histochemical and molecular differences among esophageal adenocarcinomas (EAC). Since pathogenesis and biology of this tumor are far to be well defined, our study aimed to examine intra- and inter-tumor heterogeneity and to solve crucial controversies through different molecular approaches. Target sequencing was performed for sorted cancer subpopulations from formalin embedded material obtained from 38 EACs, not treated with neoadjuvant therapy. 35 out 38 cases carried at least one somatic mutation, not present in the corresponding sorted stromal cells. 73.7% of cases carried mutations in TP53 and 10.5% in CDKN2A. Mutations in other genes occurred at lower frequency, including HNF1A, not previously associated with EAC. Sorting allowed us to isolate clones with different mutational loads and/or additional copy number amplifications, confirming the high intra-tumor heterogeneity of these cancers. In our cohort TP53 gene abnormalities correlated with a better survival (P = 0.028); conversely, loss of SMAD4 protein expression was associated with a higher recurrence rate (P = 0.015). Shifting the focus on the epigenetic characterization of EAC, miR-221 and miR-483-3p resulted upregulated from the MicroRNA Array card analysis and confirmed with further testing. The up-regulation of both miRNAs correlated with clinical outcomes, in particular with a reduced cancer-specific survival (miR483-3p P=0.0293; miR221 P=0.0059). In vitro analyses demonstrated an increase for miR-483-3p (fold-change=2.7) that appear to be inversely correlated with SMAD4 expression in FLO-1 cell-line. In conclusion, selective sorting allowed to define the real mutation status and to isolate different cancer subclones. MiRNA expression analysis revealed a significant up-regulation of miR-221 and miR-483-3p, which correlated with worst prognosis, implying that they can be considered oncogenic factors in EAC. Therefore, cell sorting technologies, coupled with next generation sequencing, and the analysis of microRNA profiles seem to be promising strategies to guide treatment and help classify cancer prognosis.
- Published
- 2020
17. Addressing tumor heterogeneity in esophageal adenocarcinoma through different molecular approaches
- Author
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Daddi, Niccolo', Isidori, Federica <1990>, Daddi, Niccolo', and Isidori, Federica <1990>
- Abstract
Several studies have shown epidemiologic, clinical, immune-histochemical and molecular differences among esophageal adenocarcinomas (EAC). Since pathogenesis and biology of this tumor are far to be well defined, our study aimed to examine intra- and inter-tumor heterogeneity and to solve crucial controversies through different molecular approaches. Target sequencing was performed for sorted cancer subpopulations from formalin embedded material obtained from 38 EACs, not treated with neoadjuvant therapy. 35 out 38 cases carried at least one somatic mutation, not present in the corresponding sorted stromal cells. 73.7% of cases carried mutations in TP53 and 10.5% in CDKN2A. Mutations in other genes occurred at lower frequency, including HNF1A, not previously associated with EAC. Sorting allowed us to isolate clones with different mutational loads and/or additional copy number amplifications, confirming the high intra-tumor heterogeneity of these cancers. In our cohort TP53 gene abnormalities correlated with a better survival (P = 0.028); conversely, loss of SMAD4 protein expression was associated with a higher recurrence rate (P = 0.015). Shifting the focus on the epigenetic characterization of EAC, miR-221 and miR-483-3p resulted upregulated from the MicroRNA Array card analysis and confirmed with further testing. The up-regulation of both miRNAs correlated with clinical outcomes, in particular with a reduced cancer-specific survival (miR483-3p P=0.0293; miR221 P=0.0059). In vitro analyses demonstrated an increase for miR-483-3p (fold-change=2.7) that appear to be inversely correlated with SMAD4 expression in FLO-1 cell-line. In conclusion, selective sorting allowed to define the real mutation status and to isolate different cancer subclones. MiRNA expression analysis revealed a significant up-regulation of miR-221 and miR-483-3p, which correlated with worst prognosis, implying that they can be considered oncogenic factors in EAC. Therefore, cell sorting technologies
- Published
- 2020
18. Addressing tumor heterogeneity in esophageal adenocarcinoma through different molecular approaches
- Author
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Daddi, Niccolò, Isidori, Federica <1990>, Daddi, Niccolò, and Isidori, Federica <1990>
- Abstract
Several studies have shown epidemiologic, clinical, immune-histochemical and molecular differences among esophageal adenocarcinomas (EAC). Since pathogenesis and biology of this tumor are far to be well defined, our study aimed to examine intra- and inter-tumor heterogeneity and to solve crucial controversies through different molecular approaches. Target sequencing was performed for sorted cancer subpopulations from formalin embedded material obtained from 38 EACs, not treated with neoadjuvant therapy. 35 out 38 cases carried at least one somatic mutation, not present in the corresponding sorted stromal cells. 73.7% of cases carried mutations in TP53 and 10.5% in CDKN2A. Mutations in other genes occurred at lower frequency, including HNF1A, not previously associated with EAC. Sorting allowed us to isolate clones with different mutational loads and/or additional copy number amplifications, confirming the high intra-tumor heterogeneity of these cancers. In our cohort TP53 gene abnormalities correlated with a better survival (P = 0.028); conversely, loss of SMAD4 protein expression was associated with a higher recurrence rate (P = 0.015). Shifting the focus on the epigenetic characterization of EAC, miR-221 and miR-483-3p resulted upregulated from the MicroRNA Array card analysis and confirmed with further testing. The up-regulation of both miRNAs correlated with clinical outcomes, in particular with a reduced cancer-specific survival (miR483-3p P=0.0293; miR221 P=0.0059). In vitro analyses demonstrated an increase for miR-483-3p (fold-change=2.7) that appear to be inversely correlated with SMAD4 expression in FLO-1 cell-line. In conclusion, selective sorting allowed to define the real mutation status and to isolate different cancer subclones. MiRNA expression analysis revealed a significant up-regulation of miR-221 and miR-483-3p, which correlated with worst prognosis, implying that they can be considered oncogenic factors in EAC. Therefore, cell sorting technologies
- Published
- 2020
19. RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
- Author
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Isidori, Federica, primary, Bozzarelli, Isotta, additional, Ferrari, Simona, additional, Godino, Lea, additional, Innella, Giovanni, additional, Turchetti, Daniela, additional, and Bonora, Elena, additional
- Published
- 2020
- Full Text
- View/download PDF
20. A New Homozygous CACNB2 Mutation has Functional Relevance and Supports a Role for Calcium Channels in Autism Spectrum Disorder
- Author
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Graziano, Claudio, primary, Despang, Patrick, additional, Palombo, Flavia, additional, Severi, Giulia, additional, Posar, Annio, additional, Cassio, Alessandra, additional, Pippucci, Tommaso, additional, Isidori, Federica, additional, Matthes, Jan, additional, and Bonora, Elena, additional
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- 2020
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21. A new homozygous CACNB2 mutation has functional relevance and supports a role for calcium channels in autism spectrum disorder
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Graziano, Claudio, primary, Despang, Patrick, additional, Palombo, Flavia, additional, Severi, Giulia, additional, Posar, Annio, additional, Cassio, Alessandra, additional, Pippucci, Tommaso, additional, Isidori, Federica, additional, Matthes, Jan, additional, and Bonora, Elena, additional
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- 2019
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22. Two novel families with RUNX1 variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML diagnosis.
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Kamiya, Laureano J., Barozzi, Serena, Isidori, Federica, Ganiewich, Daiana, De Luca, Geraldine, Bozzi, Valeria, Marta, Rosana F., Melazzini, Federica, Pippucci, Tommaso, Heller, Paula G., Glembotsky, Ana C., and Pecci, Alessandro
- Abstract
Correct interpretation of the pathogenicity of germline RUNX1 variants is essential for FPD/AML diagnosis, clinical management and leukaemia surveillance. We report two families with clear FPD/AML phenotypic features harbouring missense variants at RHD critical residue Gly168. Although classified as of unknown significance (VUS) by RUNX1‐specific curation guidelines, these variants should rather be considered likely pathogenic, as supported by computational tools, structural modelling and dysregulated platelet expression of RUNX1‐targets, adding Gly168 among amino acids currently recognised as mutational hotspots. Our data could help reduce the number of variants classified as VUS, providing evidence for updating RUNX1 guidelines, thus improving FPD/AML diagnosis. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Additional file 2: of Genomic profiles of primary and metastatic esophageal adenocarcinoma identified via digital sorting of pure cell populations: results from a case report
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Isidori, Federica, Malvi, Deborah, Fittipaldi, Silvia, Forcato, Claudio, Bozzarelli, Isotta, Sala, Claudia, Raulli, Giovanni, D’Errico, Antonia, Fiorentino, Michelangelo, Seri, Marco, Kausilia Krishnadath, Bonora, Elena, and Mattioli, Sandro
- Abstract
Figure S1. Plots of Copy Number Analysis and phylogenetic tree using WES data. A 18 Mb region on chromosome 6 (q21-22.33) is indicated (red box), where CNV analysis identified a copy gain in PT (A) and M1 (B), as reported in Additional file 1: Table S2. (C) In the second chest metastasis (M2) a focal amplification was detected in the 6q22.33 region, spanning RNF146 and ECHDC1 genes (black arrowhead). (D) SNPhylo analysis results, showing the genetic distance between the three tumor samples. Numbers indicate the branch length from central node. The distance between two tumors is equal to the sum of their branch length. Analysis was performed according to [6]. (PDF 137 kb)
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- 2018
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24. Additional file 1: of Genomic profiles of primary and metastatic esophageal adenocarcinoma identified via digital sorting of pure cell populations: results from a case report
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Isidori, Federica, Malvi, Deborah, Fittipaldi, Silvia, Forcato, Claudio, Bozzarelli, Isotta, Sala, Claudia, Raulli, Giovanni, DâErrico, Antonia, Fiorentino, Michelangelo, Seri, Marco, Kausilia Krishnadath, Bonora, Elena, and Mattioli, Sandro
- Abstract
Supplementary methods and metarials. (DOCX 79 kb)
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- 2018
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25. PS02.055: IN ESOPHAGEAL ADENOCARCINOMA (EAC) BARRET LIKE AND CARDIO PYLORIC LIKE SUB TYPES ARE DIFFERENTIATED ACCORDING TO MICRORNA (MIRNA) 221 AND 483–3.P EXPRESSION PROFILES
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Bonora, Elena, primary, Isidori, Federica, additional, Bozzarelli, Isotta, additional, Lugaresi, Marialuisa, additional, Malvi, Deborah, additional, Räsänen, Jari, additional, Kauppi, Juha, additional, Sala, Claudia, additional, Castellani, Gastone, additional, D’Errico, Antonietta, additional, Fiocca, Roberto, additional, Seri, Marco, additional, Krishnadath, Kausilia, additional, and Mattioli, Sandro, additional
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- 2018
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26. PS02.046: UNRAVELING TUMOR HETEROGENEITY OF ESOPHAGEAL ADENOCARCINOMA (EAC) THROUGH HIGH-THROUGHPUT OF SORTED TUMOR CELL POPULATIONS
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Bonora, Elena, primary, Isidori, Federica, additional, Bozzarelli, Isotta, additional, Lugaresi, Marialuisa, additional, Malvi, Deborah, additional, Söderström, Henna, additional, Bolognesi, Chiara, additional, Forcato, Claudio, additional, D’Errico, Antonietta, additional, Fiocca, Roberto, additional, Seri, Marco, additional, Krishnadath, Kausilia, additional, and Mattioli, Sandro, additional
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- 2018
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27. PS02.040: EXPRESSION OF INTESTINAL/NON-INTESTINAL DIFFERENTIATION MARKERS IN ADENOCARCINOMAS OF THE ESOPHAGUS CORRELATES WITH ESOPHAGO-GASTRIC INTESTINAL METAPLASIA
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Bonora, Elena, primary, Isidori, Federica, additional, Lugaresi, Marialuisa, additional, Sala, Claudia, additional, Malvi, Deborah, additional, Fittipaldi, Silvia, additional, Castellani, Gastone, additional, Räsänen, Jari, additional, D’Errico, Antonietta, additional, Fiocca, Roberto, additional, and Mattioli, Sandro, additional
- Published
- 2018
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28. Mutant MYO1F alters the mitochondrial network and induces tumor proliferation in thyroid cancer
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Diquigiovanni, Chiara, primary, Bergamini, Christian, additional, Evangelisti, Cecilia, additional, Isidori, Federica, additional, Vettori, Andrea, additional, Tiso, Natascia, additional, Argenton, Francesco, additional, Costanzini, Anna, additional, Iommarini, Luisa, additional, Anbunathan, Hima, additional, Pagotto, Uberto, additional, Repaci, Andrea, additional, Babbi, Giulia, additional, Casadio, Rita, additional, Lenaz, Giorgio, additional, Rhoden, Kerry J., additional, Porcelli, Anna Maria, additional, Fato, Romana, additional, Bowcock, Anne, additional, Seri, Marco, additional, Romeo, Giovanni, additional, and Bonora, Elena, additional
- Published
- 2018
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29. HDAC8 Loss of Function and SHOX Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype
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Severi, Giulia, primary, Bonora, Elena, additional, Perri, Annamaria, additional, Scarano, Emanuela, additional, Mazzanti, Laura, additional, Isidori, Federica, additional, Zuntini, Roberta, additional, Menabò, Soara, additional, and Graziano, Claudio, additional
- Published
- 2018
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30. Search for genetic factors in bicuspid aortic valve disease: ACTA2 mutations do not play a major role
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Tortora, Giada, primary, Wischmeijer, Anita, additional, Berretta, Paolo, additional, Alfonsi, Jacopo, additional, Di Marco, Luca, additional, Barbieri, Andrea, additional, Marconi, Caterina, additional, Isidori, Federica, additional, Rossi, Cesare, additional, Leone, Ornella, additional, Di Bartolomeo, Roberto, additional, Seri, Marco, additional, and Pacini, Davide, additional
- Published
- 2017
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- View/download PDF
31. A de novo PUF60 mutation in a child with a syndromic form of coloboma and persistent fetal vasculature
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Graziano, Claudio, primary, Gusson, Elena, additional, Severi, Giulia, additional, Isidori, Federica, additional, Wischmeijer, Anita, additional, Brugnara, Milena, additional, Seri, Marco, additional, and Rossi, Cesare, additional
- Published
- 2017
- Full Text
- View/download PDF
32. A New Homozygous CACNB2 Mutation has Functional Relevance and Supports a Role for Calcium Channels in Autism Spectrum Disorder
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Graziano, Claudio, Despang, Patrick, Palombo, Flavia, Severi, Giulia, Posar, Annio, Cassio, Alessandra, Pippucci, Tommaso, Isidori, Federica, Matthes, Jan, Bonora, Elena, Graziano, Claudio, Despang, Patrick, Palombo, Flavia, Severi, Giulia, Posar, Annio, Cassio, Alessandra, Pippucci, Tommaso, Isidori, Federica, Matthes, Jan, and Bonora, Elena
33. A New Homozygous CACNB2 Mutation has Functional Relevance and Supports a Role for Calcium Channels in Autism Spectrum Disorder
- Author
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Graziano, Claudio, Despang, Patrick, Palombo, Flavia, Severi, Giulia, Posar, Annio, Cassio, Alessandra, Pippucci, Tommaso, Isidori, Federica, Matthes, Jan, Bonora, Elena, Graziano, Claudio, Despang, Patrick, Palombo, Flavia, Severi, Giulia, Posar, Annio, Cassio, Alessandra, Pippucci, Tommaso, Isidori, Federica, Matthes, Jan, and Bonora, Elena
34. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy
- Author
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Pierluigi Martelli, Tom J. de Koning, Takema Kato, Irene Liparulo, Mariko Taniguchi-Ikeda, Tatsushi Toda, Hisayoshi Nakamura, Wilfred F. A. den Dunnen, Giovanna Cenacchi, Sanjiban Chakrabarty, Yu Sheng Yeh, Sushil Kumar Mishra, Rita Casadio, Akira Ohtake, Ichizo Nishino, Roberto De Giorgio, Paolo Picco, Pasquale Striano, Chiara Fiorillo, Isabella Ceccherini, Tsuyoshi Goto, Elisa Boschetti, Makiko Tsutsumi, Eleonora Aronica, Georgios Kellaris, Mariel Alders, Gabor E. Linthorst, Jantima Tanboon, Angela Rita Sementa, Floor A. M. Duijkers, Yu Ichi Goto, Hiroki Kurahashi, Masakazu Mimaki, Gerard Dijkstra, Dik C. van Gent, Mariasavina Severino, Yoshinobu Oyazato, Christian Bergamini, Ikuya Nonaka, Yoshiki Yamaguchi, Ivana Matera, Giuseppe Raiola, Karin Van Spaendonck, Nicholas Katsanis, Luca Masin, Shumpei Uchino, Kenjiro Kosaki, Sara Signa, Anja Raams, Federica Isidori, Elena Bonora, Serena Arrigo, Kandai Nozu, Marc Engelen, Farid Ullah, Ichiro Morioka, Chiara Diquigiovanni, Marco Seri, Valerio Carelli, Francesca Bianco, Mariapia Giuditta Cratere, Nicola Rizzardi, Romana Fato, Alessandra Maresca, Alyson W. MacInnes, Valentina Papa, Kazumoto Iijima, Movement Disorder (MD), Molecular Neuroscience and Ageing Research (MOLAR), Groningen Institute for Organ Transplantation (GIOT), Translational Immunology Groningen (TRIGR), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, Neurology, Paediatric Neurology, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Endocrinology, Pathology, Bonora, Elena, Chakrabarty, Sanjiban, Kellaris, Georgio, Tsutsumi, Makiko, Bianco, Francesca, Bergamini, Christian, Ullah, Farid, Isidori, Federica, Liparulo, Irene, Diquigiovanni, Chiara, Masin, Luca, Rizzardi, Nicola, Cratere, Mariapia Giuditta, Boschetti, Elisa, Papa, Valentina, Maresca, Alessandra, Cenacchi, Giovanna, Casadio, Rita, Martelli, Pierluigi, Matera, Ivana, Ceccherini, Isabella, Fato, Romana, Raiola, Giuseppe, Arrigo, Serena, Signa, Sara, Sementa, Angela Rita, Severino, Mariasavina, Striano, Pasquale, Fiorillo, Chiara, Goto, Tsuyoshi, Uchino, Shumpei, Oyazato, Yoshinobu, Nakamura, Hisayoshi, Mishra, Sushil K, Yeh, Yu-Sheng, Kato, Takema, Nozu, Kandai, Tanboon, Jantima, Morioka, Ichiro, Nishino, Ichizo, Toda, Tatsushi, Goto, Yu-Ichi, Ohtake, Akira, Kosaki, Kenjiro, Yamaguchi, Yoshiki, Nonaka, Ikuya, Iijima, Kazumoto, Mimaki, Masakazu, Kurahashi, Hiroki, Raams, Anja, MacInnes, Alyson, Alders, Mariel, Engelen, Marc, Linthorst, Gabor, de Koning, Tom, den Dunnen, Wilfred, Dijkstra, Gerard, van Spaendonck, Karin, van Gent, Dik C, Aronica, Eleonora M, Picco, Paolo, Carelli, Valerio, Seri, Marco, Katsanis, Nichola, Duijkers, Floor A M, Taniguchi-Ikeda, Mariko, De Giorgio, Roberto, and Molecular Genetics
- Subjects
Male ,0301 basic medicine ,Mitochondrial DNA ,Gastrointestinal Disease ,Mitochondrial disease ,LIG3, mtDNA replication, mtDNA repair, MNGIE, CIPO ,LIG3 ,Biology ,Mitochondrion ,CIPO ,MNGIE ,mtDNA repair ,mtDNA replication ,LS3_11 ,Mitochondrial Encephalomyopathie ,NO ,DNA Ligase ATP ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,LS5_1 ,LS4_1 ,medicine ,LS2_6 ,Ligase activity ,LS5_2 ,Poly-ADP-Ribose Binding Protein ,Zebrafish ,Exome sequencing ,Mitochondrial Encephalomyopathies ,Animal ,medicine.disease ,Molecular biology ,Pedigree ,030104 developmental biology ,Mitochondrial DNA repair ,030220 oncology & carcinogenesis ,Mutation ,Female ,Neurology (clinical) ,Gastrointestinal Motility ,Human - Abstract
Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities. Bonora et al. identify a new mitochondrial recessive disorder caused by biallelic variants in the LIG3 gene encoding DNA ligase III, which is responsible for mitochondrial DNA repair. Clinical signs include gut dysmotility and neurological features such as leucoencephalopathy, epilepsy and stroke-like episodes.
- Published
- 2021
35. Targeted Sequencing of Sorted Esophageal Adenocarcinoma Cells Unveils Known and Novel Mutations in the Separated Subpopulations
- Author
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Marco Seri, Luca Mastracci, Isotta Bozzarelli, Marialuisa Lugaresi, Jari Räsänen, Deborah Malvi, Henna Söderström, Chiara Molinari, Antonia D'Errico, Federica Isidori, Sandro Mattioli, Elena Bonora, Roberto Fiocca, Kausilia K. Krishnadath, Gastroenterology and Hepatology, CCA - Cancer biology and immunology, Amsterdam Gastroenterology Endocrinology Metabolism, Isidori, Federica, Bozzarelli, Isotta, Mastracci, Luca, Malvi, Deborah, Lugaresi, Marialuisa, Molinari, Chiara, Söderström, Henna, Räsänen, Jari, D'Errico, Antonia, Fiocca, Roberto, Seri, Marco, Krishnadath, Kausilia K., Bonora, Elena, and Mattioli, Sandro
- Subjects
Adult ,Male ,Esophageal Mucosa ,Stromal cell ,esophageal adenocarcinoma ,Esophageal Neoplasms ,DNA Mutational Analysis ,Cell Separation ,Adenocarcinoma ,Disease-Free Survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Esophagus ,Humans ,Medicine ,NGS, single cell sorting ,Lymph node ,Aged ,Aged, 80 and over ,business.industry ,Genetic heterogeneity ,Gastroenterology ,High-Throughput Nucleotide Sequencing ,Cancer ,Middle Aged ,Cell sorting ,medicine.disease ,Immunohistochemistry ,Esophagectomy ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer cell ,Cancer research ,Female ,030211 gastroenterology & hepatology ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
INTRODUCTION: Our study aimed at investigating tumor heterogeneity in esophageal adenocarcinoma (EAC) cells regarding clinical outcomes. METHODS: Thirty-eight surgical EAC cases who underwent gastroesophageal resection with lymph node dissection in 3 university centers were included. Archival material was analyzed via high-throughput cell sorting technology and targeted sequencing of 63 cancer-related genes. Low-pass sequencing and immunohistochemistry (IHC) were used to validate the results. Results Thirty-five of 38 EACs carried at least one somatic mutation that was absent in the stromal cells; 73.7%, 10.5%, and 10.5% carried mutations in tumor protein 53, cyclin dependent kinase inhibitor 2A, and SMAD family member 4, respectively. In addition, 2 novel mutations were found for hepatocyte nuclear factor-1 alpha in 2 of 38 cases. Tumor protein 53 gene abnormalities were more informative than p53 IHC. Conversely, loss of SMAD4 was more frequently noted with IHC (53%) and was associated with a higher recurrence rate (P = 0.015). Only through cell sorting we were able to detect the presence of hyperdiploid and pseudodiploid subclones in 7 EACs that exhibited different mutational loads and/or additional copy number amplifications, indicating the high genetic heterogeneity of these cancers. DISCUSSION: Selective cell sorting allowed the characterization of multiple molecular defects in EAC subclones that were missed in a significant number of cases when whole-tumor samples were analyzed. Therefore, this approach can reveal subtle differences in cancer cell subpopulations. Future studies are required to investigate whether these subclones are responsible for treatment response and disease recurrence.
- Published
- 2020
36. Mutant MYO1F alters the mitochondrial network and induces tumor proliferation in thyroid cancer
- Author
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Andrea Repaci, Anne M. Bowcock, Natascia Tiso, Romana Fato, Elena Bonora, Kerry J. Rhoden, Christian Bergamini, Uberto Pagotto, Francesco Argenton, Cecilia Evangelisti, Anna Maria Porcelli, Andrea Vettori, Chiara Diquigiovanni, Rita Casadio, Giulia Babbi, Marco Seri, Giorgio Lenaz, Federica Isidori, Hima Anbunathan, Anna Costanzini, Giovanni Romeo, Luisa Iommarini, Diquigiovanni, Chiara, Bergamini, Christian, Evangelisti, Cecilia, Isidori, Federica, Vettori, Andrea, Tiso, Natascia, Argenton, Francesco, Costanzini, Anna, Iommarini, Luisa, Anbunathan, Hima, Pagotto, Uberto, Repaci, Andrea, Babbi, Giulia, Casadio, Rita, Lenaz, Giorgio, Rhoden, Kerry J., Porcelli, Anna Maria, Fato, Romana, Bowcock, Anne, Seri, Marco, Romeo, Giovanni, and Bonora, Elena
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Embryo, Nonmammalian ,Protein Conformation ,Papillary ,Mutant ,MYO1F ,Non-Medullary Thyroid Carcinoma ,TCO locus ,mitochondrial network ,whole exome sequencing ,Apoptosis ,Thyroid Cancer ,Exon ,0302 clinical medicine ,80 and over ,Child ,Zebrafish ,Thyroid cancer ,Exome sequencing ,Cells, Cultured ,Aged, 80 and over ,Cultured ,Nonmammalian ,Thyroid ,Middle Aged ,non-medullary thyroid carcinoma ,Adolescent ,Adult ,Aged ,Animals ,Chromosomes, Human, Pair 19 ,Female ,Genetic Predisposition to Disease ,Genotype ,Humans ,Mitochondria ,Myosin Type I ,Oxygen Consumption ,Pedigree ,Thyroid Cancer, Papillary ,Thyroid Neoplasms ,Young Adult ,Cell Proliferation ,Mutation ,medicine.anatomical_structure ,Oncology ,Embryo ,030220 oncology & carcinogenesis ,Human ,Cells ,TCO locu ,Locus (genetics) ,Biology ,Chromosomes ,03 medical and health sciences ,medicine ,Mitochondrial network ,Pair 19 ,Non-medullary thyroid carcinoma ,Whole exome sequencing ,biology.organism_classification ,medicine.disease ,Molecular biology ,Exon skipping ,030104 developmental biology - Abstract
Familial aggregation is a significant risk factor for the development of thyroid cancer and familial non-medullary thyroid cancer (FNMTC) accounts for 5-7% of all NMTC. Whole exome sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G > A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p.Gly134Ser protein, we observed an altered mitochondrial network, with increased mitochondrial mass and a significant increase in both intracellular and extracellular reactive oxygen species, compared to cells expressing the wild-type (wt) protein or carrying the empty vector. The mutation conferred a significant advantage in colony formation, invasion and anchorage-independent growth. These data were corroborated by in vivo studies in zebrafish, since we demonstrated that the mutant MYO1F p.Gly134Ser, when overexpressed, can induce proliferation in whole vertebrate embryos, compared to the wt one. MYO1F screening in additional 192 FNMTC families identified another variant in exon 7, which leads to exon skipping, and is predicted to alter the ATP-binding domain in MYO1F. Our study identified for the first time a role for MYO1F in NMTC.
- Published
- 2018
37. A de novo PUF60 mutation in a child with a syndromic form of coloboma and persistent fetal vasculature
- Author
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Federica Isidori, Marco Seri, Giulia Severi, Elena Gusson, Claudio Graziano, Cesare Rossi, Anita Wischmeijer, Milena Brugnara, Graziano, Claudio, Gusson, Elena, Severi, Giulia, Isidori, Federica, Wischmeijer, Anita, Brugnara, Milena, Seri, Marco, and Rossi, Cesare
- Subjects
0301 basic medicine ,Genetics ,child ,Coloboma ,Pathology ,medicine.medical_specialty ,business.industry ,PUF 60 de novo mutation: coloboma ,030105 genetics & heredity ,medicine.disease ,persistent fetal vasculature ,PUF60 ,03 medical and health sciences ,Ophthalmology ,Iris abnormalities ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Medicine ,Missense mutation ,business ,Persistent fetal vasculature ,Rare disease ,Genetics (clinical) - Abstract
We performed whole exome sequencing (WES) in a patient with a clinical diagnosis of possible CHARGE syndrome, where CHD7 analysis and array CGH did not identify any pathogenic variant. The boy presented prenatal and postnatal growth retardation, bilateral coloboma, a complex heart defect, hemivertebrae, monolateral renal agenesis and dysmorphic features. WES analysis identified a de novo c.532G>A mutation leading to pGlu178Lys change in PUF60, a gene predicted to be involved in some of the clinical aspects of 8q24.3 microdeletion syndrome. In this regard, rare copy number variants (CNVs) encompassing PUF60 and a single de novo missense variant in this gene were previously described. Patients showed a similar phenotype and manipulation of zebrafish attributed to PUF60 haploinsufficiency a fraction of clinical features, while coloboma and kidney anomalies were thought to be caused by haploinsufficiency of the neighboring SCRIB gene. Our results indicate that mutations in PUF60 may be fully responsible of this clinical entity, which shows a significant overlap with CHARGE syndrome.
- Published
- 2017
38. Search for genetic factors in bicuspid aortic valve disease: ACTA2 mutations do not play a major role
- Author
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Luca Di Marco, Jacopo Alfonsi, Roberto Di Bartolomeo, Davide Pacini, Paolo Berretta, Andrea Barbieri, Marco Seri, Federica Isidori, Giada Tortora, Ornella Leone, Cesare Rossi, Anita Wischmeijer, Caterina Marconi, Tortora, Giada, Anita, Wischmeijer, Berretta, Paolo, Alfonsi, Jacopo, Di Marco, Luca, Barbieri, Andrea, Marconi, Caterina, Isidori, Federica, Rossi, Cesare, Leone, Ornella, Di Bartolomeo, Roberto, Seri, Marco, and Pacini, Davide
- Subjects
0301 basic medicine ,Adult ,Genetic Markers ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Heart disease ,Adolescent ,Bicuspid aortic valve ,DNA Mutational Analysis ,Heart Valve Diseases ,Disease ,030204 cardiovascular system & hematology ,Thoracic aortic aneurysm ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Bicuspid Aortic Valve Disease ,Risk Factors ,Internal medicine ,medicine ,Humans ,First-degree relatives ,Elective surgery ,Risk factor ,Exome ,Aortic Aneurysm, Thoracic ,business.industry ,DNA ,Middle Aged ,medicine.disease ,Actins ,030104 developmental biology ,Phenotype ,Aortic Valve ,Mutation ,Cardiology ,Female ,Surgery ,ACTA2 ,business ,Cardiology and Cardiovascular Medicine ,Follow-Up Studies - Abstract
Objectives Mutations in ACTA2 have been reported as a cause of familiar thoracic aortic aneurysm (TAA) with associated bicuspid aortic valve (BAV) in some individuals. Our aim is to investigate the role of ACTA2 mutations in BAV associated with TAA in 20 patients. Methods We recruited 20 patients who underwent surgery for BAV and TAA; clinical genetic evaluation and ACTA2 mutation analysis were performed on each patient, along with next-generation sequencing analysis of BAV-related genes. Available first-degree relatives were enrolled and evaluated with echocardiography and clinical genetic examination. Results No mutations were found in ACTA2 or in BAV-related genes in our probands nor any common clinical signs possibly related to their heart disease. One-third of probands did not have any cardiovascular risk factor. Surgery was required at a young age (mean age 47.2 years) and at relatively small ascending aortic diameters (mean size 49.7 mm). In 77 first-degree relatives, 1 new diagnosis of TAA requiring surgery was made and 8 previous BAV/TAA diagnoses (9/77 = 11.7%) were confirmed. The phenotype BAV ± TAA segregated in 25% of our families. Conclusions Although based on a small cohort, our results seemed to justify the conclusion that ACTA2 did not play a significant role in the pathogenesis of BAV aortopathy. The underlying genetic factors of this condition remain elusive and both large association studies and exome or genome sequencing could represent promising tools to unravel its pathogenesis. Aortic resection of TAA at elective surgery in these patients should be recommended as well as echocardiography in their first-degree relatives.
- Published
- 2017
39. Glutamine Supplementation as a Novel Metabolic Therapeutic Strategy for LIG3-Dependent Chronic Intestinal Pseudo-obstruction.
- Author
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Diquigiovanni C, Rizzardi N, Cataldi-Stagetti E, Gozzellino L, Isidori F, Valenti F, Orsini A, Astolfi A, Giangregorio T, Pironi L, Boschetti E, Arrigo S, Maresca A, Magnoni P, Costanzini A, Carelli V, Taniguchi-Ikeda M, Fato R, Bergamini C, De Giorgio R, and Bonora E
- Abstract
Background & Aims: We recently identified a recessive syndrome due to DNA ligase 3 (LIG3) mutations in patients with chronic intestinal pseudo-obstruction, leukoencephalopathy, and neurogenic bladder. LIG3 mutations affect mitochondrial DNA maintenance, leading to defective energy production. We aimed at identifying altered molecular pathways and developing possible targeted treatments to revert/ameliorate the cellular energy impairment., Methods: Whole transcriptome analysis was performed on patient-derived fibroblasts total RNA and controls. Mitochondrial function, mitophagy, and l-glutamine supplementation effects were analyzed by live cell analysis, immunostaining, and Western blot. Patients were treated with Dipeptiven (Fresenius-Kabi) according to standard protocols. Patients' symptoms were analyzed by the Gastrointestinal Symptom Rating Scale questionnaire., Results: We identified deregulated transcripts in mutant fibroblasts vs controls, including overexpression of genes involved in extracellular matrix development and remodeling and mitochondrial functions. Gut biopsy specimens of LIG3-mutant patients documented collagen and elastic fiber accumulation. Mutant fibroblasts exhibited impaired mitochondrial mitophagy indicative of dysfunctional turnover and altered Ca
2+ homeostasis. Supplementation with l-glutamine (6 mmol/L), previously shown to increase mitochondrial DNA-defective cell survival, improved growth rate and adenosine 5'-triphosphate production in LIG3-mutant fibroblasts. These data led us to provide parenterally a dipeptide containing l-glutamine to 3 siblings carrying biallelic LIG3 mutations. Compared with baseline, gastrointestinal and extra-gastrointestinal symptoms significantly improved after 8 months of treatment., Conclusions: LIG3 deficiency leads to mitochondrial dysfunction. High levels l-glutamine supplementation were beneficial in LIG3-mutant cells and improved symptom severity without noticeable adverse effects. Our results provide a proof of concept to design ad hoc clinical trials with l-glutamine in LIG3-mutant patients., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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40. HDAC8 Loss of Function and SHOX Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype.
- Author
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Severi G, Bonora E, Perri A, Scarano E, Mazzanti L, Isidori F, Zuntini R, Menabò S, and Graziano C
- Subjects
- Child, Comparative Genomic Hybridization, De Lange Syndrome genetics, Female, Growth Disorders genetics, Haploinsufficiency, Humans, Osteochondrodysplasias genetics, Pedigree, Phenotype, Exome Sequencing, De Lange Syndrome diagnosis, Frameshift Mutation, Gene Deletion, Growth Disorders diagnosis, Histone Deacetylases genetics, Osteochondrodysplasias diagnosis, Repressor Proteins genetics, Short Stature Homeobox Protein genetics
- Abstract
We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis., (© 2019 S. Karger AG, Basel.)
- Published
- 2019
- Full Text
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