117 results on '"E. Morini"'
Search Results
2. Oncotype DX genomic prostate score and final tumor pathology: A new instrument in pre-radical prostatectomy counseling
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B. Filippi, M.C. Sighinolfi, L. Sarchi, E. Morini, M. Moschovas, S. Toso, B. Seetharam, B. Rocco, and V. Patel
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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3. Development of a simple and practical nomogram for predicting stone-free rate after flexible ureteroscopy or percutaneous nephrolithotomy for solitary medium sized renal stones in adults.
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S. Micali, A. El Sherbiny, L. Bevilacqua, F. Fidanza, C. Di Pietro, E. Morini, S. Ciarlariello, S. Kaleci, A. Eissa, A. Zoeir, G. Bianchi, and B. Rocco
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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4. Correlation between mpMRI-detected lesions and definite neoplastic foci at radical prostatectomy: Level of agreement in terms of size and proximity to the capsule
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E. Morini, L. Marzotta, M.C. Sighinolfi, B. Filippi, C. Del Prete, A. Iseppi, A. Eissa, B. Reggiani, M. Rizzo, P. Torricelli, M. Sandri, M. Paterlini, S. Micali, G. Bianchi, and B. Rocco
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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5. Multiparametric magnetic resonance imaging (mpMRI): Which variable better predicts extracapsular extension of prostate cancer?
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M.C. Sighinolfi, A. Eissa, M. Rizzo, A. Iseppi, E. Morini, B. Filippi, L. Reggianibonetti, P. Torricelli, M. Sandri, S. Micali, G. Bianchi, and B. Rocco
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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- View/download PDF
6. 5- and 10-years follow up of radical prostatectomy with pelvic lymphadenectomy: A cancer-specific survival analysis on a 1274 prostate cancer series
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G. Bonfante, M.C. Sighinolfi, E. Morini, M. Sandri, R. Sabbatini, M.G. Vitale, A. Bruni, A. Romano, G. Peracchia, R. Grisanti, L. Reggiani Bonetti, I. Bgni, S. Micali, G. Bianchi, and B. Rocco
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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7. Does the number of nodes removed at the pelvic lymphadenectomy impact on cancer specific survival of pca patients with adverse pathological outcomes at radical prostatectomy? A retrospective 5- and 10-years analysis on 1274 series
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E. Morini, A. Eissa, M.C. Sighinolfi, G. Bonfante, M.G. Vitale, M. Sandri, R. Sabbatini, A. Bruni, A. Romano, G. Peracchia, R. Grisanti, L. Reggiani Bonetti, I. Bagni, S. Micali, and B. Rocco
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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- View/download PDF
8. Ex vivo fluorescence confocal microscopy in the assessment of urothelial carcinoma grading in bladder and ureter: Our preliminary experience
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S. Puliatti, A. Eissa, L. Bevilacqua, E. Morini, C. Del Prete, S. Ciarlariello, M.C. Sighinolfi, V. Spandri, P. Azzoni, L. Bertoni, L. Reggiani Bonetti, G. Bozzini, C. Buizza, B. Rocco, G. Pellacani, and G. Bianchi
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Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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9. Effects of COVID-19 pandemic on cardiac surgery and practice. Did we hit the mark: strategy or casuality?
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M Di Gaetano, A S Minotti, F Usai, E Morini, and M L Contristano
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AcademicSubjects/MED00200 ,Cardiology and Cardiovascular Medicine ,Abstract Supplement ,Cardiac Care Unit (CCU), Intensive, and Critical Cardiovascular Care - Abstract
Background COVID-19 pandemic is having a collateral health effect on delivery of surgical therapies and reports from management and maintaining surgical care are little. Purpose Investigate the impact of COVID-19 in our cardiac surgical ward and practice by scoping review of the last two years of activity, between 1st March 2019 and 28th February 2021. Methods Our Hospital is a private institution accredited with the National Health Service with a global volume load of 750 cardiac cases per year. We analized the pre-pandemic and the ongoing pandemic period on volume activity, the capacity of satisfying the needs of cardiosurgical patient and the mortality rate. Results We observed a minimal cardiac surgery caseload decline of 14.8%, probably due to environmental factor, the absence of E.D. in our institute, the rapid re-organization pathways, the hospital surveillance, the supply of personal protective equipment, the informative measures to improve patient and personnel welfare. In order to enhance the pshycological impact of this devastating event, we invited all the health workers to fill a questionnaire regarding concerns and worries about the risk of transmitting the infection to their families or to aquire it themselves. Conclusion During this devastating pandemic the rapid response in re-organization pathways and hospital surveillance allowed us to preserve the cardiac surgery volume of life-saving and non deferrable cases. Funding Acknowledgement Type of funding sources: None.
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- 2021
10. Does the number of nodes removed at the pelvic lymphadenectomy impact on cancer specific survival of pca patients with adverse pathological outcomes at radical prostatectomy? A retrospective 5- and 10-years analysis on 1274 series
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L. Reggiani Bonetti, G. Peracchia, E. Morini, Salvatore Micali, Marco Sandri, G. Bonfante, Alessio Bruni, Bernardo Rocco, Ilaria Bagni, Maria Giuseppa Vitale, Ahmed Eissa, R. Sabbatini, M. C. Sighinolfi, R. Grisanti, and Alberto Romano
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medicine.medical_specialty ,Series (stratigraphy) ,business.industry ,Prostatectomy ,Urology ,medicine.medical_treatment ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Cancer specific survival ,medicine ,Pelvic lymphadenectomy ,business ,Pathological - Published
- 2020
11. Nutritional and quality comparison between organic and conventional fresh and processing tomato: Results of a two-year project
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L. Sandei, Maria A. Rao, Paola Adamo, E. Morini, D. Agrelli, C. Stingone, M. Zaccardelli, Sandei, L., Stingone, C., Morini, E., Zaccardelli, M., Adamo, Paola, Agrelli, Diana, and Rao, MARIA ANTONIETTA
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Polyphenol ,food.ingredient ,media_common.quotation_subject ,Tomato processing ,Organic production ,Horticulture ,Ascorbic acid ,Total dissolved solids ,Lycopene ,Tomato puree ,chemistry.chemical_compound ,food ,chemistry ,Quality (business) ,Food science ,Cultivar ,Organic agriculture ,Vitamin C ,media_common - Published
- 2015
12. PPAR{gamma}2 P12A polymorphism and albuminuria in patients with type 2 diabetes: a meta-analysis of case-control studies
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S. De Cosmo, S. Prudente, O. Lamacchia, E. Morini, R. Di Paola, M. Copetti, P. Ruggenenti, G. Remuzzi, M. Cignarelli, V. T.r.i.s.c.h.i.t.t.a., LAPICE, EMANUELA, VACCARO, OLGA, S., De Cosmo, S., Prudente, O., Lamacchia, Lapice, Emanuela, E., Morini, R., Di Paola, M., Copetti, P., Ruggenenti, G., Remuzzi, Vaccaro, Olga, M., Cignarelli, and V. T. r. i. s. c. h. i. t. t., A.
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meta-analysis ,PPAR g poymorphism ,albuminuria - Published
- 2011
13. Handgrip and phalangeal ultrasound are predictive of fracture risk in postmenopausal women screened for osteoporosis
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Nancy Morabito, Antonino Lasco, Giorgio Basile, M. Papalia, Sergio Fusco, Andrea Crucitti, Antonino Catalano, E. Morini, G. Castagna, and R. Schepisi
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Fracture risk ,medicine.medical_specialty ,Postmenopausal women ,business.industry ,Obstetrics ,Osteoporosis ,Ultrasound ,medicine ,Geriatrics and Gerontology ,medicine.disease ,business ,Gerontology - Published
- 2013
14. Metabolic Syndrome (MS) and Erectile Dysfunction (ED) among Obese non Diabetic Subjects
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Susanna Morano, Andrea Lenzi, F. Maiani, M. Fallarino, Antonio F. Radicioni, A. Gatti, E. Morini, E. Mandosi, and Vincenzo Trischitta
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Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Cross-sectional study ,erectile dysfunction ,Endocrinology, Diabetes and Metabolism ,metabolic syndrome ,diabetes mellitus ,Prevalence ,Body Mass Index ,Male infertility ,Endocrinology ,Surveys and Questionnaires ,Internal medicine ,medicine ,Humans ,Insulin ,Testosterone ,Obesity ,business.industry ,Testosterone (patch) ,medicine.disease ,Cross-Sectional Studies ,Erectile dysfunction ,Metabolic syndrome ,business ,Body mass index - Abstract
Objective: To investigate whether MS is associated with erectile dysfunction (ED) among obese non diabetic individuals. Methods: A cross-sectional study was carried out to examine the association between the cluster of abnormalities related to the MS and ED as evaluated by the International Index of Erectile Function (IIEF). Fifty consecutive obese [i.e. body mass index (BMI) ≥30 kg/m2], non-diabetic whites (age 42.1±11.3 yr, BMI 43.3±8.7 kg/m2) were recruited. Results: The prevalence of MS as well as that of any MS component were not different between subjects with or without ED. Neither the prevalence of ED (34.3% vs 33.4%, p=0.6), nor IIEF score (21.5±3.9 vs 21.7±3.7, p=0.8), were different between patients with or without MS. IIEF was similar across subgroups of individuals stratified according to the number of MS components and was not related to HOMAIR index. Hypogonadism was observed in 30.8% and 28.1% individuals with and without MS (p=0.58). Testosterone and BMI levels were inversely related (r=−0.3, p=0.04). Conclusion: Among obese non-diabetic individuals the risk of developing ED is independent of the presence of MS factors. Testosterone levels progressively decrease with increasing body weight.
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- 2009
15. Study of the quasi-free np→npπ+π− reaction with a deuterium beam at 1.25 GeV/nucleon
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G. Agakishiev, A. Balanda, D. Belver, A.V. Belyaev, A. Blanco, M. Böhmer, J.L. Boyard, P. Braun-Munzinger, P. Cabanelas, E. Castro, S. Chernenko, T. Christ, M. Destefanis, J. Díaz, F. Dohrmann, A. Dybczak, L. Fabbietti, O.V. Fateev, P. Finocchiaro, P. Fonte, J. Friese, I. Fröhlich, T. Galatyuk, J.A. Garzón, R. Gernhäuser, A. Gil, C. Gilardi, K. Göbel, M. Golubeva, D. González-Díaz, F. Guber, M. Gumberidze, T. Hennino, R. Holzmann, A. Ierusalimov, I. Iori, A. Ivashkin, M. Jurkovic, B. Kämpfer, T. Karavicheva, D. Kirschner, I. Koenig, W. Koenig, B.W. Kolb, R. Kotte, F. Krizek, R. Krücken, W. Kühn, A. Kugler, A. Kurepin, A. Kurilkin, P. Kurilkin, V. Ladygin, S. Lang, J.S. Lange, K. Lapidus, T. Liu, L. Lopes, M. Lorenz, L. Maier, A. Mangiarotti, J. Markert, V. Metag, B. Michalska, J. Michel, E. Morinière, J. Mousa, C. Müntz, L. Naumann, J. Otwinowski, Y.C. Pachmayer, M. Palka, Y. Parpottas, V. Pechenov, O. Pechenova, J. Pietraszko, W. Przygoda, B. Ramstein, A. Reshetin, A. Rustamov, A. Sadovsky, P. Salabura, A. Schmah, E. Schwab, Yu.G. Sobolev, S. Spataro, B. Spruck, H. Ströbele, J. Stroth, C. Sturm, A. Tarantola, K. Teilab, P. Tlusty, M. Traxler, R. Trebacz, H. Tsertos, V. Wagner, T. Vasiliev, M. Weber, M. Wisniowski, T. Wojcik, J. Wüstenfeld, S. Yurevich, Y. Zanevsky, and P. Zhou
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Two-pion production ,np collisions ,Resonance excitations ,Physics ,QC1-999 - Abstract
The tagged quasi-free np→npπ+π− reaction has been studied experimentally with the High Acceptance Di-Electron Spectrometer (HADES) at GSI at a deuteron incident beam energy of 1.25 GeV/nucleon (s∼2.42 GeV/c for the quasi-free collision). For the first time, differential distributions of solid statistics for π+π− production in np collisions have been collected in the region corresponding to the large transverse momenta of the secondary particles. The invariant mass and angular distributions for the np→npπ+π− reaction are compared with different models. This comparison confirms the dominance of the t-channel with ΔΔ contribution. It also validates the changes previously introduced in the Valencia model to describe two-pion production data in other isospin channels, although some deviations are observed, especially for the π+π− invariant mass spectrum. The extracted total cross section is also in much better agreement with this model. Our new measurement puts useful constraints for the existence of the conjectured dibaryon resonance at mass M∼2.38 GeV and with width Γ∼70 MeV.
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- 2015
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16. A Measurement of the Space-Like Pion Electromagnetic Form-Factor
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S.R. Amendolia, M. Arik, B. Badelek, G. Batignani, G.A. Beck, F. Bedeschi, E.H. Bellamy, E. Bertolucci, D. Bettoni, H. Bilokon, G. Bologna, L. Bosisio, C. Bradaschia, M. Budinich, A. Codino, M. Dell'Orso, B. D'Ettorre Piazzli, M. Enorini, F.L. Fabbri, F. Fidecaro, L. Foà, E. Focardi, S.G.F. Frank, A. Giazotto, M.A. Giorgi, M.G. Green, J. Harvey, G.P. Heath, M.P.J. Landon, P. Laurelli, F. Liello, G. Mannocchi, P.V. March, P.S. Marrocchesi, A. Menzione, E. Meroni, E. Morini, L. Moroni, E. Milotti, P. Picchi, F. Ragusa, L. Ristori, L. Rolandi, S. Sala, C.G. Saltmarsh, A. Saoucha, L. Satta, A. Scribano, P. Spillantini, A. Stefanini, D. Storey, J.A. Strong, R. Tenchini, G. Tonelli, G. Triggiani, W. Von Schlippe, E. Van Herwijnen, A. Zallo, Rolandi, Luigi, S. R., Amendolia, M., Arik, B., Badelek, G., Batignani, G. A., Beck, F., Bedeschi, E. H., Bellamy, E., Bertolucci, D., Bettoni, H., Bilokon, G., Bologna, L., Bosisio, C., Bradaschia, M., Budinich, A., Codino, M., Dell'Orso, D'ETTORRE PIAZZOLI, Benedetto, M., Enorini, F. L., Fabbri, F., Fidecaro, L., Foà, E., Focardi, S. G. F., Frank, A., Giazotto, M. A., Giorgi, M. G., Green, J., Harvey, G. P., Heath, M. P. J., Landon, P., Laurelli, F., Liello, G., Mannocchi, P. V., March, P. S., Marrocchesi, A., Menzione, E., Meroni, E., Morini, L., Moroni, E., Milotti, P., Picchi, F., Ragusa, L., Ristori, L., Rolandi, S., Sala, C. G., Saltmarsh, A., Saoucha, L., Satta, A., Scribano, P., Spillantini, A., Stefanini, D., Storey, J. A., Strong, R., Tenchini, G., Tonelli, G., Triggiani, W., Von Schlippe, E., Van Herwijnen, A., Zallo, Franco, Bedeschi, Bosisio, Luciano, Budinich, Marco, B., D'Ettorre Piazzoli, L., Foa, John, Harvey, Milotti, Edoardo, and Gigi, Rolandi
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Nuclear and High Energy Physics ,Particle physics ,FORWARD SPECTROMETER ,elastic scattering ,Electron ,Space (mathematics) ,Nuclear physics ,Pion ,Charge radius ,angular distribution ,Nuclear Experiment ,EXPERIMENTAL RESULTS ,Physics ,Scattering ,ELECTRON PI ELASTIC SCATTERING ,Settore FIS/01 - Fisica Sperimentale ,Form factor (quantum field theory) ,Charge (physics) ,Radius ,elastic scattering. electron pi ,CERN SPS ,PI FORM FACTOR ,ANGULAR DISTRIBUTION ,300 GEV ,0.014 < T < 0.260 (GEV/C)**2 ,High Energy Physics::Experiment ,Particle Physics - Experiment ,experimental results - Abstract
The pion form factor has been measured in the space-like q 2 region 0.014 to 0.26 (GeV/ c ) 2 by scattering 300 GeV pions from the electrons of a liquid hydrogen target. A detailed description is given of the apparatus, data analysis and corrections to the data. The mean square charge radius extracted from the data is model-dependent. We find that a form which includes a realistic description of the form factor phase gives a similar results to the naive pole form, and conclude 〈r 2 π 〉 = 0.438±0.008 fm 2 .
- Published
- 1986
17. Use of phase change materials during compressed air expansion for isothermal CAES plants.
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B Castellani, A Presciutti, E Morini, M Filipponi, A Nicolini, and F Rossi
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- 2017
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18. Beneficial effects of retroreflective materials in urban canyons: results from seasonal monitoring campaign.
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F Rossi, E Morini, B Castellani, A Nicolini, E Bonamente, E Anderini, and F Cotana
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- 2015
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19. Greek Monasticim in Southern Italy. The Encounter between East and West
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MORINI, ENRICO, INES ANGELI MURZAKU, PH.D, and E. Morini
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BENEDECTINE MONASTICISM ,GREEK CHURCH ,MONASTICISM ,ITALO-GREEK SAINTS ,SOUTH ITALY - Abstract
Aim of the essay on Greek monasticism in Italy is the description and understanding of its specific characteristics and functions, up to its disappearing just before the Modern Age (its only legacy being the Monastery of Grottaferrata, near Rome). Reading the sources, the author demonstrates how the peripheral location of this monasticism, both geographic and cultural toward Orthodoxy, did not compromise the completeness of its affiliation, even in its organization structures, and spiritual threads, to the hellenophone oriental monasticism. Thus, the Italo-Greek monasticism is an authentic witness of this great ascetic tradition, contributing to the enrichment of interreligious dialogue, both inter-christian and inter-ecclesial. This is shown in the first part of the essay, where, following the sources, the author draws an history, a geography, and a prosopography of this monasticism, describing the places where it mainly flourished, and the figures which better expressed its spiritual teaching and the shapes assumed by its sanctity. Dopo avere ricordato due caratteristiche peculiari del monachesimo italo-greco – il suo essere un monachesimo di frontiera, per motivi storici e geografici, ed il suo essere in perenne movimento – il contributo presenta dapprima le fonti letterarie per lo studio di questi monasteri, cioè principalmente agiografiche – soffermandosi in particolare sul panegyrikon di Daniele (scritto al monastero di S. Salvatore di Messina nel 1307-08). Esamina poi luoghi e figure di questo monachesimo per soffermarsi infine sulla riforma monastica avviata, tra X ed XI secolo negli ambienti monastici ellenofoni: essa recepisce la sintesi micro-asiatica, elaborata poco prima nella aree monastiche dell’Asia Minore, con un accentuato spirito “studita”, in apparente dissociazione con un palese primato riconosciuto ancora alla “esichia”, che non si esprime visibilmente a livello istituzionale, ma piuttosto nei valori ascetico-spirituali che essa trasmette. Nell’ultima parte si considerano i contatti di questo monachesimo con quello latino, nel corso dei costanti spostamenti di queste comunità ellenofone verso il Nord della penisola.
- Published
- 2013
20. An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease.
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Vancheri C, Quatrana A, Morini E, Mariotti C, Mongelli A, Fichera M, Rufini A, Condò I, Testi R, Novelli G, Malisan F, and Amati F
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- Humans, Male, Prognosis, Female, Adult, RNA-Seq, Adolescent, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear pathology, Child, Young Adult, Middle Aged, Child, Preschool, ROC Curve, Case-Control Studies, Friedreich Ataxia genetics, Friedreich Ataxia pathology, Friedreich Ataxia blood, MicroRNAs genetics, MicroRNAs blood, Biomarkers blood
- Abstract
Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77-0.95; p-value < 0.0001). An in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients' group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology., (© 2024. The Author(s).)
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- 2024
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21. Author Correction: Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.
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Harripaul R, Morini E, Salani M, Logan E, Kirchner E, Bolduc J, Chekuri A, Currall B, Yadav R, Erdin S, Talkowski ME, Gao D, and Slaugenhaupt S
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- 2024
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22. A comparison between vapor tunnel and virtual basket for the treatment of proximal ureteral stones using holmium:YAG laser (Cyber Ho): which is the best tool to reduce retropulsion?
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Perri D, Besana U, Mazzoleni F, Pacchetti A, Morini E, Verzotti E, Maltagliati M, Romero-Otero J, Pastore AL, Gozen AS, Kallidonis P, Pushkar D, Govorov A, and Bozzini G
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- Humans, Holmium, Constriction, Pathologic etiology, Ureteroscopy adverse effects, Treatment Outcome, Postoperative Complications etiology, Lasers, Solid-State therapeutic use, Ureteral Calculi surgery, Lithotripsy, Laser adverse effects
- Abstract
Purpose: To compare vapor tunnel (VT) and virtual basket (VB) tools to reduce retropulsion in the treatment of proximal ureteral stones., Methods: Patients with a single proximal ureteral stone were randomly assigned to holmium laser lithotripsy with the use of VT (Group A) or VB (Group B) tool. The 150W holmium:YAG cyber Ho generator was used. We compared operative time, dusting time, need for flexible ureteroscopy due to stone push-up and occurrence of ureteral lesions. The stone-free rate (SFR) and the occurrence of postoperative ureteral strictures were assessed., Results: 186 patients were treated, of which 92 with the VT (49.5%, Group A) and 94 with the VB (50.5%, Group B). Mean stone size was 0.92 vs. 0.91 cm in Groups A vs. B (p = 0.32). Mean total operative time and dusting time were comparable between groups. 7 (7.6%) vs. 6 (6.4%) patients in Groups A vs. B required a flexible ureteroscope because of stone push-up (p = 0.12). Ureteral mucosa lesions were observed in 15 (16.3%) vs. 18 (19.1%) cases in the VT vs. VB group (p = 0.09). 1-Month SFR was comparable (97.8% vs. 95.7%, p = 0.41). We observed one case (1.1%) of postoperative ureteral stricture in the VT group vs. two cases (2.1%) in the VB group (p = 0.19)., Conclusions: VT and VB are equally safe and effective tools in reducing retropulsion of ureteral stones. Operative time, dusting time and SFR were comparable. They also equally avoided stone push-up and prevented ureteral lesions, which may later occur in ureteral strictures., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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23. Evaluation of the learning curve for Thulium laser enucleation of the prostate in a contemporary cohort.
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Perri D, Pacchetti A, Morini E, Besana U, Mazzoleni F, Verzotti E, Maltagliati M, Romero-Otero J, Pastore AL, Broggini P, Rocco B, Gozen AS, Kallidonis P, and Bozzini G
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- Male, Humans, Aged, Prostate surgery, Thulium, Learning Curve, Treatment Outcome, Laser Therapy methods, Prostatic Hyperplasia surgery, Lasers, Solid-State therapeutic use
- Abstract
Purpose: To assess the learning curve of Thulium laser enucleation of the prostate (ThuLEP) of a single surgeon., Methods: Hundred patients suffering from benign prostatic hyperplasia were treated by the same surgeon. In all cases, a well-trained urologist was present in the operating room. Patients urinary function was assessed preoperatively using the International Prostate Symptoms Score (IPSS), maximum flow rate and Post-Void Residual volume. Preoperative prostate volume was recorded. Enucleation and morcellation efficiency and complication rate were evaluated. Patients were divided into 5 cohorts of 20 consecutive cases to assess changes in outcomes through time., Results: Mean age of patients was 73.1 years (SD 17.5) and mean prostate volume was 89.7 ml (SD 55.1). Overall, mean enucleation and morcellation efficiency were 1.7 (SD 2.9) and 5.1 (SD 2.7) g/min. A statistically significant increase in enucleation efficiency was observed when comparing cohort 1 vs 2 (0.9 vs 1.3 g/min, p = 0.03) and cohort 2 vs 3 (1.3 vs 1.7 g/min, p = 0.02). A statistically significant increase in morcellation efficiency was observed when comparing cohort 1 vs 2 (2.8 vs 3.7 g/min, p = 0.02) and cohort 2 vs 3 (3.7 vs 4.9 g/min, p = 0.03). In both cases, no significant differences were observed when comparing the following cohorts. Complication rate showed no significant differences throughout the caseload., Conclusions: In our single-surgeon experience, we observed a learning curve of nearly 60 cases for the ThuLEP procedure in presence of a well-trained surgeon. Complication rate was low from the beginning of surgical experience., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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24. Towards a Deeper Understanding: Utilizing Machine Learning to Investigate the Association between Obesity and Cognitive Decline-A Systematic Review.
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Veneziani I, Grimaldi A, Marra A, Morini E, Culicetto L, Marino S, Quartarone A, and Maresca G
- Abstract
Background/Objectives : Several studies have shown a relation between obesity and cognitive decline, highlighting a significant global health challenge. In recent years, artificial intelligence (AI) and machine learning (ML) have been integrated into clinical practice for analyzing datasets to identify new risk factors, build predictive models, and develop personalized interventions, thereby providing useful information to healthcare professionals. This systematic review aims to evaluate the potential of AI and ML techniques in addressing the relationship between obesity, its associated health consequences, and cognitive decline. Methods : Systematic searches were performed in PubMed, Cochrane, Web of Science, Scopus, Embase, and PsycInfo databases, which yielded eight studies. After reading the full text of the selected studies and applying predefined inclusion criteria, eight studies were included based on pertinence and relevance to the topic. Results : The findings underscore the utility of AI and ML in assessing risk and predicting cognitive decline in obese patients. Furthermore, these new technology models identified key risk factors and predictive biomarkers, paving the way for tailored prevention strategies and treatment plans. Conclusions : The early detection, prevention, and personalized interventions facilitated by these technologies can significantly reduce costs and time. Future research should assess ethical considerations, data privacy, and equitable access for all.
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- 2024
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25. Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat.
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McLean ZL, Gao D, Correia K, Roy JCL, Shibata S, Farnum IN, Valdepenas-Mellor Z, Kovalenko M, Rapuru M, Morini E, Ruliera J, Gillis T, Lucente D, Kleinstiver BP, Lee JM, MacDonald ME, Wheeler VC, Mouro Pinto R, and Gusella JF
- Subjects
- Humans, Exons genetics, Gene Expression Profiling, Heterozygote, Homozygote, MutL Proteins, Neoplasm Proteins, Huntington Disease genetics
- Abstract
Huntington's disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin's polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites., (© 2024. The Author(s).)
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- 2024
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26. A proposed mathematical model to help preoperative planning between RIRS and MiniPerc for renal stones between 10 and 20 mm using holmium:Yag laser (Cyber Ho): the stone management according to size-hardness (SMASH) score.
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Perri D, Mazzoleni F, Besana U, Pacchetti A, Morini E, Calandriello M, Pastore AL, Romero-Otero J, Bruyere F, Sighinolfi MC, Rocco B, Micali S, Gozen AS, Liatsikos E, Roche JB, and Bozzini G
- Subjects
- Humans, Holmium, Hardness, Treatment Outcome, Lasers, Solid-State adverse effects, Nephrostomy, Percutaneous methods, Kidney Calculi surgery
- Abstract
To evaluate the performance of a mathematical model to drive preoperative planning between RIRS and MiniPerc (MP) for the treatment of renal stones between 10 and 20 mm. Patients with a renal stone between 10 and 20 mm were enrolled. A mathematical model named Stone Management According to Size-Hardness (SMASH) score was calculated: hounsfield units (HU) χ stone maximum size (cm)/100. Patients were divided into 4 groups: RIRS with score < 15 (Group A), RIRS with score ≥ 15 (Group B), MP with score < 15 (Group C), MP with score ≥ 15 (Group D). Cyber Ho device was always used. Stone free rate (SFR) was assessed after 3 months. Complication rate and need for auxiliary procedures were evaluated. Between January 2019 and December 2021, 350 patients were enrolled (87, 88, 82 and 93 in Groups A, B, C and D). Mean stone size was 13.1 vs 13.3 mm in Group A vs B (p = 0.18) and 16.2 vs 18.1 mm in Group C vs D (p = 0.12). SFR was 82%, 61%, 75% and 85% for Groups A, B, C and D. SFR was comparable between Groups C and D (p = 0.32) and Groups A and C (p = 0.22). SFR was significantly higher in Group A over B (p = 0.03) and in Group D over B (p = 0.02). Complication rate was 2.2%, 3.4%, 12.1%, 12.9% for Groups A, B, C, D. RIRS and MP are both safe and effective. The mathematical model with the proposed cut-off allowed a proper allocation of patients between endoscopic and percutaneous approaches.Registration number of the study ISRCTN55546280., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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27. Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models.
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Tai DJC, Razaz P, Erdin S, Gao D, Wang J, Nuttle X, de Esch CE, Collins RL, Currall BB, O'Keefe K, Burt ND, Yadav R, Wang L, Mohajeri K, Aneichyk T, Ragavendran A, Stortchevoi A, Morini E, Ma W, Lucente D, Hastie A, Kelleher RJ, Perlis RH, Talkowski ME, and Gusella JF
- Published
- 2024
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28. Evaluating adherence, tolerability and safety of oral calcium citrate in elderly osteopenic subjects: a real-life non-interventional, prospective, multicenter study.
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Rondanelli M, Minisola S, Barale M, Barbaro D, Mansueto F, Battaglia S, Bonaccorsi G, Caliri S, Cavioni A, Colangelo L, Corbetta S, Coretti F, Dito G, Gavioli V, Ghigo E, Giannattasio R, Lapi P, Maiorana B, Marra C, Mazzantini M, Morini E, Nannipieri F, Nuzzo V, Parri F, Perna S, Santori R, and Procopio M
- Subjects
- Humans, Female, Aged, Male, Calcium, Prospective Studies, Calcium, Dietary, Dietary Supplements adverse effects, Calcium Citrate adverse effects, Osteoporosis drug therapy
- Abstract
Background: Osteoporosis is a common concern in the elderly that leads to fragile bones. Calcium supplementation plays a crucial role in improving bone health, reducing fracture risk, and supporting overall skeletal strength in this vulnerable population. However, there is conflicting evidence on the safety of calcium supplements in elderly individuals., Aim: The aim of this study was to evaluate the adherence, safety and tolerability of calcium citrate supplementation in elderly osteopenic subjects., Methods: In this non-interventional, prospective, multicenter study, subjects received daily 500 mg calcium citrate supplementation for up to one year. Adherence was calculated based on compliance and persistence. Safety was assessed through adverse reactions (ARs), deaths, and clinical laboratory evaluations., Results: A total of 268 Caucasian subjects (91.4% female, mean age 70 ± 4.5 years) participated in the study. Mean adherence to treatment was 76.6 ± 29.5% and half of subjects had an adherence of 91% and ~ 33% of participants achieved complete (100%) adherence. ARs were reported by nine (3.9%) subjects, primarily gastrointestinal disorders, with no serious ARs. The frequency of all adverse events (including ARs) was significantly higher in subjects with adherence of < 80% (41.6%; 32/77) vs. those with adherence ≥ 80% (11%; 16/145, p < 0.0001). Both systolic and diastolic blood pressure decreased from baseline to follow-up visit (change of -2.8 ± 13.9 mmHg, p = 0.0102 and -2.1 ± 10.4 mmHg, p = 0.0116, respectively)., Conclusion: This study demonstrated favorable adherence to calcium citrate supplementation in elderly osteopenic subjects. The occurrence of ARs, though generally mild, were associated with lower adherence to calcium supplementation., (© 2024. The Author(s).)
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- 2024
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29. Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.
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Harripaul R, Morini E, Salani M, Logan E, Kirchner E, Bolduc J, Chekuri A, Currall B, Yadav R, Erdin S, Talkowski ME, Gao D, and Slaugenhaupt S
- Subjects
- Humans, Mice, Animals, Carrier Proteins metabolism, Peripheral Nervous System metabolism, Sensory Receptor Cells metabolism, Gene Expression Profiling, Gene Expression, Dysautonomia, Familial genetics, Dysautonomia, Familial metabolism, Dysautonomia, Familial pathology
- Abstract
Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in a tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse model TgFD9; Elp1
Δ20/flox . This mouse recapitulates the same tissue-specific ELP1 mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-length ELP1 transcript. These genes, defined as ELP1 dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease., (© 2024. The Author(s).)- Published
- 2024
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30. Indocyanine green-marked fluorescence-guided off-clamp versus intraoperative ultrasound-guided on-clamp robotic partial nephrectomy: Outcomes on surgical procedure.
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Mazzoleni F, Perri D, Pacchetti A, Morini E, Berti L, Besana U, Faiella E, Moramarco L, Santucci D, Fior D, and Bozzini G
- Abstract
Objectives: To compare surgical and functional outcomes between off-clamp robot-assisted partial nephrectomy with indocyanine-green tumour marking through preliminary superselective embolization and on-clamp robot-assisted partial nephrectomy with intraoperative ultrasound identification of the renal mass., Material and Methods: One hundred and forty patients with a single renal mass underwent indocyanine-green fluorescence-guided off-clamp robot-assisted partial nephrectomy with preoperative superselective embolization (Group A, 70 patients) versus intraoperative ultrasound-guided on-clamp robot-assisted partial nephrectomy without embolization (Group B, 70 patients). We assessed operative time, intraoperative blood loss, complications, length of stay, renal function, need for ancillary procedures and blood transfusions., Results: Mean tumour size was 24 versus 25 mm in Group A versus Group B ( p = 0.19). Mean operative time was 86.5 versus 121.8 min ( p = 0.02), mean blood loss was 72.8 versus 214.2 mL ( p = 0.02), and mean haemoglobin drop on postoperative day 1 was 1.1 versus 2.6 g/dL ( p = 0.04) in Group A versus Group B. One-month creatinine, hospital stay and enucleated tumour volume were comparable. Ten postoperative complications occurred in Group A (13.3%) and 11 in Group B (15.3%). Following superselective embolization, no patients required blood transfusions versus two patients in Group B. Postoperative selective renal embolization was needed in one case per group., Conclusions: Preoperative superselective embolization of a renal mass with indocyanine-green before off-clamp robot-assisted partial nephrectomy significantly reduces operative time and intraoperative blood loss compared to on-clamp intraoperative ultrasound-guided robot-assisted partial nephrectomy. A longer follow-up is needed to establish the effect on renal function., Competing Interests: The authors have no competing interests., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)
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- 2023
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31. Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators.
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Schultz A, Cheng SY, Kirchner E, Costello S, Miettinen H, Chaverra M, King C, George L, Zhao X, Narasimhan J, Weetall M, Slaugenhaupt S, Morini E, Punzo C, and Lefcort F
- Subjects
- Mice, Animals, Humans, Retinal Ganglion Cells metabolism, RNA Splicing, Genetic Therapy, Transcriptional Elongation Factors genetics, Transcriptional Elongation Factors metabolism, Dysautonomia, Familial genetics, Dysautonomia, Familial therapy, Dysautonomia, Familial metabolism, Neurodegenerative Diseases metabolism
- Abstract
Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients., (© 2023. The Author(s).)
- Published
- 2023
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- View/download PDF
32. Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.
- Author
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Harripaul R, Morini E, Salani M, Logan E, Kirchner E, Bolduc J, Chekuri A, Currall B, Yadav R, Erdin S, Talkowski ME, Gao D, and Slaugenhaupt S
- Abstract
Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 ( ELP1 ) gene. This mutation results in a tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse model TgFD9 ; Elp1
Δ 20/flox . This mouse recapitulates the same tissue-specific ELP1 mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-length ELP1 transcript. These genes, defined as ELP1 dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease.- Published
- 2023
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- View/download PDF
33. Three-Dimensional Customized Imaging Reconstruction for Urological Surgery: Diffusion and Role in Real-Life Practice from an International Survey.
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Sighinolfi MC, Menezes AD, Patel V, Moschovas M, Assumma S, Calcagnile T, Panio E, Sangalli M, Turri F, Sarchi L, Micali S, Varca V, Annino F, Leonardo C, Bozzini G, Cacciamani G, Gregori A, Morini E, Terzoni S, Eissa A, and Rocco B
- Abstract
Despite the arising interest in three-dimensional (3D) reconstruction models from 2D imaging, their diffusion and perception among urologists have been scarcely explored. The aim of the study is to report the results of an international survey investigating the use of such tools among urologists of different backgrounds and origins. Beyond demographics, the survey explored the degree to which 3D models are perceived to improve surgical outcomes, the procedures mostly making use of them, the settings in which those tools are mostly applied, the surgical steps benefiting from 3D reconstructions and future perspectives of improvement. One hundred responders fully completed the survey. All levels of expertise were allowed; more than half (53%) were first surgeons, and 59% had already completed their training. Their main application was partial nephrectomy (85%), followed by radical nephrectomy and radical prostatectomy. Three-dimensional models are mostly used for preoperative planning (75%), intraoperative consultation and tailoring. More than half recognized that 3D models may highly improve surgical outcomes. Despite their recognized usefulness, 77% of responders use 3D models in less than 25% of their major operations due to costs or the extra time taken to perform the reconstruction. Technical improvements and a higher availability of the 3D models will further increase their role in surgical and clinical daily practice.
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- 2023
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34. Pulsed-wave vs Continuous-wave Thulium Fiber Laser Enucleation of the Prostate (ThuFLEP): A Comparison of Perioperative Outcomes.
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Perri D, Mazzoleni F, Besana U, Pacchetti A, Morini E, Berti L, Calandriello M, Pastore AL, Romero-Otero J, Bruyere F, Sighinolfi MC, Rocco B, Micali S, Gozen AS, Liatsikos E, Roche JB, and Bozzini G
- Subjects
- Male, Humans, Prostate surgery, Thulium therapeutic use, Prostate-Specific Antigen, Treatment Outcome, Lasers, Quality of Life, Prostatic Hyperplasia surgery, Transurethral Resection of Prostate methods, Laser Therapy, Lower Urinary Tract Symptoms surgery, Lasers, Solid-State therapeutic use
- Abstract
Objective: To compare intra and early postoperative outcomes between pulsed-wave and continuous-wave Thulium Fiber Laser Enucleation of the Prostate (PW-ThuFLEP vs CW-ThuFLEP) for the treatment of benign prostatic hyperplasia., Methods: 238 patients with lower urinary tract symptoms due to benign prostatic hyperplasia underwent PW-ThuFLEP (118 patients) vs CW-ThuFLEP (120 patients). Preoperative prostate volume, adenoma volume, prostate-specific antigen (PSA), and hemoglobin values were recorded. International Prostate Symptom Score (IPSS), maximum flow rate (Qmax), post-void residual volume, and International Index of Erectile Function-5 score (IIEF-5) were assessed. Operative time, enucleation time, enucleation efficiency, catheterization time, irrigation volume, hospital stay, hemoglobin drop, and postoperative complications were recorded. Micturition improvements and sexual outcomes were evaluated 3months after surgery., Results: CW-ThuFLEP showed shorter operative time (61.5 vs 67.4 minutes, P = .04). Enucleation time (50.2 vs 53.3 minutes, P = .12), enucleation efficiency (0.8 vs 0.7 g/min, P = .38), catheterization time (2.2 vs 2.1days, P = .29), irrigation volume (32.9 vs 32.8L, P = .71), hospital stay (2.8 vs 2.6days, P = .29) and hemoglobin drop (0.38 vs 0.39 g/dL, P = .53) were comparable. No significant difference in complication rate was observed. At 3-month follow-up, the procedures did not show any significant difference in IPSS, Qmax, post-void residual volume, IIEF-5, and PSA value., Conclusion: PW-ThuFLEP and CW-ThuFLEP both relieve lower urinary tract symptoms equally, with high efficacy and safety. Operative time was significantly shorter with CW-ThuFLEP, but with a small difference with low clinical impact. Enucleation time, enucleation efficiency, catheterization time, irrigation volume, hospital stay, hemoglobin and PSA drop, complication rate, and sexual outcomes showed no differences., Competing Interests: DECLARATION OF COMPETING INTEREST None., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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35. PMS1 as a target for splice modulation to prevent somatic CAG repeat expansion in Huntington's disease.
- Author
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McLean ZL, Gao D, Correia K, Roy JCL, Shibata S, Farnum IN, Valdepenas-Mellor Z, Rapuru M, Morini E, Ruliera J, Gillis T, Lucente D, Kleinstiver BP, Lee JM, MacDonald ME, Wheeler VC, Pinto RM, and Gusella JF
- Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose motor, cognitive, and behavioral manifestations are caused by an expanded, somatically unstable CAG repeat in the first exon of HTT that lengthens a polyglutamine tract in huntingtin. Genome-wide association studies (GWAS) have revealed DNA repair genes that influence the age-at-onset of HD and implicate somatic CAG repeat expansion as the primary driver of disease timing. To prevent the consequent neuronal damage, small molecule splice modulators (e.g., branaplam) that target HTT to reduce the levels of huntingtin are being investigated as potential HD therapeutics. We found that the effectiveness of the splice modulators can be influenced by genetic variants, both at HTT and other genes where they promote pseudoexon inclusion. Surprisingly, in a novel hTERT-immortalized retinal pigment epithelial cell (RPE1) model for assessing CAG repeat instability, these drugs also reduced the rate of HTT CAG expansion. We determined that the splice modulators also affect the expression of the mismatch repair gene PMS1 , a known modifier of HD age-at-onset. Genome editing at specific HTT and PMS1 sequences using CRISPR-Cas9 nuclease confirmed that branaplam suppresses CAG expansion by promoting the inclusion of a pseudoexon in PMS1 , making splice modulation of PMS1 a potential strategy for delaying HD onset. Comparison with another splice modulator, risdiplam, suggests that other genes affected by these splice modulators also influence CAG instability and might provide additional therapeutic targets., Competing Interests: Competing interests J.F.G. and V.C.W. were founding scientific advisory board members with a financial interest in Triplet Therapeutics Inc. Their financial interests were reviewed and are managed by Massachusetts General Hospital (MGH) and Mass General Brigham (MGB) in accordance with their conflict of interest policies. J.F.G. consults for Transine Therapeutics, Inc. and has previously provided paid consulting services to Wave Therapeutics USA Inc., Biogen Inc. and Pfizer Inc. V.C.W. is a scientific advisory board member of LoQus23 Therapeutics Ltd. and has provided paid consulting services to Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc. and Passage Bio. R.M.P. and V.C.W. have received research support from Pfizer Inc. B.P.K. is a consultant for EcoR1 capital and Curie.Bio, and is an advisor to Acrigen Biosciences, Life Edit Therapeutics and Prime Medicine. B.P.K. has a financial interest in Prime Medicine, Inc., a company developing therapeutic CRISPR-Cas technologies for gene editing. B.P.K.’s interests were reviewed and are managed by MGH and MGB in accordance with their conflict-of-interest policies. J-M.L. consults for Life Edit Therapeutics and serves on the scientific advisory board of GenEdit Inc. E.M. is inventor on an International Patent Application Number PCT/US2021/012103, assigned to Massachusetts General Hospital and PTC Therapeutics entitled “RNA Splicing Modulation” related to use of BPN-15477 in modulating splicing.
- Published
- 2023
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36. Sexual Dysfunctions in Females with Parkinson's Disease: A Cross-Sectional Study with a Psycho-Endocrinological Perspective.
- Author
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De Luca R, Bonanno M, Morini E, Marra A, Arcadi FA, Quartarone A, and Calabrò RS
- Subjects
- Humans, Female, Cross-Sectional Studies, Quality of Life, Testosterone, Cholecalciferol, Parkinson Disease complications, Sexual Dysfunction, Physiological etiology
- Abstract
Background and Objectives : Normal human sexual functioning is a complex integration of an intact neuroanatomic substrate, vascular supply, a balanced hormonal profile, and a predominance of excitatory over inhibitory psychological mechanisms. However, sexual functioning in Parkinson's disease (PD) is often overlooked in clinical practice, especially in female patients. Materials and Methods : In this cross-sectional study, we have investigated the frequency of sexual dysfunction and the possible correlation with psycho-endocrinological factors in a sample of women with idiopathic PD. Patients were assessed using a semi-structured sexual interview, in addition to psychometric tools, including the Hamilton Rating Scale for Anxiety and for Depression and the Coping Orientation to the Problems Experiences-New Italian Version. Specific blood tests, including testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen E2, prolactin (PRL), and vitamin D3 were also evaluated. Results : Our results reported a statistical difference in sexual intercourse frequency before and after the onset of PD ( p < 0.001). The percentage of women who complained about reduced sexual desire increased after diagnosis (52.7%) compared to the period before the onset of the illness (36.8%). The endocrinological profile in females with PD revealed statistically significant differences regarding testosterone ( p < 0.0006), estradiol ( p < 0.00), vitamin D3 ( p < 0.006), and calcium (0.002). Depression (44% characterized by perceived feelings of anger and frustration during sexual intercourse) and anxiety symptoms (29.5% reported feelings of fear and anxiety for not satisfying the partner) with abnormal coping strategies (48.14% experienced feelings of anger and intolerance) were also found to be statistically significant. This study showed a high frequency of sexual dysfunction in female patients with PD, which correlated with sexual hormone abnormalities, mood/anxiety, and coping strategies alterations. This supports the idea that there is a need to better investigate the sexual function of female patients with PD to provide them with an adequate therapeutic approach and potentially improve quality of life.
- Published
- 2023
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37. Treatment of ureteral stones with LithoEVO device and Vapor Tunnel tool.
- Author
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Perri D, Berti L, Pacchetti A, Morini E, Besana U, Marcangeli P, Maltagliati M, Sighinolfi MC, Romero-Otero J, Pastore AL, Gözen AS, Broggini P, Rocco B, Mazzoleni F, and Bozzini G
- Subjects
- Humans, Constriction, Pathologic, Ureteroscopy adverse effects, Postoperative Complications epidemiology, Postoperative Complications etiology, Ureteral Calculi surgery, Lithotripsy adverse effects, Lithotripsy, Laser adverse effects
- Abstract
Background: Vapor Tunnel (VT) technology is the result of a pulse modulation during holmium laser emission which reduces stone retropulsion. We present the outcomes of this tool in the treatment of ureteral stones., Methods: Two hundred ten patients with a ureteral stone were randomly assigned to holmium laser lithotripsy with (group A) or without (group B) the VT technology. The 35 W LithoEVO laser generator (Quanta System, Samarate, Varese, Italy) was used. We compared operative time, dusting time, delivered energy, retreatment rate due to stone push-up, ureteral lesions, and stone-free rate (SFR) and postoperative strictures at 1 month. We also compared outcomes according to stone position., Results: VT technology was associated with significantly lower mean operative time (25.7 vs. 37.2 min), dusting time (9.7 vs. 15.3 min), delivered energy (7.7 vs. 19.9 KJ). In group B 9 patients (8.5%) were retreated due to stone push-up (P=0.01) for a proximal or middle stone, 6 (5.7%) postoperative strictures occurred (P=0.03) and a higher ureteral lesion rate was observed (7.6% vs 35.2%, P=0.04). 1-month SFR was comparable (93.4% vs. 88.6%, P=0.11). Postoperative complication rate was higher in group B (P=0.05). Without VT technology, ureteral lesions and strictures rates were significantly higher independently from stone position., Conclusions: The VT technology is associated with significantly lower operative and dusting time independently from stone position, due to a reduced retropulsion, which makes treatment quicker and easier. It also avoids stone push-up especially for proximal and middle stones and reduces ureteral lesions, postoperative complications, and ureteral strictures.
- Published
- 2023
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38. Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.
- Author
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Morini E, Chekuri A, Logan EM, Bolduc JM, Kirchner EG, Salani M, Krauson AJ, Narasimhan J, Gabbeta V, Grover S, Dakka A, Mollin A, Jung SP, Zhao X, Zhang N, Zhang S, Arnold M, Woll MG, Naryshkin NA, Weetall M, and Slaugenhaupt SA
- Subjects
- Mice, Animals, Kinetin, Gait Ataxia, Administration, Oral, Dysautonomia, Familial genetics, Retinal Degeneration, Neurodegenerative Diseases
- Abstract
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1
Δ20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD., Competing Interests: Declaration of interests The authors declare the following competing financial interests. J.N., V.G., S.G., A.D., A.M., S.J., X.Z., N.Z., S.Z., M.A., M.G.W., N.A.N., and M.W. are/were employees of PTC Therapeutics, Inc., a biotechnology company. In connection with such employment, the authors receive salary, benefits, and stock-based compensation, including stock options, restricted stock, other stock-related grants, and the right to purchase discounted stock through PTC’s employee stock purchase plan. S.A.S. is a paid consultant to PTC Therapeutics and is an inventor on several U.S. and foreign patents and patent applications assigned to the Massachusetts General Hospital, including U.S. Patents 8,729,025 and 9,265,766, both entitled “Methods for altering mRNA splicing and treating familial dysautonomia by administering benzyladenine,” filed on August 31, 2012 and May 19, 2014 and related to use of kinetin and U.S. Patent 10,675,475, entitled “Compounds for improving mRNA splicing,” filed on July 14, 2017 and related to use of BPN-15477. E.M., V.G., A.D., N.A.N., and S.A.S. are inventors on an International Patent Application Number PCT/US2021/012103, assigned to Massachusetts General Hospital and PTC Therapeutics, entitled "RNA Splicing Modulation," related to use of BPN-15477 in modulating splicing., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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39. Bone Health Status in Individuals with Amyotrophic Lateral Sclerosis: A Cross-Sectional Study on the Role of the Trabecular Bone Score and Its Implications in Neurorehabilitation.
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Morini E, Portaro S, Leonetti D, De Cola MC, De Luca R, Bonanno M, Quartarone A, and Calabrò RS
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- Humans, Cancellous Bone, Cross-Sectional Studies, Bone Density physiology, Absorptiometry, Photon methods, Lumbar Vertebrae, Amyotrophic Lateral Sclerosis, Osteoporosis, Fractures, Bone
- Abstract
Background and Objectives : Osteoporosis is a metabolic skeletal disease resulting in low bone mass with increased bone fragility and susceptibility to fractures. May lead to rapid loss of bone mineral density (BMD) due to physical inactivity and reduced muscle contractions. Generally, the diagnosis of osteoporosis is made using dual X-ray absorptiometry (DXA), by measuring BMD and the trabecular bone score (TBS), which can be useful for detecting bone fragility and susceptibility to fractures. Therefore, the aim of this study was to investigate, using BMD and TBS, the bone health status in a sample of amyotrophic lateral sclerosis (ALS) inpatients attending neurorehabilitation. Materials and Methods: Thirty-nine patients were included in the study and underwent electrocardiogram and blood tests, including calcium and parathyroid hormone, as well as vitamin D dosage, and DXA. Results: We found that the TBS of patients with osteoporosis was lower than that of those ALS patients with osteopenia or normal bone status, both in the lumbar spine and femoral neck, although no statistical significance was reached. In addition, Spearman's correlation coefficient indicated a moderate correlation between TBS and lumbar spine BMD (r = -0.34) and a mild correlation between TBS and femoral neck BMD (r = -0.28). Conclusions : This study confirmed the hypothesis that ALS patients may exhibit deteriorated bone health with lower bone density and focused on the possible role of the TBS in the multidisciplinary approach to ALS.
- Published
- 2023
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40. Downregulation of Circulating Hsa-miR-200c-3p Correlates with Dyslipidemia in Patients with Stable Coronary Artery Disease.
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Vancheri C, Morini E, Prandi FR, Barillà F, Romeo F, Novelli G, and Amati F
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- Humans, Down-Regulation genetics, Pilot Projects, Gene Expression Profiling methods, Biomarkers, Coronary Artery Disease genetics, MicroRNAs metabolism, Dyslipidemias
- Abstract
Coronary heart disease (CHD), one of the leading causes of disability and death worldwide, is a multifactorial disease whose early diagnosis is demanding. Thus, biomarkers predicting the occurrence of this pathology are of great importance from a clinical and therapeutic standpoint. By means of a pilot study on peripheral blood cells (PBMCs) of subjects with no coronary lesions (CTR; n = 2) and patients with stable CAD (CAD; n = 2), we revealed 61 differentially methylated regions (DMRs) (18 promoter regions, 24 genes and 19 CpG islands) and 14.997 differentially methylated single CpG sites (DMCs) in CAD patients. MiRNA-seq results displayed a peculiar miRNAs profile in CAD patients with 18 upregulated and 32 downregulated miRNAs (FC ≥ ±1.5, p ≤ 0.05). An integrated analysis of genome-wide DNA methylation and miRNA-seq results indicated a significant downregulation of hsa-miR-200c-3p (FCCAD = −2.97, p ≤ 0.05) associated to the hypermethylation of two sites (genomic coordinates: chr12:7073122-7073122 and chr12:7072599-7072599) located intragenic to the miR-200c/141 genomic locus (encoding hsa-miR-200c-3p) (p-value = 0.009) in CAD patients. We extended the hsa-miR-200c-3p expression study in a larger cohort (CAD = 72, CTR = 24), confirming its reduced expression level in CAD patients (FCCAD = −2; p = 0.02). However, when we analyzed the methylation status of the two CpG sites in the same cohort, we failed to identify significant differences. A ROC curve analysis showed good performance of hsa-miR-200c-3p expression level (AUC = 0.65; p = 0.02) in distinguishing CAD from CTR. Moreover, we found a significant positive correlation between hsa-miR-200c-3p expression and creatinine clearance (R2 = 0.212, p < 0.005, Pearson r = 0.461) in CAD patients. Finally, a phenotypic correlation performed in the CAD group revealed lower hsa-miR-200c-3p expression levels in CAD patients affected by dyslipidemia (+DLP, n = 58) (p < 0.01). These results indicate hsa-miR-200c-3p as potential epi-biomarker for the diagnosis and clinical progression of CAD and highlight the importance of deeper studies on the expression of this miRNA to understand its functional role in coronary artery disease development.
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- 2023
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41. Pathological report and prognostic meaning of Bosniak IV cysts: results from a contemporary cohort.
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Perri D, Mazzoleni F, Pacchetti A, Rossini M, Morini E, Berti L, Buizza C, Besana U, and Bozzini G
- Abstract
Introduction: Surgery is the recommended treatment for Bosniak IV renal cysts. We performed a retrospective analysis of Bosniak IV lesions surgically removed to increase evidence on their prognostic meaning., Material and Methods: Patients with a Bosniak IV cyst were considered. A contrast-enhanced computed tomography (CT) scan or magnetic resonance imaging (MRI) detected a solid component with contrast enhancement. In no case a percutaneous biopsy was performed. A radical (9, 21.4%) or partial (33, 78.6%) nephrectomy was performed with laparoscopic (14, 33.3%) or robot-assisted (28, 66.7%) approach. Analysis of the final pathology was performed, and recurrence rate was assessed., Results: 42 patients were included. Median lesion size was 54.7 mm (IQR 20.0-81.2). A solid tumour was detected in 40 patients (95.2%), whereas in 2 cases (4.8%) a benign cyst without neoplastic component was diagnosed. Final pathology revealed a low-grade clear cell renal cell carcinoma (ccRCC) in 16 cases (38.0%), a multilocular cystic renal neoplasm of low malignant potential in 6 cases (14.3%), a low-grade papillary RCC (pRCC) type I in 4 cases (9.5%), a clear cell papillary RCC (ccpRCC) in 10 cases (23.8%) and an oncocytoma in 2 cases (4.8%). A high-grade ccRCC was detected in 2 cases (4.8%), whereas no patients had a pRCC type II. In all cases surgical margins were negative. Median follow-up was 24 months and no recurrence occurred., Conclusions: Our results increase evidence on the favourable pathology and good prognosis of Bosniak IV renal cysts, supporting the role of surgery as a definitive treatment and suggesting the need for a low-intensity follow-up., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)
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- 2023
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42. Thulium: YAG vs continuous-wave thulium fiber laser enucleation of the prostate: do potential advantages of thulium fiber lasers translate into relevant clinical differences?
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Bozzini G, Berti L, Maltagliati M, Besana U, Micali S, Roche JB, Romero-Otero J, Pacchetti A, Perri D, Morini E, Saredi G, Mazzoleni F, Sighinolfi MC, Buizza C, and Rocco B
- Subjects
- Male, Humans, Prostate surgery, Thulium, Treatment Outcome, Erectile Dysfunction, Prostatic Hyperplasia complications, Prostatic Hyperplasia surgery, Laser Therapy, Lasers, Solid-State therapeutic use, Lower Urinary Tract Symptoms etiology, Lower Urinary Tract Symptoms surgery
- Abstract
Purpose: To compare endoscopic enucleation of the prostate using a thulium: yttrium-aluminum-garnet (Tm:YAG) laser and a super-pulsed thulium fiber laser set in continuous-wave (CW) mode, and to evaluate whether theoretical advantages of thulium fiber lasers, related to their shorter wavelength, translate into relevant clinical differences., Methods: In total, 110 patients suffering from lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia were randomized to undergo either thulium:YAG laser enucleation of the prostate (ThuLEP) or CW thulium fiber laser enucleation of the prostate (CW-ThuFLEP). Intraoperative and postoperative variables and complications were compared. Micturition improvement was assessed at 3-month follow-up using the International Prostate Symptom Score (IPSS), post-void residual urine (PVR) and maximum flow rate (Qmax). Erectile function was evaluated using the International Index of Erectile Function-5 (IIEF-5)., Results: No significant differences between the ThuLEP and CW-ThuFLEP groups were found in terms of operative time (70.69 vs 72.41 min), enucleation time (50.23 vs 53.33 min), enucleated tissue weight (40.2 vs 41.9 g), enucleation efficiency (0.80 vs 0.79 g/min), catheterization time (2.45 vs 2.57 days), hospital stay (2.82 vs 2.95 days) and hemoglobin drop (1.05 vs 1.27 g/dl). At 3-month follow-up, no significant differences were found in IPSS (5.09 vs 5.81), Qmax (26.51 vs 27.13 ml/s), PVR (25.22 vs 23.81 ml) and IIEF-5 (14.01 vs 14.54)., Conclusion: ThuLEP and CW-ThuFLEP were equivalent in relieving patients from LUTS and improving micturition. Theoretical advantages of the TFL, such as shallower penetration depth and improved vaporization capacity, did not translate into relevant perioperative outcomes or clinical differences., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2023
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43. "Bordeaux Neobladder": First Evaluation of the Urodynamic Outcomes.
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Asimakopoulos AD, Gubbiotti M, Agrò EF, Morini E, Giommoni V, Piechaud T, Gaston R, and Annino F
- Abstract
Background: The intracorporeal orthotopic modified-Y "Bordeaux" neobladder (iYNB) was first described in 2016. No urodynamic evaluation of this neobladder has yet been performed., Objective: To present the urodynamic features of the iYNB and incontinence-specific health-related quality of life (HRQoL) outcomes., Design Setting and Participants: We prospectively assessed 26 patients operated between September 2018 and November 2020., Surgical Procedure: Robotic radical cystectomy for malignant disease of the bladder and iYNB, performed by a single surgeon, were used., Measurements: Three months after surgery and in November 2021, consenting patients underwent clinical evaluation and multichannel urodynamic study (UDS). The incontinence quality of life (I-QoL) questionnaire was used to evaluate HRQoL. Continence was classified into day- and nighttime, and clinically defined as the use of zero pads. A descriptive statistical analysis was performed., Results and Limitations: The mean age at surgery was 65.4 yr. The mean follow-up period was 27 mo (12-38). The mean time for the neobladder reconstruction was 192 min (110-340). The mean maximum capacity was 431 cm
3 (range 200-553). The mean postvoid residual was 101.6 ml (0-310), and the rate of clean intermittent catheterization was 17.6%. With the exception of a significant reduction in the volume of the first sensation of bladder fullness, no other statistically significant changes in the UDS parameters of both the storage and the voiding phase were observed over time. Day- and nighttime continence rates were 58.8% and 23.5%, respectively. The mean postoperative I-QoL score was 103.3 (89-110). Limitations include the small number of patients and short follow-up., Conclusions: The UDS evaluation of iYNB demonstrates that both the volumetric and the pressure characteristics are acceptable and may enhance quality of life. Prospective studies with larger numbers of patients and longer follow-up are needed to further evaluate the iYNB., Patient Summary: The "Bordeaux" neobladder provides acceptable urodynamic outcomes. It is associated with high levels of health-related quality of life and good rates of continence in patients., (© 2022 The Author(s).)- Published
- 2022
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44. Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models.
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Tai DJC, Razaz P, Erdin S, Gao D, Wang J, Nuttle X, de Esch CE, Collins RL, Currall BB, O'Keefe K, Burt ND, Yadav R, Wang L, Mohajeri K, Aneichyk T, Ragavendran A, Stortchevoi A, Morini E, Ma W, Lucente D, Hastie A, Kelleher RJ, Perlis RH, Talkowski ME, and Gusella JF
- Subjects
- Animals, Calbindin 2 genetics, Cerebral Cortex, Chromosome Deletion, Chromosomes, Human, Pair 16 genetics, DNA Copy Number Variations, Genomics, Humans, Mice, Neurons, RNA, Autism Spectrum Disorder genetics, Chromosome Disorders genetics, Intellectual Disability genetics
- Abstract
Chromosome 16p11.2 reciprocal genomic disorder, resulting from recurrent copy-number variants (CNVs), involves intellectual disability, autism spectrum disorder (ASD), and schizophrenia, but the responsible mechanisms are not known. To systemically dissect molecular effects, we performed transcriptome profiling of 350 libraries from six tissues (cortex, cerebellum, striatum, liver, brown fat, and white fat) in mouse models harboring CNVs of the syntenic 7qF3 region, as well as cellular, transcriptional, and single-cell analyses in 54 isogenic neural stem cell, induced neuron, and cerebral organoid models of CRISPR-engineered 16p11.2 CNVs. Transcriptome-wide differentially expressed genes were largely tissue-, cell-type-, and dosage-specific, although more effects were shared between deletion and duplication and across tissue than expected by chance. The broadest effects were observed in the cerebellum (2,163 differentially expressed genes), and the greatest enrichments were associated with synaptic pathways in mouse cerebellum and human induced neurons. Pathway and co-expression analyses identified energy and RNA metabolism as shared processes and enrichment for ASD-associated, loss-of-function constraint, and fragile X messenger ribonucleoprotein target gene sets. Intriguingly, reciprocal 16p11.2 dosage changes resulted in consistent decrements in neurite and electrophysiological features, and single-cell profiling of organoids showed reciprocal alterations to the proportions of excitatory and inhibitory GABAergic neurons. Changes both in neuronal ratios and in gene expression in our organoid analyses point most directly to calretinin GABAergic inhibitory neurons and the excitatory/inhibitory balance as targets of disruption that might contribute to changes in neurodevelopmental and cognitive function in 16p11.2 carriers. Collectively, our data indicate the genomic disorder involves disruption of multiple contributing biological processes and that this disruption has relative impacts that are context specific., Competing Interests: Declaration of interests J.F.G. is a founder and member of the scientific advisory board of Triplet Therapeutics and has been a paid consultant to Biogen, Pfizer, and Wave Biosciences. M.E.T. receives research funding and/or reagents from Illumina, Levo Therapeutics, and Microsoft. E.M. receives research funding and reagents from PTC Therapeutics. The following co-authors are currently employed by for-profit companies or non-profit organizations: P.R. is founder and CEO of Kumuda; K.M. is currently employed by Tornado Bio; T.A. is a founder and CEO of Independent Data Lab and OmicsChart; and A.H. is currently employed by Bionano Genomics., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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45. A comparison among RIRS and MiniPerc for renal stones between 10 and 20 mm using thulium fiber laser (Fiber Dust): a randomized controlled trial.
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Perri D, Berti L, Pacchetti A, Morini E, Maltagliati M, Besana U, Pastore AL, Romero-Otero J, Saredi G, Centrella D, Sighinolfi MC, Rocco B, Micali S, Broggini P, Boldini M, Mazzoleni F, and Bozzini G
- Subjects
- Dust, Humans, Lasers, Prospective Studies, Thulium therapeutic use, Treatment Outcome, Kidney Calculi surgery, Nephrostomy, Percutaneous methods
- Abstract
Purpose: We performed a prospective randomized comparison among Retrograde IntraRenal Surgery (RIRS) and MiniPerc (MP) for stones between 10 and 20 mm to evaluate outcomes with the same laser device: Fiber Dust., Methods: Patients with a single renal stone between 10 and 20 mm were randomized to RIRS (Group A) versus MP (Group B). Exclusion criteria were age < 18 or > 75, presence of acute infection, coagulation impairments, cardiovascular or pulmonary comorbidities. In both groups, the Fiber Dust laser was used. A CT scan after 3 months was performed. A negative CT scan or asymptomatic patients with stone fragments < 3 mm and a negative urinary culture were the criteria to assess the stone-free status. A statistical analysis was carried out to assess success, complication and retreatment rates and need for auxiliary treatments., Results: Between January 2021 and January 2022, 186 patients were enrolled (90 in Group A and 96 in Group B). Mean stone size was 15.8 mm and 14.9 mm in Group A and B, respectively (p = 0.23). The overall stone-free rate (SFR) was 73.3% for Group A and 84.4% for Group B. A higher SFR was reached for upper calyceal stones in Group A (90.4%) lower calyceal stones in Group B (91.6%). Retreatment rate (p = 0.31) and auxiliary procedure rate (p = 0.18) were comparable. Complication rate was 5.5% and 5.2% for Groups A and B, respectively., Conclusions: RIRS and MP are both effective to obtain a postoperative SFR with Fiber Dust. According to the stone position one treatment is superior to the other one., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2022
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46. Expression analysis of miRNA hsa-let7b-5p in naso-oropharyngeal swabs of COVID-19 patients supports its role in regulating ACE2 and DPP4 receptors.
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Latini A, Vancheri C, Amati F, Morini E, Grelli S, Matteucci C, Petrone V, Colona VL, Murdocca M, Andreoni M, Malagnino V, Raponi M, Cocciadiferro D, Novelli A, Borgiani P, and Novelli G
- Subjects
- Angiotensin-Converting Enzyme 2 genetics, Dipeptidyl Peptidase 4 genetics, Dipeptidyl Peptidase 4 metabolism, Humans, SARS-CoV-2 genetics, COVID-19 genetics, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for worldwide coronavirus disease (COVID-19). We previously observed that Angiotensin-converting enzyme 2 (ACE2) and Dipeptidyl peptidase-4 (DPP4) are significantly overexpressed in naso-oropharyngeal swabs (NPS) of COVID-19 patients, suggesting their putative functional role in the disease progression. ACE2 and DPP4 overexpression in COVID-19 patients may be associated to epigenetic mechanism, such as miRNA differential expression. We investigated if hsa-let7b-5p, reported to target both ACE2 and DPP4 transcripts, could be involved in the regulation of these genes. We verified that the inhibition and overexpression of hsa-let7b-5p matched to a modulation of both ACE2 and DPP4 levels. Then, we observed a statistically significant downregulation (FC = -1.5; p < 0.05) of hsa-let7b-5p in the same COVID-19 and control samples of our previous study. This is the first study that shows hsa-let7b-5p low expression in naso-oropharyngeal swabs of COVID-19 patients and demonstrates a functional role of this miR in regulating ACE2 and DPP4 levels. These data suggest the involvement of hsa-let7b-5p in the regulation of genes necessary for SARS-CoV-2 infections and its putative role as a therapeutic target for COVID-19., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
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- 2022
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47. Effects of COVID-19 in Endocrine Patients: A Cross-Sectional Study.
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Morini E, Maresca G, Bonanno L, Corallo F, Lo Buono V, and De Cola MC
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- Humans, Cross-Sectional Studies, SARS-CoV-2, Life Style, Surveys and Questionnaires, Communicable Disease Control, Feeding Behavior psychology, COVID-19, Sleep Wake Disorders epidemiology, Sleep Wake Disorders etiology, Sleep Wake Disorders psychology
- Abstract
Introduction: Home confinement due to COVID-19 lockdown led to changes in daily routines, including social interactions, as well as restrictions on the possibility of playing sports and eating habits. These changes could have a greater impact on patients suffering from chronic diseases, such as endocrine patients, especially in emotional and behavioral dimensions. Materials and Methods: This study aimed to assess the effects of COVID-19-induced quarantine on daily habits in a group of patients with endocrine disorders, focusing on food consumption, eating habits and sleep during the confinement. Eighty-five endocrine patients were enrolled. A structured interview was administered to investigate socio-demographic information, general medical conditions, and habits adopted during quarantine. All patients underwent the Spielberger State Anxiety Inventory (STAI-Y1) to assess state anxiety. Result: Results showed that subjects mainly had a sedentary lifestyle. We found a significant increase in the number of cigarettes in smokers and in meals consumed during confinement, as well as a high rate of sleep disturbance, especially insomnia. Notably, physical well-being resulted to be a predictive factor (OR = 0.38; 95%CI = [0.95,0.66]), whereas anxiety was a risk factor for sleep disorder (OR = 1.22; 95%CI = [1.10,1.40]), as was working in public and private offices and being a student. Conclusions: Changes in daily habits were likely due to the alterations in routine, resulting in greater boredom and inactivity during the day. In addition, future research should focus on the importance of patient adherence to therapy.
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- 2022
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48. Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.
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Romano G, Riccardi F, Bussani E, Vodret S, Licastro D, Ragone I, Ronzitti G, Morini E, Slaugenhaupt SA, and Pagani F
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- Animals, Disease Models, Animal, Exons genetics, Humans, Mice, RNA Precursors genetics, RNA Splicing genetics, RNA, Small Nuclear genetics, RNA, Small Nuclear metabolism, Dysautonomia, Familial genetics, Neurodegenerative Diseases genetics
- Abstract
Familial dysautonomia (FD) is a currently untreatable, neurodegenerative disease caused by a splicing mutation (c.2204+6T>C) that causes skipping of exon 20 of the elongator complex protein 1 (ELP1) pre-mRNA. Here, we used adeno-associated virus serotype 9 (AAV9-U1-FD) to deliver an exon-specific U1 (ExSpeU1) small nuclear RNA, designed to cause inclusion of ELP1 exon 20 only in those cells expressing the target pre-mRNA, in a phenotypic mouse model of FD. Postnatal systemic and intracerebral ventricular treatment in these mice increased the inclusion of ELP1 exon 20. This also augmented the production of functional protein in several tissues including brain, dorsal root, and trigeminal ganglia. Crucially, the treatment rescued most of the FD mouse mortality before one month of age (89% vs 52%). There were notable improvements in ataxic gait as well as renal (serum creatinine) and cardiac (ejection fraction) functions. RNA-seq analyses of dorsal root ganglia from treated mice and human cells overexpressing FD-ExSpeU1 revealed only minimal global changes in gene expression and splicing. Overall then, our data prove that AAV9-U1-FD is highly specific and will likely be a safe and effective therapeutic strategy for this debilitating disease., Competing Interests: Declaration of interests F.P. is listed as inventor of the U.S. patent n. 9,669,109 “A modified human U1snRNA molecule, a gene encoding for the modified human U1snRNA molecule, an expression vector including the gene, and the use thereof in gene therapy of familial dysautonomia and spinal muscular atrophy.” As such, the inventors could potentially benefit from any future commercial exploitation of patent rights, including the use of ExSpeU1s in FD. S.A.S. is a paid consultant to PTC Therapeutics and is an inventor on several U.S. and foreign patents and patent applications assigned to the Massachusetts General Hospital, including U.S. Patents 8,729,025 and 9,265,766, both entitled “Methods for altering mRNA splicing and treating familial dysautonomia by administering benzyladenine,” filed on August 31, 2012 and May 19, 2014 and related to use of kinetin; and U.S. Patent 10,675,475 entitled, “Compounds for improving mRNA splicing” filed on July 14, 2017 and related to use of BPN-15477. E.M. and S.A.S. are inventors on an International Patent Application Number PCT/US2021/012,103, assigned to Massachusetts General Hospital and entitled “RNA Splicing Modulation” related to use of BPN-15477 in modulating splicing., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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49. Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage.
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Morini E, Gao D, Logan EM, Salani M, Krauson AJ, Chekuri A, Chen YT, Ragavendran A, Chakravarty P, Erdin S, Stortchevoi A, Svejstrup JQ, Talkowski ME, and Slaugenhaupt SA
- Subjects
- Animals, Disease Models, Animal, Gene Expression, Homozygote, Humans, Mice, Sequence Deletion, Carrier Proteins genetics, Dysautonomia, Familial genetics, Dysautonomia, Familial metabolism
- Abstract
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that leads to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1
-/- ) and observed that human ELP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression., Competing Interests: Conflict of interest The authors declare competing financial interests. Funding: Research support from PTC Therapeutics, Inc. (S.A.S.). Personal financial interests: Susan A. Slaugenhaupt is a paid consultant to PTC Therapeutics and is an inventor on several US and foreign patents and patent applications assigned to the Massachusetts General Hospital, including U.S Patents 8,729,025 and 9,265,766, both entitled ‘Methods for altering mRNA splicing and treating familial dysautonomia by administering benzyladenine’, filed on August 31, 2012, and May 19, 2014, and related to use of kinetin; and U.S. Patent 10,675,475 entitled, ‘Compounds for improving mRNA splicing’ filed on July 14, 2017, and related to use of BPN-15477. Elisabetta Morini, Dadi Gao, Michael E. Talkowski and Susan A. Slaugenhaupt are inventors on an International Patent Application Number PCT/US2021/012103, assigned to Massachusetts General Hospital and entitled “RNA Splicing Modulation” related to the use of BPN-15477 in modulating splicing., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
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50. Hsa-miR223-3p circulating level is upregulated in Friedreich's ataxia and inversely associated with HCLS1 associated protein X-1, HAX-1.
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Quatrana A, Morini E, Tiano F, Vancheri C, Panarello L, Romano S, Marcotulli C, Casali C, Mariotti C, Mongelli A, Fichera M, Rufini A, Condò I, Novelli G, Testi R, Amati F, and Malisan F
- Subjects
- Humans, Myocytes, Cardiac metabolism, RNA, Messenger genetics, Adaptor Proteins, Signal Transducing genetics, Friedreich Ataxia pathology, MicroRNAs blood, Neuroblastoma metabolism
- Abstract
Frataxin (FXN) deficiency is responsible for Friedreich's ataxia (FRDA) in which, besides the characteristic features of spinocerebellar ataxia, two thirds of patients develop hypertrophic cardiomyopathy that often progresses to heart failure and premature death. Different mechanisms might underlie FRDA pathogenesis. Among them, the role of miRNAs deserves investigations. We carried out an miRNA PCR-array analysis of plasma samples of early-, intermediate- and late-onset FRDA groups, defining a set of 30 differentially expressed miRNAs. Hsa-miR223-3p is the only miRNA shared between the three patient groups and appears upregulated in all of them. The up-regulation of hsa-miR223-3p was further validated in all enrolled patients (n = 37, Fc = +2.3; P < 0.0001). Using a receiver operating characteristic curve analysis, we quantified the predictive value of circulating hsa-miR223-3p for FRDA, obtaining an area under the ROC curve value of 0.835 (P < 0.0001) for all patients. Interestingly, we found a significant positive correlation between hsa-miR223-3p expression and cardiac parameters in typical FRDA patients (onset < 25 years). Moreover, a significant negative correlation between hsa-miR223-3p expression and HAX-1 (HCLS1-associated protein X-1) at mRNA and protein level was observed in all FRDA patients. In silico analyses suggested HAX-1 as a target gene of hsa-miR223-3p. Accordingly, we report that HAX-1 is negatively regulated by hsa-miR223-3p in cardiomyocytes (AC16) and neurons (SH-SY5Y), which are critically affected cell types in FRDA. This study describes for the first time the association between hsa-miR223-3p and HAX-1 expression in FRDA, thus supporting a potential role of this microRNA as non-invasive epigenetic biomarker for FRDA., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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