Molecular Genetic Aberrations in Chronic Lymphocytic Leukemia With Richter Transformation

Jackie Broadway-Duren pictured. Department of Leukemia Presented at JADPRO Live 2021.https://openworks.mdanderson.org/aprn-week-22/1017/thumbnail.jp

Spectrum of genetic disorders and gene variants in the United Arab Emirates national population: insights from the CTGA database

Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 307 pathogenic/likely pathogenic variants from CTGA’s Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders

Rituximab and obinutuzumab differentially hijack the B-cell receptor and NOTCH1 signaling pathways

The anti-CD20 monoclonal antibodies rituximab and obinutuzumab differ in their mechanisms of action, with obinutuzumab evoking greater direct B-cell death. To characterize the signaling processes responsible for improved B-cell killing by obinutuzumab, we undertook a phosphoproteomics approach and demonstrate that rituximab and obinutuzumab differentially activate pathways downstream of the B-cell receptor. While both antibodies induce strong ERK and MYC activation sufficient to promote cell cycle arrest and B-cell death, obinutuzumab exceeds rituximab in supporting apoptosis induction by means of aberrant SYK phosphorylation. In contrast, rituximab elicits stronger anti-apoptotic signals by activating AKT, impairing pro-apoptotic BAD, and by releasing membrane-bound NOTCH1 to up-regulate pro-survival target genes. As a consequence, rituximab appears to reinforce BCL2-mediated apoptosis resistance. The unexpected complexity and differences by which rituximab and obinutuzumab interfere with signaling pathways essential for lymphoma pathogenesis and treatment provide important impetus to optimize and personalize the application of different anti-CD20 treatments

Luigi Settembrini. Periodico letterario educativo mensile. A. 2, n.1(1892)-A. 3, n.10(1894)

A.2, n.1(nov.1892): G. Olivieri, Ad Antonio Bartolini, P. 1-2 ; G. Olivieri, Prospero Viani, P. 2-11; R. Sabbatini, Ancora Quom o Quum?, P. 11-2 ; Pensieri del Settembrini, P. 12-3 ; E. Perito, Ad nubem, P. 13; F. Lagrance, Dell’educazione fisica, p. 14-15 ; Cronaca dell’Istituto L. Settembrini, P. 15-6.A. 2, n. 2(dic. 1892): G. Lanzalone, La morale nell’arte, P. 17-23 ; B. ( dal Bibliografo), Per i libri di testo nelle scuole elementari, P. 23-5 ; V. Notari, In Gutembergium artis typograficae inventorem, P. 25; Progressi della navigazione aerea, P. 26-8 ; Pensieri del Settembrini, P. 28-9 ; Il nostro concorso, P. 29 ; G. Lanzalone, La prima pioggia d’autunno, P. 30-1A. 2, n.3(gen. 1893): Bonghi, Una lettera del Bonghi, P. 33-4 ; G. Lanzalone, Ancora della morale nell’arte, P. 34-8 ; Pensieri del Settembrini, P. 38-9 ; C. Arlìa, Buon dì e tre anguille, P. 39-41 ; G. Lanzalone , All’amico G. Olivieri , P. 42-3 ; P. Lioy, Bagni e villeggiature, P. 43-5.A. 2, n. 4(feb. 1893): C. A. Alemagna, Per la morale nell’arte, P. 49-55.A. 2, n. 5(mar. 1893): R. Sabbatini, L’epistola di Saffo a Faone, P. 65-6 ; G. Lanzalone, Il drammaturgo(caricatura), P. 66-7 ; G. Lanzalone, Ancora per la morale dell’arte, P. 67-70 ; F. De Falco, Un’altra lettera!, P. 71-2 ; Il Settembrini, Per una petizione al Parlamento, P. 72; E. Perito, A mia sorella morta, P. 73-4.A. 2, n.6(apr. 1893): Il Settembrini, Petizione al Parlamento, P. 81-3 ; C. Arlia, Noterelle filologiche, P. 84-5 ; G. Bigoni, Ricordi Picentini (2 sonetti), P. 85 ; C. A. Alemagna, Lettera con annotazioni, P. 86-90 ; V. Caputo, Il giuramento, P. 90-1 ; A. Buscaino Campo, Il piè fermo di Dante, P. 92-3.A.2, n.7(apr. 1893): G. Lanzalone, Professori e maestri, P. 97-9 ; il Settembrini, Petizione al Parlamento, P. 100-2 ; Lista delle adesioni, P. 102-4 ; Guido Bigoni, Domenica Rusticana, P. 105 ; Pensieri del Settembrini, P. 105-7 ; Dal Gazzettino d’oro, Utili varietà, P. 107-8 ; G. Lanzalone, Al maggiore Vincenzo Notari, P. 108 ; V. Notarius, Risposta, P. 109 ; F. Accinelli, La poesia della vita, P. 109-10.A. 2, n.8(giu. 1893): C. Arlìa, Noterelle filologiche, P. 113-16 ; Guido Bigoni, La quercia del Tasso, P. 116 ; G. Lanzalone, La ginnastica con la neve, P. 116-17 ; Luigi Settembrini, Una lettera inedita di L. Settembrini, P. 118-19 ; V. Notaro, In Ariostum, P. 119 ; L’arte di respirare, P. 120-21 ; F. De Falco, Il suicidio e la religione, P. 122-24.A.2, n.9/10(lug.-ago. 1893): R. Mariano, Ad un banchetto nunziale, P. 129-132 ; G. Lanzalone, A Cristoforo Colombo, P. 132-34 ; C. Arlìa, Note filologiche, P. 135-36 ; G. Olivieri, Il terzo libro della vita di G. Cristo, P. 136-39 ; F. Persico, La pace, P. 140-41 ; L. A. Villari, Cesare Dalbono, P. 141-45.A.2, n.11/12(sett.-ott. 1893): Luigi Settembrini, Una lettera inedita di L. Settembrini, P. 153-54 ; A. De Leo, Vite di illustri salernitani, P. 154-62 ; G. Franciosi, I sogni, P. 162-63 ; A. Frabasile, Bozzetti ellenici, P. 164-70 ; L. A. Villari , Errori Giudiziari, P. 171-75 ; G. Lanzalone, Verismo, P. 175-76.A.3,n.1/2 (nov.-dic. 1893): M. Giordano, La pubblica educazione e l’ateismo, P. 1-4 ; il Settembrini, Concorso, P. 4 ; Per una forca conservata in un museo, P. 5 ; G. Lanzalone, L’Ora presente, P. 5 ; C. Mariano Pilar, Silvio Spaventa, P. 6-19 ; C. Arlìa, Note filologiche, P. 20-1 ; G. Grammatica, Ideale, P. 22 ; G. Olivieri, Funesta rimembranza, P. 31-2 ; G. Olivieri, La notte della vigilia del Natale, P. 32.A.3, n.3/4(gen.-feb. 1894): G. Lanzalone, E la nostra petizione?, P. 33-5 ; Dall’albo di Luigi Antonio Villari, P. 36 ; G. Olivieri, Una visita inaspettata, P. 37-46 ; A. Frabasile, Alla signora G. P., P. 47 ; M. Giordano, Il Governo, i Municipi e l’istruzione religiosa, P. 48-53 ; G. Lanzalone, Esercizi militari, P. 53 ; C. Arlìa, Note filologiche, P. 54 ; G. Lanzalone, Un dubbio proposto al prof. Sabbadini, P. 54-5 ; G. L., Risultato del passato concorso e concorso nuovo, P. 55-6 ; R. Galdi, Epistola di Catullo ad Ortalo, P. 57.A.3, n.5/6(mar-apr 1894): G. Lanzalone, Dell’educazione nelle scuole classiche, P. 65-70 ; G. L., Un epigramma di Leone XIII, P. 70-1 ; V. Caputo, Vita di borso, P. 72-6 ; C. Arlìa, Note filologiche, P. 76-7 ; G. Lanzalone, Amore, P. 78 ; Aniello Gaeta, Dulcissime Rerum, P. 79-81 ; Francesco De Falco, La duchessa Ravaschieri e il dormitorio, P. 81-2 ; Carmine Zottoli, Risultato del passato concorso e concorso nuovo, P. 82-6.A.3, n. 7/8(mag. – giu 1894): C. Arlìa, Note filologiche, P. 97-8 ; G. Lanzalone, Per il 1°Maggio, P. 98-101 ; M. Giordano, La libertà d’insegnamento e di coscienza, P. 101-10 ; L. A. Villari, Il capitano Tim- Tim, P. 111- 15 ; C. A. Alemagna, L’opera recente di Herbert Spencer, P. 115-16 ; Nicc. Castagna, Sospiro, P. 116 ; G. Cuomo, Sovra un passo del carme “I Sepolcri”, P. 117-20.A.3, n.9(lug. 1894): Concorso nuovo, P. 125 ; C. Arlìa, Note filologiche, P. 126-27 ; Il manicomio dei genii, P. 127 ; G. Lanzalone, Elena, P. 128 ; Giovanni Cuomo, Nunzio del giorno, P. 128-29 ; Giovanni Manfredi, Ofelia, P. 129 ; G. Lanzalone, Da Anacreonte, P. 139.A.3, n.10(ago. 1894): R. Sabbadini, L’anno della nascita di Gasparino Barziza, P. 141-42 ; G. Lanzalone, Il Discredito dei versi, P. 142-46 ; C. Arlìa, Note filologiche, P. 147-48 ; E. Perito, L’ultima rosa d’estate, P. 148 ; D’Aloja, L’arte e la critica, P. 149-51 ; Epigrammi, P. 151-52

Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience

Background: A considerable minority of patients on waiting lists for kidney transplantation either have no diagnosis (and fall into the subset of undiagnosed cases) because kidney biopsy was not performed or histological findings were non-specific, or do not fall into any well-defined clinical category. Some of these patients might be affected by a previously unrecognised monogenic disease. Methods: Through a multidisciplinary cooperative effort, we built an analytical pipeline to identify patients with chronic kidney disease (CKD) with a clinical suspicion of a monogenic condition or without a well-defined diagnosis. Following the stringent phenotypical and clinical characterization required by the flowchart, candidates meeting these criteria were further investigated by clinical exome sequencing followed by in silico analysis of 225 kidney-disease-related genes. Results: By using an ad hoc web-based platform, we enrolled 160 patients from 13 different Nephrology and Genetics Units located across the Piedmont region over 15\ua0months. A preliminary \u201cremote\u201d evaluation based on well-defined inclusion criteria allowed us to define eligibility for NGS analysis. Among the 138 recruited patients, 52 (37.7%) were children and 86 (62.3%) were adults. Up to 48% of them had a positive family history for kidney disease. Overall, applying this workflow led to the identification of genetic variants potentially explaining the phenotype in 78 (56.5%) cases. Conclusions: These results underline the importance of clinical exome sequencing as a versatile and highly useful, non-invasive tool for genetic diagnosis of kidney diseases. Identifying patients who can benefit from targeted therapies, and improving the management of organ transplantation are further expected applications