131 research outputs found
RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report
No full textMalignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in RB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the RB1 transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ~3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in TP53, SMAD4, FGFR3, and MSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness. © 2020 Gelli, Fallerini, Valentino, Giliberti, Castiglione, Laschi, Palmieri, Fabbiani, Tita, Mencarelli, Renieri and Ariani
A Unique Patient Presenting with Concomitant Klinefelter Syndrome, Alport Syndrome and Craniopharyngioma.
No full textA 31 years old Caucasian male was referred for panhypopituitarism resulting from an operated craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage-renal-disease due to X-linked Alport syndrome (ATS). Subsequent Quantitative-Fluorescent-Polymerase-Chain-Reaction-analysis indicated a 47,XXY-karyotype, consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: i) KS was an unexpected finding due to a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; ii) the discovery of a de novo p.G406S substitution causing ATS; iii) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS and craniopharyngioma
Prognostic value of glomerular collagen IV immunofluorescence studies in male patients with X-linked Alport syndrome.
No full textIndagine di correlazioni anatomo cliniche in 22 pazienti con sindrome di alport x-linked per valutare il significato prognostico della espressione del collagene di tipo IV nella membrana basale dei glomerul
A Unique Patient Presenting with Concomitant Klinefelter Syndrome, Alport Syndrome and Craniopharyngioma.
No full textA 31 years old Caucasian male was referred for panhypopituitarism resulting from an operated craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage-renal-disease due to X-linked Alport syndrome (ATS). Subsequent Quantitative-Fluorescent-Polymerase-Chain-Reaction-analysis indicated a 47,XXY-karyotype, consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: i) KS was an unexpected finding due to a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; ii) the discovery of a de novo p.G406S substitution causing ATS; iii) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS and craniopharyngioma
Prognostic Value of Glomerular Collagen IV Immunofluorescence Studies in Male Patients with X-Linked Alport Syndrome
No full textBackground and objectives X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV a5 chain (a5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS. Design, setting, participants, & measurements The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of a1, a3, and a5(COLIV) chains was assessed by immunofluorescence microscopy. Results GBM distribution of the a5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the a3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the a3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m2 at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal a3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse a3(COLIV) chain glomerular distribution. © 2013 by the American Society of Nephrology
Development Activities on an Advanced Propellant Flow Control Unit
No full textA new generation of propellant control equipment for
electric propulsion systems is needed in order to
improve performance and operating ranges, symplify
h/w configuration, reduce mass and dimensions,
eliminate mass flow ripple, reduce time response. In
this frame, the development of key components, their
assembly and experimental investigation/ validation is
on-going at Alenia Spazio-Laben/Business Unit Proel
Tecnologie ( Proel in the following ) in the frame of an
ESA GSTP program.
The new components shall support different EP
technologies, future EP multi-tasking capability and
wide operating ranges.
This paper reports about the development effort, its
achievements and perspectives
Dionysios Solomós: dall’isola di Zante la formazione del linguaggio poetico neogreco
No full textThe purpose of this essay is to investigate the issue of linguistic identity in countries in which geographical and cultural boundaries are not clearly defined, as in the case of modern Greece and the Ionian Islands. This issue will be pursued by the analysis of Theo Angelopoulos’ movie Eternity and a day, inspired by the Eighteenth-century Greek poet Dionysios Solomos, in which the Greek director considers the language as a possibility to recover a lost identity. The bilingualism characterizing Solomos’ poetry, switching from Italian to modern Greek, should be considered in the light of the peculiar history of the Ionian Islands, which had been under Venetian Authority for centuries. Having explored the linguistic topic in the Ionian Islands and in Greece, the author’s attention is then focused on the bilingualism of the Greek poet, with samples in Italian and modern Greek idioms, and frequent references to essays and writings exploiting the linguistic issue. Angelopoulos’ movie will be then illustrated, emphasizing its main themes: time and words. Focusing on this last aspect, the sections of the movie which draw direct or indirect inspiration from Solomos’ literary and poetic production will be analyzed, basing on the original screenplay in modern Greek. The connection between identity and language has been developed according also to Heidegger’s philosophy. Finally it will be demonstrated that the importance Angelopoulos assigns to Solomos’ figure in order to explain the meaning of linguistic identity is not so appropriate. Infact the Greek director doesn’t seem to keep in adequate consideration the significance of bilingualism in Solomos’ poetry.</p
Advances in Alport syndrome diagnosis using next-generation sequencing.
No full textAlport syndrome (ATS) is a hereditary nephropathy often associated with sensorineural hypoacusis and ocular abnormalities. Mutations in the COL4A5 gene cause X-linked ATS. Mutations in COL4A4 and COL4A3 genes have been reported in both autosomal recessive and autosomal dominant ATS. The conventional mutation screening, performed by DHPLC and/or Sanger sequencing, is time-consuming and has relatively high costs because of the absence of hot spots and to the high number of exons per gene: 51 (COL4A5), 48 (COL4A4) and 52 (COL4A3). Several months are usually necessary to complete the diagnosis, especially in cases with less informative pedigrees. To overcome these limitations, we designed a next-generation sequencing (NGS) protocol enabling simultaneous detection of all possible variants in the three genes. We used a method coupling selective amplification to the 454 Roche DNA sequencing platform (Genome Sequencer junior). The application of this technology allowed us to identify the second mutation in two ATS patients (p.Ser1147Phe in COL4A3 and p.Arg1682Trp in COL4A4) and to reconsider the diagnosis of ATS in a third patient. This study, therefore, illustrates the successful application of NGS to mutation screening of Mendelian disorders with locus heterogeneity
Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features
No full textThe impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores ((Formula presented.) and (Formula presented.)). By applying a logistic regression with both IPGS, ((Formula presented.) (or indifferently (Formula presented.)) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%
- …
