Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells

open7siBesides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumorigenesis through extra-telomeric functions. The possible therapeutic effects of BIBR1532 (BIBR), a powerful TERT inhibitor, have been evaluated in different cellular backgrounds, but no data are currently available regarding Epstein-Barr virus (EBV)-driven B-cell malignancies. Our aim was to characterize the biological effects of TERT inhibition by BIBR on EBV-immortalized lymphoblastoid cell lines (LCLs) and fully transformed Burkitt's lymphoma (BL) cell lines. We found that BIBR selectively inhibits telomerase activity in TERT-positive 4134/Late and 4134/TERT+ LCLs and EBV-negative BL41 and EBV-positive BL41/B95.8 BL cell lines. TERT inhibition led to decreased cell proliferation, accumulation of cells in the S-phase and ultimately to increased apoptosis, compared with mock-treated control cells. All these effects occurred within 72 h and were not observed in BIBR-treated TERT-negative 4134/TERT- and U2OS cells. The cell cycle arrest and apoptosis, consequent upon short-term TERT inhibition, were associated with and likely dependent on the activation of the DNA damage response (DDR), highlighted by the increased levels of γH2AX and activation of ATM and ATR pathways. Analyses of the mean and range of telomere lengths and telomere dysfunction-induced foci indicated that DDR after short-term TERT inhibition was not related to telomere dysfunction, thus suggesting that TERT, besides stabilizing telomere, may protect DNA via telomere-independent mechanisms. Notably, TERT-positive LCLs treated with BIBR in combination with fludarabine or cyclophosphamide showed a significant increase in the number of apoptotic cells with respect to those treated with chemotherapeutic agents alone. In conclusion, TERT inhibition impairs cell cycle progression and enhances the pro-apoptotic effects of chemotherapeutic agents in TERT-positive cells. These results support new therapeutic applications of TERT inhibitors in EBV-driven B-cell malignancies.openCeleghin, Andrea; Giunco, Silvia; Freguja, Riccardo; Zangrossi, Manuela; Nalio, Silvia; Dolcetti, Riccardo; De Rossi, AnitaCeleghin, Andrea; Giunco, Silvia; Freguja, Riccardo; Zangrossi, Manuela; Nalio, Silvia; Dolcetti, Riccardo; DE ROSSI, Anit

Metabolic syndrome and cardiovascular risk after liver transplantation: a single-center experience.

Excessive weight gain, hypertension, hyperlipidemia, and diabetes are frequently observed among orthotopic liver transplantation (OLT) patients. These alterations, which are probably multifactorial in origin, contribute to posttransplantation metabolic syndrome (PTMS), which increases the risk of cardiovascular events. We assessed the prevalence of PTMS (diagnosed according to modified NCEP Adult Treatment Panel III criteria) in 156 OLT patients undergoing regular follow-up after transplantation (median 68 months; range, 6 to 234 months). Several pre- and post-OLT data were collected to identify the factors associated with the presence of PTMS which was found in 28% of cases. The only independent predictive factors for PTMS were diabetes mellitus and patients who were overweight or obese before-OLT. The prevalence of PTSM was lower among patients on tacrolimus immunosuppression. In our population, 21% of patients showed a high cardiovascular risk score with a 4% incidence of cardiovascular events, which was higher among subjects with PTMS. Close follow-up is mandatory to prevent the development of PTMS mainly among overweight and diabetic patients before transplantation

A surge of late-occurring meiotic double-strand breaks rescues synapsis abnormalities in spermatocytes of mice with hypomorphic expression of SPO11

Meiosis is the biological process that, after a cycle of DNA replication, halves the cellular chromosome complement, leading to the formation of haploid gametes. Haploidization is achieved via two successive rounds of chromosome segregation, meiosis I and II. In mammals, during prophase of meiosis I, homologous chromosomes align and synapse through a recombination-mediated mechanism initiated by the introduction of DNA double-strand breaks (DSBs) by the SPO11 protein. In male mice, if SPO11 expression and DSB number are reduced below heterozygosity levels, chromosome synapsis is delayed, chromosome tangles form at pachynema, and defective cells are eliminated by apoptosis at epithelial stage IV at a spermatogenesis-specific endpoint. Whether DSB levels produced in Spo11 +/− spermatocytes represent, or approximate, the threshold level required to guarantee successful homologous chromosome pairing is unknown. Using a mouse model that expresses Spo11 from a bacterial artificial chromosome, within a Spo11 −/− background, we demonstrate that when SPO11 expression is reduced and DSBs at zygonema are decreased (approximately 40 % below wild-type level), meiotic chromosome pairing is normal. Conversely, DMC1 foci number is increased at pachynema, suggesting that under these experimental conditions, DSBs are likely made with delayed kinetics at zygonema. In addition, we provide evidences that when zygotene-like cells receive enough DSBs before chromosome tangles develop, chromosome synapsis can be completed in most cells, preventing their apoptotic elimination

Maternity, science and pandemic: an urgent call for action!

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Il Catasto Ragionato Informatico delle Grotte Archeologiche – C.R.I.G.A. on-line

Da oltre un secolo è noto in ambiente speleologico, geologico, archeologico che il Carso triestino è un’area ad alta concentrazione di grotte, molte delle quali – 165 stando ai dati dell’Archivio Storico della Società Alpina delle Giulie – con tracce della presenza umana in antico. Le grotte hanno catalizzato l’interesse sia di ricercatori professionisti, sia di appassionati o curiosi, e questo ha comportato il susseguirsi dagli ultimi decenni dell’800 ad oggi di moltissimi interventi di scavo, sistematici e non, che hanno dato una quantità ingente di materiali rimasti largamente inediti. Al fine di recuperare e organizzare la documentazione presente in letteratura e negli archivi, e di contestualizzare le tracce dell’uomo nell’ambiente naturale, in primis nelle singole grotte, una decina di anni fa si è avviato un progetto interdisciplinare che ha coinvolto specialisti di discipline diverse dell’Università degli Studi di Trieste nella costruzione di una banca dati geo-archeologica denominata Catasto Ragionato Informatico delle Grotte Archeologiche – C.R.I.G.A. Al di là della possibilità di soddisfare gli obiettivi originari di ricerca scientifica, il C.R.I.G.A. ha grandi potenzialità anche a fini di didattica, divulgazione, tutela delle grotte e pianificazione degli interventi sul territorio. In considerazione di questi aspetti, il database è stato reso accessibile a chiunque, all’indirizzo web www. units.it/criga. Nel presente contributo si presentano brevemente la storia del C.R.I.G.A., la situazione attuale e le prospettive future.For more than a century, it is well known in speleological, geological and archaeological fields that the Karst Plateau is an area with a high concentration of caves, many of which – 165 according to data from the Historical Archive of the Julian Alpine Society – contain traces of ancient human presence. The caves have attracted the interest of both professional researchers and curious enthusiasts, resulting in a succession of excavation work, systematic and non-systematic, from the last decades of the 1800s up until today, which has produced a large quantity of material that has remained for the most part unpublished. In order to retrieve and organize the documentation found in literature and archives, and to contextualize the traces of mankind in the natural environment, primarily in the single caves, a decade or so ago an interdisciplinary program was started up involving specialists in various fields from the University of Trieste in the creation of geo-archaeological database called the Computerized Cadastre of Archaeological Caves (CRIGA – Catasto Ragionato Informatico delle Grotte Archeologiche). Aside from the possibility to meet the original objectives of scientific research, CRIGA also has great potential for teaching, promotion, cave protection and the planning of operations in the area. In view of these aspects, the database has been made accessible by the general public, at the web address www. units.it/criga. This contribution provides a brief history of CRIGA, its actual situation and its future prospects