L'associazione Tipifarnib-Bortezomib nel trattamento delle leucemie acute mieloidi: risultati di uno studio multicentrico di fase I/II e validazione di un profilo genico predittivo di risposta

Background. Outcome of elderly acute myeloid leukemia (AML) patients is dismal. Targeted-therapies might improve current results by overcoming drug-resistance and reducing toxicity. Aim. We conduced a phase II study aiming to assess efficacy and toxicity of Tipifarnib (Zarnestra®) and Bortezomib (Velcade®) association in AML patients >18 years, unfit for conventional therapy, or >60 years, in relapse. Furthermore, we aimed to evaluated the predictive value of the RASGRP1/APTX ratio, which was previously found to be associated to treatment sensitivity in patients receiving Zarnestra alone. Methods. Velcade (1.0 mg/m2) was administered as weekly infusion for 3 weeks (days 1, 8, 15). Zarnestra was administered at dose of 300-600 mg BID for 21 consecutive days. Real-time quantitative-PCR (q-PCR) was used for RASGRP1/APTX quantification. Results. 50 patients were enrolled. Median age was 71 years (56-89). 3 patients achieved complete remission (CR) and 1 partial response (PR). 2 patients obtained an hematological improvement (HI), and 3 died during marrow aplasia. 10 had progressive disease (PD) and the remaining showed stable disease (SD). RASGRP1/APTX was evaluated before treatment initiation on bone marrow (BM) and/or peripheral blood (PB). The median RASGRP/APTX value on BM was higher in responder (R) patients than in non responders (NR) ones, respectively (p=0.006). Interestingly, no marrow responses were recorded in patients with BM RASGRP1/APTX ratio <12, while the response rate was 50% in patients with ratio >12. Toxicity was overall mild, the most common being febrile neutropenia. Conclusion. We conclude that the clinical efficacy of the combination Zarnestra-Velcade was similar to what reported for Zarnestra alone. However we could confirm that the RASGPR1/APTX level is an effective predictor of response. Though higher RASGRP1/APTX is relatively rare (~10% of cases), Zarnestra (±Velcade) may represent an important option in a subset of high risk/frail AML patients.

La gestione dei beni fiscali da parte di Federico II di Svevia: Il "Quaternus excadenciarum capitinate". Edizione e commento

La ricerca è stata incentrata su di una fonte di grande importanza per una più puntuale comprensione della vita del regno di Federico II: il Quaternus excadenciarum Capitinate. Essa ha tenuto presenti le altre fonti coeve: Liber Augustalis, Registro della Cancelleria di Federico II degli anni 1239-1240, fonti cronachistiche. Il Quaternus è un inventario di talune particolari categorie di beni demaniali, le excadencie, la cui concessione è scaduta e pertanto ritornano al fisco. Tali beni sono situati in 33 località del Giustizierato di Capitanata. Senza data, è stato redatto tra il 1249 e il 1250 (risultano inseriti i beni confiscati a Pier della Vigna, bollato di tradimento nel febbraio 1249). Obiettivo della ricerca è stato duplice: 1) analizzare e approfondire le questioni di natura giuridico-istituzionale ed economica implicate nel documento e tentare di ricostruire uno spaccato della Capitanata del XIII sec.; 2) offrire una nuova e più corretta edizione del testo. La prima parte dello studio ha inteso inquadrare il documento nel contesto delle esigenze proprie delle monarchie del tempo di tenere sotto controllo i beni immobili di ciascun regno ed analizzare la politica economica fridericiana (capp. I, II). La seconda parte è stata dedicata agli approfondimenti innanzi ricordati. Essa è struttura in sette capitoli (I. Il Quaternus excadenciarum Capitinate; II. Beni e diritti costituenti le excadencie Capitinate; III. Il Quaternus come specchio di una politica dispotica; IV. La gestione delle excadencie; V. Pesi e misure; VI. Monete e valori; VII. Il Quaternus come documento sullo stato della Capitanata nel XIII secolo). In appendice: tabelle che offrono per ciascuna delle 33 località considerate, puntuali indicazioni dei beni e diritti censiti, dei nomi dei titolari delle concessioni (spesso personaggi di rango) e delle relative rendite.

EBV Type II latency relies on PARP1 activity and is essential for gastric epithelial cell transformation in EBV-associated Gastric Cancer (EBVaGC)

Epstein-Barr virus (EBV) establishes a lifelong asymptomatic infection by replicating its chromatinized genome, called episome, together with the host genome. EBV exhibits different latency-associated transcriptional repertoires that mirror its three-dimensional structures of the genome. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents almost 10% of all gastric cancers globally. EBVaGC exhibit an intermediate viral transcription profile known as "Latency II", expressing specific viral genes and non-coding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed a destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and consequently, an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II, and III latencies display different 3D episomal structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched chromatin interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV episomes at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.