HDAC class I inhibitor domatinostat sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation

Pancreatic ductal adenocarcinoma (PDAC) represents an unmet clinical need due to the very poor prognosis and the lack of effective therapy. Here we investigated the potential of domatinostat (4SC-202), a new class I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize PDAC to first line standard gemcitabine (G)/taxol (T) doublet chemotherapy treatment. Methods: Synergistic anti-tumor effect of the combined treatment was assessed in PANC1, ASPC1 and PANC28 PDAC cell lines in vitro as well as on tumor spheroids and microtissues, by evaluating combination index (CI), apoptosis, clonogenic capability. The data were confirmed in vivo xenograft models of PANC28 and PANC1 cells in athymic mice. Cancer stem cells (CSC) targeting was studied by mRNA and protein expression of CSC markers, by limiting dilution assay, and by flow cytometric and immunofluorescent evaluation of CSC mitochondrial and cellular oxidative stress. Mechanistic role of forkhead box M1 (FOXM1) and downstream targets was evaluated in FOXM1-overexpressing PDAC cells. Results: We showed that domatinostat sensitized in vitro and in vivo models of PDAC to chemotherapeutics commonly used in PDAC patients management and particularly to GT doublet, by targeting CSC compartment through the induction of mitochondrial and cellular oxidative stress. Mechanistically, we showed that domatinostat hampers the expression and function of FOXM1, a transcription factor playing a crucial role in stemness, oxidative stress modulation and DNA repair. Domatinostat reduced FOXM1 protein levels by downregulating mRNA expression and inducing proteasome-mediated protein degradation thus preventing nuclear translocation correlated with a reduction of FOXM1 target genes. Furthermore, by overexpressing FOXM1 in PDAC cells we significantly reduced domatinostatinducing oxidative mitochondrial and cellular stress and abolished GT sensitization, both in adherent and spheroid cells, confirming FOXM1 crucial role in the mechanisms described. Finally, we found a correlation of FOXM1 expression with poor progression free survival in PDAC chemotherapy-treated patients

Traian and the Danubian Provinces. The political, economic and religious life in the Danubian Provinces: Proceedings of the 4th International Conference on the Roman Danubian Provinces, Zagreb, 15th - 17th November 2017.

The “Department of Archaeology“ of the Faculty of Humanities and Social Sciences of the University of Zagreb gladly hosted the 4th International Conference on the Roman Danubian Provinces in 2017. The Conference was organized with the support of the Faculty of Humanities and Social Sciences of the University of Zagreb, the Croatian Archaeological Society, and the Croatian Science Foundation through the project 6505 Between the Danube and the Mediterranean. Exploring the role of Roman military in the mobility of people and goods in Croatia during the Roman Era. Since it was organized in Zagreb, the Conference remained in Pannonia, not far from Siscia, the capital of Pannonia Savia, and in the territory of the Res publica Andautoniensium. The main topic of the Conference was Traian and the Roman Danubian Provinces or, more specifically, the political, economic and religious life in the Danubian Provinces.(from the Foreword)The “Department of Archaeology“ of the Faculty of Humanities and Social Sciences of the University of Zagreb gladly hosted the 4th International Conference on the Roman Danubian Provinces in 2017. The Conference was organized with the support of the Faculty of Humanities and Social Sciences of the University of Zagreb, the Croatian Archaeological Society, and the Croatian Science Foundation through the project 6505 Between the Danube and the Mediterranean. Exploring the role of Roman military in the mobility of people and goods in Croatia during the Roman Era. Since it was organized in Zagreb, the Conference remained in Pannonia, not far from Siscia, the capital of Pannonia Savia, and in the territory of the Res publica Andautoniensium. The main topic of the Conference was Traian and the Roman Danubian Provinces or, more specifically, the political, economic and religious life in the Danubian Provinces.(from the Foreword

Traian and the Danubian Provinces. The political, economic and religious life in the Danubian Provinces: Proceedings of the 4th International Conference on the Roman Danubian Provinces, Zagreb, 15th - 17th November 2017.

The “Department of Archaeology“ of the Faculty of Humanities and Social Sciences of the University of Zagreb gladly hosted the 4th International Conference on the Roman Danubian Provinces in 2017. The Conference was organized with the support of the Faculty of Humanities and Social Sciences of the University of Zagreb, the Croatian Archaeological Society, and the Croatian Science Foundation through the project 6505 Between the Danube and the Mediterranean. Exploring the role of Roman military in the mobility of people and goods in Croatia during the Roman Era. Since it was organized in Zagreb, the Conference remained in Pannonia, not far from Siscia, the capital of Pannonia Savia, and in the territory of the Res publica Andautoniensium. The main topic of the Conference was Traian and the Roman Danubian Provinces or, more specifically, the political, economic and religious life in the Danubian Provinces.(from the Foreword)The “Department of Archaeology“ of the Faculty of Humanities and Social Sciences of the University of Zagreb gladly hosted the 4th International Conference on the Roman Danubian Provinces in 2017. The Conference was organized with the support of the Faculty of Humanities and Social Sciences of the University of Zagreb, the Croatian Archaeological Society, and the Croatian Science Foundation through the project 6505 Between the Danube and the Mediterranean. Exploring the role of Roman military in the mobility of people and goods in Croatia during the Roman Era. Since it was organized in Zagreb, the Conference remained in Pannonia, not far from Siscia, the capital of Pannonia Savia, and in the territory of the Res publica Andautoniensium. The main topic of the Conference was Traian and the Roman Danubian Provinces or, more specifically, the political, economic and religious life in the Danubian Provinces.(from the Foreword

Tra epigrafia e archeobotanica: i giardini sepolcrali e la loro cura. Un caso di studio: Mutina (Italia, regio VIII )

Si prende in esame la cura che veniva prestata ai giardini che in et\ue0 romana circondavano le sepolture dei personaggi pi\uf9 abbienti. Grazie alle analisi archeobotaniche effettuate durante gli scavi archeologici di una necropoli di Mutina (Modena) si pu\uf2 risalire al tipo di vegetazione che caratterizzava questi giardini

Le analisi archeobotaniche del sarcofago di Piazza Grande (Modena)

Gli studi archeobotanici applicati alle necropoli possono fornire informazioni su aspetti e pratiche del rituale funebre, sulla tipologia delle risorse vegetali destinate al viaggio del defunto dalla vita terrena a quella ultraterrena, dando talvolta anche notizie sulla sua condizione sociale . Nel periodo romano e tardo-antico erano comuni offerte funerarie, tra le quali anche quelle vegetali , coinvolte nei riti funebri anche successivi alla deposizione della salma. In questa analisi condotta per il sarcofago di Piazza Grande si \ue8 verificato se vi fossero tracce di offerte funerarie vegetali

Analisi archeobotaniche a confronto tra la necropoli suburbana di Mutina (scavo ex Parco Novi Sad) e una necropoli prediale nell’agro centuriato mutinese (scavi cava Corpus Domini – Marzaglia). In: Marchetti C.M. (ed.) Theoretical Roman Archaeology Conference 26/Roman Archaeology Conference 12, 16-19 March 2016, Roma. Edizioni Quasar, Roma, p. 106. ISBN 978-88-7140-701-2.

I recenti scavi in necropoli romane dell’agro Mutinense e la crescente attenzione verso le tracce archeologiche più esigue, ha permesso di individuare elementi relativi alla frequentazione delle necropoli. L’importanza di questi tipi di rinvenimenti è decisiva, poiché essi riflettono direttamente le procedure di seppellimento e le azioni che accompagnavano la frequentazione rituale delle aree sepolcrali: esaminandoli con attenzione si possono dunque ricavare informazioni fondamentali per comprendere i comportamenti legati alle pratiche funerarie. Le tombe analizzate sono quelle delle necropoli in parte già indagate di Mutina e dell'agro Mutinense. In particolare, per l'ambito urbano, si prenderà in esame la necropoli dell’area “Novi Sad”, che fiancheggiava un ramo della Via Emilia e ha restituito alcune centinaia di tombe, la cui cronologia va dal I secolo a.C. al IV d.C. Per quanto riguarda il suburbio, verrà presa in considerazione la necropoli rinvenuta in località Marzaglia, sito che può fornire importanti dati di confronto tra le due realtà territoriali. La ricerca si prefigge di analizzare l’ideologia funeraria romana nelle sue numerose sfaccettature, soprattutto attraverso lo studio dei resti archeobotanici ed archeologici rinvenuti nei contesti di necropoli, dove si possono riconoscere consistenti tracce delle offerte legate al culto funerario. Le osservazioni che sono state riportate sono una parte preliminare delle analisi archeologiche e archeobotaniche oggetto di un progetto di dottorato in corso presso il Laboratorio di Palinologia e Paleobotanica con la collaborazione della Soprintendenza ai Beni archeologici dell’Emilia Romagna

Analisi archeobotaniche per il sito di Piazza della Vittoria a Reggio Emilia

Durante lo scavo di Piazza della Vittoria nel centro di Reggio Emilia sono stati prelevati numerosi campioni per analisi archeobotanche: semi/frutti, carboni e pollin

Multiproxy approach for the analysis of the Roman funerary ritual in Mutina (N Italy)

The research focused on the foodstuffs, the offers that were widespread during the Roman funerary rituals (Toynbee 1971). An interdisciplinary method involving different disciplines of archeology was carried out on the necropolis of Mutina and the ager Mutinense, analysing hundreds graves, especially cremation type. These remains of meals left on the graves (animals bones, seeds and fruit) and of the objects involved in the ceremonies, are evidences resulting from the attendance of the funeral space and their identification necessarily requires a strategy for their systematic collection, during the excavation phase and a focused analysis, in order to reconstruct the activities carried out around the death, which characterize three important moments: funeral, implementation of the tomb and visit to the dead (Ortalli 2011). ... The multidisciplinary approach was essential to have a complete view of the funerary rituals. Recurring behaviors have been noticed maybe for custom, social rule or emulation, such as the redundancy of fava bean, figs and dates above all, or of balsamari and table wares; although some differences in territorial settings or in the same necropolis have been found. The choice of both food offerings and objects are linked to a funerary symbology. The criteria that determined the collection of wood are very difficult to establish; it could be assumed that it is likely that both functional and cultural factors influenced the choices of wood for cremation rites

ADVANCED TECHNOLOGIES FOR THE MULTIPROXY ANALYSIS OF THE ROMAN FUNERARY RITUAL IN MUTINA

The research is a key example of integrated analyses in order to adapt the archaeological and archaeobotanical strategy to identify and interpret funerary practices. An interdisciplinary method involving different disciplines of archaeology was carried out on Mutina necropolis, analysing hundreds of graves, especially cremation type, in order to have a complete view of the funerary rituals. In addition to traditional methods, advanced technologies helped to study funerary rituals. For what concerns NoviSad necropolis, the research focused on the foodstuffs and offers that were common during the Roman Age from the 1st to the 2nd century AD. A combination of Computer Tomography Scanning (CT-scan) and Small Angle X-ray Scattering (SAXS) were performed in order to obtain a more detailed data about the potential temperature of burning and the identification of some samples. For what concerns via Cesana and Tangenziale Pasternak necropolis, the urns still intact of their contents were examined by scanner computed tomography, thanks to the collaboration of TECEUROLAB (Mo). Once the scanner images had been taken, a traditional micro excavation and a virtual excavation were carried out at the same time, in order to compare the two different methods. Finally, some IR analysis were performed on the balsamari found inside the urns in order to check cosmetics traces

Archaeological and archaeobotanical analysis of the funerary ritual in urban and peri-urban necropolis of a Roman colony of Northern Italy

An interdisciplinary method involving different disciplines of archeology was carried out on the necropolis of Mutina, in order to have a complete view of the funerary rituals. For a multidisciplinary approach in order to study the funerary rituals, epigraphic, litterary, iconographic, archaeological and archaeobotanical evidences have been taken into consideration. A total of 142 graves and 4 structures have been analysed, coming from 8 necropolis (1st – 4th century AD). Over 2131 liters of soil was sieved and then archaeobotanical (seeds/fruit, charcoals) and archaeological findings were collected. These remains of meals left on the graves and of the objects involved in the ceremonies, are evidences resulting from the attendance of the funeral space. In addition to traditional methods, new technologies (CT-scan and SAXS - in collaboration with Huddersfield University) helped to study offerings presence