Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

A fish assemblage from an early Miocene horizon from Jabal Zaltan, Libya

Recent excavations and prospecting in the early to middle Miocene deposits of the Maradah Formation in Jabal Zaltan, Libya, yielded a diverse fish assemblage coming from an early Miocene locality. The material described here includes more than 18 marine and freshwater taxa most of which were previously unreported from the area. Jabal Zaltan is one of the very few early Miocene Afroarabian fossil sites that produced such a diverse fish sample. Therefore, the fossils described here provide a unique insight into the composition of the early Miocene fish faunas from the northern African coast; a critical time period for faunas of the continent, as contact with Eurasia ended 100 million years of African isolation. In addition, the Jabal Zaltan fossils help consolidate the validity of Galeocerdo mayumbensis and extend its geographic range to include the Tethys. The Maradah deposits also host the first occurrences of two genera (Pteromylaeus, Distichodus) in the fossil record. The fish finds support the presumed depositional environment that of tropical shallow estuarine to deltaic conditions, and the freshwater fishes document the presence of a modern-type Nilosudanian fauna containing elements with both African and Asian affinities. The Jabal Zaltan ichthyofauna, with its diversity of taxa, has the potential to become a key reference fauna for future studies of early Miocene African fishes