MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer

MicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether it represents a bystander event or actually drives tumor progression in vivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment

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

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

First indications that northern bottlenose whales are sensitive to behavioural disturbance from anthropogenic noise

Contributions of P.M., P.T., C.C., S.D., F.V., P.W., L.M.L., T.N. and S.H. were funded by the US Office of Naval Research. Contributions of P.K., L.K. and L.S. were funded by the Norwegian Ministry of Defence. Contributions of F.L., S.v.IJ. and A.v.B. were funded by The Netherlands Ministry of Defence. Fieldwork contributions of L.M.L. and T.N. were funded by the Strategic Environmental Research and Development Program (SERDP). The analysis component of L.M.L.'s contribution was funded by DGA French Ministry of Defence. P.T. acknowledges the support of the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) in the completion of this study. MASTS is funded by the Scottish Funding Council (grant no. HR09011) and contributing institutions.Although northern bottlenose whales were the most heavily hunted beaked whale, we have little information about this species in its remote habitat of the North Atlantic Ocean. Underwater anthropogenic noise and disruption of their natural habitat may be major threats, given the sensitivity of other beaked whales to such noise disturbance. We attached dataloggers to 13 northern bottlenose whales and compared their natural sounds and movements to those of one individual exposed to escalating levels of 1–2 kHz upsweep naval sonar signals. At a received sound pressure level (SPL) of 98 dB re 1 μPa, the whale turned to approach the sound source, but at a received SPL of 107 dB re 1 μPa, the whale began moving in an unusually straight course and then made a near 180° turn away from the source, and performed the longest and deepest dive (94 min, 2339 m) recorded for this species. Animal movement parameters differed significantly from baseline for more than 7 h until the tag fell off 33–36 km away. No clicks were emitted during the response period, indicating cessation of normal echolocation-based foraging. A sharp decline in both acoustic and visual detections of conspecifics after exposure suggests other whales in the area responded similarly. Though more data are needed, our results indicate high sensitivity of this species to acoustic disturbance, with consequent risk from marine industrialization and naval activity.Publisher PDFPeer reviewe

Configural Cue Performance in Identical Twins Discordant for Posttraumatic Stress Disorder: Theoretical Implications for the Role of Hippocampal Function

Background: A significant subgroup of individuals with posttraumatic stress disorder (PTSD) exhibits chronic, unremitting symptomatology that has also been associated with smaller hippocampal volume. The hippocampus plays a significant role in configural processing of contextual cues that facilitates context-appropriate extinction of conditioned fear. We test the hypothesis that hippocampus-based configural processing deficits are a pre-existing vulnerability factor for unremitting forms of PTSD. Methods: Participants included male monozygotic twin pairs who were discordant for combat trauma. In 18 twin pairs the combat-exposed brother developed unremitting PTSD, whereas in 23 pairs the combat-exposed brother never developed PTSD. Participants were compared in the capacity to solve allocentric spatial processing tasks, and this performance was examined for its relationship to the severity of PTSD symptomatology and hippocampal volume. Results: Although not completely differentiated from overall IQ, PTSD combat veterans demonstrated significantly impaired performance in configural processing relative to non-PTSD combat veterans. Despite having neither combat-exposure nor PTSD, the unexposed co-twins of combat veterans with PTSD displayed the same decrements as their brothers. Deficits were significantly related to PTSD severity and hippocampal volume. Conclusions: The current study provides the first evidence that the relevance of the hippocampus in PTSD might be related to pre-existing configural cue processing deficits that predispose individuals to develop unremitting forms of the disorder