Elevated Flt3L predicts long-term survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms

BACKGROUND: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. METHODS: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. RESULTS: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients' progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. CONCLUSIONS: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions

Continental-scale geographic change across zealandia during paleogene subduction initiation

Data from International Ocean Discovery Program (IODP) Expedition 371 reveal vertical movements of 1-3 km in northern Zealandia during early Cenozoic subduction initiation in the western Pacific Ocean. Lord Howe Rise rose from deep (~1 km) water to sea level and subsided back, with peak uplift at 50 Ma in the north and between 41 and 32 Ma in the south. The New Caledonia Trough subsided 2-3 km between 55 and 45 Ma. We suggest these elevation changes resulted from crust delamination and mantle flow that led to slab formation. We propose a "subduction resurrection" model in which (1) a subduction rupture event activated lithospheric-scale faults across a broad region during less than ~5 m.y., and (2) tectonic forces evolved over a further 4-8 m.y. as subducted slabs grew in size and drove plate-motion change. Such a subduction rupture event may have involved nucleation and lateral propagation of slip-weakening rupture along an interconnected set of preexisting weaknesses adjacent to density anomalies

Expansion and diversification of high-latitude radiolarian assemblages in the late Eocene linked to a cooling event in the southwest Pacific

The long-term cooling trend from middle to late Eocene was punctuated by several large-scale climate perturbations that culminated in a shift to "icehouse" climates at the Eocene–Oligocene transition. We present radiolarian micro-fossil assemblage and foraminiferal oxygen and carbon stable isotope data from Deep Sea Drilling Project (DSDP) sites 277, 280, 281, and 283 and Ocean Drilling Project (ODP) Site 1172 to identify significant oceanographic changes in the southwest Pacific through this climate transition (~ 40–30 Ma). We find that the Middle Eocene Climatic Optimum at ~ 40 Ma, which is truncated but identified by a negative shift in foraminiferal ?18O values at Site 277, is associated with a small increase in radiolarian taxa with low-latitude affinities (5 % of total fauna). In the early late Eocene at ~ 37 Ma, a positive oxygen isotope shift at Site 277 is correlated with the Priabonian Oxygen Isotope Maximum (PrOM). Radiolarian abundance, diversity, and preservation increase within this cooling event at Site 277 at the same time as diatom abundance. A negative ?18O excursion above the PrOM is correlated with a late Eocene warming event (~ 36.4 Ma). Radiolarian abundance and diversity decline within this event and taxa with low-latitude affinities reappear. Apart from this short-lived warming event, the PrOM and latest Eocene radiolarian assemblages are characterised by abundant high-latitude taxa. High-latitude taxa are also abundant during the late Eocene and early Oligocene (~ 38–30 Ma) at DSDP sites 280, 281, 283 and 1172 and are associated with very high diatom abundance. We therefore infer a northward expansion of high-latitude radiolarian taxa onto the Campbell Plateau in the latest Eocene. In the early Oligocene there is an overall decrease in radiolarian abundance and diversity at Site 277, and diatoms are scarce. These data indicate that, once the Antarctic Circumpolar Current was established in the early Oligocene (~ 30 Ma), a frontal system similar to present day developed, with nutrient-depleted Subantarctic waters bathing the area around DSDP Site 277, resulting in a more restricted siliceous plankton assemblage