12 research outputs found
Geochemistry of lavas from the 2005â2006 eruption at the East Pacific Rise, 9°46âČNâ9°56âČN : implications for ridge crest plumbing and decadal changes in magma chamber compositions
Author Posting. © American Geophysical Union, 2010. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 11 (2010): Q05T09, doi:10.1029/2009GC002977.Detailed mapping, sampling, and geochemical analyses of lava flows erupted from an âŒ18 km long section of the northern East Pacific Rise (EPR) from 9°46âČN to 9°56âČN during 2005â2006 provide unique data pertaining to the short-term thermochemical changes in a mid-ocean ridge magmatic system. The 2005â2006 lavas are typical normal mid-oceanic ridge basalt with strongly depleted incompatible trace element patterns with marked negative Sr and Eu/Eu* anomalies and are slightly more evolved than lavas erupted in 1991â1992 at the same location on the EPR. Spatial geochemical differences show that lavas from the northern and southern limits of the 2005â2006 eruption are more evolved than those erupted in the central portion of the fissure system. Similar spatial patterns observed in 1991â1992 lavas suggest geochemical gradients are preserved over decadal time scales. Products of northern axial and off-axis fissure eruptions are consistent with the eruption of cooler, more fractionated lavas that also record a parental melt component not observed in the main suite of 2005â2006 lavas. Radiogenic isotopic ratios for 2005â2006 lavas fall within larger isotopic fields defined for young axial lavas from 9°N to 10°N EPR, including those from the 1991â1992 eruption. Geochemical data from the 2005â2006 eruption are consistent with an invariable mantle source over the spatial extent of the eruption and petrogenetic processes (e.g., fractional crystallization and magma mixing) operating within the crystal mush zone and axial magma chamber (AMC) before and during the 13 year repose period. Geochemical modeling suggests that the 2005â2006 lavas represent differentiated residual liquids from the 1991â1992 eruption that were modified by melts added from deeper within the crust and that the eruption was not initiated by the injection of hotter, more primitive basalt directly into the AMC. Rather, the eruption was driven by AMC pressurization from persistent or episodic addition of more evolved magma from the crystal mush zone into the overlying subridge AMC during the period between the two eruptions. Heat balance calculations of a hydrothermally cooled AMC support this model and show that continual addition of melt from the mush zone was required to maintain a sizable AMC over this time interval.This work has been supported by
NSF grants OCEâ0525863 and OCEâ0732366 (D. J. Fornari
and S. A. Soule), OCEâ0636469 (K. H. Rubin), and OCEâ
0138088 (M. R. Perfit), as well as postdoctoral fellowship funds
from the University of Florida
Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label therapy
Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense, but not frameshift, mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We further conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds that are approved for non-cancer indications and that perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and for identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.ISSN:2666-979
Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment.
Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense- but not frameshift mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks