Description: Hornblende in the Kuna Crest lobe (KCL) of the Tuolumne Intrusive Complex (TIC) and the upper zone of the Wooley Creek batholith (WCB) precipitated over a temperature range of ~835 to 700 °C, and thus has the potential to record magmatic processes. We measured trace element concentrations in hornblende from the WCB, from the KCL of the TIC, and from one sample from an adjacent interior unit of the TIC to compare and contrast magmatic processes in these two mid-crustal intrusions. In both systems the magmatic amphibole is magnesiohornblende in which Ti, Zr, Hf, Nb, Sr, Ba, and rare earth elements (REE) typically decrease from crystal interiors to rims, an indication of compatible behavior of these elements, and the size of the negative Eu anomaly decreases. In the Kuna Crest lobe, hornblende from individual mapped units differs in trace element abundances and zoning trends. Some samples contain at least two distinct hornblende populations, which is particularly evident in the shapes of REE patterns. In contrast, compositions of hornblende from all structural levels of the upper WCB and related dacitic roof-zone dikes form a single broad array and the REE patterns are essentially indistinguishable, regardless of rock type, from quartz diorite to granite. In the WCB, Zr/Hf ratios in hornblende are consistent with crystallization from a melt with chondritic Zr/Hf values. In contrast, most hornblende in the KCL has Zr/Hf values lower than expected from crystallization from a melt with chondritic values, suggesting that zircon fractionation occurred before and during crystallization of the hornblende. Simple fractional crystallization models indicate that REE, high field strength elements, Sr, and Ba were compatible in KCL and WCB magmas as hornblende grew; these trends require removal of hornblende + plagioclase + zircon ± ilmenite ± biotite. The uniform variations of trace element concentrations and patterns in the upper WCB and roof-zone dikes indicates crystallization from a large magma body that was compositionally uniform; probably stirred by convection caused by influx of mafic magmas at the base of the zone ( Coint et al. 2013a , 2013b ; cf. Burgisser and Bergantz 2011 ). In contrast, in the KCL, each analyzed sample displays distinct hornblende compositions and zoning patterns, some of which are bimodal. These features indicate that each analyzed sample represents a distinct magma and that individual magmas were variably modified by fractionation and mixing. Hornblende trace element contents and zoning patterns prove to be powerful tools for identification of magma batches and for assessing magmatic processes, and thereby relating plutonic rocks to hypabyssal and volcanic equivalents.

Description: Camptothecin and its derivatives, topotecan and irinotecan, are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, and the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop novel drug combinations, we conducted a synthetic lethal siRNA screen using a library that targets nearly 7,000 human genes. Depletion of ATR, the main transducer of replication stress, came as a top candidate gene for camptothecin synthetic lethality. Validation studies using ATR siRNA and the ATR inhibitor VE-821 confirmed marked antiproliferative synergy with camptothecin and even greater synergy with LMP-400. Single-cell analyses and DNA fiber combing assays showed that VE-821 abrogates the S-phase replication elongation checkpoint and the replication origin–firing checkpoint induced by camptothecin and LMP-400. As expected, the combination of Top1 inhibitors with VE-821 inhibited the phosphorylation of ATR and Chk1; however, it strongly induced γH2AX. In cells treated with the combination, the γH2AX pattern changed over time from the well-defined Top1-induced damage foci to an intense peripheral and diffuse nuclear staining, which could be used as response biomarker. Finally, the clinical derivative of VE-821, VX-970, enhanced the in vivo tumor response to irinotecan without additional toxicity. A key implication of our work is the mechanistic rationale and proof of principle it provides to evaluate the combination of Top1 inhibitors with ATR inhibitors in clinical trials. Cancer Res; 74(23); 6968–79. ©2014 AACR.

Description: Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. Cancer Res; 75(12); 2489–500. ©2015 AACR.

Description: The Wooley Creek batholith is a Late Jurassic, arc-related, calc-alkaline plutonic complex in the Klamath Mountain province of California. Post-emplacement tilting and erosion have exposed ~12 km of structural relief. The complex consists of an older (~159.1 Ma) lower zone (pyroxenite to tonalite) assembled by piecemeal emplacement of many magma batches, a younger (~158.2 Ma) upper zone (quartz diorite to granite), and a transitional central zone. In the lower zone, pyroxenes are too Fe rich to be in equilibrium with a melt whose composition was that of the host rock. Mass-balance calculations and simulations using rhyolite-MELTS indicate that these rocks are cumulates of pyroxenes and plagioclase ± olivine and accessory apatite and oxides. Percentages of interstitial melt varied from ~7.5–83%. The plagioclase/pyroxene ratios of cumulates vary considerably among the most mafic rocks, but are relatively uniform among quartz diorite to tonalite. This near-constant ratio results in compositional trends that mimic a liquid line of descent. In the upper zone, bulk-rock compositional trends are consistent with differentiation of andesitic parental magmas. Upward gradation from quartz dioritic to granitic compositions, modeled via mass-balance calculations and rhyolite-MELTS simulations, indicate that structurally lower parts of the upper zone are cumulates of hornblende and plagioclase ± biotite and accessory minerals, with 37–80% trapped melt. In contrast, the structurally higher part of the upper zone represents differentiated magma that escaped the subjacent cumulates, representing differentiated melt fractions remaining from 92–54%. The ratio of cumulate plagioclase/(plagioclase + mafic minerals) ~0.48 among upper-zone cumulates, mimicking a liquid line of descent. The results suggest that compositional variation in many calc-alkaline plutons may be at least as representative of crystal accumulation as of fractional crystallization. If so, then the assumption that arc plutons geochemically resemble frozen liquids is dubious and should be tested on a case-by-case basis. Moreover, comparisons of plutonic rock compositions with those of potentially comagmatic volcanic rocks will commonly yield spurious results unless accumulation in the plutons is accounted for.