Description: Compressively strained Ge quantum well devices have a spin-splitting in applied magnetic field that is entirely consistent with a Zeeman effect in the heavy hole valence band. The spin orientation is determined by the biaxial strain in the quantum well with the relaxed SiGe buffer layers and is quantized in the growth direction perpendicular to the conducting channel. The measured spin-splitting in the resistivity ρ xx agrees with the predictions of the Zeeman Hamiltonian where the Shubnikov-deHaas effect exhibits a loss of even filling factor minima in the resistivity ρ xx with hole depletion from a gate field, increasing disorder or increasing temperature. There is no measurable Rashba spin-orbit coupling irrespective of the structural inversion asymmetry of the confining potential in low p-doped or undoped Ge quantum wells from a density of 6 × 10 10  cm −2 in depletion mode to 1.7 × 10 11  cm −2 in enhancement.

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.

Description: In the central Klamath Mountains, the English Peak plutonic complex (EPC) invaded the faulted contact between the outboard Eastern Hayfork and inboard North Fork terranes of the Western Paleozoic and Triassic Belt (WTrPz). This calc-alkaline igneous complex is composed of two small, ~1–2-km-diameter, relatively mafic satellitic plutons peripheral to the younger, much larger, ~10–15-km-diameter English Peak zoned granitic pluton. The EPC magmas were mantle derived and reflect temporary residence and mixing at various depths in the overlying crust, with initial storage and modification near the Moho, and uppermost crustal emplacement at 5–10 km depths. Phase assemblages suggest pre-emplacement magma storage at a depth of ~20–25 km for the early satellitic plutons, versus ~15–20 km for samples from the larger zoned granitic pluton. We obtained zircon U-Pb geochronologic results (reported as internal and external weighted-mean 207 Pb-corrected 206 Pb/ 238 U ages, 95% confidence level) from seven samples in the complex via laser ablation–inductively coupled plasma–mass spectrometry (LA-ICP-MS). The 172.3 ± 2.0 [3.7] Ma Uncles Creek and 166.9 ± 1.6 [3.4] Ma Heiney Bar satellitic plutons range from gabbro–quartz diorite to granodiorite in bulk-rock composition. The main English Peak pluton consists of an early stage of gabbro-tonalite (three samples: 160.4 ± 1.1 [3.1] Ma, 158.1 ± 1.1 [3.1] Ma, and 158.0 ± 1.2 [3.1] Ma) and a late stage (two samples: 156.3 ± 1.3 [3.1] Ma and 155.3 ± 1.2 [3.0] Ma) passing inward from tonalite through granodiorite to a central zone of granite. The 172 Ma age of the Uncles Creek pluton makes it coeval with Middle Jurassic Western Hayfork arc magmatism. In contrast, Heiney Bar and the main English Peak igneous ages overlap some of the oldest and youngest components, respectively, of the Middle to Late Jurassic Wooley Creek plutonic suite. Study of this multiple-intrusion complex provides an illuminating example of the gradual intermediate-to-felsic modification of the upper crust in the central Klamath Mountains. Inherited zircon ages of ca. 172 Ma in two other EPC samples indicate potential Middle Jurassic crustal sources or contaminants. Geochronologic correlation of the EPC with geologic histories of other Klamath terranes provides fresh insights for understanding spatial and temporal elements of Middle to Late Jurassic arc magmatism in the Klamath Mountains sector of the Cordilleran margin. This igneous activity illuminates some petrotectonic processes whereby accreted ophiolitic basement terranes were modified and incorporated into the evolving Jurassic continental crust. It took place prior to the earliest Cretaceous onset of westward transport of the stack of Klamath allochthons relative to the active Jura-Cretaceous Sierran calc-alkaline arc.

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: Michael Cohen, Karen M. Page, Ruben Perez-Carrasco, Chris P. Barnes, and James Briscoe

Description: The Late Jurassic English Peak plutonic complex was emplaced in an upper crustal retro-arc setting in the central Klamath Mountains province, northern California. Emplacement of the main, central pluton was preceded by intrusion of two satellite bodies: the Uncles Creek pluton crystallized from H 2 O-rich quartz dioritic magma with hornblende as the liquidus mafic phase; in contrast, the Heiney Bar pluton is a c. 2·5 km diameter body zoned from gabbro to granodiorite. Al-in-hornblende barometry from these two plutons indicates a stage of magma storage at c. 600–500 MPa. The central English Peak pluton is a c. 15 km diameter body composed of early and late stages. Early stage rocks range from gabbro to tonalite, with variable proportions of augite, orthopyroxene, hornblende and biotite. The early stage lacks discernible zoning and rock types vary at the outcrop scale. This diversity is reflected in bulk-rock compositions, which do not form a compositional array. The late-stage intrusion consists of three concentric units that are zoned from outer, more mafic rocks (quartz diorite, tonalite, quartz monzodiorite) to inner, compositionally evolved rocks (granodiorite and granite). Late-stage samples plot in smooth, typically linear arrays for most major and trace elements. Al-in-hornblende pressures indicate that late-stage hornblende cores grew in a reservoir at c. 400 MPa and that rims grew at the level of final emplacement (c. 250 MPa). The mid-crustal reservoir was the site of late-stage magma evolution, including episodic magma mixing. Oxygen and Sr isotopes indicate initial evolution of English Peak pluton magmas in a deep crustal region of mixing, assimilation, storage, and homogenization (MASH zone), where they were contaminated by metasedimentary rocks. Thus, the English Peak pluton represents a crustal-scale system, with mantle-derived magmas that differentiated near the Moho, storage and crystallization of satellite-pluton magmas in the middle crust (c. 600–500 MPa), development of a large, episodically recharged, magma chamber in the upper middle crust (c. 400 MPa) and final emplacement in the upper crust.

Description: Objectives To describe the potential workload for patients with multimorbidity when applying existing clinical practice guidelines. Design Systematic analysis of clinical practice guidelines for chronic conditions and simulation modelling approach. Data sources National Guideline Clearinghouse index of US clinical practice guidelines. Study selection We identified the most recent guidelines for adults with 1 of 6 prevalent chronic conditions in primary care (ie hypertension, diabetes, coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), osteoarthritis and depression). Data extraction From the guidelines, we extracted all recommended health-related activities (HRAs) such as drug management, self-monitoring, visits to the doctor, laboratory tests and changes of lifestyle for a patient aged 45–64 years with moderate severity of conditions. Simulation modelling approach For each HRA identified, we performed a literature review to determine the potential workload in terms of time spent on this HRA. Then, we used a simulation modelling approach to estimate the potential workload needed to comply with these recommended HRAs for patients with several of these chronic conditions. Results Depending on the concomitant chronic condition, patients with 3 chronic conditions complying with all the guidelines would have to take a minimum of 6 to a maximum of 13 medications per day, visit a health caregiver a minimum of 1.2 to a maximum of 5.9 times per month and spend a mean (SD) of 49.6 (27.3) to 71.0 (34.5) h/month in HRAs. The potential workload increased greatly with increasing number of concomitant conditions, rising to 18 medications per day, 6.6 visits per month and 80.7 (35.8) h/month in HRAs for patients with 6 chronic conditions.

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: We examined the spectral properties of a selection of Titan's impact craters that represent a range of degradation states. The most degraded craters have rims and ejecta blankets with spectral characteristics that suggest they are more enriched in water ice than the rims and ejecta blankets of the freshest craters on Titan. The progression is consistent with the chemical weathering of Titan's surface. We propose an evolutionary sequence such that Titan's craters expose an intimate mixture of water ice and organic materials, and chemical weathering by methane rainfall removes the soluble organic materials, leaving the insoluble organics and water ice behind. These observations support the idea that fluvial processes are active in Titan's equatorial regions.

Description: Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7–specific isatin-5-sulfonamide 18 F-ICMT-11 ( 18 F-( S )-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluoro-phenoxymethyl)-pyrrolidine-1-sulfonyl)isatin) and 18 F-FLT (3'-deoxy-3'- 18 F-fluorothymidine), were used to detect early treatment-induced changes in tumor biology and determine whether any of these changes indicate a response to cetuximab, administered as monotherapy or combination therapy with gemcitabine. Methods: In mice bearing cetuximab-sensitive H1975 tumors (non–small lung cancer), the effects of single or repeated doses of the antiepidermal growth factor receptor antibody cetuximab (10 mg/kg on day 1 only or on days 1 and 2) or a single dose of gemcitabine (125 mg/kg on day 2) were investigated by 18 F-ICMT-11 or 18 F-FLT on day 3. Imaging was also performed after 2 doses of cetuximab (days 1 and 2) in mice bearing cetuximab-insensitive HCT116 tumors (colorectal cancer). For imaging–histology comparison, tumors were evaluated for proliferation (Ki-67 and thymidine kinase 1 [TK1]), cell death (cleaved caspase-3 and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling [TUNEL]), and target engagement (epidermal growth factor receptor expression) by immunohistochemistry, immunofluorescence, and immunoblotting, respectively. Tumor and plasma were analyzed for thymidine and gemcitabine metabolites by liquid chromatography–mass spectrometry. Results: Retention of both tracers was sensitive to cetuximab in H1975 tumors. 18 F-ICMT-11 uptake and ex vivo cleaved caspase-3 staining notably increased in tumors treated with repeated doses of cetuximab (75%) and combination treatment (46%). Although a single dose of cetuximab was insufficient to induce apoptosis, it did affect proliferation. Significant reductions in tumor 18 F-FLT uptake (44%–50%; P 〈 0.001) induced by cetuximab monotherapy and combination therapy were paralleled by a clear decrease in proliferation (Ki-67 decrease, 72%–95%; P 〈 0.0001), followed by a marked tumor growth delay. TK1 expression and tumor thymidine concentrations were profoundly reduced. Neither imaging tracer depicted the gemcitabine-induced tumor changes. However, cleaved caspase-3 and Ki-67 staining did not significantly differ after gemcitabine treatment whereas TK1 expression and thymidine concentrations increased. No cetuximab-induced modulation of the imaging tracers or other response markers was detected in the insensitive model of HCT116. Conclusion: 18 F-ICMT-11 and 18 F-FLT are valuable tools to assess cetuximab sensitivity depicting distinct and time-variant aspects of treatment response.