Description: Context Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. Design, Setting, and Participants A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS . A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Main Outcome Measures Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P  = .08) in patients with wild-type KRAS , and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P  = .38) in patients with mutated KRAS , with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P  〈 .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P  〈 .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Conclusion Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration clinicaltrials.gov Identifier: NCT00079274

Description: Cortney M. Bouldin, Alyssa J. Manning, Yu-Hsuan Peng, Gist H. Farr III, King L. Hung, Alice Dong, and David Kimelman Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2 . We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cell-autonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16 , which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial high-Wnt environment.

Description: The vertebrate body forms from a multipotent stem cell-like progenitor population that progressively contributes newly differentiated cells to the most posterior end of the embryo. How the progenitor population balances proliferation and other cellular functions is unknown due to the difficulty of analyzing cell division in vivo. Here, we show that proliferation is compartmentalized at the posterior end of the embryo during early zebrafish development by the regulated expression of cdc25a , a key controller of mitotic entry. Through the use of a transgenic line that misexpresses cdc25a , we show that this compartmentalization is critical for the formation of the posterior body. Upon misexpression of cdc25a , several essential T-box transcription factors are abnormally expressed, including Spadetail/Tbx16, which specifically prevents the normal onset of myoD transcription, leading to aberrant muscle formation. Our results demonstrate that compartmentalization of proliferation during early embryogenesis is critical for both extension of the vertebrate body and differentiation of the multipotent posterior progenitor cells to the muscle cell fate.

Description: We develop a theory of minors for alternating dimaps—orientably embedded digraphs where, at each vertex, the incident edges (taken in the order given by the embedding) are directed alternately into, and out of, the vertex. We show that they are related by the triality relation of Tutte. They do not commute in general, though do in many circumstances, and we characterize the situations where they do. We give a characterization of alternating dimaps of at most a given genus, using a finite set of excluded minors. We also use the minor operations to define simple Tutte invariants for alternating dimaps and characterize them. We establish a connection with the Tutte polynomial, and pose the problem of characterizing universal Tutte-like invariants for alternating dimaps based on these minor operations.

Description: Author(s): Jian Wei Tay, Warrick G. Farr, Patrick M. Ledingham, Dmitry Korystov, and Jevon J. Longdell We report on a narrow linewidth laser diode system that is stabilized using both optical and electronic feedback to a spectral hole in cryogenic Tm:YAG. The large group delay of the spectral hole leads to a laser with very low phase noise. The laser has proved useful for quantum optics and sensing a... [Phys. Rev. A 87, 063824] Published Mon Jun 17, 2013

Description: Optically stimulated luminescence (OSL) has been employed successfully to determine the ages of palaeosols from earthen mounds in the southeastern USA, providing archaeologists with a means of dating monument construction in the absence of carbonaceous materials and geologists with a setting for understanding factors that can affect the luminescence intensity (i.e., burial dose) of soils. However, OSL dating has not been adequately tested on mounds whose principal component is sand, shell, or a combination of these two, despite the fact that monuments composed of such materials are common to the coasts and interior coastal plains of the region. Radiocarbon dating of bone collagen and soil-carbon and OSL dating of quartz grains extracted from the fill of mounds at the Crystal River and Roberts Island sites on the west-central coast of Florida, USA are used to determine the timing and history of mound construction at the sites. Comparison of OSL and radiocarbon ages on materials from the same or closely related contexts provides insight into factors influencing age determinations in mound fill deposits, particularly the type of construction material (sand or shell) and the manner in which these were deposited. The results contribute to the understanding of the temporal context of platform mound construction in southeastern USA.

Description: We examine the performance of a variety of different estimators for the mass of galaxy groups, based on their galaxy distribution alone. We draw galaxies from the Sloan Digital Sky Survey for a set of groups and clusters for which hydrostatic mass estimates based on high-quality Chandra X-ray data are available. These are used to calibrate the galaxy-based mass proxies, and to test their performance. Richness, luminosity, galaxy overdensity, rms radius and dynamical mass proxies are all explored. These different mass indicators all have their merits, and we argue that using them in combination can provide protection against being misled by the effects of dynamical disturbance or variations in star formation efficiency. Using them in this way leads us to infer the presence of significant non-statistical scatter in the X-ray based mass estimates we employ. We apply a similar analysis to a set of mock groups derived from applying a semi-analytic galaxy formation code to the Millennium dark matter simulation. The relations between halo mass and the mass proxies differ significantly in some cases from those seen in the observational groups, and we discuss possible reasons for this.

Description: Background Stromal cell-derived factor-1 (SDF-1) promotes tissue repair through mechanisms of cell survival, endogenous stem cell recruitment, and vasculogenesis. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure (STOP-HF) is a Phase II, double-blind, randomized, placebo-controlled trial to evaluate safety and efficacy of a single treatment of plasmid stromal cell-derived factor-1 (pSDF-1) delivered via endomyocardial injection to patients with ischaemic heart failure (IHF). Methods Ninety-three subjects with IHF on stable guideline-based medical therapy and left ventricular ejection fraction (LVEF) ≤40%, completed Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and 6-min walk distance (6 MWD), were randomized 1 : 1 : 1 to receive a single treatment of either a 15 or 30 mg dose of pSDF-1 or placebo via endomyocardial injections. Safety and efficacy parameters were assessed at 4 and 12 months after injection. Left ventricular functional and structural measures were assessed by contrast echocardiography and quantified by a blinded independent core laboratory. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was powered based on change in 6 MWD and MLWHFQ at 4 months. Results Subject profiles at baseline were (mean ± SD): age 65 ± 9 years, LVEF 28 ± 7%, left ventricular end-systolic volume (LVESV) 167 ± 66 mL, N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) 1120 ± 1084 pg/mL, MLWHFQ 50 ± 20 points, and 6 MWD 289 ± 99 m. Patients were 11 ± 9 years post most recent myocardial infarction. Study injections were delivered without serious adverse events in all subjects. Sixty-two patients received drug with no unanticipated serious product-related adverse events. The primary endpoint was a composite of change in 6 MWD and MLWHFQ from baseline to 4 months follow-up. The primary endpoint was not met ( P = 0.89). For the patients treated with pSDF-1, there was a trend toward an improvement in LVEF at 12 months (placebo vs. 15 mg vs. 30 mg LVEF: –2 vs. –0.5 vs. 1.5%, P = 0.20). A pre-specified analysis of the effects of pSDF-1 based on tertiles of LVEF at entry revealed improvements in EF and LVESV from lowest-to-highest LVEF. Patients in the first tertile of EF (〈26%) that received 30 mg of pSDF-1 demonstrated a 7% increase in EF compared with a 4% decrease in placebo (LVEF = 11%, P = 0.01) at 12 months. There was also a trend towards improvement in LVESV, with treated patients demonstrating an 18.5 mL decrease compared with a 15 mL increase for placebo at 12 months (LVESV = 33.5 mL, P = 0.12). The change in end-diastolic and end-systolic volume equated to a 14 mL increase in stroke volume in the patients treated with 30 mg of pSDF-1 compared with a decrease of –11 mL in the placebo group (SV = 25 mL, P = 0.09). In addition, the 30 mg-treated cohort exhibited a trend towards improvement in NTproBNP compared with placebo at 12 months (–784 pg/mL, P = 0.23). Conclusions The blinded placebo-controlled STOP-HF trial demonstrated the safety of a single endocardial administration of pSDF-1 but failed to demonstrate its primary endpoint of improved composite score at 4 months after treatment. Through a pre-specified analysis the STOP-HF trial demonstrates the potential for attenuating LV remodelling and improving EF in high-risk ischaemic cardiomyopathy. The safety profile supports repeat dosing with pSDF-1 and the degree of left ventricular remodelling suggests the potential for improved outcomes in larger future trials.

Description: Author(s): Warrick G. Farr, Maxim Goryachev, Daniel L. Creedon, and Michael E. Tobar We report the study of interactions between cavity photons and paramagnetic Cr3+ spins in a ruby (Cr3+:Al2O3) whispering gallery mode (WGM) resonator. Examining the system at microwave frequencies and millikelvin temperatures, spin-photon couplings up to 610 MHz or about 5% of photon energy are obse... [Phys. Rev. B 90, 054409] Published Wed Aug 13, 2014

Description: This work demonstrates strong coupling regime between an erbium ion spin ensemble and microwave hybrid cavity-whispering gallery modes in a yttrium aluminium garnet dielectric crystal. Coupling strengths of 220 MHz and mode quality factors in excess of 10 6 are demonstrated. Moreover, the magnetic response of high-Q modes demonstrates behaviour which is unusual for paramagnetic systems. This behaviour includes hysteresis and memory effects. Such qualitative change of the system's magnetic field response is interpreted as a phase transition of rare earth ion impurities. This phenomenon is similar to the phenomenon of dilute ferromagnetism in semiconductors. The clear temperature dependence of the phenomenon is demonstrated.