Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941

SummaryHerceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors

Factors associated with poor control of 9/11-related asthma 10–11 years after the 2001 World Trade Center terrorist attacks

Objective: To identify key factors associated with poor asthma control among adults in the World Trade Center (WTC) Health Registry, a longitudinal study of rescue/recovery workers and community members who were directly exposed to the 2001 WTC terrorist attacks and their aftermath. Methods: We studied incident asthma diagnosed by a physician from 12 September 2001 through 31 December 2003 among participants aged ≥18 on 11 September 2001, as reported on an enrollment (2003–2004) or follow-up questionnaire. Based on modified National Asthma Education and Prevention Program criteria, asthma was considered controlled, poorly-controlled, or very poorly-controlled at the time of a 2011–2012 follow-up questionnaire. Probable post-traumatic stress disorder, depression, and generalized anxiety disorder were defined using validated scales. Self-reported gastroesophageal reflux symptoms (GERS) and obstructive sleep apnea (OSA) were obtained from questionnaire responses. Multinomial logistic regression was used to examine factors associated with poor or very poor asthma control. Results: Among 2445 participants, 33.7% had poorly-controlled symptoms and 34.6% had very poorly-controlled symptoms in 2011–2012. Accounting for factors including age, education, body mass index, and smoking, there was a dose–response relationship between the number of mental health conditions and poorer asthma control. Participants with three mental health conditions had five times the odds of poor control and 13 times the odds of very poor control compared to participants without mental health comorbidities. GERS and OSA were significantly associated with poor or very poor control. Conclusions: Rates of poor asthma control were very high in this group with post-9/11 diagnosed asthma. Comprehensive care of 9/11-related asthma should include management of mental and physical health comorbidities

DFT calculation of the intermolecular exchange interaction in the magnetic Mn4_4 dimer

The dimeric form of the single-molecule magnet [Mn$_4$O$_3$Cl$_4$(O$_2$CEt)$_3$(py)$_3$]$_2$ recently revealed interesting phenomena: no quantum tunneling at zero field and tunneling before magnetic field reversal. This is attributed to substantial antiferromagnetic exchange interaction between different monomers. The intermolecular exchange interaction, electronic structure and magnetic properties of this molecular magnet are calculated using density-functional theory within generalized-gradient approximation. Calculations are in good agreement with experiment.Comment: 4 page

On the Circular Orbit Approximation for Binary Compact Objects In General Relativity

One often-used approximation in the study of binary compact objects (i.e., black holes and neutron stars) in general relativity is the instantaneously circular orbit assumption. This approximation has been used extensively, from the calculation of innermost circular orbits to the construction of initial data for numerical relativity calculations. While this assumption is inconsistent with generic general relativistic astrophysical inspiral phenomena where the dissipative effects of gravitational radiation cause the separation of the compact objects to decrease in time, it is usually argued that the timescale of this dissipation is much longer than the orbital timescale so that the approximation of circular orbits is valid. Here, we quantitatively analyze this approximation using a post-Newtonian approach that includes terms up to order ({Gm/(rc^2)})^{9/2} for non-spinning particles. By calculating the evolution of equal mass black hole / black hole binary systems starting with circular orbit configurations and comparing them to the more astrophysically relevant quasicircular solutions, we show that a minimum initial separation corresponding to at least 6 (3.5) orbits before plunge is required in order to bound the detection event loss rate in gravitational wave detectors to < 5% (20%). In addition, we show that the detection event loss rate is > 95% for a range of initial separations that include all modern calculations of the innermost circular orbit (ICO).Comment: 10 pages, 12 figures, revtex

Infinite factorization of multiple non-parametric views

Combined analysis of multiple data sources has increasing application interest, in particular for distinguishing shared and source-specific aspects. We extend this rationale of classical canonical correlation analysis into a flexible, generative and non-parametric clustering setting, by introducing a novel non-parametric hierarchical mixture model. The lower level of the model describes each source with a flexible non-parametric mixture, and the top level combines these to describe commonalities of the sources. The lower-level clusters arise from hierarchical Dirichlet Processes, inducing an infinite-dimensional contingency table between the views. The commonalities between the sources are modeled by an infinite block model of the contingency table, interpretable as non-negative factorization of infinite matrices, or as a prior for infinite contingency tables. With Gaussian mixture components plugged in for continuous measurements, the model is applied to two views of genes, mRNA expression and abundance of the produced proteins, to expose groups of genes that are co-regulated in either or both of the views. Cluster analysis of co-expression is a standard simple way of screening for co-regulation, and the two-view analysis extends the approach to distinguishing between pre- and post-translational regulation

The Star Formation and Extinction Co-Evolution of UV-Selected Galaxies over 0.05<z<1.2

We use a new stacking technique to obtain mean mid IR and far IR to far UV flux ratios over the rest near-UV/near-IR color-magnitude diagram. We employ COMBO-17 redshifts and COMBO-17 optical, GALEX far and near UV, Spitzer IRAC and MIPS Mid IR photometry. This technique permits us to probe infrared excess (IRX), the ratio of far IR to far UV luminosity, and specific star formation rate (SSFR) and their co-evolution over two orders of magnitude of stellar mass and redshift 0.1<z<1.2. We find that the SSFR and the characteristic mass (M_0) above which the SSFR drops increase with redshift (downsizing). At any given epoch, IRX is an increasing function of mass up to M_0. Above this mass IRX falls, suggesting gas exhaustion. In a given mass bin below M_0 IRX increases with time in a fashion consistent with enrichment. We interpret these trends using a simple model with a Schmidt-Kennicutt law and extinction that tracks gas density and enrichment. We find that the average IRX and SSFR follows a galaxy age parameter which is determined mainly by the galaxy mass and time since formation. We conclude that blue sequence galaxies have properties which show simple, systematic trends with mass and time such as the steady build-up of heavy elements in the interstellar media of evolving galaxies and the exhaustion of gas in galaxies that are evolving off the blue sequence. The IRX represents a tool for selecting galaxies at various stages of evolution.Comment: Accepted for publication in GALEX Special Ap.J.Suppl., December, 200

IR and UV Galaxies at z=0.6 -- Evolution of Dust Attenuation and Stellar Mass as Revealed by SWIRE and GALEX

We study dust attenuation and stellar mass of $\rm z\sim 0.6$ star-forming galaxies using new SWIRE observations in IR and GALEX observations in UV. Two samples are selected from the SWIRE and GALEX source catalogs in the SWIRE/GALEX field ELAIS-N1-00 ($\Omega = 0.8$ deg$^2$). The UV selected sample has 600 galaxies with photometric redshift (hereafter photo-z) $0.5 \leq z \leq 0.7$ and NUV$\leq 23.5$ (corresponding to \rm L_{FUV} \geq 10^{9.6} L_\sun). The IR selected sample contains 430 galaxies with $f_{24\mu m} \geq 0.2$ mJy (\rm L_{dust} \geq 10^{10.8} L_\sun) in the same photo-z range. It is found that the mean $\rm L_{dust}/L_{FUV}$ ratios of the z=0.6 UV galaxies are consistent with that of their z=0 counterparts of the same $\rm L_{FUV}$. For IR galaxies, the mean $\rm L_{dust}/L_{FUV}$ ratios of the z=0.6 LIRGs (\rm L_{dust} \sim 10^{11} L_\sun) are about a factor of 2 lower than local LIRGs, whereas z=0.6 ULIRGs (\rm L_{dust} \sim 10^{12} L_\sun) have the same mean $\rm L_{dust}/L_{FUV}$ ratios as their local counterparts. This is consistent with the hypothesis that the dominant component of LIRG population has changed from large, gas rich spirals at z$>0.5$ to major-mergers at z=0. The stellar mass of z=0.6 UV galaxies of \rm L_{FUV} \leq 10^{10.2} L_\sun is about a factor 2 less than their local counterparts of the same luminosity, indicating growth of these galaxies. The mass of z=0.6 UV lunmous galaxies (UVLGs: \rm L_{FUV} > 10^{10.2} L_\sun) and IR selected galaxies, which are nearly exclusively LIRGs and ULIRGs, is the same as their local counterparts.Comment: 27 pages, 8 figures, to be published in the Astrophysical Journal Supplement series dedicated to GALEX result