Growth factor receptor-bound protein-7 (Grb7) is an adapter-type signaling protein recruited to various tyrosine kinases, including HER2/neu. Grb7-specific inhibitors are in early development. As ...with other targeted therapies, response to therapy might be associated with target expression.
Tissue microarrays containing 638 primary breast cancer specimens with 15-year patient follow-up were employed to assess Grb7 expression using our Automated QUantitative Analysis method; cytokeratin defines pixels as breast cancer (tumor mask) within the histospot, and Grb7 expression within the mask is measured with Cy5-conjugated antibodies.
High Grb7 expression was strongly associated with decreased survival in the entire cohort and in the node-positive subset (P=0.0034 and P= 0.0019, respectively). On multivariable analysis, it remained an independent prognostic marker (P =0.01). High Grb7 was strongly associated with high HER2/neu, and coexpression of these molecules was associated with worse prognosis than HER2/neu overexpression alone.
High Grb7 defines a subset of breast cancer patients with decreased survival, indicating that Grb7 might be a valuable prognostic marker and drug target. Coexpression with HER2/neu indicates that cotargeting these molecules might be an effective approach for treating HER2/neu-positive breast cancers. Future studies using Grb7-targeting agents should include assessment of Grb7 levels.
Summary Objective To identify attributes of zoological institutions and surveillance system factors that were associated with participation in the West Nile Virus Surveillance System for Zoological ...Institutions in the USA, and to assess the potential effectiveness of zoos as a novel data source for surveillance of emerging infectious zoonoses. Study design Retrospective. Methods The number of specimens submitted between August 2001 and December 2006 for West Nile virus testing was determined for each institution. Descriptive statistics were used to summarize the distribution of number of specimens submitted and features of the institutions. Student’s t -test was used to assess potential associations between institutional and animal collection characteristics and the total number of specimens submitted by each institution. Results Factors associated with institutional participation include: submitting specimens for specific purposes of serosurvey testing, sentinel surveillance, vaccine titre checks, vaccine effectiveness, submitting specimens for multiple reasons, and communication with public health. Conclusion Understanding how zoo and surveillance system characteristics are associated with participation in this surveillance effort may enhance public health efforts and the design of future zoological surveillance efforts.
12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid ...mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.
The population of Milky Way (MW) satellites contains the faintest known galaxies and thus provides essential insight into galaxy formation and dark matter microphysics. Here we combine a model of the ...galaxy-halo connection with newly derived observational selection functions based on searches for satellites in photometric surveys over nearly the entire high Galactic latitude sky. In particular, we use cosmological zoom-in simulations of MW-like halos that include realistic Large Magellanic Cloud (LMC) analogs to fit the position-dependent MW satellite luminosity function. We report decisive evidence for the statistical impact of the LMC on the MW satellite population due to an estimated 6 2 observed LMC-associated satellites, consistent with the number of LMC satellites inferred from Gaia proper-motion measurements, confirming the predictions of cold dark matter models for the existence of satellites within satellite halos. Moreover, we infer that the LMC fell into the MW within the last 2 Gyr at high confidence. Based on our detailed full-sky modeling, we find that the faintest observed satellites inhabit halos with peak virial masses below at 95% confidence, and we place the first robust constraints on the fraction of halos that host galaxies in this regime. We predict that the faintest detectable satellites occupy halos with peak virial masses above , highlighting the potential for powerful galaxy formation and dark matter constraints from future dwarf galaxy searches.
ABSTRACT
Modelling self-gravity of collisionless fluids (e.g. ensembles of dark matter, stars, black holes, dust, and planetary bodies) in simulations is challenging and requires some force ...softening. It is often desirable to allow softenings to evolve adaptively, in any high-dynamic range simulation, but this poses unique challenges of consistency, conservation, and accuracy, especially in multiphysics simulations where species with different ‘softening laws’ may interact. We therefore derive a generalized form of the energy-and-momentum conserving gravitational equations of motion, applicable to arbitrary rules used to determine the force softening, together with consistent associated time-step criteria, interaction terms between species with different softening laws, and arbitrary maximum/minimum softenings. We also derive new methods to maintain better accuracy and conservation when symmetrizing forces between particles. We review and extend previously discussed adaptive softening schemes based on the local neighbour particle density, and present several new schemes for scaling the softening with properties of the gravitational field, i.e. the potential or acceleration or tidal tensor. We show that the ‘tidal softening’ scheme not only represents a physically motivated, translation and Galilean invariant and equivalence-principle respecting (and therefore conservative) method but also imposes negligible time-step or other computational penalties, ensuring that pairwise two-body scattering is small compared to smooth background forces and can resolve outstanding challenges in properly capturing tidal disruption of substructures (minimizing artificial destruction) while also avoiding excessive N-body heating. We make all of this public in the GIZMO code.
To assess the efficacy of a lifestyle intervention program that can be readily translated into clinical practice for obese patients with type 2 diabetes.
The study consisted of a 12-month randomized ...controlled trial of 147 health plan members with type 2 diabetes and obesity (BMI >or=27 kg/m(2)). Participants were randomized to lifestyle case management or usual care. Case management entailed individual and group education, support, and referral by registered dietitians; intervention cost was US dollars 350 per person. Individuals treated with usual care received educational material. Both groups received ongoing primary care. Outcomes were difference between groups for change in weight (kilograms), waist circumference (centimeters), HbA(1c), fasting lipid levels, use of prescription medications, and health-related quality of life.
Case management resulted in greater weight loss (P < 0.001), reduced waist circumference (P < 0.001), reduced HbA(1c) level (P = 0.02), less use of prescription medications (P = 0.03), and improved health-related quality of life (P < 0.001) compared with usual care. The 12-month group difference in weight loss and waist circumference was 3.0 kg (95% CI -5.4 to -0.6) and -4.2 cm (-6.8 to -1.6). HbA(1c) differences were greatest at 4 months (-0.59%, P = 0.006) but not significant by 12 months (-0.19%, P = 0.45). Participants in the case management group lowered their use of medications, primarily diabetes medications, by 0.8 medications per day more than participants treated with usual care (P = 0.03). In seven of nine quality-of-life domains, the case management group improved compared with usual care (P < 0.05).
Moderate-cost dietitian-led lifestyle case management may improve diverse health indicators among obese patients with type 2 diabetes.
Abstract
We report the discovery of six ultra-faint Milky Way satellites identified through matched-filter searches conducted using Dark Energy Camera (DECam) data processed as part of the second ...data release of the DECam Local Volume Exploration (DELVE) survey. Leveraging deep Gemini/GMOS-N imaging (for four candidates) as well as follow-up DECam imaging (for two candidates), we characterize the morphologies and stellar populations of these systems. We find that these candidates all share faint absolute magnitudes (
M
V
≥ −3.2 mag) and old, metal-poor stellar populations (
τ
> 10 Gyr, Fe/H < −1.4 dex). Three of these systems are more extended (
r
1/2
> 15 pc), while the other three are compact (
r
1/2
< 10 pc). From these properties, we infer that the former three systems (Boötes V, Leo Minor I, and Virgo II) are consistent with ultra-faint dwarf galaxy classifications, whereas the latter three (DELVE 3, DELVE 4, and DELVE 5) are likely ultra-faint star clusters. Using data from the Gaia satellite, we confidently measure the proper motion of Boötes V, Leo Minor I, and DELVE 4, and tentatively detect a proper-motion signal from DELVE 3 and DELVE 5; no signal is detected for Virgo II. We use these measurements to explore possible associations between the newly discovered systems and the Sagittarius dwarf spheroidal, the Magellanic Clouds, and the Vast Polar Structure, finding several plausible associations. Our results offer a preview of the numerous ultra-faint stellar systems that will soon be discovered by the Vera C. Rubin Observatory and highlight the challenges of classifying the faintest stellar systems.
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