A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy

BACKGROUND: The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available. METHODS: We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents. RESULTS: Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol. CONCLUSIONS: Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients

Ocean heat uptake processes: a model intercomparison

We compare the quasi-equilibrium heat balances, as well as their responses to 4×CO2 perturbation, among three global climate models with the aim to identify and explain inter-model differences in ocean heat uptake (OHU) processes. We find that, in quasi-equilibrium, convective and mixed layer processes, as well as eddy-related processes, cause cooling of the subsurface ocean. The cooling is balanced by warming caused by advective and diapycnally diffusive processes. We also find that in the CO2-perturbed climates the largest contribution to OHU comes from changes in vertical mixing processes and the mean circulation, particularly in the extra-tropics, caused both by changes in wind forcing, and by changes in high-latitude buoyancy forcing. There is a substantial warming in the tropics, a significant part of which occurs because of changes in horizontal advection in extra-tropics. Diapycnal diffusion makes only a weak contribution to the OHU, mainly in the tropics, due to increased stratification. There are important qualitative differences in the contribution of eddy-induced advection and isopycnal diffusion to the OHU among the models. The former is related to the different values of the coefficients used in the corresponding scheme. The latter is related to the different tapering formulations of the isopycnal diffusion scheme. These differences affect the OHU in the deep ocean, which is substantial in two of the models, the dominant region of deep warming being the Southern Ocean. However, most of the OHU takes place above 2000 m, and the three models are quantitatively similar in their global OHU efficiency and its breakdown among processes and as a function of latitude

The influence of eddy parameterizations on the transport of the Antarctic Circumpolar Current in coupled climate models

The transport of the Antarctic Circumpolar Current (ACC) varies strongly across the coupled GCMs (general circulation models) used for the IPCC AR4. This note shows that a large fraction of this across-model variance can be explained by relating it to the parameterization of eddy-induced transports. In the majority of models this parameterization is based on the study by Gent and McWilliams (1990). The main parameter is the quasi-Stokes diffusivity kappa (often referred to less accurately as ’’thickness diffusion’’). The ACC transport and the meridional density gradient both correlate strongly with kappa across those models where kappa is a prescribed constant. In contrast, there is no correlation with the isopycnal diffusivity jiso across the models. The sensitivity of the ACC transport to kappa is larger than to the zonal wind stress maximum. Experiments with the fast GCM FAMOUS show that changing kappa directly affects the ACC transport by changing the density structure throughout the water column. Our results suggest that this limits the role of the wind stress magnitude in setting the ACC transport in FAMOUS. The sensitivities of the ACC and the meridional density gradient are very similar across the AR4 GCMs (for those models where kappa is a prescribed constant) and among the FAMOUS experiments. The strong sensitivity of the ACC transport to kappa needs careful assessment in climate models

Improved climate simulations through a stochastic parameterization of ocean eddies

In climate simulations, the impacts of the sub-grid scales on the resolved scales are conventionally represented using deterministic closure schemes, which assume that the impacts are uniquely determined by the resolved scales. Stochastic parameterization relaxes this assumption, by sampling the sub-grid variability in a computationally inexpensive manner. This study shows that the simulated climatological state of the ocean is improved in many respects by implementing a simple stochastic parameterization of ocean eddies into a coupled atmosphere–ocean general circulation model. Simulations from a high-resolution, eddy-permitting ocean model are used to calculate the eddy statistics needed to inject realistic stochastic noise into a low-resolution, non-eddy-permitting version of the same model. A suite of four stochastic experiments is then run to test the sensitivity of the simulated climate to the noise definition, by varying the noise amplitude and decorrelation time within reasonable limits. The addition of zero-mean noise to the ocean temperature tendency is found to have a non-zero effect on the mean climate. Specifically, in terms of the ocean temperature and salinity fields both at the surface and at depth, the noise reduces many of the biases in the low-resolution model and causes it to more closely resemble the high-resolution model. The variability of the strength of the global ocean thermohaline circulation is also improved. It is concluded that stochastic ocean perturbations can yield reductions in climate model error that are comparable to those obtained by refining the resolution, but without the increased computational cost. Therefore, stochastic parameterizations of ocean eddies have the potential to significantly improve climate simulations

Implementation and evaluation of the new wind algorithm in NASA's 50 MHz doppler radar wind profiler

The purpose of this report is to document the Applied Meteorology Unit's implementation and evaluation of the wind algorithm developed by Marshall Space Flight Center (MSFC) on the data analysis processor (DAP) of NASA's 50 MHz doppler radar wind profiler (DRWP). The report also includes a summary of the 50 MHz DRWP characteristics and performance and a proposed concept of operations for the DRWP

The Association Between Sedentary Behaviors During Weekdays and Weekend with Change in Body Composition in Young Adults

Background: High sedentary time has been considered an important chronic disease risk factor but there is only limited information on the association of specific sedentary behaviors on weekdays and weekend-days with body composition. The present study examines the prospective association of total sedentary time and specific sedentary behaviors during weekdays and the weekend with body composition in young adults. Methods: A total of 332 adults (50% male; 27.7 ±3.7 years) were followed over a period of 1 year. Time spent sedentary, excluding sleep (SED), and in physical activity (PA) during weekdays and weekend-days was objectively assessed every 3 months with a multisensor device over a period of at least 8 days. In addition, participants reported sitting time, TV time and non-work related time spent at the computer separately for weekdays and the weekend. Fat mass and fat free mass were assessed via dual x-ray absorptiometry and used to calculate percent body fat (%BF). Energy intake was estimated based on TDEE and change in body composition. Results: Cross-sectional analyses showed a significant correlation between SED and body composition (0.18 ≤ r ≤ 0.34). Associations between body weight and specific sedentary behaviors were less pronounced and significant during weekdays only (r ≤ 0.16). Nevertheless, decrease in SED during weekends, rather than during weekdays, was significantly associated with subsequent decrease in %BF (β = 0.06, p \u3c0.01). After adjusting for PA and energy intake, results for SED were no longer significant. Only the association between change in sitting time during weekends and subsequent %BF was independent from change in PA or energy intake (β%BF = 0.04, p = 0.01), while there was no significant association between TV or computer time and subsequent body composition. Conclusions: The stronger AIMS Public Health Volume 3, Issue 2, 375-388. prospective association between sedentary behavior during weekends with subsequent body composition emphasizes the importance of leisure time behavior in weight management

Stroke impact on mortality and psychologic morbidity within the Childhood Cancer Survivor Study.

BackgroundPoor socioeconomic and health-related quality of life (HRQOL) outcomes in survivors of childhood cancer can lead to distress and overall negatively impact the lives of these individuals. The current report has highlighted the impact of stroke and stroke recurrence on mortality, psychological HRQOL, and socioeconomic outcomes within the Childhood Cancer Survivor Study (CCSS).MethodsThe CCSS is a retrospective cohort study with longitudinal follow-up concerning survivors of pediatric cancer who were diagnosed between 1970 and 1986. Mortality rates per 100 person-years were calculated across 3 periods: 1) prior to stroke; 2) after first stroke and before recurrent stroke; and 3) after recurrent stroke. Socioeconomic outcomes, the standardized Brief Symptoms Inventory-18, the Medical Outcomes Study 36-Item Short Form Health Survey, and the CCSS-Neurocognitive Questionnaire also were assessed.ResultsAmong 14,358 participants (median age, 39.7 years), 224 had a stroke after their cancer diagnosis (single stroke in 161 patients and recurrent stroke in 63 patients). Based on 2636 deaths, all-cause late mortality rates were 0.70 (95% CI, 0.68-0.73) prior to stroke, 1.03 (95% CI, 0.73-1.46) after the first stroke, and 2.42 (95% CI, 1.48-3.94) after the recurrent stroke. Among 7304 survivors, those with stroke were more likely to live with a caregiver (single stroke odds ratio [OR], 2.3 [95% CI, 1.4-3.8]; and recurrent stroke OR, 5.3 [95% CI, 1.7-16.8]) compared with stroke-free survivors. Stroke negatively impacted task efficiency (single stroke OR, 2.4 [95% CI, 1.4-4.1] and recurrent stroke OR, 3.3 [95% CI, 1.1-10.3]) and memory (single stroke OR, 2.1 [95% CI, 1.2-3.7]; and recurrent stroke OR, 3.5 [95% CI, 1.1-10.5]).ConclusionsStroke and stroke recurrence are associated with increased mortality and negatively impact HRQOL measures in survivors of pediatric cancer

The Association Between Sedentary Behaviors During Weekdays and Weekend with Change in Body Composition in Young Adults

Background: High sedentary time has been considered an important chronic disease risk factor but there is only limited information on the association of specific sedentary behaviors on weekdays and weekend-days with body composition. The present study examines the prospective association of total sedentary time and specific sedentary behaviors during weekdays and the weekend with body composition in young adults. Methods: A total of 332 adults (50% male; 27.7 ±3.7 years) were followed over a period of 1 year. Time spent sedentary, excluding sleep (SED), and in physical activity (PA) during weekdays and weekend-days was objectively assessed every 3 months with a multisensor device over a period of at least 8 days. In addition, participants reported sitting time, TV time and non-work related time spent at the computer separately for weekdays and the weekend. Fat mass and fat free mass were assessed via dual x-ray absorptiometry and used to calculate percent body fat (%BF). Energy intake was estimated based on TDEE and change in body composition. Results: Cross-sectional analyses showed a significant correlation between SED and body composition (0.18 ≤ r ≤ 0.34). Associations between body weight and specific sedentary behaviors were less pronounced and significant during weekdays only (r ≤ 0.16). Nevertheless, decrease in SED during weekends, rather than during weekdays, was significantly associated with subsequent decrease in %BF (β = 0.06, p \u3c0.01). After adjusting for PA and energy intake, results for SED were no longer significant. Only the association between change in sitting time during weekends and subsequent %BF was independent from change in PA or energy intake (β%BF = 0.04, p = 0.01), while there was no significant association between TV or computer time and subsequent body composition. Conclusions: The stronger AIMS Public Health Volume 3, Issue 2, 375-388. prospective association between sedentary behavior during weekends with subsequent body composition emphasizes the importance of leisure time behavior in weight management

Preliminary Design of the SAFE Platform

SAFE is a clean-slate design for a secure host architecture. It integrates advances in programming languages, operating systems, and hardware and incorporates formal methods at every step. Though the project is still at an early stage, we have assembled a set of basic architectural choices that we believe will yield a high-assurance system. We sketch the current state of the design and discuss several of these choices.Engineering and Applied Science

Free-living dietary intake in tactical personnel and implications for nutrition practice: a systematic review

Tactical personnel (including military, law enforcement, and fire and rescue) are responsible for ensuring national and public safety. Dietary intake is an important consideration to support optimal health and performance. The aims of this systematic review were to: (1) describe the reported free-living dietary intake (energy and macronutrients) of tactical personnel, and (2) describe the practical implications of reported dietary intakes to support the physical and dietary requirements of tactical personnel. A systematic search of databases (MEDLINE, EMBASE, CINAHL and Web of Science) was conducted following the PRISMA guidelines. English and full text research articles were identified and screened against inclusion and exclusion criteria. Demographic and dietary intake data were extracted, tabulated, and synthesized narratively. The quality of the studies was assessed using the Academy of Nutrition and Dietetics Quality Criteria Checklist. Twenty-two studies (15 military, 4 law enforcement, and 2 fire and rescue) were eligible to inform this review. The volume of evidence suggested that tactical personnel met dietary protein and exceeded dietary fat recommendations but failed to meet energy and carbohydrate recommendations. Therefore, practical approaches to support optimized energy, fat and carbohydrate intake in tactical personnel is important