Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice

INTRODUCTION Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. METHODS Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues. RESULTS Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors. CONCLUSION Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.This work was supported by grants from the US Army Medical Research and Materiel Command (W81XWH0410385 to KAD and DAMD17-01-1-0315 to ACB) and the National Institutes of Health (RO1-CA095164 to DJJ)

MODIS NDVI Change Detection Techniques and Products Used in the Near Real Time ForWarn System for Detecting, Monitoring, and Analyzing Regional Forest Disturbances

This presentation discusses MODIS NDVI change detection methods and products used in the ForWarn Early Warning System (EWS) for near real time (NRT) recognition and tracking of regionally evident forest disturbances throughout the conterminous US (CONUS). The latter has provided NRT forest change products to the forest health protection community since 2010, using temporally processed MODIS Aqua and Terra NDVI time series data to currently compute and post 6 different forest change products for CONUS every 8 days. Multiple change products are required to improve detectability and to more fully assess the nature of apparent disturbances. Each type of forest change product reports per pixel percent change in NDVI for a given 24 day interval, comparing current versus a given historical baseline NDVI. EMODIS 7 day expedited MODIS MOD13 data are used to obtain current and historical NDVIs, respectively. Historical NDVI data is processed with Time Series Product Tool (TSPT); and 2) the Phenological Parameters Estimation Tool (PPET) software. While each change products employ maximum value compositing (MVC) of NDVI, the design of specific products primarily differs in terms of the historical baseline. The three main change products use either 1, 3, or all previous years of MVC NDVI as a baseline. Another product uses an Adaptive Length Compositing (ALC) version of MVC to derive an alternative current NDVI that is the freshest quality NDVI as opposed to merely the MVC NDVI across a 24 day time frame. The ALC approach can improve detection speed by 8 to 16 days. ForWarn also includes 2 change products that improve detectability of forest disturbances in lieu of climatic fluctuations, especially in the spring and fall. One compares current MVC NDVI to the zonal maximum under the curve NDVI per pheno-region cluster class, considering all previous years in the MODIS record. The other compares current maximum NDVI to the mean of maximum NDVI for all previous MODIS years

Role of MODIS Vegetation Phenology Products in the ForWarn System for Monitoring of Forest Disturbances in the Conterminous United States

This presentation discusses MODIS vegetation phenology products used in the ForWarn Early Warning System (EWS) tool for near real time regional forest disturbance detection and surveillance at regional to national scales. The ForWarn EWS is being developed by the USDA Forest Service NASA, ORNL, and USGS to aid federal and state forest health management activities. ForWarn employs multiple historical land surface phenology products that are derived from MODIS MOD13 Normalized Difference Vegetation Index (NDVI) data. The latter is temporally processed into phenology products with the Time Series Product Tool (TSPT) and the Phenological Parameter Estimation Tool (PPET) software produced at NASA Stennis Space Center. TSPT is used to effectively noise reduce, fuse, and void interpolate MODIS NDVI data. PPET employs TSPT-processed NDVI time series data as an input, outputting multiple vegetation phenology products at a 232 meter resolution for 2000 to 2011, including NDVI magnitude and day of year products for seven key points along the growing season (peak of growing season and the minima, 20%, and 80% of the peak NDVI for both the left and right side of growing season), cumulative NDVI integral products for the most active part of the growing season and sequentially across the growing season at 8 day intervals, and maximum value NDVI products composited at 24 day intervals in which each product date has 8 days of overlap between the previous and following product dates. MODIS NDVI phenology products are also used to compute nationwide NRT forest change products refreshed every 8 days. These include percent change in forest NDVI products that compare the current NDVI from USGS eMODIS products to historical MODIS MOD13 NDVI. For each date, three forest change products are produced using three different maximum value NDVI baselines (from the previous year, three previous years, and all previous years). All change products are output with a rainbow color table in which forests with the most severe NDVI decreases are assigned hot colors (yellow to red) and forests with prominent NDVI increases are assigned cold colors (blue tones). All mentioned products have been integrated as data layers into ForWarn s geospatial data viewer known as the U.S. Forest Change Assessment Viewer (FCAV). The latter is used to view and assess the context of the mentioned forest change products with respect to ancillary data layers, such as land cover, elevation, hydrologic features, climatic data, storm data, aerial disturbance surveys, fire data, and land ownership. The FCAV also includes a temporal NDVI profiler for viewing phenological change in multi-year NDVI associated with known or suspected regionally apparent forest disturbances (e.g., from fire and insects). ForWarn forest change products have been used to detect, track, and assess several biotic and abiotic regional forest disturbance events across the country, including ephemeral and longer lasting damage from storms, drought, and insects. Such change products are most effective for viewing severe disturbances affecting multiple MODIS pixels. MODIS vegetation phenology products contribute vital current information on forest conditions to the ForWarn system and this role is expected to grow as these products are refined and derivative products are added

Roles for estrogen and progesterone in breast cancer prevention

Prevention has long been the holy grail of breast cancer research. The significant reduction in breast cancer risk afforded by a full-term pregnancy early in life suggests the great potential of preventive strategies. In contrast to the risks associated with prolonged exposures, exogenous estrogen and progesterone for short durations can mimic the protective effects of pregnancy in carcinogen-induced mammary tumor models. Rajkumar and coworkers have now demonstrated that these hormones protect mice from mammary tumors initiated by a spectrum of oncogenic alterations that are common in breast cancers. Although differences between rodent models and humans remain, the results reveal that exogenous estrogen and progesterone potently inhibit tumorigenesis through multiple pathways and establish a foundation for strategies to prevent breast cancer

Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients The ROADMAP Study 2-Year Results

OBJECTIVES The authors sought to provide the pre-specified primary endpoint of the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) trial at 2 years. BACKGROUND The ROADMAP trial was a prospective nonrandomized observational study of 200 patients (97 with a left ventricular assist device [LVAD], 103 on optimal medical management [OMM]) that showed that survival with improved functional status at 1 year was better with LVADs compared with OMM in a patient population of ambulatory New York Heart Association functional class IIIb/IV patients. METHODS The primary composite endpoint was survival on original therapy with improvement in 6-min walk distance \u3e= 75 m. RESULTS Patients receiving LVAD versus OMM had lower baseline health-related quality of life, reduced Seattle Heart Failure Model 1-year survival (78% vs. 84%; p = 0.012), and were predominantly INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 4 (65% vs. 34%; p \u3c 0.001) versus profiles 5 to 7. More LVAD patients met the primary endpoint at 2 years: 30% LVAD versus 12% OMM (odds ratio: 3.2 [95% confidence interval: 1.3 to 7.7]; p = 0.012). Survival as treated on original therapy at 2 years was greater for LVAD versus OMM (70 +/- 5% vs. 41 +/- 5%; p \u3c 0.001), but there was no difference in intent-to-treat survival (70 +/- 5% vs. 63 +/- 5%; p = 0.307). In the OMM arm, 23 of 103 (22%) received delayed LVADs (18 within 12 months; 5 from 12 to 24 months). LVAD adverse events declined after year 1 for bleeding (primarily gastrointestinal) and arrhythmias. CONCLUSIONS Survival on original therapy with improvement in 6-min walk distance was superior with LVAD compared with OMM at 2 years. Reduction in key adverse events beyond 1 year was observed in the LVAD group. The ROADMAP trial provides risk-benefit information to guide patient- and physician-shared decision making for elective LVAD therapy as a treatment for heart failure. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients [ROADMAP]; NCT01452802

Biobehavioral effects of Tai Chi Qigong in men with prostate cancer: Study design of a three-arm randomized clinical trial.

Fatigue is often one of the most commonly reported symptoms in prostate cancer survivors, but it is also one of the least understood cancer-related symptoms. Fatigue is associated with psychological distress, disruptions in sleep quality, and impairments in health-related quality of life. Moreover, inflammatory processes and changes related to the hypothalamic-pituitary-adrenal (HPA) axis and/or autonomic nervous system may also play a role in cancer-related fatigue. Thus, effective treatments for fatigue in prostate cancer survivors represent a current unmet need. Prior research has shown that Tai Chi Qigong, a mind-body exercise intervention, can improve physical and emotional health. Herein, we describe the protocol of the ongoing 3-arm randomized controlled Health Empowerment & Recovery Outcomes (HERO) clincal trial. One hundred sixty-six prostate cancer survivors with fatigue are randomized to a modified Tai Chi Qigong intervention (TCQ), intensity-matched body training intervention (BT), or usual care (UC) condition. Guided by biopsychosocial and psychoneuroimmunology models, we propose that TCQ, as compared to BT or UC will: i) reduce fatigue (primary outcome) in prostate cancer survivors; ii) reduce inflammation; and iii) regulate the expression of genes from two major functional clusters: a) inflammation, vasodilation and metabolite sensing and b) energy and adrenergic activation. Assessments are conducted at baseline, the 6-week midpoint of the intervention, and 1 week, 3 months, and 12 months post-intervention. If our findings show that TCQ promotes recovery from prostate cancer and its treatment, this type of intervention can be integrated into survivorship care plans as the standard of care. The study's findings will also provide novel information about underlying biobehavioral mechanisms of cancer-related fatigue. Trial registration number:NCT03326713; clinicaltrials.gov