Sensitization of renal carcinoma cells to TRAIL-induced apoptosis by rocaglamide and analogs

Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells. Rocaglamide alone induced cell cycle arrest, but not apoptosis. Rocaglates averaged 4–5-fold higher potency as TRAIL sensitizers than as protein synthesis inhibitors suggesting a potential window for maximizing TRAIL sensitization while minimizing effects of general protein synthesis inhibition. A wide range of other rocaglate effects (e.g. on JNK or RAF-MEK-ERK signaling, death receptor levels, ROS, ER stress, eIF4E phosphorylation) were assessed, but did not contribute to TRAIL sensitization. Other than a rapid loss of MCL-1, rocaglates had minimal effects on mitochondrial apoptotic pathway proteins. The identification of structurally diverse/mechanistically similar TRAIL sensitizing rocaglates provides insights into both rocaglate structure and function and potential further development for use in RCC-directed combination therapy.This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research. Research performed at Boston University was supported in part by NIH R35 GM118173. Work at the BU-CMD is supported by R24 GM111625. (HHSN261200800001E - National Cancer Institute, National Institutes of Health; Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research; R35 GM118173 - NIH; R24 GM111625)Published versio

Critical Issues for Psychiatric Medication Shared Decision Making With Youth and Families

This is the publisher's version, also found here: http://doi.org/10.1606/1044-3894.4135The primary aims of this article are to describe the current context for youth shared decision making (SDM) within the U.S. children’s mental health system and to identify important considerations for the development of this approach as a research and service domain. The notion is substantiated in the literature that participation in treatment decisions can prepare youth for making their own decisions as adults, can be therapeutic, and can have positive effects on their self-confidence and self-esteem. Still, the complex youth–family–provider dynamic raises important issues that need to be addressed before SDM can be successfully implemented

No Association of Obesity and Type 2 Diabetes Mellitus Related Genetic Variants With Colon Cancer

Background: Obesity and type 2 diabetes mellitus (T2D) are known risk factors for colon cancer. Recent reports from a number of genome wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with obesity and T2D. Here we tested the hypothesis that these SNPs may also be associated with risk of colon cancer. Methods: We genotyped nine SNPs reported in GWAS of obesity and/or T2D, including SNPs in HHEX, KCNJ11, SLC30A8, FTO, CDKN2, CDKAL1, TCF2, and the rs9300039 SNP in an intergenic region, in 561 colon cancer cases and 721 population controls. Results: None of these SNPs were statistically significantly associated with colon cancer in our sample. Conclusions: Overall, these results suggest that these obesity and T2D genetic susceptibility loci are unlikely to influence the risk of colon cancer

Characterization of Surface Geology and Hydrogeology in the Upper Ulua River Basin, Honduras

This research includes a hydrogeologic assessment in and around La Union, Honduras to determine the contribution of groundwater to the surface water system and understand the geological control of groundwater storage and movement. Field methods were employed and focused on spring characterization, geochemical signatures, and structural data. Field data was gathered, and locations determined using cellular-integrated GPS signal and the Fulcrum mapping software mobile application. During the summer of 2017, data on 111 geologic points and 34 water points were collected to understand the hydrogeology of the region. Streams and springs were monitored for pH, flow characteristics and conductance as a measure of total-dissolved-solids (TDS). TDS ranged from 22.6 to 485 mg/L with higher values indicating groundwater influx into the surface system. In comparison, lower TDS values are attributed to runoff. Structural information was collected using a Brunton transit compass for strike and dip of lithologic contacts. Structural trends include strikes around 240 degrees, dip direction and approximate magnitudes at 330 and 40 degrees, respectively. Geologic data indicate significant structural deformation, supportive of tectonic activity in the region. For many of the springs in this area, the data can be used to interpret that water is stored in the Jaitique Formation as a perched aquifer controlled by stratigraphy and structure. The groundwater moves down dip through secondary porosity in the Jaitique Formation until it comes into contact with the Lower Valle de Angeles. This Lower Valle de Angeles unit acts as an aquiclude preventing percolation into the ground and resulting in springs at the surface

Tumor-infiltrating lymphocytes: Streamlining a complex manufacturing process

Adoptive cell therapy of tumor-infiltrating lymphocytes has shown promise for treatment of refractory melanoma and other solid malignancies; however, challenges to manufacturing have limited its widespread use. Traditional manufacturing efforts were lengthy, cumbersome and used open culture systems. We describe changes in testing and manufacturing that decreased the process cycle time, enhanced the robustness of critical quality attribute testing and facilitated a functionally closed system. These changes have enabled export of the manufacturing process to support multi-center clinical trials

Facing the Facets: No Association Between Dispositional Mindfulness Facets and Positive Momentary Stress Responses During Active Stressors

Mindfulness has been associated with enhanced coping with stress. However, it remains unclear how dispositional mindfulness impacts the nature and valence of experiences during active stressors. Across 1,001 total participants, we used cardiovascular responses from the biopsychosocial model of challenge/threat to assess the degree to which individuals cared about a stressor in the moment and had a positive versus negative psychological experience. Although we found a small association between mindfulness—particularly the acting with awareness facet—and responses consistent with caring more about the stressor(i.e., greater task engagement), we found no evidence that mindfulness was associated with exhibiting a more positive psychological response (i.e., greater challenge)during the stressor. Despite no differences in the valence of momentary experiences as a function of mindfulness, individuals higher in mindfulness self-reported more positive experiences afterward. These findings suggest that dispositional mindfulness may benefit responses to active stressors only after they have passed

Ecology of the Invasive Red Alga Gracilaria salicornia (Rhodophyta) on O'ahu, Hawai'i

The red alga Gracilaria salicornia (C. Agardh) E. Y. Dawson was introduced intentionally to two reefs on O'ahu, Hawai'i, in the 1970s for experimental aquaculture for the agar industry. Some 30 yr later, this species has spread from the initial sites of introduction and is now competing with native marine flora and fauna. The goals of this study were to quantify various aspects of G. salicornia ecology in Hawai'i in an effort to develop control or eradication tools. Experimental plots were established to determine cover and biomass of G. salicornia per square meter and to determine the amount of time and person hours needed to remove G. salicornia from these plots. Substantial amounts of G. salicornia become dislodged from the reef during large wave events and periodically become deposited onto the beach in front of the Waikiki Aquarium. Algal beach wash biomass was quantified and positive relationships were established between swell height and the amount of algae that washed up onto the beach in this location. We then quantified the ability of G. salicornia vegetative fragments to regrow after desiccation to determine if algal biomass stranded on shore survives the tidal cycle until being washed back out on the reef at high tide. Gracilaria salicornia was remarkably resistant to temperature, salinity, and chemical treatments examined as possible in situ control options. Herbivore preference tests showed that a native Gracilaria species is consumed far more frequently than the alien congener. Finally, large-scale community volunteer efforts were organized to remove drifting G. salicornia fragments from the reef area in front of the Waikiki Aquarium. Over 20,000 kg of alien algal fragments were removed from this location in five 4-hr cleanup events. However, based on G. salicornia growth rates, ability to fragment, physical tolerance, and low herbivory, it is clear that a large-scale dedicated effort will be needed to control this invasive species on Waikiki's reefs

Estradiol effects on the dopamine transporter – protein levels, subcellular location, and function

BACKGROUND: The effects of estrogens on dopamine (DA) transport may have important implications for the increased incidence of neurological disorders in women during life stages when hormonal fluctuations are prevalent, e.g. during menarche, reproductive cycling, pregnancy, and peri-menopause. RESULTS: The activity of the DA transporter (DAT) was measured by the specific uptake of (3)H-DA. We found that low concentrations (10(-14 )to 10(-8 )M) of 17β-estradiol (E(2)) inhibit uptake via the DAT in PC12 cells over 30 minutes, with significant inhibition taking place due to E(2 )exposure during only the last five minutes of the uptake period. Such rapid action suggests a non-genomic, membrane-initiated estrogenic response mechanism. DAT and estrogen receptor-α (ERα) were elevated in cell extracts by a 20 ng/ml 2 day NGFβ treatment, while ERβ was not. DAT, ERα and ERβ were also detectable on the plasma membrane of unpermeabilized cells by immunocytochemical staining and by a fixed cell, quantitative antibody (Ab)-based plate assay. In addition, PC12 cells contained RNA coding for the alternative membrane ER GPR30; therefore, all 3 ER subtypes are candidates for mediating the rapid nongenomic actions of E(2). At cell densities above 15,000 cells per well, the E(2)-induced inhibition of transport was reversed. Uptake activity oscillated with time after a 10 nM E(2 )treatment; in a slower room temperature assay, inhibition peaked at 9 min, while uptake activity increased at 3 and 20–30 min. Using an Ab recognizing the second extracellular loop of DAT (accessible only on the outside of unpermeabilized cells), our immunoassay measured membrane vs. intracellular/nonvesicular DAT; both were found to decline over a 5–60 min E(2 )treatment, though immunoblot analyses demonstrated no total cellular loss of protein. CONCLUSION: Our results suggest that physiological levels of E(2 )may act to sequester DAT in intracellular compartments where the transporter's second extramembrane loop is inaccessible (inside vesicles) and that rapid estrogenic actions on this differentiated neuronal cell type may be regulated via membrane ERs of several types

Post Irradiation Evaluation of Thermal Control Coatings and Solid Lubricants to Support Fission Surface Power Systems

The development of a nuclear power system for space missions, such as the Jupiter Icy Moons Orbiter or a lunar outpost, requires substantially more compact reactor design than conventional terrestrial systems. In order to minimize shielding requirements and hence system weight, the radiation tolerance of component materials within the power conversion and heat rejection systems must be defined. Two classes of coatings, thermal control paints and solid lubricants, were identified as material systems for which limited radiation hardness information was available. Screening studies were designed to explore candidate coatings under a predominately fast neutron spectrum. The Ohio State Research Reactor Facility staff performed irradiation in a well characterized, mixed energy spectrum and performed post irradiation analysis of representative coatings for thermal control and solid lubricant applications. Thermal control paints were evaluated for 1 MeV equivalent fluences from 10(exp 13) to 10(exp 15) n per square centimeters. No optical degradation was noted although some adhesive degradation was found at higher fluence levels. Solid lubricant coatings were evaluated for 1 MeV equivalent fluences from 10(exp 15) to 10(exp 16) n per square centimeters with coating adhesion and flexibility used for post irradiation evaluation screening. The exposures studied did not lead to obvious property degradation indicating the coatings would have survived the radiation environment for the previously proposed Jupiter mission. The results are also applicable to space power development programs such as fission surface power for future lunar and Mars missions