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排序方式: 共有298条查询结果,搜索用时 15 毫秒
41.
B Dave MD Landis LE Dobrolecki MF Wu X Zhang TF Westbrook SG Hilsenbeck D Liu MT Lewis DJ Tweardy JC Chang 《PloS one》2012,7(8):e30207
Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors. 相似文献
42.
The objective of this study was to identify subareas inside and near an Atlantic Rain Forest reserve, the Parque Estadual Turístico do Alto Ribeira (PETAR), most likely to be affected by land use in the vicinity of the area. In addition, the study aimed to compare risks per stressor source (agriculture, human settlements and mining) to both epigean (surface) and hypogean (subterranean) aquatic fauna. The methodological approach included the relative vulnerability of endpoints to the stressors (pesticides, metals, nutrients, and particles) and ranking of stressor sources and habitats (epigean and hypogean streams) based on their relative distribution in 14 subareas within the catchment areas of the main rivers that cross PETAR: Pilões, Betari and Iporanga. Four subareas presented high risk for both epigean and hypogean fauna. Three of those areas were located inside the Betari catchment area, where most of the settlements and abandoned lead mines are located. The fourth area was situated in the headwaters of the Pilões River, where agricultural activities are intense. Agriculture and human settlements were the activities most likely to cause impacts on aquatic ecosystems. Uses of risk assessment results include management of the PETAR and communication to stakeholders by the Park Administration. 相似文献
43.
Wayne G. Landis 《人类与生态风险评估》2002,8(1):193-204
Uncertainty is inherent in extrapolating from effects upon the individual to alterations in ecological structure or function. Subtle differences in individuals within a population can give rise to significant evolutionary events. Populations are part of ecological structures, systems that are clearly complex, requiring an understanding of the interacting components, stochastic inputs and spatial scales. A series of patch-dynamic models is used to illustrate the importance of spatial arrangement and initial population size in predicting effects at a landscape level. The importance of understanding the spatial structure of a population in uncertainty reduction is addressed. 相似文献
44.
Melissa A. Kacena Paul Todd Louis C. Gerstenfeld William J. Landis 《Cytotechnology》2002,39(3):147-154
Substrate attachment is crucial for normal growth and differentiation of many cell types. To better understand the role of
gravity in osteoblast attachment and growth in vitro, 17-day-old embryonic chick calvarial osteoblasts were subjected to directional variations with respect to gravity. Osteoblasts,
grown in MEM or DME supplemented with 10% FBS and attached to type I collagen-coated coverslips, were loaded into cylindrical
containers completely filled with medium and oriented so that cells were either atop or beneath, or coverslips continuously
rotated (∼2 rpm) in a clinostat, thereby continuously changing their orientation with respect to gravity. Cells in these three
conditions were collected daily for up to 6 days, and cell viability, two osteoblast functions, and proliferation were assessed.
Data suggest the number and function of attached osteoblasts is unaltered by inversion or clino-rotation in initially confluent
cultures. In sparsely plated cultures, however, osteoblast viability was significantly decreased (∼50%) in inverted and rotated
cultures during the first 3 days of sampling, but from days 4–6 no significant difference was found in viable cell number
for the three conditions. Decreases in viable cell number within the first days of the experiments could result from death
followed by detachment, detachment followed by death, differences in proliferation rate, or lag-phase duration. To help distinguish
among these, BrdU labeling for 2 or 24 hr was used to assess cell proliferation rate. Log-phase growth rates were calculated
and were unchanged among the three conditions tested. These results point to an increase in lag-phase duration in inverted
and rotated cultures. In summary, changing the cell-substrate attachment direction with respect to gravity causes an immediate
response in the form of diminished viable osteoblast number in sparse, early cultures, but the effect disappears after 3–4
days and does not occur in mature, confluent cultures.
This revised version was published online in September 2006 with corrections to the Cover Date. 相似文献
45.
Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells. To determine the contribution of Irs-2-dependent PI3K signaling to this selective regulation, we generated an Irs-2 mutant deficient in the recruitment of PI3K. We identified four tyrosine residues (Tyr-649, Tyr-671, Tyr-734, and Tyr-814) that are essential for the association of PI3K with Irs-2 and demonstrate that combined mutation of these tyrosines inhibits glucose uptake and lactate production, two measures of aerobic glycolysis. Irs-2-dependent activation of PI3K regulates the phosphorylation of specific Akt substrates, most notably glycogen synthase kinase 3β (Gsk-3β). Inhibition of Gsk-3β by Irs-2-dependent PI3K signaling promotes glucose uptake and aerobic glycolysis. The regulation of unique subsets of Akt substrates by Irs-1 and Irs-2 may explain their non-redundant roles in mammary tumor biology. Taken together, our study reveals a novel mechanism by which Irs-2 signaling preferentially regulates tumor cell metabolism and adds to our understanding of how this adaptor protein contributes to breast cancer progression. 相似文献
46.
Xiao Xiao Mei Xu Chao Yang Yao Yao Li-na Liang Philip ED Chung Qun Long Eldad Zacksenhaus Zhixu He Sheng Liu Yaacov Ben-David 《Bioorganic & medicinal chemistry》2018,26(23-24):6096-6104
Carbazole derivatives show anti-cancer activity and are of great interest for drug development. In this study, we synthesized and analyzed several new alkylamide derivatives of racemocin B, a natural indolo[3,2-a]carbazole molecule originally isolated from the green alga Caulerpa racemose. Several alkylamide derivatives were found to exhibit moderate to strong growth inhibition against human breast cancer cell lines. They induced G2/M cell cycle arrest and apoptosis in the aggressive triple-negative breast cancer cell line MDA-MB-231. Among these derivatives, compound 25 with the lowest IC50 induced cell death by suppressing autophagy. This was accompanied by inhibition of autophagic flux and accumulation of autophagy protein 1 light chain 3, LC3II, and p62. The novel alkylamide derivative offers a potential new treatment for human breast cancer. 相似文献
47.
Margaret S. Landis Shobha Bhattachar Mehran Yazdanian John Morrison 《AAPS PharmSciTech》2018,19(1):1-10
This commentary reflects the collective view of pharmaceutical scientists from four different organizations with extensive experience in the field of drug discovery support. Herein, engaging discussion is presented on the current and future approaches for the selection of the most optimal and developable drug candidates. Over the past two decades, developability assessment programs have been implemented with the intention of improving physicochemical and metabolic properties. However, the complexity of both new drug targets and non-traditional drug candidates provides continuing challenges for developing formulations for optimal drug delivery. The need for more enabled technologies to deliver drug candidates has necessitated an even more active role for pharmaceutical scientists to influence many key molecular parameters during compound optimization and selection. This enhanced role begins at the early in vitro screening stages, where key learnings regarding the interplay of molecular structure and pharmaceutical property relationships can be derived. Performance of the drug candidates in formulations intended to support key in vivo studies provides important information on chemotype-formulation compatibility relationships. Structure modifications to support the selection of the solid form are also important to consider, and predictive in silico models are being rapidly developed in this area. Ultimately, the role of pharmaceutical scientists in drug discovery now extends beyond rapid solubility screening, early form assessment, and data delivery. This multidisciplinary role has evolved to include the practice of proactively taking part in the molecular design to better align solid form and formulation requirements to enhance developability potential. 相似文献
48.
William J. Barr Amy E. Landis 《The International Journal of Life Cycle Assessment》2018,23(5):1141-1150
Purpose
The purpose of this study was to compare the environmental impacts of omega-3 fatty acid (n-3), high protein feed and biofuel production from algae to the impacts of the production of those products from fish.Methods
The functional unit was the production of one metric ton of omega-3 fatty acids from algae (fish) and the accompanying co-products of biofuel and high protein feed. This was a cradle to gate LCA. Four scenarios were used in this model. The algae multiproduct model (MPM) scenario was the baseline using only unit operations currently in use at the reference facility (Cellana LLC). A low-energy centrifuge replaced the existing conventional centrifuge (MPM (LE)) to reduce energy consumption. The MPM was improved in a different manner, employing membrane filtration prior to centrifugation (MPM (MF)). These three scenarios were compared to the conventional production of the same products from fish (conventional product model: CPM). This life cycle assessment investigated the following impacts: ozone depletion potential, global warming potential, smog formation potential, acidification potential, and eutrophication potential.Results and discussion
The environmental impacts of producing omega-3 fatty acids from algae were higher than producing omega-3 fatty acids from fish if membrane filtration was not used. Membrane filtration reduced most of the environmental impacts of the algae system by more than 50%. Fuel consumption was the only factor that caused the fish systems to change by greater than 10% from the baseline. Productivity, membrane filtration electricity, and annual operating days could each affect the environmental impacts of the algae system by greater than 10% from the baseline. Improvements to the algae system depend on improvements to cultivation and harvesting, with the impacts from processing being very small.Conclusions
This study presented results comparing the environmental impacts from a multiproduct system from algae and from fish. The results of this study can serve as a benchmark for the environmental impacts of an algal multiproduct biorefinery compared to the conventional production of those same products from fish. Areas of improvement have been identified for the algae production system for dewatering and cultivation. The amount of n-3 had little impact on the n-3 market but had a significant effect on the existing algal n-3 market. The amount of fuel and feed produced had a negligible effect on both markets.49.
Regional Ecological Risk Assessment of a Near Shore Marine Environment: Cherry Point,WA 总被引:1,自引:0,他引:1
We conducted a regional ecological risk assessment for a near shore marine environment in northwestern Washington State using the Relative Risk Model. The objectives of this study were threefold: (1) to analyze cumulative impacts from multiple sources of chemical and non-chemical stressors in the near shore region and upland watersheds of Cherry Point (2) to determine the utility of Monte Carlo type uncertainty analysis in a rank-based regional risk assessment and (3) to investigate the effects of model habitat characterization on risk estimates. We used geographic information systems to compile and compare spatial data to determine ranks for sub-regions within the study area. By quantitatively combining ranks with exposure and effects filters, we estimated total relative risk between sub-regions and relative contributions of stressors. Finally, we used Monte Carlo analysis and an alternative ranking scheme to evaluate the effects of model and parameter uncertainty on risk predictions. The regional risk assessment results suggest the major contributors of risk are vessel traffic, upland urban and agricultural land use and shoreline recreational activities. This assessment demonstrated the applicability of regional risk assessment to marine near shore regions and the benefit of Monte Carlo analysis in describing uncertainty in a Relative Risk Model regional risk assessment. 相似文献
50.
It has been 10 years since the publication of the relative risk model (RRM) for regional scale ecological risk assessment. The approach has since been used successfully for a variety of freshwater, marine, and terrestrial environments in North America, South America, and Australia. During this period the types of stressors have been expanded to include more than contaminants. Invasive species, habitat loss, stream alteration and blockage, temperature, change in land use, and climate have been incorporated into the assessments. Major developments in the RRM have included the extensive use of geographical information systems, uncertainty analysis using Monte Carlo techniques, and its application to retrospective assessments to determine causation. The future uses of the RRM include assessments for forestry and conservation management, an increasing use in invasive species evaluation, and in sustainability. Developments in risk communication, the use of Bayesian approaches, and in uncertainty analyses are on the horizon. 相似文献