Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). This review provides insights into the mode of action and the pharmacological ...properties of ATO, and summarizes the most relevant results of more than 20 treatment studies in relapsed or newly diagnosed APL published between 1997 and 2011. ATO acts by targeting multiple pathways in APL leading to apoptosis and myeloid differentiation. It induces complete remission without myelosuppression and causes only few adverse effects. In relapsed APL, ATO-based salvage therapy has been able to induce long-lasting remissions and possible cure in 50-81% of patients. In newly diagnosed APL, two main strategies are currently pursued. ATO is either included into induction therapy with the aim to minimize or eliminate chemotherapy, or it is incorporated as an additive into established first-line concepts with all-trans-retinoic acid and chemotherapy to reinforce their anti-leukemic efficacy. Recent results suggest a high efficacy of ATO in both concepts. In conclusion, experimental research and clinical studies have made contributions toward a better understanding of the molecular mechanisms induced by ATO in APL cells and have established this historic substance as an important candidate for the further improvement of APL therapy.
•Tree planting scenarios were developed to meet Baltimore’s goal of 40% tree cover.•Each scenario optimized a single ecosystem service, benefit, or proxy.•Tradeoffs between scenarios were ...evident.•Differences in ecosystem services and benefits between scenarios were quantified.•Methodology could be expanded into a decision support system for urban forestry.
Urban trees can help mitigate some of the environmental degradation linked to the rapid urbanization of humanity. Many municipalities are implementing ambitious tree planting programs to help remove air pollution, mitigate urban heat island effects, and provide other ecosystem services and benefits but lack quantitative tools to explore priority planting locations and potential tradeoffs between services. This work demonstrates a quantitative method for exploring priority planting and ecosystem service tradeoffs in Baltimore, Maryland using spatially explicit biophysical iTree models. Several planting schemes were created based on the individual optimization of a number of metrics related to services and benefits of air pollution and heat mitigation ecosystem services. The results demonstrate that different tree planting schemes would be pursued based on the ecosystem service or benefit maximized, revealing tradeoffs between services and priority planting locations. With further development including consideration of additional ecosystem services, disservices, user input, and costs of tree planting and maintenance, this approach could provide city planners, urban foresters, and members of the public with a powerful tool to better manage urban forest systems.
Second-harmonic generation (SHG) imaging can help reveal interactions between collagen fibers and cancer cells. Quantitative analysis of SHG images of collagen fibers is challenged by the ...heterogeneity of collagen structures and low signal-to-noise ratio often found while imaging collagen in tissue. The role of collagen in breast cancer progression can be assessed post acquisition via enhanced computation. To facilitate this, we have implemented and evaluated four algorithms for extracting fiber information, such as number, length, and curvature, from a variety of SHG images of collagen in breast tissue. The image-processing algorithms included a Gaussian filter, SPIRAL-TV filter, Tubeness filter, and curvelet-denoising filter. Fibers are then extracted using an automated tracking algorithm called fiber extraction (FIRE). We evaluated the algorithm performance by comparing length, angle and position of the automatically extracted fibers with those of manually extracted fibers in twenty-five SHG images of breast cancer. We found that the curvelet-denoising filter followed by FIRE, a process we call CT-FIRE, outperforms the other algorithms under investigation. CT-FIRE was then successfully applied to track collagen fiber shape changes over time in an in vivo mouse model for breast cancer.
The present contribution reviews the principle of RF separation and explains its dependence on different parameters of beam optics and hardware. The first examination of potential showstoppers for ...the RF-separated beam implementation for Phase-2 of the AMBER experiment in the M2 beam line of the North Area is presented. Different beam optics settings have been examined, providing either focused or parallel beams inside the RF cavities. The separation and transmission capability of the different optics settings for realistic characteristics of RF cavities are discussed and the preliminary results of the potential purity and intensity of the RF-separated beam are presented. These show that a trade-off between the overall beam intensity and the share of the required particle type in the overall beam needs to be established. No showstoppers have been identified for achieving the beam parameters required for AMBER’s kaonic Primakoff reactions, kaon spectroscopy, prompt-photon production and kaon charge-radius programs. However, the high beam intensity requirements of the AMBER Drell–Yan programme cannot be satisfied with an RF-separated beam.
The contribution of molecular alterations in bone marrow mesenchymal stromal cells (BM-MSC) to the pathogenesis of acute myeloid leukemia (AML) is poorly understood. Thus we assessed genome-wide ...genetic, transcriptional and epigenetic alterations in BM-MSC derived from AML patients (AML BM-MSC). Whole-exome sequencing (WES) of AML BM-MSC samples from 21 patients revealed a non-specific pattern of genetic alterations in the stromal compartment. The only mutation present in AML BM-MSC at serial time points of diagnosis, complete remission and relapse was a mutation in the PLEC gene encoding for cytoskeleton key player Plectin in one AML patient. Healthy donor controls did not carry genetic alterations as determined by WES. Transcriptional profiling using RNA sequencing revealed deregulation of proteoglycans and adhesion molecules as well as cytokines in AML BM-MSC. Moreover, KEGG pathway enrichment analysis unravelled deregulated metabolic pathways and endocytosis in both transcriptional and DNA methylation signatures in AML BM-MSC. Taken together, we report molecular alterations in AML BM-MSC suggesting global changes in the AML BM microenvironment. Extended investigations of these altered niche components may contribute to the design of niche-directed therapies in AML.
•Determination of the bioavailability of plasticizers in house dust.•Identifying house dust as an exposure source for children.•This data can help to improve risk assessments.
Phthalates and other ...plasticizers are detected in high amounts in the indoor environment and therefore house dust can be an exposure source. Especially children have a relatively high unintended uptake of house dust, thus a higher exposure to plasticizers compared to adults may be possible. As accurate as possible exposure assessment data of the oral bioavailability of these compounds are necessary, however only one in vivo study with piglets is available so far. The aim of this study was to examine the oral bioavailability of phthalates and DINCH® in humans, which occur in typical house dust samples. We focused on the high molecular weight phthalates DEHP and DINP and their substitute DINCH®. Eleven volunteers ingested 6 g of house dust sieved to 2 mm. The urine was collected over a period of 36 h. The excreted plasticizers metabolites were quantified by an LC–MS/MS method. The mean recovery of urine metabolites was 51 % ± 20 % for DEHP, 26 % ± 13 % for DINP and 19 % ± 6% for DINCH® based on the parent compounds administered as dust samples. The metabolites of DEHP, DINP and DINCH® reached their maximum concentration after 2–19 hours post dose in urine. The bioavailability of DEHP was in agreement among the different dust samples. For DEHP, we were able to confirm previous findings from the oral bioavailability study with piglets and we could not observe a significant difference between the dust particle size (65 μm vs 2 mm) and the bioavailability. Considering the observed bioavailability, an estimated dust intake of 50 mg/d for toddlers can substantially contribute to the total plasticizer exposure.
Outdoor particulate matter (PM10) is associated with detrimental health effects. However, individual PM10 exposure occurs mostly indoors. We therefore compared the toxic effects of classroom, ...outdoor, and residential PM10. Indoor and outdoor PM10 was collected from six schools in Munich during teaching hours and in six homes. Particles were analyzed by scanning electron microscopy and X‐ray spectroscopy (EDX). Toxicity was evaluated in human primary keratinocytes, lung epithelial cells and after metabolic activation by several human cytochromes P450. We found that PM10 concentrations during teaching hours were 5.6‐times higher than outdoors (117 ± 48 μg/m3 vs. 21 ± 15 μg/m3, P < 0.001). Compared to outdoors, indoor PM contained more silicate (36% of particle number), organic (29%, probably originating from human skin), and Ca‐carbonate particles (12%, probably originating from paper). Outdoor PM contained more Ca‐sulfate particles (38%). Indoor PM at 6 μg/cm2 (10 μg/ml) caused toxicity in keratinocytes and in cells expressing CYP2B6 and CYP3A4. Toxicity by CYP2B6 was abolished with the reactive oxygen species scavenger N‐acetylcysteine. We concluded that outdoor PM10 and indoor PM10 from homes were devoid of toxicity. Indoor PM10 was elevated, chemically different and toxicologically more active than outdoor PM10. Whether the effects translate into a significant health risk needs to be determined. Until then, we suggest better ventilation as a sensible option.
Practical Implications
Indoor air PM10 on an equal weight base is toxicologically more active than outdoor PM10. In addition, indoor PM10 concentrations are about six times higher than outdoor air. Thus, ventilation of classrooms with outdoor air will improve air quality and is likely to provide a health benefit. It is also easier than cleaning PM10 from indoor air, which has proven to be tedious.
A comprehensive collection of results on longitudinal double-spin asymmetries is presented for charged pions and kaons produced in semi-inclusive deep-inelastic scattering of electrons and positrons ...on the proton and deuteron, based on the full HERMES data set. The dependence of the asymmetries on hadron transverse momentum and azimuthal angle extends the sensitivity to the flavor structure of the nucleon beyond the distribution functions accessible in the collinear framework. No strong dependence on those variables is observed. In addition, the hadron charge-difference asymmetry is presented, which under certain model assumptions provides access to the helicity distributions of valence quarks.
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