Current evidence indicates that a stem cell-like sub-population within malignant glioblastomas, that overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters, is ...responsible for multidrug resistance and tumour relapse. Eradication of the brain tumour stem cell (BTSC) compartment is therefore essential to achieve a stable and long-lasting remission.
Melatonin actions were analysed by viability cell assays, flow cytometry, quantitative PCR for mRNA expression, western blot for protein expression and quantitative and qualitative promoter methylation methods.
Combinations of melatonin and chemotherapeutic drugs (including temozolomide, current treatment for malignant gliomas) have a synergistic toxic effect on BTSCs and A172 malignant glioma cells. This effect is correlated with a downregulation of the expression and function of the ABC transporter ABCG2/BCRP. Melatonin increased the methylation levels of the ABCG2/BCRP promoter and the effects on ABCG2/BCRP expression and function were prevented by preincubation with a DNA methyltransferase inhibitor.
Our results point out a possible relationship between the downregulation of ABCG2/BCRP function and the synergistic toxic effect of melatonin and chemotherapeutic drugs. Melatonin could be a promising candidate to overcome multidrug resistance in the treatment of glioblastomas, and thus improve the efficiency of current therapies.
Operation of distributed energy resources and resilience related problems are becoming of most importance in the pursuit for a more sustainable electricity delivery. Microgrids (MGs) could contribute ...significantly to both issues and may play an important role in the new decentralized paradigm of power systems. This paper proposes a hierarchical organizational scheme of MGs with a clear distinction of the Microgrid, Nanogrid and Picogrid concepts, and addresses a detailed technical literature review to identify and classify MGs main features and design alternatives. Definitions; descriptions of MGs, Nanogrids, Picogrids; operation modes; business models and communication protocols are dispersed in the literature. In order to gather clearly all the existing information, this review has been organized according to four functional layers, inspired by the ones commonly used in Smart Grid architecture description. For each one and whenever possible, the paper classifies the outcomes of the review in a table kind of format that helps summarizing the different MGs׳ options. Regarding the first layer, the paper describes the different physical devices involved in MGs, such as generators, converters, electric vehicles (EV) and energy storage systems (DS) and the DC levels that are being discussed. For the second layer the paper addresses a review of the communication protocols currently used or proposed. Then, the intelligence layer is analyzed concerning any decision making issue related to operation and planning of the MGs as well as any other aspect that may be relevant for taking advantage of MGs potentiality. In the last layer, the paper reviews different business models adapted to a future where MGs will be deployed. Finally, the paper ends with an exhaustive review of the practical MG experiences in place worldwide, classified according to the issues presented previously, and a brief discussion of the key points to be addressed in the MGs deployment.
Chemotherapy remains as the only systemic treatment option available for basal-like breast cancer (BC) patients. Preclinical models and several phase II studies suggested that platinum salts are ...active drugs in this BC subtype though there is no randomized study supporting this hypothesis. This study investigates if the addition of carboplatin to a combination of an alkylating agent together with anthracyclines and taxanes is able to increase the efficacy in the neoadjuvant treatment context. Patients with operable breast cancer and immunophenotypically defined basal-like disease (ER-/PR-/HER2- and cytokeratin 5/6+ or EGFR+) were recruited. Patients were randomized to receive EC (epirubicin 90 mg/m
2
plus cyclophosphamide 600 mg/m
2
for 4 cycles) followed either by D (docetaxel 100 mg/m
2
× 4 cycles; EC–D) or DCb (docetaxel 75 mg/m
2
plus carboplatin AUC 6 × 4 cycles; EC–DCb). The primary end point was pathological complete response (pCR) in the breast following the Miller and Payne criteria. Ninety-four patients were randomized (46 EC–D, 48 EC–DCb). pCR rate in the breast was seen in 16 patients (35 %) with EC–D and 14 patients (30 %) with EC–DCb (
P
value = 0.61). pCR in the breast and axilla was seen in 30 % of patients in both arms. The overall clinical response rate was 70 % (95 % CI 56–83) in the EC–D arm and 77 % (95 % CI 65–87) in the EC–DCb arm. Grade 3/4 toxicity was similar in both arms. The addition of carboplatin to conventional chemotherapy with EC–D in basal-like breast cancer patients did not improve the efficacy probably because they had already received an alkylating agent. These findings should be taken into consideration when developing new agents for this disease.
Inflammatory breast cancer (IBC) is a rare, but aggressive entity of breast carcinoma with rapid dermal lymphatic invasion in young females. It is either poorly or misdiagnosed as mastitis because of ...the absence of a distinct lump. Small extracellular vesicles (sEVs) circulating in liquid biopsies are a novel class of minimally invasive diagnostic alternative to invasive tissue biopsies. They modulate cancer progression via shuttling their encapsulated cargo including microRNAs (miRNAs) into recipient cells to either trigger signaling or induce malignant transformation of targeted cells. Plasma sEVs < 200 nm were isolated using a modified cost-effective polyethylene glycol (PEG)-based precipitation method and compared to standard methods, namely ultracentrifugation and a commercial kit, where the successful isolation was verified by different approaches. We evaluated the expression levels of selected sEV-derived miR-181b-5p, miR-222-3p and let-7a-5p using quantitative real PCR (qPCR). Relative to non-IBC, our qPCR data showed that sEV-derived miR-181b-5p and miR-222-3p were significantly upregulated, whereas let-7a-5p was downregulated in IBC patients. Interestingly, receiver operating characteristic (ROC) curves analysis revealed that diagnostic accuracy of let-7a-5p alone was the highest for IBC with an area under curve (AUC) value of 0.9188, and when combined with miR-222-3p the AUC was improved to 0.973. Further, 38 hub genes were identified using bioinformatics analysis. Together, circulating sEV-derived miR-181b-5p, miR-222-3p and let-7a-5p serve as promising non-invasive diagnostic biomarkers for IBC.
This paper presents trends in downward surface shortwave radiation (SSR) over Europe, which are based on the 56 longest series available from the Global Energy Balance Archive that are mainly ...concentrated in central Europe. Special emphasis has been placed on both ensuring the temporal homogeneity and including the most recent years in the data set. We have generated, for the first time, composite time series for Europe covering the period 1939–2012, which have been studied by means of running trend analysis. The mean annual SSR series shows an increase from the late 1930s to the early 1950s (i.e., early brightening), followed by a reduction until mid‐1980s (i.e., global dimming) and a subsequent increase up to the early 2000s (i.e., global brightening). The series ends with a tendency of stabilization since the early 21st century, but the short time period is insufficient with regard to establishing whether a change in the trend is actually emerging over Europe. Seasonal and regional series are also presented, which highlight that similar variations are obtained for most of the seasons and regions across Europe. In fact, due to the strong spatial correlation in the SSR series, few series are enough to capture almost the same interannual and decadal variability as using a dense network of stations. Decadal variations of the SSR are expected to have an impact on the modulation of the temperatures and other processes over Europe linked with changes in the hydrological cycle, agriculture production, or natural ecosystems. For a better dissemination of the time series developed in this study, the data set is freely available for scientific purposes.
Key Points
Global irradiance has been studied for the period 1939–2012 over Europe
There is no statistically significant increase since the 1950s or before
Stabilization since 2000 may be due stabilization of anthropogenic emissions
Carnivore and humans live in proximity due to carnivore recovery efforts and ongoing human encroachment into carnivore habitats globally. The American West is a region that uniquely exemplifies these ...human-carnivore dynamics, however, it is unclear how the research community here integrates social and ecological factors to examine human-carnivore relations. Therefore, strategies promoting human-carnivore coexistence are urgently needed. We conducted a systematic review on human-carnivore relations in the American West covering studies between 2000 and 2018. We first characterized human-carnivore relations across states of the American West. Second, we analyzed similarities and dissimilarities across states in terms of coexistence, tolerance, number of ecosystem services and conflicts mentioned in literature. Third, we used Bayesian modeling to quantify the effect of social and ecological factors influencing the scientific interest on coexistence, tolerance, ecosystem services and conflicts. Results revealed some underlying biases in human-carnivore relations research. Colorado and Montana were the states where the highest proportion of studies were conducted with bears and wolves the most studied species. Non-lethal management was the most common strategy to mitigate conflicts. Overall, conflicts with carnivores were much more frequently mentioned than benefits. We found similarities among Arizona, California, Utah, and New Mexico according to how coexistence, tolerance, services and conflicts are addressed in literature. We identified percentage of federal/private land, carnivore family, social actors, and management actions, as factors explaining how coexistence, tolerance, conflicts and services are addressed in literature. We provide a roadmap to foster tolerance towards carnivores and successful coexistence strategies in the American West based on four main domains, (1) the dual role of carnivores as providers of both beneficial and detrimental contributions to people, (2) social-ecological factors underpinning the provision of beneficial and detrimental contributions, (3) the inclusion of diverse actors, and (4) cross-state collaborative management.
The purpose of this investigation was to determine whether differences in body composition, pharmacological treatment, and physical activity explain the increased resting metabolic rate (RMR) and ...impaired insulin sensitivity in hypertension. Resting blood pressure, RMR (indirect calorimetry), body composition (dual‐energy X‐ray absorptiometry), physical activity (accelerometry), maximal oxygen uptake (VO2max) (ergospirometry), and insulin sensitivity (Matsuda index) were measured in 174 patients (88 men and 86 women; 20–68 years) with overweight or obesity. Hypertension (HTA) was present in 51 men (58%) and 42 women (49%) (p = .29). RMR was 6.9% higher in hypertensives than normotensives (1777 ± 386 and 1663 ± 383 kcal d−1, p = .044). The double product (systolic blood pressure × heart rate) was 18% higher in hypertensive than normotensive patients (p < .001). The observed differences in absolute RMR were non‐significant after adjusting for total lean mass and total fat mass (estimated means: 1702 kcal d−1, CI: 1656–1750; and 1660 kcal d−1, CI: 1611–1710 kcal d−1, for the hypertensive and normotensive groups, respectively, p = .19, HTA × sex interaction p = .37). Lean mass, the double product, and age were the variables with the higher predictive value of RMR in hypertensive patients. Insulin sensitivity was lower in hypertensive than in normotensive patients, but these differences disappeared after accounting for physical activity and VO2max. In summary, hypertension is associated with increased RMR and reduced insulin sensitivity. The increased RMR is explained by an elevated myocardial oxygen consumption due to an increased resting double product, combined with differences in body composition between hypertensive and normotensive subjects.
•Price-maker optimization model for planning and operation of aggregated DER.•3 Case studies are proposed, considering different electricity pricing scenarios.•Analysis of benefits and effect on ...electricity prices produced by DER aggregation.•Results showed considerable benefits even for relatively small aggregations.•Results suggest that the impact on prices should not be overlooked.
This paper analyzes the optimal planning and operation of aggregated distributed energy resources (DER) with participation in the electricity market. Aggregators manage their portfolio of resources in order to obtain the maximum benefit from the grid, while participating in the day-ahead wholesale electricity market. The goal of this paper is to propose a model for aggregated DER systems planning, considering its participation in the electricity market and its impact on the market price. The results are the optimal planning and management of DER systems, and the appropriate energy transactions for the aggregator in the wholesale day-ahead market according to the size of its aggregated resources. A price-maker approach based on representing the market competitors with residual demand curves is followed, and the impact on the price is assessed to help in the decision of using price-maker or price-taker approaches depending on the size of the aggregated resources. A deterministic programming problem with two case studies (the average scenario and the most likely scenario from the stochastic ones), and a stochastic one with a case study to account for the market uncertainty are described. For both models, market scenarios have been built from historical data of the Spanish system.
The results suggest that when the aggregated resources have enough size to follow a price-maker approach and the uncertainty of the markets is considered in the planning process, the DER systems can achieve up to 50% extra economic benefits, depending on the market share, compared with a non-aggregated business-as-usual approach (not implementing DER systems).
Elevated by the support: 2‐Alkynyl aniline cycloisomerization to indole is catalyzed by cationic Au NPs on a carbon support. Electroneutral and rich 2‐aryl indoles are further converted into ...3,3′‐biindoles by oxidative homocoupling that is readily catalyzed by the Au NPs on carbon, and exclusively but also somewhat sluggishly by the carbon support.
Despite recent advances in cancer therapy, the 5-year survival rate for Ewing's sarcoma is still very low, and new therapeutic approaches are necessary. It was found previously that melatonin induces ...cell death in the Ewing's sarcoma cell line, SK-N-MC, by activating the extrinsic apoptotic pathway.
Melatonin actions were analysed by metabolic viability/survival cell assays, flow cytometry, quantitative PCR for mRNA expression, western blot for protein activation/expression and electrophoretic mobility shift assay for transcription factor activation.
Melatonin increases the expression of Fas and its ligand Fas L, this increase being responsible for cell death induced by the indolamine. Melatonin also produces a transient increase in intracellular oxidants and activation of the redox-regulated transcription factor Nuclear factor-kappaB. Inhibition of such activation prevents cell death and Fas/Fas L upregulation. Cytotoxic effect and Fas/Fas L regulation occur in all Ewing's cell lines studied, and do not occur in the other tumour cell lines studied where melatonin does not induce cell death.
Our data offers new insights in the study of alternative therapeutic strategies in the treatment of Ewing's sarcoma. Further attention deserves to be given to the differences in the cellular biology of sensitive tumours that could explain the cytotoxic effect of melatonin and the increase in the level of free radicals caused by this molecule, in particular cancer types.
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