Summary The May 2008 earthquake in Wenchuan drew attention to the important but largely unrecognised public-health problem of injury-related mortality and morbidity in China. Injuries account for ...more than 10% of all deaths and more than 30% of all potentially productive years of life lost due to premature mortality in China. Traffic-related injuries (mainly among cyclists and pedestrians), suicide, drowning, and falls account for 79% of all injury deaths. Rural injury death rates are double those of urban rates and male rates are double those of female rates. Despite an 81% increase in the traffic-related mortality from 1987 to 2006—associated with rapid motorisation—the overall injury mortality decreased by 17%, largely due to a surprising (and unexplained) 57% reduction in the suicide rate. Low-cost prevention measures that are most likely to produce large reductions in injury deaths include enforcement of laws for drinking and driving and for seat belt and helmet use, restriction of access to the most potent pesticides, and teaching children to swim. China needs to improve monitoring of fatal and non-fatal injuries, promote intersectoral collaboration, build institutional capacities, and, most importantly, mobilise community support and political will for investment in prevention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Apremilast works intracellularly to regulate inflammatory mediators. Objective ESTEEM 1 evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque ...psoriasis. Methods This phase III, multicenter, double-blind, placebo-controlled study randomized adults (2:1) to apremilast or placebo. At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Binary end points were analyzed using χ2 test; continuous end points used analysis of covariance. Results In all, 844 patients were randomized (n = 282, placebo; n = 562, apremilast). At week 16, significantly more patients taking apremilast achieved 75% or greater reduction from baseline Psoriasis Area and Severity Index score (PASI-75) (33.1%) versus placebo (5.3%, P < .0001; primary end point). Most (61.0%) patients rerandomized to apremilast at week 32 achieved PASI-75 at week 52 versus 11.7% rerandomized to placebo. Of patients rerandomized to apremilast at week 32, mean percentage change from baseline PASI score was −88% to −81% (weeks 32-52). During the placebo-controlled period, 55.7% and 69.3% of patients randomized to placebo and apremilast, respectively, had 1 or more adverse events. Most adverse events were mild/moderate in severity. No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period. Limitations Data were limited to 52 weeks and may not generalize to nonplaque psoriasis. Conclusions Apremilast was effective in moderate to severe plaque psoriasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to ...metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c
CD64
double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.
Methylation associated inactivation of RASSF1, a putative tumor suppressor identified at 3p21.3, has been frequently observed in several human malignancies, including lung and breast cancers. To ...explore the penetrance of RASSF1 in gastric carcinogenesis, we performed expression and mutation analyses of 3 isotypes of RASSF1 (A, B, and C) in 150 gastric specimens, including 15 carcinoma cell lines. RASSF1A and RASSF1B transcripts were not expressed in 60% (9 of 15) and 33% (5 of 15) of gastric carcinoma cell lines, respectively, whereas RASSF1C was detectable in all cell lines. Bisulfite DNA sequencing analysis revealed that the CpG island in the RASSF1A promoter is hypermethylated in all RASSF1A-nonexpressing cell lines. In addition, both RASSF1A and RASSF1B were re-expressed by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Among 90 primary gastric adenocarcinomas examined, 41 (46%) and 19 (21%) expressed no or abnormally low levels of RASSF1A and RASSF1B, respectively, and 12 (13%) tumors showed no expression of both isoforms. Loss or abnormal down-regulation of RASSF1A correlated with tumor stage and grade but not with histological types of tumors. Methylation-specific PCR analysis demonstrated that 95% (39 of 41) of RASSF1A-nonexpressing primary tumors are methylated at the CpG sites in the promoter, whereas none of the adjacent noncancerous or normal tissues are methylated. No somatic mutations were detected in RASSF1 transcripts expressed in unmethylated tumors. However, 10 methylated tumors, including 4 cell lines, showed low genomic levels of RASSF1 and expressed no RASSF1A transcripts, suggesting that RASSF1A inactivation might be caused by both epigenetic and genetic mechanisms in a subset of gastric adenocarcinomas. In conclusion, our data indicate that epigenetic transcriptional silencing of RASSF1, especially RASSF1A isoform, is a frequent event in gastric tumorigenesis and might play an important role in the malignant progression of gastric adenocarcinomas.
This paper presents a study on an adaptive traffic signal controller for real-time operation. The controller aims for three operational objectives: dynamic allocation of green time, automatic ...adjustment to control parameters, and fast revision of signal plans. The control algorithm is built on approximate dynamic programming (ADP). This approach substantially reduces computational burden by using an approximation to the value function of the dynamic programming and reinforcement learning to update the approximation. We investigate temporal-difference learning and perturbation learning as specific learning techniques for the ADP approach. We find in computer simulation that the ADP controllers achieve substantial reduction in vehicle delays in comparison with optimised fixed-time plans. Our results show that substantial benefits can be gained by increasing the frequency at which the signal plans are revised, which can be achieved conveniently using the ADP approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The May 2008 earthquake in Wenchuan drew attention to the important but largely unrecognised public-health problem of injury-related mortality and morbidity in China. Injuries account for more than ...10% of all deaths and more than 30% of all potentially productive years of life lost due to premature mortality in China. Traffic-related injuries (mainly among cyclists and pedestrians), suicide, drowning, and falls account for 79% of all injury deaths. Rural injury death rates are double those of urban rates and male rates are double those of female rates. Despite an 81% increase in the traffic-related mortality from 1987 to 2006-associated with rapid motorisation-the overall injury mortality decreased by 17%, largely due to a surprising (and unexplained) 57% reduction in the suicide rate. Low-cost prevention measures that are most likely to produce large reductions in injury deaths include enforcement of laws for drinking and driving and for seat belt and helmet use, restriction of access to the most potent pesticides, and teaching children to swim. China needs to improve monitoring of fatal and non-fatal injuries, promote intersectoral collaboration, build institutional capacities, and, most importantly, mobilise community support and political will for investment in prevention. PUBLICATION ABSTRACT
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although a great deal is known biochemically about peroxiredoxins (Prxs), little is known about their real physiological function. We show here that two cytosolic yeast Prxs, cPrxI and II, which ...display diversity in structure and apparent molecular weights (MW), can act alternatively as peroxidases and molecular chaperones. The peroxidase function predominates in the lower MW forms, whereas the chaperone function predominates in the higher MW complexes. Oxidative stress and heat shock exposure of yeasts causes the protein structures of cPrxI and II to shift from low MW species to high MW complexes. This triggers a peroxidase-to-chaperone functional switch. These in vivo changes are primarily guided by the active peroxidase site residue, Cys
47, which serves as an efficient “H
2O
2-sensor” in the cells. The chaperone function of these proteins enhances yeast resistance to heat shock.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aim:
To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth ...factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa.
Methods:
This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A.
Results:
In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240–0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B).
Conclusion:
The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.
Trial Registration: ClinicalTrials.gov identifier: NCT02763566.
The new thermal triple-axis spectrometer at the NIST Center for Neutron Research (NCNR) is located at the BT-7 beam port. The 165 mm diameter reactor beam is equipped with a selection of Söller ...collimators, beam-limiters, and a pyrolytic graphite (PG) filter to tailor the beam for the dual 20×20 cm(2) double-focusing monochromator system that provides monochromatic fluxes exceeding 10(8) n/cm(2)/s onto the sample. The two monochromators installed are PG(002) and Cu(220), which provide incident energies from 5 meV to above 500 meV. The computer controlled analyzer system offers six standard modes of operation, including a diffraction detector, a position-sensitive detector (PSD) in diffraction mode, horizontal energy focusing analyzer with detector, a Q-E mode employing a flat analyzer and PSD, a constant-E mode with the analyzer crystal system and PSD, and a conventional mode with a selection of Söller collimators and detector. Additional configurations for specific measurement needs are also available. This paper discusses the capabilities and performance for this new state-of-the-art neutron spectrometer.
Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain ...regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A. Prenatal exposure to green tea polyphenols containing EGCG protects from brain defects induced by overexpression of DYRK1A.
In order to produce more robust and possibly more active analogues of the natural compound EGCG, here we synthetized new EGCG-like molecules with several structural modifications to the EGCG skeleton. We replaced the ester boun of EGCG with a more resistant amide bond. We also replaced the oxygen ring by a methylene group. And finally, we positioned a nitrogen atom within this ring. The selected compound was shown to maintain the non-competitive property of EGCG and to correct biochemical and behavioral defects present in a DS mouse model. In addition it showed high stability and specificity.
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•Novel epigallocatechin gallate (EGCG) analogues as a new class of DYRK1A inhibitors.•EGCG derivatives were synthesized.•7cc showed IC50 value of 0.5 μM against DYRK1A and was shown to act as a non competitive inhibitor.•7cc showed inhibited ERK2 phosphorylation in mouse brain.•7cc was more stable in plasma compared to EGCG.•7cc showed no toxicity during embryogenesis and corrected working memory deficit in a Down syndrome model.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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