Regulation of early signaling and gene expression in the α-particle and bystander response of IMR-90 human fibroblasts

<p>Abstract</p> <p>Background</p> <p>The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is well established. To understand early signaling and gene regulation in bystander cells, we used a bio-informatics approach, measuring global gene expression at 30 minutes and signaling pathways between 30 minutes and 4 hours after exposure to α-particles in IMR-90 fibroblasts.</p> <p>Methods</p> <p>We used whole human genome microarrays and real time quantitative PCR to measure and validate gene expression. Microarray analysis was done using BRB-Array Tools; pathway and ontology analyses were done using Ingenuity Pathway Analysis and PANTHER, respectively. We studied signaling in irradiated and bystander cells using immunoblotting and semi-quantitative image analysis.</p> <p>Results</p> <p>Gene ontology suggested signal transduction and transcriptional regulation responding 30 minutes after treatment affected cell structure, motility and adhesion, and interleukin synthesis. We measured time-dependent expression of genes controlled by the NF-κB pathway; matrix metalloproteinases 1 and 3; <it/>chemokine ligands 2, 3 and 5 and <it/>interleukins 1β, 6 and 33. There was an increased response of this set of genes 30 minutes after treatment and another wave of induction at 4 hours. We investigated AKT-GSK3β signaling and found both AKT and GSK3β are hyper-phosphorylated 30 minutes after irradiation and this effect is maintained through 4 hours. In bystander cells, a similar response was seen with a delay of 30 minutes. We proposed a network model where the observed decrease in phosphorylation of β-catenin protein after GSK3β dependent inactivation can trigger target gene expression at later times after radiation exposure</p> <p>Conclusions</p> <p>These results are the first to show that the radiation induced bystander signal induces a widespread gene expression response at 30 minutes after treatment and these changes are accompanied by modification of signaling proteins in the PI3K-AKT-GSK3β pathway.</p

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Mangroves - captured by the keen eye of a 17th century landscape painter

info:eu-repo/semantics/publishe

Mangroves–Captured By The Keen Eye Of A 17th Century Landscape Painter

Artists and scientists alike came across unfamiliar landscapes and strikingly strange fauna and flora when they embarked for the ‘colonies’. In the 17th and 18th centuries curiosity for the exotic developed into direct scientific observation, which is often still appreciated scientifically today, such as in biological taxonomy. Often observation, interpretation and reporting were geared towards functional aspects, a resourcist view on the environment in the wake of the colonial enterprise. This entailed that focus could be biased towards aspects of mercantile, political or strategic interest. Landscape vision is no exception for the possible biases. The Dutch painter Frans Post during his 7 year stay in the New World (Brazil) in the 17th century was the first to depict mangroves as a very characteristic tropical vegetation, unfamiliar to Europeans, in spite of its limited interest in the context of colonial economy. He did this in the strong and developing tradition of Dutch landscape painting.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Characterization of Brazilian spring wheat germplasm and its potential for increasing wheat genetic diversity in Canada

In the present era of climate instability, Canadian wheat production has been frequently affected by abiotic stresses and by dynamic populations of pathogens and pests that are more virulent and aggressive over time. Genetic diversity is fundamental to guarantee sustainable and improved wheat production. In the past, the genetics of Brazilian cultivars, such as Frontana, have been studied by Canadian researchers and consequently, Brazilian germplasm has been used to breed Canadian wheat cultivars. The objective of this study was to characterize a collection of Brazilian germplasm under Canadian growing conditions, including the reaction of the Brazilian germplasm to Canadian isolates/pathogens and to predict the presence of certain genes in an effort to increase genetic diversity, improve genetic gain and resilience of Canadian wheat. Over 100 Brazilian hard red spring wheat cultivars released from 1986 to 2016 were evaluated for their agronomic performance in eastern Canada. Some cultivars showed good adaptability, with several cultivars being superior or statistically equal to the highest yielding Canadian checks. Several Brazilian cultivars had excellent resistance to leaf rust, even though only a few of these tested positive for the presence of either Lr34 or Lr16, two of the most common resistance genes in Canadian wheat. Resistance for stem rust, stripe rust and powdery mildew was variable among the Brazilian cultivars. However, many Brazilian cultivars had high levels of resistance to Canadian and African - Ug99 strains of stem rust. Many Brazilian cultivars had good Fusarium head blight (FHB) resistance, which appears to be derived from Frontana. In contrast FHB resistance in Canadian wheat is largely based on the Chinese variety, Sumai-3. The Brazilian germplasm is a valuable source of semi-dwarf (Rht) genes, and 75% of the Brazilian collection possessed Rht-B1b. Many cultivars in the Brazilian collection were found to be genetically distinct from Canadian wheat, making them a valuable resource to increase the disease resistance and genetic variability in Canada and elsewhere

DNA Methylation in Newborns and Maternal Smoking in Pregnancy:Genome-wide Consortium Meta-analysis

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value &lt;2.2 x 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.</p