635 research outputs found
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Correlation of radioactive waste treatment costs and the environmental impact of waste effluents in the nuclear fuel cycle for use in establishing ''as low as practicable'' guides: nuclear fuel reprocessing
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Correlation of radioactive waste treatment costs and the environmental impact of waste effluents in the nuclear fuel cycle for use in establishing ''as low as practicable'' guides: fabrication of light-water reactor fuel from enriched uranium dioxide
Recommended from our members
Correlation of radioactive waste treatment costs and the environmental impact of waste effluents in the nuclear fuel cycle for use in establishing ''as low as practicable'' guides: fabrication of light-water reactor fuels containing plutonium
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence
Cardiovascular roles of estrogen receptors: insights gained from knockout models
The effects of estrogen are mediated through two functionally distinct receptors, estrogen receptor α (ER- α ), and estrogen receptor β (ER- β ), both of which are expressed in the cardiovascular system. The etiology of cardiovascular disease is believed to result in part from the loss of endogenous estrogen, indicating that estrogen and its receptors may play important roles in the prevention of cardiovascular disease in women
Adipose tissue pathways involved in weight loss of cancer cachexia
White adipose tissue (WAT) constitutes our most expandable tissue and largest
endocrine organ secreting hundreds of polypeptides collectively termed adipokines.
Changes in WAT mass induce alterations in adipocyte secretion and function, which
are linked to disturbed whole-body metabolism. Although the mechanisms controlling
this are not clear they are dependent on changes in gene expression, a complex process
which is regulated at several levels. Results in recent years have highlighted the role of
small non-coding RNA molecules termed microRNAs (miRNAs), which regulate gene
expression via post-transcriptional mechanisms. The aim of this thesis was to
characterize global gene expression levels and describe novel miRNAs and adipokines
controlling the function of human WAT in conditions with pathological increases or
decreases in WAT mass. Obesity and cancer cachexia were selected as two models
since they are both clinically relevant and characterized by involuntary changes in
WAT mass.
In Study I, expressional analyses were performed in subcutaneous WAT from cancer
patients with or without cachexia and obese versus non-obese subjects. In total, 425
transcripts were found to be regulated in cancer cachexia. Pathway analyses based on
this set of genes revealed that processes involving extracellular matrix, actin
cytoskeleton and focal adhesion were significantly downregulated, whereas fatty acid
metabolism was upregulated comparing cachectic with weight-stable cancer subjects.
Furthermore, by overlapping these results with microarray data from an obesity study,
many transcripts were found to be reciprocally regulated comparing the two conditions.
This suggests that WAT gene expression in cancer cachexia and obesity are regulated
by similar, albeit opposing, mechanisms.
In Study II, the focus was on the family of
fibroblast growth factors (FGFs), members of which have recently been implicated in
the development of obesity and insulin resistance. A retrospective analysis of global
gene expression data identified several FGFs (FGF1/2/7/9/13/18) to be expressed in
WAT. However, only one, FGF1, was actively secreted from WAT and predominantly
so from the adipocyte fraction. Moreover, FGF1 release was increased in obese
compared to non-obese subjects, but was not normalized by weight loss. Although the
clinical significance of these findings is not yet clear, it can be hypothesized that FGF1
may play a role in WAT growth, possibly by promoting fat cell proliferation and/or
differentiation.
In Study III, we identified adipose miRNAs regulated in obesity. Out
of eleven miRNAs regulated by changes in body fat mass, ten controlled the production
of the pro-inflammatory chemoattractant chemokine (C-C motif) ligand 2 (CCL2)
when overexpressed in fat cells and for two, miR-126 and -193b, signaling circuits
were defined.
In Study IV, a novel adipokine, semaphorin 3C (SEMA3C), was
identified by combining transcriptome and secretome data. Detailed studies focusing on
SEMA3C revealed that this factor was secreted from adipocytes and induced the
expression of extracellular matrix and matricellular genes in preadipocytes.
Furthermore, SEMA3C mRNA levels correlated with interstitial fibrosis and insulin
resistance in WAT derived from subjects with a wide range in BMI.
In summary, the results presented in this thesis have delineated transcriptional
alterations in WAT in two clinically relevant conditions, obesity and cancer cachexia.
This has allowed the identification of novel adipokines and microRNAs with potential
pathophysiological importance. These findings form the basis for further studies aiming
at understanding the central role of WAT in disorders associated with metabolic
complications
Functional and genetic analysis in type 2 diabetes of Liver X receptor alleles – a cohort study
<p>Abstract</p> <p>Background</p> <p>Liver X receptor alpha <it>(LXRA</it>) and beta (<it>LXRB</it>) regulate glucose and lipid homeostasis in model systems but their importance in human physiology is poorly understood. This project aimed to determine whether common genetic variations in <it>LXRA </it>and <it>LXRB </it>associate with type 2 diabetes (T2D) and quantitative measures of glucose homeostasis, and, if so, reveal the underlying mechanisms.</p> <p>Methods</p> <p>Eight common single nucleotide polymorphisms in <it>LXRA </it>and <it>LXRB </it>were analyzed for association with T2D in one French cohort (N = 988 cases and 941 controls), and for association with quantitative measures reflecting glucose homeostasis in two non-diabetic population-based samples comprising N = 697 and N = 1344 adults. Investigated quantitative phenotypes included fasting plasma glucose, serum insulin, and HOMA<sub>IR </sub>as measure of overall insulin resistance. An oral glucose tolerance test was performed in N = 1344 of adults. The two alleles of the proximal <it>LXRB </it>promoter, differing only at the SNP rs17373080, were cloned into reporter vectors and transiently transfected, whereupon allele-specific luciferase activity was measured. rs17373080 overlapped, according to <it>in silico </it>analysis, with a binding site for Nuclear factor 1 (NF1). Promoter alleles were tested for interaction with NF1 using direct DNA binding and transactivation assays.</p> <p>Results</p> <p>Genotypes at two <it>LXRB </it>promoter SNPs, rs35463555 and rs17373080, associated nominally with T2D (P values 0.047 and 0.026). No <it>LXRA </it>or <it>LXRB </it>SNP associated with quantitative measures reflecting glucose homeostasis. The rs17373080 C allele displayed higher basal transcription activity (P value < 0.05). The DNA-mobility shift assay indicated that oligonucleotides corresponding to either rs17373080 allele bound NF1 transcription factors in whole cell extracts to the same extent. Different NF1 family members showed different capacity to transactivate the <it>LXRB </it>gene promoter, but there was no difference between promoter alleles in NF1 induced transactivation activity.</p> <p>Conclusion</p> <p>Variations in the <it>LXRB </it>gene promoter may be part of the aetiology of T2D. However, the association between <it>LXRB </it>rs35463555 and rs17373080, and T2D are preliminary and needs to be investigated in additional larger cohorts. Common genetic variation in <it>LXRA </it>is unlikely to affect the risk of developing T2D or quantitative phenotypes related to glucose homeostasis.</p
Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol
© 2017 The Author(s). Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-ΰ B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-ΰ B signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-k B translocation into the nucleus that resulted in high NF-k B transcription activity. The overall magnitude of NF-k B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-k B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-k B transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-k B transcription factor
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