Analysis of drug resistance and the role of the stem cell niche in leukaemia

Glucocorticoids and etoposide are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoblasts through the glucocorticoid receptor (GR) and p53. However, glucocorticoid resistance, cell death mechanisms and the contribution of the bone marrow microenvironment to drug response/resistance all require investigation. Using microenvironment-mimicking conditioned media (CM), dexamethasone (a synthetic glucocorticoid) and etoposide to treat glucocorticoid-sensitive (C7-14) and glucocorticoid-resistant (C1-15) cells, pathways by which the microenvironment exerts its chemoprotective effect have been investigated. CM reduced caspase-3/8 activation, downregulated RIPK1 (necroptotic marker), and limited chemotherapy-induced BECN1 downregulation, suggesting protective effects of CM. Glucocorticoids upregulated BIRC3 (which ubiquitinates RIPK1), whilst CM altered GR phosphorylation. GR occupancy was observed on the RIPK1, BECN1 and BIRC3 promoters and changed depending on its phosphorylation. High-molecular weight proteins reacting with the RIPK1 antibody increased with CM, and reduced following AT406 BIRC3 inhibitor treatment suggesting they represent ubiquitinated RIPK1. These results suggest mechanisms by which CM promotes survival, as well as indicating novel glucocorticoid-regulated pathways. Complementing laboratory investigation is the construction of a Boolean model of the GR interaction network (GEB052, GR “interactome”) containing 52 nodes (proteins, inputs/outputs) connected by 241 interactions. In silico mutations and analyses have generated predictions that were subsequently validated on a genome-wide scale via comparison to microarray data. GEB052 demonstrated high prediction accuracy, consistently achieving a better prediction rate than a randomised model. Quantitative algorithmic analysis via microarray superimposition has also been performed, and lastly the model has been preliminarily validated as a clinical tool via superimposition of patient microarray data and comparing model predictions to clinical data. In summary, this thesis provides novel insight into the effects of the microenvironment, and identifies new glucocorticoid-regulated pathways. The GEB052 model of GR signalling represents the novel application of this modelling approach to GR research, and generates accurate predictions

Anti-CTLA-4 therapy for malignant mesothelioma

Immunotherapy is an emerging therapeutic strategy with a promising clinical outcome in some solid tumors, particularly metastatic melanoma. One approach to immunotherapy is immune checkpoint inhibitors, such as blockage of CTLA-4 and PD-1/PD-L1. This special report aims to describe the state of clinical trials of tremelimumab in patients with unresectable malignant mesothelioma (MM) in particular with regard to the clinical efficacy, safety and tolerability. Criticism and perspective of this treatment are also discussed. Biological and clinical considerations rule out the use of tremelimumab as single agent for MM and, more generally, the use of immune checkpoint inhibitors for MM is still largely questionable and not supported by evidences

Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression. Methodology/Principal Findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl- CoA isomerase (PECI) on chromosome 6. Conclusions: Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclearencoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis

Whole shaft visibility and mechanical performance for active MR catheters using copper-nitinol braided polymer tubes

<p>Abstract</p> <p>Background</p> <p>Catheter visualization and tracking remains a challenge in interventional MR.</p> <p>Active guidewires can be made conspicuous in "profile" along their whole shaft exploiting metallic core wire and hypotube components that are intrinsic to their mechanical performance. Polymer-based catheters, on the other hand, offer no conductive medium to carry radio frequency waves. We developed a new "active" catheter design for interventional MR with mechanical performance resembling braided X-ray devices. Our 75 cm long hybrid catheter shaft incorporates a wire lattice in a polymer matrix, and contains three distal loop coils in a flexible and torquable 7Fr device. We explored the impact of braid material designs on radiofrequency and mechanical performance.</p> <p>Results</p> <p>The incorporation of copper wire into in a superelastic nitinol braided loopless antenna allowed good visualization of the whole shaft (70 cm) <it>in vitro </it>and <it>in vivo </it>in swine during real-time MR with 1.5 T scanner. Additional distal tip coils enhanced tip visibility. Increasing the copper:nitinol ratio in braiding configurations improved flexibility at the expense of torquability. We found a 16-wire braid of 1:1 copper:nitinol to have the optimum balance of mechanical (trackability, flexibility, torquability) and antenna (signal attenuation) properties. With this configuration, the temperature increase remained less than 2°C during real-time MR within 10 cm horizontal from the isocenter. The design was conspicuous <it>in vitro </it>and <it>in vivo</it>.</p> <p>Conclusion</p> <p>We have engineered a new loopless antenna configuration that imparts interventional MR catheters with satisfactory mechanical and imaging characteristics. This compact loopless antenna design can be generalized to visualize the whole shaft of any general-purpose polymer catheter to perform safe interventional procedures.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Pervasive Sharing of Genetic Effects in Autoimmune Disease

Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases—as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple—but not all—immune-mediated diseases (SNP-wise PCPMA<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis

Clear and independent associations of several HLA-DRB1 alleles with differential antibody responses to hepatitis B vaccination in youth

To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV+) youth and 80 HIV-1 seronegatives (HIV−) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration ≥ 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10–1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). These immunogenetic relationships were all independent of non-genetic factors, including HIV-1 infection status and immunodeficiency. Alternative analyses confined to HIV+ youth or Hispanic youth led to similar findings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of differential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to effective immune response to recombinant vaccines

An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems

New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous WIA in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little, while not much new information has been gathered on soil organisms. The impact on marine coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal classneonicotinoids and fipronil. , withContinued large scale – mostly prophylactic – use of these persistent organochlorine pesticides has the potential to greatly decreasecompletely eliminate populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates, and their deleterious impacts on growth, reproduction and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015)