Targeted radiotherapy of neuroblastoma: future directions

No abstract available

The suppression of DNA repair induced by PARP-1 inhibitors rucaparib and olaparib in combination with the radiopharmaceutical 131I-MIBG in noradrenaline transporter-expressing xenograft tumors

No abstract available

Study Of Spatial Biological Systems Using a Graphical User Interface

Proceedings of the Tenth International Conference on Human-Computer Interaction, Crete, Greece, 22-27 June 2003In this paper, we describe a Graphical User Interface (GUI) designed to manage large quantities of image data of a biological system. After setting the design requirements for the system, we developed an ecology quantification GUI that assists biologists in analysing data. We focus on the main features of the interface and we present the results and an evaluation of the system. Finally, we provide some directions for some future work

Carbapenem resistance in bacteria isolated from soil and water environments in Algeria.

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordOBJECTIVES: Recent research has demonstrated that natural populations of bacteria carry large numbers of mobile genetic elements which may harbour antibiotic resistance determinants. The aim of this study was to investigate carbapenem resistance in Gram negative bacteria isolated from natural environments in Bejaia (Algeria), and determine the horizontal gene transfer potential of a subset of these resistance genes. METHODS: Resistant bacteria were isolated and host identified with MALDI-TOF/16S rRNA sequencing. Resistance gene carriage was investigated using double disc synergy, metallo-β-lactamase (MBL) production tests and PCR screening for carbapenemase resistance genes. To determine potential mobility, conjugation experiments were performed. To identify resistance genes, genomic libraries were constructed, functionally screened; then inserts were sequenced. RESULTS: From soil and water samples, 62 resistant strains were classified as belonging to the Enterobacteriaceae, Pseudomonadaceae, Xanthomonadaceae and Aeromonadaceae families. Four highly imipenem and cefotaxime resistant (MICs >64μg/ml and >8μg/ml, respectively), clinically relevant strains were selected for further characterization. All four strains produced extended spectrum β-lactamases, but MBL production was not confirmed. Imipenem and cefotaxime resistance was transferable to E. coli strains but was not conferred by blaAMPc, blaIMP, blaNDM, blaKPC, blaOXA-48 or blaGES genes. Novel putative resistance mechanisms were identified, including a novel DHA β-lactamase which conferred clinical resistance to cefotaxime. CONCLUSIONS: The environment is a reservoir of carbapenem resistant bacteria. Further investigation of evolution and dissemination of antibiotic resistance in environmental bacteria is required, to understand and prevent the emergence of resistance in clinical environment

Comparing the selective and co-selective effects of different antimicrobials in bacterial communities

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordBacterial communities are exposed to a cocktail of antimicrobial agents, including antibiotics, heavy metals and biocidal antimicrobials such as quaternary ammonium compounds (QACs). The extent to which these compounds may select or co-select for antimicrobial resistance (AMR) is not fully understood. In this study, human associated, wastewater derived, bacterial communities were exposed to either benzalkonium chloride (BAC), ciprofloxacin or trimethoprim at sub-point of use concentrations for one week, in order to determine selective and co-selective potential. Metagenome analyses were performed to determine effects on bacterial community structure and prevalence of antibiotic resistance genes (ARGs) and metal or biocide resistance genes (MBRGS). Ciprofloxacin had the greatest co-selective potential, significantly enriching for resistance mechanisms to multiple antibiotic classes. Conversely, BAC exposure significantly reduced relative abundance of ARGs and MBRGS, including the well characterised qac efflux genes. However, BAC exposure significantly impacted bacterial community structure. This suggests BAC and potentially other QACs did not play as significant a role in co-selection for AMR relative to antibiotics such as ciprofloxacin at below point of use concentrations in this study. This approach can be used to identify priority compounds for further study, to better understand evolution of AMR in bacterial communities exposed to sub-point of use concentrations of antimicrobials.Natural Environment Research Council (NERC)Biotechnology and Biological Sciences Research Council (BBSRC

Environmental monitoring of Mycobacterium bovis in badger feces and badger sett soil by real-time PCR, as confirmed by immunofluorescence, immunocapture, and cultivation

Real-time PCR was used to detect and quantify Mycobacterium bovis cells in naturally infected soil and badger faeces. Immunomagnetic capture, immunofluorescence and selective culture confirmed species identification and cell viability. These techniques will prove useful for monitoring M. bovis in the environment and for elucidating transmission routes between wildlife and cattle

Inhibition of Poly(ADP-Ribose) polymerase enhances the toxicity of 131I-Metaiodobenzylguanidine/Topotecan combination therapy to cells and xenografts that express the noradrenaline transporter

Targeted radiotherapy using [131I]meta-iodobenzylguanidine ([131I]MIBG) has produced remissions in some neuroblastoma patients. We previously reported that combining [131I]MIBG with the topoisomerase I (Topo-I) inhibitor topotecan induced long-term DNA damage and supra-additive toxicity to NAT-expressing cells and xenografts. This combination treatment is undergoing clinical evaluation. This present study investigated the potential of PARP-1 inhibition, in vitro and in vivo, to further enhance [131I]MIBG/topotecan efficacy

Evolution of antibiotic resistance at low antibiotic concentrations including selection below the minimal selective concentration

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: The datasets associated with Figs. 1–6 are included in this published article as a Supplementary Data file. Metagenome sequence files have been deposited in the European Nucleotide Archive. Accession number: PRJEB38942.Code availability: Code used for metagenome analysis: FastQC; MultiQC; FLASH2; Metaphlan2; Hclust2 and ARGs-OAP v2.Determining the selective potential of antibiotics at environmental concentrations is critical for designing effective strategies to limit selection for antibiotic resistance. This study determined the minimal selective concentrations (MSCs) for macrolide and fluoroquinolone antibiotics included on the European Commission's Water Framework Directive's priority hazardous substances Watch List. The macrolides demonstrated positive selection for ermF at concentrations 1-2 orders of magnitude greater (>500 and 7.8 and <15.6 µg/L). This highlights the need for compound specific assessment of selective potential. In addition, a sub-MSC selective window defined by the minimal increased persistence concentration (MIPC) is described. Differential rates of negative selection (or persistence) were associated with elevated prevalence relative to the no antibiotic control below the MSC. This increased persistence leads to opportunities for further selection over time and risk of human exposure and environmental transmission.Biotechnology and Biological Sciences Research Council (BBSRC)Natural Environment Research Council (NERC

Novel Insights into Selection for Antibiotic Resistance in Complex Microbial Communities

This is the final version of the article. Available from American Society for Microbiology via the DOI in this record.Recent research has demonstrated that selection for antibiotic resistance occurs at very low antibiotic concentrations in single-species experiments, but the relevance of these findings when species are embedded in complex microbial communities is unclear. We show that the strength of selection for naturally occurring resistance alleles in a complex community remains constant from low subinhibitory to above clinically relevant concentrations. Selection increases with antibiotic concentration before reaching a plateau where selection remains constant over a 2-order-magnitude concentration range. This is likely to be due to cross protection of the susceptible bacteria in the community following rapid extracellular antibiotic degradation by the resistant population, shown experimentally through a combination of chemical quantification and bacterial growth experiments. Metagenome and 16S rRNA analyses of sewage-derived bacterial communities evolved under cefotaxime exposure show preferential enrichment for blaCTX-M genes over all other beta-lactamase genes, as well as positive selection and co-selection for antibiotic resistant, opportunistic pathogens. These findings have far-reaching implications for our understanding of the evolution of antibiotic resistance, by challenging the long-standing assumption that selection occurs in a dose-dependent manner.Aimee K. Murray was supported by a BBSRC/AZ CASE Studentship, BB/L502509/1. Lihong Zhang was supported by Natural Environment Research Council grant NE/ M011259/1. Chemical quantification was performed at the University of Exeter Streatham Campus by Maciek Trnzadel and Malcolm Hetheridge, cofunded by Astra Zeneca Global SHE and the University of Exeter