1,037 research outputs found
Prosper: image and robot-guided prostate brachytherapy
Brachytherapy for localized prostate cancer consists in destroying cancer by
introducing iodine radioactive seeds into the gland through hollow needles. The
planning of the position of the seeds and their introduction into the prostate
is based on intra-operative ultrasound (US) imaging. We propose to optimize the
global quality of the procedure by: i) using 3D US; ii) enhancing US data with
MRI registration; iii) using a specially designed needle-insertion robot,
connected to the imaging data. The imaging methods have been successfully
tested on patient data while the robot accuracy has been evaluated on a
realistic deformable phantom
Medical image computing and computer-aided medical interventions applied to soft tissues. Work in progress in urology
Until recently, Computer-Aided Medical Interventions (CAMI) and Medical
Robotics have focused on rigid and non deformable anatomical structures.
Nowadays, special attention is paid to soft tissues, raising complex issues due
to their mobility and deformation. Mini-invasive digestive surgery was probably
one of the first fields where soft tissues were handled through the development
of simulators, tracking of anatomical structures and specific assistance
robots. However, other clinical domains, for instance urology, are concerned.
Indeed, laparoscopic surgery, new tumour destruction techniques (e.g. HIFU,
radiofrequency, or cryoablation), increasingly early detection of cancer, and
use of interventional and diagnostic imaging modalities, recently opened new
challenges to the urologist and scientists involved in CAMI. This resulted in
the last five years in a very significant increase of research and developments
of computer-aided urology systems. In this paper, we propose a description of
the main problems related to computer-aided diagnostic and therapy of soft
tissues and give a survey of the different types of assistance offered to the
urologist: robotization, image fusion, surgical navigation. Both research
projects and operational industrial systems are discussed
MOMP from Campylobacter jejuni is a trimer of 18-stranded ÎČâbarrel monomers with a Ca2+ ion bound at the constriction zone
LGMF and SG are funded by EU FP7-PEOPLE-2013-ITN Translocation network Nr. 607694. The research leading to these results was conducted as part of the Translocation consortium (www.translocation.com) and has received support from the Innovative Medicines Initiatives Joint Undertaking under Grant Agreement n°115525, resources which are composed of financial contribution from the European Unionâs seventh framework programme (FP7/2007-2013) and EFPIA companies in kind contribution. JHN is Royal Society Wolfson Merit Award holder, Senior Investigator Wellcome Trust (WT100209MA) and Chinese Academy of Science 1000 Talent Scholar.The Gram-negative organism Campylobacter jejuni is the major cause of food poisoning. Unlike Escherichia coli which has two major porins, OmpC and OmpF, C. jejuni has one, termed major outer membrane protein (MOMP) through which nutrients and antibiotics transit. We report the 2.1-Ă
crystal structure of C. jejuni MOMP expressed in E. coli and a lower resolution but otherwise identical structure purified directly from C. jejuni. The 2.1-Ă
resolution structure of recombinant MOMP showed that although the protein has timeric arrangement similar to OmpC, it is an18-stranded not 16-stranded ÎČ-barrel. The structure has identified a Ca2+ bound at the constriction zone, which molecular dynamics and single channel experiments suggest is functionally significant. The water filled channel of MOMP has a narrow constriction zone and single molecule studies show a monomeric conductivity of 0.7 ± 0.2 nS and a trimeric conductance of 2.2 ± 0.2 nS. The ion neutralizes negative charges at the constriction zone reducing the transverse electric field and reversing ion selectivity. Modelling of the transit of ciprofloxacin, an antibiotic of choice for treating Campylobacter infection, through the pore of MOMP reveals a trajectory that is dependent upon the presence metal ion.Publisher PDFPeer reviewe
Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria
In the search for an effective strategy to overcome antimicrobial resistance, a series of
new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at
position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive
and Gram-negative bacteria. Compounds (7â23) were tested for oxacillin adjuvant properties in
the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus
MRSA 19449. Compounds 14â16 were tested additionally in combination with various antibiotics.
Molecular modelling was performed to assess potential mechanism of action. Microdilution and
real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential
of compounds 7â23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were
determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings,
significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness
of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of
PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even
to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal âdual
actionâ for ÎČ-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also
satisfied solubility and safety towards CYP3A4 in vitro
How ÎČ-Lactam Antibiotics Enter Bacteria: A Dialogue with the Porins
BACKGROUND:Multi-drug resistant (MDR) infections have become a major concern in hospitals worldwide. This study investigates membrane translocation, which is the first step required for drug action on internal bacterial targets. beta-lactams, a major antibiotic class, use porins to pass through the outer membrane barrier of Gram-negative bacteria. Clinical reports have linked the MDR phenotype to altered membrane permeability including porin modification and efflux pump expression.
METHODOLOGY/PRINCIPAL FINDINGS:
Here influx of beta-lactams through the major Enterobacter aerogenes porin Omp36 is characterized. Conductance measurements through a single Omp36 trimer reconstituted into a planar lipid bilayer allowed us to count the passage of single beta-lactam molecules. Statistical analysis of each transport event yielded the kinetic parameters of antibiotic travel through Omp36 and distinguishable translocation properties of beta-lactams were quantified for ertapenem and cefepime. Expression of Omp36 in an otherwise porin-null bacterial strain is shown to confer increases in the killing rate of these antibiotics and in the corresponding bacterial susceptibility.
CONCLUSIONS/SIGNIFICANCE:
We propose the idea of a molecular "passport" that allows rapid transport of substrates through porins. Deciphering antibiotic translocation provides new insights for the design of novel drugs that may be highly effective at passing through the porin constriction zone. Such data may hold the key for the next generation of antibiotics capable of rapid intracellular accumulation to circumvent the further development MDR infections
International evaluation of the psychometrics of health-related quality of life questionnaires for use among long-term survivors of testicular and prostate cancer
Background: Understanding of the physical, functional and psychosocial health problems and needs of cancer survivors requires cross-national and cross-cultural standardization of health-related quality of life (HRQoL) questionnaires that capture the full range of issues relevant to cancer survivors. To our knowledge, only one study has investigated in a comprehensive way whether a questionnaire used to evaluate HRQoL in cancer patients under active treatment is also reliable and valid when used among (long-term) cancer survivors. In this study we evaluated, in an international context, the psychometrics of HRQoL questionnaires for use among long-term, disease-free, survivors of testicular and prostate cancer. Methods: In this cross-sectional study, we recruited long-term survivors of testicular and prostate cancer from Northern and Southern Europe and from the United Kingdom who had participated in two phase III EORTC clinical trials. Participants completed the SF-36 Health Survey, the EORTC QLQ-C30 questionnaire, the QLQ-PR25 (for prostate cancer) or the QLQ-TC26 (for testicular cancer) questionnaires, and the Impact of Cancer questionnaire. Testicular cancer survivors also completed subscales from the Nordic Questionnaire for Monitoring the Age Diverse Workforce. Results: Two hundred forty-two men (66% response rate) were recruited into the study. The average time since treatment was more than 10 years. Overall, there were few missing questionnaire data, although scales related to sexuality, satisfaction with care and relationship concern
pH Modulation of Efflux Pump Activity of Multi-Drug Resistant Escherichia coli: Protection During Its Passage and Eventual Colonization of the Colon
BACKGROUND:Resistance Nodulation Division (RND) efflux pumps of Escherichia coli extrude antibiotics and toxic substances before they reach their intended targets. Whereas these pumps obtain their energy directly from the proton motive force (PMF), ATP-Binding Cassette (ABC) transporters, which can also extrude antibiotics, obtain energy from the hydrolysis of ATP. Because E. coli must pass through two pH distinct environments of the gastrointestinal system of the host, it must be able to extrude toxic agents at very acidic and at near neutral pH (bile salts in duodenum and colon for example). The herein described study examines the effect of pH on the extrusion of ethidium bromide (EB). METHODOLOGY/PRINCIPAL FINDINGS:E. coli AG100 and its tetracycline induced progeny AG100(TET) that over-expresses the acrAB efflux pump were evaluated for their ability to extrude EB at pH 5 and 8, by our recently developed semi-automated fluorometric method. At pH 5 the organism extrudes EB without the need for metabolic energy (glucose), whereas at pH 8 extrusion of EB is dependent upon metabolic energy. Phe-Arg beta-naphtylamide (PAbetaN), a commonly assumed inhibitor of RND efflux pumps has no effect on the extrusion of EB as others claim. However, it does cause accumulation of EB. Competition between EB and PAbetaN was demonstrated and suggested that PAbetaN was preferentially extruded. A K(m) representing competition between PAbetaN and EB has been calculated. CONCLUSIONS/SIGNIFICANCE:The results suggest that E. coli has two general efflux systems (not to be confused with a distinct efflux pump) that are activated at low and high pH, respectively, and that the one at high pH is probably a putative ABC transporter coded by msbA, which has significant homology to the ABC transporter coded by efrAB of Enterococcus faecalis, an organism that faces similar challenges as it makes its way through the toxic intestinal system of the host
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 Ă 10-20), ER-negative BC (P=1.1 Ă 10-13), BRCA1-associated BC (P=7.7 Ă 10-16) and triple negative BC (P-diff=2 Ă 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 Ă 10-3) and ABHD8 (P<2 Ă 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3âČ-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk
The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCMâ/â patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors
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