Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 (10B) in the oral mucosa to the biological effectiveness of the 10B(n,α)7Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 ± 0.02. This compares with a previously published CBE factor for BPA of 4.87 ± 0.16. It was concluded that variations in the microdistribution profile of 10B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiation-induced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT. © 2000 Cancer Research Campaig

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Publications by university Departments of Anaesthesiology from Germany, Austria and Switzerland in 2011-2015. Scientific publications by university hospitals in D-A-CH

BackgroundThis study presents acount of publications and citations for all articles published by university Departments of Anaesthesiology in Germany, Austria and Switzerland between 2011 and 2015. The results were compared with former analyses of these countries from 2001-2010 as well as similar international studies.MethodsWe performed aPubMed search based on PERL-scripts for all publications originating from university Departments of Anaesthesiology in Germany, Austria and Switzerland between 2011 and 2015. According to their author's affiliation, articles were assigned to their affiliated university department. Publications were considered an original article if the category of publication was classified as original research in PubMed. Predatory journals were omitted by using PubMed-listed journals only. Data of citations was retrieved from Thomson Reuter's ISI Web of Knowledge. The following indicators were reported: the number of publications and original articles (counting each author and first authors only) and the share of original articles out of all publications. With regard to citations, we reported the overall number, the percentage of publications, which were cited at least once and the median of citations per publication and per original article as well as the calculated h-index.ResultsThe 47university Departments of Anaesthesiology published 4.697 articles between 2011 and 2015, which make up 89% of all anaesthesiology research originating from Germany, Austria and Switzerland (overall 5.284 publications). Of these, 1.037 (22%) were classified as original articles. Considering only articles with first authors, equalizing a change of PubMed's affiliation field policy in 2012 to compare the numbers with previous periods, 3.709 publications and 821 original articles were published. 90% of all publications and 96% of original articles, respectively, were cited at least once. Publications were cited six times, while original articles were cited nine times. The university department of Anaesthesiology in Zurich published most (n=245), while most original articles were published in Vienna (n=77). The highest share of original articles was achieved by Vienna (37%). Publications from Berlin - Benjamin Franklin and Jena (11citations per publication) and original articles from Essen (23,5 citations per original article) achieved the highest citation rates.DiscussionIn contrast to the worldwide increasing trend, the number of publications of the university Departments of Anaesthesiology in Germany, Austria and Switzerland stagnated. The share of original articles out of all publications continues to decline in comparison to 2001-2010 (-6%). Despite this, original articles were cited more frequently and thus had a higher value for the scientific community. The reasons of the decrease in the number of original articles remain unclear and require further investigation to reverse this negative trend.ConclusionStrategies to foster academic work in anaesthesiology in Germany, Austria and Switzerland are required