Bayesian spatial modelling of childhood cancer incidence in Switzerland using exact point data: a nationwide study during 1985-2015

BACKGROUND: The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. This study is the first investigation of the spatial disease mapping of childhood cancers using exact geocodes of place of residence. METHODS: We included 5947 children diagnosed with cancer in Switzerland during 1985-2015 at 0-15 years of age from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardisation to adjust for age and year of diagnosis. We examined whether the spatial variation of risk can be explained by modelled ambient air concentration of NO$_{2}$, modelled exposure to background ionising radiation, area-based socio-economic position (SEP), linguistic region, duration in years of general cancer registration in the canton or degree of urbanisation. RESULTS: For all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for central nervous system (CNS) tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was weak evidence of an association of CNS tumour incidence with modelled exposure to background ionising radiation (RR per SD difference 1.17; 0.98-1.40) and with SEP (1.6; 1.00-1.13). CONCLUSION: Of the investigated diagnostic groups, childhood CNS tumours showed the largest spatial variation. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role

Identification of antibiotic agents directed against gram-negative bacteria by exploiting interspecies communication

Arising antibiotic resistances in bacteria pose a major global threat resulting in increased morbidi-ty, mortality and healthcare costs. Recently, the WHO stressed the need to develop new antibac-terial strategies and discover novel bactericidal compounds to turn the tides in the race against emerging treatment failures. Within the scope of this thesis, we contribute to that effort, focussing on the human pathogens Neisseria gonorrhoeae, causative of the sexually transmittable disease gonorrhea and Moraxella catarrhalis, a major player in pulmonary and middle ear infections. In a first approach we addressed the mechanism of gonococcal infection, and evaluated the gene transcription change of the pathogen upon interaction with its human epithelial receptors of the carcinoembryonic antigen related cell adhesion molecule (CEACAM) family. To observe in-teraction specific changes, we developed a cell free in vitro stimulation system to allow the bac-terium untainted contact with its human receptors CEACAM1 and 5. Transcriptomic analysis of stimulated samples revealed little to no changes upon receptor binding. This might indicate that the expression pattern is not influenced by the recognition of epithelial CEACAM-receptors or hint towards a non-changing transcription of gonococci when infecting their human host. Secondly, we prospected the potential of Pseudomonas aeruginosa, which is known to secure its dominance over other bacterial species through an intricate quorum sensing system. We found an inhibiting effect of Pseudomonas in direct growth competition and screened for poten-tial responsible candidates. Indeed, we identified several alkyl-quinolone-N-oxide agents, which conferred a remarkably strong and specific growth suppression on pathogenic Neisseria, while not impeding growth of commensals originating from the same genus. Out of these, nonyl-quinolone-N-oxide (NQNO) proofed to be the most efficient compound with a minimum inhibitory concentration of 5 µM (1.44 µg/mL). The compound is even able to supress proliferation in gon-ococcal strains which are resistant to multiple current treatment options, marking it as a promising candidate for the ambitious goals set by the WHO. Functionally, NQNO seems to influence bac-terial metabolism, as a reduction of ATP and an elevated production of reactive oxygen species was detected. The excellent cytotolerance displayed on cervix carcinoma cells paved the way for the medical use of NQNO. In vivo application in a humanized mouse model showed promising results, reducing the gonococcal load over a hundred fold compared to control treatment. To expand on this promising compound repertoire, we assessed the antimicrobial potential of PQS, the namesake of one of the pseudomonal quorum sensing systems. Indeed, PQS proved to strongly impair the growth of Moraxella catarrhalis. Through successive changes in the gen-eral scaffold of the agent we introduced optimizations resulting in compound 8 which harbours a nitrogen to sulphur substitution and an elongated alkyl chain. Compound 8 displayed a tenfold increased efficacy compared to PQS and was also able to inhibit growth of all tested clinical iso-lates of Moraxella catarrhalis. In this regard we detected an influence on the bacteria’s primary metabolism, reducing DNA, RNA, protein and ATP levels while leaving cellular integrity intact. Further, it inhibits growth substantially and lastingly already within 20 minutes after application starting at 0.5 µM (0.158 µg/mL). Comparable to NQNO, the compound does not negatively af-fect growth of commensal representatives of the genus and proofed to be well tolerated on hu-man pulmonary cells with a therapeutical window spanning two powers of magnitudes. Concluding, we can report, that we have identified and optimized two novel compounds derivat-ing from Pseudomonas aeruginosa that have ample potential in the fight against multiresistant gram-negative pathogenic bacteria.publishe

Signaling by epithelial members of the CEACAM Family - mucosal docking sites for pathogenic bacteria

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a group of immunoglobulin-related vertebrate glycoproteins. Several family members, including CEACAM1, CEA, and CEACAM6, are found on epithelial tissues throughout the human body. As they modulate diverse cellular functions, their signaling capacity is in the focus of current research. In this review we will summarize the knowledge about common signaling processes initiated by epithelial CEACAMs and suggest a model of signal transduction by CEACAM family members lacking significant cytoplasmic domains. As pathogenic and non-pathogenic bacteria exploit these receptors during mucosal colonization, we try to highlight the connection between CEACAMs, microbes, and cellular responses. Special emphasis in this context is placed on the functional interplay between CEACAMs and integrins that influences matrix adhesion of epithelial cells. The cooperation between these two receptor families provides an intriguing example of the fine tuning of cellular responses and their manipulation by specialized microorganisms

Bayesian spatial modelling of childhood cancer incidence in Switzerland using exact point data: a nationwide study during 1985-2015.

BACKGROUND The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. This study is the first investigation of the spatial disease mapping of childhood cancers using exact geocodes of place of residence. METHODS We included 5947 children diagnosed with cancer in Switzerland during 1985-2015 at 0-15 years of age from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardisation to adjust for age and year of diagnosis. We examined whether the spatial variation of risk can be explained by modelled ambient air concentration of NO2, modelled exposure to background ionising radiation, area-based socio-economic position (SEP), linguistic region, duration in years of general cancer registration in the canton or degree of urbanisation. RESULTS For all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for central nervous system (CNS) tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was weak evidence of an association of CNS tumour incidence with modelled exposure to background ionising radiation (RR per SD difference 1.17; 0.98-1.40) and with SEP (1.6; 1.00-1.13). CONCLUSION Of the investigated diagnostic groups, childhood CNS tumours showed the largest spatial variation. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role

A thiochromenone antibiotic derived from the Pseudomonas quinolone signal selectively targets the Gram-negative pathogen Moraxella catarrhalis

The Pseudomonas quinolone signal (PQS) is an important quorum sensing signal of the pathogen Pseudomonas aeruginosa. We discovered an additional activity of PQS as a narrow spectrum antibiotic. Exploiting the privileged structure of PQS by the synthesis of heteroatom-substituted analogues led to a class of 2-alkyl-3-hydroxythiochromen-4-ones with highly potent antibiotic activity against the nasopharyngeal pathogen Moraxella catarrhalis. Synthetic optimization resulted in minimum inhibitory concentrations in the nanomolar range even for clinical isolates of M. catarrhalis. Surprisingly, the growth of other human pathogens and commensals, including closely related Moraxella species, was not inhibited, indicating exceptional species selectivity. Mechanistic studies revealed that the antibiotic was bactericidal and likely inhibits a target in the primary energy metabolism causing rapid depletion of the cellular ATP pool.publishe