Variants in the host genome may inhibit tumour growth in devil facial tumours: evidence from genome-wide association

Devil facial tumour disease (DFTD) has decimated wild populations of Tasmanian devils (Sarcophilus harrisii) due to its ability to avoid immune detection and pass from host to host by biting. A small number of devils have been observed to spontaneously recover from the disease which is otherwise fatal. We have sequenced the genomes of these rare cases and compared them to the genomes of devils who succumbed to the disease. Genome-wide association, based on this limited sampling, highlighted two key genomic regions potentially associated with ability to survive DFTD. Following targeted genotyping in additional samples, both of these loci remain significantly different between cases and controls, with the PAX3 locus retaining significance at the 0.001 level, though genome-wide significance was not achieved. We propose that PAX3 may be involved in a regulatory pathway that influences the slowing of tumour growth and may allow more time for an immune response to be mounted in animals with regressed tumours. This provides an intriguing hypothesis for further research and could provide a novel route of treatment for this devastating disease

Genome-Wide Association Studies in Dogs and Humans Identify ADAMTS20 as a Risk Variant for Cleft Lip and Palate

Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10-13; adjusted p= 2.2 x 10-3). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 – 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans

Non-neutralizing antibodies elicited by recombinant Lassa-Rabies vaccine are critical for protection against Lassa fever

Lassa fever (LF), caused by Lassa virus (LASV), is a viral hemorrhagic fever for which no approved vaccine or potent antiviral treatment is available. LF is a WHO priority disease and, together with rabies, a major health burden in West Africa. Here we present the development and characterization of an inactivated recombinant LASV and rabies vaccine candidate (LASSARAB) that expresses a codon-optimized LASV glycoprotein (coGPC) and is adjuvanted by a TLR-4 agonist (GLA-SE). LASSARAB elicits lasting humoral response against LASV and RABV in both mouse and guinea pig models, and it protects both guinea pigs and mice against LF. We also demonstrate a previously unexplored role for non-neutralizing LASV GPC-specific antibodies as a major mechanism of protection by LASSARAB against LF through antibody-dependent cellular functions. Overall, these findings demonstrate an effective inactivated LF vaccine and elucidate a novel humoral correlate of protection for LF.NIH grants R01 AI105204 to M.J.S., by the Jefferson Vaccine Center, and by the Fundação para a Ciência e Tecnologia (FCT) scholarship PD/BD/105847/2014 (to T.A.-M.). This work was also funded in part through the NIAID Division of Intramural Research and the NIAID Division of Clinical Research, Battelle Memorial Institute’s prime contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016Iinfo:eu-repo/semantics/publishedVersio

Chemoprevention of Human Cancer:A Reasonable Strategy?

The field of chemoprevention of cancer in humans is at a teenage level of maturity. There is anticipation and energy, and some promising results have come in, but it's unclear whether the entire enterprise is worth the effort. Reflecting on the status of the organism and where we are in its developmental history is therefore an important exercise at this time. Empirical and philosophical perspectives are offered for several key questions: Why prevent Cancer? What is the preclinical evidence that chemoprevention of cancer in humans should work? What is the clinical evidence that chemoprevention agents work? What is the clinical evidence that chemoprevention agent don't work? What is the status of ongoing randomized phase III/IV chemoprevention trials? The answers to each of these questions provide a part of the scaffold for a logical platform for the launching of the chemoprevention imperative as an integral part of our approach to the overall management of human cancer

Molecular basis for a new bovine model of Niemann-Pick type C disease

Niemann-Pick type C disease is a lysosomal storage disease affecting primarily the nervous system that results in premature death. Here we present the first report and investigation of Niemann-Pick type C disease in Australian Angus/Angus-cross calves. After a preliminary diagnosis of Niemann-Pick type C, samples from two affected calves and two obligate carriers were analysed using single nucleotide polymorphism genotyping and homozygosity mapping, and NPC1 was considered as a positional candidate gene. A likely causal missense variant on chromosome 24 in the NPC1 gene (NM_174758.2:c.2969C>G) was identified by Sanger sequencing of cDNA. SIFT analysis, protein alignment and protein modelling predicted the variant to be deleterious to protein function. Segregation of the variant with disease was confirmed in two additional affected calves and two obligate carrier dams. Genotyping of 403 animals from the original herd identified an estimated allele frequency of 3.5%. The Niemann-Pick type C phenotype was additionally confirmed via biochemical analysis of Lysotracker Green, cholesterol, sphingosine and glycosphingolipids in fibroblast cell cultures originating from two affected calves. The identification of a novel missense variant for Niemann-Pick type C disease in Angus/Angus-cross cattle will enable improved breeding and management of this disease in at-risk populations. The results from this study offer a unique opportunity to further the knowledge of human Niemann-Pick type C disease through the potential availability of a bovine model of disease