Unravelling cylindromas : a molecular dissection of CYLD defective tumours

Ph. D.Patients with germline mutations in the tumour suppressor gene CYLD develop multiple cutaneous tumours on the head and neck; historically this has been termed “turban tumour” syndrome. Cylindromas and spiradenomas, hair follicle related tumours seen in this syndrome, cause significant clinical morbidity. Here we characterise the clinical phenotype of these patients, utilising tumour mapping to determine the location of tumours in mutation carriers from two large pedigrees. We demonstrate the disease often affects sites outwith the head and neck, and that androgen stimulated hair follicles are particularly vulnerable to tumour formation. The impact of this disease is severe, with 1 in 4 carriers of this gene undergoing complete scalp removal. To improve this outcome, we performed whole genome profiling of CYLD defective tumours, characterising genomic and transcriptomic changes to determine targetable signalling pathways. High resolution analysis using whole genome array based comparative genomic hybridisation and single nucleotide polymorphism analysis suggest that loss of heterozygosity at the CYLD locus may be the only change required for tumour phenotype. Gene expression profiling highlighted transcriptomic similarity between cylindromas and spiradenomas. Threedimensional reconstruction in silico from serial sections of tumours demonstrated contiguous growth between cylindromas and spiradenomas, in support of this finding. In both tumour types, dysregulated tropomyosin receptor kinase (TRK) signalling was found. Consistent with this, was the finding that TRKB and TRKC protein was overexpressed selectively in the tumour samples, demonstrated on a tissue microarray. Therapeutic utility of targeting this pathway was demonstrated by reduced viability of CYLD defective primary cell cultures in the presence of TRK inhibitors. These preliminary data support the use of TRK inhibitors as a therapeutic strategy in severely affected CYLD mutation carriers.North East Skin Research fund, The Newcastle Hospital Trustees, Breakthrough Breast Cancer Research, The Medical Research Counci

Unravelling cylindromas : a molecular dissection of CYLD defective tumours

Patients with germline mutations in the tumour suppressor gene CYLD develop multiple cutaneous tumours on the head and neck; historically this has been termed “turban tumour” syndrome. Cylindromas and spiradenomas, hair follicle related tumours seen in this syndrome, cause significant clinical morbidity. Here we characterise the clinical phenotype of these patients, utilising tumour mapping to determine the location of tumours in mutation carriers from two large pedigrees. We demonstrate the disease often affects sites outwith the head and neck, and that androgen stimulated hair follicles are particularly vulnerable to tumour formation. The impact of this disease is severe, with 1 in 4 carriers of this gene undergoing complete scalp removal. To improve this outcome, we performed whole genome profiling of CYLD defective tumours, characterising genomic and transcriptomic changes to determine targetable signalling pathways. High resolution analysis using whole genome array based comparative genomic hybridisation and single nucleotide polymorphism analysis suggest that loss of heterozygosity at the CYLD locus may be the only change required for tumour phenotype. Gene expression profiling highlighted transcriptomic similarity between cylindromas and spiradenomas. Threedimensional reconstruction in silico from serial sections of tumours demonstrated contiguous growth between cylindromas and spiradenomas, in support of this finding. In both tumour types, dysregulated tropomyosin receptor kinase (TRK) signalling was found. Consistent with this, was the finding that TRKB and TRKC protein was overexpressed selectively in the tumour samples, demonstrated on a tissue microarray. Therapeutic utility of targeting this pathway was demonstrated by reduced viability of CYLD defective primary cell cultures in the presence of TRK inhibitors. These preliminary data support the use of TRK inhibitors as a therapeutic strategy in severely affected CYLD mutation carriers.EThOS - Electronic Theses Online ServiceNorth East Skin Research Fund : Newcastle Hospital Trustees : Breakthrough Breast Cancer Research : Medical Research CouncilGBUnited Kingdo

Onchocerca volvulus heat shock protein 70 is a major immunogen in amicrofilaremic individuals from a filariasis-endemic area

Infestation with organisms causing lymphatic filariasis (i.e. Wuchereria bancrofti and Brugia malayi) results in a variety of clinical presentations. It is possible that some of the variation is due to differences in host response to parasite. To determine whether individuals who live in an endemic area but differ in their clinical manifestations respond to different filarial antigens, we screened Onchocerca volvulus expression libraries with sera from a number of individuals belonging to different clinical groups. The results of the study demonstrate that there are indeed differences in the recognition of three cloned filarial antigens and that this differential recognition is related to clinical symptomatology. The most striking finding is that an Onchocerca volvulus protein homologous to the 70 kDa Xenopus laevis heat shock protein is primarily recognized by individuals who are amicrofilaremic. Further analysis is required to determine whether these antigens play any role in the pathogenesis of filarial infection or have any potential value in protective immunity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28013/1/0000449.pd

Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome

Abstract: Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis

Capacity building for wildlife health professionals: the Wildlife Health Bridge

The Wildlife Health Bridge was established in 2009 with the aim of improving the expertise and knowledge base of wildlife health professionals in biodiverse low- and middle-income countries. The Wildlife Health Bridge centres around partnerships among educational institutions: the Zoological Society of London, the Royal Veterinary College, the University of Edinburgh’s Royal (Dick) School of Veterinary Studies, the Wildlife Institute of India, and the University of Melbourne Veterinary School. The Wildlife Health Bridge provides quality education in wildlife health, ecosystem health, and wildlife biology, facilitates the interchange of students between collaborating countries for research studies and provides a global graduate network of wildlife health professionals. In addition to established Masters’ level wildlife health training programmes run by the partner organisations, the Wildlife Health Bridge has developed a collaborative field-based course, Interventions in Wild Animal Health, provided annually in India since 2016, which has trained 138 veterinarians to date, enhancing local and international capacity in managing emerging wildlife health issues and building global professional linkages. The Wildlife Health Bridge’s Wild Animal Alumni network facilitates networking and exchange between Wildlife Health Bridge institutions and graduates, with over 701 members from 67 countries, half of which are biodiverse low- and middle-income countries. Collaboration between educational institutions has enabled new ideas and ongoing developments in the delivery of materials and learning outcomes. The Wildlife Health Bridge is building global capacity in trained wildlife health professionals, through educational programmes and a synergised network, with the aim of impacting conservation practice to benefit human, domestic animal and wildlife health

A real-time, scalable, fast and highly resource efficient decoder for a quantum computer

Quantum computers promise to solve computing problems that are currently intractable using traditional approaches. This can only be achieved if the noise inevitably present in quantum computers can be efficiently managed at scale. A key component in this process is a classical decoder, which diagnoses the errors occurring in the system. If the decoder does not operate fast enough, an exponential slowdown in the logical clock rate of the quantum computer occurs. Additionally, the decoder must be resource efficient to enable scaling to larger systems and potentially operate in cryogenic environments. Here we introduce the Collision Clustering decoder, which overcomes both challenges. We implement our decoder on both an FPGA and ASIC, the latter ultimately being necessary for any cost-effective scalable solution. We simulate a logical memory experiment on large instances of the leading quantum error correction scheme, the surface code, assuming a circuit-level noise model. The FPGA decoding frequency is above a megahertz, a stringent requirement on decoders needed for e.g. superconducting quantum computers. To decode an 881 qubit surface code it uses only $4.5\%$ of the available logical computation elements. The ASIC decoding frequency is also above a megahertz on a 1057 qubit surface code, and occupies 0.06 mm$^2$ area and consumes 8 mW of power. Our decoder is optimised to be both highly performant and resource efficient, while its implementation on hardware constitutes a viable path to practically realising fault-tolerant quantum computers.Comment: 11 pages, 4 figure

High contrast imaging at the LBT: the LEECH exoplanet imaging survey

In Spring 2013, the LEECH (LBTI Exozodi Exoplanet Common Hunt) survey began its $\sim$130-night campaign from the Large Binocular Telescope (LBT) atop Mt Graham, Arizona. This survey benefits from the many technological achievements of the LBT, including two 8.4-meter mirrors on a single fixed mount, dual adaptive secondary mirrors for high Strehl performance, and a cold beam combiner to dramatically reduce the telescope's overall background emissivity. LEECH neatly complements other high-contrast planet imaging efforts by observing stars at L' (3.8 $\mu$m), as opposed to the shorter wavelength near-infrared bands (1-2.4 $\mu$m) of other surveys. This portion of the spectrum offers deep mass sensitivity, especially around nearby adolescent ($\sim$0.1-1 Gyr) stars. LEECH's contrast is competitive with other extreme adaptive optics systems, while providing an alternative survey strategy. Additionally, LEECH is characterizing known exoplanetary systems with observations from 3-5$\mu$m in preparation for JWST.Comment: 12 pages, 5 figures. Proceedings of the SPIE, 9148-2