8 research outputs found
The Genetics of Basal Cell Carcinoma of the Skin
BCC is the commonest cancer in European-derived populations and Australia has the highest recorded incidence in the world, creating enormous individual and societal cost in management of this disease. The incidence of this cancer has been increasing internationally, with evidence of a 1 to 2% rise in incidence in Australia per year over the last two decades. The main four epidemiological risk factors for the development of BCC are ultraviolet radiation (UVR) exposure, increasing age, male sex, and inability to tan. The pattern and timing of UVR exposure is important to BCC risk, with childhood and intermittent UVR exposure both associated with an increased risk. The complex of inherited characteristics making up an individual’s ‘sun sensitivity’ is also important in determining BCC risk. Very little is known about population genetic susceptibility to BCC outside of the rare genodermatosis Gorlin syndrome. Mutations in the tumour suppressor gene patched (PTCH) are responsible for this BCC predisposition syndrome and the molecular pathway and target genes of this highly conserved pathway are well described. Derangments in this pathway occur in sporadic BCC development, and the PTCH gene is an obvious candidate to contribute to non-syndromic susceptibility to BCC. The melanocortin 1 receptor (MC1R) locus is known to be involved in pigmentary traits and the cutaneous response to UVR, and variants have been associated with skin cancer risk. Many other genes have been considered with respect to population BCC risk and include p53, HPV, GSTs, and HLAs. There is preliminary evidence for specific familial aggregation of BCC, but very little known about the causes. 56 individuals who developed BCC under the age of 40 in the year 2000 were recruited from the Skin and Cancer Foundation of Australia’s database. This represents the youngest 7 – 8% of Australians with BCC from a database that captures approximately 10% of Sydney’s BCCs. 212 of their first degree relatives were also recruited, including 89 parents and 123 siblings of these 56 probands. All subjects were interviewed with respect to their cancer history and all reports of cancer verified with histopathological reports where possible. The oldest unaffected sibling for each proband (where available) was designated as an intra-family control. All cases and control siblings filled out a questionnaire regarding their pigmentary and sun sensitivity factors and underwent a skin examination by a trained examiner. Peripheral blood was collected from these cases and controls for genotyping of PTCH. All the exons of PTCH for which mutations have been documented in Gorlin patients were amplified using PCR. PCR products were screened for mutations using dHPLC, and all detectable variants sequenced. Prevalence of BCC and SCC for the Australian population was estimated from incidence data using a novel statistical approach. Familial aggregation of BCC, SCC and MM occurred within the 56 families studied here. The majority of families with aggregation of skin cancer had a combination of SCC and BCC, however nearly one fifth of families in this study had aggregation of BCC to the exclusion of SCC or MM, suggesting that BCCspecific risk factors are also likely to be at work. Skin cancer risks for first-degree relatives of people with early onset BCC were calculated: sisters and mothers of people with early-onset BCC had a 2-fold increased risk of BCC; brothers had a 5-fold increased risk of BCC; and sisters and fathers of people with early-onset BCC had over four times the prevalence of SCC than that expected. For melanoma, the increased risk was significant for male relatives only, with a 10-fold increased risk for brothers of people with early-onset BCC and 3-fold for fathers. On skin examination of cases and controls, several phenotypic factors were significantly associated with BCC risk. These included increasing risk of BCC with having fair, easyburning skin (ie decreasing skin phototype), and with having signs of cumulative sun damage to the skin in the form of actinic keratoses. Signs reflecting the combination of pigmentary characteristics and sun exposure - in the form of arm freckling and solar lentigines - also gave subjects a significantly increased risk BCC. Constitutive red-green reflectance of the skin was associated with decreased risk of BCC, as measured by spectrophotometery. Other non-significant trends were seen that may become significant in larger studies including associations of BCC with propensity to burn, moderate tanning ability and an inability to tan. No convincing trend for risk of BCC was seen with the pigmentary variables of hair or eye colour, and a non-significant reduced risk of BCC was associated with increasing numbers of seborrhoeic keratoses. Twenty PTCH exons (exons 2, 3, 5 to 18, and 20 to 23) were screened, accounting for 97% of the coding regions with published mutations in PTCH. Nine of these 20 exons were found to harbour single nucleotide polymorphisms (SNPs), seen on dHPLC as variant melting curves and confirmed on direct sequencing. SNPs frequencies were not significantly different to published population frequencies, or to Australian general population frequencies where SNP database population data was unavailable. Assuming a Poisson distribution, and having observed no mutations in a sample of 56, we can be 97.5% confident that if there are any PTCH mutations contributing to early-onset BCC in the Australian population, then their prevalence is less than 5.1%. Overall, this study provides evidence that familial aggregation of BCC is occurring, that first-degree relatives are at increased risk of all three types of skin cancer, and that a combination of environmental and genetic risk factors are likely to be responsible. The PTCH gene is excluded as a major cause of this increased susceptibility to BCC in particular and skin cancer in general. The weaknesses of the study design are explored, the possible clinical relevance of the data is examined, and future directions for research into the genetics of basal cell carcinoma are discussed
Documentation and Modelling of the {IPC} Mechanism in the {L4} Kernel
Summary My diploma thesis is a part of the project "Verification of the L4 operating system kernel". The aim of this project ist to formally verify the L4 kernel in order to guarantee its correctness. In my thesis I have documented the implementation of the IPC mechanism in the L4 kernel. I proved the correctness of the message passing protocol of the IPC mechanism. This was done in three steps: At first I have created the formal specification of that protocol. After that I built a model of the IPC mechanism in PVS and at last I proved that the created model fulfils the specification. The model which is built in this work is not meant to be a precise representation of the original protocol. The proof of such a model is not the same as proofs for the original C code, but they may allow to write a correct source code. Therefore for software verification we need some tool that we can work with C-code or any programming language in order to verify its correctness
Using Isabelle/HOL to develop and maintain separation invariants for an operating system
We describe work on an Isabelle/HOL model for the specification of a separation kernel done within the EURO-MILS (http://www.euromils.eu/) project. We chose to extensible records to specify the state. By an example of a theory specifying a group of "event" API calls, it is shown how lemmas on local state are used for obtaining proof obligations for a global separation property
Formal Specification of a Generic Separation Kernel
Item does not contain fulltextIntransitive noninterference has been a widely studied topic in the last few decades. Several well-established methodologies apply interactive theorem proving to formulate a noninterference theorem over abstract academic models. In joint work with several industrial and academic partners throughout Europe, we are helping in the certification process of PikeOS, an industrial separation kernel developed at SYSGO. In this process, established theories could not be applied. We present a new generic model of separation kernels and a new theory of intransitive noninterference. The model is rich in detail, making it suitable for formal verification of realistic and industrial systems such as PikeOS. Using a refinement-based theorem proving approach, we ensure that proofs remain manageable
Formal API Specification of the PikeOS Separation Kernel
PikeOS is an industrial operating system for safety and security critical applications in, for example, avionics and automotive contexts. A consortium of several European partners from industry and academia works on the certification of PikeOS up to at least Common Criteria EAL5+, with "+" being applying formal methods compliant up to EAL7. We have formalized the hardware independent security-relevant part of PikeOS that is to be used in a certification context. Over this model, intransitive noninterference has been proven. We present the model and the methodology used to create the model. All results have been formalized in the Isabelle/HOL theorem prover
L'indice de gestion et d'efficacité en natation (IGEN)
Un exemple d'évaluation simultanée de la performance et de la maîtrise technique en natatio