An investigation into the prognosis of electromagnetic relays.

Electrical contacts provide a well-proven solution to switching various loads in a wide variety of applications, such as power distribution, control applications, automotive and telecommunications. However, electrical contacts are known for limited reliability due to degradation effects upon the switching contacts due to arcing and fretting. Essentially, the life of the device may be determined by the limited life of the contacts. Failure to trip, spurious tripping and contact welding can, in critical applications such as control systems for avionics and nuclear power application, cause significant costs due to downtime, as well as safety implications. Prognostics provides a way to assess the remaining useful life (RUL) of a component based on its current state of health and its anticipated future usage and operating conditions. In this thesis, the effects of contact wear on a set of electromagnetic relays used in an avionic power controller is examined, and how contact resistance combined with a prognostic approach, can be used to ascertain the RUL of the device. Two methodologies are presented, firstly a Physics based Model (PbM) of the degradation using the predicted material loss due to arc damage. Secondly a computationally efficient technique using posterior degradation data to form a state space model in real time via a Sliding Window Recursive Least Squares (SWRLS) algorithm. Health monitoring using the presented techniques can provide knowledge of impending failure in high reliability applications where the risks associated with loss-of-functionality are too high to endure. The future states of the systems has been estimated based on a Particle and Kalman-filter projection of the models via a Bayesian framework. Performance of the prognostication health management algorithm during the contacts life has been quantified using performance evaluation metrics. Model predictions have been correlated with experimental data. Prognostic metrics including Prognostic Horizon (PH), alpha-Lamda (α-λ), and Relative Accuracy have been used to assess the performance of the damage proxies and a comparison of the two models made

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common type of leukemia. The Cancer Genome Atlas Research Network has demonstrated the increasing genomic complexity of acute myeloid leukemia (AML). In addition, the network has facilitated our understanding of the molecular events leading to this deadly form of malignancy for which the prognosis has not improved over past decades. AML is a highly heterogeneous disease, and cytogenetics and molecular analysis of the various chromosome aberrations including deletions, duplications, aneuploidy, balanced reciprocal translocations and fusion of transcription factor genes and tyrosine kinases has led to better understanding and identification of subgroups of AML with different prognoses. Furthermore, molecular classification based on mRNA expression profiling has facilitated identification of novel subclasses and defined high-, poor-risk AML based on specific molecular signatures. However, despite increased understanding of AML genetics, the outcome for AML patients whose number is likely to rise as the population ages, has not changed significantly. Until it does, further investigation of the genomic complexity of the disease and advances in drug development are needed. In this review, leading AML clinicians and research investigators provide an up-to-date understanding of the molecular biology of the disease addressing advances in diagnosis, classification, prognostication and therapeutic strategies that may have significant promise and impact on overall patient survival

Development of fluorine-18 radiolabelled peptides for targeted imaging of the CXCR4 chemokine receptor

The chemokine receptor CXCR4 has been shown to be over-expressed in multiple cancer types and is often linked to a poor prognosis, making it a significant target of interest for both imaging and therapeutics. Early diagnosis, imaging and identification of this receptor, along with others shown to be over-expressed, can inform treatment selection and lead to improved outcomes for patients.The development of a fluorine-18 based CXCR4 targeting tracer is intended to facilitate an increase in clinical availability due to the longer half-life than the more commonly used gallium-68 tracers such as Pentixafor. A range of novel tracers were synthesised with different length PEG chain spacers, building on previous work by the Archibald group. Competition binding assays and calcium mobilisation assays showed the length of these spacers did not appear to impact on the binding properties of the tracer, with CPCR4-PEG2-PEG3-F and CPCR4-PEG4-PEG4-F having very similar IC50 values (198.95 ± 4.75 nM and 199 ± 48.6 nM respectively, by competition binding assay).Multiple synthetic routes were developed to increase yields and ease of purification before CPCR4- PEG4-PEG4-18F was progressed to in vivo testing, with final formulated yields of 37 % ± 15 % (decay corrected) delivering 103 ± 53 MBq (n = 5).Imaging and in vivo studies show significant tumour uptake, with a tumour: muscle ratio of 2.9 at 50 minutes after tracer’s administration. Analysis by HPLC also showed a reasonable average tracer stability in the tumour, urine and liver (59, 69 and 78% respectively), with metabolites almost undetectable in the plasma.In vivo studies showed that, while the lipophilicity of this novel tracer is lower than the previous derivatives produced by the Archibald group (-1.13 ± 0.01 compared to the previous value of -0.14 ± 0.02), the excretion route is primarily via the biliary system and gut, rather than the renal system. It is still a significant improvement on the previous attempt and shows promise for future development of this tracer class for fluorine-18

Biotechnology

Biotechnological problems of man machine systems required for long duration space flight

Hunting a Silent Killer. Biomolecular Approaches in Ovarian Cancer

Ovarian cancer is a heterogeneous disease and recent advances in improving patient outcome havebeen limited. It is estimated that a woman’s risk of developing ovarian cancer during her lifetime is about 1 in 70, making it a frequently occurring cancer type in women.This thesis investigated biological events in ovarian cancer, which were translated into clinically relevant observations using different biomolecular approaches.Study I investigated the use of sex steroid hormone receptor expression as a prognostic marker in ovarian cancer. We evaluated the expression of estrogen receptor (ER)α, ERβ, progesterone receptor (PR) and androgen receptor (AR) in a cohort of serous and endometrioid cancers. We found that expression of PR and AR was associated with favorable outcome, and co-expression of AR and PR granted an additional prognostic effect. Although we were unable to detect any association between mRNA expression and a favorable outcome in an independent data set, molecular subtypes in the data set differentially expressed PGR and ESR1. Whether this effect accounted for the reported improved outcome in some of the subgroups remains to be investigated.Study II characterized ovarian clear cell carcinomas (OCCC) with the purpose of identifying potential treatment candidates. OCCC presents a distinct molecular subtype of ovarian cancer, with high chemoresistance. Through integrative bioinformatics we evaluated combined gene expression data, DNA sequencing data and protein expression data from OCCC tumors. The collective data suggested Rho GTPases as a potential treatment candidate in OCCC.Study III evaluated the effect of targeting Rho GTPases in OCCC using simvastatin and CID-1067700 in OCCC cell lines. All OCCC cell lines were more sensitive to simvastatin as compared to conventional platinum-based chemotherapy. Both of the drugs we evaluated were found to disorganize the cytoskeleton and inhibit migration. The cellular response mechanisms differed between cell lines, however a potential effect on both the PI3K/AKT/mTOR and RAS/ERK pathways was suggested.Study IV aimed at evaluating the effects of screening prediagnostic liquid based vaginal samples for TP53 mutations, an approach applied for early detection of ovarian cancer. We identified 8 women with somatic TP53 mutations in high-grade serous ovarian cancer (HGSOC) and analyzed both prediagnostic (presymptomatic) and diagnostic vaginal samples. We used ultrasensitive droplet digital PCR (ddPCR) (IBSAFE™) and found mutations in diagnostic samples from 75% (6/8) of the patients; however, no mutations were detected in the prediagnostic samples. Despite this ddPCR was able to analyze samples with very limited DNA, where other methods would fail. This provides a basis for the further evaluation of IBSAFE™ in a larger cohort of patients.In conclusion, these studies further characterized ovarian cancer biology and heterogeniety, and have provided the basis for future studies in ovarian cancer with the potential of improving outcome

Metastatic Breast Cancer: Biomolecular Characterization and Targeted Therapy

Metastasis is a complex process that remains a major challenge in the clinical management of cancer, because most cancer-related deaths are attributed to disseminated disease rather than the primary tumor. Despite the significant advances in the prediction of prognosis, and therapeutic management of primary breast cancers, coupled with the substantial improvement in our understanding of the molecular determinants of metastasis, breast cancer relapse and death rates remain unacceptably high. The aim of the research presented in this thesis was to characterize the biomolecular heterogeneity of breast cancer across tumor progression stages and to identify novel biomarkers and therapeutic strategies which may improve prognostication and personalization of therapy for women diagnosed with metastatic breast cancer. By analysis of tumor biopsies collected at different stages of disease progression, we showed that, in general, the phenotype of the primary tumor is typically conserved during tumor progression. However, in a clinically relevant number of cases, a phenotypic drift in biomarkers and tumor molecular subtypes occurs longitudinally with disease progression, with a change to a more aggressive phenotype being associated with an inferior clinical outcome. We also uncovered that breast cancer liver metastases are transcriptionally different from metastases in other anatomical sites and identified candidate liver metastasis-selective genes with the potential to specifically predict liver metastatic relapse and more generally, the time to any recurrence in early stage breast cancer. Furthermore, we demonstrated that co-targeting of PARP1 and PI3K may represent an improved and specific treatment strategy for BRCA1 deficient breast cancers. The results we present continue to emphasize the clinical significance of breast cancer heterogeneity and highlight possible ways to improve the accuracy of predicting prognosis and effectively treating patients with metastatic disease, a step towards achieving the promise of personalized cancer management and overcoming the clinical burden of metastatic breast cancer

A characterization and comparison of the microRNA expression profile in breast cancer cell lines and exosomes

Breast cancer is the leading cause in cancer deaths among woman worldwide, and one in ten women will experience the disease during their lifetime. Breast cancer accounted for 23% of the total new cancer incidences and 14% of the total cancer deaths in Norway in 2008. One way to potentially improve long-term cancer survival statistics is earlier detection. That includes the discovery and characterization of minimally invasive and unique breast cancer biomarkers to aid early diagnosis. The presence of circulating microRNAs (miRNAs) in blood components (including serum and plasma) has been repeatedly observed in cancer patients as well as healthy controls. Since the deregulation of miRNA is associated with cancer development and progression, profiling of circulating miRNAs has been used in a number of studies that aim to identify novel miRNA biomarkers. MiRNAs are small RNA molecules that regulate gene expression post-transcriptionally. They play a key role in diverse biological processes, including development, cell proliferation, differentiation, and apoptosis. Hence, altered miRNA expression contributes to the development and progression of human disease, including cancer. In this thesis, we used a strategy of small RNA profiling by Applied Biosystem’s next-generation sequencing system (SOLiD) to analyze the different genome-wide miRNA expression profiles in breast cancer cell lines and exosomes originating from breast cancer cell lines. We found a number of key miRNAs that were highly expressed in both the breast cancer cell lines and exosomes; miRNAs that could have potential as biomarkers for early breast cancer detection. We also sequenced miRNA from 14 breast cancer cell lines of different subtypes and miRNA from exosomes from 9 of those cell lines. This was done to investigate the potential differences in the miRNA expression patterns, both between the different subtypes of breast cancer cell lines and the exosomes originating from the cell lines. We identified miRNAs with a consistent high expression among all the cell lines and exosomes and miRNAs that were differentially expressed between the cell lines and exosomes. Finally, a comparison of the miRNA expression pattern between the exosomes and the cell lines revealed that the miRNA profiles in exosomes did not reflect the miRNA profiles observed in the parental cells

THE AIRCRAFT MAINTENANCE ENGINEER COMPETENCE WITHIN THE CONTEXT OF AVIATION SAFETY REGULATIONS

This thesis is intended to serve as a guide for operation of a flight safety function within international safety organizations. This paper is specifically focused on the impact of European Aviation Safety Agency (EASA) Regulations as they are strongly applied to Aircraft Maintenance. The paper is intended on responsibilities for releasing Aircraft Maintenance Engineer License to sign off aircraft for flight. It also includes guidance to competency requirements of the Aircraft Maintenance Engineer

Point-of-Care Detection Devices for Healthcare

With recent technological advances in multiple research fields such as materials science, micro-/nano-technology, cellular and molecular biology, bioengineering and the environment, much attention is shifting toward the development of new detection tools that not only address needs for high sensitivity and specificity but fulfil economic, environmental, and rapid point-of-care needs for groups and individuals with constrained resources and, possibly, limited training. Miniaturized fluidics-based platforms that precisely manipulate tiny body fluid volumes can be used for medical, healthcare or even environmental (e.g., heavy metal detection) diagnosis in a rapid and accurate manner. These new detection technologies are potentially applicable to different healthcare or environmental issues, since they are disposable, inexpensive, portable, and easy to use for the detection of human diseases or environmental issues—especially when they are manufactured based on low-cost materials, such as paper. The topics in this book (original and review articles) would cover point-of-care detection devices, microfluidic or paper-based detection devices, new materials for making detection devices, and others