Sphingosine Kinases in B-lineage Acute Lymphoblastic Leukaemia

The work presented in this thesis examines firstly, the effects of the sphingosine like immunomodulatory drug FTY720 on B-lineage acute lymphoblastic leukaemia (ALL) cells. Secondly, the research focuses on a related area, namely, the intra-cellular enzymes called sphingosine kinases (SphKs). FTY720 resulted in cytotoxic effects and the induction of autophagy, in vitro in ALL cells. However, disparate in vivo effects were seen in Ph+ and Ph- ALL with a reduction in disease burden seen only in the former, highlighting the importance of pharmacological testing in both in vitro and in vivo settings. Sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (SphK2) are over-expressed in ALL with inhibition producing cytotoxic effects, autophagy and predominantly caspase-independent cell death. SphK1 and SphK2 gene deletion resulted in reduced leukaemia penetrance in a murine Ph+ ALL disease model and SphK2 inhibition reduced the growth of human ALL xenografts. SphK2 inhibition resulted in lower MYC gene and protein expression through reduced association of acetylated histone H3 with the MYC promoter. This establishes a completely novel insight into the interactions of SphK2 in ALL and signifies the importance of sphingolipid signalling in this aggressive malignancy

Sydney Conservatorium of Music Postgraduate Handbook 2009

In stage III breast carcinoma, metastasized disease needs to be determined. In the past, conventional imaging by liver ultrasound, chest X-ray and bone scintigraphy was the work-up of choice. Recently, FDG-PET/CT was found to have additional value, but clinicians are hesitant to introduce this technique. We present three patients in whom FDG-PET/CT was applied. A 61-year-old woman with stage III breast carcinoma after conventional work-up was upstaged to stage IV breast carcinoma by FDG-PET/CT, upon which her treatment was changed. A 55-year-old woman suspected of stage IV breast carcinoma after conventional imaging was downstaged to stage III after FDG-PET/CT. Her treatment was changed as well. In a 78-year-old woman with recurrent breast carcinoma, the diagnostic certainty of stage III breast carcinoma was increased by FDG-PET/CT. We conclude that FDG-PET/CT is valuable for adequately diagnosing metastases in patients with stage III breast carcinoma and can replace conventional imaging

The Herschel view of the environment of the radio galaxy 4C+41.17 at z = 3.8

We present Herschel observations at 70, 160, 250, 350 and 500 μm of the environment of the radio galaxy 4C+41.17 at z = 3.792. About 65 per cent of the extracted sources are securely identified with mid-infrared sources observed with the Spitzer Space Telescope at 3.6, 4.5, 5.8, 8 and 24 μm. We derive simple photometric redshifts, also including existing 850 and 1200 μm data, using templates of active galactic nuclei, starburst-dominated systems and evolved stellar populations. We find that most of the Herschel sources are foreground to the radio galaxy and therefore do not belong to a structure associated with 4C+41.17. We do, however, find that the spectral energy distribution (SED) of the closest (∼25 arcsec offset) source to the radio galaxy is fully consistent with being at the same redshift as 4C+41.17. We show that finding such a bright source that close to the radio galaxy at the same redshift is a very unlikely event, making the environment of 4C+41.17 a special case. We demonstrate that multiwavelength data, in particular on the Rayleigh–Jeans side of the SED, allow us to confirm or rule out the presence of protocluster candidates that were previously selected by single wavelength data setsPeer reviewe

Asymptomatic Pulmonary Hypertension in Systemic Lupus Erythematosus

Introduction Pulmonary arterial hypertension (PAH) is a serious and often fatal complication of systemic lupus erythematosus (SLE). Because the diagnosis of PAH often is made years after symptom onset, early diagnostic strategies are essential. Doppler echocardiography currently is considered the noninvasive screening test of choice for evaluating pulmonary hypertension. Aim Screening for asymptomatic pulmonary hypertension in systemic lupus erythematosus patients using Doppler echocardiography, and correlating it with inflammatory parameters of the disease. Patients and Methods Doppler echocardiography was performed in 74 patients with systemic lupus erythematosus over one year (66 adult and 8 juvenile), adult SLE included 57 patients with adult-onset and 9 patients with childhood-onset. Pulmonary hypertension was diagnosed if the peak systolic pressure gradient at the tricuspid valve was more than 30 mmHg. All patients were subjected to full history taking, rheumatological examination, laboratory studies and chest x-ray. Results In seventy four SLE patients, the pulmonary hypertension was detected in 8 patients (10.8%), 7 adult-onset SLE patients (aged from 19 to 30 years) and 1 juvenile SLE (aged 12 years). The range of pulmonary artery systolic pressure was 34–61.2 mmHg (43.19 ± 9.28). No significant differences between patients with and those without pulmonary hypertension as regard clinical features. Significantly higher frequencies of rheumatoid factor and anti-cardiolipin antibodies were found in patients with pulmonary hypertension versus those without ( P = 0.02, P = 0.008 respectively). Positive rheumatoid factor and ACL were significantly associated with occurrence of PAH in SLE ( P = 0.007, P = 0.006 respectively). No significant correlations were found between pulmonary artery pressure, disease duration, SLE Disease Activity Index (SLEDAI), ESR, and anti-ds DNA. Conclusion Patients with SLE have an increased risk of pulmonary arterial hypertension. Echocardiography should be used as a screening tool in patients at high risk for development of pulmonary hypertension. Positive anti-cardiolipin antibodies and rheumatoid factor were significant predictors of pulmonary hypertension in our study

The role of 18F-FDG-PET/CT in the management of patients with high-risk breast cancer: case series and guideline comparison

Objectives: In grade III-IV breast cancer, dissemination of disease needs to be assessed. Until now this was done by conventional imaging (liver ultrasonography, chest X-ray and bone scintigraphy), but evidence favoring the use of FDG-PET/CT is accumulating. Methods: Patients with high-risk breast cancer, who had received conventional imaging and FDG-PET/CT, were included. Patients were staged and assigned a treatment after 1) conventional imaging and 2) FDG-PET/CT, both by a multidisciplinary oncology team. Equivocal FDG-PET/CT findings were histologically confirmed. Results: 16 patients were included (mean age 59 years). TNM-stage changed in 5 patients (31%) after FDG-PET/CT. In 3 patients (19%) unknown distant metastases were detected by FDG-PET/CT. An adjustment of treatment took place in 4 patients (25%). Conclusions: Our case series emphasizes the role of FDG-PET/CT in the staging of high-risk breast carcinoma, especially in the assessment of distant metastases. We suggest replacing conventional imaging with FDG-PET/CT

Laser irradiation of parylene disks with a 1.06 mumum laser

Parylene disks supported on glass stalks were irradiated with 1.06 $mu$m wavelength laser light pulses focused to flux intensities in the range from 10$sup 15$ to 10$sup 17$ W/cm$sup 2$. According to photodiode measurements the fraction of laser light absorbed, 25 to 50 percent, increased slightly as the laser intensity was increased. However, box calorimeter measurements implied that the fraction absorbed was approximately 30 percent and insensitive to irradiation intensity. Some x-ray spectra are discussed. (MOW

Evaluatie Politiewet 2012 in de Eenheid Oost-Nederland en landelijke thema's

At the request of the commission ‘Evaluatie Politiewet 2012’, the Rotterdam School of Management, Erasmus University, conducted an evaluation of the functioning of the Police Unit East-Netherlands (Eenheid Oost-Nederland). In addition, the nationally relevant themes with respect to ‘the role of the corps chef’, ‘the use of the right to appoint’, and the ‘construction of the police force as a separate legal entity’ were included in the evaluation at the request of the minister of Security and Justice of the Netherlands. The goal of the evaluation is to gain insights into the consequences of the implementation of the national police for the Unit East-Netherlands. The main question of th