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No description available.

Thesis--Karolinska Institute. / Includes bibliographical references.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24289号 / 医博第4905号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小濱 和貴, 教授 妹尾 浩, 教授 長船 健二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Computational investigations were carried out on an advanced serpentine jet engine inlet duct to understand the development and propagation of secondary flow structures. Computational analysis which went in tandem with experimental investigation was required to aid secondary flow control required for enhanced pressure recovery and decreased distortion at the engine face. In the wake of earlier attempts with modular fluidic actuators used for this study, efforts were directed towards optimizing the actuator configurations. Backed by both computational and experimental resources, many variations in the interaction of fluidic actuators with the mainstream flow were attempted in the hope of best controlling secondary flow formation. Over the length of the studies, better understanding of the flow physics governing flow control for 3D curved ducts was developed. Blowing tangentially, to the wall at the bends of the S-duct, proved extremely effective in enforcing active flow control. At practical jet momentum coefficients, significant improvements characterized by an improved pressure recove ry of 37% and a decrease in distortion close to 90% were seen.

This study was conducted to determine the effects of compression on pressure drops in non-metallic flexible duct. Duct sizes of 12”, 14” and 16” diameters were tested at a five different compression ratios (maximum stretch, 4%, 15%, 30% and 45%) following the draw through methodology in ASHRAE Standard 120 -1999 – Methods of Testing to Determine Flow Resistance of Air Ducts and Fittings. With the pressure drop data gathered, equations were developed to approximate the pressure loss at a given air flow rate for a given duct size. The data gathered showed general agreement with previous studies showing an increase in compression ratio leads to an increase in static pressure loss through the duct. It was determined that pressure losses for compression ratios greater than 4% were over four times greater than maximum stretched flexible duct of corresponding duct size. The increased static pressure losses can lead to decreased performance in HVAC systems. The findings of this study add to the existing ASHRAE and industry data for flexible duct with varying compression ratios.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 5 uppsatser.

Pancreatic Ductal Adenocarcinoma (PDA) is one of the most lethal solid malignancies primarily because it is staunchly resistant to conventional cytotoxic chemotherapies. Xenograft models are typically not sophisticated enough to reproduce the complex pathophysiology of the clinical disease. This is the main reason why treatments that have shown promise in preclinical mouse models have not translated into improvements in median survival in the clinic. Genetically engineered KPC mice develop PDA in situ which recapitulates the genetic, molecular and pathophysiological features of human PDA. Spontaneous KPC tumours are also chemoresistant and this mouse model therefore provides an ideal platform from which to study the biology of PDA. Recent evidence suggests that poor perfusion and extensive fibrosis may prevent the delivery of cytotoxic agents to neoplastic PDA cells and are therefore at least in part responsible for the chemoresistance demonstrated by human PDA tumours and spontaneous KPC tumours. In this thesis we use non-invasive Magnetic Resonance Imaging techniques (Dynamic ContrastEnhanced (DCE-) MRI, Magnetisation Transfer Imaging (MTI)) and SHG microscopy to evaluate the perfusion properties and fibrosis of three different mouse models of PDA: spontaneous KPC tumours, allografts initiated by transplantation of pancreatic tumour cells derived from a KPC tumour, and allografts initiated by co-transplantation of these cells with pancreatic stellate cells (fibrotic allografts). Using DCE-MRI and MTI we showed that the perfusion of spontaneous KPC tumours and fibrotic allografts decreases with increasing tumour volume while the tumour macromolecular content increases with increasing tumour volume. This is in contrast to the viable portion of non-fibrotic allografts which have a low macromolecular content and exhibit sustained moderate perfusion irrespective of tumour volume. Ex viva SHG microscopy clearly showed differences in the type, distribution and magnitude of fibrosis in these models. Using MTI, we showed a differential between spontaneous and transplanted tumours, but not between fibrotic and non-fibrotic allografts. We subsequently investigated the ability of MTI to detect treatment-induced depletion of the stroma in spontaneous KPC tumours, to assess its possible application as a non-invasive biomarker for treatment response in the clinic. However, we were unable to detect such depletion by MTI, although ex viva SHG microscopy confirmed that it did occur. In summary, our results contribute to the body of know_ledge on the biology of PDA and strengthen the evidence that early detection of PDA would be required to improve the chances of effective drug delivery to PDA tumours.

Cholangiocarcinoma (CCA) is a rare cancer with a poor prognosis. Much of medical research has focused on investigating cancers with a higher incidence and little focus has been devoted to this disease. The aim of this thesis was to perform a protein analysis of CCA and cholangiocyte cell lines. Differences between immortalised cancer and normal cells were sought in order to identify potential therapeutic targets and/or diagnostic tools. A variety of CCA cell lines were used, reflecting both intra and extrahepatic disease. The different subtypes of CCA through the developed and developing world are also represented so differences were also sought between them. Proteomic analysis was performed using DIGE with subsequent spot selection. Identified spots were extracted and processed using mass spectrometry. In addition, available chemotherapy agents were tested in vitro against the same cell lines to check for their action and how this could be enhanced. A benzodiazepine receptor antagonist (PK11195) was used to demonstrate apoptosis promotion in the presence of established cytotoxic agents (gemcitabine, etoposide, 5 fluorouracil and cisplatin). Cytotoxic assays were carried out using the SRB (Sulphorhodamine B) assay. Cell lines were tested for benzodiazepine receptor status using qRTPCR and response was correlated.

The cortical collecting duct of the mammalian kidney plays a critical role in the regulation of body volume, sodium pH and osmolarity and is composed of two distinct cells types, principal cells and intercalated cells. Each cell type is detectable in the kidney by the localization of specific transport proteins such as Aqp2 and ENaC in principal cells and V-ATPase B1 and Cx30 in intercalated cells. mCCDcl1 cells have been widely used as a mouse principal cell line on the basis of their physiological characteristics. In this study, the mCCDcl1 parental cell line and three sub-lines cloned from isolated single cells (Ed1, Ed2, and Ed3) were grown on filters to assess their transepithelial resistance, transepithelial voltage, equivalent short circuit current and expression of the cell-specific markers Aqp2, ENaC, V-ATPaseB1 and Cx30. The parental mCCDcl1 cell line presented amiloride-sensitive electrogenic sodium transport indicative of principal cell function, however immunocytochemistry and RT-PCR showed that some cells expressed the intercalated cell-specific markers V-ATPase B1 and Cx30, including a subset of cells also positive for Aqp2 and ENaC. The three subclonal lines contained cells that were positive for both intercalated and principal cell-specific markers. The vertical transmission of both principal and intercalated cell characteristics via single cell cloning, reveals the plasticity of mCCDcl1 cells, and a direct lineage relationship between these two physiologically important cell types, and is consistent with mCCDcl1 cells being precursor cells. For observation of live mCCDcl1 in an environment closer to in vivo conditions, a model of collecting duct was designed and developed using 3D printing of porous polymers. mCCDcl1 were cultured successfully and demonstrated improved characteristics compared to classic culture such as improved lifespan, different morphology and increased protein expression, and retained their phenotypic plasticity.