Source: Masters Abstracts International, Volume: 47-06, page: 3545. Adviser: Leona K. Bartholomew. Includes bibliographical references.

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Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / "May 2002." Typescript. Vita. Includes bibliographical references (leaves 104-114).

A thesis presented to the Faculty of Medicine, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Medicine / Since changes occur in size, shape and haemoglobin content of red cells in disease a classification of the anaemias based on the morphology of the red cell has been widely used ( Wintrobe, 1956 ) . While such classification has a limited usefulness from the diagnostic and therapeutic approach it has two serious defects.. / IT2018

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Haematology. Johannesburg, March 2015 / The incidence of leukaemia in South Africa is 2.5 per 100 000 and has increased due to HIV. Accurate and timeous diagnosis of leukaemia directly impacts success of patient treatment and consequent survival. Usually the Full Blood count (FBC), white blood cell (WBC) differential count and review of the peripheral blood smear alerts the clinician to the possibility of leukaemia. However the number of qualified and skilled technologists in peripheral and central laboratories is on a continual decline making the performance of the critical function of peripheral blood review a challenge. The Advia 2120 haematology analyser performs a WBC and differential count using principles of flow cytometry and the cytograms generated can be used to classify haematological malignancies through the Peroxidase and nuclear density analysis (PANDA) classification system. The presence of myeloperoxidase (MPO) activity in 3% or more leukaemic blasts confirms acute myeloid leukaemia, and enzyme activity can be detected by immunophenotypic analysis or conventional cytochemistry . Research on the comparison of the Advia 2120 and manual morphologic assessment in the classification of leukaemias is limited in the South African setting, where leukaemia often coincides with infection. The aim of this study was to determine if the FBC, differential count and cytogram assessment by the Advia 2120 using the PANDA classification is as reliable as morphologic assessment in the initial classification of haematological malignancies from peripheral blood samples when using flow cytometry as the gold standard.. 150 cases of confirmed leukaemia were collected. The diagnosis obtained from either PANDA analysis and/or morphological assessment was compared to the diagnosis obtained by immunophenotypic analysis. Secondly, the MPO activity obtained by the Advia peroxidase cytogram was compared to the MPO obtained by conventional methods of immunophenotypic analysis and/or cytochemistry. Using the PANDA analysis system, only 48% (72/150) of cases overall were accurately classified. The inaccuracy was 9.3% (14/150) and 42.7% of cases could not be classified. The positive predictive value (PPV) was 88%. The most significant finding was all of the acute Page | iv promyelocytic leukaemia (APL) cases (8/8) had a distinct pattern and were accurately classified on cytogram analysis alone. Accurate sub-classification of other types of acute myeloid leukaemia using PANDA analysis alone was inconsistent. However, the accuracy in classifying leukaemia was improved when the Advia cytogram was used in conjunction with morphological analysis, as 90% (135/150) of cases were accurately classified. The sensitivity and specificity of the peroxidase cytogram in evaluating myeloperoxidase (MPO) activity was 85% and 88.6% respectively. The agreement between cytogram peroxidase activity and the reference methods was 89.1% and the Cohen’s kappa was 76.9%. To the best of our knowledge, there is no data comparing peroxidase activity on the cytogram to other methods. In conclusion, it was shown that the routine use of the Advia cytograms in conjunction with the morphology findings provides invaluable information in the initial screening of leukaemia. In cases with indistinct morphology, the cytograms have the potential to aid in a provisional classification. The peroxidase activity from the cytogram could be used as a surrogate marker for myeloperoxidase activity in leukaemia. Moreover, a tentative diagnosis of an APL is possible by simple analysis of the cytogram resulting in earlier diagnosis which could be life-saving.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 104-114).

The Fanconi Anemia (FA)/BRCA DNA damage repair pathway plays a critical role in the cellular response to stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA DNA damage repair pathway genes are overexpressed and causative for resistance in multiple myeloma (MM) cell lines selected for resistance to melphalan. We hypothesized that the FA/BRCA DNA damage repair pathway mediates response and resistance to chemotherapeutic agents used to treat multiple myeloma and other cancers, and targeting this pathway is vital to overcoming drug resistance. In this dissertation, we show that FA/BRCA pathway genes are collectively overexpressed in MM, prostate, and ovarian cancer cell lines selected for resistance to melphalan and cisplatin, respectively. Interestingly, cells selected for resistance to topoisomerase II inhibitors selectively overexpress only FANCF. We also show that FA/BRCA pathway expression can be inhibited by the proteasome inhibitor bortezomib. FA/BRCA pathway mRNA expression was inhibited by bortezomib in myeloma cell lines and patient samples. FANCD2 gene and protein expression are downregulated by bortezomib, and remain attenuated in the face of melphalan treatment. Melphalan-induced FANCD2 foci formation was also inhibited by bortezomib, and this drug enhanced melphalan-induced DNA damage, likely via inhibition of FA-mediated DNA damage repair. Next, we analyzed regulation of the FA/BRCA pathway. We demonstrate that NF-kappaB, specifically the Re1B/p50 subunits, transcriptionally regulates members of the FA/BRCA pathway, and inhibition of these subunits by siRNA, BMS-345541, and bortezomib reduces FA/BRCA pathway expression. Furthermore, knocking down Re1B and p50 simultaneously attenuates FANCD2 protein expression and results in diminished DNA repair and enhanced sensitivity to melphalan. Importantly, melphalan resistance was restored when FANCD2 was re-expressed in these cells. We also show that bortezomib regulates FANCD2 protein expression directly, by inhibiting FANCD2 synthesis. Finally, we demonstrate that low-dose bortezomib arrests cells in G0/G1 and also overcomes the S-phase arrest induced by melphalan, likely via inhibition of ATR. Overall, our findings provide evidence for targeting the FA/BRCA pathway, either directly or indirectly, via inhibition of NF-kappaB or ATR, to enhance chemotherapeutic response and reverse drug resistance in multiple myeloma and other cancers.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.