Browsing by Department "Division of Clinical Haematology"

Now showing 1 - 14 of 14
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    The development of a flow cytometric method to detect the presence of mutated nucleophosmin in Acute Myeloid Leukaemia
    (2014) Du Pisani, Louis Almero; Shires, Karen
    Nucleophosmin (NPM1) is an acidic, nucleo-cytoplasmic, shuttling protein with predominant nucleolar localisation that plays multiple roles in cell growth and proliferation. Deletion insertion mutations of NPM1 (NPM1 DIM) seem to disrupt it normal physiologic role as a molecular chaperone, which likely leads to its oncogenic potential.NPM1 if present alone (not associated with FLT3 internal tandem duplications (FLT3-ITD)) is associated with significantly better overall survival and disease free survival in AML and has been entered as a provisional category in the World Health Organisation (2008) classification of Acute Myeloid Leukaemia with recurrent genetic abnormalities. Current methodology uses reverse transcriptase polymerase chain reaction (RT-PCR) and genomic deoxyribonucleic acid (DNA) PCR techniques to detect NPM1 DIM. Although these methods are robust and relatively easy to perform they can be expensive, labour intensive and not universally available. Six major variants of NPM1 DIM (Types A-F) have been described all leading to frame shift. All six types share the same last five amino acids in the C-terminal.The aim of this study was to develop a robust flow cytometry methodology that could be used in the routine assessment of AML samples to determine the mutational state of NPM, using a commercially available polyclonal antibody against the mutated NPM1.
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    Development of a rapid diagnostic screen for telomerase mutations associated with immunosuppressive therapy failure in patients with aplastic anaemia
    (2013) Xulu, Khethelo Richman; Shires, Karen; Mowla, Shaheen
    Includes abstract. Includes bibliographical references.
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    The diagnostic utility of bone marrow biopsies performed for the investigation of fever and/or cytopenias in HIV-infected adults at Groote Schuur Hospital.
    (2009) Van Schalkwyk, Willem Adendorff; Opie, Jessica
    This is a retrospective review of the results of consecutive bone marrow biopsies performed at our institution over a three year period on HIV positive patients for the investigation of fever and cytopenias. Clinical data, haematological parameters, morphology of bone marrow biopsy, Ziehl-Neelsen staining and microbiological culture results were analyzed. The aim of the study was to determine the diagnostic yield of this investigation.
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    Effects of bFGF (Basic Fibroblast growth factor) on the Haematopoietic Sequelae that follow transplantation
    (2000) Makgoka, Seretloane Japhtaline; Novitzky, Nicolas
    Recovery following bone marrow transplantation is associated with the reduction in the clonogenic potential of stroma-adherent CD34⁺ progenitors. The bone marrow stroma is also affected, resulting in poor support for the growth of stroma-adherent multipotent progenitors that form blastic colonies (CFU-bl). To determine the possible mechanisms of marrow damage in patients treated with peripheral blood stem cells (PBSCs) and bone marrow transplantation (BMT), we studied the effects of bFGF, a cytokine known to stimulate the survival and proliferation of fibroblasts, on the propagation of clonogenic progenitors and the marrow stroma. METHODS: In order to obtain the optimal bFGF concentrations to be used on patients' haematopoietic progenitors and bone marrow rnicroenvironment, haematologically normal individuals were studied in dose response studies. Control mononuclear cells from the Ficoll-Histopaque interface layer were divided into two aliquots: one to establish a stromal layer and to culture fibroblastic progenitors (CFU-Fs) in the presence of 0, 2 and 20 ng/ml bFGF with and without 20 ng/ml heparan sulphate (HS). The second aliquot was for the selection of the progenitor population. Stroma was quantitated by placing culture dishes on a grid containing 1mm squares and scoring the number of squares occupied by stromal layers as the percentage area covered. After 3 weeks of culture, a single cell suspension was prepared by incubation of stroma with 5% trypsin solution, and number of cells in the dishes enumerated with a particle counter. CFU-Fs were terminated on the 9th day of culture, stained with May-Grilnwald-Giemsa and scored using an inverted microscope. From the second aliquot, CD34⁺ cells were incubated with paramagnetic beads and target cells isolated with a magnet. Selected l x l 04/ml cells were cultured on prefom1ed controls' stroma that has been treated with 0, 2 and 20 ng/ml bFGF. Stroma-adhered cells were covered with 0.3% agar and cultured for 6 days. Aggregates of more than 20 cells were counted as CFU-bl. RESULTS: In normal individuals, the median surface area of the petri dish covered by stroma at 3 weeks of culture was 55% (range 30-65) and was significantly improved upon the addition of 2 ng/ml (median 70%; range 50-95 ; p= <0.05) and 20 ng/ml bFGF (median 80%; range 65-99; p= 0.004). Stromal cell numbers were 0.61 x 10⁶/2ml (range 0. 15-1.66), and they increased significantly with the addition of 2 and 20 ng/ml bFGF (p=0.03). The median colony forming unit-blasts (CFU-bl) scores were 121.8 x 10⁴/ml (range 43-271), and they expanded significantly with the addition of 20 ng/ml bFGF with and without heparan sulphate (p=0.03 and 0.01). It was then concluded that the 2 and 20 ng/ml bFGF with heparan sulphate be used on patients' cells in vitro. The median surface area covered by stromal layers in patients' samples at 3 weeks was 40% (range 0-55 vs. normal 50%), and it was in1proved significantly upon the addition of bFGF (median 78 vs. 50%; p= 0.001). Supplementation of stromal layers with bFGF accounted for a significant increase in patients stromal cell numbers (2.11 vs. normal 0.61 x 106/2ml; p< 0.05). Patients' CD34⁺ cells panned on normal stromal layers resulted in significantly fewer CFU-bl (median 40 vs. normal 90 x 10⁴/ml CFU-bl; p=0.009), but CFU-bl numbers were corrected following the addition of bFGF, matching the scores achieved by normal individuals (85 vs. normal 90 x l 04/ml). Normal CD34⁺ cells proliferated poorly on patients' stromal layers in the absence of bFGF (3 9 vs. normal 90 x 10⁴/ml), but colony numbers increased significantly upon addition of bFGF (91 vs. normal 90 x 10⁴/ml CFU-bl). Thirteen patients receiving peripheral blood stem cells (PBSCs) and nine patients undergoing bone marrow transplantation (BMT) were compared. These two stem cell sources were then compared to the normal population. Stromal layers in patients receiving PBSC grafts covered a greater surface area than the area covered in patients undergoing BMT (median 65 vs. 30%). They also had higher blastic colony than scores from BMT recipients (47 vs. 12 x 10⁴/ml CFU-bl; p= 0.2). Results can be summarized that bone marrow stroma from patients receiving mobilized progenitor cells proliferates better than those receiving bone marrow grafts. It can be concluded that poor stromal layer and CD34⁺ cell proliferation following peripheral blood stem cell transplantation can be corrected by addition of basic Fibroblastic Growth Factor.
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    HIV-associated Hodgkin lymphoma at Groote Schuur Hospital, Western Cape, South Africa
    (2017) Swart, Luhan; Opie, Jessica; Novitzky, Nicolas
    Background: Human immunodeficiency virus (HIV) is associated with an increased risk of developing Hodgkin lymphoma (HL). South Africa (SA) has the highest HIV prevalence rate in the world. There is currently no 5-year overall survival (OS) outcome based data for HIV-associated HL from SA. Methods: A bone marrow database was compiled of all bone marrow biopsies (BMB) reported at National Health Laboratory Service (NHLS) Groote Schuur Hospital (GSH) between January 2005 and December 2012. Patients who had a BMB performed for staging of HL or where HL was diagnosed on the BMB were included for further analysis. Clinical and laboratory data was extracted from medical and laboratory records. Primary outcome measures included histological subtype, bone marrow infiltration (BMI) by HL, CD4 count, HIV-viral load (HIV-VL), tuberculosis (TB) data, treatment with chemotherapy and 5-year overall survival (OS). Results: The database included 6569 BMB and 219 patients of these had HL and were included for analysis. The median age at presentation (32 years) was similar in the HIV+ and HIV-populations. While males predominated in the HIV-group, females predominated in the HIV+ group (male:female ratio of 1.5:1 vs 0.7:1, respectively). The majority of patients (71%) were HIV negative (HIV-) and 29% were HIV positive (HIV+). The diagnosis of HL was made on BMB in 17% of cases. BMI was seen in 37%(82/219) overall, and was found in more HIV+ patients (61%; 39/64) than HIV-patients (28%; 43/155; p= 0.03). The histological subtype varied according to HIV status with nodular sclerosis classical Hodgkin lymphoma (NSCHL) being most frequent in the HIV-group and classical Hodgkin lymphoma (CHL)-unclassifiable the most frequent in the HIV+ group. HIV+ patients had a median CD4 count of 149 x106/L and 39% were anti-retroviral therapy (cART) naive at HL diagnosis. HIV+ patients had received anti-TB therapy more frequently than HIV-patients (72% vs 17%; p= 0.007). More HIV+ patients did not receive chemotherapy than HIV-patients (31% vs 3%; p= 0.001). The 5-year OS was 56%. HIV+ patients with BMI had a 5-year OS of 18%. BMI, HIV status, low CD4 count, histological subtype and TB therapy had a statistical significant impact on 5-year OS (p< 0.01). Conclusion: BMB provided the diagnosis of HL in 17% of cases, confirming its diagnostic utility in our setting. BMI by HL was more common in HIV+ patients and was associated with significantly worse survival. Our cohort showed similar survival outcomes to other countries in Africa, Asia and Central America with comparable socio-economic constraints to SA.
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    Identification and characterisation of micrornas involved in the pathogenesis of HIV–associated non-Hodgkin's lymphoma
    (2017) Goolam Hoosen, Taahira; Mowla, Shaheen B
    Background: Since its discovery about three decades ago, the Human Immunodeficiency Virus (HIV) has claimed over millions of lives globally. Although our understanding of the mode of transmission and action of this causative agent for the Acquired Immune Deficiency Syndrome (AIDS) has increased through research, and treatment regimens developed and improved, in certain parts of the world the pandemic continues to expand. Sub-Saharan Africa, which is the epicentre of this global health concern, accounts for approximately 66% of the total number of individuals affected, with South Africa enduring the heaviest burden. South Africa has the world's largest antiretroviral therapy (ART) programme and as such, HIV infected people are living longer, and consequently the incidence of HIV co-morbidities has increased dramatically. HIV/AIDS defining cancers are such co-morbidities with Non- Hodgkin's lymphomas (NHL) being the second most common HIV-associated cancer. Diffuse Large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL) are the main subtypes and both present aggressively in HIV positive patients with rapid progression. The use of highly active antiretroviral therapy (HAART) has decreased the incidence of DLBCL in HIV positive patients, however the prevalence of these cancers still remain high in some settings. It has been suggested that the pathogenesis of these cancers in HIV infected individuals is complex and different to that in HIV uninfected individuals, with the possibility that the virus may have an oncogenic role. This has already been demonstrated in the case of the HIV/AIDSdefining cancer Kaposi Sarcoma. However, the same has not been unequivocally demonstrated in HIV-associated NHL. In light of this, the mechanisms through which viruses and viral components promote cellular transformation is an area of active research. One of these mechanisms manipulated by viruses is through the dysregulation of cellular microRNAs (miRNAs) which are small non-coding RNA molecules that are key regulators of gene expression. While they are essential for normal cellular functioning, their expression has been found to be deregulated in diseases including cancer. Several studies have described specific miRNA signatures for NHLs including for DLBCL and BL but none have been described for the HIV-association of these cancers. Aim: The aim of this project was to identify and characterise miRNAs involved in the pathogenesis of HIV-associated NHLs. This thesis reports on the changes in expression of miRNAs in B-cells exposed to an attenuated form (structurally intact but non-infectious) of HIV. Methods: We designed a custom miRNA microarray to identify deregulated miRNAs in the BL cell line Ramos that were exposed to HIV compared to microvesicle treated cells. It was initially planned to use both normal B-cells (L1439A) and BL cells for analysis but Ramos was selected due to technical reasons for this step. Thereafter we validated selected miRNAs by quantitative real-time PCR (qPCR) using single-tube TaqMan® Assays which was predominantly performed in the lymphoblastoid cell line L1439A, which is derived from a healthy donor. We then focused on further characterising the role of one miRNA in the development of HIV-associated NHL by using prediction programmes to predict its putative gene targets and then confirmed its target by using qPCR and western blot analyses. Results: Extensive and comprehensive analysis of the array data led to the identification of a large number of miRNAs which were differentially expressed, with 32 being selected for further studies. These 32 miRNAs include 16 upregulated and 16 downregulated miRNAs, and were selected because they displayed changes in expression by two or more folds. Thereafter, four miRNAs, namely miR-363-3p, miR-222-3p, miR-200c-3p and miR-575, were chosen for validation based on their reported involvement in cancer for validation. The results of two miRNAs (miR-575 (upregulated) (p<0.05) and miR-200c-3p (downregulated) (p<0.05)) were found to be consistent with the results obtained from the miRNA microarray whilst the other two were opposite to that result (both downregulated) (p<0.05). Using online tools as well as the published literature, several potential target genes of miR-575 were identified, namely DENND5A, CDK1, CSTA and ATAD5. One particular target, the BH3- like motif containing inducer of cell death (BLID), which is involved in apoptosis, has previously been confirmed as a gene target in non small cell lung cancer. Using qPCR, we found that BLID messenger RNA (mRNA) was downregulated in normal B-cells when exposed to HIV-1 AT-2. Unfortunately, the BLID protein could not be detected using western blot analysis despite several attempts at detecting varying concentrations of the protein and using two different positive control cell lines. Conclusion: The reverse correlation, between miR-575 and BLID mRNA expression in the same cell line and under the same treatment conditions, supports the notion that the downregulation of miR-575 may be physiologically relevant. However, this could not be further verified as the BLID protein could not be detected in the L1439A cells, even in the microvesicle treated control cells. Future studies should look at further characterisation of miR- 575 in the pathogenesis of HIV-associated NHLs by investigating other predicted gene targets of the miRNA. This will then be followed by loss and gain of function assays to confirm the miRNA:mRNA relationship. Furthermore, functional analyses, such as measure of apoptosis, expression of key regulators of the cell cycle, and other cellular events characteristic of cancer should be carried out to define the role of the miR-575 in the development of HIV-associated lymphoma.
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    Interactions between the haematopoietic stem cell and the myeloid microenvironment in aplastic anaemia
    (1993) Novitzky, Nicolas; Jacobs, Peter
    In patients with aplastic anaemia that respond to immunosuppressive therapy, quantitative, morphological and functional haematologic derangement have been reported. To explain these findings, abnormalities in the marrow stroma or the stem cell have been postulated. To define the relative contribution of each of the latter, the integrity of the bone marrow from sixteen patients that responded to anti-lymphocyte globulin and high dose methyl prednisolone was compared to normal individuals. Bone marrow mononuclear cells were divided into two fractions. From the first, stroma was cultured in aMEM containing 12.5% of both horse and foetal calf serum and 10-5 M hydrocortisone at 37° C in 5% CO2 in 90% humidity. The medium was changed weekly. Upon confluence, these stromal layers were studied morphologically and with cytospin preparations stained with Sudan black, 0 red oil, alkaline and acid phosphatases. The remainder was monocyte and lymphocyte depleted, CD 34+ progenitors were selected with paramagnetic beads and the population morphologically and immunophenotypically defined. To determine the functional status, control or patient CD 34+ progenitors, were suspended for two hours on normal or aplastic stroma for adherence to take place. The non-adhesive fraction was decanted by standardised washing and cultured for fourteen days in the presence of PHA-conditioned medium in the CFU-gm assay. Strama-adherent progenitors were covered with 0.3% agar and cultured for five days. Aggregates with more than twenty cells were scored (CFU-bl). The remaining CD 34+ cells were cultured in the mixed colony assay with combinations of recombinant cytokines belonging to the G protein super-family and the tyrosine kinase group in dose response studies. Light density cells from patients with treated aplasia contained significantly fewer CD 34+ cells than those present in the control suspensions (mean 0.65%, SD 0.35% vs 1.62%, SD 1.4%; p= 0.002). Normal and aplastic stroma became confluent at three and four weeks. There was no difference on the morphology or the cytochemical stains between the two groups. Functionally, aplastic bone marrow stroma supported CFU-bl formation no differently from normal layers. However, CD 34+ precursors from the patients cultured on control stroma resulted in significantly fewer CFU-bl (p= 0.0002,) and CFU-gm (p= 0.0009). This work provides original evidence supporting the reduced clonogenicity of the corresponding populations of CFU-bl from patients with aplasia is unrelated to attachment to the stroma, but intrinsic to the CD 34+ cells. Moreover, this study shows for the first time that exposure of these progenitors to growth factors belonging to the G protein and tyrosine kinase receptor families have defective responses, correctable only at supra physiological concentrations, while effects on combinations containing c-kit ligand, appear preserved. Following immunosuppressive therapy, the bone marrow is repopulated by a hypoproliferative progenitor cell population which responds suboptimally to physiological cytokine stimulation. This suggests that abnormal interactions between receptors and their ligands or alterations in the signal transduction for cell division by the cytokines belonging to the G superfamily lead to suboptimal growth.
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    Investigation of the role of the DNA-modifying enzyme, activation-induced cytidine deaminase (AID), in cancer
    (2016) Godsmark, Grant Kenneth; Mowla, Shaheen
    The DNA-editing enzyme, Activation-Induced cytidine Deaminase (AID) is essential for antibody diversification and plays an important role in immunity. AID is specifically expressed in activated B-cells and mutates targeted DNA sites, diversifying the antibody repertoire. Due to its mutagenic nature, AID expression is tightly regulated, however, its overexpression has been associated with translocation of the c-MYC oncogene, a characteristic of the B-cell derived cancer, Burkitt's lymphoma (BL). Although currently uncharacterised, AID overexpression has also been implicated in non-lymphoid cancers including prostate, liver and colon. The function of AID in the oncogenic process is not well defined and therefore this project is aimed at using cell culture models to study the function of AID in cancer. AID mRNA and protein expression levels were determined in five cell lines of B-cell origin, and 16 epithelial cell lines (colon, prostate, head and neck and oesophageal). While AID expression was easily detected in the B-cell derived cell lines, no significant expression of both AID mRNA and protein expression was found in all the epithelial derived cell lines. The B lymphoblastoid cell line, L1439A, which is derived from a healthy donor, and harboured relatively low AID expression, was originally selected for ectopic expression of AID. Transfection of this cell line using conventional methods and lipid and polymer based transfection reagents was not successful, and therefore, nucleofection was used, which caused successful uptake of the AID-expressing plasmids as well as corresponding controls. However, this method was too harsh for the L1439A cell line as it did not survive post-nucleofection. Based on this result, the BL cell line Ramos, which expresses relatively low AID compared to the other BL cell lines used in the screen, was selected as an alternative. Plasmids constitutively expressing AID, as well as their corresponding empty vector, were successfully introduced into these cells using an established nucleofection protocol. While cells containing the empty vectors could be selected and expanded in culture, cells overexpressing AID underwent apoptosis approximately three days post-transfection. This is likely due to the highly mutagenic nature of the enzyme. As an alternative approach to studying the function of AID in cancer, a knockdown approach was taken, using siRNA.
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    The iron-binding proteins of iron-absorbing rat intestinal mucosa
    (1983) Johnson, Glynis; Purvis, Langley R; Jacobs, Peter
    Iron deficiency anaemia is perhaps the most widespread nutritional deficiency disease; as result, the topic of iron absorption has received intensive investigation over a relatively long period of time. Most of the investigative thrust has come from clinical medicine and allied fields, with some associated biochemical investigation. Evidence from the latter has pointed towards the involvement of iron-binding proteins especially ferritin and transferrin in the absorptive process. While the biochemical literature on these two proteins, particularly transferrin, is vast, their roles in iron absorption are obscure. This study was undertaken, therefore, as an investigation into these proteins, their quantitation and role in iron absorption. The physiology of absorption was studied by injection of radiolabelled ferrous ascorbate into isolated intestinal loops and the determination of mucosal, blood and carcass uptake.
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    The platelet laminin receptor : discovery of a 67kDA receptor for laminin on the membranes of human platelets : characterisation and isolation
    (1995) Holland, Errol Anthony; Jacobs, Peter; Jamieson, Graham A
    Previous work on the binding of resting platelets to the basement membrane glycoprotein, laminin, has identified the Ic/IIa integrin c01aplex (CD49f/CD29), also known as VLA-6, as the receptor. There exists however, another protein with a molecular weight of 67kDa, that mediates this function on other cells. It is abundantly expressed on the membranes of breast cancer cells, where it plays a key role in both the localisation at, and penetration of vascular beds, by metastases. The objectives of this study were: * The development of a micro-titre assay similar to those used in previous studies, standardised and calibrated to characterize the adhesion of unstimulated normal human platelets to laminin-coated surfaces. * To determine the effect on adhesion of platelet activation, enzymatic surface-glycoprotein removal, antibodies to specific receptors and interaction with other adhesive proteins known to bind to platelet membranes. * To establish the in vivo relevance of the experimental findings, by the assay of adhesion of glycoprotein IIb/IIIa-deficient platelets of two patients with Glanzmann's Thrombasthenia. These studies serve d to distinguish specific binding sites for laminin from the known surface receptors of platelets. The methodology used to isolate laminin receptors from the membranes of breast carcinoma cells was then applied to platelet concentrates. Membranes were obtained by centrifuging the ultrasonic lysate of a unit of platelets. These were solubilized and passed over a laminin-Sepharose column. The bound components were eluted and identified by means of SDS-gel electrophoresis, after which a concentrate was tested for laminin binding by means of dot-blot methodology. The principle contribution of this work is the finding of a 67kDa receptor for laminin on the surface membranes of platelets. The combination of the various approaches applied to characterise the adhesion of platelets to laminin, show that this is a specific, Mg²⁺-dependent process, inhibited by Ca²⁺ and not enhanced by platelet activation. Adhesion was decreased by proteolysis with trypsin and chymotrypsin, showing that the adhesion is mediated by a surface glycoprotein. Proteolysis with the Serratia marcescens metalloprotease, which cleaves off glycoprotein lb, did not affect adhesion, proving that this well-known receptor for platelet adhesion is not involved in the adhesion. The receptors GPIV and glycocalicin were also excluded, as the presence of antibodies to these receptors had no effect. Prior incubation with fibrinogen or von Willebrand factor, which binds to specific receptors on the platelet membrane, inhibited adhesion, most likely due to spatial interference with the receptor site for laminin. The presence of the tetrapeptide recognised by the membrane receptors for many adhesive proteins, RGDS, at concentrations of up to 1mM, had no effect. The platelets of the two subjects with Glanzmann's Thrombasthenia adhered normally, definitively ruling out the involvement of GPIIb/IIIa, which is absent from these platelets. The isolation process recovered a membrane component from the laminin-Sepharose column with an elution pattern identical to that for the well characterised 67kDa receptor for laminin on the surface of breast carcinoma cells. They have the same molecular weights in both the reduced (67kDa) and non-reduced (53kDa) states. Blot identification demonstrated laminin binding by the eluate. In the last part of the work, collaborative studies using more sophisticated methodology have confirmed that platelet receptors for laminin play a role in their adhesion to living tissue. Anti-laminin Fab antibodies significantly decreased the adhesion when whole blood was perfused over isolated rabbit aortic segments. That these receptors are identical to the 67kDa receptor of breast carcinoma cells was shown by the specific, high affinity binding of antibodies directed at the carcinoma receptors to the surface of platelets when examined by flow cytometry. In addition, they inhibit platelet adhesion by 50-60% in the micro-titre assay. It is proposed that both the VLA-6 and the 67kDa receptors are required for platelet adhesion to laminin, possibly as a two-stage process, similar to the systems for adhesion to von Willebrand factor, where binding is initially to GPIb, followed by binding to GPIIb/IIIa. The possible relevance of this receptor in the pathophysiology of the metastatic process is discussed.
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    Review and re-appraisal of patients treated with splenectomy for immune thrombocytopenic purpura at five years and beyond
    (2002) Seth, Yunus S; Novitzky, Nicholas
    The risk of pneumococcal infection post splenectomy is life long so all patients undergoing splenectomy are given polyvalent (23-valent) unconjugated pneumococcal polysaccharide vaccine, preoperatively. The aim of this study was 1. to measure the success of splenectomy at a tertiary institution at 5 years and beyond. 2. To review the incidence of complications peri-operatively and long term. 3. Review the need for possible re-vaccination (as recommended in American and British guidelines and 4. perform a re-appraisal of patients found to be refractory to treatment.
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    The cytopenias in systemic lupus erythematosus
    (1989) Aronson, Ingrid
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