Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 2000. / Includes bibliographical references.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

In the normal adult human, hemopoiesis appears to be maintained by the simultaneous activity of many stem cell-derived clones. Conversely, most examples of human myeloid malignancies have been shown to represent clonal populations arising as a result of the unregulated expansion of a single transformed hemopoietic stem cell. The limits of the proliferative capacity of normal hemopoietic stem cells in humans and their persistence in hemopoietic malignancies have, however, not been extensively Investigated. One of the most likely reasons for this is the lack, until very recently, of a widely applicable method to analyze the clonality status of human cell populations. Methylation analysis of two polymorphic genes. HPRT and PGK, now allows such studies to be performed in approximately 50 % of females. The possibility that normal human hemopoietic stem cells might have the capacity to mimic the behaviour of some transformed stem cells by generating clones of progeny that could dominate the entire hemopoietic system was then examined. Such a phenomenon has been well documented in animal models of marrow cell transplantation. I therefore undertook an analysis of all allogeneic marrow transplants performed over a 1 to 1-1/2 year period where the genotype of the donor made clonality analysis using the HPRT or PGK systems possible. Using this approach, I obtained evidence in two patients suggesting that a single or, at most, a very small number of normal primitive hemopoietic stem cells were able to reconstitute the hemopoietic system. In one case the data suggested that such reconstitution was likely to have derived from a stem cell with both lymphopoietic and myelopoietic potential. However, in all other cases hemopoiesis in the transplant recipient was found to be polyclonal. Such findings indicate that clonal dominance in the hemopoietic system is not sufficient to infer that a genetically determined neoplastic change has occurred. In addition, these findings have implications for the design of future gene therapy protocols. The same methodology was also applied to investigate the clonality of different hemopoietic cell populations in patients with chronic myelogenous leukemia (CML) and essential thrombocytosis (ET). In both of these myeloproliferative disorders, the neoplastic clone produces terminally differentiated progeny that appear minimally different from normal. Data from the CML studies confirmed the non-clonal nature of the cells emerging in long-term CML marrow cultures. Similarly, patients transplanted with cultured autologous marrow were shown to undergo polyclonal and bcr-negative reconstitution of their hemopoietic system. Analysis of a series of patients with a clinical diagnosis of ET showed that polyclonal hemopoiesis in the presence of an amplified neoplastic clone is not a rare event in this disorder, and that clonality results do not always correlate with other neoplastic markers associated with myeloproliferative diseases in general. Another example of polyclonal hemopoiesis in the presence of an amplified neoplastic clone was demonstrated in a patient with Ph¹-positive ALL whose disease appeared to have originated in a lymphoid-restricted stem cell. The studies described in this thesis reveal a level of complexity of normal and neoplastic stem cell dynamics not previously documented. They highlight the need for more precise information about the molecular basis of regulatory mechanisms that govern hemopoietic cell proliferation and survival at every level of differentiation. Finally they support the accumulating evidence that acquisition of full malignant potential requires several additive genetic changes first postulated many years ago as the somatic mutation theory of carcinogenesis. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

No description available.

Yuen Mong Ting. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 155-169). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract (English) --- p.ii / Abstract (Chinese) --- p.v / Contents --- p.vi / Chapter Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Developmental biology of the prostate --- p.1 / Chapter 1.1.1 --- Development of the prostate gland in humans and rodents --- p.1 / Chapter 1.1.2 --- Mesenchymal-epithelial interaction --- p.2 / Chapter 1.2 --- Overview of the endocrinology of prostate --- p.3 / Chapter 1.3 --- Estrogen in male and prostate gland --- p.4 / Chapter 1.3.1 --- Stimulating effect of estrogen on prostate gland --- p.4 / Chapter 1.3.2 --- Inhibitory effect of estrogen on prostate gland --- p.5 / Chapter 1.4 --- Study of the role of estrogen receptors in prostate gland with the use of estrogen receptor knockout mice --- p.6 / Chapter 1.4.1 --- The two isoforms of estrogen receptors (ER): ERα and ERβ --- p.6 / Chapter 1.4.2 --- The use of estrogen receptor knockout mice for the study of ER --- p.7 / Chapter 1.5 --- Estrogen as a carcinogen --- p.8 / Chapter 1.5.1 --- Formation of DNA adducts --- p.8 / Chapter 1.5.2 --- Formation of oxidants --- p.9 / Chapter 1.5.3 --- Estrogen as a microtubule-disrupting agent --- p.10 / Chapter 1.6 --- Estrogen carcinogenicity in animal models --- p.11 / Chapter 1.6.1 --- Syrian golden hamster model --- p.11 / Chapter 1.6.2 --- Rat model --- p.12 / Chapter 1.7 --- Animal models of prostate cancer by hormonal induction --- p.12 / Chapter 1.7.1 --- Canine model --- p.13 / Chapter 1.7.2 --- Noble rat model --- p.13 / Chapter 1.7.3 --- Sprague-Dawley rat model --- p.15 / Chapter 1.7.4 --- Wistar and F344 rat model --- p.15 / Chapter 1.8 --- Perinatal estrogen exposure and prostate development --- p.16 / Chapter 1.8.1 --- Prenatal estrogen exposure --- p.15 / Chapter 1.8.2 --- Neonatal estrogen exposure --- p.17 / Chapter 1.9 --- Therapeutic use of synthetic estrogen --- p.18 / Chapter 1.9.1 --- Use of diethylstilbestrol in treating prostate cancer --- p.18 / Chapter 1.9.2 --- Use of diethylstilbestrol during pregnancy --- p.19 / Chapter 1.10 --- Estrogen contamination in food --- p.20 / Chapter 1.10.1 --- Estrogen in milk and dairy products --- p.20 / Chapter 1.10.2 --- Estrogen in meat --- p.21 / Figure 1.1 --- p.23 / Chapter Chapter 2. --- Materials and methods --- p.25 / Chapter 2.1 --- In vitro study of estrogen carcninogenicity in normal prostatic cell line --- p.25 / Chapter 2.1.1 --- NRP-152 cell line --- p.25 / Chapter 2.1.2 --- In vitro estrogen treatment on NRP-152 cells --- p.25 / Chapter 2.1.3 --- Colony formation by soft agar assay --- p.27 / Chapter 2.1.4 --- Determination of growth parameters of estrogen-treated and untreated NRP-152 cells --- p.29 / Chapter 2.1.5 --- Gene expression profiling in estrogen-transformed and untreated parental NRP-152 cells by cDNA microarray --- p.30 / Chapter 2.1.6 --- Immunohistochemistry of cultured cells --- p.34 / Chapter 2.1.7 --- Immunofluorescence on cultured cells --- p.36 / Chapter 2.1.8 --- Electron microscopy of the estrogen-transformed and untreated parental NRP-152 cells --- p.37 / Chapter 2.1.9 --- Tumorigenicity in nude mice --- p.38 / Chapter 2.1.10 --- Protein expressions and Western blottings in estrogen-transformed and untreated parental NRP-152 cells --- p.39 / Chapter 2.2 --- In vivo study of estrorgen carcinogenicity in rat protstate gland --- p.41 / Chapter 2.2.1 --- Origin and supply of Noble rats --- p.41 / Chapter 2.2.2 --- Perinatal estrogen imprinting on male Noble rats with diethylstilbestrol --- p.42 / Chapter 2.2.3 --- Long-term hormonal treatment with sex steroids on male Noble rats at adulthood --- p.43 / Chapter 2.2.4 --- Morphological study of Noble rat prostates --- p.44 / Chapter 2.2.5 --- Protein expressions by immunohistochemistry in estrogen-primed and hormone-treated Noble rat prostates --- p.45 / Tables 2.1 -2.2 --- p.48 / Chapter Chapter 3. --- Results --- p.50 / Chapter 3.1 --- In vitro study --- p.50 / Chapter 3.1.1 --- Dose selection for estrogen treatment of NRP-152 cells from cell proliferation assay --- p.50 / Chapter 3.1.2 --- Colony formation in soft agar --- p.50 / Chapter 3.1.3 --- Morphology of NRP-152 cells and the estrogen-transformed clones --- p.51 / Chapter 3.1.4 --- Study of growth parameters --- p.52 / Chapter 3.1.5 --- CDNA array analysis of differentia] gene pattern --- p.53 / Chapter 3.1.6 --- Immunohistochemistry of untreated parental and estrogen- transformed NRP-152 cells --- p.55 / Chapter 3.1.7 --- Electron microscopy --- p.58 / Chapter 3.1.8 --- Tumorigenicity of NRP-152 cells and the estrogen-transformed clones --- p.59 / Chapter 3.1.9 --- Western blottings --- p.59 / Chapter 3.2 --- In vivo study --- p.52 / Chapter 3.2.1 --- Survival of male Nobel rats during perinatal and long-term hormone treatment --- p.62 / Chapter 3.2.2 --- Histological studies of Noble rat prostates --- p.63 / Chapter 3.2.3 --- Immunohistochemistry of the hormone-treated and control Noble rat prostates --- p.65 / Figure 3.1.1 -3.1.44 --- p.73 / Figure 3.2.1 - 3.2.50 --- p.97 / Table 3.1 -3.4 --- p.117 / Chapter Chapter 4. --- Discussions --- p.121 / Chapter 4.1 --- The study on the transformation of cells and soft agar assay --- p.121 / Chapter 4.2 --- Growth patterns of the estrogen-transformed clones --- p.123 / Chapter 4.3 --- Altered differential gene expression --- p.124 / Chapter 4.3.1 --- TUBA --- p.124 / Chapter 4.3.2 --- PTEN --- p.125 / Chapter 4.3.3 --- RAP 1A --- p.126 / Chapter 4.3.4 --- BRCA2 --- p.126 / Chapter 4.4 --- Ultrastructural study in the estrogen-transformed and untreated parental NRP-152 cells --- p.127 / Chapter 4.5 --- Neoplastic lesions induced in prostates of estrogen-imprinted and long-term combined hormone treated Noble rats --- p.129 / Chapter 4.6 --- Altered protein expressions in estrogen-transformed NRP-152 cells and estrogen-imprinted and hormone-treated Noble rat prostates --- p.132 / Chapter 4.6.1 --- Alteration in steroid hormone receptors --- p.132 / Chapter 4.6.2 --- Alternation in cytoskeleton (tubulin-α) --- p.138 / Chapter 4.6.3 --- Alternation in PTEN --- p.141 / Chapter 4.6.4 --- Alternation in Rap1 --- p.143 / Chapter 4.6.5 --- Alternation in BRCA2 --- p.145 / Chapter 4.6.6 --- "Altered in scavenger enzyme (Superoxide dismutase, SOD-1)" --- p.147 / Chapter Chapter 5. --- Summary --- p.150 / Reference --- p.155

by Yang Lei. / Publication date from spine. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 110-126). / Acknowledgement --- p.i / Abstract --- p.ii / Abbreviations --- p.v / Table of Contents --- p.vi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter Chapter 2 --- Literature Review --- p.4 / Chapter Chapter 3 --- Materials and Methods --- p.41 / Chapter Chapter 4 --- Results --- p.58 / Chapter Chapter 5 --- Discussion --- p.86 / References --- p.110 / Appendix --- p.120 / Publications --- p.125 / Illustrations --- p.127

Thesis (Ph. D.)--University of Alabama at Birmingham, 2006. / Title from first page of PDF file (viewed Oct. 31, 2007). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.