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1
Drake, Mary. "Characterisation of mononuclear cells in peripheral blood stem cell harvests." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287206.
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Harrison, Simon James. "Immunotherapy in multiple myeloma." Thesis, University of Glasgow, 2005. http://theses.gla.ac.uk/1054/.
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The BDCA antibodies allowed reliable measurement of dendritic cell (DC) subsets and B cell numbers in the blood of normal subjects, and patients with MM throughout the disease course. The numbers of blood myeloid DC (BmDC) and blood plasmacytoid DC (BpDC) are low throughout the course of the disease, and only improve for a short period of time following autologous HSCT. Thalidomide therapy of patients with relapsed disease was associated with an increase in BmDC1 and BpDC numbers. Monocytes, mobilised at the time of stem cell collection, were used to produce mature DC (matDC) from MM patients and normal donors (ND). The matDC produced from MM patients were of poorer quality as compared to those from ND, despite using combinations of GM/IL-4, GM/IL-13, X4 and MIMIC in the production process. The combinations that contained the X4 maturation cocktail produced the best quality matDC. The DC/T cell system is abnormal in MM patients. Despite this, it is possible to produce antigen loaded mature MoDC from MM patients. When combined with T cell pre-stimulation and IL-2 expansion, these DC are capable of inducing anti-MM cytotoxic T cells, which exhibit considerable anti-MM cytolytic activity. However, the DC from MM patients still display abnormal chemokine receptor expression, which may inhibit their capability to migrate to lymph nodes in-vivo in order to generate these cytotoxic T cell responses. These observations will aid in the optimisation of DC based immune therapies for MM, and suggest that a combined immunotherapy approach using pre-stimulated T cells, MM Ag primed DC and IL-2 may produce better clinical responses in MM patients.
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Dimberg, Lina. "Apoptosis Regulation in Multiple Myeloma." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7099.
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Mhadgut, Hemendra M. D., Alay Mansurov, Rabia Zafar, and Koyamangalath Krishnan. "Liver Mass: An Unusual Presentation of Multiple Myeloma." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/22.
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Multiple myeloma is characterized by proliferation of plasma cells in the bone marrow, producing monoclonal immunoglobulin. It accounts for 17% of hematologic malignancies in the US. Diagnosis is often suspected in the setting of bone lytic lesions, anemia, hypercalcemia or renal failure. Rarely, multiple myeloma can present with soft tissue involvement which can be difficult to diagnose. Below we present one such presentation.
Our patient is a 53-year-old who was initially diagnosed with multiple myeloma six years back when he presented to hospital with back and right leg pain. On admission he was found to have multiple lytic lesions involving the appendicular and axial skeleton. On further workup, bone marrow biopsy showed 30% plasma cells with IgG kappa monoclonal protein elevation. Patient was diagnosed with ISS stage II multiple myeloma. He was treated with standard regimen with Velcade, Revlimid and dexamethasone with excellent response. Patient was evaluated for stem cell transplant however did not qualify for it due to social challenges. Patient was continued on maintenance therapy with Velcade and Revlimid for 8 cycles prior to clinical relapse with lytic lesions in the C-spine. At this point patient was switched to different therapeutic regimen with pomalidomide, carfilzomib and dexamethasone and had excellent response for 35 cycles on this regimen. Patient had interruption in treatment for 3 months due to other medical comorbidities. A repeat bone marrow biopsy which was done in November of 2019 revealed extensive bone marrow involvement with 70% plasma cells concerning for relapse. Patient was started on single agent daratumumab in December 2019 however had a difficult course interrupted by right-sided abdominal pain, persistent nausea and decreased appetite requiring hospital admission. Further workup revealed a 2.7 cm lesion in the liver as well as a 4.9 x 7.3 cm T11 left paraspinal soft tissue mass. Biopsy of the liver lesion revealed sheets of kappa restricted abnormal plasma cells concerning for progression of disease. Given the involvement of the visceral organ and the extent of his disease, it was decided to switch patient's treatment from single agent daratumumab to a multi agent chemotherapy regimen with dexamethasone, cyclophosphamide, etoposide and cisplatin. Patient received his 1st cycle inpatient and had marked symptomatic improvement and was discharged home. His M-protein spike reduced from 3.9 to 1.8 g/dl post once cycle of treatment.
Soft tissue involvement by multiple myeloma is rare event. Though malignant plasma cells may diffusely infiltrate the liver parenchyma, the nodular spread is unique. In review by Talamo et al, out of 2,584 patients with MM, only 11 had liver plasmacytomas. This phenomenon is driven by lack of expression of adhesion molecules, increased heparanase-1 expression and loss of chemokine receptors on myeloma cells. Such alterations in cell architecture lead to more aggressive disease behavior. At present time treatment for this unique patient population does not differ from other MM cases. It is important for clinicians to recognize the possibility of such event.
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Cook, Gordon. "Immune regulation in multiple myeloma : the host-tumour conflict." Thesis, University of Glasgow, 2000. http://theses.gla.ac.uk/6140/.
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The data presented in this thesis demonstrates that the malignant plasma cells of multiple myeloma are capable of suppressing the activation of T lymphocytes. The myeloma cells prevent activation of T cells from healthy donors by allo-antigen, mitogen and IL-2, mediated by the production of soluble, immuno-suppressive factor. This factor was responsible for inducing cell cycle arrest and failure of the T cells to progress into the autocrine IL-2 autocrine pathway, which is of critical importance in the activation of T cells. To further investigate this interaction an in vitro model system was developed to examine the key stages of T cell activation and homeostasis. Myeloma cells constitutively expressed high levels of TGF-1 mRNA transcripts as detected by RT-PCR which were translated into latent protein and secreted as detected by immunohistochemistry and ELSIA, respectively. The reversal of the immuno-suppression induced by the myeloma cells using the specific TGF-1 antagonist, Latency Associated Peptide, confirmed that TGF-1 is a major factor in myeloma-associated suppression of T lymphocyte activation. It was demonstrated that the myeloma cells prevent the T cells, upon activation, from up-regulating the surface expression of the -chain of the IL-2R thus preventing the formation of the high-affinity receptor. The reduced expression of IL-2R resulted from altered transcription of the -chain gene in response to re-stimulation of primary T cells with IL-2. When signalling events in primary T cells responding to re-stimulation with Il-2 was examined, myeloma cells inhibited the phosphorylation of both STAT3 and STAT5. However, using a novel IL-2-dependnet T cell line (IDBL), which does not require the expression of the high affinity IL-2R for its responses to IL-2, it was shown that these cells are insensitive to the myeloma-derived TGF-, in terms of DNA synthesis and proliferation, despite demonstrating failure of phosphorylation of STAT5. It was demonstrated that phosphorylation of STAT3 was unchanged when IDBL cells were co-cultured with myeloma cell lines.
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Okumura, Setsuko. "Feasibility of breast-conserving therapy for macroscopically multiple breast cancer." Kyoto University, 2004. http://hdl.handle.net/2433/147559.
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Faiman, Beth Marie. "Peripheral Neuropathy and Diarrhea Symptoms in Multiple Myeloma." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1417619492.
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Machin, Reinaldo Franqui. "Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6104.
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Multiple Myeloma (MM) is an incurable plasma cell malignancy and, although novel treatment regimes in the past decade have improved patient outcome, long-term treatment leads to relapse and refractory disease. The centrosomal kinase NEK2 is found overexpressed in MM and promotes chromosomal instability, drug resistance and increased proliferation. Although much research shows NEK2 having a detrimental effect in cancer, much of its mechanisms of overexpression and drug resistance has not been studied in detail. In this work we expand our understanding of NEK2 in MM.
Using Tandem Affinity Purification coupled with Mass Spectrometry, we show that NEK2 directly interacts with the de-ubiquitinase USP7. We confirm this interaction in cell lines of MM and lung cancer. Since USP7 has been shown to have important cancer-promoting roles we tested if USP7 was necessary for NEK2-driven bortezomib resistance. We found that USP7 shRNA was sufficient to sensitize the bortezomib resistant NEK2 overexpressing cells to bortezomib. Surprisingly, we found that USP7 inhibition with shRNA or by treatment with the small molecule USP7 inhibitor P5091 led to depletion of NEK2 protein in every cell line tested. Previous research shows USP7’s main function is a de-ubiquitinase and, since NEK2 is a target of the ubiquitin-proteasome system, we hypothesized USP7 may be de-ubiquitinating NEK2. Through western blots and immunoprecipitations, we show the NEK2-USP7 interaction promotes the de-ubiquitination and subsequent stabilization of NEK2, presenting USP7 as the first discovered de-ubiquitinating enzyme of NEK2. To understand how NEK2 promotes drug resistance in cancer we studied a previously published list of NEK2-regulated genes and, using the UCSC genome browser (Track Name:GM12878+TNFa RELA) ChIP-seq data, we found approximately half of these genes have the NF-κB transcription factor p65 bound throughout the gene sequence. We also produced a signaling score using an average of 11 known targets of NF-κB and patients with high NEK2 showed a significantly increased score of NF-κB signaling. Additionally, through western blots and immunofluorescence, we found that patients with high NEK2 protein levels consisitently had activation higher signal of p65 protein and phosphorylated p65 at Serine 536, indicative of increased activity. We then causally show NEK2 activates canonical NF-κB by performing western blots and a dual-luciferase reporter assay on control and NEK2 overexpressing cells. Using AKT and PP1α inhibitors, we found that NEK2 drives NF-κB by phosphorylating and inactivating PP1α, leading to hyperactive AKT. Using this model of NEK2-NF-κB activation, we aimed at targeting NEK2 directly with the small molecule drugs INH1 (depletes NEK2 protein) and P5091 (inhibits USP7 activity) in empty vector control cells, NEK2 overexpressing cells or cells with an acquired drug resistance phenotype. Our results show that both INH1 and P5091 can overcome bortezomib resistance in cell lines and in vivo.
Another aspect of MM disease we targeted in this work was bone disease. Bone disease in MM is common and causes bone pain and fractures but a much is still regarding what drives these lesions. We found that NEK2 expression in patients correlates with a presence of bone lesions, based on FDG-PET scan and MRI. Using our previously published list of NEK2 regulated genes, we found Heparanase (HPSE) is directly correlated to NEK2 expression. HPSE is an extracellular protein shown to promote differentiation of the bone destroying cell, osteoclast. Using western blots, RT-qPCR and ELISA, we found NEK2 increases HPSE expression and extracellular release. HPSE was also on the list of genes upregulated by NEK2 found to have p65 bound to the gene, thus we tested if NEK2 was driving HPSE through the NF-κB. Accordingly, we found NEK2 drives HPSE through the NF-κB pathway and, consistent with our previous results, in a USP7-dependent manner. Using bone marrow macrophages and conditioned media from empty vector control or NEK2 overexpressing cells, we found NEK2 promtoes increased differentiation of osteoclasts and inhibition of HPSE blocked this effect, strongly suggesting HPSE is the mediator of this effects. Importantly these findings were recapitulated in vivo. Empty vector or NEK2 overexpressing cells were injected through the tail vein to allow dissemination to the bone marrow. microCT and Xray revealed mice injected with NEK2 overexpressing cells showed reduced bone density, compared to empty vector cells. Additionally, H&E and TRAP staining confirmed our in vitro results by showing higher osteoclast levels in bone sections of mice injected with NEK2 overexpressing cells.
Lastly, we show a novel role for the ATPase TRIP13 as a cofactor for USP7 de-ubiquitinating activity. TRIP13 is overexpressed in cancer, has been shown to be an oncogene and promotes drug resistance. By systematically targeting TRIP13 overexpressing cells with drugs that inhibit different pathways we found TRIP13 drug resistance is diminished by inhibiting USP7. We found that TRIP13 binds with USP7 and by western blots and immunoprecipitations we show it is necessary for the de-ubiquitination of NEK2. Furthermore, we also found TRIP13 shows a hyperactive USP7 phenotype, shuttling PTEN out of the nucleus and stabilizing MDM2, in a USP7 dependent manner.
In summary, this work shows the de-ubiquitinase USP7, coupled with the ATPase TRIP13 stabilizes NEK2 by de-ubiquitination, this leads to accumulation of NEK2 and activation of the canonical NF-κB pathway through PP1α/AKT, which promotes drug resistance and activates HPSE, increasing osteoclast differentiation and bone destruction.
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Zabalo, Joaquin. "A Mathematical Model Describing the Early Development of Multiple Myeloma." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/366.
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Multiple myeloma is a malignant bone marrow plasma cell tumor which is responsible for approximately 12,000 deaths per year in the United States and two percent of all cancer deaths. It is recognized clinically by the presence of more than ten percent bone marrow plasma cells, the detection of a monoclonal protein (M-protein), anemia, hypercalcemia, renal insufficiency, and lytic bone lesions. The disease is usually preceded by a premalignant tumor called monoclonal gammopathy of undetermined significance (MGUS), which is present in one percent of adults over the age of fifty, three percent over the age of seventy and ten percent of those in the tenth decade. MGUS is also recognized by the detection of M-protein, but with less than ten percent bone marrow plasma cells and without the other features exhibited by myeloma. The majority of MGUS patients remain stable for long periods without ever developing myeloma. Only a small percentage of patients with MGUS eventually develop multiple myeloma. However, the reason for this is not yet known. Once the myeloma stage is reached, a sequence of well-understood mutational evets eventually lead to the escape of the tumor from the control of the immune system. We propose a mathematical model of tumor-immune system interactions at the onset of the disease in an effort to better understand the early events that take place and their influence on the outcome of the disease. The model is calibrated with parameter values obtained from available data and we study the resulting dynamics. Next, we study how the behavior of the system is affected as parameters are varied. Finally, we interpret the results and draw some conclusions.
10
Kendrick, Felicity. "Modelling immunoglobulin metabolism and its effect on prognostic utility in multiple myeloma." Thesis, University of Warwick, 2018. http://wrap.warwick.ac.uk/104030/.
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Multiple myeloma is a cancer of plasma cells. In multiple myeloma, a clone of plasma cells in the bone marrow secretes a unique, monoclonal immunoglobulin (Ig), whose biological properties depend on its type and structure. The monoclonal Ig offers a convenient opportunity for clinicians to monitor the response of the tumour to therapy via the secreted protein, which is readily quantified in a blood sample. Responses to treatment are assigned based on the percentage reduction in monoclonal Ig; however, response criteria do not take into account the different metabolic half-lives of the proteins. 70% of multiple myeloma patients have either monoclonal IgA- or monoclonal IgG-producing clones. IgA and IgG have metabolic half-lives of 6 days and 23 days, at normal concentrations, respectively. The large difference in their metabolic half-lives suggests that they would respond at different rates during therapy. The elimination rate of IgG is concentration-dependent due to saturable recycling by a receptor. This could further impact upon its response during therapy, with the possibility that IgG is eliminated from the body at different rates at the beginning of therapy, when its concentration is high, and at the end of therapy, when its concentration has decreased. In this thesis compartmental models of IgG metabolism from the literature are analysed and parameter values are estimated from available data. A model of IgA metabolism is sourced in the literature. These models are used to predict the responses of monoclonal IgA and IgG during therapy. The simulations are able to replicate typical monoclonal IgA and IgG responses seen in a clinical trial of patients with relapsed and refractory multiple myeloma. Importantly, the plasma cell clone is not directly accessible to measurement and therefore not available to validate model-based predictions. However, monoclonal Ig responses are not evaluated by their ability to predict the tumour burden, but by the strength of their association with patient survival. In this thesis, a prediction is made of how the different metabolic properties of IgA and IgG may influence their association with survival outcomes. Evidence for this effect is then evaluated in data from a clinical trial using the methods of survival analysis.
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Dorjsuren, Delgerzul, Holly Abigail Adams, Dawnna Elisabeth Metcalfe, and Victoria E. Palau. "Finding Novel and Synergistic Cytotoxic Agents for the Treatment of Multiple Myeloma." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/180.
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Multiple Myeloma is cancer of plasma cells and is known to be highly invasive. Multiple Myeloma makes up 1% of cancer diagnosis in western countries and affects men more predominantly than women. The American Cancer Association estimates that 32,110 new cases will be diagnosed in the United States in 2019. Lenalidomide is one of the main therapies used for multiple myeloma patients, but it has toxic side effects such as thrombocytopenia, neutropenia, and anemia. The purpose of the study is to investigate new cytotoxic agents for the treatment of multiple myeloma. In addition to lenalidomide alone, this study examined the effects of doxycycline alone and in combination with lenalidomide. Lenalidomide cell cultures were treated at concentrations from 0.5μM to 10μM on untreated 24 well plates and doxycycline concentration ranging from 10μM-80μM. Following incubation, cell viability was tested using MTT assay and the samples were analyzed using spectrophotometry. When compared to lenalidomide, doxycycline monotherapy showed a greater decrease in overall cell viability in preliminary results. Our results show that there is benefit of using 10μM of Doxycycline at higher concentration of 5μM and 10μM of lenalidomide. The potential decrease in the concentration of lenalidomide used by adding doxycycline, may reduce the toxic side effects of lenalidomide. Further studies are necessary to confirm these preliminary results and investigate the mechanism of action in order to determine optimal combinations of these drugs.
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Corrias, Maria Elena. "A statistical mechanics approach to cancer dynamics: a model for multiple myeloma bone disease." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2019. http://amslaurea.unibo.it/18021/.
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L’utilizzo di modelli matematici sta assumendo un ruolo sempre più centrale nella ricerca oncologica. La complessità del cancro ha stimolato gruppi di ricerca interdisciplinare nello sviluppo di modelli quantitativi per rispondere alle numerose domande aperte che riguardano l’insorgenza, la progressione, la diagnosi, la risposta al trattamento terapeutico e l’acquisizione della resistenza ai farmaci dei tumori. La varietà di approcci matematico-fisici ben si adatta allo studio di una materia così eterogenea. In questo lavoro presentiamo innanzitutto gli aspetti biologico-clinici che caratterizzano il cancro, per poi introdurre i modelli che sono stati utilizzati per comprenderli. Abbiamo preso in considerazione il caso del mieloma multiplo, una neoplasia che colpisce le plasmacellule. In particolare proponiamo un modello matematico per lo studio della patogenesi delle lesioni ossee causate dal mieloma. L’insorgere di questo tumore rompe l’equilibrio fisiologico del tessuto osseo, causando un aumento dell’attività degli osteoclasti ed una diminuzione dell’attività degli osteoblasti, fenomeni che, combinati, comportano le caratteristiche fratture. Abbiamo optato per un approccio di tipo ecologico, in cui i diversi tipi di cellule sono considerati come specie interagenti in meccanismi di cooperazione o sfruttamento. Questo fenomeno è stato modellizzato all’interno della classe degli Interacting Particle Systems, che sono sistemi di processi di Markov localmente interagenti. Abbiamo inizialmente studiato il caso dell’osso sano per poi passare a quello in cui sono presenti le cellule del mieloma. Infine, abbiamo svolto simulazioni per delineare l’evoluzione nel tempo delle specie cellulari. Abbiamo riservato una particolare attenzione alla definizione dei parametri del modello: non solo essi ci permettono di riprodurre diversi stadi e forme del mieloma, ma possono descrivere l’intervento terapeutico sul tumore, costituendo un nuovo strumento per la ricerca oncologica.
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Abdalla, Amir Osman. "Immunological and clinical long-term effects of idiotype vaccination in multiple myeloma patients /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-114-2/.
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Jacobson, Timothy. "A Trans-Dimensional View of Drug Resistance Evolution in Multiple Myeloma Patients." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6099.
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Multiple Myeloma (MM) is a treatable, yet incurable, malignancy of bone marrowplasma cells. This cancer affects many patients and many succumb to relapse of tumor burden despite a large number of available chemotherapeutic agents developed for therapy. This is because MM tumors are heterogeneous and receive protection from therapeutic agents by the microenvironment and other mechanisms including homologous MM-MM aggregation. Therefore, therapy failure and frequent patient relapse is due to the evolution of drug resistance, not a lack of available drugs. To analyze and understand this problem, the evolution of drug resistance has been explored and presented herein. We seek to describe the methods through which MM cells become resistant to therapy, and how this resistance evolves throughout a patient’s treatment history. We achieve this in five steps.
First we review the patient’s clinical history, including treatments and changes in tumor burden. Second, we trace the evolutionary tree of sub-clones within the tumor burden using standard of care fluorescence in situ hybridization (FISH). Thirdly, immunohistochemistry slides are stained and aligned to quantify the level of environmental protection received by surrounding cells and plasma in the bone marrow microenvironment (coined environment mediated drug resistance score [EMDR]). The fourth analysis type is produced through a novel 384-well plate ex vivo chemosensitivity assay to quantify sensitivity of primary MM cells to chemotherapeutic agents and extrapolate these findings to 90-day clinical response predictions. In addition to direct clinical application in the choice of best treatment, this tool was also used to study changes in sensitivity of patient tumors to other drugs, and it was observed that, upon relapse, in addition to developing resistance to the current line of therapy, tumors become cross-resistant to agents that they were never exposed to. Finally, MM-MM homologous aggregation is quantified to assess the level of drug resistance contributed by clustering of patient tumor cells, which causes upregulation of Bcl-2 expression and other resistance mechanisms1.
The findings of such experimentation improve comprehension of the driving factors that contribute to drug resistance evolution on a personalized treatment basis. The aforementioned factors all contribute in varying degrees for unique patient cases, seven of which are presented in depth for this project. In summary: Environmental protection plays a critical initial role in drug resistance, which is followed by increase in tumor genetic heterogeneity as a result of mutations and drug-induced Darwinian selection. Eventually, environment-independent drug resistant subpopulations emerge, allowing the tumor to spread to unexplored areas of the bone marrow while maintaining inherited drug resistant phenotype2. It is our hope that these findings will help in shifting perspective regarding optimal management of MM by finding new therapeutic procedures that address all aspects of drug resistance to minimize chance of relapse and improve quality of life for patients.
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Goodyear, Oliver Charles. "A study of cancer-germline antigen specific T cell responses in patients with multiple myeloma." Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433641.
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Turtle, Cameron J. "The CMRF-56+ blood dendritic cell preparation as a vehicle for multiple myeloma immunotherapy /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18657.pdf.
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Probert, Adam. "The genetic epidemiology of multiple primary breast and ovarian cancer /." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=20971.
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Breast and ovarian cancers are among the most common tumours affecting Canadian women. A proportion of these tumours was thought to be due to family history and the breast cancer susceptibility gene and are more likely to occur before the age of 50. It is hypothesized that women who have both primary tumours of the breast and ovary are more likely to have a mutation in this gene. The main objective of this study is to examine the role of family history in those women with breast cancer that subsequently develop ovarian cancer. The role of chemotherapy and radiotherapy in the treatment of breast cancer, as a risk factor for future development of ovarian cancer, was also assessed.This was a case-control study. The cases studied were women with multiple primary breast and ovarian cancers and were identified from the Quebec Tumour Registry and a database at Sunnybrook Hospital in Toronto.
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Probert, Adam. "The genetic epidemiology of multiple primary breast and ovarian cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0024/MQ50860.pdf.
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Soerjomataram, Isabelle. "Multiple primary cancers in patients with breast ans skin cancer." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10779.
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Yeung, Ka Yu. "The role of mitochondrial DNA in the tumor biology of glioblastoma multiforme and multiple myeloma." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/62061/.
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Cancer cells preferentially metabolise glucose via aerobic glycolysis (the Warburg effect), which is less energy efficient in teens of ATP production compared to oxidative phosphorylation (OXPHOS). Mitochondrial DNA (mtDNA) encodes proteins of the electron transfer chain and is crucial for functional OXPHOS. MtDNA exists as multiple copies in cells and, often in cancer, there is co-existence of mutant and wild-type mtDNA. There is evidence for mitochondria to contribute towards the tumor biology of multiple myeloma (MM) and glioblastoma multiforme (GBM). The mtDNA from both these cancer types were explored to determine its role in tumor biology. Sequencing of MM cells and tumor samples using the Ion Torrent next generation sequencer identified Cytochrome C Oxidase and ATP 6 to contain critical variants that are capable of disrupting protein function. Gene expression analysis determined that glycolysis is essential to maintaining MM cell proliferation. Without glycolysis, there was up-regulation in the expression of tumor survival genes, which was only effective in MM cells that had sufficient mtDNA copy numbers above the mtDNA set point. Sequencing of GBM cell lines, tumor and normal patient samples suggested that there is a predisposition of GBM tumors to acquire a set of GBM-specific mtDNA variants during tumor development. Conserved mtDNA regions, such as Cytochrome C Oxidase I, tend to be least susceptible to mutations. The presence of variants in these conserved regions carry more detrimental effects at the protein-level than at other mtDNA regions. Differentiation of GBM cells decreased the tumor phenotype, as assessed by gene expression analysis. Altogether, this thesis provides support for the importance of mtDNA in tumor biology. The implications are that the variants identified could be used to screen MM and GBM tumors in a clinical diagnostic lab for the treatment of both these cancer types.
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Bagratuni, Tina. "Modulation of endoplasmic reticulum stress as a cancer therapeutic strategy using multiple myeloma as a model." Thesis, Institute of Cancer Research (University Of London), 2010. http://publications.icr.ac.uk/10367/.
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The presence of correctly folded nascent immunoglobulin within the endoplasmic reticulum (ER) provides an effective checkpoint for plasma cell development. A signalling pathway called the unfolded protein response (UPR) allows cells to handle the proper folding of proteins and ensures cell survival. The transcription factor XBP1, a central control point in mediating plasma cell development is also a major regulator of the UPR providing a link between the UPR and plasma cell differentiation. My hypothesis was that inhibition of the UPR and the ER stress pathways will provide a unique differential marker which can be exploited to kill myeloma plasma cells. In order to study this, I initially characterised the role of XBP1 and IRE1a in myeloma patients and determined that the active form of XBP1, XBP1s, is an independent prognostic factor. In addition, by performing RNAi knockdown experiments I determined that suppression of the expression of XBP1 and IRE1a in myeloma cells resulted in impaired myeloma cell survival. Finally, as this study forms part of a drug discovery project aiming to therapeutically target IRE1a/XBP1, I designed and validated two assays to measure IRE1a endoribonuclease activity. Using these assays I identified a number of compounds which suppressed the kinase/endoribonuclease activity of IRE1a resulting in an impaired generation of active XBP1s and cell death. Identification of compounds which target the activity of IREa/XBP1, may therefore lead to a potential therapeutic strategy for multiple myeloma.
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Adesanya, M. A. "Thrombin generation, tissue factor microvesicles and the endothelium in multiple myeloma and pancreatic cancer during treatment." Thesis, University of York, 2018. http://etheses.whiterose.ac.uk/22051/.
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Cancer and its anti-neoplastic treatment are frequently complicated by venous thromboembolism (VTE) occurrence. Multiple myeloma (MM), a haematological malignancy and Pancreatic cancer (PC), a solid tumour are two common malignancies with similarly high VTE incidence, which worsens during treatment. Thrombin production is a key step in the pathologic evolution of VTE and may play an important role in determining VTE risk in cancer patients. The calibrated automated thrombography (CAT) assay is emerging as a reliable tool for real time estimation of thrombin generation (TG) potential, and there is a clinical need for such knowledge on the dynamic pathways underlying the thrombotic phenotype of various malignancies. Hypothetically, TG measurement may also provide a view of the haemostatic variances that exist in MM and PC as cancers with high VTE incidences. Therefore, this thesis aimed to explore the TG changes that exist in both malignancies in patients before, during and after treatment. It also explores the interaction of Tissue Factor (TF) associated with Microvesicles (MVs) or TFMVs with tumour stroma especially the endothelium, or any procoagulant changes such as thrombin production due to this interaction; and thus, aimed to study TFMVs involvement through the disruption of endothelial haemostasis. The results presented in this thesis demonstrate that solid and haematological malignant cells have significantly differing TG kinetics that may correlate with TF expression levels, and that TG parameters identified changes in MM during treatment, specifically the Lag times and Times-to-Peak parameters were progressively elevated until the third chemotherapy cycle. In summary, procoagulant activity on the endothelium can be stimulated by TFMVs produced by cancer cells in vitro, and this study of thrombin as a procoagulant factor in MM and PC and its relationship to TFMVs may lead to future understanding of their important role in cancer VTE development, and thus merits further study.
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Lee, Min Jae. "THE DEVELOPMENT OF NOVEL PROTEASOME INHIBITORS FOR THE TREATMENT OF MULTIPLE MYELOMA AND ALZHEIMER’S DISEASE." UKnowledge, 2019. https://uknowledge.uky.edu/pharmacy_etds/99.
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Over a decade, proteasome inhibitors (PIs), bortezomib, carfilzomib (Cfz) and ixazomib, have contributed to a significant improvement in the overall survival for multiple myeloma (MM) patients. However, the response rate of PI was fairly low, leaving a huge gap in MM patient care. Given this, mechanistic understanding of PI resistance is crucial towards developing new therapeutic strategies for refractory/relapsed MM patients.
In this dissertation work, we found H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). It indicated H727 cells may serve as a cell line model for de novo Cfz resistance and remains UPS dependent for survival. To examine the potential link between proteasome catalytic subunit composition and cellular response to Cfz, we altered the composition of proteasome catalytic subunits via interferon-γ treatment or siRNA knockdown in H727 cells. Our results showed alteration in composition of proteasome catalytic subunits results in sensitization of H727 cells to Cfz. It supported that proteasome inhibition by alternative PIs may still be a valid therapeutic strategy for patients with relapsed MM after having received treatment with Cfz. With this in mind, we designed and synthesized a small library of epoxyketone-based PIs by structural modifications at the P1′ site. We observed that a Cfz analog, harboring a hydroxyl substituent at its P1′ position was cytotoxic against cancer cell lines with de novo or acquired resistance to Cfz. These results suggested that peptide epoxyketones incorporating P1′-targeting moieties may have the potential to overcome Cfz resistance mechanisms in cells.
The immunoproteasome (IP), an inducible proteasome variant which is harboring distinct catalytic subunits, LMP2, MECL1 and LMP7 of the proteasome typically expressed in cells of hematopoietic origin, plays a role in immune response and is closely linked to inflammatory diseases. It has been reported that the IP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients and AD animal models.
To investigate whether the IP is involved in the pathogenesis of AD, we examined the impact of IP inhibition on cognitive function in AD mouse models. We observed that YU102, an epoxyketone peptide targeting the IP catalytic subunit LMP2, improved cognitive dysfunction in AD mice without clearance of Aβ deposition or tau aggregation. Our cell line model study also showed a potential mode of action of YU102 which is suppressing pro-inflammatory cytokine production in microglial cells. It suggested that LMP2 contributes to microglia-mediated inflammatory response. These findings supported that LMP2 may offers a valuable therapeutic target for treatment of Alzheimer’s disease, expanding the therapeutic potential of the LMP2-targeting strategy.
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Green, Ashley E. "Examination of Genetic Changes Associated with Breast Cancer Disparities Across Multiple Ethnicities." Scholarly Repository, 2011. http://scholarlyrepository.miami.edu/oa_theses/284.
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Breast cancer is of a primary concern in women, although it can occur in men. It is the second leading cause of cancer related deaths amongst women, and it is estimated that roughly 39,840 women will die of this disease this year. Breast cancer occurs across all populations and ethnicities. When African-Americans (AA) present with breast cancer, they usually have poorly differentiated tumors, and are more likely to be diagnosed with an advanced stage tumor. When compared to Caucasian (Cau) women, African-American women also have higher breast cancer mortality. The causes of these differences are not yet definitively known, but it has been suggested that the disparities that are present between African-American and Caucasian women are due to a number of factors. A few which have been mentioned are differences in Body Mass Index (BMI), socioeconomic status, health care coverage, and the level of obtained education that exists between the two ethnic groups. Although these factors may account for a small percentage of the difference seen between the two ethnic groups, the underlying cause that may explain why African-American women are at a greater risk of developing aggressive breast cancer may be due to differences in gene expression. A focus of my research project is the comparison of genome-wide gene expression differences between African-American and Caucasian women. Preliminary results from the comparison of normal breast tissue (obtained from reduction mammoplasty) from Caucasian and African-American women suggest there are marked differences in gene expression patterns. Pathway analysis of differentially expressed genes shows that they are involved in protein folding and the immune response. I am currently expanding this study to include a comparison of 10 AA to 10 Cau normal breast samples. These samples are being LCM dissected to separately compare gene expression in epithelial and stromal tissue. Cross comparisons between ethnic groups and tissue types will provide an understanding of normally occurring differences between AA and Cau women, which may help to explain the observed cancer disparities. Data from the study of normal tissue will be compared to gene expression data from triple negative breast cancer (TNBC) patients from both ethnicities.
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Issa, Mark E., E. M. K. Wijeratne, A. A. L. Gunatilaka, and Muriel Cuendet. "Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells." FRONTIERS MEDIA SA, 2017. http://hdl.handle.net/10150/625811.
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In spite of recent therapeutic advances, multiple myeloma (MM) remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs). MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND), a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp) efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.
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Lajmi, Nesrine [Verfasser], and Walter [Akademischer Betreuer] Fiedler. "The biological function of Cancer-testis antigen MAGE-C2/CT10 in Multiple Myeloma / Nesrine Lajmi. Betreuer: Walter Fiedler." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1101695935/34.
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Lajmi, Nesrine Verfasser], and Walter [Akademischer Betreuer] [Fiedler. "The biological function of Cancer-testis antigen MAGE-C2/CT10 in Multiple Myeloma / Nesrine Lajmi. Betreuer: Walter Fiedler." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1101695935/34.
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Duhachek, Muggy Sara. "Multiple isoforms of ADAM12 in breast cancer: differential regulation of expression and unique roles in cancer progression." Diss., Kansas State University, 2014. http://hdl.handle.net/2097/18685.
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Doctor of PhilosophyDepartment of Biochemistry and Molecular Biophysics
Anna Zolkiewska
The ADAM (A Disintegrin and Metalloprotease) family of multi-domain proteins modulates a number of cellular signaling pathways in both normal and cancerous cells. ADAM12 has been shown to be a candidate cancer gene for breast cancer and its expression is up-regulated in breast tumors. The human ADAM12 transcript is alternatively spliced. One of these splice variants encodes a transmembrane ADAM12 isoform, ADAM12-L, which has been demonstrated to release cell signaling molecules from the cell surface. Another variant encodes a secreted protease, ADAM12-S, which cleaves extracellular matrix proteins and other secreted proteins. Although these variants are expressed from the same promoter, their relative expression levels are highly discordant. Here, I demonstrate variant-specific regulation of ADAM12 transcripts by microRNAs. Members of the microRNA-29 and microRNA-200 families target the unique 3’UTR of the ADAM12-L transcript and cause transcript degradation. Additionally, I show the presence of a novel ADAM12 splicing event in which 9 additional nucleotides are inserted in the region encoding the autoinhibitory pro-domain. I demonstrate that this novel variant is expressed in breast epithelial cells and breast cancer cell lines. The resulting protein isoform does not undergo proteolytic processing to activate the protease. Additionally, trafficking of the novel isoform to the cell surface is impaired and this isoform is localized to the endoplasmic reticulum. Finally, I determined a role for ADAM12-L in the progression of triple negative breast cancers (TNBCs). These tumors are lacking expression of hormone receptors and the HER2 receptor. HER2 is a member of the epidermal growth factor receptor (EGFR) family and the loss of the HER2 receptor causes tumors to rely on EGFR for propagating pro-growth signals. I show here that, in TNBC tumors, ADAM12-L expression is strongly correlated with poor patient prognosis and increased activation of EGFR. These data suggest that in TNBCs, ADAM12-L enhances tumor growth via EGFR activation. Collectively, the data presented here demonstrate (a) transcript-specific regulation of ADAM12 in breast cancer, (b) the existence of a novel splice variant and protein isoform with impaired cellular trafficking, and (c) an important role of the ADAM12-L isoform in EGFR activation in TNBC.
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Christensen, Kimberly Laura. "The developmental regulator SIX1 plays multiple roles in breast cancer initiation and progression /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
Find full textAbstract:
Thesis (Ph.D. in Biophysics & Genetics, Program in Molecular Biology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 115-132). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Maharaj, Lenushka. "Use of in vitro primary culture models to investigate the activity of standard and novel therapies in haematological malignancies." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8532.
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Despite improved treatments for Non-Hodgkin’s Lymphoma (NHL) and Multiple Myeloma (MM), most patients eventually relapse and these diseases remain largely incurable. This has precipitated recent research into more clinically relevant in vitro models to enable development of more effective therapies. We have validated and standardised two in vitro primary culture models using tumour samples derived from patients with NHL, Chronic Lymphocytic Leukaemia (CLL) and MM. Several novel findings have been demonstrated. In vitro sensitivity of primary NHL cells cocultured in a CD40L model predicted clinical response to bortezomib in patients receiving the drug in a phase II trial. In vitro sensitivity correlated with CD40 expression, identifying a potential surrogate biomarker for response to bortezomib. The novel HDAC inhibitor, UCL67022 was 10-fold more potent than vorinostat in NHL and produced synergy when combined with bortezomib. UCL67022 maintained its potency in primary MM samples grown in an HS-5 stromal model. It modulated cytokine secretion resulting in downregulation of cytokine-induced signalling pathways (JAK/STAT3). A novel Hsp90 inhibitor, KW-2478 maintained activity in the HS-5 model and enhanced the activity of bortezomib and melphalan. Hsp70 was identified as a potential surrogate biomarker to monitor the combinatorial effect in future clinical trials. A highly synergistic and schedule-dependent cytotoxic effect occurred when primary MM cells were pre-treated with melphalan followed by bortezomib, with important implications for future clinical trial design. IL-6, IL-8 and VEGF levels correlated with resistance to bortezomib and melphalan and were associated with activation of JAK/STAT, MAPK and PI3K/Akt signalling pathways. Antibody neutralization of IL-6, IL-8 and VEGF resulted in restoration of drug sensitivity. We have therefore demonstrated the ability of primary culture models to predict response to chemotherapy, to identify therapeutically beneficial novel agents and to enable study of tumour microenvironmental interactions responsible for drug resistance in patients with haematological malignancies.
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Rodrigues, Margret S. Tong Alex W. "Growth inhibition of human multiple myeloma cells by a conditional-replicative, oncolytic adenovirus armed with the CD154 (CD40-ligand) transgene." Waco, Tex. : Baylor University, 2006. http://hdl.handle.net/2104/5016.
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Gadaleta, Emanuela. "A multidisciplinary computational approach to model cancer-omics data : organising, integrating and mining multiple sources of data." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8141.
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It is imperative that the cancer research community has the means with which to effectively locate, access, manage, analyse and interpret the plethora of data values being generated by novel technologies. This thesis addresses this unmet requirement by using pancreatic cancer and breast cancer as prototype malignancies to develop a generic integrative transcriptomic model. The analytical workflow was initially applied to publicly available pancreatic cancer data from multiple experimental types. The transcriptomic landscape of comparative groups was examined both in isolation and relative to each other. The main observations included (i) a clear separation of profiles based on experimental type, (ii) identification of three subgroups within normal tissue samples resected adjacent to pancreatic cancer, each showing disruptions to biofunctions previously associated with pancreatic cancer (iii) and that cell lines and xenograft models are not representative of changes occurring during pancreatic tumourigenesis. Previous studies examined transcriptomic profiles across 306 biological and experimental samples, including breast cancer. The plethora of clinical and survival data readily available for breast cancer, compared to the paucity of publicly available pancreatic cancer data, allowed for expansion of the pipeline’s infrastructure to include functionalities for cross-platform and survival analysis. Application of this enhanced pipeline to multiple cohorts of triple negative and basal-like breast cancers identified differential risk groups within these breast cancer subtypes. All of the main experimental findings of this thesis are being integrated with the Pancreatic Expression Database and the Breast Cancer Campaign Tissue Bank bioinformatics portal, which enhances the sharing capacity of this information and ensures its exposure to a wider audience.
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Wallace, Julie. "Deciphering the Functions of Ets2, Pten and p53 in Stromal Fibroblasts in Multiple Breast Cancer Models." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1365496427.
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Sims, Jonathan Thomas. "c-ABL AND ARG DRIVE CANCER CHEMORESISTANCE VIA ACTIVATION OF MULTIPLE SIGNALING PATHWAYS." UKnowledge, 2012. http://uknowledge.uky.edu/pharmacol_etds/1.
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Despite 35 years of clinical trials, there has been little improvement in one-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma due to resistance to all known agents. Regardless of advances in detection and prevention, diagnosis of metastatic disease remains a death sentence. Resistance mechanisms, including aberrant kinase signaling and drug transport pumps, indicate a need for identification of other therapeutic targets that impinge upon multiple signaling pathways. The Abl family of non-receptor tyrosine kinases (c-Abl, Arg) has been indicted as a causative force in leukemia for more than three decades; however, their role in solid tumors has only recently been described. We first demonstrated that activated Abl family kinases promote breast cancer development and progression, and recently identified them to be novel therapeutic targets in metastatic melanoma cells by demonstrating that they promote proliferation, survival, invasion, and metastasis. We now present evidence that inhibitors of Abl family kinases abrogate resistance to a number of commonly used chemotherapeutics (i.e., 5-fluorouracil, cisplatin, paclitaxel, camptothecin) in a panel of breast cancer cells. We proceed to show that inhibitors of Abl family kinases, likewise, sensitize both breast cancer and melanoma cells to doxorubicin by blocking cell proliferation and dramatically inducing apoptosis. These findings were extended to advanced multi-drug resistant melanoma cells, in which we show for the first time that c- Abl promotes expression of the drug transporter, ABCB1, during acquired resistance, and drugs that inhibit c-Abl/Arg prevent ABCB1 expression and function. Moreover, c-Abl/Arg also promote acquired chemoresistance independent of ABCB1 by modulating multiple survival pathways. We demonstrate that c-Abl/Arg promote chemoresistance by upregulating STAT3, preventing doxorubicin-mediated conversion of NF-κB into a transcriptional repressor, activating an HSP27/p38/Akt survival pathway, and modulating ERK signaling. Therefore, c-Abl/Arg promote chemoresistance in highly resistant melanoma cells by impinging on drug transporter and cell survival pathways. Taken together, these data indicate that c-Abl/Arg inhibitors are likely to reverse acquired resistance in metastatic melanomas harboring activated c-Abl/Arg, and thus, may be effective in a combination regimen.
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Hawkins, William Tressel II. "Combinatorial Modulation of Multiple Signaling Pathways to Gain Therapeutic Response in Breast and Prostate Cell Carcinomas." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/1043.
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Our laboratory is primarily interested in novel pharmacological intervention of cell proliferation and survival pathways expressed in various types of cancer. These cyto-protective pathways can be activated in response to growth factor stimulation, toxic insult and radiation. In our studies, we utilized novel drug combinations with and without radiation to enhance breast & prostate tumor cell death both in vitro and in vivo. Previous studies from our group have shown that UCN-01 and MEK1/2 inhibitors interact to cause tumor cell death in transformed cell lines in vitro. We extended this observation to an in vivo animal model system using the estrogen dependent breast cell carcinoma line MCF-7 and the estrogen independent breast cell carcinoma line MDA-MB-231. This drug combination was shown to profoundly reduce tumor cell proliferation in vivo and also exhibited the ability to significantly reduce ex-vivo tumor cell colony formation 30 days after cessation of the combination drug treatment. In addition, tumor cell death coincided with decreased ERK112 phosphorylation, reduced immunoreactivity of Ki67 and CD31. Overall, these studies demonstrate that UCN-01 and MEK112 inhibitors have the potential to suppress mammary tumor growth in vivo which is independent of p53 status, estrogen dependency, caspase-3 levels or oncogenic K-RAS expression. In our LnCap prostate carcinoma cell studies we demonstrated the impact of hCG and lovastatin in combination with ionizing radiation to radiosensitize and enhance tumor cell lethality. This enhancement was attributed to the hCG-induced activation of ERBB1 via a GPCR, MEK112 and metalloprotease dependent paracrine mechanism which was further enhanced by radiation. This enhanced cell killing effect was shown to involve prolonged activation of PARP1 which could be suppressed by inhibition of ERBB1, MEKl , PI3 kinase or PARP1. Therefore, the combination of hCG, lovastatin and radiation may represent a novel approach to kill prostate cancer cells and potential new therapy.
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Moreira, dos Santos Dirley. "Distinguishing the effects of time dependence from the effects of frailty in multiple spell breast cancer data." Thesis, Lancaster University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385269.
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Payne, Kyle K. "Immunotherapy of Cancer: Reprogramming Tumor/Immune Cellular Crosstalk to Improve Anti-Tumor Efficacy." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3939.
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Immunotherapy of cancer has been shown to be promising in prolonging patient survival. However, complete elimination of cancer and life-long relapse-free survival remain to be major challenge for anti-cancer therapeutics. We have previously reported that ex vivo reprogramming of tumor-sensitized immune cells by bryostatin 1/ionomycin (B/I) and the gamma-chain (γ-c) cytokines IL-2, IL-7, and IL-15 resulted in the generation of memory T cells as well as CD25+ NKT cells and CD25+ NK cells. Adoptive cellular therapy (ACT) utilizing these reprogrammed immune cells protected FVBN202 mice from tumor challenge, and overcame the suppressive functions of myeloid-derived suppressor cells (MDSCs). We then demonstrated that the presence of CD25+ NKT cells was required for anti-tumor efficacy of T cells as well as their resistance to MDSCs. Similar results were obtained by reprogramming of peripheral blood mononuclear cells (PBMC) from patients with early stage breast cancer, demonstrating that an increased frequency of CD25+ NKT cells in reprogrammed immune cells was associated with modulation of MDSCs to CD11b-HLA-DR+ immune stimulatory cells. Here, we tested the efficacy of immunotherapy in a therapeutic setting against established primary breast cancer (Chapter One), experimental metastatic breast cancer (Chapter Three) as well as against minimal residual disease (MRD) in patients with multiple myeloma (Chapter Two). We evaluated the ability of reprogrammed immune cells, including CD25+ NKT cells, to convert MDSCs to myeloid immune stimulatory cells, in vivo; this resulted in the identification and characterization of a novel antigen presenting cell (APC). These novel immune stimulatory cells differed from conventional APCs, including dendritic cells (DCs) and macrophages. We have also demonstrated that enhancing immunogenicity of mammary tumors by treatment with Decitabine (Dec) along with overcoming MDSCs by utilizing reprogrammed T cells and NKT cells in ACT prolongs survival of animals, but fails to eliminate the tumor. However, targeting cancer during a setting of MDR, when tumor cells are dormant, results in objective responses as evidenced in our multiple myeloma studies. This suggests that targeting breast cancer with immunotherapy following conventional therapies, in a setting of residual disease when tumor cells are dormant, may be effective in eliminating such residual cells or maintaining dormancy and extending time-to-relapse for breast cancer patients.
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Puyade, Mathieu. "Parcours de soins des patients atteints d'hémopathies malignes en Poitou-Charentes." Thesis, Poitiers, 2017. http://www.theses.fr/2017POIT1407/document.
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La réduction des inégalités d'accès aux soins a toujours été un axe majeur des politiques de lutte contre le cancer. Alors qu'il existe de nombreuses études en cancérologie solide, peu d'études avec une méthodologie correcte existent en onco-hématologie, notamment chez les patients atteints de Myélome Multiple (MM). Cette maladie a vu son pronostic transformé par l'arrivée de nouvelles thérapeutiques dont l'usage a été rapidement intégré dans les recommandations de la Société Française d'Hématologie. L'objectif de travail intitulé Parcours de Soins des patients atteints d'hémopathie maligne en Poitou Charentes était donc de décrire et d'analyser les écarts aux recommandations, en prenant le MM comme premier exemple. Grâce au registre des Cancers Poitou-Charentes et à l'exhaustivité des cas qu'il assure, notre travail a permis de déterminer des variables associées à une inégalité d'accès aux soins. Ces variables sont démographiques (âge, distance entre le domicile et l'hôpital), liées à la tumeur (maladie symptomatique ou non), mais aussi organisationnelles (niveau de l'hôpital, passage en réunion de concertation pluridisciplinaire). De plus nous avons pu montrer que ces inégalités avaient un impact sur la survie globale des patients, notamment chez les plus âgés. Notre travail se poursuit par une analyse plus fine de la survie globale et l'étude des longs survivants du Myélome Multiple. A plus long terme, nous souhaitons appliquer cette approche à d'autres hémopathiesFrench national Cancer plans aimed to reduce health care inequalities. These inequalities are well known in solid cancers but few data with correct methodology exist in Hematology, especially in Multiple Myeloma (MM). The new treatments in this disease have dramatically improved Overall Survival. So guidelines of the Société Française d'Hématologie have quickly recommended the use of these new drugs. The aim of our work: Care Pathway of patients with hematological malignancies in Poitou Charentes area was to describe and analyze non compliance to guidelines. Based on the exhaustivity of the Poitou Charentes Cancer Registry, our work revealed variables associated with healthcare inequalities. They were demographical (age, distance between home and hospital), tumor-related (symptomatic MM or not) but also organizational (level of the hospital, multidisciplinary meeting). Moreover we showed that those inequalities had a negative impact on overall survival, especially in elderly people. Our work continues with more accurate analysis of overall survival and a study on MM long survivors. Longer-term studies would be to transfer this approach to other hemopathies
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Hartman, Mikael. "Risk and prognosis of breast cancer among women at high risk of the disease /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-303-0/.
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Tao, Wang. "Adapting multiple datasets for better mammography tumor detection." Thesis, KTH, Skolan för elektroteknik och datavetenskap (EECS), 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-231867.
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In Sweden, women of age between of 40 and 74 go through regular screening of their breasts every 18-24 months. The screening mainly involves obtaining a mammogram and having radiologists analyze them to detect any sign of breast cancer. However reading a mammography image requires experienced radiologist, and the lack of radiologist reduces the hospital's operating efficiency. What's more, mammography from different facilities increases the difficulty of diagnosis. Our work proposed a deep learning segmentation system which could adapt to mammography from various facilities and locate the position of the tumor. We train and test our method on two public mammography datasets and do several experiments to find the best parameter setting for our system. The test segmentation results suggest that our system could play as an auxiliary diagnosis tool for breast cancer diagnosis and improves diagnostic accuracy and efficiency.I Sverige går kvinnor i åldrarna mellan 40 och 74 igenom regelbunden screening av sina bröst med 18-24 månaders mellanrum. Screeningen innbär huvudsakligen att ta mammogram och att låta radiologer analysera dem för att upptäcka tecken på bröstcancer. Emellertid krävs det en erfaren radiolog för att tyda en mammografibild, och bristen på radiologer reducerar sjukhusets operativa effektivitet. Dessutom, att mammografin kommer från olika anläggningar ökar svårigheten att diagnostisera. Vårt arbete föreslår ett djuplärande segmenteringssystem som kan anpassa sig till mammografi från olika anläggningar och lokalisera tumörens position. Vi tränar och testar vår metod på två offentliga mammografidataset och gör flera experiment för att hitta den bästa parameterinställningen för vårt system. Testsegmenteringsresultaten tyder på att vårt system kan fungera som ett hjälpdiagnosverktyg vid diagnos av bröstcancer och förbättra diagnostisk noggrannhet och effektivitet.
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Zhao, Helong. "Roles of Slit-Robo Signaling in Pathogenesis of Multiple Human Diseases: HIV-1 Infection, Vascular Endothelial Inflammation and Breast Cancer." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1428088097.
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Pliuskys, Laurynas. "Epigenetic regulation of the myeloid cell lineage." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:f4ee6659-ce0b-4730-ae5b-95c141f82e10.
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The myeloid cell lineage is a fundamental element of the immune system and it can give rise to a diverse set of terminally differentiated cells, such as macrophages or osteoclasts among many others. Mutations or misregulation of gene expression may lead to severe clinical conditions, such as arthritis, osteoporosis or cancers. Epigenetics, the regulation of gene expression and chromatin remodelling, is implicated in cell differentiation, function and disease, and hence it is a promising new area to explore in order to explain underlying cellular mechanisms. Firstly, human macrophage subtypes were studied. Chemokine (C-C motif) ligand (CCL) 1 and mannose receptor were validated to be granulocyte macrophage (GM) colony stimulating factor (CSF) induced macrophage markers, while CCL2 was specifically expressed in macrophage CSF (MCSF) macrophage population. By utilising publicly available high-throughput sequencing data, new biomarkers dehydrogenase/reductase (SDR family) member 2 and CCL26 were discovered to be MCSF-macrophage specific while guanylate binding protein 5 and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A were highly up-regulated in GMCSF cells. Secondly, a range of gene knock-down techniques for the myeloid cell lineage were optimised and established. Lentiviral short-hairpin RNA (shRNA) delivery methods were shown to induce an undesirable pro-inflammatory response in macrophages. Furthermore, the frequently utilised cytomegalovirus promoter for gene expression was shown to be completely silenced in macrophage populations. Locked nucleic acids were selected as a suitable alternative to shRNA knock-down and by employing this new tool it was shown that a histone demethylase lysine (K)-specific demethylase (KDM) 6B is fundamental for macrophage differentiation. Finally, a small molecule GSK-J4, a potent inhibitor of histone demethylases KDM6A, KDM6B and KDM5B specific for H3K27me3 and H3K4me3, respectively, was used to dissect epigenetic signalling in osteoclasts and multiple myeloma. In osteoclasts it was shown to act mainly by inhibiting transcriptional changes required for osteoclastogenesis when MCSF-macrophages are stimulated with Receptor Activator Of Nuclear Factor Kappa-B Ligand (RANKL), as indicated by the differential increase in H3K27me3 marks, leading to inhibition of c-Jun and potentially abolition of transcription factor AP-1, required for the transcriptional initiation of nuclear factor of activated T-cells 1 (NFATc1). In multiple myeloma cells, GSK-J4 causes a dramatic increase in expression, further supported by the build-up of global H3K4me3 marks, which results in the upregulation of the unfolded protein response pathway. In both cell systems, there is an early upregulation of metallothionein genes, which in multiple myeloma was shown to increase potentially due to rapid influx of zinc ions within the first 30 minutes, and as such may cause induction of apoptosis in multiple myeloma and may inhibit differentiation of osteoclasts.
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Lemaitre, Léa. "Caractérisations phénotypiques et fonctionnelles des cellules stromales mésenchymateuses au cours du traitement du myélome multiple." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30279.
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Le myélome multiple (MM) est une hémopathie caractérisée par l'accumulation de plasmocytes (PC) malins dans la moelle osseuse pouvant occasionner entre autres des lésions ostéolytiques. Il s'agit d'une maladie extrêmement hétérogène, tant au niveau de la présentation clinique, de la réponse aux traitements, de la survie globale, que sur le plan biologique. L'hypothèse actuelle est que cette hétérogénéité est non seulement due à l'énorme variabilité moléculaire présente au sein des cellules tumorales mais également au microenvironnement des PC tumoraux. Dans ce microenvironnement nous nous intéressons plus particulièrement aux cellules stromales mésenchymateuses (MSC). Leur interaction avec les PC a des conséquences multiples : promotion de la prolifération, de la survie, de la migration et de la chimiorésistance des PC, stimulation de l'angiogenèse, stimulation de l'ostéoclastogenèse et inhibition de l'ostéoblastogenèse. Mon sujet de thèse porte sur l'analyse phénotypique et fonctionnelle des MSC retrouvées associées aux PC au diagnostic de la maladie et tout au long du traitement. Mon travail de recherche a consisté en la comparaison de différents prélèvements de MSC afin 1) de mettre en évidence le rôle des MSC dans la physiopathologie du myélome aux différents stades de la maladie et 2) d'identifier une cible thérapeutique potentielle au sein du microenvironnement tumoral. Les prélèvements de patients ont tout d'abord été sélectionnés pour constituer trois groupes homogènes composés de 10 prélèvements de moelle osseuse saine (HD BM-MSC), 12 de moelle osseuse de patients nouvellement diagnostiqués (D BM-MSC), 10 de moelle osseuse de patients dit en rémission (CR BM-MSC) et 9 prélèvements de patients en première rechute (ER BM-MSC). Les MSC ont été isolées à partir des moelles de ces différents groupes et une analyse transcriptomique a été réalisée. Nous avons confirmé les résultats antérieurs du laboratoire soit que les MSC de patients MM ont un profil transcriptomique différents des HD BM-MSC. Parmi les 845 gènes différentiellement exprimés entre HD et MM BM-MSC, nous avons identifié des facteurs connus dans la physiopathologie du myélome (IL6, GDF15, SERPINB2, DKK1, Runx2 ...) mais aussi des facteurs non répertoriés à ce jour. La voie Wnt, et certains facteurs de différenciation osseuse semblent être impliqués. De façon intéressante le profil transcriptomique des MSC ne varie pratiquement pas lors des différents stades du MM et plus particulièrement suite au traitement que le patient soit en rémission ou en rechute de sa maladie. Ces données suggèrent que le contact des PC avec les MSC pourrait conduire à une modification pérenne du transcriptome des MSC. Nous avons réalisé une analyse fonctionnelle des différentes MSC afin de corréler la différence transcriptomique observée avec une éventuelle différence de fonction. Les résultats montrent que les MSC issus de patients présentent une perte de capacité de différenciation en ostéoblastes et une différenciation facilitée en adipocytes. Concernant leur capacité immuno-modulatrice, les CR BM-MSC ont une fonction immuno suppressive altérée lorsqu'on les compare à celle des ER BM-MSC. [...]Multiple myeloma (MM) is a B-cell malignancy characterized by clonal expansion of malignant plasma cells (PC) within the bone marrow (BM). MM patients often experience multiple relapses due to the presence of chemo-resistant residual MM clones. Therefore, there is a critical need to understand the mechanisms that regulate MM chemo-resistance and relapse. The interactions between microenvironment BM cells and malignant PCs play an essential role In MM growth and survival. Mesenchymal stromal cells (MSC) are multipotent BM stromal cells, able to differentiate into osteoblasts and adipocytes which support malignant PC growth through the release of different factors. A better understanding of the role of these cells in MM relapse is critically required. My work consisted in comparing different samples of MSC to understand their role at different stage of the disease and find a therapeutic target. To address this question, I created a homogeneous cohort of samples: 10 BM of healthy donors (HD BM-MSC), 12 from newly diagnosis MM patients (D BM-MSC), 10 from MM remission patients (CR BM-MSC) and 9 from MM patients with early relapse (ER BM-MSC). Then I isolated MSC from BM of these different groups and performed a transcriptomic analysis. My results reveal significant differences in expression of 845 genes between HD and MM BM-MSC. Wnt signaling, blood coagulation and angiogenesis appear to be involved in this pathological process. Surprisingly, the transcriptomic profile of MSC was very similar after treatment in relapse or remission patient. These data indicate that the alteration in MSC gene expression associated with MM development can persist even in the absence of clinical sign of the disease. This suggests that a deep imprinting of MSC cellular program occurs by the contact with MM PCs. Futhermore, I compare the functional capacity of HD and MM-MSC to differentiate, improve the MM cell growth and immunomodulation. MM-MSC differentiate preferentially into adipocytes than osteoblasts compared to HD BM-MSC. They both support MM tumor growth by secreted factors. Interestingly, CR BM-MSC decreased their capacity to immunosuppress T cells compared to ER BM-MSC. Finally, we observed an increase of toll like receptor 4 (TLR4) gene expression by MM BM-MSC compared to HD BM-MSC. TLR4 is a Pattern Recognition Receptor widely describe in innate immunology but not in MM. In vitro analysis performed by the laboratory suggest an important role of TLR4 to support tumor growth and TLR4 inhibitor, C34, inhibit MM cell lines growth. I performed this treatment on most relevant MM mouse model, VkMyC, and treatment delayed MM growth. These results suggest a clinical application of our data
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Erdem, Munire Tugba. "Modeling Diseases With Multiple Disease Characteristics: Comparison Of Models And Estimation Methods." Master's thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613531/index.pdf.
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Epidemiological data with disease characteristic information can be modelled in several ways. One way is taking each disease characteristic as a response and constructing binary or polytomous logistic regression model. Second way is using a new response which consists of disease subtypes created by cross-classification of disease characteristic levels, and then constructing polytomous logistic regression model. The former may be disadvantageous since any possible covariation between disease characteristics is neglected, whereas the latter can capture that covariation behaviour. However, cross-classifying the characteristic levels increases the number of categories of response, so that dimensionality problem in parameter space may occur in classical polytomous logistic regression model. A two staged polytomous logistic regression model overcomes that dimensionality problem. In this thesis, study is progressen in two main directions: simulation study and data analysis parts. In simulation study, models that capture the covariation behaviour are compared in terms of the response model parameter estimators. That is, performances of the maximum likelihood estimation (MLE) approach to classical polytomous logistic regression, Bayesian estimation approach to classical polytomous logistic regression and pseudo-conditional likelihood (PCL) estimation approach to two stage polytomous logistic regression are compared in terms of bias and variation of estimators. Results of the simulation study revealed that for small sized sample and small number of disease subtypes, PCL outperforms in terms of bias and variance. For medium scaled size of total disease subtypes situation when sample size is small, PCL performs better than MLE, however when the sample size gets larger MLE has better performance in terms of standard errors of estimates. In addition, sampling variance of PCL estimators of two stage model converges to asymptotic variance faster than the ML estimators of classical polytomous logistic regression model. In data analysis, etiologic heterogeneity in breast cancer subtypes of Turkish female cancer patients is investigated, and the superiority of the two stage polytomous logistic regression model over the classical polytomous logistic model with disease subtypes is represented in terms of the interpretation of parameters and convenience in hypothesis testing.
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Allen, Stephanie D. "Therapeutic peptidomimetic strategies for costimulation blockade in multiple sclerosis and transplantation / conformational peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1150479940.
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Kalra, Jessica. "Integrin Linked Kinase as a therapeutic target for treating breast cancer : the value of using multiple endpoints to assess therapeutic effects of targeted drugs and drug combinations." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/27023.
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Substantial preclinical evidence indicates that inhibition of Integrin Linked-Kinase (ILK) correlates with cytotoxic/cytostatic cellular effects, delayed tumour growth in animal models of cancer and inhibition of angiogenesis. It is increasingly evident that optimal therapeutic benefits obtained using ILK targeting strategies will only be achieved in combination settings. For this reason the therapeutic potential of the ILK small molecule inhibitor, QLT0267, alone or in combination with chemotherapies commonly used to treat breast cancer patients was investigated. The results suggested that the combination of QLT0267 and docetaxel (Dt) interacted synergistically when assessing metabolic activity as a therapeutic endpoint. Further endpoint analysis in cell lines with low Her2/neu levels revealed that the QLT0267/Dt combinations resulted in a 3- fold decrease in concentration of QLT0267 required to achieve 50% inhibition of P-AKT. For Her2/neu positive cell lines the QLT0267/Dt combination was antagonistic. In vivo studies using breast cancer cells (LCC6) implanted orthotopically demonstrated that treatment with QLT0267/Dt engendered improved therapeutic effects. Using luciferase positive LCC6 cells metastatic, orthotopic and ascites tumour models were characterized. The results suggested that the orthotopic LCC6 tumour model was most sensitive to docetaxel. Using the more docetaxel treatment refractory LCC6 model (disseminated disease) it was shown that QLT0267 could not sensitize the tumours to Dt treatment. These data suggest that clinical benefits of QLT0267/Dt in patients with breast cancer would most likely be observed used in the adjuvant or neoadjuvant setting. Finally, preliminary studies indicate that the effects of QLT0267 were influenced by Her2/neu expression. To understand how, six Her2/neu positive breast cancer cell lines were evaluated following treatment with QLT0267. These cell lines demonstrated suppression (32 to 87%) of total Her2/neu protein. Attenuation of ILK activity or expression was associated with decreases in YB-1 protein and transcript levels and decreased YB-1 promoter activity. YB-1 is a known transcriptional regulator of Her2/neu expression. ILK inhibition also engendered suppression in TWIST (a regulator of YB-1 expression) protein expression. Taken together, these data indicate that ILK regulates the expression of Her2/neu through TWIST and YB-1, lending support to the use of ILK inhibitors in the treatment of aggressive Her2/neu positive tumours.
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Ghanem, Ali [Verfasser], and Stefan [Akademischer Betreuer] Wölfl. "On the Regulation and Multiple Functions of the Key Gluconeogenic Enzyme Fbp1 in Rapidly Proliferating Cells: Insights from Yeast and Breast Cancer Cells / Ali Ghanem ; Betreuer: Stefan Wölfl." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177149605/34.
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Duberg, Ann-Sofi. "Hepatitis C virus infection a nationwide study of associated morbidity and mortality /." Doctoral thesis, Örebro : Örebro universitet, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-7835.
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Tran, Xuan Quang. "Les modèles de régression dynamique et leurs applications en analyse de survie et fiabilité." Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0147/document.
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Cette thèse a été conçu pour explorer les modèles dynamiques de régression, d’évaluer les inférences statistiques pour l’analyse des données de survie et de fiabilité. Ces modèles de régression dynamiques que nous avons considérés, y compris le modèle des hasards proportionnels paramétriques et celui de la vie accélérée avec les variables qui peut-être dépendent du temps. Nous avons discuté des problèmes suivants dans cette thèse.Nous avons présenté tout d’abord une statistique de test du chi-deux généraliséeY2nquiest adaptative pour les données de survie et fiabilité en présence de trois cas, complètes,censurées à droite et censurées à droite avec les covariables. Nous avons présenté en détailla forme pratique deY2nstatistique en analyse des données de survie. Ensuite, nous avons considéré deux modèles paramétriques très flexibles, d’évaluer les significations statistiques pour ces modèles proposées en utilisantY2nstatistique. Ces modèles incluent du modèle de vie accélérés (AFT) et celui de hasards proportionnels (PH) basés sur la distribution de Hypertabastic. Ces deux modèles sont proposés pour étudier la distribution de l’analyse de la duré de survie en comparaison avec d’autre modèles paramétriques. Nous avons validé ces modèles paramétriques en utilisantY2n. Les études de simulation ont été conçus.Dans le dernier chapitre, nous avons proposé les applications de ces modèles paramétriques à trois données de bio-médicale. Le premier a été fait les données étendues des temps de rémission des patients de leucémie aiguë qui ont été proposées par Freireich et al. sur la comparaison de deux groupes de traitement avec des informations supplémentaires sur les log du blanc du nombre de globules. Elle a montré que le modèle Hypertabastic AFT est un modèle précis pour ces données. Le second a été fait sur l’étude de tumeur cérébrale avec les patients de gliome malin, ont été proposées par Sauerbrei & Schumacher. Elle a montré que le meilleur modèle est Hypertabastic PH à l’ajout de cinq variables de signification. La troisième demande a été faite sur les données de Semenova & Bitukov, à concernant les patients de myélome multiple. Nous n’avons pas proposé un modèle exactement pour ces données. En raison de cela était les intersections de temps de survie.Par conséquent, nous vous conseillons d’utiliser un autre modèle dynamique que le modèle de la Simple Cross-Effect à installer ces donnéesThis thesis was designed to explore the dynamic regression models, assessing the sta-tistical inference for the survival and reliability data analysis. These dynamic regressionmodels that we have been considered including the parametric proportional hazards andaccelerated failure time models contain the possibly time-dependent covariates. We dis-cussed the following problems in this thesis.At first, we presented a generalized chi-squared test statisticsY2nthat is a convenient tofit the survival and reliability data analysis in presence of three cases: complete, censoredand censored with covariates. We described in detail the theory and the mechanism to usedofY2ntest statistic in the survival and reliability data analysis. Next, we considered theflexible parametric models, evaluating the statistical significance of them by usingY2nandlog-likelihood test statistics. These parametric models include the accelerated failure time(AFT) and a proportional hazards (PH) models based on the Hypertabastic distribution.These two models are proposed to investigate the distribution of the survival and reliabilitydata in comparison with some other parametric models. The simulation studies were de-signed, to demonstrate the asymptotically normally distributed of the maximum likelihood estimators of Hypertabastic’s parameter, to validate of the asymptotically property of Y2n test statistic for Hypertabastic distribution when the right censoring probability equal 0% and 20%.n the last chapter, we applied those two parametric models above to three scenes ofthe real-life data. The first one was done the data set given by Freireich et al. on thecomparison of two treatment groups with additional information about log white blood cellcount, to test the ability of a therapy to prolong the remission times of the acute leukemiapatients. It showed that Hypertabastic AFT model is an accurate model for this dataset.The second one was done on the brain tumour study with malignant glioma patients, givenby Sauerbrei & Schumacher. It showed that the best model is Hypertabastic PH onadding five significance covariates. The third application was done on the data set given by Semenova & Bitukov on the survival times of the multiple myeloma patients. We did not propose an exactly model for this dataset. Because of that was an existing oneintersection of survival times. We, therefore, suggest fitting other dynamic model as SimpleCross-Effect model for this dataset
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Swift, Brenna. "Natural Killer Cell Line Therapy in Multiple Myeloma." Thesis, 2011. http://hdl.handle.net/1807/31456.
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Multiple myeloma (MM) is an incurable plasma cell malignancy. NK cells have demonstrated anti-MM activity in allogeneic transplants and donor lymphocyte infusions, and may provide a more effective therapy for MM. This work demonstrates cytotoxicity of NK-92 and KHYG-1 against MM cells in chromium release and flow cytometry cytotoxicity assays. At a 10:1 effector to target ratio, the cytotoxicity of NK cell lines against MM cells is 50-90%. Blocking NKp30 significantly reduces the cytotoxicity of NK-92 and KHYG-1, while blocking NKG2D and DNAM-1 only reduces the cytotoxicity of NK-92. Notably, NK-92 and KHYG-1 have shown preferential cytotoxicity against the clonogenic population, killing 89-99% in a methylcellulose cytotoxicity assay. Preliminary results in a xenograft bioluminescent mouse model show that NK-92, but not KHYG-1, reduces the tumor burden detected by bioluminescence imaging and bone marrow engraftment by flow cytometry. Therefore, NK cell lines may offer a more effective therapy for MM.