Effect of Low Density Lipoproteins on the Progression of Chronic Lymphocytic Leukemia

Hypercholesterolemia is a known risk factor for many cancers, including Chronic Lymphocytic Leukemia (CLL). CLL is incurable with conventional chemotherapy and it would be valuable to develop strategies to prevent CLL cells from progressing to the point of causing symptoms that require treatment. Statin drugs have been shown to prolong the time to first chemotherapy treatment, suggesting that one strategy to slow the progression of CLL may be to lower levels of low-density lipoprotein (LDL)-cholesterol. The studies in this thesis were designed to investigate how LDLs affect CLL cells. The results indicate that LDLs enhance a number of signaling pathways in CLL cells in vitro that are associated with leukemic growth. These biological effects depend on the internalization and subsequent breakdown of LDL particles into various components. Overall, the results provide a biological rationale for using methods to decrease LDL-cholesterol such as diet and/or statins to slow disease progression.M.Sc

Is falls risk an independent contributor to everyday problem solving as measured by the EPT in community-dwelling seniors?

MPT Systematic Reviews and Research Projects.Medicine, Faculty ofPhysical Therapy, Department ofUnreviewedGraduat

Persistent janus kinase‐signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial

Abstract Methods to deepen clinical responses to ibrutinib are needed to improve outcomes for patients with chronic lymphocytic leukemia (CLL). This study aimed to determine the safety and efficacy of combining a janus kinase (JAK)‐inhibitor with ibrutinib because JAK‐mediated cytokine‐signals support CLL cells and may not be inhibited by ibrutinib. The JAK1/2 inhibitor ruxolitinib was prescribed to 12 CLL patients with abnormal serum beta‐2 microglobulin levels after 6 months or persistent lymphadenopathy or splenomegaly after 12 months on ibrutinib using a 3 + 3 phase 1 trial design (NCT02912754). Ibrutinib was continued at 420 mg daily and ruxolitinib was added at 5, 10, 15, or 20 mg BID for 3 weeks out of five for seven cycles. The break was mandated to avoid anemia and thrombocytopenia observed with ruxolitinib as a single agent in CLL. The combination was well‐tolerated without dose‐limiting toxicities. Cyclic changes in platelets, lymphocytes, and associated chemokines and thrombopoietic factors were observed and partial response criteria were met in 2 of 12 patients. The results suggest that JAK‐signaling helps CLL cells persist in the presence of ibrutinib and ruxolitinib with ibrutinib is well‐tolerated and may be a useful regiment to use in combination therapies for CLL

Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells

Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6 ± 10.4 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the “watch-and-wait” phase of management

Matrix metalloproteinase inhibition therapy for vascular diseases

The matrix metalloproteinases (MMPs) are 23 secreted or cell surface proteases that act together and with other protease classes to turn over the extracellular matrix, cleave cell surface proteins and alter the function of many secreted bioactive molecules. In the vasculature MMPs influence the migration proliferation and apoptosis of vascular smooth muscle, endothelial cells and inflammatory cells, thereby affecting intima formation, atherosclerosis and aneurysms, as substantiated in clinical and mouse knockout and transgenic studies. Prominent counterbalancing roles for MMPs in tissue destruction and repair emerge from these experiments. Naturally occurring tissue inhibitors of MMPs (TIMPs), pleiotropic mediators such as tetracyclines, chemically-synthesised small molecular weight MMP inhibitors (MMPis) and inhibitory antibodies have all shown effects in animal models of vascular disease but only doxycycline has been evaluated extensively in patients. A limitation of broad specificity MMPis is that they prevent both matrix degradation and tissue repair functions of different MMPs. Hence MMPis with more restricted specificity have been developed and recent studies in models of atherosclerosis accurately replicate the phenotypes of the corresponding gene knockouts. This review documents the established actions of MMPs and their inhibitors in vascular pathologies and considers the prospects for translating these findings into new treatments.The matrix metalloproteinases (MMPs) are 23 secreted or cell surface proteases that act together and with other protease classes to turn over the extracellular matrix, cleave cell surface proteins and alter the function of many secreted bioactive molecules. In the vasculature MMPs influence the migration proliferation and apoptosis of vascular smooth muscle, endothelial cells and inflammatory cells, thereby affecting intima formation, atherosclerosis and aneurysms, as substantiated in clinical and mouse knockout and transgenic studies. Prominent counterbalancing roles for MMPs in tissue destruction and repair emerge from these experiments. Naturally occurring tissue inhibitors of MMPs (TIMPs), pleiotropic mediators such as tetracyclines, chemically-synthesised small molecular weight MMP inhibitors (MMPis) and inhibitory antibodies have all shown effects in animal models of vascular disease but only doxycycline has been evaluated extensively in patients. A limitation of broad specificity MMPis is that they prevent both matrix degradation and tissue repair functions of different MMPs. Hence MMPis with more restricted specificity have been developed and recent studies in models of atherosclerosis accurately replicate the phenotypes of the corresponding gene knockouts. This review documents the established actions of MMPs and their inhibitors in vascular pathologies and considers the prospects for translating these findings into new treatments