Biomedical subjects

Kezhi Dai

Publications and source records attributed to Kezhi Dai.

3 recordsLinked to original sources

PubMed2006

Endothelial progenitor cells display clonal restriction in multiple myeloma.

BACKGROUND: In multiple myeloma (MM), increased neoangiogenesis contributes to tumor growth and disease progression. Increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis in MM, and, importantly, covary with disease activity and response to treatment. In order to understand the mechanisms responsible for increased EPC levels and neoangiogenic function in MM, we investigated whether these cells were clonal by determining X-chromosome inactivation (XCI) patterns in female patients by a human androgen receptor assay (HUMARA). In addition, EPCs and bone marrow cells were studied for the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement, which indicates clonality in B cells; thus, its presence in EPCs would indicate a close genetic link between tumor cells in MM and endothelial cells that provide tumor neovascularization. METHODS: A total of twenty-three consecutive patients who had not received chemotherapy were studied. Screening in 18 patients found that 11 displayed allelic AR in peripheral blood mononuclear cells, and these patients were further studied for XCI patterns in EPCs and hair root cells by HUMARA. In 2 patients whose EPCs were clonal by HUMARA, and in an additional 5 new patients, EPCs were studied for IGH gene rearrangement using PCR with family-specific primers for IGH variable genes (VH). RESULTS: In 11 patients, analysis of EPCs by HUMARA revealed significant skewing (> or = 77% expression of a single allele) in 64% (n = 7). In 4 of these patients, XCI skewing was extreme (> or = 90% expression of a single allele). In contrast, XCI in hair root cells was random. Furthermore, PCR amplification with VH primers resulted in amplification of the same product in EPCs and bone marrow cells in 71% (n = 5) of 7 patients, while no IGH rearrangement was found in EPCs from healthy controls. In addition, in patients with XCI skewing in EPCs, advanced age was associated with poorer clinical status, unlike patients whose EPCs had random XCI. CONCLUSION: Our results suggest that EPCs in at least a substantial subpopulation of MM patients are related to the neoplastic clone and that this is an important mechanism for upregulation of tumor neovascularization in MM.

Age Factors↗

PubMed2004

Circulating endothelial progenitor cells in multiple myeloma: implications and significance.

Angiogenesis governs the progression of multiple myeloma (MM). Circulating endothelial cells (CECs) contribute to angiogenesis and comprise mature ECs and endothelial progenitor cells (EPCs). The present study sought to characterize CECs and their relation to disease activity and therapeutic response in 31 consecutive patients with MM. CECs, identified as CD34(+)/CD146(+)/CD105(+)/CD11b(-) cells, were 6-fold higher in patients compared to controls and correlated positively with serum M protein and beta(2)-microglobulin. Circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation on matrigel; these processes were inhibited after effective thalidomide treatment. Co-expression of vascular endothelial growth factor receptor-2 (KDR) and CD133 characterized EPCs in MM, and KDR mRNA elevations correlated with M protein levels. In vitro exposure of ECs to thalidomide or its derivative CC-5013 inhibited gene expression of the receptors for transforming growth factor-beta and thrombin. Thus, elevated levels of CECs and EPCs covary with disease activity and response to thalidomide, underscoring the angiogenic aspect of MM and suggesting that angioblastlike EPCs are a pathogenic biomarker and a rational treatment target in MM. The results also highlight the anti-angiogenic properties of thalidomide and CC-5013 and further elucidate possible mechanisms of their effectiveness against MM. (Blood. 2005;105:3286-3294).

Adult↗

PubMed2003

Microsomal triglyceride transfer protein: a multifunctional protein.

Microsomal triglyceride transfer protein (MTP) is a heterodimeric protein that transfers neutral lipids between membranes in vitro. Absence of this lipid transfer activity in the microsomes of abetalipoproteinemia patients established its pivotal function in lipoprotein assembly. Recent studies indicate that the lipid transfer activity is involved in importing triglycerides into the lumen of the endoplasmic reticulum. In addition to its lipid transfer activity, MTP physically interacts with apoB. This led to speculation that MTP may act as a chaperone. It remains to be determined whether the binding of MTP to apoB plays a role in either proper folding or net lipidation of nascent apoB. Both functions, lipid transfer and apoB binding, may be involved in the initial step of lipidation of nascent apoB resulting in the synthesis of primordial lipoprotein particles. Furthermore, it has been shown that MTP stably associates with lipid vesicles. The lipid-associated MTP may be important in core expansion of primordial lipoproteins. In summary, three independent functions (lipid transfer, apoB binding and membrane association) of MTP have been identified. Here, we propose these functions are carried out by a combination of different structural motifs. Based on sequence homology with lipovitellin, the M subunit of MTP is predicted to contain three beta-sheets (A, C, and N) and one alpha-helical domain. The A- and C-sheets may be involved in lipid transfer, the N-sheet and the helical domain in apoB binding, and the N- and A-sheets in membrane association. It is also speculated that MTP may function in physiologic processes beyond lipoprotein assembly.

Animals↗