Citations

Abstract The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1–dependent migration was regulated by the PI3K and ERK/MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.

AbstractWe previously reported a lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism. Evidence has linked genetic variants involved in one-carbon metabolism to NHL. We investigated 30 polymorphisms in 18 genes for their main effect on NHL among 1141 incident cases and 949 population-based controls and examined gene-nutrient interactions in a subgroup of 386 cases and 319 controls who provided detailed food-frequency information. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for age, sex, and race. We observed a decreased risk of NHL overall with BHMT Ex8+453A>T and increased risk with CBS Ex13+41C>T, FPGS Ex15-263T>C, and SHMT1 Ex12+138C>T and Ex12+236C>T. Furthermore, significant gene-nutrient interactions limited the protective association comparing high versus low vitamin B6 to FPGS Ex15-263T>C CC (OR = 0.22; 95% CI = 0.10-0.52), MTHFS IVS2-1411T>G TT/TG (OR = 0.54; 95% CI = 0.36-0.81), and MTR Ex26-20A>G AA (OR = 0.55; 95% CI = 0.35-0.86) genotypes, and the protective association of methionine to FTHFD Ex10-40G>T GG (OR = 0.63; 95% CI = 0.44-0.91), MTHFR Ex8-62A>C CC (OR = 0.13; 95% CI = 0.04-0.39), and MTRR Ex5+136T>C TT (OR = 0.67; 95% CI = 0.47-0.97) genotypes. Warranting replication, our finding of gene-nutrient interactions in one-carbon metabolism supports their etiologic involvement in lymphomagenesis.

ABSTRACTWhileCryptosporidium parvuminfection of the intestine has been reported in both immunocompetent and immunocompromised individuals, biliary infection is seen primarily in adult AIDS patients and is associated with development of AIDS cholangiopathy. However, the mechanisms of pathogen-induced AIDS cholangiopathy remain unclear. Since we previously demonstrated that the Fas/Fas ligand (FasL) system is involved in paracrine-mediatedC. parvumcytopathicity in cholangiocytes, we also tested the potential synergistic effects of human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat)-mediated FasL regulation onC. parvum-induced apoptosis in cholangiocytes by semiquantitative reverse transcription-PCR, immunoblotting, immunofluorescence analysis, and immunogold electron microscopy. H69 cells do not express CXCR4 and CCR5, which are receptors required for direct HIV-1 viral infection. However, recombinant biologically active HIV-1-associated Tat protein increased FasL expression in the cytoplasm of cholangiocytes without a significant increase in apoptosis. We found thatC. parvum-induced apoptosis was associated with translocation of intracellular FasL to the cell membrane surface and release of full-length FasL from infected H69 cells. Tat significantly (P< 0.05) increasedC. parvum-induced apoptosis in bystander cells in a dose-dependent manner. Moreover, Tat enhanced bothC. parvum-induced FasL membrane translocation and release of full-length FasL. In addition, the FasL neutralizing antibody NOK-1 and the caspase-8 inhibitor Z-IETD-fmk both blockedC. parvum-induced apoptosis in cholangiocytes. The data demonstrated that HIV-1 Tat enhancesC. parvum-induced cholangiocyte apoptosis via a paracrine-mediated, FasL-dependent mechanism. Our results suggest that concurrent active HIV replication, with associated production of Tat protein, andC. parvuminfection synergistically increase cholangiocyte apoptosis and thus jointly contribute to AIDS-related cholangiopathies.

AbstractThe effect of lecithin on jejunal absorption of fatty acids and octadecenoylglycerol was studied in healthy volunteers with a jejunal perfusion system which excluded pancreatic and biliary secretions from the test segment. Lecithin significantly reduced the absorption of oleic acid (P<0.05) and octadecenoylglycerol (P<0.01), while it had no effect on the absorption of ricinoleic acid. In vitro, lecithin reduced monomer activities of all three lipids; the changes were greater for oleic acid and octadecenoylglycerol than for ricinoleic acid (P<0.02). From these data it is concluded that lecithin reduces monomer activity of fatty acids in mixed micellar solutions and that it can thereby reduce the absorption rates of micellar lipids. Intact lecithin is not absorbed under these conditions. Maldigestion of lecithin in pancreatic insufficiency may, therefore, aggravate the steatorrhea observed in this condition.

AbstractAn analysis of the phospholipid, cholesterol, and phospholipid fatty acyl composition of isolated plasma membranes of 3T3 and SV3T3 mouse embryo cells has been performed. The results show that the plasma membrane of SV3T3 cells contain relatively less phosphatidylethanolamine and sphingomyelin and more cholesterol than 3T3 plasma membranes. The fatty acyl composition of individual phospholipid classes as determined by gas liquid chromatography also showed differences between 3T3 and SV3T3 plasma membranes. The plasma membranes of SV40 transformed 3T3 cells contain: (a) a higher percentage of 18∶1 and less 20∶3 and 20∶4 in phosphatidylethanolamine; (b) a higher percentage of 18∶1 in phosphatidylserine; and (c) a higher percentage of 18∶2 and 20∶4 in phosphatidylinositol.

AbstractThe lipid composition of plasma membranes isolated from differentialted and undifferentiated L6 myoblasts has been compared. In general, the plasma membranes of differentiated L6 myoblasts have a higher cholesterol to phospholipid molar ratio than plasma membranes of undifferentiated cells. Differentiated L6 myoblasts have increased relative amounts of phosphatidylethanolamine and phosphatidylcholine in their plasma membrane and a decreased relative amount of sphingomyelin when compared with the plasma membranes of undifferentiated myoblasts. In addition, preliminary results show that differentiated L6 myoblasts plasma membrane phospholipid shows differences in the fatty acyl composition, specifically there appears to be relatively more 17∶0 and 24∶1 and less 16∶1 and 18∶1 than in plasma membrane phospholipids of undifferentiated L6 myoblasts. These observations indicate that significant changes in plasma membrane lipid composition occur during myoblast differentiation. The role that changes in lipid composition play in control of cellular differentiation, however, remains to be elucidated.

AbstractTwo simplified methods for quantitative lipoprotein analysis have been calibrated and compared with each other using analytic ultracentrifugation as a standard reference procedure. The first method was the Friedewald procedure and the second was an automated agarose gel electrophoresis system. Both procedures offer comparable quantitative lipoprotein analysis with potential for large scale screening purposes at low cost ($4.00–$5.00 per analysis). There were advantages and limitations to both procedures. The Friedwald procedure can be used on frozen sera but requires 3 ml sera. In contrast, the electrophoresis system must be used with fresh serum but requires only 50 μl serum and the electrophoretic slides may be quantitatively analyzed several years retrospectively.

AbstractCholestanol (4.6%) and plant sterols (0.2%) have been demonstrated, for the first time, in avian skin by argentation and gas liquid chromatography. In contrast to results of previous studies with rat and human skin, cholestanol represented a significant amount in the pigeon. The proportion of campesterol was always higher than that of β‐sitosterol.

AbstractUptake of oleic acid by the everted sac of rat intestine has been shown to be net absorption and not merely exchange. Sodium fluoride, 10 mM, has been shown to inhibit absorption of oleic acid.

Abstract DNA microarray has been widely used in cancer research to better predict clinical outcomes and potentially improve patient management. The new approach provides accurate tumor classification and outcome predictions, such as tumor stage, metastatic status, and patient survival, and offers some hope for individualized medicine. However, growing evidence suggests that gene-based prediction is not stable and little is known about the prediction power of gene expression profiles compared with well-known clinical and pathologic predictors. This review summarized up-to-date publications in microarray-based lung cancer clinical outcome prediction and conducted secondary analyses for those with sufficient sample sizes and associated clinical information. Among the most commonly used analytic approaches, unsupervised clustering mainly recaptures tumor histology and provides variable degrees of prediction for tumor stage, lymph node status, or survival. Overall, most studies lack an independent validation. Supervised learning and testing generally offer a better prediction. Noted is that when conventional predictors of age, gender, stage, cell type, and tumor grade are considered collectively, the predictive advantage of the gene expression profiles diminishes. We conclude that outcome prediction from gene expression signatures selected by current analytic approaches can be mostly explained by well-known conventional predictors, particularly histologic subtype and grade of differentiation. A strategy for establishing independent or more accurate signatures is commented. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2063–8)