Interferon-␥ (IFN-␥ IFN-␥3 is a multifunctional cytokine produced mainly by NK cells and activated T cells that plays a critical role in host immune responses against pathogens and cancer (1). Mice deficient in IFN-␥, the R1 subunit of the IFN-␥ receptor, or the transcription factor STAT1 are more susceptible to spontaneous tumor development (1-3). IFN-␥ has also been found to have direct anti-proliferative and pro-apoptotic effects on tumor cells in animal models (4, 5); however, administration of high dose IFN-␥ to patients with advanced renal and ovarian cancer has had only limited success and failed to improve overall survival (1, 6).IFN-␥ has been shown to regulate bone cell differentiation and function with complex effects on skeletal health. However, the role of IFN-␥ in pathological bone disease is largely controversial. Previously, it has been reported that IFN-␥ can inhibit the critical osteoclast regulator, receptor activator of NFB ligand (RANKL), by activating ubiquitin-mediated degradation of its signaling pathway adaptor protein 8). Mice deficient for IFN-␥ or its receptor develop enhanced bone loss associated with collagen-induced arthritis (9 -11). In contrast, Gao et al. (12) recently found that IFN-␥ indirectly stimulates osteoclast formation and bone loss after ovariectomy via antigen-driven T cell activation, resulting in the production of osteoclast-activating factors. Interestingly, IFN-␥ has been used to treat infantile osteopetrosis in which patients suffered from high bone mass secondary to osteoclast dysfunction or osteoblast hyperactivity, but the mechanism of action may be through modulation of the host immune system rather than direct effects on bone cells (13-15). However, the role of IFN-␥ in the treatment of osteolytic bone metastases has not been elucidated.We evaluated the effects of IFN-␥ in HTLV-1-Tax transgenic mice that develop osteolytic bone tumors and hypercalcemia (16,17). Previously, it was shown that HTLV-1-Taxmice develop increased numbers of soft tissue tumors with enhanced tumor-associated angiogenesis and up-regulation of vascular endothelial growth factor expression; however, the impact on bone metastases and hypercalcemia in these mice * This work was supported, in whole or in part, by National Institutes of Health Grants PPG CA100730 and R01 CA 097250 (to Z. X., M. H., H. D., M. C. E., D. H. F., E. A. H., and K. N. W.), Grant T32 CA09547 (cancer biology training grant to O. U. and M. H.), and Grant RO1 CA100730 (to T. J. R. and W. P. D. and NCRR to S. S.), as well as by the St. Louis Men's Club Against Cancer (to K. N. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Acyl chain-labeled NBD-phosphatidylcholine (NBD-PC) has been used to identify three gene products (Lem3p, Dnf1p, and Dnf2p) that are required for normal levels of inward-directed phospholipid transport (flip) across the plasma membrane of yeast. Although the head group structure of acyl chain-labeled NBD phospholipids has been shown to influence the mechanism of flip across the plasma membrane, the extent to which the acyl chain region and the associated fluorophore affect flip has not been assessed. Given the identification of these proteins required for NBD-PC flip, it is now possible to determine whether the fluorophore attached to a phospholipid acyl chain influences the mechanism of flip. Thus, flip of phosphatidylcholine molecules with three different Bodipy fluorophores (Bodipy FL, Bodipy 530, and Bodipy 581) was tested and compared with that of NBD-PC in strains carrying deletions in LEM3, DNF1, and DNF2. Deletion of these genes significantly reduced the flip of NBD-PC and Bodipy FL-PC but had no effect on that of Bodipy 581-PC and Bodipy 530-PC. These data, in combination with comparisons of the effect of ATP depletion, collapse of the proton electrochemical gradient across the plasma membrane, and culture density led to the conclusion that at least three different flip pathways exist in yeast that are selective for the structure of the fluorophore attached to the acyl chain of phosphatidylcholine molecules.Fluorescent acyl chain-labeled phospholipids have been used extensively as reporters to study the transport and intracellular trafficking of phospholipids in a wide range of cells (for recent reviews see Refs. 1-3). Attachment of the fluorophore to the terminal end of one acyl chain permits the synthesis of glycerophospholipids and sphingolipids with a wide range of different head groups. The fluorophore is generally attached to a shortened acyl chain in the sn-2 position to facilitate the introduction of these reporter phospholipids into the outer leaflet of the plasma membrane. This approach has demonstrated that the nature of the head group is a major determinant of the pathway of internalization and subsequent intracellular trafficking and localization of these reporter phospholipids (4).Application of genetic and genomic approaches available for Saccharomyces cerevisiae has led to the identification of three gene products that are required for the normal uptake of a phosphatidylcholine reporter labeled in the sn-2 acyl chain with NBD 4 (7-nitrobenz-2-oxa-1,3-diazol-4-yl). NBD-PC uptake is greater than 80% inhibited in strains in which the LEM3/ROS3 gene is deleted (5, 6). A similar inhibition of NBD-PC internalization is observed in strains deleted in both DNF1 and DNF2 (7). Dnf1p and Dnf2p are members of the P-type ATPase family that couple ATP hydrolysis to the transmembrane transport of a wide spectrum of ions. They belong to a subfamily of P-type ATPases that has been reported to actively transport phospholipids (8, 9). Lem3p encodes an integral membrane protein that is necessary for exit of...
Intraplacental hepatic nodules are extremely rare and range from incidentally identified microscopic nodules to large mass-forming lesions. We describe the case of an incidentally identified intraparenchymal hepatic nodule in the placenta from a near-term delivery of a male infant at 36 weeks gestation. Lesional cells were positive for HepPar1, focally positive for glypican3, and negative for calretinin and alpha-fetoprotein, supportive of hepatocellular origin. Fluorescence in-situ hybridization and chromosomal microarray both showed a male sex chromosome complement (XY) within the nodule, confirming the fetal origin of this nodule. We provide the first report of the confirmed fetal origin of these rare lesions, lending support to the hypothesis that placental hepatic nodules may represent an embryonal rest or residua of abnormal cell migration.
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