EFFECTS OF LOW-DOSE-GAMMA RAYS ON THE IMMUNE SYSTEM OF DIFFERENT ANIMAL MODELS OF DISEASE

We reviewed the beneficial or harmful effects of low-dose ionizing radiation on several diseases based on a search of the literature. The attenuation of autoimmune manifestations in animal disease models irradiated with low-dose γ-rays was previously reported by several research groups, whereas the exacerbation of allergic manifestations was described by others. Based on a detailed examination of the literature, we divided animal disease models into two groups: one group consisting of collagen-induced arthritis (CIA), experimental encephalomyelitis (EAE), and systemic lupus erythematosus, the pathologies of which were attenuated by low-dose irradiation, and another group consisting of atopic dermatitis, asthma, and Hashimoto’s thyroiditis, the pathologies of which were exacerbated by low-dose irradiation. The same biological indicators, such as cytokine levels and Tcell subpopulations, were examined in these studies. Low-dose irradiation reduced interferon (IFN)-gamma (γ) and interleukin (IL)-6 levels and increased IL-5 levels and the percentage of CD4+CD25+Foxp3+Treg cells in almost all immunological disease cases examined. Variations in these biological indicators were attributed to the attenuation or exacerbation of the disease’s manifestation. We concluded that autoimmune diseases caused by autoantibodies were attenuated by low-dose irradiation, whereas diseases caused by antibodies against external antigens, such as atopic dermatitis, were exacerbated

High-endothelial cell-derived S1P regulates dendritic cell localization and vascular integrity in the lymph node

While the sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor-1 (S1PR1) axis is critically important for lymphocyte egress from lymphoid organs, S1PR1-activation also occurs in vascular endothelial cells (ECs), including those of the high-endothelial venules (HEVs) that mediate lymphocyte immigration into lymph nodes (LNs). To understand the functional significance of the S1P/S1PR1-Gi axis in HEVs, we generated Lyve1;Spns2Δ/Δ conditional knockout mice for the S1P-transporter Spinster-homologue-2 (SPNS2), as HEVs express LYVE1 during development. In these mice HEVs appeared apoptotic and were severely impaired in function, morphology and size; leading to markedly hypotrophic peripheral LNs. Dendritic cells (DCs) were unable to interact with HEVs, which was also observed in Cdh5CRE-ERT2;S1pr1Δ/Δ mice and wildtype mice treated with S1PR1-antagonists. Wildtype HEVs treated with S1PR1-antagonists in vitro and Lyve1-deficient HEVs show severely reduced release of the DC-chemoattractant CCL21 in vivo. Together, our results reveal that EC-derived S1P warrants HEV-integrity through autocrine control of S1PR1-Gi signaling, and facilitates concomitant HEV-DC interactions

Lysophosphatidate Induces Chemo-Resistance by Releasing Breast Cancer Cells from Taxol-Induced Mitotic Arrest

Taxol is a microtubule stabilizing agent that arrests cells in mitosis leading to cell death. Taxol is widely used to treat breast cancer, but resistance occurs in 25-69% of patients and it is vital to understand how Taxol resistance develops to improve chemotherapy. The effects of chemotherapeutic agents are overcome by survival signals that cancer cells receive. We focused our studies on autotaxin, which is a secreted protein that increases tumor growth, aggressiveness, angiogenesis and metastasis. We discovered that autotaxin strongly antagonizes the Taxol-induced killing of breast cancer and melanoma cells by converting the abundant extra-cellular lipid, lysophosphatidylcholine, into lysophosphatidate. This lipid stimulates specific G-protein coupled receptors that activate survival signals.In this study we determined the basis of these antagonistic actions of lysophosphatidate towards Taxol-induced G2/M arrest and cell death using cultured breast cancer cells. Lysophosphatidate does not antagonize Taxol action in MCF-7 cells by increasing Taxol metabolism or its expulsion through multi-drug resistance transporters. Lysophosphatidate does not lower the percentage of cells accumulating in G2/M by decreasing exit from S-phase or selective stimulation of cell death in G2/M. Instead, LPA had an unexpected and remarkable action in enabling MCF-7 and MDA-MB-468 cells, which had been arrested in G2/M by Taxol, to normalize spindle structure and divide, thus avoiding cell death. This action involves displacement of Taxol from the tubulin polymer fraction, which based on inhibitor studies, depends on activation of LPA receptors and phosphatidylinositol 3-kinase.This work demonstrates a previously unknown consequence of lysophosphatidate action that explains why autotaxin and lysophosphatidate protect against Taxol-induced cell death and promote resistance to the action of this important therapeutic agent

Epigenetic regulation of mucin genes in human cancers

Mucins are high molecular weight glycoproteins that play important roles in diagnostic and prognostic prediction and in carcinogenesis and tumor invasion. Regulation of expression of mucin genes has been studied extensively, and signaling pathways, transcriptional regulators, and epigenetic modification in promoter regions have been described. Detection of the epigenetic status of cancer-related mucin genes is important for early diagnosis of cancer and for monitoring of tumor behavior and response to targeted therapy. Effects of micro-RNAs on mucin gene expression have also started to emerge. In this review, we discuss the current views on epigenetic mechanisms of regulation of mucin genes (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC16, and MUC17) and the possible clinical applications of this epigenetic information

Mineralogy and petrology of comet 81P/wild 2 nucleus samples

The bulk of the comet 81P/Wild 2 (hereafter Wild 2) samples returned to Earth by the Stardust spacecraft appear to be weakly constructed mixtures of nanometer-scale grains, with occasional much larger (over 1 micrometer) ferromagnesian silicates, Fe-Ni sulfides, Fe-Ni metal, and accessory phases. The very wide range of olivine and low-Ca pyroxene compositions in comet Wild 2 requires a wide range of formation conditions, probably reflecting very different formation locations in the protoplanetary disk. The restricted compositional ranges of Fe-Ni sulfides, the wide range for silicates, and the absence of hydrous phases indicate that comet Wild 2 experienced little or no aqueous alteration. Less abundant Wild 2 materials include a refractory particle, whose presence appears to require radial transport in the early protoplanetary disk

Actual therapeutic efficacy of pre-transplant treatment on hepatocellular carcinoma and its impact on survival after salvage living donor liver transplantation.

BACKGROUND: The exact efficacy of pre-liver transplant (LT) therapy for hepatocellular carcinoma (HCC) and the impact on survival after LT remain controversial in regard to salvage LT. MATERIALS AND METHODS: Of 79 patients transplanted in Nagasaki University Hospital between August 1997 and December 2007, 29 patients (36.7%) were indicated for HCC based on the Milan criteria using computed tomography and magnetic resonance imaging. Pre-LT therapy other than liver resection had been performed in 18 cases (62.1%) for 24 lesions. Treated lesions were analyzed histologically using thin slices of the whole explanted liver. RESULTS: Pre-LT therapy included transarterial chemoembolization (TACE) for 10 lesions, percutaneous ethanol injection (PEI) + TACE for 1 lesion, PEI in 6 lesions and ablation therapy in 7 lesions. Under preoperative imaging study, 19 lesions (79.1%) were "thought-to-be" necrotic by pre-LT therapy. However, histologically, viable HCCs were still observed in 9 lesions (9/19 47%). A median interval between the first pre-therapy and LT was 22 months, while last pre-LT therapy and LT was 11 months. No sarcomatous HCC or forced portal venous tumor thrombus was found in all cases with residual lesions. One peritoneal recurrence has occurred after LT, in whom PEI and RFA had been performed before LDLT. The disease free survival after LDLT was comparable to that of cases without pre-LT therapy. CONCLUSION: Half of the preoperatively "thought-to-be" necrotic lesions still contained viable HCC cells after the pre-LT treatment. Overall, the history of pre-LT therapy does not preclude or interfere with subsequent LT, although percutaneous treatment may spread disseminated tumor cell growth under immunosuppression

Mineralogy and Petrology of Comet Wild 2 Nucleus Samples

The bulk of the Wild 2 samples appear to be weakly-constructed mixtures of nanometerscale grains with occasional much larger (>1{micro}m) ferromagnesian silicates, Fe-Ni sulfides, Fe-Ni metal and accessory phases. The very wide range of olivine and low-Ca pyroxene compositions in Wild 2 require a wide range of formation conditions, probably reflecting different formation locations in the protoplanetary disk. The restricted compositional ranges of Fe-Ni sulfides, the wide range for silicates, and absence of hydrous phases indicate that Wild 2 experienced little or no aqueous alteration. Less abundant Wild 2 materials include a refractory particle, whose presence appears to require large-scale radial transport in the early protoplanetary disk. The nature of cometary solids is of fundamental importance to our understanding of the early solar nebula and protoplanetary history. Until now we have had to study comets from afar using spectroscopy, or settle for analyses of interplanetary dust particles (IDPs) of uncertain provenance. We report here mineralogical and petrographic analyses of particles derived directly from Comet Wild 2. All of the Wild 2 particles we have thus far examined have been modified in various ways by the capture process. All particles that may have been loose aggregates, ''traveling sand piles'', disaggregated into individual components with the larger, denser components penetrating more deeply into the aerogel. Individual grains experienced a wide range of heating effects that range from excellent preservation to melting (Fig. 1); such behavior was expected (1, 2 ,3). What is remarkable is the extreme variability of these modifications and the fact that severely modified and unmodified materials can be found within a micrometer of each other, requiring tremendous local temperature gradients. Fortunately, we have an internal gauge of impact collection heating. Fe-Ni sulfides are ubiquitous in the Wild 2 samples, are very sensitive indicators of heating, and accurate chemical analyses can reveal which have lost S, and which have not (and are therefore stoichiometric) (Fig. 2). Our surveys show that crystalline grains are found along the entire lengths of tracks, not just at track termini