[Show abstract][Hide abstract] ABSTRACT: Neutron yield for 250 MeV protons incident on a tungsten target has been measured using the water bath method. The target was made of many randomly placed tungsten grains. Through analyzing the activity of Au foils, the neutron flux distribution in water was obtained. The neutrons slowing down process shows that the neutrons from tungsten have an average energy lower than neutrons from the lead target. The neutron yield was experimentally determined to be 2.02 ± 0.15 neutron/proton. Detailed simulation was also performed with the Geant4 toolkit. Comparison has been made with the experimentally derived neutron yield. It was found that, around 250 MeV, experimental results were described satisfactorily with a combination of high-energy spallation, low-energy neutron reaction and scattering. It was shown that the grain-packed target does not affect much the main neutronic properties, which are of crucial importance for the design of the spallation target.
European Physical Journal A 08/2015; 51(8). DOI:10.1140/epja/i2015-15106-0 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer-associated antigen 66 (OVA66), also known as CML66 (GenBank Accession No. AF283301) was first identified in an ovarian carcinoma cDNA expression library and was shown to play a role in tumorigenesis. Here, we find that OVA66 influences tumorigenesis by regulating the type I insulin-like growth factor receptor (IGF-1R) signaling pathway. Stable knockdown of OVA66 in cancer cells attenuated phosphorylation of IGF-1R and ERK1/2-Hsp27; similarly, a higher level of p-IGF-1R and ERK1/2-Hsp27 signaling were also detected after OVA66 overexpression in HO8910 cells. In vivo, knockdown of OVA66 both reduced tumor burden in nude mice and decreased phosphorylation of IGF-1R, ERK1/2, and hsp27. We blocked IGF-1R function both by siRNA and with the chemical inhibitor Linsitinib (OSI-906). By either method, tumorigenesis was inhibited regardless of OVA66 expression; thus, mechanistically, IGF-1R likely lies downstream of OVA66 in cancer cells. We also found that OVA66 regulates expression of MDM2; this attenuates ubiquitination of IGF-1R in response to IGF-1 stimulation and promotes active ERK1/2 signaling. Thus, we propose that combined overexpression of OVA66 and MDM2 promotes oncogenesis by enhancing activation of the IGF-1R-ERK1/2 signaling pathway.
[Show abstract][Hide abstract] ABSTRACT: The tumor associated antigen OVA66 has been demonstrated to be highly expressed in malignant tumors and implicated in various cellular processes. To further elucidate its oncogenic character, we established an OVA66 stably overexpressed NIH3T3 cell line and a vector transfected control, named NIH3T3-flagOVA66 and NIH3T3-mock, respectively. NIH3T3-flagOVA66 cells showed faster cell cycling, proliferation, cell migration and more resistance to 5-fluorouracil-induced apoptosis. When NIH3T3-flagOVA66 and NIH3T3-mock cells were injected into nude mice for xenograft tumorigenicity assays, the NIH3T3-flagOVA66 cells formed tumors whereas no tumors were observed in mice inoculated with NIH3T3-mock cells. Analysis of PI3K/AKT and ERK1/2 MAPK signaling pathways by serum stimulation indicated hyperactivation of AKT and ERK1/2 in NIH3T3-flagOVA66 cells compared with NIH3T3-mock cells, while a decreased level of p-AKT and p-ERK1/2 were observed in OVA66 knocked down HeLa cells. To further validate if the p-AKT or p-ERK1/2 is essential for OVA66 induced oncogenic transformation, we treated the cells with the PI3K/AKT specific inhibitor LY294002 and the ERK1/2 MAPK specific inhibitor PD98059 and found either inhibitor can attenuate the cell colony forming ability in soft agar and the cell viability of NIH3T3-flagOVA66 cells, suggesting aberrantly activated AKT and ERK1/2 signaling be indispensible of the tumorigenic role of OVA66. Our results indicate that OVA66 is important in oncogenic transformation, promoting proliferation, cell migration and reducing apoptosis via hyperactivating PI3K/AKT and ERK1/2 MAPK signaling pathway. Thus, OVA66 might be a novel target for early detection, prevention and treatment of tumors in the future.
PLoS ONE 03/2014; 9(3):e85705. DOI:10.1371/journal.pone.0085705 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Trastuzumab resistance is a challenging problem in ErbB2/HER2-positive breast cancers. Multiple mechanisms of resistance have been proposed and, thus, may require the development of more personalized therapies. In this study, we report the establishment of a mouse mammary cancer cell line, designated MT104T, obtained from spontaneous tumors in genetically engineered FVB/N-ErbB2/Neu-positive-PTEN-deficient mice. The critical molecular phenotype of MT104T cells was confirmed by genotyping and western blot analysis. This cell line was tumorigenic in immunologically intact syngeneic mice, forming tumors of generally similar histology as its origin. PTEN loss led to hyperactivation of Akt and conferred resistance to anti-ErbB2/Neu antibody treatment in MT104T cells. Addition of the Akt inhibitor triciribine (TCN) inhibited the viability of MT104T cells in a dose- and time-dependent manner as evaluated by MTT assay. ErbB2/Neu antibody and TCN combination treatment greatly induced apoptosis of MT104T cells as indicated by Annexin V-FITC staining. Moreover, this combination treatment also significantly reduced both Akt and Erk activities, which are responsible for the inhibitory effect on MT104T cells. Therefore, MT104T cells could represent an alternative model system to investigate the nature of ErbB2‑positive breast cancer and for the experimental therapeutics studies of this disease. Our findings also suggest that combination of TCN may be a potential strategy for the treatment of trastu-zumab-resistant breast cancer mediated by PTEN loss or PI3K hyperactivation, which may facilitate the development of more personalized therapies for breast cancer patients.
International Journal of Oncology 01/2014; 44(4). DOI:10.3892/ijo.2014.2271 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: G-protein-coupled receptor 120 (GPR120) functions as a receptor for unsaturated long-chain free fatty acids and has an important role in regulating lipid and glucose metabolism. However, a role for GPR120 in the development of tumors has not yet been clarified. Here, we show that GPR120 signaling promotes angiogenic switching and motility of human colorectal carcinoma (CRC) cells. We show that the expression of GPR120 is significantly induced in CRC tissues and cell lines, which is associated with tumor progression. Activation of GPR120 signaling in human CRC promotes angiogenesis in vitro and in vivo, largely by inducing the expression and secretion of proangiogenic mediators such as vascular endothelial growth factor (VEGF), interleukin-8 and cyclooxygenase-2-derived prostaglandin E2. The PI3K/Akt-NF-κB pathway is activated by GPR120 signaling and is required for GPR120 signaling-induced angiogenic switching in CRC cells. And, GPR120 activation enhances the motility of CRC cells and induces epithelial-mesenchymal transition. Furthermore, in vivo study shows that activation of GPR120 promotes angiogenesis and tumor growth. Finally, we find that GPR120 expression is positively correlated with VEGF expression and inversely correlated with the epithelial marker E-cadherin in CRC tissues. Collectively, our results demonstrate that GPR120 functions as a tumor-promoting receptor in CRC and, therefore, shows promise as a new potential target for cancer therapeutics.Oncogene advance online publication, 15 July 2013; doi:10.1038/onc.2013.264.
[Show abstract][Hide abstract] ABSTRACT: Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN-loss- mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine (TCN) effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and MAPK signaling accompanied by increased T cell infiltration in the tumor microenvironment. We demonstrated that both CD8+ and CD4+ T cells were essential to the optimal anti-tumor effect of this combination treatment in an IFN-γ-dependent manner. Importantly, the anti-tumor activities of HER2/Neu antibody and TCN combination treatment were further improved when co-inhibitory receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) was blocked to enhance the T cell response. Our data indicate that multi-targeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies.
[Show abstract][Hide abstract] ABSTRACT: Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN loss-mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and mitogen-activated protein kinase signaling accompanied by increased T-cell infiltration in the tumor microenvironment. We showed that both CD8(+) and CD4(+) T cells were essential to the optimal antitumor effect of this combination treatment in an IFN-γ-dependent manner. Importantly, the antitumor activities of HER2/Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T-lymphocyte-associated antigen 4 was blocked to enhance the T-cell response. Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity, suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies.
Cancer Research 07/2012; 72(17):4417-28. DOI:10.1158/0008-5472.CAN-12-1339-T · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allogeneic umbilical cord blood haematopoietic stem cells (UCB-HSCs) can be transplanted into a host with the intact innate immunity with limited immuno-reaction, although the mechanisms remain unclear. The present studies aimed at investigating potential mechanisms of allogeneic UCB-HSCs escape from the cytolysis of natural killer (NK) cells. We compared UCB-HSCs ability to protect from NK-mediated cytotoxicity with peripheral blood or bone marrow haematopoietic stem cells (PB-HSCs and BM-HSCs). HSCs expressed lower levels of natural cytotoxicity receptor ligands including NKp30L, NKp44L and NKp46L than monocytes. Blocking these ligands respectively or in combination could increase the resistance of HSCs against NK cell mediated cytotoxicity. High expression of HLA-G was noticed on UCB-HSCs, rather than PB-HSCs or BM-HSCs, whereas blockade of HLA-G significantly elevated NK cell mediated cytolysis to UCB-HSCs. Thus, we conclude that natural cytotoxicity receptors and HLA-G on HSCs may contribute to the escape from NK cells, and activate and inhibitory NK cell receptors and their ligands can be novel therapeutic targets in cell transplantation.
Journal of Cellular and Molecular Medicine 11/2010; 15(10):2040-5. DOI:10.1111/j.1582-4934.2010.01214.x · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin-like growth factor-I receptor (IGFIR) has been shown to regulate the tumor development. The objective of the current study is to determine the association of IGFIR with lymph node metastasis and to explore the related mechanism in human colorectal cancer in clinic.
In a random series of 98 colorectal cancer patients, the expressions of IGFIR, vascular endothelial growth factor (VEGF) and VEGF-C were investigated by immunohistochemistry, and the association of these expressions with lymph node metastasis was statistically analyzed. The expressions of VEGF and VEGF-C in colorectal cancer cells stimulated with IGF-I were also examined by real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay.
Higher rates of IGFIR (46%), VEGF (53%), and VEGF-C (46%) expression were found in colorectal cancer tissues than in normal and colorectal adenoma tissues. These expressions were significantly associated with clinicopathologic factors and lymph node status. We also found the concomitant high expressions of IGFIR/VEGF (P < 0.001) and IGFIR/VEGF-C (P = 0.001) had a stronger correlation with lymph node metastasis than did each alone or both low expressions. In addition, IGF-I could effectively induce the VEGF and VEGF-C mRNA expression and protein secretion in colorectal cancer cells expressing IGFIR molecules. Moreover, Patients who had strong staining for IGFIR, VEGF and VEGF-C showed significantly less favorable survival rates compared with patients who had low staining for these molecules (P < 0.001). The survival rates of patients who were both high expression of IGFIR/VEGF and IGFIR/VEGF-C also were significantly lower compared with patients who were negative or one of high expression of these molecules (P < 0.001).
Together the findings indicated for the first time that simultaneous examination of the expressions of IGFIR, VEGF and VEGF-C will benefit the diagnosis of lymph node metastasis in order to assay the prognosis and determine the treatment strategy in patients with colorectal cancer undergoing surgery.
BMC Cancer 05/2010; 10(1):184. DOI:10.1186/1471-2407-10-184 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously found that dendritic cell (DC) precursors could be recruited into the peripheral blood of B6 mice by administration of macrophage inflammatory protein (MIP)-1alpha. These MIP-1alpha-recruited DCs could induce anti-tumor protective immunity when pulsed with tumor cell lysate. In this study, MIP-1alpha-recruited DCs could not effectively suppress preestablished tumor when pulsed with B16 tumor cell lysate. However, inoculation with these DCs expressing MAGE-1 induced an anti-tumor immunity against preestablished solid and metastatic tumor from B16-MAGE-1 cells. These MIP-1alpha-recruited DCs expressed higher level of CCR7 and displayed a more significant chemotactic response toward secondary lymphoid tissue. Therefore, they are superior in the induction of cytotoxic T lymphocytes and the inhibition of tumor development and metastasis than bone marrow-derived DCs. This study established a novel approach to the treatment of preestablished solid and metastatic tumors using MIP-1alpha-recruited DCs transduced with tumor antigen gene.
Cancer letters 03/2010; 295(1):17-26. DOI:10.1016/j.canlet.2010.02.009 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemokines and chemokine receptors play critical roles in directing the migration of alloreactive donor T cells into graft-vs-host disease (GVHD) target organs. However, blockade of GVHD by antagonist Ab against chemokine receptors remains an elusive goal. Using a mouse model of human GVHD, we demonstrate that in vivo administration of anti-CXCR3 Ab for 21 days (long-term), but not for 7 days (short-term), inhibits alloreactive CD8(+) T cell-mediated GVHD. During a graft-vs-host reaction, infused donor CD8(+) T cells generate two subsets of potent inducers of GVHD: CXCR3(+)CD8(+) and CXCR3(-)CD8(+) T cells. Compared with CXCR3(+)CD8(+) T cells, CXCR3(-)CD8(+) T cells produce less granzyme B, Fas ligand, IFN-gamma, and TNF-alpha. Interestingly, stimulation with either dendritic cells or IL-2 induces a dynamic conversion between CXCR3(+)CD8(+) and CXCR3(-)CD8(+) T cells. Short-term anti-CXCR3 Ab treatment inhibits only CXCR3(+)CD8(+) T cell-mediated GVHD, but not the disease induced by CXCR3(-)CD8(+) T cells. Prolonged in vivo administration of anti-CXCR3 Ab significantly reduces the infiltration of alloreactive CD8(+) T cells into GVHD target organs and inhibits GVHD mediated by either CXCR3(+)CD8(+) or CXCR3(-)CD8(+) T cells. Thus, we have established a novel and effective approach with the potential to give rise to new clinical methods for preventing and treating GVHD after allogeneic hematopoietic stem cell transplantation.
The Journal of Immunology 12/2009; 181(11):7581-92. DOI:10.4049/jimmunol.181.11.7581 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously showed that hematopoietic progenitor cells (HPCs) with the (Lin)(-)c-kit(+) phenotype isolated from day 13 postcoitus murine fetal liver (FL) can develop into dendritic cells (DCs) in vitro in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), Flt3 ligand (Flt3L) and tumor necrosis factor (TNF)-alpha. This differentiation is dependent upon the presence of PA6 stromal cells. In the present study, we show that after intravenous transfer into lethally irradiated mice, the FL Lin(-)c-kit(+) HPCs generate E-cadherin(+) Langerhans cells, and splenic DCs that express high levels of Ia, CD11c, DEC205 and intermediate levels of CD40. These cells are capable of stimulating a T cell response. Interestingly, neutralizing anti-interleukin (IL)-3 antibody suppresses generation of FL HPC-derived DC in vivo. Moreover, addition to FL HPCs culture of IL-3 along with GM-CSF, SCF, Flt3L and TNF-alpha results in DC development from without the support of PA6 cells. This study provides the first evidence that IL-3 plays a critical role in DC development from FL Lin-c-kit(+) HPCs.
Frontiers in Bioscience 01/2009; 14(10):3814-3824. DOI:10.2735/3490 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acquisition of dendritic cells (DCs) or DC precursors in vitro is critical for DC-based immunotherapy. We reported previously that administration of MIP-1alpha mobilized a population of F4/80(-)B220(-)CD11c+ DC precursors into peripheral blood by the expression of CCR1 and CCR5. In this study, we identified a new subset of CCR6+CCR1(-)CCR5(-)B220(-)CD11c(+) cells in MIP-1alpha-administered mice. When cultured with GM-CSF, IL-4, and TNF-alpha, these cells differentiated into mature DCs, possessing the typical morphologic characteristics, phenotypes, and antigen-presenting function (termed CCR6+ DC precursors). Although it did not directly drive the CCR6+ DC precursors, MIP-1alpha could recruit a population of F4/80+CD11c(-) monocyte/macrophage-producing MIP-3alpha in the peripheral blood to mobilize a CCR6+ DC precursor subset of B220(-)CD11c+ DC precursors. Importantly, exogenous administration of MIP-3alpha significantly enhanced MIP-1alpha-induced mobilization of DC precursors. Moreover, these MIP-3alpha- and MIP-1alpha-mobilized DC precursors could be prepared for a DC vaccine capable of eliciting CTL responses to tumor cells, leading to tumor rejection in vitro and in vivo. Taken together, this study further demonstrates the mechanism of DC precursor mobilization induced by MIP-1alpha; that is, besides mobilizing DC precursors with CCR1 and CCR5 expressions, MIP-1alpha recruited F4/80+CD11c(-) monocyte/macrophage-producing MIP-3alpha, which finally mobilized the CCR6+ DC precursor subset to amplify the B220(-)CD11c+ DC precursor population. Furthermore, combined administration of MIP-3alpha and MIP-1alpha may be an efficient strategy for collecting a large number of DCs appropriate for immunotherapy.
[Show abstract][Hide abstract] ABSTRACT: CML66 is a novel, promising tumor antigen; however, its biological roles remain unclear. In present study, we applied a short hairpin RNA triggered RNA interfering to suppress CML66 expression in HeLa cervical carcinoma cells. Knockdown of CML66 inhibited proliferation, migration and invasion activities of HeLa cells in vitro. Meanwhile, in nude mice, CML66 silencing suppressed tumor growth and pulmonary metastasis with HeLa cells injected subcutaneously. Furthermore, using metastasis-related genes cDNA microarrays, we found 9 genes were significantly down-regulated after CML66 silencing, including cathepsin L, MMP15, uPAR, VEGF, COX-2, S100A4, MUC1, MDM2 and RAC1. These results imply that CML66 may play an oncogenic role in ways of favoring tumor cells proliferation, invasion and metastasis-associated with multiple pathways. Thus, CML66 might be a potential target for development of cancer therapy.
Cancer letters 07/2008; 269(1):127-38. DOI:10.1016/j.canlet.2008.04.035 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CD1d-restricted natural killer T (NKT) cells and CD4+CD25+ regulatory T (Treg) cells are two thymus-derived subsets of regulatory T cells that play an important role in the maintenance of self-tolerance. Yet the functional changes of the two subsets of regulatory T cells in the development of diabetes in non-obese diabetic (NOD) mice remain unclear, and how NKT cells and CD4+CD25+ Treg cells cooperate functionally in the regulation of autoimmune diabetes is also uncertain. We provide evidence that in NOD mice, an animal model of human type 1 diabetes, the functions of both NKT cells and CD4+CD25+ Treg cells decrease in an age-dependent manner. We show that treatment with alpha-galactosylceramide increases the size of the CD4+CD25+ Treg cell compartment in NOD mice, and augments the expression of forkhead/winged helix transcription factor and the potency of CD4+CD25+ Treg cells to inhibit proliferation of CD4+CD25- T cells. Our data indicate that NKT cells and CD4+CD25+ Treg cells might cooperate in the prevention of autoimmune diabetes in NOD mice treated with alpha-galactosylceramide. Induced cooperation of NKT cells and CD4+CD25+ Treg cells could serve as a strategy to treat human autoimmune disease, such as type 1 diabetes.
[Show abstract][Hide abstract] ABSTRACT: As reported previously, the lack of the transcriptional co-activator OBF-1 prevented development of autoimmunity in Aiolos knockout mice. To further investigate the role and mechanism of OBF-1 in autoimmunity, we crossed OBF-1 null mice with MRL-lpr mice and generated OBF-1-deficent MRL-lpr mice. OBF-1 deletion abrogated all autoantibodies in the MRL-lpr mice, including anti-dsDNA Ab and anti-Sm Ab. The failure to produce autoantibodies was not related to development of immature or mature B cells, but correlated with severely reduced antibody-secreting cells (ASCs). The loss of OBF-1 protected against hypergammaglobulinemia, immune complex deposition, glomerulonephritis, and early mortality in MRL-lpr mice. In addition, accumulation of CD4(-)CD8(-)B220(+)CD3(+) T cells that characteristically develop in Fas mutation mice were markedly reduced in MRL-lpr mice without OBF-1. These results identify OBF-1 as a critical gene in the development of autoantibodies and reveal an essential role for OBF-1 in the generation of antibody/autoantibody-secreting cells in vivo.
Journal of Autoimmunity 09/2007; 29(2-3):87-96. DOI:10.1016/j.jaut.2007.05.001 · 8.41 Impact Factor