The role of prognostic nutritional index for clinical outcomes of gastric cancer after total gastrectomy.

The purpose of this article is to evaluate the relationship between the nutrition-based microenvironment and clinicopathological information for gastric cancer patients and to investigate the prognostic value of nutrition index for gastric cancer patients undergoing total gastrectomy. We retrospectively collected clinical information of 245 gastric cancer patients who underwent total gastrectomy in our hospital between January 1st 2005 and December 30th 2015. According to the prognostic nutritional index (PNI) level, they were divided into low PNI (< 43) group and high PNI (≥ 43) group. The relationship between PNI and the disease-free survival (DFS) and overall survival (OS) were analyzed by statistical analysis. Univariate analyses demonstrated that TNM stage (p = 0.025), patients age (p = 0.042), lymph node metastasis (p = 0.028), tumor differentiation (p = 0.037) and a low PNI (p = 0.033) were closely correlated with a poor prognosis. In multivariate analysis, TNM stage (p = 0.027) and a low PNI (p = 0.041) were found to be independently associated with poor survival. Additionally, when age was considered as a stratified factor, univariate analyses demonstrated that low PNI correlated with shorter DFS in non-elderly (< 65) patients (p = 0.022) and shorter DFS (p = 0.036) and OS (p = 0.047) in elderly (≥ 65) patients. The low prognostic nutritional index is an independent risk factor associated with poor gastric cancer survival which represents the nutritional microenvironment. Patients with low pre-operative prognostic nutritional index levels should be observed more closely after surgery to prevent the occurrence of post-operative complications in the near future.

Jagged-2 enhances immunomodulatory activity in adipose derived mesenchymal stem cells.

Adipose derived Mesenchymal stem cells (AMSCs) are able to expand in vitro and undergo differentiation into multiple cell lineages, yet have low immunogenicity while exhibiting several immunoregulatory characteristics. We sought to investigate the immunomodulatory mechanisms of AMSCs to better understand their immunogenic properties. Following 10 days of chondrogenic differentiation or 48 hours of IFN-γ pretreatment, AMSCs retained low level immunogenicity but prominent immunoregulatory activity and AMSC immunogenicity was enhanced by chondrogenic differentiation or IFN-γ treatment. We found Jagged-2 expression was significantly elevated following chondrogenic differentiation or IFN-γ pretreatment. Jagged-2-RNA interference experiments suggested that Jagged-2-siRNA2 suppresses Jagged-2 expression during chondrogenic differentiation and in IFN-γ pretreated AMSCs. Besides, Jagged-2 interference attenuated immunosuppressive activity by mixed lymphocyte culture and mitogen stimulation experiments. So, the immunoregulatory activity of AMSCs, to some extent dependent upon Jagged-2, might be stronger after multilineage differentiation or influence from inflammatory factors. This may also be why rejection does not occur after allogeneic AMSCs differentiate into committed cells.

MicroRNA-320a acts as a tumor suppressor by targeting BCR/ABL oncogene in chronic myeloid leukemia.

Accumulating evidences demonstrated that the induction of epithelial-mesenchymal transition (EMT) and aberrant expression of microRNAs (miRNAs) are associated with tumorigenesis, tumor progression, metastasis and relapse in cancers, including chronic myeloid leukemia (CML). We found that miR-320a expression was reduced in K562 and in CML cancer stem cells. Moreover, we found that miR-320a inhibited K562 cell migration, invasion, proliferation and promoted apoptosis by targeting BCR/ABL oncogene. As an upstream regulator of BCR/ABL, miR-320a directly targets BCR/ABL. The enhanced expression of miR-320a inhibited the phosphorylation of PI3K, AKT and NF-κB; however, the expression of phosphorylated PI3K, AKT and NF-κB were restored by the overexpression of BCR/ABL. In K562, infected with miR-320a or transfected with SiBCR/ABL, the protein levels of fibronectin, vimentin, and N-cadherin were decreased, but the expression of E-cadherin was increased. The expression of mesenchymal markers in miR-320a-expressing cells was restored to normal levels by the restoration of BCR/ABL expression. Generally speaking, miR-320a acts as a novel tumor suppressor gene in CML and miR-320a can decrease migratory, invasive, proliferative and apoptotic behaviors, as well as CML EMT, by attenuating the expression of BCR/ABL oncogene.

Mouse Flk-1+Sca-1- mesenchymal stem cells: functional plasticity in vitro and immunoregulation in vivo.

OBJECTIVES: Mesenchymal stem cells (MSCs) represent a powerful tool in regenerative medicine because of their differentiation and migration capacities. Moreover, the immunomodulatory ability of MSCs may be used to develop therapies for the treatment of autoimmune diseases. METHODS: In this study, we isolated Flk-1Sca-1 MSCs from bone marrow (bMSCs). Next, we studied their biological characteristics and immunologic functions. We also investigated their effects on graft-versus-host disease (GVHD) associated with allogeneic bone marrow transplantation in mice. RESULTS: Flk-1Sca-1 bMSCs were able to differentiate into fat and cartilage cells, indicating that the isolated cells had stem cell properties. They could also suppress alloantigen-induced T cell proliferation in vitro in a dose-dependent manner. Infusion of bMSCs into allogeneic bone marrow-transplanted mice alleviated the lethal GVHD that occurred in control recipient mice. There was significantly lower mortality among the recipients of the Flk-1Sca-1 bMSCs that also ameliorated the clinical symptoms and GVHD histopathology. Beneficial effects on GVHD by Flk-1Sca-1 bMSCs were also observed when MSCs were engineered to express anti-inflammatory cytokines IL-4 and IL-10 and decrease expression of proinflammatory cytokines IFN-γ, TNF-α, and IL-2. CONCLUSION: Flk-1Sca-1 bMSCs have stem cell properties and can efficiently ameliorate the GVHD associated with allogeneic bone marrow transplantation in mice.

Comparison of the effects of human adipose and bone marrow mesenchymal stem cells on T lymphocytes.

Mesenchymal stem cells (MSCs) are multipotent cells that can be derived either from the bone marrow (bMSCs) or adipose tissue (aMSCs). We have compared the immune regulatory properties of cells derived from bone marrow and adipose tissue to provide a theoretical basis for the choice of stem cell source for transplantation. The phenotypes of bMSCs and aMSCs are similar, differing only in the expression of CD106. aMSCs proliferate faster than bMSCs, but aMSCs suppressed T-lymphocyte proliferation and activation more poorly than bMSCs. Thus cell origin and abundance are important factors in determining the suitability of MSCs for transplantation. Adipose tissue offers a more promising source of cells for such an application.

Impaired immunomodulatory function of chronic myeloid leukemia cancer stem cells and the possible mechanism involved in it.

BACKGROUND: Cancer stem cells (CSCs) are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Development of specific therapies targeted at CSCs holds hope for the improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease. This is particularly true in chronic myeloid leukemia (CML). METHODS: In this study, we isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with stem cells property. We examined their biological characteristics as well as immunological function and further detected the possible molecular mechanism involved in the leukemia genesis. RESULTS: We showed that CML patient-derived Flk1(+)CD31(-)CD34(-) MSCs had normal morphology, phenotype and karyotype but appeared impaired immunomodulatory function. The capacity of Flk1(+)CD31(-)CD34(-) MSCs from CML patients to inhibit T lymphocyte activation and proliferation was impaired in vitro. CML patient-derived MSCs have dampening immunomodulatory functions, suggesting that the dysregulation of hematopoiesis and immune response might originate from MSCs rather than HSCs. These Ph(+) putative CML hemangioblast upregulated TGF-ß1 and resultantly activated matrix metalloproteinase-9 (MMP-9) to enhance s-KitL and s-ICAM-1 secretion, which activated c-kit(+) HSCs from the quiescent state to proliferative state. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor (NF)-κB signaling pathway was involved in CML pathogenesis. CONCLUSIONS: Flk1(+)CD31(-)CD34(-) MSCs that express BCR/ABL leukemia oncogene are CSCs of CML and they play a critical role in the progression of CML through PI3K/Akt/NF-κB/MMP-9/s-ICAM-1/s-KitL signaling pathway beyond HSCs.

Hemangioblastic characteristics of cancer stem cells in chronic myeloid leukemia.

BACKGROUND: Overwhelming evidence from Chronic Myeloid Leukemia (CML) research indicates that patients harbor quiescent CML stem cells that are responsible for blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, recently CML-initiating cells beyond HSCs are also being investigated. METHODS: Here we isolated fetal liver kinase-1-positive (Flk1+) cells from CML patients and we tested their biological characteristics. In addition, endothelial and hematopoietic differentiation assays were also performed to test their cancer stem cell ability. RESULTS: We found these cells expressed the BCR/ABL specific CML oncogene. Co-culture assay also indicated they could promote HSC blast colonies. Further studies showed they could differentiate not only into endothelial lineages but also into erythroid cells at the single-cell level. CONCLUSIONS: Fetal bone marrow-derived Flk1+CD34- multipotent stem cells have the capacity for self-renewal and multilineage differentiation even after being expanded for more than 50 cell doublings, they might be the cancer stem cells and a target source in the treatment of CML.

The research on the immuno-modulatory defect of mesenchymal stem cell from Chronic Myeloid Leukemia patients.

Overwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, recently CML-initiating cells beyond HSCs are also being investigated. We have previously isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with hemangioblast property. Here, we showed that CML patient-derived Flk1(+)CD31(-)CD34(-) MSCs had normal morphology, phenotype and karyotype but appeared impaired in immuno-modulatory function. The capacity of patient Flk1(+)CD31(-)CD34(-) MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro. CML patient-derived MSCs have impaired immuno-modulatory functions, suggesting that the dysregulation of hematopoiesis and immune response may originate from MSCs rather than HSCs. MSCs might be a potential target for developing efficacious cures for CML.