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Deficiency in DNA damage response (DDR) pathway and accumulation of DNA damage increases mutation rates resulting in genomic instability and eventually increases the risk of cancer. The aim of our study was to investigate expressions of DNA repair genes as new prognostic biomarkers in acute myeloid leukemia (AML). We utilized The Cancer Genome Atlas AML project (TCGA-LAML cohort, 15 acute promyelocytic leukemia (APL) and 155 non-APL AML) for the expression data of DNA repair genes. For validation, clinical samples (Ewha study group, 9 APL and 72 non-APL AML patients) were analyzed for the expression of 22 DNA repair genes using a custom RT2 Profiler PCR Array. APL patients presented significantly lower expression of DNA repair genes than non-APL AML patients in both study groups. Among non-APL AML patients, high expression levels of PARP1, XRCC1, and RAD51 were associated with poor overall survival (OS) probability in both study groups. Furthermore, Cox regression analysis showed that increased expression levels of PARP1, XRCC1, RAD51, BRCA1 and MRE11A could be independent risk factors for OS in the Ewha study group. Among non-APL patients of the Ewha study group, the OS probability of DDR-overexpressed group with at least one gene or more showing Z score greater than 1.5 was poorer than that of DDR non-overexpressed group. In the current study, the DNA repair gene expression profile of APL patients was different from that of non-APL AML patients. Overexpression of DNA repair genes could be a poor prognostic biomarker in non-APL AML. [ABSTRACT FROM AUTHOR]

Portulaca oleracea L. is a traditional oriental medicine known for its pharmacological effects. The present study aimed to investigate the immunostimulatory effects of PPCE on cyclophosphamide-stimulated rat model and in isolated spleen cells. The result showed that PPCE exerted an immunostimulatory effect in vivo and in vitro. Specifically, PPCE significantly enhanced splenocyte proliferation and upregulated inflammatory cytokines (IL-2, IL-12, TNF-α, and IFN-γ) and NK cell activity in vitro. The immunostimulatory effect was further investigated through various immunological assays. Oral administration of PPCE increased the swimming time and number of immune cells in rats. Histological analysis revealed that PPCE administration exerted splenic recovery. Thus, P. oleracea L. based complex extracts may be used as an immunostimulatory agent in medicine or functional foods. [ABSTRACT FROM AUTHOR]

Oxidative stress activates macroautophagy/autophagy and contributes to atherogenesis via lipophagic flux, a form of lipid removal by autophagy. However, it is not known exactly how endogenous antioxidant enzymes are involved in lipophagic flux. Here, we demonstrate that the antioxidant PRDX1 (peroxiredoxin 1) has a crucial role in the maintenance of lipophagic flux in macrophages. PRDX1 is more highly expressed than other antioxidant enzymes in monocytes and macrophages. We determined that Prdx1 deficiency induced excessive oxidative stress and impaired maintenance of autophagic flux in macrophages. Prdx1-deficient macrophages had higher intracellular cholesterol mass and lower cholesterol efflux compared with wild type. This perturbation in cholesterol homeostasis was due to impaired lipophagic cholesterol hydrolysis caused by excessive oxidative stress, resulting in the inhibition of free cholesterol formation and the reduction of NR1H3 (nuclear receptor subfamily 1, group H, member 3) activity. Notably, impairment of both lipophagic flux and cholesterol efflux was restored by the 2-Cys PRDX-mimics ebselen and gliotoxin. Consistent with this observation, apoe −/− mice transplanted with bone marrow from prdx1−/−apoe−/− mice had increased plaque formation compared with apoe−/− BM-transplanted recipients. This study reveals that PRDX1 is crucial to regulating lipophagic flux and maintaining macrophage cholesterol homeostasis against oxidative stress. We suggest that PRDX1-dependent control of oxidative stress may provide a strategy for treating atherosclerosis and autophagy-related human diseases. [ABSTRACT FROM AUTHOR]

Spliceosome mutations are associated with myelodysplasia. Here, we aimed to evaluate the frequency and clinical associations of these mutations in 204 patients with acute myeloid leukemia with myelodysplasia-related changes (AML with MRC) and 37 with therapy-related AML (t-AML). The frequency of mutation-positive patients was 17.0%, includingU2AF1(8.3%),SRSF2(5.8%) andSF3B1(2.9%). Mutations were detected almost exclusively in patients with AML with MRC, especially in cases with a preceding myelodysplastic syndrome (MDS) history or myelodysplastic morphology. By contrast, mutations were rare in patients with only MDS-related cytogenetics or t-AML. The presence of a mutation had no impact on survival. In a paired analysis, 16.7% of mutation-negative patients in the MDS phase acquired mutations during leukemogenesis. Our observations highlight the preponderance of spliceosome mutations within a specific AML subgroup with myelodysplasia, and suggest that these mutations might contribute pathologically to leukemogenesis in such patients. [ABSTRACT FROM PUBLISHER]

Purpose: No previous study regarding the correlation between post-operative thyroid function and underlying thyroid histopathology has been published. This study assessed the relationship between postoperative thyroid function after lobectomy and multiple factors in papillary thyroid microcarcinoma (PTMC) patients. Materials and methods: From January 2010 to December 2010, 338 patients who had undergone thyroid lobectomy for PTMC were enrolled. Patients with pre-operative hyperthyroidism or those with hypothyroidism but no pre-operative serological data were excluded, leaving a cohort of 285 patients. The relationships between post-operative thyroid function (based on successful cessation of thyroxine replacement therapy) and multiple factors (patient age and sex, serological data, the Pre-operative anteroposterior diameter of the thyroid gland, underlying histopathology of the thyroid gland, and number of attempts to stop thyroxine replacement therapy) were analyzed. Results: Out of 285 patients, 157 attempted to stop thyroxine replacement therapy once or twice after lobectomy; 91 successfully stopped thyroxine replacement therapy during the study period. The final histopathologic diagnoses after surgery included Hashimoto's thyroiditis ( n = 5), non-Hashimoto type of lymphocytic thyroiditis ( n = 17), and normal thyroid parenchyma ( n = 135). Pre-operative thyroid-stimulating hormone (TSH) levels differed significantly between patients with postoperative hypothyroidism and those with postoperative euthyroidism (univariate logistic regression analysis, p = 0.0028; multivariate logistic regression analysis, p = 0.0029). No statistically significant differences were found for any other factors. Conclusions: The study results demonstrated that the Pre-operative TSH level was the only predictor for the development of post-operative hypothyroidism after thyroid lobectomy in PTMC patients. [ABSTRACT FROM AUTHOR]

Background aims. Although mesenchymal stromal cells (MSC) from human palatine tonsils (tonsillar MSC, T-MSC) have been isolated, whether T-MSC isolated from multiple donors are feasible for cell banking has not been studied. Methods. T-MSC before and after a standard protocol of cryopreservation and thawing were assessed regarding several basic characteristics, including colony-forming unit-fibroblast features, MSC-specific surface antigen profiles, and inhibition of alloreactive T-cell proliferation. In vitro mesodermal differentiation potentials to adipocytes, osteocytes and chondrocytes were detected by staining with either cell-specific dyes or antibody after incubation with each appropriate differentiation medium. Expression of mesoderm-specific genes was also quantified by real-time polymerase chain reaction (PCR) assay. Expression profiles of endoderm-specific genes were identified by reverse transcription PCR assay. The feasibility of T-MSC in future engraftment was tested by short tandem repeat (STR) analysis using genomic DNA isolated randomly from three independent subjects. Results. Both fresh and cryopreserved-thawed T-MSC showed a similar high proliferation capacity and expressed primitive cell-surface markers. Hematopoietic cell markers, HLA-DR, co-stimulatory molecules and follicular dendritic cell markers were not detected. In addition to mesodermal differentiation, fresh and cryopreserved-thawed cells also underwent endodermal differentiation, as evidenced by the expression of endoderm-specific genes including forkhead box A2 (FoxA2), SIX homeobox 1 (Six1) and chemokine (C-C motif) ligand 21 (CCL21). Both cells significantly decreased phorbol 12- myristate 13-acetate (PMA)-induced T-cell proliferation. T-MSC from three independent donors formed chimerism in STR analysis. Conclusions. Our results demonstrate for the first time that T-MSC are a potentially good source for MSC banking. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been implicated in the pathogenesis and progression of brain tumors. miR-21 is one of the most highly overexpressed miRNAs in glioblastoma multiforme (GBM), and its level of expression correlates with the tumor grade. Programmed cell death 4 (PDCD4) is a well-known miR-21 target and is frequently downregulated in glioblastomas in accordance with increased miR-21 expression. Downregulation of miR-21 or overexpression of PDCD4 can inhibit metastasis. Here, we investigate the role of heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) in the metastatic potential of the glioblastoma cell line T98G. hnRNPC bound directly to primary miR-21 (pri-miR-21) and promoted miR-21 expression in T98G cells. Silencing of hnRNPC lowered miR-21 levels, in turn increasing the expression of PDCD4, suppressing Akt and p70S6K activation, and inhibiting migratory and invasive activities. Silencing of hnRNPC reduced cell proliferation and enhanced etoposide-induced apoptosis. In support of a role for hnRNPC in the invasiveness of GBM, highly aggressive U87MG cells showed higher hnRNPC expression levels and hnRNPC abundance in tissue arrays and also showed elevated levels as a function of brain tumor grade. Taken together, our data indicate that hnRNPC controls the aggressiveness of GBM cells through the regulation of PDCD4, underscoring the potential usefulness of hnRNPC as a prognostic and therapeutic marker of GBM. [ABSTRACT FROM AUTHOR]