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Peroxynitrite-induced p38 MAPK pro-apoptotic signaling in enterocytes
Biochemical and Biophysical Research Communications, 2009
Enterocyte apoptosis in necrotizing enterocolitis is partly due the elaboration of toxic intermediates of nitric oxide (NO), such as peroxynitrite (PN). Because p38 mitogen-activated protein kinase (MAPK) and serine-threonine kinase (AKT) are well-characterized pro-and anti-apoptotic mediators respectively, we hypothesized that PN could induce enterocyte apoptosis via activation of p38 and deactivation of AKT. To test this hypothesis, the rat intestinal cell line, IEC-6, was treated with PN. PN caused phosphorylation of p38, its upstream activator, MKK3/6, and downstream effector, transcription factor ATF2. PN-induced apoptosis was inhibited by the p38 inhibitor, SB202190, and by p38 siRNA. PN decreased AKT phosphorylation; this effect was abrogated by pre-treatment with SB202190 or p38 siRNA. PN exposure also increased the activity of the protein phosphatase 2A (PP2A). These data demonstrate that PN-mediated apoptosis depends on the p38 pathway and that p38 mediates deactivation of AKT survival pathways possibly by the involvement of PP2A.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2000
A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 (n = 116) received four-drug chemotherapy for 9 months (cisplatin, cyclophosphamide, doxorubicin, and etoposide), with surgery and local radiation to residual disease. After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 t...
Transcriptosomic Profiling at IGF-2 Promoters Through Biotinylated-Dna ‘Fishing’; Analysis
Neuro-Oncology, 2013
INTRODUCTION: Ginsenoside Rg3 is a natural active ingredient that is extracted from Korean red ginseng root. It elevates therapeutic effect of radiotherapy and chemotherapy, but the study found that the application of Rg3 is heavily limited by its low bioavailability and poor absorption via oral administration. METHOD: Rg3-loaded PEG-PLGA-NPs (Rg3-NPs) were prepared by the modified spontaneous emulsification solvent diffusion (SESD) method, and the physicochemical characteristics of Rg3-NPs were investigated in our study. We treated primary glioblastoma with 50 mM Rg3-NPs for 48h. We then used gene expression arrays (Illumina) for genome-wide expression analysis and validated the results for genes of interest by means of Real-Time PCR. Functional annotations were then performed using the DAVID and KEGG online tools. RESULTS: MTT shows that the growth of cells can be significantly inhibited by Rg3-NPs in a dose-dependence manner. FCM test shows Rg3-NPs can be released from the conjugate nanoparticle and react with the genes in the cell nuclei causing changes in the gene molecules. We also found that cancer cells treated with Rg3-NPs undergo cell-cycle arrest at different checkpoints. This arrest was associated with a decrease in the mRNA levels of core regulatory genes as determined by microarray-analysis and verified by Real-Time PCR. Furthermore, Rg3-NPs induced the expression of apoptotic and anti-migratory proteins p53 in cell lines. CONCLUSIONS: The results of the present study, together with the results of earlier studies show that Rg3-NPs targets genes involved in the progression of the M-phase of the cell cycle. It is associated with several important pathways, which include apoptosis (p53). Rg3-NPs may be a potent cell-cycle regulation drug targeting the M-phase in glioblastoma cell lines.
Cancer research, 1985
Ferritin was measured in sera obtained at diagnosis from 241 patients with neuroblastoma to determine (a) the incidence of elevated ferritin and (b) the relationship between ferritin level and outcome. Ferritin was infrequently elevated in sera from patients with Stages I and II disease but was abnormally elevated in 37 and 54% of those with Stages III and IV neuroblastoma, respectively. The mean and median levels for each stage were compared and were highest for Stages III and IV disease. Analysis of progression-free survival for children with Stages III and IV disease indicated that elevated ferritin was associated with a significantly poorer prognosis than was normal ferritin and that this correlation was independent of stage and age at diagnosis. Progression-free survival at 24 months of follow-up for patients with Stage III disease with normal ferritin was 76% and with elevated ferritin was 23%. For those with Stage IV disease, progression-free survival was 27 and 3% with norma...
Cancer Research
Ferritin was measured in sera obtained at diagnosis from 241 patients with neuroblastoma to determine (a) the incidence of elevated ferritin and (b) the relationship between ferritin level and outcome. Ferritin was infrequently elevated in sera from patients with Stages I and II disease but was abnormally elevated in 37 and 54% of those with Stages III and IV neuroblastoma, respec tively. The mean and median levels for each stage were com pared and were highest for Stages III and IV disease. Analysis of progression-free survival for children with Stages III and IV disease indicated that elevated ferritin was associated with a significantly poorer prognosis than was normal ferritin and that this correlation was independent of stage and age at diagnosis. Progression-free survival at 24 months of follow-up for patients with Stage III disease with normal ferritin was 76% and with elevated ferritin was 23%. For those with Stage IV disease, progression-free survival was 27 and 3% with normal and ele vated ferritin, respectively. We conclude that determination of the level of ferritin in serum at diagnosis is useful for selecting appropriate therapy for patients with Stage III neuroblastoma. Those with normal ferritin (63% of patients) have a good outcome with current therapy, but those with elevated ferritin (37%) do poorly and require more effective therapy. Although ferritin de fines subgroups with Stage IV disease, the outcome of all groups must be improved.
Purpose: From 1986 to 1992, ''eight-drugs-in-one- day'' (8-in-1) chemotherapy both before and after radia- tion therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and pred- nisone (VCP) after XRT in children with untreated, high- stage medulloblastoma (MB). Patients and Methods: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years. Results: Survival and progression-free survival (PFS) 6 SE at 7 years were 55% 6 5% and 54% 6 5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63% 6 5% versus 45% 6 5%, respectively (P 5 .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of P...
Journal of neuro-oncology, 1999
This study was undertaken to evaluate the response of recurrent brain tumors to intravenous etoposide and to evaluate the efficacy of mannitol in augmenting etoposide's tumoricidal effect. Ninety-nine children between one and 21 years of age with recurrent brain tumors were randomly assigned to treatment with intravenous etoposide 150 mg/M2, with or without mannitol 15 gm/M2, daily for five days every three weeks for one year or until disease progression or death. Computerized tomographic (CT) or magnetic resonance image (MRI) scans, obtained after three cycles of therapy, were compared with pre-therapy scans. Scans were centrally reviewed. Of 87 evaluable patients, 12 (13.8%) were determined to have had an objective response by the institutional radiologist. On central review, 7/66 (10.6%) responses were documented. Responses in centrally reviewed patients were observed in 2/12 (16.7%) low grade astrocytomas, 4/26 (15.4%) medulloblastoma or primitive neuroectodermal tumors (PNE...
British Journal of Haematology, 2003
Historically, the survival of children and adolescents with Burkitt's and Burkitt-like lymphoma had been poor. Recently, short and intensive chemotherapy appears to have improved disease outcome. We therefore reviewed the results of four successive Children's Cancer Group trials conducted on 470 children with disseminated Burkitt's and Burkitt-like lymphoma. Of the patients studied, the median age was 8 years (0-21 years), the male:female ratio was 4:1, 58% had lactate dehydrogenase (LDH) ‡ 500 IU/l, 23% had M2 or M3 bone marrow (BM), and 12% demonstrated central nervous system involvement. In a multivariate analysis, the 4-year event-free survival (EFS) in patients ‡ 15-years-old compared with < 15-year-old was 34 ± 7 versus 59 ± 2% (P < 0AE05), the 4-year EFS of M2/M3 compared with M1 BM was 38 ± 5 versus 63 ± 3% (P < 0AE001), and the 4-year EFS with LDH ‡ 500 IU/l compared with LDH < 500 IU/l was 49 ± 3 versus 71 ± 4% (P < 0AE001). Furthermore, patients treated on the most recent protocol, which was short and more intensive, had a significantly improved survival compared with those on previous trials (4-year EFS 80 ± 6 versus 54 ± 2%, P < 0AE001). In summary, the outcome for childhood Burkitt's and Burkitt-like lymphoma has recently improved with the use of short and intensive B-cell non-Hodgkin's lymphoma-directed therapy.