Highlights • Global histone H4 acetylation is frequently lost in pediatric BCP-ALL. • Relatively preserved histone H4 acetylation is associated with favorable outcome in BCP-ALL. • Cases with ...ETV6-RUNX1 fusion gene and PAX5 deletions demonstrated higher histone H4 acetylation.
Background: Stem cells (SC)have been shown to have beneficial effects during autoimmune demyelination but underlying mechanisms remain unknown. In mice, lineage negative cells expressing the Sca1 ...molecule (Lin-Sca1+) represent a pluripotent population of bone marrow SC (BMSC) depleted of mature hematopoietic precursors and enriched in mesenchymal SC. Objective: In this study we have assessed the immunoregulatory role of pluripotent Lin-Sca1+ bone marrow stem cells (Lin-Sca1+BMSC) in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Methods: Syngeneic pluripotent Lin-Sca1+BMSC were transferred at peak of disease to mice with PLP139-151-induced EAE. At different time points after transplantation proliferation of T cells and IFN-gamma secretion were assessed. Accumulation of PKH26 stained SC in mouse organs was analyzed by flow cytometry. The role of indoleamine 2,3-dioxygenase (IDO) was established using Western blot analysis and specific competitive inhibition with 1-methy1-DL-tryptophan (1-MT). Results: Lin-Sca1+BMSC transfer enhanced recovery (p=0.000950), prevented relapses (p=0.0076), reduced central nervous system damage and enhanced remyelination. T cells from treated mice showed decreased proliferation to PLP139-151 (p=0.0019) and elevated interferon-gamma production. In dendritic cells (DC) increased induction of IDO was observed. Specificity of IDO involvement was confirmed by demonstration that in the presence of CD11c+ DC, with high IDO expression, PLP-induced proliferation was inhibited and the IDO-inhibitor, 1-MT, abrogated the immunoregulatory effect of Lin-Sca1+BMSC (p=0.000912). Relapse prevention correlated with inhibition of antigen spreading, the latter evidenced by loss of T cell responsiveness to PLP178-191 and MBP85-99 during chronic disease. Conclusions: Thus, pluripotent SC induce IDO in DC, leading to inhibition of antigen reactivity and spreading in EAE.
Abstract Syngeneic, pluripotent Lin− Sca1+ bone marrow stem cells (SC), transferred to mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis, enhanced recovery, prevented ...relapses and promoted myelin repair. SC-treated mice showed elevated interferon-γ production and induction of indoleamine 2,3-dioxygenase (IDO) in CD11c+ dendritic cells (DC). IDO induction was specific since in the presence of IDO-producing CD11c+ DC, PLP stimulated T cell proliferation was inhibited and the IDO-inhibitor, 1-MT, abrogated the SC effect. Relapse prevention during chronic disease correlated with decreased responsiveness to PLP178–191 and MBP85–99 . Thus, pluripotent SC induce IDO in DC leading to inhibition of antigen reactivity and spreading in EAE.
Citric acid is currently produced by submerged fermentation of sucrose with the aid of
mold. Its strains are characterized by a high yield of citric acid biosynthesis and no toxic by-products. ...Currently, new substrates are sought for production of citric acid by submerged fermentation. Waste materials such as glycerol or pomace could be used as carbon sources in the biosynthesis of citric acid. Due to the complexity of the metabolic state in fungus, there is an obvious need to optimize the important medium constituents to enhance the accumulation of desired product. Potential optimization approach is a statistical method, such as the central composite rotatable design (CCRD). The aim of this study was to increase the yield of citric acid biosynthesis by
PD-66 in media with waste glycerol as the carbon source. A mathematical method was used to optimize the culture medium composition for the biosynthesis of citric acid. In order to maximize the efficiency of the biosynthesis of citric acid the central composite, rotatable design was used. Waste glycerol and ammonium nitrate were identified as significant variables which highly influenced the final concentration of citric acid (Y
), volumetric rate of citric acid biosynthesis (Y
), and yield of citric acid biosynthesis (Y
). These variables were subsequently optimized using a central composite rotatable design. Optimal values of input variables were determined using the method of the utility function. The highest utility value of 0.88 was obtained by the following optimal set of conditions: waste glycerol-114.14 g∙L
and NH
NO
-2.85 g∙L
.
The pH of the medium is the key environmental parameter of chemical selectivity of oxalic acid biosynthesis by
Aspergillus niger
. The activity of the enzyme oxaloacetate hydrolase, which is ...responsible for decomposition of oxaloacetate to oxalate and acetate inside the cell of the fungus, is highest at pH 6. In the present study, the influence of pH in the range of 3–7 on oxalic acid secretion by
A. niger
W78C from sucrose was investigated. The highest oxalic acid concentration, 64.3 g dm
−3
, was reached in the medium with pH 6. The chemical selectivity of the process was 58.6% because of the presence of citric and gluconic acids in the cultivation broth in the amount of 15.3 and 30.2 g dm
−3
, respectively. Both an increase and a decrease of medium pH caused a decrease of oxalic acid concentration. The obtained results confirm that pH 6 of the carbohydrate medium is appropriate for oxalic acid synthesis by
A. niger
, but the chemical selectivity of the process described in this paper was high in comparison to values reported previously in the literature.
Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation of ASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell ...lines. This adaptive transcriptional upregulation is blocked by neoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylated ASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquine accelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in a subset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpG island retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two key genes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate that methylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to arginine deprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for which we have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/brain barrier.
While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA ...methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include
,
,
, and
. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis.
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