Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls.

PURPOSE: The fusion gene BCR-ABL has an important role to the progression of chronic myeloid leukemia (CML) and several signaling pathways have been characterized as responsible for the terminal blastic phase (BP). However, the initial phase, the chronic phase (CP), is long lasting and there is much yet to be understood about the critical role of BCR-ABL in this phase. This study aims to evaluate transcriptional deregulation in CD34+ hematopoietic cells (CD34+ cells) from patients with untreated newly diagnosed CML compared with CD34+HC from healthy controls. METHODS: Gene expression profiling in CML-CD34 cells and CD34 cells from healthy controls were used for this purpose with emphasis on five main pathways important for enhanced proliferation/survival, enhanced self-renewal and block of myeloid differentiation. RESULTS: We found 835 genes with changed expression levels (fold change ≥ ±2) in CML-CD34 cells compared with CD34 cells. These include genes belonging to PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways. Four of these pathways converge to MYC activation. We also identified five transcripts upregulated in CD34-CML patients named OSBPL9, MEK2, p90RSK, TCF4 and FZD7 that can be potential biomarkers in CD34-CML-CP. CONCLUSION: We show several mRNAs up- or downregulated in CD34-CML during the chronic phase.

Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients.

Autologous hematopoietic SCT (AHSCT) has been investigated in the past as a therapeutic alternative for multiple sclerosis (MS). Despite advances in clinical management, knowledge about mechanisms involved with clinical remission post transplantation is still limited. Abnormal microRNA and gene expression patterns were described in MS and have been suggested as disease biomarkers and potential therapeutic targets. Here we assessed T- and B-cell reconstitution, microRNAs and immunoregulatory gene expression after AHSCT. Early immune reconstitution was mainly driven by peripheral homeostatic proliferation. AHSCT increased CD4(+)CD25(hi)FoxP3(+) regulatory T-cell counts and expression of CTLA-4 and GITR (glucocorticoid-induced TNFR) on CD4(+)CD25(hi) T cells. We found transient increase in exhausted PD-1(+) T cells and of suppressive CD8(+)CD28(-)CD57(+) T cells. At baseline, CD4(+) and CD8(+) T cells from MS patients presented upregulated miR-16, miR-155 and miR-142-3p and downregulated FOXP3, FOXO1, PDCD1 and IRF2BP2. After transplantation, the expression of FOXP3, FOXO1, PDCD1 and IRF2BP2 increased, reaching control levels at 2 years. Expression of miR-16, miR-155 and miR-142-3p decreased towards normal levels at 6 months post therapy, remaining downregulated until the end of follow-up. These data strongly suggest that AHSCT normalizes microRNA and gene expression, thereby improving the immunoregulatory network. These mechanisms may be important for disease control in the early periods after AHSCT.

Microarray profiles of ex vivo expanded hematopoietic stem cells show induction of genes involved in noncanonical Wnt signaling.

The low number of hematopoietic stem cells (HSC) in umbilical cord blood (UCB) is directly related to increased risk of transplant failure. Effective ex vivo expansion of HSC has been tried for many years, with conflicting results because of the inability to reproduce in vitro HSC proliferation in the same way it occurs in vivo. We compared freshly isolated HSC with their expanded counterparts by microarray analysis and detected activation of the noncanonical Wnt (wingless-type MMTV integration site family) pathway. Study of early alterations during ex vivo UCB-HSC expansion could contribute to improvement of ex vivo expansion systems.

The effect of hypoxia and recuperation on carbohydrate metabolism in pacu (Piaractus mesotamicus)

A study of the hematological parameters, glycogen, glucose, and lactate, and the activity of malate and lactate dehydrogenases was carried out in blood and tissues of fishes submitted to two, four, and six hours of hypoxia and recuperation. Only after 4 h of hypoxia was there a drop in liver glucose. After 6 h, a drop in lactate and a rise in glucose in practically all tissues signaled a recuperation of the metabolism, probably due to ASR (aerial surface respiration). Lactate formed during hypoxia was canalized to heart and brain for oxidation and used for neoglucogenesis. There were no changes in hematological parameters nore in the activity of malate and lactate dehydrogenases during normoxia and hypoxia, which suggest that these adaptive mechanisms may not be involved during hypoxia. Glycogen concentrations did not show variation during hypoxia either

The effect of hypoxia and recuperation on carbohydrate metabolism in pacu (Piaractus mesopotamicus).

A study of the hematological parameters, glycogen, glucose, and lactate, and the activity of malate and lactate dehydrogenases was carried out in blood and tissues of fishes submitted to two, four, and six hours of hypoxia and recuperation. Only after 4 h of hypoxia was there a drop in liver glucose. Alter 16 h, a drop in lactate and a rise in glucose in practically all tissues signaled a recuperation of the metabolism, probably due to ASR (aerial surface respiration). Lactate formed during hypoxia was canalized to heart and brain for oxidation and used for neoglucogenesis. There were no changes in hematological parameters nore in the activity of malate and lactate dehydrogenases during normoxia and hypoxia, which suggest that these adaptive mechanisms may not be involved during hypoxia. Glycogen concentrations did not show variation during hypoxia either.