Altered microRNA expression profile is linked to T-cell exhaustion-related pathways in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: Although the phenotype and functions of exhausted T cells in several cancers have been identified, the involved molecular mechanisms remain to be further elucidated. In this regard, we have recently reported that the immunoregulatory cells, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), share common dysregulated miRNAs that target specific immunosuppressive pathways in patients with in acute lymphoblastic leukemia (ALL). AIM: In this study, we aimed to further explore whether similar dysregulation in miRNA expression is linked to T cell exhaustion and dysfunctionality in B cell ALL patients. METHODS: Peripheral blood samples from pediatric patients with ALL were recruited before and after induction chemotherapy as well as from healthy donors. Affymetrix microarray platform was used for miRNA profiling, and qRT-PCR was used to validate the expression of certain miRNAs that are related to T cell exhaustion. Bioinformatics analysis was performed to explore whether the dysregulated miRNAs were linked to T-cell exhaustion related pathways. RESULTS: A total of 516 miRNAs were dysregulated in ALL patients as compared to the healthy donor. Furthermore, among the total analyzed miRNAs, 10 were found to be linked to the key genes implicated in three exhaustion-related pathways; TGF-ß, FOXO, and MAPK, as revealed by miR-pathway analysis. Moreover, qRT-PCR analysis showed similar expression pattern to those obtained by microarray analysis. CONCLUSION: Our pilot study suggests the implication of certain miRNAs in T cell exhaustion pathways via targeting the specific key genes in those pathways.

Beneficial Modulatory Effects of Treatment With Bone Marrow Lysate on Hematopoietic Stem Cells and Myeloid Cells in Tumor-Bearing Mice.

Introduction: Leukopenia is one of the major side effects of myelosuppressive chemotherapy such as cyclophosphamide (CTX). We and others have used CTX either alone or in combination with G-CSF for the mobilization of hematopoietic stem cells (HSCs). This mobilization can induce expansion of myeloid cells with immunosuppressive phenotype. In this pilot study, we aimed to test whether bone marrow lysate (BML)/CTX, a rich source of growth factors, can lower the expansion of myeloid cells with immunosuppressive phenotypes in tumor-bearing mice without interfering with the anti-tumor effects of CTX or with the mobilization of HSCs. Methods: Female CD1 mice were treated on day 0 with an i.p. injection of Ehrlich ascites carcinoma (EAC). On day 7, the mice were i.p. injected with CTX followed by s.c. injection of G-CSF for 5 consecutive days, single s.c. injection of BML/PBS or BML/CTX or single i.v. injection of BMC/PBS or BMC/CTX. Results: Treatment of EAC-bearing mice with BML/PBS or BML/CTX did not interfere with the anti-tumor effect of CTX. EAC increased the numbers of immature polymorphonuclear cells (iPMN; neutrophils) in both blood and spleen. Treatment of EAC-bearing mice with CTX further increased the numbers of these cells, which were decreased upon treatment with BML/CTX. Treatment with BML/PBS or BML/CTX increased the numbers of stem cells (C.Kit+Sca-1+) in BM; the effect of BML/CTX was higher, but with no significant effect on the numbers of HSCs. Future studies are needed to analyze the molecular components in BM lysate and to determine the underlying mechanisms.

Two distinctive types of telocytes in gills of fish: A light, immunohistochemical and ultra-structure study.

Telocytes (TCs) are a vital constituent of interstitial tissue. They contribute to regulating cell function in heterotypic connections via direct contact or paracrine singling. Few studies mentioned intraepithelial TCs; however, they have been identified with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). In this study, we investigated the intraepithelial and interstitial TCs using immunohistochemistry (IHC) and TEM. TCs can be identified by their distinctive telopodes (TPs), which consist of podoms and podomere, using TEM and immunohistochemical staining with CD34, CD117, and VEGF antibodies. Intraepithelial TCs established heterocontact with the lamellar capillary and interstitial TCs connected with the blood vessel in lamina propria. Intraepithelial TCs established direct contact with epithelial cells, which formed the lymph space while interstitial TCs connected with the secondary vascular vessels. The study provides evidence for TCs' heterocontact with lamellar blood capillaries, the blood vessels, chloride cells, and immune cells, such as rodlet cells and lymphocytes. In conclusion, TCs have a role in regulating respiratory activities, maintaining osmotic pressure, modulating the immune response, and conducting immunosurveillance. RESEARCH HIGHLIGHTS: We investigated the intraepithelial and interstitial TCs using immunohistochemistry (IHC) and TEM. TCs can be identified by their distinctive telopodes (TPs), which consist of podoms and podomere, using TEM and immunohistochemical staining with CD34, CD117, and VEGF antibodies. Intraepithelial TCs established heterocontact with the lamellar capillary and interstitial TCs connected with the blood vessel in lamina propria.