AML-derived Extracellular Vesicles Confer De Novo Chemoresistance to Leukemic Myeloblast Cells by Promoting Drug Export Genes Expression and ROS Inhibition.

In spite of successful initial remission, chemo-resistance and relapse are still concerning points in acute myeloid leukemia (AML) treatment strategies. Multidrug resistance (MDR) appears to be the major contributor of chemo-resistance, arising in some sub-clones of cancers and could be developed in others. The aim of this study was to investigate the role of extracellular vesicles (EVs) derived from AML patients on the transmission of chemo-resistance phenotype. Ultracentrifugation was employed to isolate EVs from healthy controls, new cases, and relapsed AML patients. The EVs size, morphology, and immunophenotype were determined by dynamic light scattering, TEM, and flow cytometry respectively. Bradford assay was performed to measure the protein content of EVs. MTT assay and flow cytometry analysis were also used to determine the viability index, induction of apoptosis, and ROS generation in U937 cells. The expression level of two efflux pumps was assessed using qRT-PCR analysis. Findings of TEM, DLS, and flow cytometry confirmed that EVs had a desirable shape, size, and surface markers. EVs derived from both new cases and relapsed AML patients significantly reduced idarubicin-induced apoptosis in the U937 cells. The analysis of drug efflux pumps gens revealed that EVs over-express MRD1 and MRP1 in the target cells. These findings suggested a novel role of EVs in mediating the acquired chemo-resistance in AML patients by inducing the expression of the drug efflux pumps; however, further investigations will be required to elucidate other underlying mechanisms of resistance that are mediated by EVs.

Acute promyelocytic leukemia derived extracellular vesicles conserve PML-RARα transcript from storage-inflicted degradation: a stable diagnosis tool in APL patients.

The early death, which is more common in acute promyelocytic leukemia (APL) patients rather than other types of acute myelocytic leukemia (AML) highlights the importance of appropriate diagnostic method for early detection of this disease. The low sensitivity of the conventional methods, low tumor burden in some patients, and the need for bone marrow sampling are some of the diagnostic challenges on the way of proper detection of APL. Given these, we aimed to compare the efficacy of extracellular vesicles (EVs), as a diagnostic tool, with the existing methods. RT-PCR, qPCR, and flow cytometry were applied on EVs and their corresponding associated cellular component collected from 18 APL new cases, 23 patients with minimal residual disease (MRD), and NB4 cell line. RT-PCR results were positive in both cellular and vesicular components of all new cases, NB4 cells, and EVs in contrary to MRD cases. Normalized copy numbers (NCN) of PML-RARα were 5100 and 3950 for cell and EVs, respectively (p < 0.05). There was a significant difference in the NCN of PML-RARα between cells and EVs in BM samples. Investigating the effect of storage at room temperature revealed that PML-RARα level was retained near to the baseline level in EVs, but there was a significant reduction in its copy number in the cellular component during 7 days. Taken together, given to the acceptable stability, EVs could be introduced as a non-invasive liquid biopsy that alongside existing methods could remarkably change the paradigm of APL diagnostic approaches.

A concise review on factors influencing the hematopoietic stem cell transplantation main outcomes.

BACKGROUND AND AIMS: As a curative procedure, hematopoietic stemcell transplantation (HSCT) is an approved treatment for many malignant orbenign hematologic and non-hematologic diseases. There are different outcomes of HSCT, as well as several parameters influencing these outcomes. METHODS: We had searched scientific sources like Web ofScience and PubMed with a combination of keywords such as HSCT, engraftment,survival, outcomes, etc. Totally, 80 articles were included. RESULTS: Here we have reviewed the effective factors onmain outcomes of HSCT including engraftment, survival, graft versus hostdisease, and Mobilization. Also, the prediction of hematological reconstitutionand some novel suggestions leading to better outcomes are reviewed. CONCLUSION: The study will be applicable for improvedmanagement of autologous and allogeneic HSCT process to increase the procedureefficiency.

Antiproliferative Effect of Gaillardin from Inula oculus-christi in Human Leukemic Cells.

Gaillardin (GLN) is a sesquiterpene lactone isolated from the chloroform extract of Inula oculus-christi L. This natural compound has shown cytotoxicity in various cancerous cell line. However, its effect on leukemic cells is ambiguous. Due to the neurotoxicity of vincristine (VCR) in acute lymphoblastic leukemia (ALL), we aimed to examine the cytotoxic effects of GLN alone and in combination with vincristine on induction of apoptosis, and cell cycle progression in ALL cell lines (NALM-6 and MOLT-4). Our results displayed that GLN could induce cytotoxic effects in MOLT-4 and NALM-6 with IC50 values of 7.3 and 6.1 µM, respectively. In this study, we demonstrated that GLN induces cytotoxicity through G0/G1 phase arrest followed by apoptosis in a dose-dependent manner. Fortunately, this natural compound did not show significant cytotoxic effects on normal cells. This study demonstrated that GLN was capable to extend chemotherapeutic sensitivity in ALL cells by reducing VCR concentration without constraining its effectiveness. Therefore, it might act as a promising anticancer agent for the treatment of leukemia.

Standardization of Plasma Rich in Growth Factors (PRGF) and its effects on androgenic hair loss.

Androgenic alopecia (AGA), as the most common cause of hair loss, is a chronic process that affects 80% of men and 50% of women throughout life. Existing and approved treatments for this condition are limited, and unfortunately, the length of treatment is long, while its efficacy is not much suitable. Plasma rich in growth factors (PRGF) autologous therapy is based on the delivery of a pool of bioactive molecules impressive for the treatment of AGA.Thirteen patients were included in this study. Our patients were evaluated in two groups: the first group was injected once and the second group was injected thrice, then evaluated for the number and diameter of the hair.Both groups of patients showed hopeful results so that in the first group hairs number and thickness increased by 9-54% and 11-76% respectively (p < .01). For patients who underwent PRGF injection thrice, the increases in hairs number and thickness were remarkably higher with an average of 211 and 221 respectively (p < .001). No adverse effect was reported in any patient.Our results revealed that PRGF platelet concentration using a higher volume of blood compared to previous protocols has higher effectiveness in treating AGA. However, more randomized clinical studies with longer follow up courses as well as larger sample sizes are needed to standardize an optimum protocol for PRGF based treatments.

Down-Regulation of Ribosomal S6 kinase RPS6KA6 in Acute Myeloid Leukemia Patients.

OBJECTIVE: Signaling pathways such as extracellular regulated kinase/mitogen activated protein kinase (ERK/MAPK) have increased activity in leukemia. Ribosomal 6 kinase (RSK4) is a factor downstream of the MAPK/ERK pathway and an important tumor suppressor which inhibits ERK trafficking. Decrease in RSK4 expression has been reported in some malignancies, which leads to an increase in growth and proliferation and eventually poor prognosis. In this study we measured RSK4 expression rate in acute myeloid leukemia (AML). MATERIALS AND METHODS: This cross-sectional study was undertaken in 2013-2014 at Ghaem Hospital in Mashhad, Iran, on 40 AML patients and 10 non-AML patients as the control group. The expression rate was measured by real-time polymerase change reaction (PCR) and employing the ΔΔCT method. Data were analyzed using Mann-Whitney and Spearman tests using SPSS (version 11.5). RESULTS: Expression rate of RSK4 was significantly decreased in the AML group in comparison with the non-AML group (P<0.001). There was also a significant decrease in RSK4 expression in AML with t(15;17) in comparison to other translocations (P=0.004). CONCLUSION: We detected a down-regulation of RSK4 in AML patients. This may lead to an increase in the activity of the ERK/MPAK pathway and exacerbate leukemogenesis or the prognosis of the patients.