Distinct power of bone marrow microRNA signatures and tumor suppressor genes for early detection of acute leukemia

BackgroundAcute leukemia involving lymphocytic and myeloid cells is cancer with a high mortality rate. Swift and timely diagnosis might be a potential approach to improving patient prognosis and survival. The microRNA (miRNA) signatures are emerging nowadays for their promising diagnostic potential. MiRNA levels from bone marrow can be used as prognostic biomarkers.MethodsThe current study was designed to evaluate if the microRNAs and tumor suppressor genes (TSGs) profiling of hematopoietic bone marrow could help in acute leukemia early detection. Also, we assessed the DNA methyltransferase 3A (DNMT3A) expression and its possible epigenetic effects on miRNAs plus TSGs expression levels. The expression levels of ten miRNAs and four TSGs involved in acute lymphocytic leukemia (ALL) as well as acute myeloid leukemia (AML) were quantified in 43 and 40 bone marrow samples of ALL and AML patients in comparison with cancer-free subjects via real-time quantitative PCR (RT-qPCR). The receiver-operating-characteristic (ROC) analysis of miRNAs was performed in the study groups. Further, the correlation between the DNMT3A and TSGs was calculated.ResultsSignificant differences were detected in the bone marrow expression of miRNAs and TSGs (P < 0.05) between acute leukemia patients and healthy group. ROC analysis confirmed the ability of miR-30a, miR-101, miR-132, miR-129, miR-124, and miR-143 to discriminate both ALL and AML patients with an area under the ROC curve of ≥ 0.80 (P < 0.001) and high accuracy. The correlation between DNMT3A and P15/P16 TSGs revealed that DNMT3A plays a vital role in epigenetic control of TSGs expression. Our findings indicated that the downregulation of bone marrow miRNAs and TSGs was accompanied by acute leukemia development.ConclusionsThe authors conclude that this study could contribute to introducing useful biomarkers for acute leukemia diagnosis.

Occurrence and genetic evaluation of potentially pathogenic Acanthamoeba genotypes in nasal mucosa of immunocompromised patients: a case-control study in Iran.

BACKGROUND: The occurrence of granulomatous amoebic encephalitis (GAE) was investigated due to the exposure of a large number of immunocompromised patients to opportunistic Acanthamoeba infections, which in most cases are fatal. METHODS: In this case-control study, 160 samples from the nasal mucosa of immunocompromised patients were collected between February 2019 to February 2020 in Isfahan, central Iran, using sterile cotton swabs; 150 ethnically matched controls were included. The pathogenic potential of the identified isolates was evaluated using temperature and osmotolerance assays. The identification of Acanthamoeba infection was confirmed by both morphological and phylomolecular tools. RESULTS: Of 310 collected samples, 32 strains, including 25 (15.6%) and 7 (4.6%) isolates, were positive for the Acanthamoeba genus in the patient and control groups, respectively. The topology of the phylogenetic tree indicated that all the Acanthamoeba strains belonged to the T4 genotype. Only five of the isolates genotyped as T4 were positive for potential pathogenic assays. The heterogeneity analysis of 18S ribosomal RNA sequences of Acanthamoeba in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and hepatitis B and C patients revealed significant genetic diversity (haplotype diversity [Hd] 0.511) compared with that of healthy individuals (Hd 0.210). CONCLUSIONS: The circulation of pathogenic isolates of Acanthamoeba, particularly in HIV/AIDS patients, along with their genetic traits, indicates that clinicians should be more aware of fatal cases of GAE, especially in suspected encephalitis, in Iran and worldwide.

Distinct power of bone marrow microRNA signatures and tumor suppressor genes for early detection of acute leukemia.

BACKGROUND: Acute leukemia involving lymphocytic and myeloid cells is cancer with a high mortality rate. Swift and timely diagnosis might be a potential approach to improving patient prognosis and survival. The microRNA (miRNA) signatures are emerging nowadays for their promising diagnostic potential. MiRNA levels from bone marrow can be used as prognostic biomarkers. METHODS: The current study was designed to evaluate if the microRNAs and tumor suppressor genes (TSGs) profiling of hematopoietic bone marrow could help in acute leukemia early detection. Also, we assessed the DNA methyltransferase 3A (DNMT3A) expression and its possible epigenetic effects on miRNAs plus TSGs expression levels. The expression levels of ten miRNAs and four TSGs involved in acute lymphocytic leukemia (ALL) as well as acute myeloid leukemia (AML) were quantified in 43 and 40 bone marrow samples of ALL and AML patients in comparison with cancer-free subjects via real-time quantitative PCR (RT-qPCR). The receiver-operating-characteristic (ROC) analysis of miRNAs was performed in the study groups. Further, the correlation between the DNMT3A and TSGs was calculated. RESULTS: Significant differences were detected in the bone marrow expression of miRNAs and TSGs (P < 0.05) between acute leukemia patients and healthy group. ROC analysis confirmed the ability of miR-30a, miR-101, miR-132, miR-129, miR-124, and miR-143 to discriminate both ALL and AML patients with an area under the ROC curve of ≥ 0.80 (P < 0.001) and high accuracy. The correlation between DNMT3A and P15/P16 TSGs revealed that DNMT3A plays a vital role in epigenetic control of TSGs expression. Our findings indicated that the downregulation of bone marrow miRNAs and TSGs was accompanied by acute leukemia development. CONCLUSIONS: The authors conclude that this study could contribute to introducing useful biomarkers for acute leukemia diagnosis.

The impact of genetic variation on metabolism of heavy metals: Genetic predisposition?

Genetic variations can be considered as internal contributing factors in susceptibility of individuals to heavy metals related toxicities. However, the exact mechanism of such inherent factors in body response to toxic materials, as well as their potentials to be considered as actual susceptibility factors are remaining to be more explored. So far, variations in different genes, which are directly/indirectly involving in the metabolism of heavy metals have been investigated by some experiments. Metallothioneins as one of the well-known groups of enzymes involving in detoxification of heavy metals, were shown to behave differentially among individuals. This phenomenon is due to the presence of some genetic variations in the middle or upper parts of their genomic sequences. The presence of different single nucleotide polymorphisms in metallothionein 2 A gene and the association of these variations with heavy metals body burden have been shown in different populations. Such genetic variations and their potential effects on heavy metal metabolisms and toxicities were shown in other genes, such as divalent metal transporter 1, glutathione related genes and methylenetetrahydrofolate reductase. However, the current data on different populations are challenging because of the presence of various other interference factors like different dietary and life habits, levels of exposure, as well as papulation related factors. Age, sex, smoking, dietary habits, ancestry differences and diverse metal exposure levels are seemed to be other effective variables in this area. In this review, we introduced several potential genes, their studied genetic variations and their impacts on heavy metal body burden, as well as body sensitivity in different populations.

Epigenetics and Epi-miRNAs: Potential markers/therapeutics in leukemia.

Epigenetic variations can play remarkable roles in different normal and abnormal situations. Such variations have been shown to have a direct role in the pathogenesis of various diseases either through inhibition of tumor suppressor genes or increasing the expression of oncogenes. Enzymes involving in epigenetic machinery are the main actors in tuning the epigenetic-based controls on gene expressions. Aberrant expression of these enzymes can trigger a big chaos in the cellular gene expression networks and finally lead to cancer progression. This situation has been shown in different types of leukemia, where high or low levels of an epigenetic enzyme are partly or highly responsible for involvement or progression of a disease. DNA hypermethylation, different histone modifications, and aberrant miRNA expressions are three main epigenetic variations, which have been shown to play a role in leukemia progression. Epigenetic based treatments now are considered as novel and effective therapies in order to decrease the abnormal epigenetic modifications in patient cells. Different epigenetic-based approaches have been developed and tested to inhibit or reverse the unusual expression of epigenetic agents in leukemia. The reciprocal behavior of miRNAs in the regulation of epigenetic modifiers, while being regulated by them, unlocks a new opportunity in order to design some epigenetic-based miRNAs able to silence or sensitize these effectors in leukemia.

C6 glioma-derived microvesicles stimulate the proliferative and metastatic gene expression of normal astrocytes.

The interaction between glioma cells and the surrounding microenvironment plays a key role in tumor invasion and infiltration ability. Recent studies reported the importance of glioma-derived microvesicles in the interaction of the tumor and the surrounding environment. The purpose of this study was to scrutinize the role of glioma-derived microvesicles in the interaction between tumor and normal astrocytes, which are the most abundant non-neoplastic cells in the tumor microenvironment (TME). To this end, we examined the effect of C6 tumor cell-derived microvesicles in the activation of normal rat astrocytes. The results showed that exposing normal astrocytes to C6MVs increase the expression of the glial fibrillary acidic protein (GFAP), and activate normal astrocytes. In addition, incubation of normal astrocytes with C6MVs affects the expression of genes involved in tumor invasion and growth in these cells. Our findings suggest that C6 tumor cells through the secretion of microvesicles (MVs) can alter the phenotype of surrounding astrocytes as well as through the changes in the expression of the genes involved in extracellular matrix remodeling can predispose their invasion and growth.

Phylogeography, genetic variability and structure of Acanthamoeba metapopulations in Iran inferred by 18S ribosomal RNA sequences: A systematic review and meta-analysis.

OBJECTIVE: To verify phylogeography and genetic structure of Acanthamoeba populations among the Iranian clinical isolates and natural/artificial environments distributed in various regions of the country. METHODS: We searched electronic databases including Medline, PubMed, Science Direct, Scopus and Google Scholar from 2005 to 2016. To explore the genetic variability of Acanthamoeba sp, 205 sequences were retrieved from keratitis patients, immunosuppressed cases and environmental sources as of various geographies of Iran. RESULTS: T4 genotype was the predominant strain in Iran, and the rare genotypes belonged to T2, T3, T5 (Acanthamoeba lenticulata), T6, T9, T11, T13 and T15 (Acanthamoeba jacobsi). A total of 47 unique haplotypes of T4 were identified. A parsimonious network of the sequence haplotypes demonstrated star-like feature containing haplogroups IR6 (34.1%) and IR7 (31.2%) as the most common haplotypes. In accordance with the analysis of molecular variance, the high value of haplotype diversity (0.612-0.848) of Acanthamoeba T4 represented genetic variability within populations. Neutrality indices of the 18S ribosomal RNA demonstrated negative values in all populations which represented a considerable divergence from neutrality. The majority of genetic diversity belonged to the infected contact lens and dust samples in immunodeficiency and ophthalmology wards, which indicated potential routes for exposure to a pathogenic Acanthamoeba sp. in at-risk individuals. A pairwise fixation index (FST) was from low to high values (0.02433-0.41892). The statistically FST points out that T4 is genetically differentiated between north-west, north-south and central-south metapopulations, but not differentiated between west-central, west-south, central-south, and north-central isolates. CONCLUSIONS: An occurrence of IR6 and IR7 displays that possibly a gene flow of Acanthamoeba T4 occurred after the founder effect or bottleneck experience through ecological changes or host mobility. This is the first systematic review and meta-analysis providing new approaches into gene migration and transmission patterns of Acanthamoeba sp, and targeting at the high-risk individuals/sources among the various regions of Iran.

Pathogenic Acanthamoeba T4 Genotype Isolated from Mucosal Tissue of a Patient with HIV Infection: A Case Report.

Opportunistic infections due to free-living amoebae such as Granulomatous Amoebic Encephalitis (GAE), cutaneous acanthamoebiasis and disseminated infections could be the causative agent of mortality in people living with HIV/AIDS. In this study, we report the occurrence of the Acanthamoeba belonging to the T4 genotype isolated from nasal and oral swabs of a 15-yr-old man with HIV infection. HIV was confirmed using ELISA kit and RT-PCR assay. The isolated strain showed pathogenic potential using thermo and osmotolerance assays. This patient might be vulnerable to develop GAE or disseminated infections and depending on the immunologic status of the patient, this could be a health threat. Monitoring of such patients, appropriate diagnostic procedures and improved-HIV related care can alter the outcome of such infections.

Isolation and molecular characterization of Acanthamoeba strains isolated from the oral cavity of immunosuppressed individuals in Tehran, Iran.

Acanthamoeba spp. is an opportunistic protozoan parasite which is the causative agent of granulomatous amoebic encephalitis (GAE) and Acanthamoeba keratitis (AK). GAE usually occurs in immunocompromised patients which in most cases is fatal. The present study was conducted to determine the genotypes of Acanthamoeba isolated from patients with compromised immunological status. For this purpose, 90 samples from the oral cavity of these individuals were collected in different hospitals of Tehran, Iran using sterile cotton swabs. Samples were cultured in 2% Non-Nutrient Agar (NNA) plates in order to check for the presence of amoebae. Identification of isolates was carried out using both morphological and molecular tools. The pathogenic potential of the obtained strains was assessed by performing osmo- and thermotolerance assays as previously described. Genotyping of the isolates was carried out by PCR/sequencing of the DF3 region of the 18S rDNA gene of Acanthamoeba. From the 90 collected samples, 11 (13.4%) were positive for Acanthamoeba genus. Molecular analysis revealed the presence of genotypes T3, T4 and T11, although most of the isolates belonged to genotype T4. Only 3 of the isolates genotyped as T4 were positive for the pathogenic potential assays. To this end if the immunological status is considered as one of the key factors for the development of GAE due to Acanthamoeba in the previous reported cases, individuals suffering from the conditions mentioned in this study should be considered as a high risk group of population in Iran and worldwide.

A new genus and species of Xyphosiini (Diptera: Tephritidae) from Iran.

Valera, a monotypic new genus (Tephritidae, Tephritinae, Xyphosiini) and Valera ariana n. sp., the type and only known species, are described from Iran. Systematic relationships with other Xyphosiini are discussed and a key to the genera of the tribe Xyphosiini is presented.

Occurrence of pathogenic Acanthamoeba genotypes in nasal swabs of cancer patients in Iran.

Incidences of Acanthamoeba granulomatous encephalitis (AGE) have been increased due to a rise in the number of high-risk people, such as immunodeficient patients. Indeed, immunosuppress situation can render the patient in acquiring opportunistic Acanthamoeba infections. In this study, analysis was carried out to verify the presence of free-living amoebae of Acanthamoeba genus in nasal swabs of cancer patients in hospitals of Tehran, Iran. Detection of isolates was based on morphotyping and PCR sequencing of the Diagnostic Fragment 3 (DF3) to identify strains at the genotype level. In addition, the pathogenic potential of the isolates was assayed using temperature and osmotolerance assays. The obtained results revealed that nine isolated strains belonging to T4 genotype-exhibited pathogenic potential. After sequencing, genotype T4 was found to be the most common one in the samples included in this study. Genotype T3 and T5 were also identified. To the best of our knowledge, this is the first study on the typing of Acanthamoeba strains at the genotype level in cancer patients in Iran and worldwide.