Drug-related mutational patterns in hepatitis B virus (HBV) reverse transcriptase proteins from Iranian treatment-Naïve chronic HBV patients

Background: Immunomodulators and Nucleotide analogues have been used globally for the dealing of chronic hepatitis B virus (HBV) infection. However, the development of drug resistance is a major limitation to their long-term effectiveness. Objectives: The aim of this study was to characterize the hepatitis B virus reverse transcriptase (RT) protein variations among Iranian chronic HBV carriers who did not receive any antiviral treatments. Materials and Methods: Hepatitis B virus partial RT genes from 325 chronic in active carrier patients were amplified and directly sequenced. Nucleotide/amino acid substitutions were identified compared to the sequences obtained from the database. Results: All strains belonging to genotype D.365 amino-acid substitutions were found. Mutations related to lamivudine, adefovir, telbivudine, and entecavir occurred in (YMDD) 4% (n = 13), (SVQ) 17.23% (n = 56), (M204I/V + L180M) 2.45% (n = 8) and (M204I) 2.76% (n = 9) of patients, respectively. Conclusions: RT mutants do occur naturally and could be found in HBV carriers who have never received antiviral therapy. However, mutations related to drug resistance in Iranian treatment-naïve chronic HBV patients were found to be higher than other studies published formerly. Chronic HBV patients should be monitored closely prior the commencement of therapy to achieve the best regimen option. © 2013, KOWSAR Corp

Evolution of hepatitis B virus surface gene and protein among Iranian chronic carriers from different provinces

Background and Objectives: Iranian chronic HBV carrier�s population has shown a unique pattern of genotype D distribution all around the country. The aim of this study was to explore more details of evolutionary history of carriers based on structural surface proteins from different provinces. Materials and Methods: Sera obtained from 360 isolates from 12 Different regions of country were used for amplification and sequencing of surface proteins. A detailed mutational analysis was undertaken. Results: The total ratio for Missense/Silent nucleotide substitutions was 0.96. Sistan and Kermanshah showed the lowest rate of evolution between provinces (P = 0.055). On the other hand, Khorasan Razavi and Khoozestan contained the highest ratio (P = 0.055). The rest of regions were laid between these two extremes. Azarbayjan and Guilan showed the highest proportion of immune epitope distribution (91.3 and 96, respectively). Conversely, Sistan and Tehran harbored the least percentage (66.6 and 68.8, respectively). Kermanshah province contained only 5.2, whereas Isfahan had 54.5 of B cell epitope distribution. In terms of T helper epitopes, all provinces showed a somehow homogeneity: 22.58 (Fars) to 46.6 (Khuzestan). On the other hand, distribution of substitutions within the CTL epitopes showed a wide range of variation between 6.6 (Khuzestan) and 63 (Kermanshah). Conclusion: Further to low selection pressure found in Iranian population, the variations between different regions designate random genetic drift within the surface proteins. These finding would have some applications in terms of specific antiviral regimen, design of more efficient vaccine and public health issues. © 2015, Tehran University of Medical Science. All rights reserved

An insight to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis; evidence from high-throughput data integration and meta-analysis

Background Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP. Results High-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein-protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12). Conclusions High-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.Peer reviewe

ORAI1 Genetic Polymorphisms Associated with the Susceptibility of Atopic Dermatitis in Japanese and Taiwanese Populations

Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD

Hepatitis B virus genotype D is the only genotype circulating in Iranian chronic carriers, the unique pattern of genotypic homogeneity

Aim: To characterize the hepatitis B virus surface protein genotypes and sequence variations among HBsAg positive chronic Iranian patients from different ethnic groups. Method: The surface genes from 312 patients were amplified and directly sequenced. Results: All strains (100) belonged to genotype D and subtypes ayw2. The average nucleotide mutation frequency was 0.91 (dN/dS < 1.0), indicated negative selection. There was no significant correlation between HBV DNA and ALT levels and the occurrence of amino acid substitutions. However, in terms of HBeAg/Anti-HBe status, the association between both groups for silent nucleotide mutation was strong, indicating selection bias on missense mutations. A higher number of amino acid mutations was found in anti-HBe positive versus HBeAg positive patients.Conclusion: The uniqueness pattern of HBV genetics hemogeniety together with the low mutational frequency indicated that HBV has introduced to Iran recently and isolation of people in the absence of intermixing with other genotypes led to a homologous pattern. © 2014 ACT

Additional effect of etanercept or infliximab on the liver function tests of patients with rheumatoid arthritis: a cohort study

Saeed Akhlaghi,1 Maryam Sahebari,2 Mahmoud Mahmoodi,1 Mehdi Yaseri,1 Mohammad Ali Mansournia,1 Houshang Rafatpanah,3 Hojjat Zeraati1 1Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; 2Rheumatic Diseases Research Center (RDRC), Mashhad University of Medical Sciences, Mashhad, Iran; 3Inflammation and Inflammatory Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Purpose: One of the most important long-term side effects of therapy for rheumatoid arthritis (RA) is the elevation of liver function tests, with earlier studies reporting an elevation of more than 1&times; the upper limit of normal (&gt;1 &times; ULN). The current study expands the literature by comparing the trends of transaminase changes caused by conventional and biologic disease-modifying antirheumatic drugs (DMARDs).Patients and methods: The drug categories examined were methotrexate (MTX) and all other nonbiologic DMARDs. Where RA patients exhibited inadequate response to conventional DMARDs (cDMARDs), we added biologic DMARDs (bDMARDs) to the treatment. We compared the trend of changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the patients receiving MTX with the trend observed in the patients whose treatment encompassed both bDMARDs and MTX. The comparison was conducted using random intercept models, which are a type of linear mixed effects model.Results: This work involved 512 RA patients (MTX: 450, MTX + infliximab [INF]: 26, MTX + etanercept [ETA]: 36), whose ALT and/or AST levels were measured in 1,786 visits (MTX: 1,543, MTX + INF: 107, MTX + ETA: 136). ALT and/or AST elevations greater than 1 &times; ULN were observed in 344 (19.3%) visits (MTX: 295 [19.1%], MTX + INF/ETA: 49 [20.2%]). In this study, the trends of ALT and AST changes increased when receiving MTX, while the INF/ETA addition decreased these trends. The random intercept models indicated that changes in the mean ALT levels were significantly different over the time for MTX and MTX + INF/ETA groups (&beta; [SE] =-0.190 [0.093], P= 0.040) but changes in the mean AST levels were nonsignificantly different over the time for such groups (&beta; [SE] =-0.099 [0.064], P=0.120).Conclusion: Despite a higher incidence of elevated transaminases during the use of MTX + INF/ETA, the combination of INF/ETA with MTX reduced transaminase levels and returned ALT levels to normal concentrations. Keywords: longitudinal, ALT, AST, DMARDs, biologic DMARDs, MT

Interferon Lambda Family along with HTLV-1 Proviral Load, Tax, and HBZ Implicated in the Pathogenesis of Myelopathy/Tropical Spastic Paraparesis

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disease related to human T lymphotropic virus type 1 (HTLV-1) infection. Interferon type III (IFN-λ), which includes IL28, IL29, and IL28R, and affects the outcome of viral infections, might be complicated in the progression of HAM/TSP. Here, we investigated the host-virus interactions in the manifestation of HAM/TSP, using IL28B, IL29, IL28R, HTLV-1 Tax, HTLV-1 basic leucine zipper factor (HBZ), and proviral load (PVL). The study groups consisted of 20 patients with HAM/TSP, 20 asymptomatic HTLV-1 carriers (ACs), and 20 healthy controls (HCs). The means of PVL, Tax, and HBZ gene expressions in the HAM/TSP group (p = 0.004, 0.006, and &lt; 0.0001, respectively) were significantly higher than in the AC group. The comparison of IL28B, IL29, and IL28R expression in the HAM/TSP, AC, and HC groups revealed no significant difference between the first 2, but lower concentrations in the HCs (IL28B: p = 0.03, 0.01; IL29: p = 0.07, 0.01; and IL28R: p &lt; 0.0001, respectively). In the HAM/TSP group, correlations were seen between Tax and HBZ (R = 0.61, p = 0.004) and between Tax and IL29 (R = 0.45, p = 0.04). Negative correlations were observed between Tax and IL28B (R = -0.49, p = 0.02) and between HBZ and IL28R (R = -0.43, p = 0.06). In the ACs, an inverse correlation was found between Tax and IL28B (R = -0.42, p = 0.06). These findings suggest that IL29, IL28B, and IL28R interfere in the infection of HAM/TSP, mainly via Tax activation

Development and Evaluation of Novel Aptamers Specific for Human PD1 Using Hybrid Systematic Evolution of Ligands by Exponential Enrichment Approach

Background: Programmed cell death protein 1 (PD1; also known as CD279) is an inhibitory receptor on T lymphocytes interacting with PD1-ligand 1 and PD1-ligand 2 in the synapse of T cells and antigen presenting cells (APC) resulting in the suppression of T cell activity. Systematic evolution of ligands by exponential enrichment (SELEX) is a method for generating aptamers which can bind specifically to the target of interest. PD-1 antagonistic aptamers could introduce an attractive alternative over the antibody-based treatments due to the distinguished advantages of aptamers including small size and efficient tissue penetration, low cost, lack of immunogenicity, and ease of manufacturing. Methods: Here, we developed single-stranded DNA aptamers which bind specifically to the human extracellular domain of PD-1. We performed hybrid SELEX, a combination of targeting of recombinant proteins and cell membrane expressed PD1 to select and identify specific aptamers and for the first time, homology of aptamer sequences selected from protein and cell SELEX pool have been evaluated in this study. Results: C42�aptamer, one of the selected aptamers, could specifically bind to human PD1 with dissociation constant in the nanomolar range. Although the developed aptamer inhibited binding of PD1 to PD-L1 but it was not able to restore the cell proliferation and cytokine production of the CD8+ CD279+ T cells. Conclusion: Further studies are required to assess the therapeutic potential of C42 aptamer and other aptamers developed in this study. The introduced PD1 specific aptamers can be used for specific detection of PD1 in diagnostic assay such as immunohistochemistry and targeted drug delivery to PD+ T cells. © 2020, © 2020 Taylor & Francis Group, LLC

Association of HLA-DRB1 Alleles with Ulcerative Colitis in the City of Kerman, South Eastern Iran

The association of HLA class II genes with ulcerative colitis (UC) as an autoimmune disease has been investigated for several years. However, factors responsible for genetic predisposition of this disease have so far not been clearly understood. In this study, for the first time, we aimed to investigate the association between HLA-DRB1 types and UC in the population of Kerman, a city southeast Iran.HLA typing was performed among 85 UC patients and 95 healthy controls using PCR amplification, employing sequence specific primers (PCR-SSP). The DRB1 frequencies were determined in the patients and controls.HLA-DRB1*04 was negatively associated with UC. Furthermore, HLA-DRB1*13 was significantly associated with severity of the disease (p=0.01) among UC patients.This is the novel result that describes an association of HLA-DRB1*13 with UC and also shows the protective role of HLA-DRB1*04 against the disease in people of Kerman