Publications by authors named "Mehran Gholamin"

40 Publications

Elucidated tumorigenic role of MAML1 and TWIST1 in gastric cancer is associated with Helicobacter pylori infection.

Microb Pathog 2021 Nov 21:105304. Epub 2021 Nov 21.

Medical Genetics Research Center, Faculty of Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Background: Epithelial-mesenchymal transition (EMT) has a fundamental role in tumor initiation, progression, and metastasis. Helicobacter pylori (HP) induces EMT and thus causes gastric cancer (GC) by deregulating multiple signaling pathways involved in EMT. TWIST1 and MAML1 have been confirmed to be critical inducers of EMT via diverse signaling pathways such as Notch signaling. This study aimed to investigate for the first time possible associations between TWIST1/MAML1 mRNA expression levels, HP infection, and clinicopathological characteristics in GC patients.

Method: TWIST1 and MAML1 mRNA expression levels were evaluated in tumoral and adjacent normal tissues in 73 GC patients using the quantitative reverse transcription PCR (RT-qPCR) method. PCR technique was also applied to examine the infection with HP in GC samples.

Results: Upregulation of TWIST1 and MAML1 expression was observed in 35 (48%) and 34 (46.6%) of 73 tumor samples, respectively. Co-overexpression of these genes was found in 26 of 73 (35.6%) tumor samples; meanwhile, there was a significant positive correlation between MAML1 and TWIST1 mRNA expression levels (P < 0.001). MAML1 overexpression exhibited meaningful associations with advanced tumor stages (P = 0.006) and nodal metastases (P ˂ 0.001). 34 of 73 (46.6%) tumors tested positive for HP, and meanwhile, MAML1 expression was positively related with T (P = 0.05) and grade (P = 0.0001) in these HP-positive samples. Increased TWIST1 expression was correlated with patient sex (P = 0.035) and advanced tumor grade (P = 0.017) in HP-infected tumors. Furthermore, TWIST1 and MAML1 expression levels were inversely linked with histologic grade in HP-negative tumor samples (P = 0.021 and P = 0.048, respectively).

Conclusion: We propose TWIST1 and MAML1 as potential biomarkers of advanced-stage GC that determine the characteristics and aggressiveness of the disease. Based on accumulating evidence and our findings, they can be introduced as promising therapeutic targets to modify functional abnormalities in cells that promote GC progression. Moreover, HP may enhance GC growth and metastasis by disrupting TWIS1/MAML1 expression patterns and related pathways.
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http://dx.doi.org/10.1016/j.micpath.2021.105304DOI Listing
November 2021

Expression and Prognostic Significance of Cancer/Testis Antigens, MAGE-E1, GAGE, and SOX-6, in Glioblastoma: An Immunohistochemistry Evaluation.

Iran J Pathol 2021 20;16(2):128-136. Epub 2020 Dec 20.

Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran.

Background & Objective: Glioblastoma is the most common primary malignancy of the brain, the prognosis of which is poor. Immunotherapy with cancer/testis (CT) antigens is a novel therapeutic approach for glioblastoma. This study aimed to investigate the expression rate of MAGE-E1, GAGE, and SOX-6 in glioblastoma tumors using the method of immunohistochemistry (IHC).

Methods: Expression of MAGE-E1, GAGE, and SOX-6 were determined by IHC in 50 paraffin blocks of glioblastoma. The results were compared between variables including age, gender, tumor location, and Karnofsky performance status (Kps) score. Survival analysis was also performed.

Results: The expression levels of SOX-6, MAGE-E1, and GAGE were 82%, 78%, and 76%, respectively. The relationship between CT antigens and age, gender, and tumor location was not significant, while the association between MAGE-E1 expression and age was statistically significant (=0.002). High expression levels of SOX-6 and MAGE-E1 were associated with low Kps scores (=0.034 and <0.001, respectively). Survival analysis showed that age >40 and Kps score <80 were associated with significant relationship with shorter survival rate. (=0.005 and =0.018, respectively). Expression of MAGE-E1 and GAGE was negatively associated with overall 2-year survival rate (=0.001 and =0.021, respectively).

Conclusion: The expression of all the three CT antigens, especially MAGE-E1 and SOX-6, was high in patients with glioblastoma. It can be concluded that these markers could be ideal targets for immunotherapy in such patients. MAGE-E1 and SOX-6 can be considered as important markers in determining the prognosis of glioblastoma.
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http://dx.doi.org/10.30699/IJP.2020.125038.2368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085292PMC
December 2020

Correlation between the immune checkpoints and EMT genes proposes potential prognostic and therapeutic targets in ESCC.

J Mol Histol 2021 Jun 21;52(3):597-609. Epub 2021 Apr 21.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

PD-1, PD-L1, CTLA-4, TIM-3, and LAG-3, crucial immune checkpoint molecules in the tumor microenvironment, identify as key targets for cancer immunotherapy. There is a correlation between immune cells and epithelial-mesenchymal transition (EMT)-related genes expression in varies human cancers. In this study, we aimed to investigate the probable association between expression of immune checkpoints and EMT in esophageal squamous cell carcinoma (ESCC) with clinical treats for providing the new therapeutic targets and prognostic value for the disease. Quantitative real-time PCR was used to investigate the gene expression profile of immune checkpoints (PD-1, PD-L1, CTLA-4, TIM-3, and LAG-3) and EMT (TWIST1 and MMP-13) genes based on the mRNA expression levels in 51 ESCC tissues. The upregulation of CTLA-4, PD-1, PD-L1, TIM-3, LAG-3, MMP-13, and TWIST1 were observed in 31.37%, 29.41%, 21.56%, 39.21%, 25.49%, 60.78%, and 56.86% of ESCC cases at the mRNA level, respectively. Dysregulation of immune checkpoints was related to lymph node involvement, stage of tumor progression, and depth of tumor invasion (P < 0.05). While overexpression of MMP-13 and TWIST1 was associated with lymph node involvement, stage of tumor progression, and grade of tumor differentiation (P < 0.05). The mRNA expression of immune checkpoint genes was significantly correlated to each other's (P = 0.000). Of importance, the data explored the significant association between the concomitant expression of immune checkpoints and EMT-related genes with each other in a variety of clinicopathological traits (P < 0.05). Consequently, immune checkpoints were positively correlated with EMT status in ESCC. The correlation between tumor immune microenvironment with the elevation of multiple immune checkpoints and EMT status may help to identify potential biomarkers for the simultaneous clinical use of multiple immune checkpoints blockade and other immunotherapies approaches for advanced ESCC patients.
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http://dx.doi.org/10.1007/s10735-021-09971-3DOI Listing
June 2021

Crosstalk between MMP-13, CD44, and TWIST1 and its role in regulation of EMT in patients with esophageal squamous cell carcinoma.

Mol Cell Biochem 2021 Jun 19;476(6):2465-2478. Epub 2021 Feb 19.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Matrix metalloproteinases (MMPs) play key roles in epithelial-mesenchymal transition (EMT) for the development of cancer cell invasion and metastasis. MMP-13 is an extracellular matrix (ECM)-degrading enzyme that plays crucial roles in angiogenesis, cell cycle regulation, niche maintenance, and transforming squamous epithelial cells in various tissues. CD44, a transmembrane glycoprotein expressed on esophageal tumor cells, is required for EMT induction and invasion in esophageal squamous cell carcinoma (ESCC). The transcription factor TWIST1, as EMT and stemness marker, regulates MMPs expression and is identified as the downstream target of CD44. In this study, we aimed to investigate the probable interplay between the expression of key genes contributing to ESCC development, including MMP-13, TWIST1, and CD44 with clinical features for introducing novel diagnostic and therapeutic targets in the disease. The gene expression profiling of MMP-13, TWIST1, and CD44 was performed using quantitative real-time PCR in tumor tissues from 50 ESCC patients compared to corresponding margin non-tumoral tissues. Significant overexpression of MMP-13, CD44S, CD44V3, CD44V6, and TWIST1 were observed in 74%, 36%, 44%, 44%, and 52% of ESCC tumor samples, respectively. Overexpression of MMP-13 was associated with stage of tumor progression, metastasis, and tumor location (P < 0.05). There was a significant correlation between TWIST1 overexpression and grade (P < 0.05). Furthermore, overexpression of CD44 variants was associated with stage of tumor progression, grade, tumor invasion, and location (P < 0.05). The results indicated the significant correlation between concomitant expression of MMP-13/TWIST1, TWIST1/CD44, and CD44/MMP-13 with each other in a variety of clinicopathological traits, including depth of tumor invasion, tumor location, stage of tumor, and lymph node involvement in ESCC tissue samples (P < 0.05). Collectively, our results indicate that the TWIST1-CD44-MMP-13 axis is involved in tumor aggressiveness, proposing these genes as regulators of EMT, diagnostic markers, and therapeutic targets in ESCC.
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http://dx.doi.org/10.1007/s11010-021-04089-2DOI Listing
June 2021

Novel Biomarkers Aim at Detecting Metastatic Sentinel Lymph Nodes in Breast Cancer

Iran Biomed J 2020 05 26;24(3):183-91. Epub 2020 Jan 26.

Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Intra-operative molecular diagnostic assays are currently used for the detection of lymph node metastases. The objective of this study was to find new biomarkers to improve diagnostic accuracy in the detection of metastatic axillary lymph nodes in breast cancer patients.

Methods: We applied an absolute quantitative real-time reverse transcription-PCR to quantitate the expression of CK19, KLK11, and CLEC3A mRNAs in 79 FFPE sentinel lymph nodes (SLNs) from 35 breast cancer patients. The CK19 was confirmed as a standard biomarker, and the level of expression of selected new markers, KLK11 and CLEC3A, was evaluated in pathologically negative and positive SLNs by using absolute quantitative real-time PCR.

Results: The overall concordance of the CK19 gene with pathological results was 92.4% (less than 250 copies) in negative SLNs and 85% in positive SLNs (more than 250 copies). The sensitivity and specificity of CK19, which were detected by real-time PCR, was 85% and 46%, respectively. Our results revealed that lower CLEC3A was associated with more lymph node involvement. We could set a cut-off point for CLEC3A with the sensitivity of 78% and specificity of 60%. Also, the mean KLK11 had a statistically significant reverse correlation with tumor grade (p = 0.017). Higher CK19 levels were related to more tumor invasion (p < 0.0001).

Conclusion: Regarding the findings, CLEC3A along with CK19 can be used as a promising marker with high sensitivity and specificity for the detection of metastatic SLN.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275625PMC
May 2020

The Role of Interleukin-4 and 13 Gene Polymorphisms in Allergic Rhinitis: A Case Control Study.

Rep Biochem Mol Biol 2019 Jul;8(2):111-118

Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Allergic Rhinitis (AR) is an IgE-mediated inflammatory disorder with high morbidity rates. The eitiology of this disease is understood to occur from a complex interaction between genetic and environmental factors. T helper type 2 cells have been shown to have a crucial role in atopic disease due to their production of the cytokines, intelukin and , involved in inflammation. Research has shown single nucleotide polymorphisms (SNP) of the and genes to be associated increased levels of IgE and with allergic diseases such as, allergic rhinitis, asthma, and atopic dermatitis. Specifically, the rs2243250 SNP of IL-4 and the rs20541 SNP of have been shown to be associated with AR.

Methods: A case-control study was designed to investigate the relationship between the two SNPs rs2243250 and rs20541 with the incidence of AR. The SNPs were examined in patients with AR and healthy controls (86 patients and 86 controls). Blood samples were collected and DNA was extracted to evaluate the SNPs by RFLP-PCR.

Results: Recessive analysis model of the gene (GG vs. AA+AG) revealed that the GG genotype was more common in AR patients (P=0.36) )OR=0.8 [81% CI 0.38-1.6]). For the gene (TC vs. TT+CC), the TC genotype was more common in AR patients (P = 0.0022)) OR=0.71 [60% CI 1.41-5.02]). Furthermore, in the IL-4 gene, the 590 T>C polymorphism had a significant association with AR. However, no association was found between AR and the rs20541 polymorphism.

Conclusion: Our findings suggest that the polymorphism (rs20541, Exo 4, G>A, Arg130Gln) and IL-4 polymorphism (rs2243250= C-590T, promoter, T>C) are co-associated with AR and sensitivity to aeroallergens. However, this study used a cohort of AR patients and healthy controls from the northeast of Iran. Given the influence of ethnicity and environment on genetics, further investigation is needed to elucidate the role of SNPs in and in AR among different populations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844616PMC
July 2019

Role of MAML1 in targeted therapy against the esophageal cancer stem cells.

J Transl Med 2019 04 16;17(1):126. Epub 2019 Apr 16.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Esophageal cancer is the sixth-leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are the main reason for tumor relapse in esophageal squamous cell carcinoma (ESCC). The NOTCH pathway is important in preservation of CSCs, therefore it is possible to target such cells by targeting MAML1 as the main component of the NOTCH transcription machinery.

Methods: In present study we isolated the CD44+ ESCC CSCs and designed a MAML1-targeted therapy to inhibit the NOTCH signaling pathway. CSCs were isolated using magnetic cell sorting utilizing the CD44 cell surface marker. Several stem cell markers were analyzed in the levels of protein and mRNA expression. The isolated CSCs were characterized in vivo in NUDE mice. Biological role of MAML1 was assessed in isolated CD44+ CSCs. A drug resistance assay was also performed to assess the role of MAML1 in CD44+ CSCs with 5FU resistance.

Results: The CD44+ CSCs had ability to form tumors in NUDE mice. MAML1 silencing caused a significant decrease (p = 0.019) and ectopic expression caused a significant increase in migration of CD44+ CSCs (p = 0.012). Moreover, MAML1 silencing and ectopic expression significantly increased and decreased 5FU resistance, respectively (p < 0.05). MAML1 silencing significantly increased the number of cells in G1 phase (p = 0.008), and its ectopic expression significantly increased the number of CD44+ CSCS in S phase (p = 0.037).

Conclusions: MAML1 may be utilized for targeted therapy with a low side effect to eliminate the CD44+ CSCs through inhibition of canonical NOTCH pathway in ESCC patients.
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http://dx.doi.org/10.1186/s12967-019-1876-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469193PMC
April 2019

Correlation between expression of CatSper1,2 and sperm parameters in the gamma irradiated adult mouse testis.

Int J Radiat Biol 2019 06 23;95(6):691-696. Epub 2019 Apr 23.

j Department of Medical Education , Brighton & Sussex Medical School, Falmer , Brighton , UK.

CatSper protein channels are responsible for the entry of Ca2+ into sperm cells. These proteins play an important role in motility and male fertility. So it is important to find out whether or not environmental factors, such as gamma radiation, have an effect on the expression of Catsper genes. In this study, we investigated the effects of gamma radiation on the expression of CatSper1 and CatSper2 genes. Twenty-one male NMRI mice were divided into three groups: a control group without gamma radiation, and two experimental groups; Group 1 treated with 1 Gy of gamma radiation, and Group 2 treated with a higher dose of 2 Gy gamma radiation. Testes were removed from all groups of animals 35 days following irradiation and the testicular tissue, processed and embedded in paraffin blocks for sectioning and histological examination. Sperm samples were also taken from the epididymis for microscopic. Sperm parameters such as sperm count, morphology, motility, and viability rates were analyzed. Expression of CatSper genes was evaluated using Real-time PCR. Data were analyzed using the SPSS software and ANOVA test. Our results showed that after treatment with gamma radiation, testes morphology was changed. Epididymal sperm count, motility, and morphology rates were significantly affected in both experimental groups compared to the control group. The relative expressions of CatSper 1 and 2 genes were significantly reduced in the irradiated mice (1 Gy and 2 Gy) than non-irradiated ones. Gamma radiations not only change testes histology and sperm parameters, but also decrease the expression of CatSper 1 and 2 genes in male mice.
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http://dx.doi.org/10.1080/09553002.2019.1552372DOI Listing
June 2019

Induction of T cell-mediated immune response by dendritic cells pulsed with mRNA of sphere-forming cells isolated from patients with gastric cancer.

Life Sci 2019 Feb 12;219:136-143. Epub 2019 Jan 12.

Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Gastric cancer (GC) as the third most common cause of cancer-associated mortality worldwide is one of the cancers with very high heterogeneity. Cancer stem cells (CSCs) as a small subset of cancer cells in solid tumors with the self-renewal, differentiation and tumorigenic ability are responsible for tumor initiation, progression, recurrence, metastasis, and resistance to current treatments. Therefore, eradication of CSCs is very vital to cure cancer. Here, we first isolated and identified sphere-forming cells in tumor tissue from four GC patients and then analyzed T cell responses induced by monocyte-derived dendritic cells (DCs) loaded with total mRNA of sphere-forming cells in terms of interferon-gamma (IFN-γ) gene expression and specific cytotoxicity. Spheroid colonies were formed in serum-free media. Sphere-forming cells dissociated from tumorspheres heterogeneously expressed CD44, CD54, and epithelial cell adhesion molecule (EpCAM) markers and generated one tumor in nude mice. These results demonstrated that gastric CSCs were enriched in tumorspheres. Cytokine-matured DCs loaded with mRNA of sphere-forming cells were able to induce IFN-γ gene expression in T-lymphocytes after a 12-day co-culture. mRNA level of IFN-γ gene in these lymphocytes was more highly expressed compared to stimulated T-lymphocytes by DCs transfected with normal tissue (6.4-9.39 folds). Cytotoxic activity of primed T-lymphocytes with antigens of sphere-forming cells was significantly higher than normal tissue antigens and mock DCs (P ≤ 0.0001). Taken together, DCs loaded with mRNA of sphere-forming cells that elicit effectively specific T cell-mediated immune responses in vitro, may be considered as a promising therapeutic vaccination in GC patients in future.
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http://dx.doi.org/10.1016/j.lfs.2019.01.016DOI Listing
February 2019

Ectopic Expression of Human Gene in ESCC Cell Line Using Retroviral System.

Avicenna J Med Biotechnol 2018 Apr-Jun;10(2):75-82

Human Genetic Division, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Cancer/Testis Antigens (CTAs) are a sub-group of tumor-associated antigens which are expressed normally in germ line cells and trophoblast, and aberrantly in a variety of malignancies. One of the most important CTAs is Developmental Pluripotency Associated-2(DPPA2) with unknown biological function. Considering the importance of in developmental events and cancer, preparing a suitable platform to analyze roles in the cells seems to be necessary.

Methods: In this study, the coding sequence of gene was amplified and cloned into the retroviral expression vector to produce recombinant retrovirus. The viral particles were transducted to Esophageal Squamous Cell Carcinoma (ESCC) cell line (KYSE-30 cells) and the stable transducted cells were confirmed for ectopic expression of gene by real-time PCR.

Results: According to the critical characteristics of retroviral expression system such as stable and long time expression of interested gene and also being safe due to deletion of retroviral pathogenic genes, this system was used to induce expression of gene and a valuable platform to analyze its biological function was prepared. Transduction results clearly showed efficient overexpression of the gene in target cells in protein level due to high level of GFP expression.

Conclusion: Such strategies can be used to produce high levels of desired protein in target cells as a therapeutic target. The produced recombinant cells may present a valuable platform to analyze the effect of ectopic expression in target cells. Moreover, the introduction of its potential capacity into the mouse model to evaluate the tumorigenesis of these cancer cells leads to an understanding of the biological importance of in tumorigenesis. In addition, our purified protein can be used in a mouse model to produce specific antibody developing a reliable detection of existence in any biological fluid through ELISA system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960063PMC
June 2018

Association of Two CD44 Polymorphisms with Clinical Outcomes of Gastric Cancer Patients

Asian Pac J Cancer Prev 2018 May 26;19(5):1313-1318. Epub 2018 May 26.

Department of Cellular and Molecular Biology, University of Science and Culture, Tehran, Iran.

Objective: CD44 is an important cell adhesion molecule that plays a key role in growth, invasion, proliferation and metastasis of cancer cells. CD44 protein over-expression is associated with a poor prognosis of gastric cancer (GC) and previous studies have shown that CD44 gene polymorphisms could affect survival and recurrence. In this study, we tested the hypothesis that polymorphisms impacting on the CD44 signaling pathway may predict clinical outcomes in patients with GC. Materials and Methods: DNA was extracted from blood of 150 healthy individuals and formalin-fixed paraffin-embedded (FFPE) tumor tissue of 150 patients. The two polymorphisms rs187116 and rs7116432 were studied by RFLP-PCR and sequencing techniques. Results: There was a strong significant correlation between single nucleotide polymorphisms (SNPs) in the CD44 gene, tumor recurrence, and overall survival (p <0.0001). The existence of a significant relationship between tumor recurrence and overall survival was proved in this study, with at least one allele G for the polymorphism rs187116 and at least one allele A for polymorphism rs7116432. Conclusion: These results provide evidence of a relationship between CD44 gene polymorphisms and clinical outcomes in our GC patients. This result could help identify individuals with GC who have a high risk of tumor recurrence.
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http://dx.doi.org/10.22034/APJCP.2018.19.5.1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031830PMC
May 2018

Isolation and identification of chemotherapy-enriched sphere-forming cells from a patient with gastric cancer.

J Cell Physiol 2018 10 10;233(10):7036-7046. Epub 2018 May 10.

Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Gastric cancer (GC) is the third and fifth cause of cancer-associated mortality for men and women throughout the world, respectively. Despite the use of surgery and chemotherapy for GC therapy, there are no efficient therapeutic protocols for it to date. Cancer stem cells (CSCs) due to their pivotal role in tumor initiation, growth, progression, invasion, distant metastasis, recurrence and resistance to anticancer drugs are very appealing targets for cancer therapies. Here, we isolated and identified CSCs from a chemotherapy-treated patient. Small subpopulation of dissociated cells after tissue digestion formed spheroid colonies in serum-free media under the non-adherent condition. These spheroid colonies differentiated into epithelial like cells in serum-containing medium. Few sphere-forming cells carried CD44 and CD54 markers overexpressed DLL4 that is responsible for tumor growth and angiogenesis. Subcutaneous injections of sphere-forming cells in different passages conferred tumorigenicity in nude mice. Sphere-forming cells upregulated CD44 polymorphisms CD44v3, -v6, and -v8 -10, stemness factors OCT4, SOX2, SALL4 and Cripto-1, self-renewal molecules IHh, Wnt, β-catenin and BMI1, and epithelial mesenchymal transition (EMT) markers Twist1 and Snail1 in vitro and in vivo. Moreover, these cells similar to sphere-forming cells isolated from a chemotherapy-free patient expressed Oct-4 and β-catenin proteins. However, the Twist1 protein was only expressed by sphere-forming cells derived from the chemotherapy-treated patient. Thus, these cells have all the characteristics of stationary and migratory CSCs, including tumorigenicity, self-renewal, pluripotency, invasion and metastasis. Taken together, targeting chemotherapy-enriched CSCs as chemo-resistance cells observed in GC patients can provide more effective therapeutic strategies compared to untreated patients.
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http://dx.doi.org/10.1002/jcp.26627DOI Listing
October 2018

Gene Polymorphisms Associated with Allergic Rhinitis in an Iranian Population.

Rep Biochem Mol Biol 2017 Apr;5(2):97-102

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.; Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: The development of allergic rhinitis (AR) is caused by the interaction between genetic predisposition and environmental factors. In this study, the association between single nucleotide polymorphisms and AR in an Iranian population was identified.

Methods: This case-control study was performed on 86 patients with AR and 86 healthy subjects. This study aimed to evaluate a potential association between two SNPs, rs1269486 and rs2229360, and AR. Blood samples were collected and DNA was extracted for the evaluation of these SNPs by RFLP-PCR.

Results: A statistically-significant association was found between rs1269486 and AR (P<0.001). The frequencies of the A and GA genotypes were less in patients than in controls. The frequencies of the G allele and the GG genotype were greater in patients than in controls (P < 0.001).

Conclusions: SNP rs1269486 of was associated with AR and sensitivity to aeroallergens in our population. Because of the significance of this gene in AR, studying the association between polymorphisms and AR is recommended for other populations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346276PMC
April 2017

Biological and Clinicopathological Significance of Cripto-1 Expression in the Progression of Human ESCC.

Rep Biochem Mol Biol 2017 Apr;5(2):83-90

Immunology Research Center, BuAli Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Human Cripto-1, a member of the EGF-CFC family, is involved in embryonic development, embryonic stem cell maintenance, and tumor progression. It also participates in multiple cell signaling pathways including Wnt, Notch, and TGF-β. Remarkably, it is expressed in cancer stem cell (CSC) compartments, boosting tumor cell migration, invasion, and angiogenesis. Although Cripto-1 is overexpressed in a variety of human malignant tumors, its expression in esophageal squamous cell carcinoma (ESCC) remains unclear. Our aim in this study was to evaluate the possible oncogenic role of Cripto-1 in ESCC progression and elucidate its association with clinicopathological parameters in patients.

Methods: In this study, Cripto-1 expression in 50 ESCC tissue samples was analyzed and compared to corresponding margin-normal esophageal tissues using quantitative real-time PCR.

Results: Cripto-1 was overexpressed in nearly 40% of ESCC samples compared with normal tissue samples. Significant correlations were observed between Cripto-1 expression and tumor differentiation grade, progression stage, and location (p < 0.05).

Conclusions: Our results indicate that overexpression of Cripto-1 is involved in the development of ESCC. Further assessment will be necessary to determine the role of Cripto-1 cross talk in ESCC tumorigenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346274PMC
April 2017

Expression analysis of matrix metalloproteinase-13 in human gastric cancer in the presence of Helicobacter Pylori infection.

Cancer Biomark 2017 ;18(4):349-356

Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Matrix metalloproteinases (MMPs) can degrade essentially the extracellular matrix (ECM) components. MMPs are important regulators of tumor growth; hence the enzymes are considered as important targets for cancer therapy. MMP-13 is specially activated in gastric cancer and promotes the invasiveness of the primary tumors. Helicobacter Pylori (H.pylori) interacts with gastric epithelial cells and stimulates it to produce MMP-13in vitro.

Objective: The relation between MMP-13 gene expression and clinicopathological characteristics of gastric cancer in the presence of H.pylori infection was investigated in fifty patients.

Methods: The level of MMP-13 gene expression was measured by quantitative Real-time PCR method and was evaluated between two groups of normal and carcinomatous tissues.

Results: The results showed 30% elevation of MMP-13 expression in tumor tissues. H.pylori infection did not have a significant effect on the expression of MMP-13. There was a correlation between gene expression and tumor type (P value = 0.032). In addition, there was a significant correlation between MMP-13 gene expression and tumor stage in intestinal group (P value = 0.023).

Conclusions: Based on the results, it might be concluded that in intestinal group, immune system plays an important role in reducing gene expression. Results also showed over expression (60%) in diffuse group. These findings suggest that using MMP-13 inhibitors in diffuse group might contribute to the control of tumor growth.
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http://dx.doi.org/10.3233/CBM-160127DOI Listing
March 2018

Cytokine networks and their association with Helicobacter pylori infection in gastric carcinoma.

J Cell Physiol 2018 04 7;233(4):2791-2803. Epub 2017 Mar 7.

Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Cytokine networks as dynamic networks are pivotal aspects of tumor immunology, especially in gastric cancer (GC), in which infection, inflammation, and antitumor immunity are key elements of disease progression. In this review, we describe functional roles of well-known GC-modulatory cytokines, highlight the functions of cytokines with more recently described roles in GC, and emphasize the therapeutic potential of targeting the complex cytokine milieu. We also focus on the role of Helicobacter pylori (HP)-induced inflammation in GC and discuss how HP-induced chronic inflammation can lead to the induction of stem cell hyperplasia, morphological changes in gastric mucosa and GC development.
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http://dx.doi.org/10.1002/jcp.25822DOI Listing
April 2018

Isolation, identification, and characterization of cancer stem cells: A review.

J Cell Physiol 2017 Aug 28;232(8):2008-2018. Epub 2017 Feb 28.

Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) as a small subset of neoplastic cells are able to produce a tumor (tumorigenesis), maintain the population of tumorigenic cells (self-renewal), and generate the heterogeneous cells constructing the entire tumor (pluripotency). The research on stationary and circulating CSCs due to resistance to conventional therapies and inability in complete eradication of cancer is critical for developing novel therapeutic strategies for a more effective reduction in the risk of tumor metastasis and cancer recurrence. This review compiles information about different methods of detection and dissociation, side population, cellular markers, and establishment culture of CSCs, as well as characteristics of CSCs such as tumorigenicity, and signaling pathways associated with self-renewal and the capability of the same histological tumor regeneration in various cancers.
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http://dx.doi.org/10.1002/jcp.25759DOI Listing
August 2017

Loss of heterozygosity and microsatellite instability as predictive markers among Iranian esophageal cancer patients.

Iran J Basic Med Sci 2016 Jul;19(7):726-33

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Variation in microsatellite sequences that are dispersed in the genome has been linked to a deficiency in cellular mismatch repair system and defects in several genes of this system are involved in carcinogenesis. Our aim in this study was to illustrate microsatellite DNA alteration in esophageal cancer.

Materials And Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) tissues from surgical and matched margin-normal samples. Microsatellite instability (MSI) and loss of heterozygosity (LOH) were studied in 50 cases of esophageal squamous cell carcinoma (ESCC) by amplifying six microsatellite markers: D13S260 (13q12.3), D13S267 (13q12.3), D9S171 (9p21), D2S123 (2p), D5S2501 (5q21) and TP53 (17p13.1) analyzed on 6% denaturing polyacrylamide gel electrophoresis.

Results: Statistical analysis indicated a near significant reverse correlation between grade and LOH (P= 0.068, correlation coefficient= -0.272). Specifically, increased LOH in tumor DNA has a significant correlation with increased differentiation from poorly differentiated to well differentiated tumors (P= 0.002 and P= 0.016 respectively). In addition, higher number of chromosomal loci with LOH showed a reverse correlation with lymph node metastasis (P= 0.026, correlation coefficient= -0.485). Furthermore, there was a positive correlation between addiction and MSI (P= 0.026, correlation coefficient= 0.465).

Conclusion: Microsatellite DNA alterations may be a prognostic tool for detection and the evolution of prognosis in patients with SCC of esophagus. It can be concluded that regional lymph node metastasis would be less likely with increased heterozygote loci and addiction with any of opium, cigarette, water pipe or alcohol can be a susceptibility factor(s) for MSI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010844PMC
July 2016

TWIST1 upregulates the MAGEA4 oncogene.

Mol Carcinog 2017 03 4;56(3):877-885. Epub 2016 Oct 4.

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Overexpression of MAGEA4 oncogene has been demonstrated in different malignancies; however, little is known about its exact mechanism for overexpression. TWIST1, as a bHLH transcription factor, activates a cell migration-invasion program involved in both embryonic and tumor development. Since MAGEA4 overexpression was statistically correlated to TWIST1, we aimed to elucidate the probable regulatory role of TWIST1 on MAGEA4 expression in KYSE30 cells.

Methods: Expression pattern of MAGEA4 and TWIST1 was analyzed in 55 ESCC patients using relative comparative real-time PCR. In silico analysis of the MAGEA4 gene was performed. Methylation status of MAGEA4 promoter was determined by quantitative methylation specific PCR (qMSP). Using a retroviral system, KYSE30 cells were transduced to ectopically express TWIST1, followed by qRT-PCR, Western blot analysis, chromatin immunoprecipitation (ChIP), and luciferase assays to elucidate the regulatory role of TWIST1 on MAGEA4 gene expression.

Results: Concomitant overexpression of MAGEA4 and TWIST1 was detected in ESCC in significant correlation with each other in different clinicopathological indices of poor prognosis (P < 0.05). The TWIST1-expressing cells showed significantly higher MAGEA4 expression compared to control cells. ChIP and luciferase assays results confirmed indirect binding of TWIST1 to the E-boxes of MAGEA4 promoter sequence and revealed a novel regulatory role of TWIST1 in MAGEA4 upregulation.

Conclusion: Since MAGEA4 is a highly expressed oncogene in a variety of malignancies in significant correlation with tumor cell invasiveness and aggressiveness, our finding may help understand one regulatory mechanism of increased expression in tumor cells. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mc.22541DOI Listing
March 2017

Applying Subtractive Hybridization Technique to Enrich and Amplify Tumor-Specific Transcripts of Esophageal Squamous Cell Carcinoma.

Pathol Oncol Res 2017 Apr 15;23(2):271-279. Epub 2016 Jul 15.

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Bu-Ali Sq, Khorasan Razavi, Mashhad, 9196773117, Iran.

Subtractive hybridization (SH) as an efficient and powerful approach can be applied to isolate differentially expressed transcripts as well as detect of involved mRNAs in various cellular processes, particularly diseases and malignancies. This procedure leads to the enrichment of specific low copy transcripts of tumor cells. Having developed a new approach for SH to isolate tumor specific transcripts, we facilitated discovery of uniquely expressed genes in esophageal squamous cell carcinoma (ESCC). Total RNA was extracted from the fresh tumoral and their adjacent normal tissues, and purified using the Switch Mechanism At the 5' end of Reverse Transcript (SMART) method. Following cDNA synthesis of normal mRNAs using magnetic beads, it was hybridized with tumor mRNAs. To enhance efficiency of subtraction, hybridization was repeated three rounds. Finally, amplification of subtracted tumor-specific transcripts was carried out using in vitro transcription. The subtracted tumoral mRNAs was analyzed quantitatively using real-time PCR for both tumor-specific and housekeeping genes. The subtracted mRNA was confirmed as tumor-specific mRNA pool using RT-PCR and quantitative real-time PCR assessment. The elevated level of tumor-specific transcripts such as MAGE-A4 and CD44 as well as declined copy number of housekeeping genes such as GAPDH, β actin and β2-microglobulin, were confirmed in subtracted tumoral mRNA. The presence of tumor genes was confirmed after the SH procedure. The designed SH method in combination with SMART technique can isolate and amplify high quality tumor-specific transcripts even from small amount of tumor tissues. Removal of common transcripts from the extracted tumoral mRNAs using SH, leads to the enrichment of tumor-specific transcripts. The isolated transcripts are of interest because of their probable roles in ESCC progression and development. In addition, these tumor-specific mRNAs can be applied for future vaccine cancer studies.
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http://dx.doi.org/10.1007/s12253-016-0090-5DOI Listing
April 2017

Matrix Metalloproteinase-13 - A Potential Biomarker for Detection and Prognostic Assessment of Patients with Esophageal Squamous Cell Carcinoma.

Asian Pac J Cancer Prev 2016 ;17(6):2781-5

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran E-mail :

Background: Matric metalloproteinase (MMP) 13 gene expression is increased in esophageal squamous cell carcinomas (ESCCs) and associated with increasing tumor invasion, lymph node involvement and decreased survival rates. Levels of the circulating enzyme may be elevated and used as a marker of tumor progression. In this study, clinical application of MMP-13 serum levels was evaluated for early detection, prediction of prognosis and survival time of ESCC patients.

Materials And Methods: Serum levels of MMP13 were determined by ELISA in 66 ESCC patients prior of any treatment and 54 healthy controls for comparison with clinicopathological data through statistical analysis with Man Whitney U and Log-Rank tests. In addition, clinical value of MMP13 levels for diagnosis was evaluated by receiver operating characteristic (ROC) test.

Results: The serum level of MMP-13 in patients (>250 pg/ml) was significantly higher than in the control group (<100 pg/ml) (p value=0.004). Also the results showed a significant correlation between MMP-13 serum levels with tumor stage (p value = 0.003), depth of tumor invasion (p value=0.008), involvement of lymph nodes (p value = 0.011), tumor size (p value = 0.018) and survival time. While there were no significant correlation with grade and location of tumors. ROC analysis showed that MMP-13 level is an accurate diagnostic marker especially to differentiate pre-invasive/ invasive lesions from normal controls (sensitivity and specificity: 100%).

Conclusions: These findings indicate a potential clinical significance of serum MMP13 measurement for early detection and prognostic assessment in ESCC patients.
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January 2017

Correlation Between Meis1 and Msi1 in Esophageal Squamous Cell Carcinoma.

J Gastrointest Cancer 2016 Sep;47(3):273-7

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Purpose: Homeobox (HOX) transcription factors are critical regulators of cell fate, stem cell functions, and gastrointestinal development. They require three-amino acid loop extension (TALE) homeodomain proteins such as Meis1 to enhance their transcriptional efficiencies. There are complicated associations between different signaling pathways such as the Wnt and NOTCH and tumor progression. It has been investigated that GSK-3 as an important component of the Wnt pathway facilitates the expression of HOX target genes. Therefore, in the present study, we assessed the probable correlation between Wnt, NOTCH, and HOX genes in esophageal squamous cell carcinoma (ESCC) progression and metastasis through the correlational study between the Msi1 as an important activator for both of the NOTCH and Wnt pathways and Meis1.

Methods: Levels of Meis1 and Msi1 messenger RNA (mRNA) expression in 51 ESCC patients were compared to the normal tissues using real-time polymerase chain reaction.

Results: Only 3 out of 51 (5.9 %) cases had Meis1/Msi1 overexpression and also 3/51 (5.9 %) cases had Meis1/Msi1 underexpression. There was a significant correlation between the Msi1 and Mesi1 mRNA expression (p = 0.037). All of the Msi1/Meis1 underexpressed tumors were poorly differentiated (p = 0.003). Meis1 under/Msi1 overexpressed cases also were in T3 tumor depth of invasion (p = 0.019). And there was a significant correlation between the Msi1/Meis1 underexpression and gender (p = 0.045).

Conclusions: Our results show that Meis1 may have a positive feedback with Msi1 during the ESCC progression.
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http://dx.doi.org/10.1007/s12029-016-9824-6DOI Listing
September 2016

Lung-derived innate cytokines: new epigenetic targets of allergen-specific sublingual immunotherapy.

Iran J Basic Med Sci 2016 Jan;19(1):64-71

Immunology Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Sublingual allergen-specific immunotherapy is a safe and effective method for treatment of IgE-mediated respiratory allergies; however, the underlying mechanisms are not fully understood. This study was planned to test whether sublingual immunotherapy (SLIT) can exert epigenetic mechanisms through which the airway allergic responses can be extinguished.

Materials And Methods: BALB/c mice were sensitized intraperitoneally and challenged intranasally. Then, they received sublingual treatment with recombinant Che a 2 (rChe a 2), a major allergen of Chenopodium album. After SLIT, allergen-specific antibodies in sera, cytokine profiles of spleen cell cultures, mRNA and protein expression of lung-derived IL-33, IL-25, and TSLP (thymic stromal lymphopoietin), and histone modifications of these three genes were assessed.

Results: Following Immunotherapy, systemic immune responses shifted from Th2 to Th1 profile as demonstrated by significant decrease in IgE and IL-4 and substantial increase in IgG2a and IFN-γ. At local site, mRNA and protein levels of lung-derived pro-inflammatory cytokines IL-33 and TSLP were markedly down-regulated following SLIT that was associated with marked enrichment of trimethylated lysine 27 of histone H3 at promoter regions of these two cytokines.

Conclusion: In our study, sublingual immunotherapy with recombinant allergen effectively attenuated allergic immune responses, at least partly, by induction of distinct histone modifications at specific loci. Additionally, the lung-derived pro-allergic cytokines IL-33 and TSLP could be promising mucosal candidates for either monitoring allergic conditions or therapeutic approaches.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823618PMC
January 2016

Role of Oxidative Stress in Modulating Unfolded Protein Response Activity in Chronic Myeloid Leukemia Cell Line.

Iran Biomed J 2016 3;20(1):63-7. Epub 2015 Oct 3.

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Unlabelled: Recently, it has been revealed that tyrosine kinase inhibitors (TKIs) act through inducing both oxidative and endoplasmic reticulum (ER) stress in chronic myeloid leukemia cells. However, ER stress signaling triggers both apoptotic and survival processes within cells. Nevertheless, mechanisms by which TKIs avoid the pro-survival effects are not clear. The aim of this study was to evaluate the potential role of oxidative stress in activity of unfolded protein response (UPR) survival pathway within K562 cell line.

Methods: The expression of UPR survival target genes, Xbp1, and Grp94 (glucose requiring protein 94) was studied in single and combined exposure to oxidative and ER stress in K562 cell line by quantitative and qualitative PCR.

Results: The expression of UPR-related survival gene Grp94 was hampered by exposing to oxidative stress in cell induced with ER stress.

Conclusion: Interaction of oxidative and ER stress may role as a mediator influencing UPR signaling activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689283PMC
http://dx.doi.org/10.7508/ibj.2016.01.009DOI Listing
September 2016

Diabetes in Pregnancy Adversely Affects the Expression of Glycogen Synthase Kinase-3β in the Hippocampus of Rat Neonates.

J Mol Neurosci 2015 Oct 5;57(2):273-81. Epub 2015 Aug 5.

Medical Genetics Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran.

Diabetes during pregnancy causes a wide range of neurodevelopmental and neurocognitive abnormalities in offspring. Glycogen synthase kinase-3 (GSK-3) is widely expressed during brain development and regulates multiple cellular processes, and its dysregulation is implicated in the pathogenesis of diverse neurodegenerative and psychological diseases. This study was designed to examine the effects of maternal diabetes on GSK-3β messenger RNA (mRNA) expression and phosphorylation in the developing rat hippocampus. Female rats were maintained diabetic from a week before pregnancy through parturition, and male offspring was killed immediately after birth. We found a significant bilateral upregulation of GSK-3β mRNA expression in the hippocampus of pups born to diabetic mothers at P0, compared to controls. Moreover, at the same time point, there was a marked bilateral increase in the phosphorylation level of GSK-3β in the diabetic group. Unlike phosphorylation levels, there was a significant upregulation in hippocampal GSK-3β mRNA expression in the insulin-treated group, when compared to controls. The present study revealed that diabetes during pregnancy strongly influences the regulation of GSK-3β in the right/left developing hippocampi. These dysregulations may be part of the cascade of events through which diabetes during pregnancy affects the newborn's hippocampal structure and function.
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http://dx.doi.org/10.1007/s12031-015-0617-3DOI Listing
October 2015

Evaluation of thymic stromal lymphopoietin (TSLP) and its correlation with lymphatic metastasis in human gastric cancer.

Med Oncol 2015 Aug 15;32(8):217. Epub 2015 Jul 15.

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Bu-Ali square, 9196773117, Mashhad, Iran.

Thymic stromal lymphopoietin (TSLP) is an IL-7-like type 1 inflammatory cytokine that is mainly produced by epithelial cells in the skin, lungs, thymus, and gastrointestinal tract. This cytokine is a master regulator involved in T helper 2 cell-type inflammation immune responses. Various cell types, including T, B, mast, dendritic, and cancer or cancer-associated cells, are activated via TSLP. TSLP expression is also associated with various human cancers and produced by Helicobacter pylori-infected human gastric epithelial cells. TSLP is a multi-functional protein that can act as both an oncogene and a tumor suppressor. The aim of this study was to examine the role of TSLP in the progression of gastric cancer (GC) and its correlation with clinicopathological features in GC patients. Because of the relationship between H. p ylori infection and GC, we also examined gastric tissue specimens for H. p ylori DNA. In this study, fresh tumoral tissues and distant tumor-free samples from 50 GC patients were assessed for TSLP mRNA expression by quantitative real-time PCR. The GC samples were also assessed for H. p ylori DNA using primers specific for H. p ylori 16S rRNA and the UreC genes by PCR. TSLP mRNA was overexpressed in 20 of the 50 (40%) GC samples relative to their corresponding normal tissues. TSLP overexpression was significantly correlated with tumor cell metastasis to lymph nodes. Of the 20 patients with TSLP overexpression, 17 (85.0%) had metastasis to lymph nodes (p = 0.023). In addition, the presence of H. p ylori was confirmed by PCR in 22 of the 50 (44%) cases and 10 (50%) of the 20 TSLP overexpressors. We show that human GC cells produce TSLP and a significant correlation was seen between TSLP overexpression and GC metastasis to lymph nodes. This is the first report to indicate that TSLP may play a role in lymph node involvement in GC patients.
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http://dx.doi.org/10.1007/s12032-015-0653-4DOI Listing
August 2015

Expression analysis of CD44 isoforms S and V3, in patients with esophageal squamous cell carcinoma.

Iran J Basic Med Sci 2015 Apr;18(4):380-4

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: CD44 is a member of the cell adhesion molecules family. Naturally, CD44S, along with CD44V3 influence the cell motility, migration, and adhesion, while in tumor cells they lead to tumor invasion, progression, and metastasis. The purpose of this research is to evaluate the CD44S and CD44V3 expression in Esophageal Squamous Cell Carcinoma (ESCC) and to reveal their correlations with clinicopathological features of patients.

Materials And Methods: Fresh tumoral and distant tumor-free esophageal tissues were obtained from 50 patients with ESCC. Using quantitative real-time PCR, the expression levels of CD44S and CD44V3 were quantified and compared in both groups of cells. The patients had not received any therapeutic interference, such as chemotherapy or radiation, prior to sampling.

Results: Significant overexpression of CD44S and CD44V3 mRNA was observed in 13 (26.0%, P=0.03) and 11 (22.0%, P=0.007) tumor specimens, respectively. The expression of the genes were significantly correlated not only with each other (P=0.0001), but also with differentiation grade of tumor (P=0.033), stage of tumor progression (P=0.003), and depth of tumor invasion (P=0.00). In addition, low level of CD44V3 mRNA expression was attended to be associated with tumor invasion.

Conclusion: There is no correlation between CD44S expression with clinicopathological features of patients; however, simultaneous expression of these genes has an important effect on tumorigenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439453PMC
April 2015

Association of ADAM33 gene polymorphisms with allergic asthma.

Iran J Basic Med Sci 2014 Sep;17(9):716-21

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Asthma results from the interaction between genetic and environmental factors. ADAM33 gene on chromosome 20p13 is associated with asthma and airway hyperresponsiveness.

Materials And Methods: This is a case-control study, where four SNPs S1 (rs3918396), T1 (rs2280091), T2 (rs2280090), V4 (rs2787094) of ADAM33 gene have been assessed in patients with allergic asthma and normal controls (95 patients and 86 normal). Blood samples of these participants have been genotyped by PCR and the RFLP method.

Results: There was no association between asthmatic patients and polymorphisms of alleles, genotypes and haplotypes of the ADAM33 gene. When categorizing the asthmatic patients in severe, moderate and mild groups, associations in the subcategories of asthmatic patients were found. There were associations between polymorphisms of C allele of T1 SNP with severe asthmatic patients and G allele of V4 SNP with moderate asthmatics respectively (P=0.006, P=0.01). There was a significant association between sensitivity to mite and polymorphism of C allele of T1 SNP (P=0.02). Besides, there was a significant association between sensitivity to weeds and genotype GG of V4 SNP (P=0.05).

Conclusion: Polymorphisms of ADAM33 gene might be associated with severe asthma and sensitivity to aeroallergens in northeast of Iran, but further studies are needed to determine the polymorphisms in this area and other regions of our country.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322157PMC
September 2014

Idiopathic lymphocytopenia.

Curr Opin Hematol 2015 Jan;22(1):46-52

Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Purpose Of Review: Idiopathic CD4⁺ lymphocytopenia (ICL) is defined by the reduction of the main lymphocyte subtype in peripheral blood and CD4⁺ T cells below 300/μl in the absence of any secondary known causes of lymphopenia, including viral causes. The present review aims to state the latest available data on clinical, pathological and therapeutic aspects related to ICL, published from 1990 to 2014. The last observed clinical presentation and complications of ICL patients are described. The latest findings and possible mechanisms involved in the development of ICL features are included in the present review; however, pathogenesis of ICL has remained mainly obscured. Finally, recent therapeutic efforts considered in ICL patients are discussed.

Recent Findings: In spite of the serious complications ICL has on the patients' quality of life, data on clinical, etiopathological and therapeutic behavior for ICL are very limited. On one side, an abnormal blood cell count may be the sole presentation; however, occurrence of disseminated malignant tumors is not uncommon in patients. Recent findings highlight the role of cytokines, especially interleukin-2, on features such as phenotype severity and responsiveness of the condition to therapy. In addition, some studies have suggested that a defect in hematopoietic stem cells may be involved in disease progression, an idea that is supported by the success of bone marrow transplantation in acquiring persistent remissions in ICL patients.

Summary: ICL is a hematologic condition of increasing importance due to its diverse clinical and pathological spectrum. Molecular studies have shown the presence of mutations involved in lymphocyte development as potential factors that may contribute to ICL occurrence. ICL patients could present either with common infections or really serious malignant conditions. The role of cytokines, especially interleukin-2, has emerged as one of the main possible mechanisms involved in clinical and pathological behavior of ICL. Today, the main therapeutic approaches are controlling life-threatening infections and underlying disorders along with efforts to cure ICL through rising CD4⁺ cell counts using cytokine interventions and transplantation.
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http://dx.doi.org/10.1097/MOH.0000000000000102DOI Listing
January 2015

Neoantigen in esophageal squamous cell carcinoma for dendritic cell-based cancer vaccine development.

Med Oncol 2014 Oct 2;31(10):191. Epub 2014 Sep 2.

Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran.

Esophageal squamous cell carcinoma (ESCC) is a highly malignant tumor which usually is diagnosed in advanced stages due to its asymptomatic course of tumorigenesis. Current therapeutic modalities are not effective enough and the 5-year survival rate of the disease is still very low which prompts the urgent need for finding novel efficient therapeutic methods. In this study, we evaluated ex vivo immune response of ESCC patients against our newly designed chimeric construct consisting of highly immunogenic cancer-testis antigens. After confirming effective expression of the in vitro transcribed chimeric mRNA in ex vivo electroporated dendritic cells (DCs) of the ESCC patients, the patients' CTLs were primed by DCs and cytotoxicity assay was performed to evaluate how the primed CTLs can recognize and target the chimeric mRNA-loaded cells. The chimeric protein was strongly expressed relative to the housekeeping gene expression in electroporated cells. The cytotoxicity of the CTLs was significantly higher in DCs loaded with chimeric mRNAs compared to mock DCs (p<0.05) in all of the tested ESCC patients. We are introducing a novel construct that our functional study showed can stimulate and induce an effective immune response in ESCC patients. The designed chimeric mRNA-loaded DCs are capable of priming CTLs effectively and induce cytotoxicity against tumor. Therefore, loading DCs with chimeric epitopes of highly immunogenic antigens, such as cancer-testis antigens, are potentially interesting and effective therapeutic modalities for immunotherapy of ESCC.
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http://dx.doi.org/10.1007/s12032-014-0191-5DOI Listing
October 2014
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