Publications by authors named "Hossein Asgarian-Omran"

59 Publications

Lymphopenia and lung complications in patients with coronavirus disease-2019 (COVID-19): A retrospective study based on clinical data.

J Med Virol 2021 May 4. Epub 2021 May 4.

Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.

Background: A rapid outbreak of novel coronavirus, COVID-19, made it a global pandemic. This study focused on the possible association between lymphopenia and Computed tomography (CT) scan features and COVID-19 patient mortality.

Method: The clinical data of 596 COVID-19 patients were collected from February 2020 to September 2020. The patients' serological survey and CT scan features were retrospectively explored.

Results: The median age of the patients was 56.7±16.4 years old. Lung involvement was more than 50% in 214 COVID-19 patients (35.9%). The average blood lymphocyte percentage was 20.35 ±10.16 (normal range 20- 50%). While the levels of C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), were high in more than 80% of COVID-19 patients; CRP, ESR, and platelet-to-lymphocyte ratio (PLR) may not indicate the in-hospital mortality of COVID-19. Patients with severe lung involvement and lymphopenia were found to be significantly associated with increased odds of death (odds ratio [OR], 9.24; 95% confidence interval [95 CI%], 4.32- 19.78). These results indicated that lymphopenia <20% along with pulmonary involvement >50% impose a multiplicative effect on the risk of mortality. The in-hospital mortality rate of this group was significantly higher than other COVID-19 hospitalized cases. Furthermore, they meaningfully experienced a prolonged stay in the hospital (P= 0.00).

Conclusion: The Lymphocyte count less than 20% and chest CT scan findings with more than 50% involvement might be related to the patient's mortality. It could act as laboratory and clinical indicators of disease severity, mortality, and outcome. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jmv.27060DOI Listing
May 2021

Cytokine profiling in Iranian patients with COVID-19; association with clinical severity.

Iran J Immunol 2021 03;18(1):54-64

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Background: SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is recognized for the first time in Wuhan, China. The cytokine storm is a known factor causing major clinical symptoms leading to death in COVID-19 patients.

Objective: To investigate and compare the serum levels of different cytokines in COVID-19 patients with different clinical severity.

Methods: Concentrations of serum cytokines, including IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, and GM-CSF, were measured in 61 COVID-19 patients and 31 normal controls with ELISA. We investigated the correlation between the levels of these cytokines and clinical severity, CRP level, neutrophil and lymphocyte count in patients with COVID-19.

Results: Our data indicated that the levels of IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF, but not IL-10 were significantly increased in COVID-19 patients compared to normal controls. Statistical analysis showed that the level of IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF were higher in severe COVID-19 than those of mild cases. The concentrations of all mentioned cytokines were negatively associated with the absolute count of lymphocytes, and positively correlated with the CRP level and the absolute count of neutrophils.

Conclusion: The current study suggests that high levels of various cytokines correlate with the disease severity and immunopathogenesis of COVID-19.
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http://dx.doi.org/10.22034/iji.2021.87630.1810DOI Listing
March 2021

Protective efficacy by a novel multi-epitope vaccine, including MIC3, ROP8, and SAG1, against acute Toxoplasma gondii infection in BALB/c mice.

Microb Pathog 2021 Apr 3;153:104764. Epub 2021 Feb 3.

Toxoplasmosis Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

Toxoplasma gondii is an intracellular apicomplexan parasite, which can cause a serious infectious disease in pregnant women and immunocompromised individuals. Therefore, the development of a polyvalent vaccine consisting of all stages of the parasite life cycle using the epitopes from tachyzoites, bradyzoites, and sporozoites is likely to be required for complete protective immunity. In this study, we designed protein vaccine candidate based on the prediction of specific epitopes (i.e., B cell and T cell) from three Toxoplasma gondii antigens. The MRS protein (MIC3: 30-180, ROP8: 85-185, and SAG1: 85-235) was expressed in Escherichia coli, and purification was performed using a HisTrap HP column and then we evaluated immunogenicity and protective property in BALB/c mice. Seventy-two mice were randomly divided into six groups, including three vaccinations (i.e., MRS, MRS-Freund, and MRS-Calcium Phosphate Nanoparticles (MRS-CaPNs)) and three control (i.e., Phosphate-buffered saline, Freund, and CaPNs) groups. All groups were immunized three times via subcutaneous injection within three-week intervals. In the vaccination groups, the BALB/c mice were injected with 20 μg of MRS protein for the first time and 10 μg of MRS for the next two times. Antibodies, cytokines, and splenocytes proliferation in the immunized mice were assayed using the enzyme-linked immunosorbent assay. Protective efficacy was analyzed by challenging the immunized mice with T. gondii of RH strain. Antibody, cytokine, and lymphocyte proliferation assays showed that the mice immunized with MRS induced stronger humoral and T helper type 1 cell-mediated immune responses, compared to the control mice. However, co-immunization with adjuvants (i.e., Freund and CaNPs) resulted in impaired immune responses. Effective protection against the parasite achieved an increase in survival time in the immunized mice, especially in the MRS-CaNPs group. The obtained results of the present study demonstrated that multi-epitope protein vaccination, MRS, is a potential strategy against toxoplasmosis infection. In addition, the vaccine co-delivered with CaPNs could provide an important key for vaccine candidate to control T. gondii infection.
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http://dx.doi.org/10.1016/j.micpath.2021.104764DOI Listing
April 2021

The Radiosensitizing Effect of Olanzapine as an Antipsychotic Medication in Glioblastoma Cell.

Curr Radiopharm 2021 Jan 19. Epub 2021 Jan 19.

Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari. Iran.

Background: Radiotherapy is used as one of the most effective regimens for cancer treatment, while radioresistance is a major drawback in cancer treatment.

Objectives: The aim of this study was to evaluate the sensitizing effect of olanzapine (OLA) with X-ray on glioblastoma (U-87 MG) cells death.

Methods: The synergistic killing effect of OLA with ionizing radiation (IR) on glioma was evaluated by colony formation assay. The generations of reactive oxygen species (ROS) and protein carbonyl (PC) as oxidized protein were determined in OLA and irradiated cells.

Results: The results of this study showed that OLA reduced the number of colonies in irradiated glioma cells. OLA elevated ROS and PC levels in irradiated cells. The synergistic killing effect of OLA with IR in U-87 MG cell was observed at concentrations 1 µM and 20 µM of OLA. The maximum radiosensitizing effect of OLA was observed at concentration of 20 µM.

Conclusion: The present study demonstrates that OLA has radiosensitizing effect on cell death induced by IR in glioma cells.
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http://dx.doi.org/10.2174/1874471014666210120100448DOI Listing
January 2021

Immune evasion mechanisms in acute myeloid leukemia: A focus on immune checkpoint pathways.

Crit Rev Oncol Hematol 2021 Jan 18;157:103164. Epub 2020 Nov 18.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran; Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

Immune surveillance mechanisms comprising of adaptive and innate immune systems are naturally designed to eliminate AML development. However, leukemic cells apply various immune evasion mechanisms to deviate host immune responses resulting tumor progression. One of the recently well-known immune escape mechanisms is over-expression of immune checkpoint receptors and their ligands. Introduction of blocking antibodies targeting co-inhibitory molecules achieved invaluable success in tumor targeted therapy. Moreover, several new co-inhibitory pathways are currently studying for their potential impacts on improving anti-tumor immune responses. Although immunotherapeutic strategies based on the blockade of immune checkpoint molecules have shown promising results in a number of hematological malignances, their effectiveness in AML patients showed less remarkable success. This review discusses current knowledge about the involvement of co-inhibitory signaling pathways in immune evasion mechanisms of AML and potential application of immune checkpoint inhibitors for targeted immunotherapy of this malignancy.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103164DOI Listing
January 2021

Atorvastatin Sensitizes Breast and Lung Cancer Cells to Ionizing Radiation.

Iran J Pharm Res 2020 ;19(2):80-88

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Tumour cells may be resistant to radiotherapy that results in unsuccessful cancer treatment in patients. The aim of this study was to evaluate the sensitizing effect of atorvastatin (ATV) on breast cancer (MDA-MB-231) and non-small cell lung cancer (A-549) cells following exposure to ionizing radiation (IR). These cells were treated with ATV and exposed to X-ray at dose 4 Gy. The radiosensitizing effects of ATV were evaluated by flow cytometry and anti-proliferation assays. The production of reactive oxygen species (ROS) was determined in irradiated and treated cells with ATV. The findings of this study showed that ATV increased the percentage of apoptotic cells in irradiated breast and lung cancer cells. ATV exhibited anti-proliferative effect on cancer cells and increased cell death induced by IR. ATV increased ROS production in irradiated cells. The present study demonstrates that ATV has radiosensitizing effect on breast and lung cancer cells through increasing apoptosis, ROS production and cell death induced by IR.
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http://dx.doi.org/10.22037/ijpr.2020.15487.13126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667559PMC
January 2020

Expression Analysis of Fyn and Bat3 Signal Transduction Molecules in Patients with Chronic Lymphocytic Leukemia.

Asian Pac J Cancer Prev 2020 Sep 1;21(9):2615-2621. Epub 2020 Sep 1.

Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.

Background: Chronic lymphocytic leukemia (CLL) is correlated with defects in T-cell function resulting imparity in antitumor immune responses. Tim-3 is a co-inhibitory immune checkpoint receptor expressed on exhausted T-cells during tumor progression. Fyn and Bat3 are two important adaptor molecules involved in inhibition and activation of Tim-3 downstream signaling, respectively. In this study, the expression of Tim-3, Fyn, and Bat3 mRNA was evaluated in CLL patients.

Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 54 patients with CLL and 34 healthy controls. Total RNA was extracted from all samples and applied for cDNA synthesis. The relative expression of Tim-3, Fyn, and Bat3 mRNA was determined by TaqMan Real-Time PCR using GAPDH as an internal control.

Results: Tim-3 mRNA expression was not significantly different between CLL patients and healthy controls. Fyn mRNA expression was significantly lower in CLL patients and conversely, Bat3 mRNA expression was higher in CLL patients compared to healthy controls. Interestingly, the mRNA expression of Fyn inhibitory adaptor molecule was remarkably associated with expression of Tim-3 in CLL patients.

Conclusion: We have highlighted for the first time the expression of Fyn and Bat3 adaptor molecules in CLL patients. Our data demonstrated the strong correlation between the expression of Tim-3 and Fyn inhibitory molecules in CLL implying an important role for Tim-3-Fyn cooperation in induction of T-cell exhaustion.
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http://dx.doi.org/10.31557/APJCP.2020.21.9.2615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779459PMC
September 2020

Apoptosis and immunophenotyping of peripheral blood lymphocytes in Iranian COVID-19 patients: Clinical and laboratory characteristics.

J Med Virol 2021 03 28;93(3):1589-1598. Epub 2020 Sep 28.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

A novel member of human coronavirus, named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been recently recognized in China and rapidly spread worldwide. Studies showed the decreasing of peripheral blood lymphocytes in a majority of patients. In this study, we have reported the clinical features, laboratory characteristics, the frequency of peripheral blood lymphocyte subpopulations, and their apoptosis pattern in Iranian coronavirus infectious disease (COVID-19) patients. Demographic and clinical data of 61 hospitalized confirmed cases with COVID-19 at Imam Khomeini Hospital were collected and analyzed. Peripheral blood mononuclear cells were isolated from all samples and the apoptosis pattern was evaluated using Annexin V/propidium iodide method. The frequency of lymphocyte subsets, including T-CD4 , T-CD8 , NK, B cells, and monocytes, was measured in all patients and 31 controls by flow cytometry. Our findings demonstrated that the percentage of lymphocytes, CD4 , and CD8 T cells were decreased in COVID-19 patients compared with the control group. Regarding the clinical severity, the number of lymphocytes, CD4 , CD8 T cells, and NK cells were also decreased in severe cases when compared with mild cases. Finally, our data have also indicated the increase in apoptosis of mononuclear cells from COVID-19 patients which was more remarkable in severe clinical cases. The frequency of immune cells is a useful indicator for prediction of severity and prognosis of COVID-19 patients. These results could help to explain the immunopathogenesis of SARS-CoV-2 and introducing novel biomarkers, therapeutic strategies, and vaccine candidates.
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http://dx.doi.org/10.1002/jmv.26505DOI Listing
March 2021

Blockade of PD-1 and TIM-3 immune checkpoints fails to restore the function of exhausted CD8 T cells in early clinical stages of chronic lymphocytic leukemia.

Immunol Res 2020 10;68(5):269-279

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Blocking antibodies targeting immune checkpoint molecules achieved invaluable success in tumor therapy and amazing clinical responses in a variety of cancers. Although common treatment protocols have improved overall survival in patients with chronic lymphocytic leukemia (CLL), they continue to relapse and progress. In the present in vitro study, the application of anti-PD-1 and anti-TIM-3 blocking antibodies was studied to restore the function of exhausted CD8 T cells in CLL. CD8 T cells were isolated from peripheral blood of 20 patients with CLL, treated with blocking antibodies, and cocultured with mitomycin-frozen non-CD8 T cell fraction as target cells. Cultures were stimulated with anti-CD3/CD28 antibodies to assess the proliferation of CD8 T cells by MTT and stimulated with PMA/ionomycin to measure the levels of CD107a expression and cytokine production by flow cytometry and ELISA, respectively. Our results showed that the blockade of PD-1 and TIM-3 does not improve the proliferation of CD8 T cells in CLL patients. No significant difference was found between control and blocked groups in terms of degranulation properties and production of IFN-γ, TNF-α, IL-2, and IL-10 by CD8 T cells. We observed that pre-treatment of CD8 T cells with blocking antibodies in CLL patients at early clinical stages had no effects on restoring their functional properties. Further in vitro and in vivo complementary studies are required to more explore the utility of checkpoint inhibitors for CLL patients.
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http://dx.doi.org/10.1007/s12026-020-09146-4DOI Listing
October 2020

Expression patterns of seven key genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a and miR-93 in gastric cancer.

Sci Rep 2020 07 23;10(1):12342. Epub 2020 Jul 23.

Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran.

Gastric cancer (GC) is one of the most prevalent cancers and a major cause of cancer related mortality worldwide. Incidence of GC is affected by various factors, including genetic and environmental factors. Despite extensive research has been done for molecular characterization of GC, it remains largely unknown. Therefore, further studies specially conducted among various ethnicities in different geographic locations, are required to know the precise molecular mechanisms leading to tumorigenesis and progression of GC. The expression patterns of seven candidate genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a, and miR-93 were determined in 24 paired GC tissues and corresponding non-cancerous tissues by quantitative Real-Time PCR. The association between the expression of these genes and clinicopathologic factors were also investigated. Our results demonstrated that overall mRNA levels of GATA6 were significantly decreased in the tumor samples in comparison with the non-cancerous tissues (median fold change (FC) = 0.3143; P = 0.0003). Overall miR-93 levels were significantly increased in the tumor samples relative to the non-cancerous gastric tissues (FC = 2.441; P = 0.0002). β-catenin mRNA expression showed a strong positive correlation with miR-34a (r = 0.5784; P = 0.0031), and miR-181a (r = 0.5652; P = 0.004) expression. miR-34a and miR-181a expression showed a significant positive correlation (r = 0.4862; P = 0.016). Moreover, lower expression of Notch1 was related to distant metastasis in GC patients with a borderline statistical significance (p = 0.0549). These data may advance our understanding of the molecular biology that drives GC as well as provide potential targets for defining novel therapeutic strategies for GC treatment.
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http://dx.doi.org/10.1038/s41598-020-69308-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378835PMC
July 2020

Fluoxetine as an antidepressant medicine improves the effects of ionizing radiation for the treatment of glioma.

J Bioenerg Biomembr 2020 06 13;52(3):165-174. Epub 2020 May 13.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Radiotherapy is a cancer treatment protocol which delivers high dose of ionizing radiation (IR) to tumor. Tumor resistance and side effects induced by IR still are the major challenges in radiotherapy. The purpose of this study was to evaluate the synergistic killing effect of fluoxetine (FL) with IR on glioma cancer cell (U-87 MG), as well as radioprotective effect of FL against cellular toxicity induced by IR on non-malignant human fibroblast cell (HFFF2). Firstly, the inhibitory effects of FL on cell proliferations were evaluated in U-87 MG and HFFF2 cells. The clonogenic and MTT assays were used to evaluate the radiosensitivity and radioprotective effects of FL on cancer and non-malignant cells. The frequencies of apoptotic cells were evaluated by flow cytometry on both cancer and normal cells. Results showed that FL exhibited anti-cancer effect on glioma cells, while cellular toxicity was low in HFFF2 cells treated with FL. FL decreased the viable colonies and enhanced apoptotic cells when U-87 cells were treated with FL prior irradiation. For comparison, FL exhibited radioprotective effect through increasing cellular proliferation rate and reducing apoptosis in HFFF2 cells against IR. The results showed that FL enhanced the IR-induced glioma cancer cell death and apoptosis, whereas it exhibited a radioprotective effect on normal fibroblast cells suggesting that FL administration may improve glioma radiotherapy.
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http://dx.doi.org/10.1007/s10863-020-09833-9DOI Listing
June 2020

Cellular apoptosis: An alternative mechanism of action for caspofungin against .

Curr Med Mycol 2019 Jun;5(2):9-15

Invasive Fungi Research Center, Mazandaran University of Medical Sciences, Sari, Iran.

Background And Purpose: Although the mechanism of action for echinocandins is known, the physiological mechanisms by which these antifungal agents cause cell death via the classical apoptotic pathways are not well-defined yet. Regarding this, the present study aimed to evaluate the mechanisms of caspofungin-induced cell death.

Materials And Methods: For the purpose of the study, the minimum inhibitory concentration (MIC) of caspofungin against (ATCC 90030) was determined using the broth microdilution reference method (CLSI M27-A2 and M27-S4). The annexin V and propidium iodide staining was performed to determine the way through which caspofungin acts against (i.e., through the induction of apoptosis and/or necrosis). Additionally, the possible effect of caspofungin on inducing the expression of two apoptotic genes, namely and was studied using the real-time polymerase chain reaction assay.

Results: According to the obtained MIC value (0.5 µg/mL), exposed to 0.25, 0.5, and 1 µg/mL of caspofungin, exhibited the features of late apoptosis/necrosis after 18 h of incubation. Furthermore, the use of 0.25, 0.5, and 1 µg/ml caspofungin induced apoptosis (early/late) in 14.67%, 17.04%, and 15.89% of the cells, respectively. The results showed a significant difference between the percentages of early-apoptotic cells at the three concentrations (). In addition, the rate of necrosis was significantly greater than that of apoptosis in response to caspofungin. Accordingly, necrosis occurred in 71.26%, 71.26%, and 61.26% of the cells at the caspofungin concentrations of 0.25, 0.5, and 1 µg/mL, respectively (<). The analysis of the data in the REST software demonstrated a significant increase in the expression of and genes ().

Conclusion: As the findings of the present study indicated, caspofungin promoted both necrosis and apoptosis of cells at concentrations higher than or equal to the MIC value.
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http://dx.doi.org/10.18502/cmm.5.2.1155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626714PMC
June 2019

Correction to: The synergistic effect of mefenamic acid with ionizing radiation in colon cancer.

J Bioenerg Biomembr 2019 Aug;51(4):311

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

The original version of this article unfortunately contained a mistake. The name of "Zohreh Noaparast" is now corrected in the author group of this article.
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http://dx.doi.org/10.1007/s10863-019-09803-wDOI Listing
August 2019

Protective efficacy induced by DNA prime and recombinant protein boost vaccination with Toxoplasma gondii GRA14 in mice.

Microb Pathog 2019 Sep 15;134:103601. Epub 2019 Jun 15.

Department of Medical Parasitology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; National Institutes for Medical Research Development (NIMAD), Tehran, Iran. Electronic address:

Toxoplasma gondii, the etiological agent of toxoplasmosis, can cause severe or lethal damages in both animals and man. So, tends to develop a more effective vaccine to prevent this disease is extremely needed and would be so prominent. The novel dense granule antigen 14 (GRA14) has been identified as a potential vaccine candidate against T. gondii infection. The aim of this study was evaluation of protective immunity induced by prime/boost vaccination strategy of GRA14 antigen with calcium phosphate (CaPNs) or Aluminum hydroxide (Alum) nano-adjuvants in BALB/c mice. The finding showed that immunization with the prime-boost strategy using plasmid DNA (pcGRA14) and recombinant protein (rGRA14) with nano-adjuvants significantly elicited levels of specific IgG antibodies and cytokines against T. gondii infection. Given that, there were the high levels of total IgG, IgG2a, IFN-γ in mice of rGRA14-CaPNs and pcGRA14 + rGRA14-CaPNs groups, which indicating a Th-1 type response. While immunization of mice with Alum based rGRA14 and pcGRA14 + rGRA14 elicited specific IgG1 and IL-4 levels, which was confirmed a Th-2 type response. Mice immunized with DNA prime-protein boost vaccine with nano-adjuvants produce more vigorous specific lymphoproliferative responses than mice immunized with other antigen formulations. In addition, the CaPNs-based prime-boost vaccine of pcGRA14 + rGRA14 showed the longest survival time in mice and the lowest parasitic load in their brain tissue compared to the other groups. The results obtained in this study show that the use of GRA14 based DNA prime-protein boost vaccination regime with CaPNs can dramatically enhanced both humoral and cellular immune responses. Therefore, this strategy can provide a promising approach to the development of an effective vaccine against T. gondii infection in the future.
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http://dx.doi.org/10.1016/j.micpath.2019.103601DOI Listing
September 2019

Expression analysis of PD-1 and Tim-3 immune checkpoint receptors in patients with vitiligo; positive association with disease activity.

Exp Dermatol 2019 06;28(6):674-681

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

The contribution of immune checkpoint receptors in the immunopathogenesis of various autoimmune diseases has been addressed in previous reports. In this study,  the expression profile of T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) checkpoint molecules was investigated in CD8 T cells of Vitiligo patients. The association of Tim-3 and PD-1 expression with disease activity was also explored. The frequency of Tim-3 /PD-1 /CD8 T cells in 30 patients with vitiligo and 30 sex- and age-matched controls was determined by flow cytometry. CD8 T cells were then positively isolated by magnetic beads, and the mRNA expression of PD-1 and Tim-3 was determined by TaqMan-based real-time PCR. To measure the cytokines production, PBMCs were stimulated with PMA/ionomycin and concentrations of IL-4, IFN-γ and TNF-α were measured in culture supernatants by ELISA. Disease activity of patients with vitiligo was determined using the Vitiligo Area Severity Index. Patients with vitiligo have significantly shown more expression of Tim-3 and PD-1 on their CD8 T cells compared with controls. Expression analysis of Tim-3 mRNA, but not PD-1, confirmed the results obtained from flow cytometry. While the production levels of TNF-α and IFN-γ were found higher by patients with vitiligo, IL-4 production was lower in patients compared with controls. A direct association was observed between the Tim-3 and PD-1 expression and also the production of pro-inflammatory cytokines with disease activity of patients with vitiligo. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of CD8 T cells in vitiligo and may introduce as potential biomarkers for disease progression and targeted immunotherapy.
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http://dx.doi.org/10.1111/exd.13952DOI Listing
June 2019

In vitro and in vivo evaluation of kojic acid against Toxoplasma gondii in experimental models of acute toxoplasmosis.

Exp Parasitol 2019 May 20;200:7-12. Epub 2019 Mar 20.

Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; Department of Parasitology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

As current toxoplasmosis chemotherapies have many side effects along with toxicity on patients, we examined the anti-Toxoplasma effect of a biologically important natural antibiotic, kojic acid, in vitro and in vivo. Vero cells were incubated with different concentrations of kojic acid or pyrimethamine (positive control), and the cellular viability was determined. Next, Vero cells were infected with T. gondii (RH strain) and treated with drugs. Then, we calculated the infection index, T. gondii intracellular proliferation and the number and measure of plaque. Moreover, the effect of kojic acid on survival times, serum levels of IFN-γ and TNF-α and histopathological changes in the liver and spleen of Balb/c mice infected with T. gondii were determined. Kojic acid reduced the infection index, intracellular proliferation, the number and measure of plaque in vitro when compared to untreated infected cells. Kojic acid (100 mg/kg/day) also showed a better survival rate than infected untreated control mice (P < 0.05). IFN-γ and TNF-α secretions were significantly increased by kojic acid treatment in comparison to untreated groups (P < 0.05). In addition, its inhibitory effects on inflammatory alterations, apoptosis, and necrosis have been shown in sections of liver and spleen. We conclude that kojic acid exhibit potent anti-Toxoplasma activity with direct and indirect effects on the parasite, although further studies are needed before consideration of clinical trials.
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http://dx.doi.org/10.1016/j.exppara.2019.03.009DOI Listing
May 2019

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia.

Oncol Res Treat 2019 14;42(4):202-208. Epub 2019 Mar 14.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran,

Background: In this study, the expression pattern of NKp30 and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3), as candidates for activating and inhibitory receptors of NK cells, were evaluated in patients with chronic lymphocytic leukemia (CLL).

Patients And Methods: 24 CLL patients and 19 healthy controls were enrolled. Fresh peripheral blood was collected from all subjects and stained with fluorochrome-conjugated antibodies. The frequency of CD56+/CD3-/NKp30+ and CD56+/CD3-/Tim-3+ cells was determined by multicolor flow cytometry.

Results: Our results revealed that Tim-3 is significantly upregulated on natural killer (NK) cells of CLL patients in comparison to healthy controls. NK cells of CLL patients showed lower expression of NKp30-activating receptor compared to controls. Tim-3 expression pattern on NK cells of CLL patients was correlated with poor prognostic factors including low hemoglobin level, high absolute lymphocyte count, and high serum C-reactive protein level.

Conclusion: Dysregulated expression of Tim-3 and NKp30 receptors confirms the exhaustion state of NK cells in CLL. Our data introduce Tim-3 as a promising biomarker and potential target for immunotherapy of CLL.
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http://dx.doi.org/10.1159/000497208DOI Listing
September 2019

The synergistic effect of mefenamic acid with ionizing radiation in colon cancer.

J Bioenerg Biomembr 2019 06 7;51(3):249-257. Epub 2019 Mar 7.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Despite radiotherapy is an effective regimen in cancer treatment, resistance to tumor therapy still is a major challenge to radiotherapy and results in cancer recurrence and metastasis. Then the sensitization of tumor cells to ionizing radiation (IR) would be beneficial in cancer treatment. The aim of this study was to evaluate the synergistic effect of mefenamic acid (MEF) on colon cancer cell (HT-29) exposure to IR. HT-29 cells were treated with MEF and then exposed to IR. The synergistic effect of MEF is evaluated by clonogenic assay and flow cytometry. The productions of reactive oxygen species (ROS) were determined in irradiated and treated cells with MEF. The findings of this study showed that MEF had anti-cancer effect on colon cancer cell line and it increased the apoptosis in irradiated HT-29 cells. Also MEF reduced the number of cell colonies when HT-29 cells pre-treated with MEF and irradiated. MEF increased ROS production in irradiated cells. This additive effect of MEF with IR in killing of HT-29 cell was observed at low (10 μM) and medium (100 μM) concentrations of MEF. The present study demonstrates that MEF to be an additive effect on apoptosis and cell death induced by IR in colon cancer cells.
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http://dx.doi.org/10.1007/s10863-019-09792-wDOI Listing
June 2019

Prevalence of specific immunoglobulin E and G against in patients with asthma.

Curr Med Mycol 2018 Dec;4(4):7-11

Invasive Fungi Research Centre, Mazandaran University of Medical Sciences, Sari, Iran.

Background And Purpose: as a ubiquitous fungus can be found in the respiratory tract of the asthmatic and healthy people. The inhalation of spores leads to an immune response in individuals with asthma and results in the aggravation of the clinical symptoms. The present study aimed to investigate the prevalence of specific immunoglobulin E and G IgE and IgG) against in asthmatic patients.

Materials And Methods: This study was conducted on 200 consecutive patients with moderate to severe asthma referring to Masih Daneshvari hospital Tehran, Iran, from January 2016 to February 2018. Skin prick test (SPT) was performed in all subjects with allergens. Moreover, all patients underwent specific IgE testing for using Hycor method. Enzyme immune assay was applied to measure total IgE and specific IgG.

Results: According to the results, the mean age of the patients was 45.8 years (age range: 18-78 years). The mean levels of total IgE and specific IgE in asthmatic patients were obtained as 316.3 (range: 6-1300 IU/ml) and 1.5 (range: 0.1-61.3 IU/ml), respectively. Out of 200 patients, 27 (13.5%), 65 (32.5%), 22 (11.0%), and 86 (43.0%) cases had positive SPT, total IgE of > 417 IU/ml, specific IgE, and IgG, respectively. The level of these variables in patients with severe asthma were 16 (16.5%), 36 (37.1%), 15 (15.5%), and 46 (47.4%), respectively.

Conclusion: As the findings indicated, reactivity to is a remarkable phenomenon in asthmatic patients. It is also emphasised that the climatic condition may affect the positive rate of hypersensitivity to .
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http://dx.doi.org/10.18502/cmm.4.4.380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386509PMC
December 2018

Effects of vitamin D supplements on frequency of CD4 T-cell subsets in women with Hashimoto's thyroiditis: a double-blind placebo-controlled study.

Eur J Clin Nutr 2019 09 29;73(9):1236-1243. Epub 2019 Jan 29.

Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Background: Vitamin D is a modulator of immune functions. Investigations on the mechanisms of vitamin D action and pathogenesis of Hashimoto's thyroiditis (HT) have revealed that vitamin D can reduce damages to thyroid cells caused by autoreactive immune cells.

Methods: Totally, 48 female patients with HT disease were introduced to the study by endocrinologists. Patients were divided into two major groups of 24 individuals and treated weekly with 50,000 IU of cholecalciferol (vitamin D group) or placebo (placebo group) using oral administration for 3 months. Eventually, 17 of the 24 patients in each group finished the study. Before and after supplementation, frequencies of Th1, Th17, Th2 and Tr1 cells and mean fluorescent intensity (MFI) of the associated cytokines, including IFN-γ, IL-17, IL-4 and IL-10, were assessed using flow cytometry. Furthermore, gene expression of IL-10 was assessed using real-time PCR.

Results: Results of this study showed that cholecalciferol supplementation caused a significant decrease in Th17/Tr1 ratio. The proportion and MFI of Th1, Th2, Tr1 and Th17 cells included no significant changes in vitamin D group, compared to those in placebo group. Expression rate and MFI of IL-10 increased in both groups. This increase was higher in vitamin D group than placebo group with no significance.

Conclusions: In this novel preliminary clinical trial study, supplementation with cholecalciferol in HT patients for 3 months changed the balance of CD4 T-cell subsets to improve the disease control. However, further studies are necessary to investigate effects of vitamin D on immune functions in HT patients.
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http://dx.doi.org/10.1038/s41430-019-0395-zDOI Listing
September 2019

Elevated Expression of Tim-3 and PD-1 Immune Checkpoint Receptors on T-CD4+ Lymphocytes of Patients with Asthma.

Iran J Allergy Asthma Immunol 2018 Dec 2;17(6):517-525. Epub 2018 Dec 2.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran AND Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Asthma is a chronic disorder of the airways characterized by reversible airflow obstruction, inflammation and bronchial hyperresponsiveness. Different immune cells and molecules have been attributed to involve in pathogenesis of asthma. In the current case-control study, the expression of T cell Ig and mucin domain-containing molecule-3 (Tim-3) and programmed death-1 (PD-1) was studied on CD4+ T cells of patients with asthma and normal controls. The frequency of Tim-3+/PD-1+/CD4+ T cells was determined by a three color flow cytometry method in 37 patients with asthma and 32 healthy controls. To evaluate the Th1/Th2 ratio, peripheral blood mononuclear cells were isolated from all samples and stimulated with phorbol 12- myristate 13- acetate ( PMA)/ionomycin for 18 h. IFN-γ) and Interleukin-4 (IL-4) were measured in culture supernatants by-(ELISA). Serum total immunoglobulin E (IgE) was also measured in all samples. Significant increase in percentage and absolute count of Tim-3+/PD-1+/CD4+, Tim-3+/CD4+ and PD-1+/CD4+ T cells was found in asthmatic patients compared to healthy controls (p=0.02 and p=0.003, respectively). The IFN-γ/IL-4 ratio (Th1/Th2 ratio) was significantly higher in healthy controls than that of asthmatic patients (p=0.029). Our data regarding the increased expression of PD-1 and Tim-3 on CD4+ T cells of patients with asthma suggest the potential roles of these immune checkpoint receptors in immune dys-regulation of asthma.
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December 2018

Anti-inflammatory effects of the Portulaca oleracea hydroalcholic extract on human peripheral blood mononuclear cells.

Med J Islam Repub Iran 2018 3;32:80. Epub 2018 Sep 3.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

, known as Purslane, is an annual growing herb with wide distribution around the world and traditionally used to manage several diseases. Different therapeutic properties as an anti-fever agent as well as anti-inflammatory and analgesic effects have been attributed to . The aim of this study was to investigate the effects of aerial extract on production of pro- and anti-inflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). Aerial parts of (stems and leaves) were collected and extracted by percolation using methanol. The optimal and non-cytotoxic dose of hydro-alcoholic extract for cell culture analysis was determined by MTT assay. To assess the antiinflammatory effects of , PBMCs obtained from 12 normal volunteers were cultured in RPMI complete medium and cotreated with E. coli lipopolysaccharide (LPS) and hydro-alcoholic extract. Following 18-hour incubation, culture supernatants were harvested for measurement of secreted TNF-α, IL-6 and IL-10 by ELISA. Statistical analyses were performed using the SPSS v.20, and data analyzed by Kolmogorov-Smirnov, Mann-Whitney U, Kruskal-Wallis and post Hoc tests. P-values<0.05 were considered significant. The optimal non-cytotoxic concentration of aerial extract was defined as 100 μg/ml based on MTT viability assay. hydro-alcoholic extract significantly decreased the concentration of both pro-inflammatory cytokines TNF-α and IL-6 in LPS-stimulated PBMCs (p<0.001 and p<0.001, respectively). However, the concentration of IL-10 as an anti-inflammatory cytokine, did not show any statistically significant change (p=0.390). Our findings highlighted the potential anti-inflammatory properties of in herbal medicine. Future analysis on different constituents of total extract may confirm its therapeutic effects as a promising anti-inflammatory compound.
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http://dx.doi.org/10.14196/mjiri.32.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325294PMC
September 2018

Radioprotective Effect of Cerium Oxide Nanoparticles Against Genotoxicity Induced by Ionizing Radiation on Human Lymphocytes.

Curr Radiopharm 2018 ;11(2):109-115

Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.

Background: Ionizing radiation induces DNA damage on normal cell results in apoptosis and cell deaths.

Objectives: The radioprotective effects of cerium oxide nanoparticles (CNPs) on genotoxicity, apoptosis and necrosis induced by Ionizing Radiation (IR) in human healthy lymphocytes as highly radiosensitive cells were investigated.

Materials And Methods: Lymphocytes were prepared from three volunteers and then treated with CNPs at different concentrations and exposed to IR at dose 1.5 Gy. The radioprotective effects of CNPs were assessed by micronucleus (MN) assay and flow cytometry. Interleukin-1 was quantified in treated samples.

Results: It was found that CNPs reduced the percentage of MN induced by IR in lymphocytes up to 73%. CNPs treatment significantly reduced IR-induced apoptotic and necrotic incidences in human lymphocytes. CNPs significantly reduced IL-1β produced in cell environment exposed to IR. The present study demonstrated that CNPs may be an effective radioprotector against DNA damage and apoptosis induced by IR mainly through mitigation of pro-inflammatory process in lymphocytes.

Conclusion: This result provides a new potential indication of CNPs for protection of normal cells during radiation therapy in the treatment of cancer or unwanted radiation exposure.
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http://dx.doi.org/10.2174/1874471011666180528095203DOI Listing
October 2018

Analysis of PD-1 and Tim-3 expression on CD4 T cells of patients with rheumatoid arthritis; negative association with DAS28.

Clin Rheumatol 2018 Aug 7;37(8):2063-2071. Epub 2018 Apr 7.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4 T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3/PD-1/CD4 T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-γ, and TNF-α were measured in culture supernatants by ELISA. The frequency of PD-1/CD4 and Tim-3/PD-1/CD4 T cells was significantly higher in patients with RA compared to that in controls (p = 0.0013 and p = 0.050, respectively). The percentage of Tim-3/CD4 T cells was similar in patients and controls (p = 0.4498). The RA patients have produced significant higher levels of TNF-α, IL-17, and IFN-γ than those of healthy controls (p = 0.0121, p = 0.0417, and p = 0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim-3/CD4 cells and DAS28 of RA patients (r = - 0.4696, p = 0.0493). Similarly, the percentage of Tim-3/PD-1/CD4 T cells was also revealed an inverse correlation with DAS28 (r = - 0.5268, p = 0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-α (r = 0.6418, p = 0.0023) and IL-17 (r = 0.4683, p = 0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression.
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http://dx.doi.org/10.1007/s10067-018-4076-4DOI Listing
August 2018

Th1-Th17 Ratio as a New Insight in Rheumatoid Arthritis Disease.

Iran J Allergy Asthma Immunol 2018 Feb;17(1):68-77

Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran.

The Th17, Th1 and dual Th17/Th1 cells are important players in rheumatoid arthritis (RA) disease. To assess their roles, the frequency and impact of these cells were investigated in patients with different disease activity. In 14 new cases and 41 established RA patients in comparison with 22 healthy controls, the percentages of Th17, Th1 and dual Th17/Th1 cells were determined by flow-cytometry and their correlations were investigated with disease activity score (DAS28). Moreover, serum levels of IL-6 and IL-17 as inducer and functional cytokines for Th17 were investigated. Finally, serum levels of anti citrullinated protein antibody (ACPA) and rheumatoid factor (RF) were assessed. Percentage of Th17 cells in RA patients were increased in comparison with healthy controls (p<0.01). In correlation with this finding, IL-17 and IL-6 cytokines in RA patients also increased (p<0.01). The Th1 cells in RA patients were less than healthy group (p<0.05) and showed negative correlation with disease activity (r=-0.328, p<0.01). Dual Th17/Th1 cell only in new cases of RA were more than healthy control groups (p<0.01). The Th1/Th17 ratio in RA patients is statistically different with healthy control group (p<0.01) and it has negative correlation with disease activity (r=-264, p<0.05). The levels of ACPA and RF were increased with disease progression. Decreasing of Th1/Th17 ratio in RA patient suggested a new paradigm in the field of autoimmune disease and indicated that imbalance or plasticity between these subsets can be important in progress, diagnosis and therapy of RA disease.
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February 2018

Radiosensitizing Effect of Cerium Oxide Nanoparticles on Human Leukemia Cells.

Pharm Nanotechnol 2018 ;6(2):111-115

Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.

Background: Radiotherapy is an important protocol in the treatment of cancers, but radioresistance of cancerous cells is a challenge in cancer treatment.

Objective: The aim of this study was to evaluate the radiosensitizing effect of Cerium oxide Nanoparticles (CNPs) on human promyelocytic leukemia cells (HL-60).

Method: HL-60 cells were treated with CNPs at different concentrations (10-100 μg/ml) and exposed to Ionizing Radiation (IR). The genotoxicity effects of CNPs or/and IR were assessed by micronuclei assay in HL-60 cells.

Results: It was found that CNPs increased the frequencies of micronuclei in HL-60 cells. CNPs pretreatment to irradiation significantly increased the IR-induced micronuclei incidences in HL-60 cells. The present study demonstrates CNPs to be an effective sensitizer on DNA damage induced by IR in HL-60 cells.

Conclusion: These findings suggest the potential application of CNPs as a highly effective radiosensitizer for the treatment of leukemia.
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http://dx.doi.org/10.2174/2211738506666180306161253DOI Listing
December 2018

CD4+ T Cells are Exhausted and Show Functional Defects in Chronic Lymphocytic Leukemia.

Iran J Immunol 2017 Dec;14(4):257-269

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. This health problem is caused due to the accumulation of mature B-lymphocytes in the peripheral blood and bone marrow. In the course of cancer, CD4+ T cells become "exhausted" and characterized with poor effector functions and the expression of multiple inhibitory receptors.

Objective: To investigate the frequency and functional properties of exhausted CD4+ T lymphocytes in patients with CLL.

Methods: Peripheral blood mononuclear cells were obtained from 25 untreated CLL patients and 15 healthy volunteers. CLL patients were clinically classified according to the Rai staging system. The frequency of CD4+/Tim-3+/PD-1+ cells was obtained by flow cytometry. To evaluate cell proliferation and cytokine production, CD4+ T cells were isolated and stimulated with phytohemagglutinin and PMA/ionomycin. Concentrations of IL-2, IFN-γ, TNF-α, and IL-10 were measured in the culture supernatants of stimulated cells by the ELISA technique.

Results: The percentage of CD4+/Tim-3+/PD-1+ cells was significantly higher in CLL patients than that of healthy controls. CD4+ T cells from CLL patients showed lower proliferative responses, a lower production of IL-2, IFN-γ, and TNF-α, and a higher production of IL-10, compared to healthy controls. CD4+ T cells from CLL patients in advanced clinical stages showed more exhaustion features than those of early stages.

Conclusion: Given that the exhaustion phase of T cells can be reversible, targeted blocking of immune inhibitory molecules could be a promising tool to restore the host immune responses against leukemic cells in CLL.
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http://dx.doi.org/IJIv14i4A1DOI Listing
December 2017

Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia

Asian Pac J Cancer Prev 2017 08 27;18(8):2269-2274. Epub 2017 Aug 27.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Background: Deviation of host immune response by engagement of inhibitory receptors is one of the well-known mechanisms of tumor cells for immune evasion and survival. PD-1/PD-L1 and Tim-3/Gal-9 axes are two major pathways in this area which their contribution has been documented in a variety of malignancies. In this study, Gal-9 and PD-L1 expression was investigated in leukemic cells from patients with Chronic Lymphocytic Leukemia (CLL). Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 25 untreated CLL patients and 15 sex- and age-matched healthy controls. CLL patients were classified into different clinical stages based on the Rai staging system. Total RNA was extracted from all samples and applied for cDNA synthesis. Relative expression of Gal-9 and PD-L1 mRNA was determined by Real-Time PCR using β-actin as a housekeeping gene. Results: Gal-9 and PD-L1 mRNA was significantly more expressed in CLL patients compared to healthy controls (p<0.0001 and p=0.005, respectively). CLL patients in advanced clinical stages showed higher expression of Gal-9 and PD-L1 in comparison to patients in early clinical stages (p<0.0001 and p=0.004, respectively). Conclusion: Our promising results regarding over-expression of Gal-9 and PD-L1 in CLL patients call future complementary studies to more evaluate and confirm these pathways for immunotherapy approaches of this malignancy. Upregulation of both Gal-9 and PD-L1 in CLL patients with advanced clinical stages introduces them as useful prognostic biomarkers for disease progression.
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http://dx.doi.org/10.22034/APJCP.2017.18.8.2269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697491PMC
August 2017

Tim-3 Up-regulation in Patients with Gastric Cancer and Peptic Ulcer Disease

Asian Pac J Cancer Prev 2017 03 1;18(3):765-770. Epub 2017 Mar 1.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Background: T-cell immunoglobulin and mucin domain protein-3 (Tim-3), an inhibitory immunoregulatory receptor, has been recently implicated in tumor biology and tumor-associated immune suppression. In the present study, expression of Tim-3 was evaluated in gastric cancer (GC) and peptic ulcer disease (PUD) at both mRNA and protein levels. Methods: A total of 133 gastric tissue biopsies, comprising 43 from GC cases, 48 from PUD and 42 from non-ulcer dyspepsia (NUD) serving as controls were collected. Additionally, non-neoplastic adjacent tissue biopsies were also obtained from 6 patients with GC. Infection with Helicobacter pylori was determined by the rapid urease test for all participants and H&E staining was conducted for GC and PUD patients. Tim-3 relative mRNA expression was determined by SYBR Green based Real-Time PCR using β-actin as a reference gene. Tim-3 protein expression was also studied by immunohistochemistry in 7 GC, 7 PUD and 10 NUD tissue samples. Results: Tim-3 was expressed at higher levels in GC (p=0.030) and PUD (p=0.022) cases compared to he NUD group. Among paired samples obtained from gastric cancer patients, tumor tissues showed elevated Tim-3 expression (p=0.019) in comparison with adjacent non-neoplastic biopsies. Tim-3 mRNA findings were supported by detection of more Tim-3 protein in cancerous (p=0.002) and ulcerative (p=0.01) tissues than in controls. Tim-3 was similarly expressed in H. pylori positive and negative cases.Conclusion: Higher Tim-3 expression in patients with gastric cancer and peptic ulcer implies that it might be involved in immune regulation and establishment of these gastrointestinal diseases. Targeted immunotherapy by blocking of inhibitory receptors like Tim-3 could be a promising approach for gastric cancer treatment.
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http://dx.doi.org/10.22034/APJCP.2017.18.3.765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464497PMC
March 2017

Frequency and functional characterization of exhausted CD8 T cells in chronic lymphocytic leukemia.

Eur J Haematol 2017 Jun 17;98(6):622-631. Epub 2017 Apr 17.

Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Objectives: The phenotypic and functional properties of Tim-3 /PD-1 /CD8 cells as exhausted T cells were investigated in chronic lymphocytic leukemia (CLL).

Methods: Frequency of CD8 /Tim-3 /PD-1 exhausted cells was determined by flow cytometry. For functional analysis, magnetic beads-isolated CD8 T cells were stimulated with PHA and PMA/ionocymin to assess their proliferative responses and cytokine production by MTT and ELISA, respectively. Cytotoxic activity of isolated CD8 T cells was determined using CD107a degranulation assay.

Results: The proportion of exhausted CD8 T cells was significantly higher in CLL compared to controls. Isolated CD8 T cells from CLL showed functional defects in proliferation, degranulation, and cytokines production. While IL-2, TNF-α, and IFN-γ were significantly lower in CLL patients, IL-10 was higher in the patients group. Patients with progressive clinical stages showed higher frequency and dysfunction of exhausted CD8 T cells.

Conclusion: Targeting immune inhibitory receptors to restore the function of tumor surrounding T cells could be helpful for immunotherapy of CLL.
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http://dx.doi.org/10.1111/ejh.12880DOI Listing
June 2017