Publications by authors named "Babak Negahdari"

62 Publications

Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity.

Pediatr Allergy Immunol 2021 Mar 27. Epub 2021 Mar 27.

Department of Pediatrics, Hamedan University of Medical Sciences, Hamedan, Iran.

Background: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunologic, and molecular data of monogenic IEI patients with and without autoimmune manifestations.

Methods: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data.

Results: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), and 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity.

Conclusions: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders, especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next-generation sequencing to discover responsible genes for the immune dysregulation at an early stage of the disease.
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http://dx.doi.org/10.1111/pai.13510DOI Listing
March 2021

Combined therapy of mesenchymal stem cells with a GLP-1 receptor agonist, liraglutide, on an inflammatory-mediated diabetic non-human primate model.

Life Sci 2021 Jul 18;276:119374. Epub 2021 Mar 18.

Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran. Electronic address:

Aims: Immunomodulation concurrent with the promotion of β-cell function is a strategy used to develop innovative therapies for type 1 diabetes (T1D). Here, we assessed the therapeutic potential of co-administration of human clonal mesenchymal stem (stromal) cells (hBM-cMSCs) and liraglutide as a glucagon-like peptide-1 agonist in a non-human primate model with streptozotocin (STZ)-induced diabetes.

Main Methods: Diabetes was induced through intravenous (i.v.) multiple low-dose (MLD) infusions of STZ at a dose of 30 mg/kg body weight (b.w.) for five consecutive days, followed by two booster injections of 35 mg/kg on days 12 and 19. After 90 days, the diabetic animals were randomly allocated to two groups: The combination therapy group (n = 4) received injections of 1.5 × 10 hBM-cMSCs/kg b.w. through celiac artery by angiography on days 91 and 105 and daily subcutaneous injections of liraglutide (up to 1.8 mg/day) until day 160 while vehicle group received phosphate-buffered saline. The monkeys were assessed for functional, immunological, and histological analysis.

Key Findings: The combined treatment group had continued reduction in FBG levels up to day 160, which was accompanied by increased b.w., C-peptide, and β-cell function, and decreased HbA1c and fructosamine levels compared to vehicle group. The combined treatment increased Tregs, IL-4, IL-10, and TGF-β1 and decreased IL-6 and IL-1β. Stereological analysis of the pancreatic tissue exhibited more total volume of insulin-secreting islets in the combined treatment group compared to vehicle group.

Significance: Our findings demonstrated this combined treatment impaired the clinical symptoms of diabetes in this animal model through immunomodulation and β-cell preservation.
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http://dx.doi.org/10.1016/j.lfs.2021.119374DOI Listing
July 2021

Immunotherapy for Breast Cancer Treatment.

Iran Biomed J 2021 Mar 8;25(3):140-56. Epub 2021 Mar 8.

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Breast cancer, as a heterogeneous disease, includes a wide range of pathological and clinical behaviors. Current treatment protocols, including radiotherapy, chemotherapy, and hormone replacement therapy, are mainly associated with poor response and high rate of recurrence. Therefore, more efforts are needed to develop alternative therapies for this type of cancer. Immunotherapy, as a novel strategy in cancer treatment, has a potential in treating breast cancer patients. Although breast cancer has long been considered problematic to treat with immunotherapy, as it is immunologically "cold," numerous newer preclinical and clinical reports now recommend that immunotherapy has the capability to treat breast cancer patients. In this review, we highlight the different immunotherapy strategies in breast cancer treatment.
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http://dx.doi.org/10.29252/ibj.25.3.140DOI Listing
March 2021

Virus against virus: strategies for using adenovirus vectors in the treatment of HPV-induced cervical cancer.

Acta Pharmacol Sin 2021 Feb 25. Epub 2021 Feb 25.

Department of Microbiology, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran.

Although most human papillomavirus (HPV) infections are harmless, persistent infection with high-risk types of HPV is known to be the leading cause of cervical cancer. Following the infection of the epithelium and integration into the host genome, the oncogenic proteins E6 and E7 disrupt cell cycle control by inducing p53 and retinoblastoma (Rb) degradation. Despite the FDA approval of prophylactic vaccines, there are still issues with cervical cancer treatment; thus, many therapeutic approaches have been developed to date. Due to strong immunogenicity, a high capacity for packaging foreign DNA, safety, and the ability to infect a myriad of cells, adenoviruses have drawn attention of researchers. Adenovirus vectors have been used for different purposes, including as oncolytic agents to kill cancer cells, carrier for RNA interference to block oncoproteins expression, vaccines for eliciting immune responses, especially in cytotoxic T lymphocytes (CTLs), and gene therapy vehicles for restoring p53 and Rb function.
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http://dx.doi.org/10.1038/s41401-021-00616-5DOI Listing
February 2021

A lectin-coupled porous silicon-based biosensor: label-free optical detection of bacteria in a real-time mode.

Sci Rep 2020 09 29;10(1):16017. Epub 2020 Sep 29.

School of Physics, Institute for Research in Fundamental Sciences, Tehran, Iran.

Accuracy and speed of detection, along with technical and instrumental simplicity, are indispensable for the bacterial detection methods. Porous silicon (PSi) has unique optical and chemical properties which makes it a good candidate for biosensing applications. On the other hand, lectins have specific carbohydrate-binding properties and are inexpensive compared to popular antibodies. We propose a lectin-conjugated PSi-based biosensor for label-free and real-time detection of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by reflectometric interference Fourier transform spectroscopy (RIFTS). We modified meso-PSiO (10-40 nm pore diameter) with three lectins of ConA (Concanavalin A), WGA (Wheat Germ Agglutinin), and UEA (Ulex europaeus agglutinin) with various carbohydrate specificities, as bioreceptor. The results showed that ConA and WGA have the highest binding affinity for E. coli and S. aureus respectively and hence can effectively detect them. This was confirmed by 6.8% and 7.8% decrease in peak amplitude of fast Fourier transform (FFT) spectra (at 10 cells mL concentration). A limit of detection (LOD) of about 10 cells mL and a linear response range of 10 to 10 cells mL were observed for both ConA-E. coli and WGA-S. aureus interaction platforms that are comparable to the other reports in the literature. Dissimilar response patterns among lectins can be attributed to the different bacterial cell wall structures. Further assessments were carried out by applying the biosensor for the detection of Klebsiella aerogenes and Bacillus subtilis bacteria. The overall obtained results reinforced the conjecture that the WGA and ConA have a stronger interaction with Gram-positive and Gram-negative bacteria, respectively. Therefore, it seems that specific lectins can be suggested for bacterial Gram-typing or even serotyping. These observations were confirmed by the principal component analysis (PCA) model.
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http://dx.doi.org/10.1038/s41598-020-72457-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525577PMC
September 2020

Oncolytic virotherapy: Challenges and solutions.

Curr Probl Cancer 2021 Feb 15;45(1):100639. Epub 2020 Aug 15.

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. Electronic address:

Viruses as cancer therapies have attracted attention since the 19th century. Scientists observation that viruses can preferentially lyse cancer cells rather than healthy cells, created the field of oncolytic virology. Like other therapeutic strategies, oncolytic virotherapy has challenges, such as penetration into tumor bulk, anti-viral immune responses, off-target infection, adverse conditions in the tumor microenvironment, and the lack of specific predictive and therapeutic biomarkers. Whilst much progress has been made, as highlighted by the first Food and Drug Administration approval of an oncolytic virus talimogene laherparepvec (T-VEC) in 2015, addressing these issues remains a significant hurdle. Here we discuss different types of oncolytic viruses, their application in clinical trials, and finally challenges faced by the field of oncolytic virotherapy and strategies to overcome them.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100639DOI Listing
February 2021

Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours.

IET Nanobiotechnol 2020 Aug;14(6):441-448

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Drug delivery is one of the major challenges in the treatment of central nervous system disorders. The brain needs to be protected from harmful agents, which are done by the capillary network, the so-called blood-brain barrier (BBB). This protective guard also prevents the delivery of therapeutic agents to the brain and limits the effectiveness of treatment. For this reason, various strategies have been explored by scientists for overcoming the BBB from disruption of the BBB to targeted delivery of nanoparticles (NPs) and cells and immunotherapy. In this review, different promising brain drug delivery strategies including disruption of tight junctions in the BBB, enhanced transcellular transport by peptide-based delivery, local delivery strategies, NP delivery, and cell-based delivery have been fully discussed.
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http://dx.doi.org/10.1049/iet-nbt.2019.0351DOI Listing
August 2020

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity.

Int Arch Allergy Immunol 2020 2;181(9):706-714. Epub 2020 Jul 2.

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

Background: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis.

Methods: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children's Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data.

Results: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity.

Conclusion: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.
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http://dx.doi.org/10.1159/000508817DOI Listing
February 2021

Strategies for enhancing intratumoral spread of oncolytic adenoviruses.

Pharmacol Ther 2020 09 30;213:107586. Epub 2020 May 30.

Department of Molecular Virology, Pasteur Institute of Iran, Tehran, Iran. Electronic address:

Oncolytic viruses, effectively replicate viruses within malignant cells to lyse them without affecting normal ones, have recently shown great promise in developing therapeutic options for cancer. Adenoviruses (Ads) are one of the candidates in oncolytic virotheraoy due to its easily manipulated genomic DNA and expression of wide rane of its receptors on the various cancers. Although systematic delivery of oncolytic adenoviruses can target both primary and metastatic tumors, there are some drawbacks in the effective systematic delivery of oncolytic adenoviruses, including pre-existing antibodies and liver tropism. To overcome these limitations, intratumural (IT) administration of oncolytic viruses have been proposed. However, IT injection of Ads leaves much of the tumor mass unaffected and Ads are not able to disperse more in the tumor microenvironment (TME). To this end, various strategies have been developed to enhance the IT spread of oncolytic adenoviruses, such as using extracellular matrix degradation enzymes, junction opening peptides, and fusogenic proteins. In the present paper, we reviewed different oncolytic adenoviruses, their application in the clinical trials, and strategies for enhancing their IT spread.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107586DOI Listing
September 2020

Genetically engineered mesenchymal stem cells: targeted delivery of immunomodulatory agents for tumor eradication.

Cancer Gene Ther 2020 Dec 18;27(12):854-868. Epub 2020 May 18.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Cancer immunotherapy emerged as a novel therapeutic option that employs enhanced or amended native immune system to create a robust response against malignant cells. The systemic therapies with immune-stimulating cytokines have resulted in substantial dose-limiting toxicities. Targeted cytokine immunotherapy is being explored to overcome the heterogeneity of malignant cells and tumor cell defense with a remarkable reduction of systemic side effects. Cell-based strategies, such as dendritic cells (DCs), fibroblasts or mesenchymal stem cells (MSCs) seek to minimize the numerous toxic side effects of systemic administration of cytokines for extended periods of time. The usual toxicities comprised of a vascular leak, hypotension, and respiratory insufficiency. Natural and strong tropism of MSCs toward malignant cells made them an ideal systemic delivery vehicle to direct the proposed therapeutic genes to the vicinity of a tumor where their expression could evoke an immune reaction against the tumor. Compared with other methods, the delivery of cytokines via engineered MSCs is safer and renders a more practical, and promising strategy. Large numbers of genes code for cytokines have been utilized to reengineer MSCs as therapeutic cells. This review highlights the recent findings on the cytokine gene therapy for human malignancies by focusing on MSCs application in cancer immunotherapy.
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http://dx.doi.org/10.1038/s41417-020-0179-6DOI Listing
December 2020

antibiotic resistance and correlation with motifs and gene.

Postgrad Med 2020 Aug 12;132(6):512-520. Epub 2020 Apr 12.

Department of Bacteriology and Virology, Shiraz Medical School, Shiraz University of Medical Sciences , Shiraz, Iran.

() infection caused by antibiotic-resistant strains represents a major public health threat that aggressively promotes gastric cancer progression. Antibiotic resistance evaluation is immensely important to counteract its emergence. Here we merely determine the prevalence of antibiotic resistance in isolates and its correlation with motifs and the gene. The antibiotic resistance pattern was investigated on 128  isolated strains utilizing the disk diffusion method and study the correlation between it and the presence of pathogenic genes, EPIYA motifs and gene, were accurately detected using the PCR. The resistance rates to four antibiotics were 70.1% for metronidazole, 35.5% for amoxicillin, 7.2% for clarithromycin and 8.2% for tetracycline. Resistance phenotypes were separated into two groups, single resistance (63.2%) and multi-resistance (12.5%). The prevalence of -ABCC resistant strains and resistant strains was significantly higher in cancer (0.04 and 0.01, respectively) than those of other diseases. The prevalence of resistance strains was 21.8% and had a significant correlation with PUD. A significant relationship was observed between amoxicillin resistant rate with ABC- ( 0.0006). The Resistance rate to selected antibiotics in Shiraz is higher than years ago. The presence of is associated with antibiotic resistance and also can be used as a marker to antibiotic resistance status prediction in isolated in this area.
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http://dx.doi.org/10.1080/00325481.2020.1753406DOI Listing
August 2020

Autoimmunity as a target for chimeric immune receptor therapy: A new vision to therapeutic potential.

Blood Rev 2020 05 28;41:100645. Epub 2019 Nov 28.

Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, Tehran, Iran. Electronic address:

Chimeric immune receptors (CIRs) are functionally pleiotropic because they are artificially expressed on diverse cell types, which gives specificity to their function to anergize, kill, or protect cognate target cells. CIRs consist of chimeric antigen receptors (CARs) and B-cell antibody receptor (BAR) or chimeric autoantibody receptors (CAARs). Approval of CAR-T cell therapy by the Food and Drug Administration (FDA) has encouraged investigators to search for autoimmune therapies that are CIR-based. Both T effector cells, particularly CD8, and T CD4 regulatory cells (Tregs) can be engineered through CIR expression. Recently, natural killer cells have been included to increase efficiency. Unwanted antibody producer B cells are effectively prevented by CAAR-T cells, B-cell antibody receptor (BAR)-T CD8+, and BAR-Treg, which represents an advantage in antibody-mediated diseases such as pemphigus vulgaris (PV) and hemophilia A. Although CAAR and BAR-T cells may have curative benefits for autoantibody-mediated immune diseases, verification of long-term efficacy and safety are a priority before clinical use. Effective CIR-T cell therapy largely depends on the reliability and stability of the receptor. Based on CIR functionality, factors that explicitly determine effectiveness of the treatment should be considered. These factors include antigen/autoantibody specificity, single chain variable fragment (scFv) affinity, and autoantibody masking. Herein, we review the current evidence of CIR therapy with a focus on their therapeutic potential for autoimmune diseases and their challenges.
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http://dx.doi.org/10.1016/j.blre.2019.100645DOI Listing
May 2020

Protective responses of an engineered PspA recombinant antigen against .

Biotechnol Rep (Amst) 2019 Dec 30;24:e00385. Epub 2019 Oct 30.

National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran.

is a major pathogen in human respiratory tract which causes significant morbidity and mortality across from the world. Currently available vaccines are not completely effective and cannot cover all pathogenic strains so there is an important need to develop an alternative cost-effective vaccine, based on conserved protein antigens. Pneumococcal surface protein A (PspA) is one of interesting candidates for development of a serotype-independent vaccine against pneumococcal infections. PspA is grouped into two major families with five clades, and broad-reacting PspA-based vaccines should contain at least one functional fragment from each of the two families. In this study, we developed two immunogenic antigens based on recombinant PspA proteins that including the different antigenic regions of PspA from both two families. The cross-reactivity of antibodies elicited against two PspA proteins PspAB1-5 and PspAABC and their role in complement deposition with three strains of pneumococci were tested. The protective effects of developed anti-PspA antibodies in mice in intranasal and intraperitoneal challenges were evaluated using a strain from clade 2. Sera from immunized mice with PspAB in comparison with PspAABC was able to deposit more C3 complement component on surface of pneumococci bearing diverse PspA from both families 1 and 2, and immunized mice with the PspAB showed a higher protection than PspAABC in pneumococcal challenges. The obtained results from this study indicate that a PspA-based antigen composed of B region from all clades in addition to conserved domains, can provide a significant protection against multiple strains of . and may overcome the limitation of polysaccharide vaccines.
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http://dx.doi.org/10.1016/j.btre.2019.e00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864353PMC
December 2019

The evaluation of neutropenia in common variable immune deficiency patients.

Expert Rev Clin Immunol 2019 11 15;15(11):1225-1233. Epub 2019 Oct 15.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication among CVID patients leading to a higher rate of infections and morbidity. Multiple factors (e.g. autoimmunity, infections, drugs and etc.) are found to underlie this complication.: In the present study, demographic, clinical and laboratory data were compared between two groups of CVID patients with and without neutropenia.: Frequency of neutropenia was 8.1%. Infectious complications were the most prevalent clinical manifestations regardless of presence of neutropenia. However, candida infection and septicemia were significantly higher in neutropenic patients ( = 0.001 and = 0.01, respectively). The most prominent clinical phenotypes of CVID patients with neutropenia were polyclonal lymphocytic infiltration and autoimmunity, both being considerably higher compared to the non-neutropenic group ( = 0.04 and = 0.009, respectively). The mortality rate in neutropenic patients was higher than in patients without neutropenia (61.1 vs. 25.2%, = 0.004).: Although neutropenia is a rare complication among CVID patients, it is associated with frequent and severe clinical complications, including autoimmunity and lymphoproliferative conditions. Also, its accompaniment with higher mortality frequency in CVID patients indicates a need for more precise attention and consideration regarding specific treatment in neutropenic patients.
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http://dx.doi.org/10.1080/1744666X.2020.1677154DOI Listing
November 2019

CEA Plasmid as Therapeutic DNA Vaccination against Colorectal Cancer.

Iran J Immunol 2019 Sep;16(3):235-245

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Human colorectal cancer cells overexpress carcinoembryonic antigen (CEA). CEA is a glycoprotein which has shown to be a promising vaccine target for immunotherapy against colorectal cancer.

Objectives: To design a DNA vaccine harboring CEA antigen and evaluate its effect on inducing immunity against colorectal cancer cells in tumor bearing mice.

Methods: In the first step the coding sequence of the CEA was cloned into the pcDNA3.1 vector. The mice were injected with the vaccine construct and the immune responses were monitored during the experiment period. The specific IgG anti-CEA, IFN-γ, IL-2 and IL-4 were measured by ELISA and levels of IFN-γ was detected by ELISpot assay. The lymphocyte proliferation was assessed using a 5-bromo-2-deoxyuridine (BrdU) cell proliferation assay kit.

Results: Immunization of the mice with the CEA plasmid resulted in stimulation of CEA-specific T cell and antibody responses. The serum level of specific IgG antibodies against CEA was increased in immunized mice. Moreover, the injection of CEA plasmid led to the stimulation of T-helper-1 by increase in the secretion of IFN-γ, IL-2 and lymphocyte proliferation response.

Conclusion: As the CEA DNA vaccine displayed encouraging antitumor effects, therefore, we suggest that it can be a potential therapeutic modality for colorectal cancer and is worthy of further investigation.
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http://dx.doi.org/10.22034/IJI.2019.80274DOI Listing
September 2019

Targeting siRNA in colorectal cancer therapy: Nanotechnology comes into view.

J Cell Physiol 2019 Mar 28. Epub 2019 Mar 28.

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Colorectal cancer (CRC) is known as one of the most important causes of death and mortality worldwide. Although several efforts have been made for finding new therapies, no achievements have been made in this area. Multidrug resistance (MDR) mechanisms are one of the key factors that could lead to the failure of chemotherapy. Moreover, it has been shown that various chemotherapy drugs are associated with several side effects. Hence, it seems that finding new drugs or new therapeutic platforms is required. Among different therapeutic approaches, utilization of nanoparticles (NPs) for targeting a variety of molecules such as siRNAs are associated with good results for the treatment of CRC. Targeting siRNA-mediated NPs could turn off the effects of oncogenes and MDR-related genes. In the current study, we summarized various siRNAs targeted by NPs which could be used for the treatment of CRC. Moreover, we highlighted other routes such as liposome for targeting siRNAs in CRC therapy.
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http://dx.doi.org/10.1002/jcp.28281DOI Listing
March 2019

Electrospun core-sheath poly(vinyl alcohol)/silk fibroin nanofibers with Rosuvastatin release functionality for enhancing osteogenesis of human adipose-derived stem cells.

Mater Sci Eng C Mater Biol Appl 2019 Jun 25;99:129-139. Epub 2019 Jan 25.

Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, MO, United States.

The aim of this study is to evaluate a core-shell nanofiber as a useful matrix for tuning Rosuvastatin (RSV) release and osteogenic differentiation in vitro. Polyvinyl alcohol (PVA) and silk fibroin were used as the shell and the core, respectively. To obtain a linear and beadless core-shell structure and an optimal release profile, the shell/core flow rate ratio was varied (0, 0.4, 0.6, 0.8, and 1). Formation of continuous nanofibers with an obvious core/sheath structure was proved using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Differential scanning calorimetry indicated the presence of two distinct phase structures in the nanofibers. Also, RSV molecules were dispersed in an amorphous state in the nanofibers. The in vitro release profile of the core-shell structure exhibited a biphasic release profile and the amount of released RSV was controlled by adjusting the shell flow rate. Human adipose-derived stem cells cultured on the RSV loaded nanofibers were found to improve cell proliferation and assist osteogenic differentiation as revealed by Alizarin red staining and real-time RT-PCR.
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http://dx.doi.org/10.1016/j.msec.2019.01.100DOI Listing
June 2019

Gold nanoparticles and hepatitis B virus.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):455-461

c lnfectious Diseases and Tropical Medicine Research Center (IDTMRC) , AJA University of Medical Sciences , Tehran , Iran.

Hepatitis B virus (HBV) infection is one of the major health issues in the world presently with high tendency of leading to hepatocarcinoma, cirrhosis, and liver cancer, especially if not properly managed. It has been estimated that there are about 2 billion people with a serological profile of HBV infection, and 360 million patients worldwide living with chronic HBV-associated liver disease, hence the need to find an efficient and precise diagnosis technique to drive a robust treatment for Hepatitis B virus cannot be over emphasized. The emergence of analytical device like biosensor which combines biological and physicochemical element to detect HBV in screened samples has been very helpful in providing a timely intervention to tame this virus. This review focuses on the current state of biosensor researches with respect to various in-depth application of gold nanoparticle for the detection of hepatitis B virus (HBV).
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http://dx.doi.org/10.1080/21691401.2018.1553786DOI Listing
December 2019

Gold nanoparticles and hepatitis B virus.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):469-474

c Infectious Diseases and Tropical Medicine Research Center (IDTMRC) , AJA University of Medical Sciences , Tehran , Iran.

Hepatitis B virus (HBV) infection is one of the major health issues in the world presently with high tendency of leading to hepatocarcinoma, cirrhosis and liver cancer, especially if not properly managed. It has been estimated that there are about 2 billion people with a serological profile of HBV infection, and 360 million patients worldwide living with chronic HBV-associated liver disease, hence the need to find an efficient and precise diagnosis technique to drive a robust treatment for Hepatitis B virus cannot be over emphasized. The emergence of analytical device like biosensor which combines biological and physicochemical element to detect HBV in screened samples has been very helpful in providing a timely intervention to tame this virus. This review focuses on the current state of biosensor researches with respect to various in-depth application of gold nanoparticle for the detection of HBV.
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http://dx.doi.org/10.1080/21691401.2018.1546185DOI Listing
December 2019

Osteogenic potential of Rosuvastatin immobilized on silk fibroin nanofibers using argon plasma treatment.

Biomed Mater 2018 12 7;14(2):025002. Epub 2018 Dec 7.

Faculty of New Sciences and Technologies, Department of Life Science Engineering, University of Tehran, Tehran, Iran.

To begin developing a silk fibroin (SF) nanofibrous scaffolds that could promote osteogenesis, whilst enabling to deliver an active amount of Rosuvastatin (RSV) to the cells in long-time period, the present study aims to immobilize RSV onto the SF nanofibers through the argon radio frequency. Thus, the effect of plasma exposure times (0, 1, 3, and 5 min) was investigated on the morphology, loading efficiency, release profile, and osteogenesis activity. The successful loading of RSV on the SF nanofibers was proved by Fourier transformed infrared spectroscopy, Differential scanning calorimetry, and energy dispersive spectroscopy. In vitro drug release studies demonstrated that the RSV release was prolonged over a period of 21 d for plasma treated mats, while the non-plasma treated samples released the whole drug after 72 h. Moreover, the dose of RSV was controlled by the plasma exposure times, in which the highest amount of the released RSV was achieved after 3 min exposing to plasma. As suggested by MTT assay, the released amounts of RSV had no toxicity on the seeded human adipose tissue-derived stem cells and enhanced their proliferation. Moreover, using real-time reverse transcriptase-polymerase chain reaction and alizarin red staining proved that RSV-immobilized SF mats stimulate both early and late osteogenic gene differentiation in comparison with pure SF nanofibers. However, the highest differentiation was observed on the SF nanofibers treated with argon plasma for 3 min. The results support the potential of plasma treatment on sustained release of the RSV from SF nanofibers for osteogenesis enhancement.
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http://dx.doi.org/10.1088/1748-605X/aaec26DOI Listing
December 2018

Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches.

J Cell Physiol 2019 06 4;234(6):8636-8646. Epub 2018 Dec 4.

Department of Molecular Virology, Pasteur Institute of Iran, Tehran, Iran.

Cancer therapy using oncolytic viruses is an emerging area, in which viruses are engineered to selectively propagate in tumor tissues without affecting healthy cells. Because of the advantages that adenoviruses (Ads) have over other viruses, they are more considered. To achieve tumor selectivity, two main modifications on Ads genome have been applied: small deletions and insertion of tissue- or tumor-specific promoters. Despite oncolytic adenoviruses ability in tumor cell lysis and immune responses stimulation, to further increase their antitumor effects, genomic modifications have been carried out including insertion of checkpoint inhibitors and antigenic or immunostimulatory molecules into the adenovirus genome and combination with dendritic cells and chemotherapeutic agents. This study reviews oncolytic adenoviruses structures, their antitumor efficacy in combination with other therapeutic strategies, and finally challenges around this treatment approach.
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http://dx.doi.org/10.1002/jcp.27850DOI Listing
June 2019

Porous MnFeO@SiO magnetic glycopolymer: A multivalent nanostructure for efficient removal of bacteria from aqueous solution.

Ecotoxicol Environ Saf 2018 Dec 28;166:277-284. Epub 2018 Sep 28.

Cosmetic Products Research Center, Iran Food and Drug Administration, Ministry of Health and Medical Education, Tehran, Iran.

The focuses of this research is to prepare an efficient magnetic glycopolymer for bacteria removal from aqueous solution. To perform this idea; porous MnFeO@SiO was functionalized with glucose and or maltose as an anchors to adhere onto bacteria cell surface. Aminopropyltriethoxysilane was employed to link the saccharides on magnetic nanoparticle surface. The hybrid materials were characterized with XRD, VSM, FT-IR, FESEM, TEM, zeta potential measurement and elemental mapping. Microscopic image showed that MnFeO is in cluster form composed from tiny nanoparticles. After saccharide functionalization hybrid composite generate hyper-crosslinked porous structure as a result of polysilicate formation due to hydrolysis of silica source. Escherichia coli and bacillus subtilis were selected as sample pathogens to evaluate the bacteria capturing ability of the magnetic glycopolymer. At the optimum conditions (pH = 6, time of 20 min, dosage of 15 mg) removal efficiency was more than 99% using both saccharide.
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http://dx.doi.org/10.1016/j.ecoenv.2018.09.086DOI Listing
December 2018

Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort.

J Allergy Clin Immunol Pract 2019 03 19;7(3):864-878.e9. Epub 2018 Sep 19.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Background: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses.

Objective: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings.

Methods: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID.

Results: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 μ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with μ heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008).

Conclusions: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.
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http://dx.doi.org/10.1016/j.jaip.2018.09.004DOI Listing
March 2019

Fusobacterium nucleatum and colorectal cancer: A mechanistic overview.

J Cell Physiol 2019 03 7;234(3):2337-2344. Epub 2018 Sep 7.

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Colorectal cancer (CRC) is the third most prevalent cancer in the world. There are many risk factors involved in CRC. According to recent findings, the tumor microenvironment and feces samples of patients with CRC are enriched by Fusobacterium nucleatum. Thus, F. nucleatum is proposed as one of the risk factors in the initiation and progression of CRC. The most important mechanisms of Fusobacterium nucleatum involved in CRC carcinogenesis are immune modulation (such as increasing myeloid-derived suppressor cells and inhibitory receptors of natural killer cells), virulence factors (such as FadA and Fap2), microRNAs (such as miR-21), and bacteria metabolism. The aim of this review was to evaluate the mechanisms underlying the action of F. nucleatum in CRC.
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http://dx.doi.org/10.1002/jcp.27250DOI Listing
March 2019

Regulation of tumor angiogenesis by microRNAs: State of the art.

J Cell Physiol 2019 02 2;234(2):1099-1110. Epub 2018 Aug 2.

Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

MicroRNAs (miRNAs, miRs) are small (21-25 nucleotides) endogenous and noncoding RNAs involved in many cellular processes such as apoptosis, development, proliferation, and differentiation via binding to the 3'-untranslated region of the target mRNA and inhibiting its translation. Angiogenesis is a hallmark of cancer, which provides oxygen and nutrition for tumor growth while removing deposits and wastes from the tumor microenvironment. There are many angiogenesis stimulators, among which vascular endothelial growth factor (VEGF) is the most well known. VEGF has three tyrosine kinase receptors, which, following VEGF binding, initiate proliferation, invasion, migration, and angiogenesis of endothelial cells in the tumor environment. One of the tumor microenvironment conditions that induce angiogenesis through increasing VEGF and its receptors expression is hypoxia. Several miRNAs have been identified that affect different targets in the tumor angiogenesis pathway. Most of these miRNAs affect VEGF and its tyrosine kinase receptors expression downstream of the hypoxia-inducible Factor 1 (HIF-1). This review focuses on tumor angiogenesis regulation by miRNAs and the mechanism underlying this regulation.
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http://dx.doi.org/10.1002/jcp.27051DOI Listing
February 2019

Incorporation of Nanoalumina Improves Mechanical Properties and Osteogenesis of Hydroxyapatite Bioceramics.

ACS Biomater Sci Eng 2018 Apr 16;4(4):1324-1336. Epub 2018 Mar 16.

School of Biomedical Engineering, University of Technology Sydney, Ultimo, New South Wales 2007 Australia.

A handful of work focused on improving the intrinsic low mechanical properties of hydroxyapatite (HA) by various reinforcing agents. However, the big challenge regarding improving mechanical properties is maintaining bioactivity. To address this issue, we report fabrication of apatite-based composites by incorporation of alumina nanoparticles (n-AlO). Although numerous studies have used micron or submicron alumina for reinforcing hydroxyapatite, only few reports are available about the use of n-AlO. In this study, spark plasma sintering (SPS) method was utilized to develop HA-nAlO dense bodies. Compared to the conventional sintering, decomposition of HA and formation of calcium aluminates phases are restricted using SPS. Moreover, n-AlO acts as a bioactive agent while its conventional form is an inert bioceramics. The addition of n-AlO resulted in 40% improvement in hardness along with a 110% increase in fracture toughness, while attaining nearly full dense bodies. The in vitro characterization of nanocomposite demonstrated improved bone-specific cell function markers as evidenced by cell attachment and proliferation, alkaline phosphatase activity, calcium and collagen detection and nitric oxide production. Specifically, gene expression analysis demonstrated that introduction of n-AlO in HA matrix resulted in accelerated osteogenic differentiation of osteoblast and mesenchymal stem cells, as expression of Runx-2 and OSP showed 2.5 and 19.6 fold increase after 2 weeks ( < 0.05). Moreover, protein adsorption analysis showed enhanced adsorption of plasma proteins to HA-nAlO sample compared to HA. These findings suggest that HA-nAlO could be a prospective candidate for orthopedic applications due to its improved mechanical and osteogenic properties.
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http://dx.doi.org/10.1021/acsbiomaterials.7b00754DOI Listing
April 2018

Overexpression of miR-219 promotes differentiation of human induced pluripotent stem cells into pre-oligodendrocyte.

J Chem Neuroanat 2018 09 9;91:8-16. Epub 2018 Mar 9.

Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Oligodendrocytes play critical roles in the central nervous system (CNS) thorough producing myelin sheaths around axons. There are a variety of approaches to produce oligodendrocytes in vitro and in vivo which are a subject of interest in many studies. A new approach to induce this differentiation is using microRNA 219 (miR-219). However, this new approach suffers from a lack of studies regarding the effect of miR-219 on differentiating human induced pluripotent stem cells (hiPSCs) to oligodendrocytes. This study aimed to assess the impact of miR-219-overexpression on hiPSCs. Initially, hiPSCs were induced with basic fibroblast growth factor (bFGF), epidermalgrowth factor (EGF) and platelet-derived growth factor (PDGF)-AA, then, miR-219- green fluorescent protein (GFP)-expressing lentiviruses were utilized for cell infection. Microscopic observation revealed significant morphological changes and data obtained from quantitative reverse transcription PCR and immunofluorescence analysis of differentiated cells showed that the expression of various oligodendrocyte stage-specific markers such as Nestin, Olig2, Sox10, PDGFRα, A2B5, O4, and MBP increased. In addition, higher expressions of pre-oligodendrocyte markers were detected in the cells transduced with miR-219 lentivirus in comparison with the cells treated with triiodothyronine (T3). These results suggest that overexpression of miR-219 promotes differentiation of hiPSCs to pre-oligodendrocyte cells, providing a potential source for cell therapy by replacing and restoring the lost cell function in neurodegenerative and demyelinating diseases.
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http://dx.doi.org/10.1016/j.jchemneu.2018.03.001DOI Listing
September 2018

Applications of Drug Anesthesia in Control Chronic Pain.

J Invest Surg 2019 Apr 19;32(3):232-237. Epub 2017 Dec 19.

b Department of Medical Biotechnology , School of Advanced Technologies in Medicine, Tehran University of Medical sciences , Tehran , Iran.

Surgery is one of the major causes of chronic pain in patients that have undergone any kind of surgeries. These complain are not only associated with major surgeries; even common minor surgeries like hernia repair have a significant risk of chronic pain. The development of chronic postsurgical pain (CPSP) depends on the type of surgical technique used. Furthermore, changes in the central nervous system have been associated with the development of persistent and chronic pain after surgical trauma and nerve injury. Anesthesia agents that block the mechanisms stimulating the process of central sensitization may be efficient in reducing the incidence of CPSP and finally psychosocial factors have been reported to be an important factor in the progression of chronic pain and as such should be addressed as part of perioperative care. The purpose of this mini-review is to give a comprehensive summary of the application of anesthesia drugs to reduce or control chronic pain during or after surgery.
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http://dx.doi.org/10.1080/08941939.2017.1397230DOI Listing
April 2019

Isolation and characterization of mesenchymal stem cells and its antitumor application on ovarian cancer cell line.

Artif Cells Nanomed Biotechnol 2018 Dec 3;46(8):1744-1753. Epub 2017 Dec 3.

b Department of Medical Biotechnology , Faculty of Advance Medical Sciences, Tehran University of Medical Sciences , Tehran , Iran.

The molecular interaction network of Oct-4 (POU5F1) and NANOG connected to regulation and growth of mesenchymal stem cells (MSCs) were supplemented with information of miRNA to find an important micro-RNAs and supplemented molecular interaction network. Following co-culturing of Bone marrow mesenchymal stem cells (BMMSCs) with SKOV3 ovarian cancer cell lines and undifferentiated BMMSCs, MTT was analyzed for cell cytotoxicity. The analyses of the expression of miRNA were performed either after oesteogenesis (hsa-miR-34 and hsa-miR-335) or chondrogenic (hsa-miR-145 and hsa-miR-455) differentiation. This molecular interaction network was imaged in using software. The results from these findings gave an understanding of the main molecular mechanisms regulating MSCs therapeutic activity and their undifferentiated state maintenance. We recommend that the downregulation of miR-335 is crucial role for tissue homeostasis.
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http://dx.doi.org/10.1080/21691401.2017.1391824DOI Listing
December 2018

Design, expression and evaluation of novel chimeric protein constructed from colorectal tumor-associated antigen.

J Cell Biochem 2018 04 11;119(4):3464-3473. Epub 2018 Jan 11.

Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.

There were 134,000 new diagnosis and 49,000 deaths in 2016 due to colorectal cancer. Similar to most cancers, early diagnosis increases the chance of successful treatment. Detection of tumor-associated antigens or the immune response against such markers is one of the most common methods of diagnosis. In that regard, we aimed to design and express a chimeric protein from the most common tumor-associated antigens in colorectal cancer and assess its ability to detect the immune response in comparison with the parental tumor-associated antigens in patient's sera. Through bioinformatics approaches a chimeric protein from carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19-9) was designed and expressed in E. coli (BL21DE3). Proper folding, expression levels and immune reactivity were assessed by western blot, ELISA and immunohistochemistry. Recombinant proteins functionality and immune reactivity were confirmed by ELISA and Western blot. Results showed that recombinant CEA, recombinant CA19.9 and chimeric protein of CEA- CA19.9 have strong reactivity with antibodies in the sera of colorectal cancer patients, whereas no reactivity was seen with the sera of healthy volunteers. Significantly stronger immune reactivity was seen with the chimeric protein than each of the CEA or CA19.9 alone. Overall, it was concluded that the designed recombinant proteins in this study could be used to detect autoantibodies produced against the colorectal tumor-associated antigens. The chimeric CEA-CA19.9 protein shows a stronger reactivity with the sera antibodies of colorectal cancer patients that CEA or CA19.9 alone.
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http://dx.doi.org/10.1002/jcb.26518DOI Listing
April 2018