Publications by authors named "Behzad Baradaran"

475 Publications

Toxoplasma gondii activates NLRP12 inflammasome pathway in the BALB/c murine model.

Acta Trop 2021 Oct 21:106202. Epub 2021 Oct 21.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Parasitology and Mycology, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

The host resistance against Toxoplasma gondii (T. gondii) infection is related to the initiation of the immune response. The study aimed to investigate the role of the leucine-rich repeat family, pyrin domain -containing protein 12 (NLRP12), and cytoplasmic nucleotide-binding domain in the inflammasome-mediated cell death during murine toxoplasmosis. Groups of BALB/c mice (n = 10) were inoculated intraperitoneally with live tachyzoites, excretory-secretory antigens (ESAs) of T. gondii RH strain, and RPMI. The gene expression levels of NLRP12, caspase-3, caspase-1, IL-1β, IL-18, ASC, and Bcl-2 were measured in the peritoneal cells using quantitative real-time PCR, while the determination of NLRP12 protein level was measured by Western blot. Also, the intracellular reactive oxygen species (ROS) production was investigated. Quantitative and comparative analyses showed that injection of tachyzoites significantly increased NLRP12, caspase-3, caspase-1, IL-1β, IL-18, and ASC genes mRNA expression levels (p<0.01). Contrary to the acute infection, the Bcl-2 gene was significantly expressed in the ESAs group (p<0.0001). The level of NLRP12 protein was significantly higher in the mice that received tachyzoites and ESAs in comparison to the control group (p<0.0001). These findings provide an inside into the host-T. gondii interaction and NLRP12 regulation, which is important for the modulation of the immunological response.
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http://dx.doi.org/10.1016/j.actatropica.2021.106202DOI Listing
October 2021

The effects of chemotherapeutic drugs on PD-L1 gene expression in breast cancer cell lines.

Med Oncol 2021 Oct 23;38(12):147. Epub 2021 Oct 23.

Immunology Research Center, Tabriz University of Medical Sciences, Golgasht St, Tabriz, Iran.

Breast cancer is the most common cancer among women in terms of prevalence and mortality, and chemotherapy is one of the most effective treatments at higher stages. However, resistance to chemotherapy is the main obstacle in the treatment of this cancer. Accumulated evidence identified the PD-L1 protein as an essential protein in the development of different cancers. Abnormal expression of this protein in various tumor cells is linked to cancer development and inhibiting the function of immune cells, which correlated with reduced beneficial effects of chemotherapy drugs. In the present study, the effects of common chemotherapy drugs including doxorubicin, paclitaxel, and docetaxel on the expression of the PD-L1 gene were investigated by qRT-PCR before and after the treatment with these drugs in MD231, MD468, SKBR3 breast cancer cell lines. Also, the MTT test was applied to examine the effects of drugs on the growth and proliferation of cancer cells considering PD-L1 expression. The expression of the PD-L1 gene increased after 24 and 48 h of treatment with chemotherapy drugs. The obtained results indicate the enhancing effects of chemotherapy drugs on PD-L1 gene expression, which have a suppressive effect on the immune system against breast cancer. The use of these drugs as the first line of chemotherapy in triple-negative breast cancer is not recommended. However, there is still a need for further experimental and clinical research on the exact effects of these drugs on undesired immune cells exhaustion in breast cancer therapy.
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http://dx.doi.org/10.1007/s12032-021-01556-0DOI Listing
October 2021

HMGA2 Supports Cancer Hallmarks in Triple-Negative Breast Cancer.

Cancers (Basel) 2021 Oct 16;13(20). Epub 2021 Oct 16.

Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, J. B. Winsløws Vej 25, 3, DK-5000 Odense C, Denmark.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that exhibits a high proliferation rate and early metastasis leading to a poor prognosis. HMGA2 is a DNA binding transcriptional regulator implicated in tumorigenesis. Here, we demonstrate that the promoter is demethylated in TNBC tumors, leading to increased expression of HMGA2 at both mRNA and protein levels. Importantly, high HMGA2 levels in TNBC tumors are correlated with poor prognosis. To detail the role of HMGA2 in TNBC development and progression, we studied its effect on core cancer phenotypes. Stable knockdown of HMGA2 in TNBC cells revealed that HMGA2 may support cell proliferation, cell migration and invasion. In addition, HMGA2 knockdown decreased cancer stem cell (CSC) features. Importantly, we found that silencing HMGA2 inhibited NF-kB signaling and lead to decreased expression of the downstream molecules IL-6 and IL-8 and reduced STAT3 pathway activation. Our results demonstrate that HMGA2 supports cancer hallmarks in TNBC and may represent a promising target for TNBC treatment.
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http://dx.doi.org/10.3390/cancers13205197DOI Listing
October 2021

On-Site Detection of Carcinoembryonic Antigen in Human Serum.

Biosensors (Basel) 2021 Oct 14;11(10). Epub 2021 Oct 14.

Nanosensor Bioplatforms Laboratory, Chemistry and Chemical Engineering Research Center of Iran, Tehran 1496-813151, Iran.

Real-time connectivity and employment of sustainable materials empowers point-of-care diagnostics with the capability to send clinically relevant data to health care providers even in low-resource settings. In this study, we developed an advantageous kit for the on-site detection of carcinoembryonic antigen (CEA) in human serum. CEA sensing was performed using cellulose-based lateral flow strips, and colorimetric signals were read, processed, and measured using a smartphone-based system. The corresponding immunoreaction was reported by polydopamine-modified gold nanoparticles in order to boost the signal intensity and improve the surface blocking and signal-to-noise relationship, thereby enhancing detection sensitivity when compared with bare gold nanoparticles (up to 20-fold in terms of visual limit of detection). Such lateral flow strips showed a linear range from 0.05 to 50 ng/mL, with a visual limit of detection of 0.05 ng/mL and an assay time of 15 min. Twenty-six clinical samples were also tested using the proposed kit and compared with the gold standard of immunoassays (enzyme linked immunosorbent assay), demonstrating an excellent correlation (R = 0.99). This approach can potentially be utilized for the monitoring of cancer treatment, particularly at locations far from centralized laboratory facilities.
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http://dx.doi.org/10.3390/bios11100392DOI Listing
October 2021

The Analysis of Herpes Simplex Virus Type 1 (HSV-1)-Encoded MicroRNAs Targets: A Likely Relationship of Alzheimer's Disease and HSV-1 Infection.

Cell Mol Neurobiol 2021 Oct 18. Epub 2021 Oct 18.

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

Alzheimer's disease (AD), the most frequently diagnosed dementia, is a senile neurodegenerative disorder characterized by amnesia and cognitive dysfunction. Unfortunately, there are still no successful strategies to prevent AD progression. Thus, the vast majority of research focuses on recognizing risk factors for developing and progressing this disease. Human spirochetes, fungi, Borrelia burgdorferi, Chlamydophila pneumoniae, Helicobacter pylori, and human herpes simplex virus type 1 (HSV-1) have all been implicated in the development and progression of AD. Identifying microRNAs (miRs) encoded by DNA viruses has indicated that viruses can be evolved to exploit RNA silencing to regulate host and viral genes. Similar to host miR, v-miR can interact with the 3' untranslated region (UTR) of the target mRNA to regulate gene expression. Although HSV-1 can also encode various miRs, their significance in the development and progression of AD is still unclear. In the present study, utilizing the bioinformatics approach (R software and related packages), we analyzed the differentially expressed genes (DEGs) in AD samples (grey matter) of GSE37263 dataset obtained from the NCBI Gene Expression Omnibus (GEO). Then, the sequences of HSV-1-encoded-miRs were retrieved from miRbase, and their targets were predicted by miRDB. Afterward, the common genes between downregulated DEGs in AD and targets of HSV-1-encoded miRs were identified to shed new light on the relationship between HSV-1 infection and AD development. Our results have indicated that HSV-1-encoded-miRs can target the downregulated DEGs in AD, and these aberrant interactions can offer valuable diagnostic/prognostic biomarkers for affected patients.
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http://dx.doi.org/10.1007/s10571-021-01154-8DOI Listing
October 2021

Combination therapy with miR-34a and doxorubicin synergistically induced apoptosis in T-cell acute lymphoblastic leukemia cell line.

Med Oncol 2021 Oct 16;38(12):142. Epub 2021 Oct 16.

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

MicroRNAs are identified to take actively part in the development of different cancers. Reduced expression of tumor suppressor miRNAs leads to cancer cell development, so restoring the expression of these miRNAs can be an appropriate treatment option for cancer. Due to the heterogeneity of cancer cells, single-drug therapy often results in drug resistance. Therefore, the combination of chemotherapy with miRNA can be a powerful strategy for cancer treatment. In the current investigation, miR-34a mimic, and negative control were purchased and transfected using jetPEI reagents. Then the synergic effects of miR-34a in combination with doxorubicin were investigated on cell death of acute T-cell lymphoblastic leukemia Jurkat cell line, as well as the expression of some genes including Caspase-3, Bcl-2, and p53 which are involved in apoptosis. Our outcomes showed that this combination remarkably reduced the expression of the Bcl-2 gene, the target gene of miR-34a. According to the results of the MTT assay, the survival rate was significantly decreased compared to the untreated cells. Results of the flow cytometry assay and DAPI staining demonstrated an increased apoptosis rate of Jurkat cells in combination therapy. Moreover, cell cycle arrest was observed at the G2/M phase in cells that were treated with miR-34a/doxorubicin. Most importantly, we showed that the transfection of the Jurkat cells with miR-34a increased the sensitivity of these cells to doxorubicin. Furthermore, the combination of miR-34a and doxorubicin drug effectively increased apoptosis of treated cells. Therefore, this method can be used as an impressive treatment for T-ALL.
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http://dx.doi.org/10.1007/s12032-021-01578-8DOI Listing
October 2021

The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment.

Int J Mol Sci 2021 Oct 3;22(19). Epub 2021 Oct 3.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 516615731, Iran.

Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.
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http://dx.doi.org/10.3390/ijms221910719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509619PMC
October 2021

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers.

Int J Mol Sci 2021 Sep 27;22(19). Epub 2021 Sep 27.

Research Center for Evidence-Based Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran.

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11-1.82, and -value = 0.01). Besides, the level of tumor-infiltrating TIGITCD8 T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43-3.29, and -value < 0.001, and HR = 1.89, 95% CI: 1.36-2.63, and -value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10-2.68, and -value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGITCD8 T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.
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http://dx.doi.org/10.3390/ijms221910389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508743PMC
September 2021

A Systematic Review of the Tumor-Infiltrating CD8 T-Cells/PD-L1 Axis in High-Grade Glial Tumors: Toward Personalized Immuno-Oncology.

Front Immunol 2021 17;12:734956. Epub 2021 Sep 17.

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

Based on preclinical findings, programmed death-ligand 1 (PD-L1) can substantially attenuate CD8 T-cell-mediated anti-tumoral immune responses. However, clinical studies have reported controversial results regarding the significance of the tumor-infiltrating CD8 T-cells/PD-L1 axis on the clinical picture and the response rate of patients with high-grade glial tumors to anti-cancer therapies. Herein, we conducted a systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements to clarify the clinical significance of the tumor-infiltrating CD8 T-cells/PD-L1 axis and elucidate the impact of this axis on the response rate of affected patients to anti-cancer therapies. Indeed, a better understanding of the impact of this axis on the response rate of affected patients to anti-cancer therapies can provide valuable insights to address the futile response rate of immune checkpoint inhibitors in patients with high-grade glial tumors. For this purpose, we systematically searched Scopus, Web of Science, Embase, and PubMed to obtain peer-reviewed studies published before 1 January 2021. We have observed that PD-L1 overexpression can be associated with the inferior prognosis of glioblastoma patients who have not been exposed to chemo-radiotherapy. Besides, exposure to anti-cancer therapies, e.g., chemo-radiotherapy, can up-regulate inhibitory immune checkpoint molecules in tumor-infiltrating CD8 T-cells. Therefore, unlike unexposed patients, increased tumor-infiltrating CD8 T-cells in anti-cancer therapy-exposed tumoral tissues can be associated with the inferior prognosis of affected patients. Because various inhibitory immune checkpoints can regulate anti-tumoral immune responses, the single-cell sequencing of the cells residing in the tumor microenvironment can provide valuable insights into the expression patterns of inhibitory immune checkpoints in the tumor micromovement. Thus, administrating immune checkpoint inhibitors based on the data from the single-cell sequencing of these cells can increase patients' response rates, decrease the risk of immune-related adverse events development, prevent immune-resistance development, and reduce the risk of tumor recurrence.
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http://dx.doi.org/10.3389/fimmu.2021.734956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486082PMC
September 2021

Surface modification with cholesteryl acetyl carnitine, a novel cationic agent, elevates cancer cell uptake of the PEGylated liposomes.

Int J Pharm 2021 Sep 29;609:121148. Epub 2021 Sep 29.

Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, Iran. Electronic address:

The present study aimed to synthesize cholesteryl acetyl carnitine (CAC), and surface modify the PEGylated liposomes with the intention of enhanced cancer cell uptake. For this, CAC synthesis was performed in amine-free esterification conditions and then four liposomal formulations of unmodified, CAC/PEG, and CAC + PEG-modified were prepared by ethanol injection method. Cytotoxicity of the liposomes was investigated in A549 cells, followed by cellular uptake assessments of coumarin 6 (C6)-loaded liposomes. The results of ATR-FTIR, HNMR, and CNMR demonstrated successful formation of CAC. A molecular docking study showed efficient binding affinities rather than carnitine to the active site of four carnitine transporters. Liposomal formulations possessed spherical morphology with a mean particle size range of 112-138 nm, narrow size distribution, and negative surface charge. All formulations had low cytotoxicity at 0.5 mg/ml, but high cytotoxicity at around 2.5 mg/ml. The lowest IC50 was obtained for CAC modified liposomes. CAC + PEG-modified liposomes had the highest cellular uptake. In conclusion, CAC + PEG modification of liposomes is an effective approach for increasing A549 cellular uptake, with low cytotoxicity at commonly applied liposome concentrations. The elevated uptake may be due to the involvement of the organic cation transporter, cationic structure, and the metabolic preference of CAC in cancer cells.
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http://dx.doi.org/10.1016/j.ijpharm.2021.121148DOI Listing
September 2021

Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects.

Biomedicines 2021 Aug 24;9(9). Epub 2021 Aug 24.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran.

Immunotherapy is a new pillar of cancer therapy that provides novel opportunities to treat solid tumors. In this context, the development of new drugs targeting immune checkpoints is considered a promising approach in colorectal cancer (CRC) treatment because it can be induce specific and durable anti-cancer effects. Despite many advances in the immunotherapy of CRC, there are still limitations and obstacles to successful treatment. The immunosuppressive function of the tumor microenvironment (TME) is one of the causes of poor response to treatment in CRC patients. For this reason, checkpoint-blocking antibodies have shown promising outcomes in CRC patients by blocking inhibitory immune checkpoints and enhancing immune responses against tumors. This review summarizes recent advances in immune checkpoint inhibitors (ICIs), such as CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3 in CRC, and it discusses various therapeutic strategies with ICIs, including the double blockade of ICIs, combination therapy of ICIs with other immunotherapies, and conventional treatments. This review also delineates a new hopeful path in the combination of anti-PD-1/anti-PD-L1 with other ICIs such as anti-CTLA-4, anti-LAG-3, and anti-TIM-3 for CRC treatment.
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http://dx.doi.org/10.3390/biomedicines9091075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467932PMC
August 2021

Revealing the role of miRNA-489 as a new onco-suppressor factor in different cancers based on pre-clinical and clinical evidence.

Int J Biol Macromol 2021 Sep 22;191:727-737. Epub 2021 Sep 22.

Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran. Electronic address:

Recently, microRNAs (miRNAs) have shown to be potential therapeutic, diagnostic and prognostic targets in disease therapy. These endogenous non-coding RNAs contribute to regulation of different cellular events that are necessary for maintaining physiological condition. Dysregulation of miRNAs is correlated with development of various pathological events such as neurological disorders, cardiovascular diseases, and cancer. miRNA-489 is a new emerging miRNA and studies are extensively investigating its role in pathological conditions. Herein, potential function of miRNA-489 as tumor-suppressor in various cancers is described. miRNA-489 is able to sensitize cancer cells into chemotherapy by disrupting molecular pathways involved in cancer growth such as PI3K/Akt, and induction of apoptosis. The PROX1 and SUZ12 as oncogenic pathways, are affected by miRNA-489 in suppressing metastasis of cancer cells. Wnt/β-catenin as an oncogenic factor ensuring growth and malignancy of tumors is inhibited via miRNA-489 function. For enhancing drug sensitivity of tumors, restoring miRNA-489 expression is a promising strategy. The lncRNAs can modulate miRNA-489 expression in tumors and studies about circRNA role in miRNA-489 modulation should be performed. The expression level of miRNA-489 is a diagnostic tool for tumor detection. Besides, down-regulation of miRNA-489 in tumors provides unfavorable prognosis.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.09.089DOI Listing
September 2021

A scoping review on the potentiality of PD-L1-inhibiting microRNAs in treating colorectal cancer: Toward single-cell sequencing-guided biocompatible-based delivery.

Biomed Pharmacother 2021 Nov 22;143:112213. Epub 2021 Sep 22.

Immunology Research Center, Tabriz University of Medical Sciences, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran. Electronic address:

Tumoral programmed cell death ligand 1 (PD-L1) has been implicated in the immune evasion and development of colorectal cancer. Although monoclonal immune checkpoint inhibitors can exclusively improve the prognosis of patients with microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) colorectal cancer, specific tumor-suppressive microRNAs (miRs) can regulate multiple oncogenic pathways and inhibit the de novo expression of oncoproteins, like PD-L1, both in microsatellite stable (MSS) and MSI-H colorectal cancer cells. This scoping review aimed to discuss the currently available evidence regarding the therapeutic potentiality of PD-L1-inhibiting miRs for colorectal cancer. For this purpose, the Web of Science, Scopus, and PubMed databases were systematically searched to obtain peer-reviewed studies published before 17 March 2021. We have found that miR-191-5p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, miR-140-3p, and miR-15b-5p can inhibit tumoral PD-L1 in colorectal cancer cells. Besides inhibiting PD-L1, miR-140-3p, miR-382-3p, miR-148a-3p, miR-93-5p, miR-200a-3p, miR-200c-3p, miR-138-5p, and miR-15b-5p can substantially reduce tumor migration, inhibit tumor development, stimulate anti-tumoral immune responses, decrease tumor viability, and enhance the chemosensitivity of colorectal cancer cells regardless of the microsatellite state. Concerning the specific, effective, and safe delivery of these miRs, the single-cell sequencing-guided biocompatible-based delivery of these miRs can increase the specificity of miR delivery, decrease the toxicity of traditional nanoparticles, transform the immunosuppressive tumor microenvironment into the proinflammatory one, suppress tumor development, decrease tumor migration, and enhance the chemosensitivity of tumoral cells regardless of the microsatellite state.
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http://dx.doi.org/10.1016/j.biopha.2021.112213DOI Listing
November 2021

The Prognostic Value of CD133 in Predicting the Relapse and Recurrence Pattern of High-Grade Gliomas on MRI: A Meta-Analysis.

Front Oncol 2021 2;11:722833. Epub 2021 Sep 2.

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

Background: Cancer stem cells have been implicated in tumor relapse, tumor invasion, and cancer therapy resistance in high-grade gliomas; thus, characterizing cancer stem cell-related markers can help determine the prognosis of affected patients. Preclinical studies have reported that CD133 is implicated in tumor recurrence and cancer therapy resistance in high-grade gliomas; however, clinical studies have reported inconclusive results regarding its prognostic value in patients with high-grade gliomas.

Methods: We systematically searched the PubMed, Scopus, Web of Science, and Embase databases to obtain peer-reviewed studies published before March 10, 2021. Then, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. By applying the random-effect model, the effect size of studies investigating the progression-free survival (PFS), time to local recurrence (TTL), and time to distant recurrence (TTD) were calculated using RevMan version 5.4. The heterogeneity between the included studies was studied by the I index and Cochran's Q test. Egger test was performed on funnel plots to investigate the potential asymmetry and publication bias among the included studies using CMA version 2.

Results: With the 10% cut-off, CD133 protein overexpression is associated with the inferior PFS of patients with high-grade gliomas. Increased CD133 protein expression is associated with sooner distant tumor recurrence on MRI in glioblastoma patients and patients with high-grade gliomas and improved TTL on MRI in glioblastoma patients.

Conclusion: Based on the current evidence from 1086 patients with high-grade gliomas, CD133 overexpression is a valuable marker to predict tumor relapse and tumor recurrence patterns in patients with high-grade gliomas.
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http://dx.doi.org/10.3389/fonc.2021.722833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445366PMC
September 2021

Carbapenem resistance in clinical isolates from northwest Iran: high prevalence of OXA genes in sync.

Iran J Microbiol 2021 Jun;13(3):282-293

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

Background And Objectives: Carbapenem treatment for infections presently faces threats owing to the production of several types of carbapenemase enzymes, prevalence of which varies among different countries. We explored the current trend of antibiotic resistance in clinical isolates from North West Iran, sought the mechanism of carbapenem resistance and addressed the sequence type groups in carbapenem resistant (CRAB).

Materials And Methods: (n=112) isolates were recovered from various clinical specimens of patients admitted in internal, surgery, burn, infectious diseases and various ICUs wards. Genetically confirmed isolates were screened for carbapenem resistance by the Kirby-Bauer and E-test and the presence of , , IS genes by PCR. Sequence groups were identified by multiplex PCR.

Results: Multidrug-resistance (MDR) was a characteristic feature of all isolates. Frequency of oxacillinase genes in combination including / , /blaand / / was 82.1%, 36.6% and 25.8% respectively. Blending of oxacillinase and MBL genes was evident in eight positive and 7 positive isolates thereby depicting synchronous etiology of carbapenem resistance. Amongst CRAB isolates, 97.3% contained IS element and 50.9% belonged to the European clone II.

Conclusion: Synchronicity among with and IS gene was a hallmark of this investigation. Though origin or route of transmission was not elucidated in this study but co-existence among OXA and MBL producing genes is a therapeutic concern demanding strict surveillance strategies and control programs to halt the dissemination of these isolates in the hospital setting.
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http://dx.doi.org/10.18502/ijm.v13i3.6388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416588PMC
June 2021

Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin-deficient congenital muscular dystrophy type 1A.

J Clin Lab Anal 2021 Sep 16:e23930. Epub 2021 Sep 16.

Department of Medical Genetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran.

Background: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is occurred by mutations in LAMA2 gene that encodes the laminin α2 chain (merosin). MDC1A is a predominant subtype of congenital muscular dystrophy. Herein, we identified two missense mutations in LAMA2 gene in compound heterozygous status in an Iranian patient with MDC1A using whole-exome sequencing (WES).

Methods: In the present study, we evaluated genetic alterations in an Iranian 35-month-old boy with MDC1A and his healthy family using WES method. The identified mutations further confirmed by Sanger sequencing method. Finally, in silico analysis was conducted to further evaluation of molecular function of the identified genetic variants.

Results: We identified two potentially pathogenic missense mutations in compound heterozygous state (c.7681G>A p.Gly2561Ser and c.4840A>G p.Asn1614Asp) in LAMA2 gene as contributing to the MDC1A phenotype. The healthy parents of our proband are single heterozygous for identified mutations. These variants were found to be pathogenic by in silico analysis.

Conclusions: In general, we successfully identified LAMA2 gene mutations in an Iranian patient with MDC1A using WES. The identified mutations in LAMA2 gene can be useful in genetic counseling, prenatal diagnosis, and predicting prognosis of MDC1A.
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http://dx.doi.org/10.1002/jcla.23930DOI Listing
September 2021

Effect of Cellular-Based Artificial Antigen Presenting Cells Expressing ICOSL, in T-cell Subtypes Differentiation and Activation.

Adv Pharm Bull 2021 May 5;11(3):537-542. Epub 2020 Aug 5.

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

Effective and selective T-cell activation and proliferation during the T-cell expansion phase of a cellular adoptive immunotherapy method, challenging because recent studies revealed the importance of each subtype of T-cells in different immunologic strategies against tumors, like CAR-T cell therapies. Artificial antigen presenting cells (aAPCs) regarded as a natural way to manipulate T-cell subtypes activation and specific proliferation. In the current study, we utilized K562 cells based aAPC method expressing the ICOSL molecule, to evaluate T-cell subtypes differentiation rate and functional status. CD3+T-cells isolated and, co-cultured with ICOSL expressing K562 cells. After 4, 6, and 10 days selective CD markers of T-cell subtypes and each subtype's activity-related genes levels evaluated by qPCR methods. During the culture period, CD4+ Th related phenotype reduced continuously, and in day 10 of culture CD4+ T-cell's population significantly reduced ( =0.029). In contrast, the CD8+ population ratio was ascending during the study period but was not statistically significant. FoxP3+CD25-, Treg population ratio was significantly increased during the time in comparison with the control group, as well as memory T-cell phenotypic marker, CD127+, expressing cells ratio. T-cell subpopulations activity-related genes expression levels evaluated too, and the Th1 related IL-2 and INF-γ reductions observed alongside regulatory T-cells gene (IL-10) and Cytotoxic T-cell's related gene (Geranzym-A) elevations. We concluded that the K562-ICOSL based aAPC system is working and effective in T-cell short to medium culture periods, and this approach preparing relatively selective milieu for CD8+ T-Cell differentiation and much less Treg differentiation.
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http://dx.doi.org/10.34172/apb.2021.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421621PMC
May 2021

The Role of Hemoglobin Subunit Delta in the Immunopathy of Multiple Sclerosis: Mitochondria Matters.

Front Immunol 2021 24;12:709173. Epub 2021 Aug 24.

Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari, Italy.

Background: Although the exact pathophysiology of MS has not been identified, mitochondrial stress can be one of the culprits in MS development. Herein, we have applied microarray analysis, single-cell sequencing analysis, and study to elucidate the role of mitochondrial stress in PBMCs of MS patients.

Methods: For this purpose, we analyzed the GSE21942 and GSE138266 datasets to identify the DEGs and hub genes in the PBMCS of MS patients and describe the expression of shared genes in the different immune cells. The GO pathway analysis of DEGs and turquoise module genes were conducted to shed light on their biological significance. To validate the obtained results, the gene expression of , as the most remarkable DEG in the PBMCS of affected patients, was measured in the PBMCS of healthy donors, treatment-naïve MS patients, and MS patients treated with GA, fingolimod, DMF, and IFNβ-1α.

Results: Based on WGCNA and DEGs analysis, , and are the identified common genes in the PMBCS. Using single-cell sequencing analysis on PBMCS, we have characterized various cell populations in MS and illustrated the common gene expression on the different immune cells. Furthermore, GO pathway analysis of DEGs, and turquoise module genes have indicated that these genes are involved in immune responses, myeloid cell activation, leukocyte activation, oxygen carrier activity, and replication fork processing bicarbonate transport pathways. Our investigation has shown that expression in the treatment-naïve RRMS patients is significantly increased compared to healthy donors. Of interest, immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α have significantly decreased expression.

Conclusion: is one of the remarkably up-regulated genes in the PBMCS of MS patients. is substantially up-regulated in treatment-naïve MS patients, and immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α can remarkably down-regulate expression. Based on the currently available evidence, the cytoprotective nature of HBD against oxidative stress can be the underlying reason for HBD up-regulation in MS. Nevertheless, further investigations are needed to shed light on the molecular mechanisms of HBD in the oxidative stress of MS patients.
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http://dx.doi.org/10.3389/fimmu.2021.709173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421544PMC
August 2021

Glimpse into Cellular Internalization and Intracellular Trafficking of Lipid-Based Nanoparticles in Cancer Cells.

Anticancer Agents Med Chem 2021 Sep 5. Epub 2021 Sep 5.

Departments of Ophthalmology and Visual Sciences, Biomedical Engineering, and Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI . United States.

Lipid-based nanoparticles as drug delivery carriers have been mainly used for delivery of anti-cancer therapeutic agents. Lipid-based nanoparticles, due to their smaller particle size and similarity to cell membranes, are readily internalized into cancer cells. Interestingly, cancer cells also overexpress receptors for specific ligands including folic acid, hyaluronic acid, and transferrin on their surface. This allows the use of these ligands for surface modification of the lipid-based nanoparticle. These modifications then allow the specific recognition of these ligand-coated nanoparticles by their receptors on cancer cells allowing the targeted gradual intracellular accumulation of the functionalized nanoplatforms. These interactions could eventually enhance the internalization of desired drugs via increasing ligand-receptor mediated cellular uptake of the nanoplatforms. The cellular internalization of the nanoplatforms also varies and depends on their physicochemical properties including particle size, zeta potential, and shape. The cellular uptake is also influenced by the types of ligand internalization pathway utilized by cells such as phagocytosis, macropinocytosis, and multiple endocytosis pathways. In this review, we will classify and discuss lipid based nanoparticles engineered to express specific ligands, and are recognized by their receptors on cancer cell, and their cellular internalization pathways. Moreover, the intracellular fate of nanoparticles decorated with specific ligands and the best internalization pathways (caveolae mediated endocytosis) for safe cargo delivery will be discussed.
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http://dx.doi.org/10.2174/1871520621666210906101421DOI Listing
September 2021

The Impact of Nrf2 Silencing on Nrf2-PD-L1 Axis to Overcome Oxaliplatin Resistance and Migration in Colon Cancer Cells.

Avicenna J Med Biotechnol 2021 Jul-Sep;13(3):116-122

Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a key role in promoting chemoresistance in various cancers. PD-L1 is one of the downstream targets of the Nrf2 signaling pathway. This molecule has some beneficial impacts on tumors growth by inhibition of the immune system. This study aimed to investigate the potential role of the Nrf2-PD-L1 axis in the promotion of oxaliplatin resistance in colon cancer cells.

Methods: We examined Nrf2, PD- L1, and CD80 expression in the tumor and margin tissue samples from CRC patients. After that role of the Nrf2-PD-L1 axis in promotion of Oxaliplatin resistance was investigated.

Results: Our data revealed that Nrf2 and PD-L1 mRNA expressions were markedly higher in tumor tissues compared to margin tissues. The PD-L1 mRNA expression level was also increased in the resistant cells. However, Nrf2 expression was decreased in SW480/Res cells and increased in LS174T/Res cells. The inhibition of Nrf2 through siRNA treatment in SW480/Res and LS174T/Res cells has decreased the IC50 values of oxaliplatin. Inhibition of the Nrf2 has significantly increased the oxaliplatin-induced apoptosis, and reduced the migration in SW480/Res cells.

Conclusion: It is suggested that effective inhibition of Nrf2-PD-L1 signaling pathways can be considered as a novel approach to improve oxaliplatin efficacy in colon cancer patients.
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http://dx.doi.org/10.18502/ajmb.v13i3.6371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377400PMC
November 2020

Expression profiles of miR-196, miR-132, miR-146a, and miR-134 in human colorectal cancer tissues in accordance with their clinical significance : Comparison regarding KRAS mutation.

Wien Klin Wochenschr 2021 Aug 31. Epub 2021 Aug 31.

Phase I-Early Clinical Trials Unit, Department of Oncology, Antwerp University Hospital (UZA) and Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium.

Background: Colorectal cancer (CRC) is among the most widespread malignancies in the world. MicroRNA (miRNA) has been identified as an important modulator of the biological processes of the cells. This group of noncoding RNAs also has a pivotal function in the growth and development of human cancers, including CRC. Among these miRNAs, miR-196, miR-132, miR-146a, and miR-134 have fundamental impacts on the regulation of cancers. The current study aimed to investigate the involvement of these miRNAs in CRC patients.

Methods: In this study, 50 pairs of tumor and tumor margin samples of CRC patients were investigated to assess the expression levels of miR-196, miR-132, miR-146a, and miR-134 in this cancer. For this purpose, firstly, quantitative real-time PCR (qRT-PCR) was applied. Also, KRAS mutation and clinicopathological characteristics of the CRC patients were analyzed in the study groups.

Results: The findings demonstrated the overexpression of miR-196 (P-value = 0.0045) and miR-146a (P-value = 0.0033) in tumor tissues compared to controls. Conversely, the expression levels of miR-132 (P-value = 0.00032) and miR-134 (P-value < 0.0001) were downregulated in tumor tissues. Also, miR-146a was the only miRNA with significant expression change in the case of the KRAS gene mutation. Interestingly, the expression ratio of these miRNAs was significantly associated with some of the clinicopathological features of the patients, such as lymph node and distant metastases.

Conclusion: Our data demonstrated that these miRNAs appear to be promising novel biomarkers for early diagnosis of CRC and may pave the way for the future establishment of novel therapeutic options for CRC.
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http://dx.doi.org/10.1007/s00508-021-01933-9DOI Listing
August 2021

Nanoparticles modified with vasculature-homing peptides for targeted cancer therapy and angiogenesis imaging.

J Control Release 2021 Oct 27;338:367-393. Epub 2021 Aug 27.

Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

The two major challenges in cancer treatment include lack of early detection and ineffective therapies with various side effects. Angiogenesis is the key process in the growth, survival, invasiveness, and metastasis of many of cancerous tumors. Imaging of the angiogenesis could lead to diagnosis of tumors in the early stage and evaluation of the therapeutic responses. Angiogenic blood vessels express specific molecular markers different from normal blood vessels (in level or kind). This fact would make the tumor vasculature a suitable site to target therapeutics and imaging agents within the tumor. Surface modified nanoparticles using peptide ligands with high binding affinity to the vasculature markers, provide efficient delivery of therapeutic and imaging agents, while avoiding undesirable side effects. In this review, we discuss discoveries of various tumor targeting peptides useful for tumor angiogenesis imaging and targeted therapy with emphasis on surface modified nanomedicines using vasculature targeting peptides.
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http://dx.doi.org/10.1016/j.jconrel.2021.08.044DOI Listing
October 2021

Regulation of CTLA-4 and PD-L1 Expression in Relapsing-Remitting Multiple Sclerosis Patients after Treatment with Fingolimod, IFNβ-1α, Glatiramer Acetate, and Dimethyl Fumarate Drugs.

J Pers Med 2021 Jul 27;11(8). Epub 2021 Jul 27.

Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", 70124 Bari, Italy.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is characterized by inflammation which typically results in significant impairment in most patients. Immune checkpoints act as co-stimulatory and co-inhibitory molecules and play a fundamental role in keeping the equilibrium of the immune system. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed death-ligand 1 (PD-L1), as inhibitory immune checkpoints, participate in terminating the development of numerous autoimmune diseases, including MS. We assessed the CTLA-4 and PD-L1 gene expression in the different cell types of peripheral blood mononuclear cells of MS patients using single-cell RNA-seq data. Additionally, this study outlines how CTLA-4 and PD-L1 expression was altered in the PBMC samples of relapsing-remitting multiple sclerosis (RRMS) patients compared to the healthy group. Finally, it investigates the impact of various MS-related treatments in the CTLA-4 and PD-L1 expression to restrain autoreactive T cells and stop the development of MS autoimmunity.
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http://dx.doi.org/10.3390/jpm11080721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400811PMC
July 2021

Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection.

J Clin Med 2021 Aug 13;10(16). Epub 2021 Aug 13.

Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand 9717853577, Iran.

The coronavirus disease-2019 (COVID-19) pandemic has caused an enormous loss of lives. Various clinical trials of vaccines and drugs are being conducted worldwide; nevertheless, as of today, no effective drug exists for COVID-19. The identification of key genes and pathways in this disease may lead to finding potential drug targets and biomarkers. Here, we applied weighted gene co-expression network analysis and LIME as an explainable artificial intelligence algorithm to comprehensively characterize transcriptional changes in bronchial epithelium cells (primary human lung epithelium (NHBE) and transformed lung alveolar (A549) cells) during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our study detected a network that significantly correlated to the pathogenicity of COVID-19 infection based on identified hub genes in each cell line separately. The novel hub gene signature that was detected in our study, including and , may shed light on the pathogenesis of COVID-19, holding promise for future prognostic and therapeutic approaches. The enrichment analysis of hub genes showed that the most relevant biological process and KEGG pathways were the type I interferon signaling pathway, signaling pathway, cytokine-mediated signaling pathway, and defense response to virus categories, all of which play significant roles in restricting viral infection. Moreover, according to the drug-target network, we identified 17 novel FDA-approved candidate drugs, which could potentially be used to treat COVID-19 patients through the regulation of four hub genes of the co-expression network. In conclusion, the aforementioned hub genes might play potential roles in translational medicine and might become promising therapeutic targets. Further in vitro and in vivo experimental studies are needed to evaluate the role of these hub genes in COVID-19.
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http://dx.doi.org/10.3390/jcm10163567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397209PMC
August 2021

A Systematic Review on the Therapeutic Potentiality of PD-L1-Inhibiting MicroRNAs for Triple-Negative Breast Cancer: Toward Single-Cell Sequencing-Guided Biomimetic Delivery.

Genes (Basel) 2021 Aug 4;12(8). Epub 2021 Aug 4.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665811, Iran.

The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients' prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various intracellular singling pathways in TNBC. Therefore, we conducted the current systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to provide a comprehensive and unbiased synthesis of currently available evidence regarding the effect of PD-L1-inhibiting miRs restoration on TNBC development and tumor microenvironment. For this purpose, we systematically searched the Cochrane Library, Embase, Scopus, PubMed, ProQuest, Web of Science, Ovid, and IranDoc databases to obtain the relevant peer-reviewed studies published before 25 May 2021. Based on the current evidence, the restoration of miR-424-5p, miR-138-5p, miR-570-3p, miR-200c-3p, miR-383-5p, miR-34a-5p, miR-3609, miR-195-5p, and miR-497-5p can inhibit tumoral PD-L1 expression, transform immunosuppressive tumor microenvironment into the pro-inflammatory tumor microenvironment, inhibit tumor proliferation, suppress tumor migration, enhance chemosensitivity of tumoral cells, stimulate tumor apoptosis, arrest cell cycle, repress the clonogenicity of tumoral cells, and regulate various oncogenic signaling pathways in TNBC cells. Concerning the biocompatibility of biomimetic carriers and the valuable insights provided by the single-cell sequencing technologies, single-cell sequencing-guided biomimetic delivery of these PD-L1-inhibiting miRs can decrease the toxicity of traditional approaches, increase the specificity of miR-delivery, enhance the efficacy of miR delivery, and provide the affected patients with personalized cancer therapy.
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http://dx.doi.org/10.3390/genes12081206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391239PMC
August 2021

Antifungal Effects of Voriconazole-Loaded Nano-Liposome on FluconazoleResistant Clinical Isolates of , Biological Activity and and Gene Expression.

Assay Drug Dev Technol 2021 Oct 25;19(7):453-462. Epub 2021 Aug 25.

Department of Parasitology and Mycology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

ERG11 CDR1 CDR2 Candida albicans C. albicans was ERG11 CDR1, CDR2 C. albicans ERG11 C. albicans CDR1 C. albicans CDR2
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http://dx.doi.org/10.1089/adt.2020.1057DOI Listing
October 2021

A Systematic Review to Clarify the Prognostic Values of CD44 and CD44CD24 Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead.

Front Oncol 2021 9;11:689839. Epub 2021 Aug 9.

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

As a unique population of tumor bulk, cancer stem cells have been implicated in tumor relapse and chemoresistance in triple-negative breast cancer (TNBC). Therefore, understanding the phenotype of cancer stem cells can pave the way for introducing novel molecular targeted therapies for treating TNBC patients. Preclinical studies have identified CD44CD24 as a cancer stem cell phenotype; however, clinical studies have reported seemingly controversial results regarding the prognostic values of CD44 and CD44CD24 phenotype in TNBC patients. To critically review the clinicopathological significance and prognostic values of CD44 and CD44CD24 phenotype in TNBC patients, the Scopus, Embase, PubMed, and Web of Science databases were systematically searched to obtain the relevant records published before 20 October 2020. Based on nine included studies, CD44 and CD44CD24 phenotype are associated with inferior prognosis in TNBC patients. Moreover, these cancer stem cell markers have been associated with advanced tumor stage, tumor size, higher tumor grade, tumor metastasis, and lymphatic involvement in TNBC patients. Our evidence has also indicated that, unlike the treatment-naïve TNBC patients, the tumoral cells of chemoradiotherapy-treated TNBC patients can upregulate the CD44CD24 phenotype and establish an inverse association with androgen receptor (AR), leading to the inferior prognosis of affected patients. In summary, CD44 and CD44CD24 phenotype can be utilized to determine TNBC patients' prognosis in the pathology department as a routine practice, and targeting these phenotypes can substantially improve the prognosis of TNBC patients.
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http://dx.doi.org/10.3389/fonc.2021.689839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381605PMC
August 2021

Novel CAR T therapy is a ray of hope in the treatment of seriously ill AML patients.

Stem Cell Res Ther 2021 08 20;12(1):465. Epub 2021 Aug 20.

German Cancer Research Center, Toxicology and Chemotherapy, No. 2, Floor 4 Unit (G401), 69120, Heidelberg, Germany.

Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.
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http://dx.doi.org/10.1186/s13287-021-02420-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377882PMC
August 2021

Silencing of HMGA2 by siRNA Loaded Methotrexate Functionalized Polyamidoamine Dendrimer for Human Breast Cancer Cell Therapy.

Genes (Basel) 2021 07 20;12(7). Epub 2021 Jul 20.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 5166-15731, Iran.

The transcription factor high mobility group protein A2 (HMGA2) plays an important role in the pathogenesis of some cancers including breast cancer. Polyamidoamine dendrimer generation 4 is a kind of highly branched polymeric nanoparticle with surface charge and highest density peripheral groups that allow ligands or therapeutic agents to attach it, thereby facilitating target delivery. Here, methotrexate (MTX)- modified polyamidoamine dendrimer generation 4 (G4) (G4/MTX) was generated to deliver specific small interface RNA (siRNA) for suppressing HMGA2 expression and the consequent effects on folate receptor (FR) expressing human breast cancer cell lines (MCF-7, MDA-MB-231). We observed that HMGA2 siRNA was electrostatically adsorbed on the surface of the G4/MTX nanocarrier for constructing a G4/MTX-siRNA nano-complex which was verified by changing the final particle size and zeta potential. The release of MTX and siRNA from synthesized nanocomplexes was found in a time- and pH-dependent manner. We know that MTX targets FR. Interestingly, G4/MTX-siRNA demonstrates significant cellular internalization and gene silencing efficacy when compared to the control. Besides, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay demonstrated selective cell cytotoxicity depending on the folate receptor expressing in a dose-dependent manner. The gene silencing and protein downregulation of HMGA2 by G4/MTX-siRNA was observed and could significantly induce cell apoptosis in MCF-7 and MDA-MB-231 cancer cells compared to the control group. Based on the findings, we suggest that the newly developed G4/MTX-siRNA nano-complex may be a promising strategy to increase apoptosis induction through HMGA2 suppression as a therapeutic target in human breast cancer.
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http://dx.doi.org/10.3390/genes12071102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303903PMC
July 2021

The synergy between miR-486-5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells.

Biomed Pharmacother 2021 Sep 19;141:111925. Epub 2021 Jul 19.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486-5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486-5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486-5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486-5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24CD44 cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486-5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486-5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC.
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http://dx.doi.org/10.1016/j.biopha.2021.111925DOI Listing
September 2021
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