Virus-Specific T Cells: Promising Adoptive T Cell Therapy Against Infectious Diseases Following Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for various hematologic disorders. Due to the bone marrow suppression and its long recovery period, secondary infections, like cytomegalovirus (CMV), Epstein-Bar virus (EBV), and adenovirus (AdV), are the leading causes of morbidity and mortality in HSCT cases. Drug resistance to the antiviral pharmacotherapies makes researchers develop adoptive T cell therapies like virus-specific T cell therapy. These studies have faced major challenges such as finding the most effective T cell expansion methods, isolating the expected subtype, defining the functionality of the end-cell population, product quality control, and clinical complications after the injection. This review discusses the viral infections after HSCT, T cells characteristics during chronic viral infection, application of virus-specific T cells (VSTs) for refractory infections, standard methods for producing VSTs and their limitation, clinical experiences on VSTs, focusing on outcomes and side effects that can be helpful in decision-making for patients and further researches.

The role of tumor microenvironment on cancer stem cell fate in solid tumors.

In the last few decades, the role of cancer stem cells in initiating tumors, metastasis, invasion, and resistance to therapies has been recognized as a potential target for tumor therapy. Understanding the mechanisms by which CSCs contribute to cancer progression can help to provide novel therapeutic approaches against solid tumors. In this line, the effects of mechanical forces on CSCs such as epithelial-mesenchymal transition, cellular plasticity, etc., the metabolism pathways of CSCs, players of the tumor microenvironment, and their influence on the regulating of CSCs can lead to cancer progression. This review focused on some of these mechanisms of CSCs, paving the way for a better understanding of their regulatory mechanisms and developing platforms for targeted therapies. While progress has been made in research, more studies will be required in the future to explore more aspects of how CSCs contribute to cancer progression. Video Abstract.

Functionality of immune cells in COVID-19 infection: development of cell-based therapeutics.

Introduction: In late December 2019, a sudden severe respiratory illness of unknown origin was reported in China. In early January 2020, the cause of COVID-19 infection was announced a new coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Examination of the SARS-CoV-2 genome sequence revealed a close resemblance to the previously reported SARS-CoV and coronavirus Middle East respiratory syndrome (MERS-CoV). However, initial testing of drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. One of the key strategies to fight the virus is to look at how the immune system works against the virus, which has led to a better understanding of the disease and the development of new therapies and vaccine designs. Methods: This review discussed the innate and acquired immune system responses and how immune cells function against the virus to shed light on the human body's defense strategies. Results: Although immune responses have been revealed critical to eradicating infections caused by coronaviruses, dysregulated immune responses can lead to immune pathologies thoroughly investigated. Also, the benefit of mesenchymal stem cells, NK cells, Treg cells, specific T cells, and platelet lysates have been submitted as promising solutions to prevent the effects of infection in patients with COVID-19. Conclusion: It has been concluded that none of the above has undoubtedly been approved for the treatment or prevention of COVID-19, but clinical trials are underway better to understand the efficacy and safety of these cellular therapies.

The Role of Epithelial Mesenchymal Transition (EMT) in Pathogenesis of Cardiotoxicity: Diagnostic & Prognostic Approach.

Cancer is one of the diseases, which it is not still completely curable; the existing treatments are associated with many complications, that double its complexity. One of the causes of cancer cell metastasis is Epithelial Mesenchymal Transition (EMT). Recently study demonstrated that EMT cause cardiotoxicity and heart diseases such as heart failure, hypertrophy and fibrosis. This study evaluated molecular and signaling pathway, which lead to cardiotoxicity via EMT. It was demonstrated that the processes of inflammation, oxidative stress and angiogenesis were involved in EMT and cardiotoxicity. The pathways related to these processes act as a double-edged sword. In relation to inflammation and oxidative stress, molecular pathways caused apoptosis of cardiomyocytes and cardiotoxicity induction. While the angiogenesis process inhibits cardiotoxicity despite the progression of EMT. On the other hand, some molecular pathways such as PI3K/mTOR despite causing the progression of EMT lead to the proliferation of cardiomyocytes and prevent cardiotoxicity. Therefore, it was concluded that the identification of molecular pathways can help in designing therapeutic and preventive strategies to increase patients' survival.

Molecular pathways in glioblastoma-derived stem cells to identify effective drug agents: A bioinformatics study.

Background and Aim: Glioblastoma multiform (GBM) is considered as one of the malignant brain tumors that affect a wide range of people every year. Cancer stem cells, as essential factors, are resistant to chemotherapy drugs and complicate treatments. Therefore, finding critical molecular pathways in GBM-derived stem cells, and selecting the appropriate drug agents can prove more effective treatment approaches for GBM. Method: In this study, using RNA-Seq data, we performed continuous bioinformatics analyses and examined the up-and down-regulated genes from GBM-derived stem cells samples. Afterward, we separated the signaling pathways using the KEGG database and measured the protein interactions with the STRING database. Then, using the Drug matrix database, we nominated drugs that could affect these genes. Results: The first 20 pathways on tumorigenesis and 41 up-regulated and 73 down-regulated genes were selected. These genes were most active in the pathways involved in cell division, metabolism, cytoskeleton, cell adhesion molecules, and extracellular space. We then examined the candidate genes and the approach of the drugs that target these genes. Chlorambucil, cyclosporine A, doxorubicin, and etoposide were selected as the drug agents. Conclusion: Using integrated bioinformatics analyses, it was found that prominent genes in the cell cycle and cytoskeletal pathways are more expressed in cancer stem cells and that Chlorambucil, cyclosporine A, doxorubicin, and etoposide can be effective compounds to attenuate these cells.

Investigating the molecular mechanisms of Tamoxifen on the EMT pathway among patients with breast cancer.

Tamoxifen is one of the most used drugs for breast cancer. This study aimed to investigate the effect of the Tamoxifen mechanism on the epithelial-mesenchymal transition (EMT) pathway among breast cancer patients due to its resistance to breast cancer cells. We selected the appropriate datasets from the GEO database using continuous and integrated bioinformatics analysis. We examined the signaling pathways, gene ontology, and protein association of genes after classifying the gene expression profile. Finally, we confirmed the candidate genes using the GEPIA database. Two groups were defined for gene expression profiles. The first group in which the expression profile of genes increased after Tamoxifen was evaluated using the expression profile of genes that decreased in the EMT pathway. The second group was the opposite of the first group. 253 genes in the first group and 302 genes in the second group were shared. The genes in the first group were involved in various pathways of cell death, focal adhesion, and cellular aging. The second group was more involved in different phases of the cell cycle. Finally, MYLK, SOCS3, and STAT5B proteins from the first group and BIRC5, PLK1, and RAPGAP1 proteins from the second group were selected as candidate proteins in connection with the effect of Tamoxifen on the EMT pathway. We evaluated Tamoxifen's effect on the EMT pathway more accurately. However, for a closer look at Tamoxifen, more studies need to be done on target genes and proteins to clarify their role.

The Impact of Different Cell Culture Mediums on CD8+ T Cells Expansion: A Bioinformatics Study.

Objective: Different Cell Culture medias can affect the expansion of T cells. The aim of this study is to assess signaling pathways, protein interactions and genes in T cells cultured in different common T cell expansion medias to select the best candidate. Materials and Methods: In this in silico observational study, with the use of bioinformatics analysis and the use of enrichment databases, gene expression profiles were investigated using microarray analysis. Results: The results of this study were the joint selection of 26 upregulated genes and 59 downregulated genes that were involved in SREBP control of lipid synthesis, co-stimulatory signal during T-cell activation mitosis and chromosome dynamics, telomeres, telomerase, and cellular aging signal pathways. Conclusion: Using bioinformatics analyzes, integrated and regular genes were selected as common genes CD80, LST1, ATM and ITM2B 4-1BBL, Akt inhibitor, interleukin 7 and 15 expansion media.

Association of Interleukin 10 (IL-10) Gene Polymorphism (819T > C) with Susceptibility to Acute Myeloid Leukemia: A Meta-Analysis.

BACKGROUND: Studies reported an association between interleukin (IL)-10 -819T>C polymorphism and the risk of developing Acute myeloid leukemia (AML), however due to inconsistency among these results, relationship between IL-10 -819T>C polymorphism and AML remained unclear. We herein performed this meta-analysis to investigate the association of IL-10 -819T >C polymorphism with the risk of AML. METHODS: A systematic search through PubMed, Embase, Scopus, Cochrane Library and OpenGrey was performed from inception to Jan 2021. Odds ratios (OR) with their corresponding 95% confidence intervals (CI) for five possible genetic models were calculated. Heterogeneity was assessed using the Cochran Q test and the I2 statistic. A total of 404 AML cases and 635 healthy controls were included in our meta-analysis. RESULTS: Our results indicated no statically significant association between IL-10 -819T>C polymorphism and the risk of developing AML; dominant model (OR=0.87, 95% CI=0.42-1.81); recessive model (OR=1.17, 95% CI = 0.43-3.16); allelic model (OR=1.00, 95% CI=0.54-1.88); CC vs. TT (OR=1.00,95% CI=0.30-3.36); and TC vs. TT (OR=0.80, 95%CI =0.46-1.37). CONCLUSION: IL-10 -819T > C polymorphism is not associated with the risk of AML. However further studies focusing on other parameters such as sex, gene-gene interactions and environmental factors are required to reveal the true association of IL-10 -819T > C polymorphism with AML.

Molecular study of the proliferation process of beta cells derived from pluripotent stem cells.

BACKGROUND: Diabetes mellitus (DM) is a chronic metabolic disorder, increasing in the number of patients and poses a severe threat to human health. Significant advances have been made in DM treatment; the most important of which is differentiation and proliferation of beta cells from IPSCs. METHODS: Data were collected from PUBMED at various time points up to the academic year of 2020. The related keywords are listed as follows: "Induced pluripotent stem cell", "Proliferation", "Growth factor", "Small molecule", "cardiotoxicity" and "Scaffold." RESULT: The use of growth factors along with small molecules can be a good strategy for beta-cell proliferation. Also, proliferation of beta cells on nanofibers scaffolds can create a similar in vivo environment, that leads to increased function of beta-cell. Some transcription factors that cause beta cells proliferation play an important role in inflammation; so, it is essential to monitor them to prevent inflammation. CONCLUSION: Finally, the simultaneous use of growth factors, micronutrients and scaffolds can be an excellent strategy to increase the proliferation and function of beta cells derived from IPSCs.

Assessment of the Effect of Infliximab on Immunomodulation Properties of Mesenchymal Stem Cells In Vitro.

Purpose: Mesenchymal stem cells (MSCs) have immunomodulatory traits making them a promising choice in the treatment of inflammatory diseases such as graft-versus-host disease (GVHD). Tumor necrosis factor-alpha (TNFα) is a major player of inflammatory disease which is blocked by infliximab to reduce the inflammation. The present study aims to assess the infliximab effects on the anti-inflammatory properties of MSCs. Methods: In this study, bone marrow mesenchymal stem cells (BMMSCs) were co-cultured with peripheral blood mononuclear cells (PBMCs) of GVHD patients in the presence of 10, 20 and 30 µg/mL of infliximab for 48 and 72 hours. The mRNA expression of indoleamine-2,3- dioxygenase (IDO) and inducible nitric oxide synthase (iNOS), as well as the secreted amount of prostaglandin E2 (PGE2) in the culture supernatant, were examined. Results: The results of this study show that the expression of IDO and iNOS genes, as well as the secretion amount of PGE2 in co-cultured groups raised dramatically, compared to the culture of BMMSCs or PBMCs alone. In co-culture groups containing infliximab, the expression of IDO and iNOS and also the amount of released PGE2 was significantly decreased compared to the control group without infliximab. However, no difference was found in the expression of assayed factors between 48 and 72 hours of treatments. Conclusion: As an anti-TNFα agent, infliximab can decrease the inflammation in the microenvironment of MSCs, which might mitigate the immunomodulatory effects of MSCs. These effects of anti-inflammatory agents on the immunomodulatory capacity of MSCs should be considered in MSC therapy.

Development of an mRNA-LNP Vaccine against SARS-CoV-2: Evaluation of Immune Response in Mouse and Rhesus Macaque.

Among the vaccines have been developed thus far against SARS-CoV-2, the mRNA-based ones have demonstrated more promising results regarding both safety and efficacy. Two remarkable features of the mRNA vaccines introduced by the Pfizer/BioNTech and Moderna companies are the use of (N1-methyl-pseudouridine-) modified mRNA and the microfluidics-based production of lipid nanoparticles (LNPs) as the carrier. In the present study, except Anti-Reverse Cap Analog (ARCA), no other nucleoside analogs were employed to synthesize Spike-encoding mRNA using the in vitro transcription (IVT) method. Furthermore, LNPs were prepared via the ethanol injection method commonly used for liposome formation as an alternative for microfluidics-based approaches. The produced mRNA-LNP vaccine was evaluated for nanoparticles characteristics, encapsulation and transfection efficiencies, in vitro cytotoxicity as well as stability and storability. The safety of vaccine was assessed in Balb/c mice injected with mRNA-LNPs containing 10 µg of spike-encoding mRNA. Eventually, the vaccine efficacy in inducing an immune response against SARS-CoV-2 was studied in Balb/c and C57BL/6 mice (received either 1 or 10 µg of mRNA) as well as in rhesus macaque monkeys (infused with mRNA-LNPs containing 100 µg of mRNA). The ELISA and virus neutralizing test (VNT) results showed a significant augmentation in the level of neutralizing antibodies against SARS-CoV-2. Moreover, the ELISA assay showed virus-specific IFN-γ secretion in immunized mice as a marker of TH1 cell-based immune response, whereas favorably no change in the production of IL-4 was detected.

Pre-Transplantation Serum Parathyroid Hormone Influences the Number of Mobilized CD34+ Hematopoietic Stem Cells in Autologous Hematopoietic Stem Cell Transplantation.

BACKGROUND: Parathyroid hormone (PTH) is a calcium homeostasis regulator and can affect bone marrow niche. PTH leads to the bone marrow stem cell niche expansion as well as the induction of stem cell mobilization from the bone marrow into peripheral blood. In this study, we evaluated the association between pre- transplantation serum PTH levels and the number of circulating CD34+ cells along with the platelets/white blood cells (Plt/WBC) engraftment in patients who underwent autologous Hematopoietic Stem Cell Transplantation. METHODS: Subjects for the study were 100 patients who received autologous hematopoietic stem cell transplantation (auto-HSCT), retrospectively. Serum levels of PTH, calcium, phosphorus, and alkaline phosphatase were measured before mobilization. Their impacts were measured on the number of mobilized CD34+ hematopoietic stem cells, and Plt/WBC engraftment. RESULTS: High levels of serum PTH (> 63.10 pg/mL) was significantly associated with higher number of CD34+ cells in peripheral blood after granulocyte- colony stimulating factor (G-CSF)-induced mobilization (p= 0.079*). Serum calcium at low levels were associated with higher number of circulating CD34+ cells post mobilization. Pre- transplantation serum levels of phosphorus and alkaline phosphatase on CD34+ numbers were not statistically significant. Serum Plt/WBC engraftment was not improved in presence of high levels of serum PTH. CONCLUSION: We suggested that serum PTH levels before transplantation could be influential in raising the number of circulating CD34+ hematopoietic stem cell after mobilization.

The risk of pancreatic adenocarcinoma following SARS-CoV family infection.

COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was "double-stranded RNA binding" and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.

Plasma exchange followed by convalescent plasma transfusion in COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerged pandemic disease with no specific treatment. One of the potential treatments in newly found infectious disease is plasma exchange (PE) with convalescent plasma transfusion (CPT). This case series aimed to evaluate the primary PE and CPT in five Iranian COVID-19 patients. METHODS: Five patients with confirmed COVID-19 who had acute respiratory distress syndrome and were supported by mechanical ventilation were treated with two consecutive PE containing fresh frozen plasma (FFP) of healthy donors and 0.9 % saline solution containing 5 % human albumin. Thereafter, CPT was performed just like PE, except that the FFP in this step was substituted with convalescent ABO-matched plasma. Clinical and laboratory factors were evaluated before and after treatments. RESULTS: Three to Four patients showed lower body temperature and improved oxygen saturation as well as reduced laboratory factors such as c-reactive protein, lactate dehydrogenase, creatine phosphokinase (total and myocardial isoform), aspartate aminotransferase, blood urea nitrogen, bilirubin (total and direct), D-dimer, interleukin-6, and CD4+/CD8 + T cells ratio initially after PE and continued to improve so that they were discharged. One patient due to secondary hemophagocytic lymphohistiocytosis and extensive lung fungal infection was expired. DISCUSSION: Overall, the PE followed by CPT was beneficial in reducing acute inflammation led to a considerable improvement in patients' clinical features. It seems that PE along with CPT could provide clearance of pro-inflammatory mediators as well as the positive effects of CPT. Controlled studies are required to confirm the effect of PE/CPT compared with other therapeutic approaches.

Contradictory Effect of Notch1 and Notch2 on Phosphatase and Tensin Homolog and its Influence on Glioblastoma Angiogenesis.

Many genes induce angiogenesis in tumors, and among them, Notch family genes have received particular attention due to their extensive network of connections with other genes active in this function. Suppression of angiogenic signaling has been studied in various cancers, confirming Notch's fundamental and extensive role. According to studies, four Notch genes work independently with many genes such as vascular endothelial growth factor, phosphatase and tensin homolog, Phosphoinositide 3-kinase/Akt, and matrix metalloproteinases, and so many other genes, as well as proteins (such as hypoxia-inducible factor-1 alpha) significantly affect tumor angiogenesis. Notch1 regular activity in a healthy person causes angiogenesis in body tissues, controlled by normal Notch2 activity. However, in many cases of glioblastoma, whether on patients or tumor xenografts or in vivo models, a mutation in one of these two essential genes or at least one of the genes and proteins that affected by them can cause better angiogenesis in hypoxic conditions and lead to become an invasive tumor. In this review, we examined the contrasting activity of Notch1 and Notch2 and the signaling cascade that each generates in the angiogenesis of glioblastoma, the most invasive cancer of the central nervous system.

Reviewing the role of cardiac exosomes in myocardial repair at a glance.

Exosome-based therapy is an emerging novel approach for myocardial infarction (MI) treatment. Exosomes are identified as extracellular vesicles that are produced within multivesicular bodies in the cells' cytosols and then are secreted from the cells. Exosomes are 30-100 nm in diameter that are released from viable cells and are different from other secreted vesicles such as apoptotic bodies and microvesicles in their origin and contents such as RNAs, proteins, and nucleic acid. The recent advances in exosome research have demonstrated the role of these bionanovesicles in the physiological, pathological, and molecular aspects of the heart. The results of in vitro and preclinical models have shown that exosomes from different cardiac cells can improve cardiac function following MI. For example, mesenchymal stem cells (MSCs) and cardiac progenitor cells (CPCs) containing exosomes can affect the proliferation, survival, and differentiation of cardiac fibroblasts and cardiomyocytes. Moreover, MSCs- and CPCs-derived exosomes can enhance the migration of endothelial cells. Exosome-based therapy approaches augment the cardiac function by multiple means, such as reducing fibrosis, stimulation of vascular angiogenesis, and proliferation of cardiomyocytes that result in replacing damaged heart tissue with newly generated functional myocytes. This review article aims to briefly discuss the recent advancements in the role of secreted exosomes in myocardial repair by focusing on cardiac cells-derived exosomes.

The effect of melatonin on in vitro maturation fertilization and early embryo development of mouse oocytes and expression of HMGB1 gene in blastocysts

Antioxidants are commonly used for maturation, fertilization and early development of embryos. Melatonin as an antioxidant have been recently proven to be useful for the assisted reproductive technology. In the present study, we evaluated the roles of melatonin in the in vitro maturation, fertilization, development and also the gene expression of high mobility group box-1 (HMGB1) in the blastocysts. The immature oocytes of BDF1 mice were transferred to the media containing different doses of melatonin (10-6, 10-9, 10-12 M). The blastocysts that developed under in vitro fertilization from each group were stained to determine the cell number of embryos and analyzed to determine the expression level of HMGB1 by real-time PCR. The most effective doses of melatonin for maturation of oocytes were 10-6 and 10-12M (P<0.05). Fertilization rate, early development and the cell number of blastocysts were significantly higher in the group that treated with 10-12 M of melatonin comparing to the other groups. The HMGB1 expression decreased in groups that treated with 10-6M and 10-9M of melatonin and increased in the group that treated with 10-12 M of melatonin, but did not show a significant difference (p˃0.05). From the results, it may be concluded that the melatonin could be effective when the embryos undergo maturation, fertilization and early developmental processes. The HMGB1 expression, as a marker of early development in mice embryos, increased in the groups that treated with low doses of melatonin

Signaling pathways involved in chronic myeloid leukemia pathogenesis: The importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells.

OBJECTIVES: Chronic myeloid leukemia (CML) is a myeloid clonal proliferation disease defining by the presence of the Philadelphia chromosome that shows the movement of BCR-ABL1. In this study, the critical role of the Musashi2-Numb axis in determining cell fate and relationship of the axis to important signaling pathways such as Hedgehog and Notch that are essential for self-renewal pathways in CML stem cells will be reviewed meticulously. MATERIALS AND METHODS: In this review, a PubMed search using the keywords of Leukemia, signaling pathways, Musashi2-Numb was performed, and then we summarized different research works . RESULTS: Although tyrosine kinase inhibitors such as Imatinib significantly kill and remove the cell with BCR-ABL1 translocation, they are unable to target BCR-ABL1 leukemia stem cells. The main problem is stem cells resistance to Imatinib therapy. Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway. CONCLUSION: The control of molecules /pathways downstream of the BCR-ABL1 and targeting Musashi2-Numb can be an effective therapeutic strategy for treatment of chronic leukemia stem cells. While Musashi2 is a poor prognostic marker in leukemia, in treatment and strategy, it has significant diagnostic value.

Autophagy regulation and its role in normal and malignant hematopoiesis.

Autophagy, the molecular machinery of self-eating, plays a dual role of a tumor promoter and tumor suppressor. This mechanism affects different clinical responses in cancer cells. Autophagy is targeted for treating patients resistant to chemotherapy or radiation. Limited reports investigate the significance of autophagy in cancer therapy, the regulation of hematopoietic and leukemic stem cells and leukemia formation. In the current review, the role of autophagy is discussed in various stages of hematopoiesis including quiescence, self-renewal, and differentiation.