Update on Mesenchymal Stem Cells: A crucial Player in Cancer Immunotherapy.

The idea of cancer immunotherapy has spread, and it has made tremendous progress with the advancement of new technology. Immunotherapy, which serves to assist the natural defenses of the body in eradicating cancerous cells, is a remarkable achievement that has revolutionized both cancer research and cancer treatments. Currently, the use of stem cells in immunotherapy is widespread and shares a special characteristic, including cancer cell migration, bioactive component release, and immunosuppressive activity. In the context of cancer, mesenchymal stem cells (MSCs) are rapidly being identified as vital stromal regulators of tumor progression. MSCs therapy has been implicated in treating a wide range of diseases, including bone damage, autoimmune diseases, and particularly hematopoietic abnormalities, providing stem cell-based therapy with an extra dimension. Moreover, the implication of MSCs does not have ethical concerns, and the complications known in pluripotent and totipotent stem cells are less common in MSCs. MSCs have a lot of distinctive characteristics that, when coupled, make them excellent for cellular-based immunotherapy and as vehicles for gene and drug delivery in a variety of inflammations and malignancies. MSCs can migrate to the inflammatory site and exert immunomodulatory responses via cell-to-cell contacts with lymphocytes by generating soluble substances. In the current review, we discuss the most recent research on the immunological characteristics of MSCs, their use as immunomodulatory carriers, techniques for approving MSCs to adjust their immunological contour, and their usages as vehicles for delivering therapeutic as well as drugs and genes engineered to destroy tumor cells.

Serological assay for anti-SARS-CoV-2 antibodies improves sensitivity of diagnosis of COVID-19 patients.

The emergence of SARS-CoV-2, responsible for coronavirus disease-2019 (COVID-19), has become a major global health problem. The molecular testing is the accepted assay in SARS-CoV-2 detection. However, there are several reasons for low sensitivity by RNA detection, causing challenges in SARS-CoV-2 diagnosis. In this study, we aimed to investigate serological patterns of SARS-CoV-2 specific IgM, and IgG in 111 hospitalized, and 34 recovered COVID-19 patients and 311 prepandemic normal serum specimens by ELISA. The validity of the ELISA kits was evaluated using samples from normal and recovered cases. This showed that 98.1%, and 98.4% of prepandemic normal samples were negative for anti-SARS-CoV-2 IgM, and IgG, respectively. Assessment of 34 COVID-19 confirmed recovered patients showed a test sensitivity of 76.5%, and 94.1% for IgM, and IgG, respectively. In COVID-19 hospitalized patients, 42.3%, and 51.4% were positive for IgM and IgG, respectively. Viral RNA was not detectable in 43.3% of the hospitalized patients. Interestingly, combined molecular and serological testing improved the sensitivity of COVID-19 diagnosis to 79.6%. Using PCR with combined IgM/IgG results augmented the patient diagnosis sensitivity to 65.3% and 87.2% in ≤ 7 days, and > 7 days intervals, respectively. Overall, serological tests in combination with PCR can improve the sensitivity of COVID-19 diagnosis.

The emerging role of microRNA in regulating the mTOR signaling pathway in immune and inflammatory responses.

The mechanistic/mammalian target of rapamycin (mTOR) is considered to be an atypical protein kinase that plays a critical role in integrating different cellular and environmental inputs in the form of growth factors, nutrients and energy and, subsequently, in regulating different cellular events, including cell metabolism, survival, homeostasis, growth and cellular differentiation. Immunologically, mTOR is a critical regulator of immune function through integrating numerous signals from the immune microenvironment, which coordinates the functions of immune cells and T cell fate decisions. The crucial role of mTOR in immune responses has been lately even more appreciated. MicroRNAs (miRNAs) are endogenous, small, noncoding single-stranded RNAs that act as molecular regulators involved in multiple processes during immune cells development, homeostasis, activation and effector polarization. Several studies have recently indicated that a range of miRNAs are involved in regulating the phosphoinositide 3-kinase/protein kinase B/mTOR (PI3K/AKT/mTOR) signaling pathway by targeting multiple components of this signaling pathway and modulating the expression and function of these targets. Current evidence has revealed the interplay between miRNAs and the mTOR pathway circuits in various immune cell types. The expression of individual miRNA can affect the function of mTOR signaling to determine the cell fate decisions in immune responses through coordinating immune signaling and cell metabolism. Dysregulation of the mTOR pathway/miRNAs crosstalk has been reported in cancers and various immune-related diseases. Thus, expression profiles of dysregulated miRNAs could influence the mTOR pathway, resulting in the promotion of aberrant immunity. This review summarizes the latest information regarding the reciprocal role of the mTOR signaling pathway and miRNAs in orchestrating immune responses.

Prevalence of Anti-SARS-CoV-2 Specific Antibodies in Health-Care Workers Compared to General Population during an Early Phase of the Pandemic, Tehran-Iran.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly transmits in general population, mainly between health-care workers (HCWs) who are in close contact with patients. OBJECTIVE: To study the seropositivity of HCWs as a high-risk group compared to general population. METHODS: 72 samples were obtained from HCWs working in Masih Daneshvari hospital as one of the main COVID-19 admission centers in Tehran, during April 4 to 6, 2020. Also we collected 2021 blood samples from general population. The SARS-CoV-2 specific IgM, and IgG antibodies in the collected serum specimens were measured by commercial ELISA kits. RESULTS: Based on the clinical manifestations, 25.0%, 47.2%, and 27.8% of HCWs were categorized as symptomatic with typical symptoms, symptomatic with atypical symptoms, and asymptomatic, respectively. Symptomatic individuals with typical and atypical symptoms were 63.2% and 36.8% positive in RT-PCR test, respectively. Anti-SARS-CoV-2 IgM and IgG antibodies were detected in 15.3% and 27.8% of HCWs samples, respectively. Antibody testing in the general population indicated that SARS-CoV-2 specific IgM and IgG were found in (162/2021) 8%, and (290/2021) 14.4%, respectively. The frequency of positive cases of IgM and IgG were significantly increased in HCWs compared to general population (p= 0.028 for IgM and p= 0.002 for IgG). CONCLUSION: The frequency of SARS-CoV-2 specific antibodies in HCWs was higher than general population indicating a higher viral transmission via close exposure with COVID-19 patients.

Osteosarcoma: A comprehensive review of management and treatment strategies.

Osteosarcoma, a bone cancer usually seen in children and young adults, is generally a high-grade malignancy presented by extreme metastases to the lungs. Osteosarcoma has a tendency for appearing in bones with rapid growth rate. The etiology of osteosarcoma is multifaceted and poorly understood. A molecular consideration of this disease will lead to a directed tumor treatment. The present treatment for osteosarcoma comprises of an arrangement of systemic chemotherapy and wide surgical resection. Survival rate is increased by the progress of destructive systemic chemotherapies. So, the development of new treatment approaches for metastatic osteosarcoma is essential. Immunomodulation has been used in clinical settings. Through targeting surface antigens expressed on tumor cells, particular antibodies and exploitation of cellular immunotherapy against sarcomas have been confirmed to be effective as cancer therapeutics. In this article, we have reviewed epidemiology, etiology, pathogenesis, diagnosis, and treatment of osteosarcoma and we have focused on different methods of immunotherapy including vaccines, cell-based immunotherapy, cytokines, and monoclonal antibodies.

The role of epigenetic changes in preeclampsia.

Preeclampsia (PE) is a disorder affecting 2-10% of pregnancies and has a major role for perinatal and maternal mortality and morbidity. PE can be occurred by initiation of new hypertension combined with proteinuria after 20 weeks gestation, as well as various reasons such as inflammatory cytokines, poor trophoblast invasion can be related with PE disease. Environmental factors can cause epigenetic changes including DNA methylation, microRNAs (miRNAs), and histone modification that may be related to different diseases such as PE. Abnormal DNA methylation during placentation is the most important epigenetic factor correlated with PE. Moreover, changes in histone modification like acetylation and also the effect of overregulation or low regulation of miRNAs or long noncoding RNAs on variety signaling pathways can be resulted in PE. The aim of this review is to describe of studies about epigenetic changes in PE and its therapeutic strategies.

mTOR Signaling pathway as a master regulator of memory CD8+ T-cells, Th17, and NK cells development and their functional properties.

The mammalian target of rapamycin (mTOR) is a member of the evolutionary phosphatidylinositol kinase-related kinases (PIKKs). mTOR plays a pivotal role in the regulation of diverse aspects of cellular physiology such as body metabolism, cell growth, protein synthesis, cell size, autophagy, and cell differentiation. Immunologically, mTOR has a fundamental part in controlling and shaping diverse functions of innate and adaptive immune cells, in particular, T-cell subsets differentiation, survival, and metabolic reprogramming to ultimately regulate the fate of diverse immune cell types. Researchers report that rapamycin, a selective mTOR inhibitor, and immunosuppressive agent, has surprising immunostimulatory effects on inducing both quantitative and qualitative aspects of virus-specific memory CD8+ T-cells differentiation and homeostasis in a T-cell-intrinsic manner. The mTOR signaling pathway also plays a critical role in dictating the outcome of regulatory T cells (Treg), T helper 17 (Th17) cells, and natural killer (NK) cells proliferation and maturation, as well as the effector functions and cytotoxic properties of NK cells. Manipulation of mTOR activity is a critical therapeutic approach for pharmacological agents that seek to inhibit mTOR. This approach should enhance specific memory CD8 + T-cells responses and induce fully functional effector properties of NK cells to provoke their antitumor and antiviral activities.

Nanocurcumin improves regulatory T-cell frequency and function in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis is a chronic incapacitating disease of the central nervous system, it has been reported that the disturbance in the development and function of Treg subpopulations is associated with the disability status in the RRMS. Accordingly, in the current study, the objective was to specify nanocurcumin effects on Treg cells frequency, and function in patients with RRMS. METHODS AND MATERIALS: 50 patients with RRMS were enrolled in this study in which 25 were treated for at least six months with nanocurcumin capsules while the other half received placebo capsules as the control group. The blood sample was collected prior to the administration of nanocurcumin and placebo capsules and following six months. At baseline and after a six-month treatment, the frequency of Treg lymphocytes, the expression of transcription factor related to these cells and the secretion levels of cytokines were assessed by flowcytometry, real-time PCR and ELISA, respectively. RESULTS: A significant reduction was observed in the proportion of peripheral Treg cell frequency, and the levels of TGF-ß, IL-10 and FoxP3 expression in patients with RRMS. Our data revealed that the frequency of Treg cells (p = .0027), the expression of FoxP3 (p = .0005), TGF-ß (p = .0005), and IL-10 (p = .0002) and the secretion levels of the TGF-ß (p = .033), and IL-10 (p = .029) in cultured PBMCs are increased in nanocurcumin-treated group compared to placebo group. CONCLUSION: The results of the current work indicated that nanocurcumin is capable of restoring the frequency and function of Treg cells in MS patients.

Altered frequency of CD8+ CD11c+ T cells and expression of immunosuppressive molecules in lymphoid organs of mouse model of colorectal cancer.

CD11c is a member of the ß2-integrin family typically used to define myeloid dendritic cells (DCs). Recent reports identify CD11c-expressing CD8+ T cells as a new subset of CD8+ regulatory T cells (Treg). Evidence exists that CD11c+ CD8+ T cells may exert their effector or regulatory functions under different conditions. To date, no studies have addressed the frequency of CD11c+ T cells in cancer. Limited evidence exists in terms of expression of immune-checkpoint receptors, programmed cell death protein 1 (PD-1) and T-lymphocyte-associated antigen 4 (CTLA-4), as well as forkhead box P3 (Foxp3) in mouse lymphoid organs. Here, we have assessed CD11c+ CD8+ and CD11c+ CD4+ T cells, Foxp3, PD-1, and CTLA-4 expressing CD4+ T cells and CD8+ T cells in different tissues from three groups of male BALB/c mice-young, mature, and those with colorectal cancer (CRC). Analysis of CD3+ CD11c+ T cells in the bone marrow (BM), spleen, and lymph nodes (LN) in each group showed a higher percentage of CD3+ CD11c+ T cells in the BM from all groups and in the lymphoid organs of the cancer group compared with the young and mature groups. CD4low and CD4high cell fractions in mice BM have different expression patterns for Foxp3 and CTLA-4. We have observed a higher frequency of CD8+ PD-1+ T cells in the BM, spleen, and LN of CRC mice compared with normal mice. T-cell exhaustion is associated with inhibitory receptor PD-1. According to the regulatory roles of CD11c expression in CD8+ T cells, we have proposed that the elevated percentage of CD11c, Foxp3, CTLA-4, and PD-1 expressing T cells were associated with immune response dysregulation in CRC.

Disturbed Th17/Treg balance, cytokines, and miRNAs in peripheral blood of patients with Behcet's disease.

Impaired inflammatory immune cells have been implicated in the pathogenesis of Behcet's disease (BD). In the current study, we aimed to evaluate the frequency of T helper (Th) 17 and regulatory T (Treg) cells, cytokine secretion, the expression of transcription factors related to Th17 and Treg cells, and microRNAs (miRNAs) targeting these transcription factors in BD patients. Blood samples from 47 BD patients and 58 healthy subjects were drawn, and the peripheral blood mononuclear cells (PBMCs) were separated and isolated. The frequency of Th17 and Treg cells was assessed using flow cytometry. Transcription factors related to these cells and miRNAs targeting these transcription factors were quantified using real-time polymerase chain reaction. Finally, the levels of associated cytokines were measured using enzyme-linked immunosorbent assay. A significant reduction in the percentage of Treg cell frequency and the levels of interleukin (IL)-10 and forkhead box P3 messenger RNA (mRNA) expressions were observed. The proportion of Th17 cells was notably increased, which was accompanied by a increased levels of IL-17, IL-23, and retinoic acid-related orphan receptor ɣ (RORɣt) mRNA expressions in BD patients. The level of Th17-associated cytokines in the supernatant was found to be elevated in BD patients. T-cell-associated miRNA expression levels, miR-25, miR-106b, miR-326, and miR-93 were significantly upregulated, while miR-146a and miR-155 levels were lower in PBMCs of patients with BD when compared with the controls. The increase in the proportion of Th17 cells alongside the decrease in Treg cells are possibly the involving factors in the pathogenesis of BD. Therefore, the evaluation of immune cells and related miRNA profile may serve as both prognostic biomarker and therapeutic approach in treating patients with BD.

Update on Fc receptor-like (FCRL) family: new immunoregulatory players in health and diseases.

INTRODUCTION: Fc receptor-like (FCRL) molecules, as recently identified members of the immunoglobulin superfamily (IgSF), are preferentially expressed by B-cells. They have variable number of extracellular immunoglobulin-like domains and cytoplasmic activating ITAMs and/or inhibitory ITIMs. FCRL1-5 are dominantly expressed in different stages of B-cells development. But, FCRL6 is preferentially expressed in different subsets of T-cells and NK cells. FCRL1-5 could regulate different features of B-cell evolution such as development, differentiation, activation, antibody secretion and isotype switching. Areas covered: Improved understanding of FCRL expression may grant B-cells and finally its signaling pathways, alone or in cooperation with other signaling molecules, as interesting new targets for diagnostic, monitoring and immunotherapeutic modalities; although further investigations remain to be defined. Recent investigations on different family members of FCRL proteins have substantiated their differential expression on different tissues, malignancies, immune related disease and infectious diseases. Expert opinion: FCRLs restricted expressions in normal B-cells and T-cell subsets accompanied with their overexpression in B-cell malignancies introduce them as logical candidates for the development of antibody- and cell-based immunotherapy approaches in B-cell malignancies, immune-mediated and infectious diseases. FCRLs would be applied as attractive and specific targets for immunodiagnostic approaches, clinical prognosis as well as disease monitoring of relevant patients.

The Importance of Checking Leishmania Promastigotes Viability in the Proteomics Analysis of Secretions.

OBJECTIVE: The aim of the present study was to compare the efficacy of checking the viability of Leishmania promastigote by flow cytometry using propidium iodide (PI) and microscopic method using trypan blue (TB) before proteomics analysis of the secretions. METHODS: The promastigotes (6×109) of Leishmania infantum in the exponential growth phase were transferred to serum-free media. Then, the viability of promastigotes was checked and compared with flow cytometry and microscopic method at 0, 2, 3, 4, 5, and 72 h. RESULTS: Flow cytometry did not show many dead cells at 0 to 4 h, and the viability was approximately 98%. The percentage of the dead promastigotes increased to 8% at 5 h and 17% at 72 h. Meanwhile, the microscopic method using TB did not show any dead cell after 4 and 72 h, and the viability was 100%. CONCLUSION: The present study confirms the importance of flow cytometry using PI in checking the viability of Leishmania promastigotes, especially before the proteomics analysis of the secretions. It also shows that flow cytometry using PI is more sensitive than microscopic method using TB.

Epigenetic modifications and epigenetic based medication implementations of autoimmune diseases.

Recent genome-wide association studies have documented a number of genetic variants to explain mechanisms underlying autoimmune diseases. However, the precise etiology of autoimmune diseases remains largely unknown. Epigenetic mechanisms like alterations in the post-translational modification of histones and DNA methylation may potentially cause a breakdown of immune tolerance and the perpetuation of autoreactive responses. Recently, several studies both in experimental models and clinical settings proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in autoimmune diseases, in some cases based on mechanistical observations. Epigenetic therapy already being employed in hematopoietic malignancies may also be associated with beneficial effects in autoimmune diseases. In this review, we will discuss on what we know and expect about the treatment of autoimmune disease based on epigenetic aberrations.

Application of nanoparticle technology in the treatment of Systemic lupus erythematous.

Systemic lupus erythematous (SLE) is a chronic heterogeneous multisystem autoimmune disease characterized by loss of tolerance to self-antigens and production of numerous autoantibodies. Current therapeutic approaches used to treat inflammatory autoimmune diseases are associated with debilitating side effects. In spite of significant advances in therapeutic options and increased understanding of the pathogenesis, novel therapeutic approaches are needed for treatment of SLE. Nanoparticle-based delivery systems that selectively deliver drugs to inflamed tissue or specific cell have the potential to improve drug delivery. This article reviews recent nanotechnology-based therapeutics strategies that are being developed for the treatment of SLE.