The Effects of Mesenchymal Stem Cells Loaded with Oncolytic Coxsackievirus A21 on Mouse Models of Colorectal Cancer.

BACKGROUND: Cancer is a major cause of death worldwide. Colorectal cancer is the second most common type. Additional treatments like chemotherapy and radiation therapy may be recommended. Developing new techniques is vital due to drug resistance and a lack of targeted therapies. OBJECTIVE: In this study, the effects of mesenchymal stem cells (MSCs) loaded with oncolytic Coxsackievirus A21 (CVA21) on a mouse model of CRC were investigated. METHODS: The therapeutic potency of MSCs loaded with oncolytic CVA21 were evaluated in an experimental mouse model of colorectal cancer which received an injection CT26 cells per mouse subcutaneously. Splenocyte proliferation index, lactate dehydrogenase (LDH) assay, nitric oxide (NO) production assessment, and cytokine assay (IFN-γ, IL-4, IL-10, and TGF-ß) in the splenocyte supernatant were all used to evaluate the impact of MSCs loaded with CVA21. RESULTS: The results of this study showed that the treatment of a mouse model of colorectal cancer with MSCs loaded with oncolytic CVA21 could significantly suppress the tumor growth, which was accompanied by stimulation of splenocytes proliferation index, an increase of NO and LDH. Also, MSCs loaded with oncolytic CVA21 increased the secretion of IFN-γ and decreased the secretion of IL-4, IL-10, and TGF-ß. CONCLUSION: The results of the current study suggest that MSCs loaded with oncolytic CVA21 therapy for the CRC mouse model may have some potential advantages. On the other hand, the results of the study showed that, in addition to activating the acquired immune system, the use of MSCs loaded with oncolytic CVA21 also stimulates the innate immune system by increasing level of nitric oxide.

Data envelopment analysis for scale elasticity measurement in the stochastic case: with an application to Indian banking.

In the nonparametric data envelopment analysis literature, scale elasticity is evaluated in two alternative ways: using either the technical efficiency model or the cost efficiency model. This evaluation becomes problematic in several situations, for example (a) when input proportions change in the long run, (b) when inputs are heterogeneous, and (c) when firms face ex-ante price uncertainty in making their production decisions. To address these situations, a scale elasticity evaluation was performed using a value-based cost efficiency model. However, this alternative value-based scale elasticity evaluation is sensitive to the uncertainty and variability underlying input and output data. Therefore, in this study, we introduce a stochastic cost-efficiency model based on chance-constrained programming to develop a value-based measure of the scale elasticity of firms facing data uncertainty. An illustrative empirical application to the Indian banking industry comprising 71 banks for eight years (1998-2005) was made to compare inferences about their efficiency and scale properties. The key findings are as follows: First, both the deterministic model and our proposed stochastic model yield distinctly different results concerning the efficiency and scale elasticity scores at various tolerance levels of chance constraints. However, both models yield the same results at a tolerance level of 0.5, implying that the deterministic model is a special case of the stochastic model in that it reveals the same efficiency and returns to scale characterizations of banks. Second, the stochastic model generates higher efficiency scores for inefficient banks than its deterministic counterpart. Third, public banks exhibit higher efficiency than private and foreign banks. Finally, public and old private banks mostly exhibit either decreasing or constant returns to scale, whereas foreign and new private banks experience either increasing or decreasing returns to scale. Although the application of our proposed stochastic model is illustrative, it can be potentially applied to all firms in the information and distribution-intensive industry with high fixed costs, which have ample potential for reaping scale and scope benefits.

Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: A comprehensive review and update.

During pregnancy, complicated connections are formed between a mother and a fetus. In a successful pregnancy, the maternal-fetal interface is affected by dynamic changes, and the fetus is protected against the mother's immune system. Natural killer (NK) cells are one of the immune system cells in the female reproductive system that play an essential role in the physiology of pregnancy. NK cells not only exist in peripheral blood (PB) but also can exist in the decidua. Studies have suggested multiple roles for these cells, including decidualization, control of trophoblast growth and invasion, embryo acceptance and maintenance by the mother, and facilitation of placental development during pregnancy. Natural killer T (NKT) cells are another group of NK cells that play a crucial role in the maintenance of pregnancy and regulation of the immune system during pregnancy. Studies show that NK and NKT cells are not only effective in maintaining pregnancy but also can be involved in infertility-related diseases. This review focuses on NK and NKT cells biology and provides a detailed description of the functions of these cells in implantation, placentation, and immune tolerance during pregnancy and their role in pregnancy complications.

Role of NKT cells in cancer immunotherapy-from bench to bed.

Natural killer T (NKT) cells are a specific T cell subset known to express the αß-T cell receptor (TCR) for antigens identification and express typical NK cell specifications, such as surface expression of CD56 and CD16 markers as well as production of granzyme. Human NKT cells are divided into two subgroups based on their cytokine receptor and TCR repertoire. Both of them are CD1-restricted and recognize lipid antigens presented by CD1d molecules. Studies have demonstrated that these cells are essential in defense against malignancies. These cells secret proinflammatory and regulatory cytokines that stimulate or suppress immune system responses. In several murine tumor models, activation of type I NKT cells induces tumor rejection and inhibits metastasis's spread. However, type II NKT cells are associated with an inhibitory and regulatory function during tumor immune responses. Variant NKT cells may suppress tumor immunity via different mechanisms that require cross-talk with other immune-regulatory cells. NKT-like cells display high tumor-killing abilities against many tumor cells. In the recent decade, different studies have been performed based on the application of NKT-based immunotherapy for cancer therapy. Moreover, manipulation of NKT cells through administering autologous dendritic cell (DC) loaded with α-galactosylceramide (α-GalCer) and direct α-GalCer injection has also been tested. In this review, we described different subtypes of NKT cells, their function in the anti-tumor immune responses, and the application of NKT cells in cancer immunotherapy from bench to bed.

Circulating CTRP5 in rheumatoid arthritis: an exploratory biomarker study.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory disease that is characterized by the overproduction of cytokines. Among the newly discovered cytokines are the adipokines which are primarily produced by and released from the adipose tissue and some immune cells, as well as synovial cells. they are involved in various immune responses and inflammatory processes. However, there are controversial data regarding the pro-inflammatory or anti-inflammatory effects of adipokines in different conditions. C1q/TNF-related protein 5 (CTRP5) is a newly identified adipokine and adiponectin paralogous protein, which has been shown to be correlated with inflammatory diseases. Accordingly, the present study was designed to investigate the serum levels of CTRP5 in RA patients and evaluate any possible alterations in comparison to healthy individuals. METHODS: Serum CTRP-5 levels were measured in 46 patients and 22 healthy controls by ELISA. The demographic, laboratory, and clinical features of the patients were also evaluated in order to find any correlations. RESULTS: Serum levels of CTRP-5 were significantly (p < 0.0001) higher in patients with RA (14.88 ± 25.55) compared to healthy controls (4.262 ± 2.374). There was a significant correlation between serum CTRP-5 levels and triglyceride (TG) (r: - 0.3010, p: 0.0498), as well as erythrocyte sedimentation rate (ESR) (r: 0.3139, p: 0.0457), C-reactive protein (CRP) (r: 0.5140, p: 0.0008), and the number of white blood cells (WBC) (r: 0.3380, p: 0.0307), which are considered as the markers indicating the extent of inflammation. Moreover, CTRP-5 was found to be correlated with interstitial lung disease (ILD) (r: 0.3416, p: 0.0385), a comorbidity associated with RA disease. CONCLUSION: This study demonstrated the increased level of circulating CTRP-5 in RA patients, which correlated with some inflammation-associated parameters and RA-associated comorbidities. Our observations suggest CTRP-5 as a putative inflammatory biomarker in RA, which may be useful besides the other disease-related markers.

Plumbagin attenuates Bleomycin-induced lung fibrosis in mice.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with limited treatment options. Plumbagin (PL) is an herbal extract with diverse pharmacological effects that have been recently used to treat various types of cancer. This study aims to explore the anti-fibrotic effect of PL and possible underlying mechanisms in IPF. METHODS: We used a bleomycin-induced experimental mouse model of lung fibrosis to assess the potential anti-fibrotic effect of PL. Histological analysis of lung tissue samples by H&E and Masson's trichrome staining and hydroxyproline assay was performed to evaluate the fibrotic alterations. ELISA and real-time quantitative PCR were conducted to determine the amount of tumor necrosis factor-alpha (TNFα), tumor growth factor-beta (TGF-ß), connective tissue growth factor (CTGF), and endothelin-1 (ET-1). RESULTS: Bleomycin exposure induced lung fibrosis, which was indicated by inflammation, collagen deposition, and structural damage. PL remarkably prevented bleomycin-induced lung fibrosis. Furthermore, PL significantly inhibited TNF-α and TGF-ß production. PL also diminished the upregulated expression of CTGF and ET-1 induced by bleomycin. CONCLUSION: Overall, our findings suggest PL as an anti-fibrotic agent acting via down-regulation of TGF-ß/CTGF or ET-1 axis, as well as TNF-α, to improve lung fibrosis.

The Trend of IgG and IgM Antibodies During 6-Month Period After the Disease Episode in COVID-19 Patients.

SARS-CoV-2 is a newly emerged coronavirus that has been widely transmitted since late 2019. It has caused a pandemic and infected roughly 450 million people globally.Hitherto, there is no approved anti-COVID-19 treatment, and vaccination is the only experienced preventive strategy. It mainly promotes the immune system, which is vital as a barrier against COVID-19. Humoral immunity (antibody-mediated immunity), among the various functions of the immune system against the coronavirus, plays an outstanding role in preventing infection. Consequently, we intended to assess IgG and IgM antibodies, 3 and 6 months after infection, to trend their titer and see how long COVID-19 antibodies remained in the human body. According to the research-designed criteria, only 98 patients out of 4500 suspected cases of SARS-CoV-2 infection remained for analysis. Blood samples were taken in three time periods (Day Zero (T 0), 3 and 6 months post-infection) and examined for COVID-19's IgG and IgM antibodies titration using the ELISA platform. Though both IgG and IgM were still detectable for some subjects at the end of the period, the decline in their levels (from 14.45 ± 5.88 to 2.52 ± 2.33 for IgG [85% decline of antibody titer] and 8.3 ± 0.99 to 0.37 ± 0.14 for IgM [95.5% decline of antibody titer]) was statistically significant (P value 0.0001). There was no correlation between gender and IgG and IgM levels. Although the levels of both antibodies were overall higher in the senior group (≥ 60 years old), statistical analysis showed a significantly higher level just for IgM in this group (P value: 0.005). Following the results, although anti-SARS-CoV-2 IgM and IgG antibodies can persist in the blood for 6 months post-infection, their levels steeply declined over time. Therefore, relying on humoral immunity as a trustworthy barrier against SARS-CoV-2 infection calls for more extensive research. Supplementary Information: The online version contains supplementary material available at 10.1007/s40995-022-01382-7.

A study on the in vitro and in vivo effects of aqueous and alcoholic extracts of Salvia mirzayanii on Leishmania major.

Salvia mirzayanii contains anti-hyperglycemic, antimicrobial, antioxidant, anti-inflammatory, and neuroprotective effects. The purpose of this study was to evaluate the anti-leishmanial efficacy of aqueous and alcoholic extracts of S. mirzayanii (both in vitro and in vivo) against Leishmania major. Aqueous and alcoholic extracts of S. mirzayanii were prepared and tested on L. major promastigotes and amastigotes. MTT test was used to evaluate the cytotoxicity of the plant against L. major. Flow cytometry was performed to assay apoptosis induced by 50 and 100 µg/ml of extracts on the promastigotes and macrophages. For the in vivo assay, the therapeutic effects of aqueous and alcoholic extracts of S. mirzayanii were tested in BALB/c mice. After 72 h, the IC50 value of aqueous and alcoholic extracts of S. mirzayanii against L. major promastigotes was 6.04 and 4.47, respectively. The inhibitory concentration (IC50) of aqueous and alcoholic extracts of S. mirzayanii to amastigotes were determined to be 47.78 µg/ml and 33.58 µg/ml, respectively. Flow cytometry revealed that the apoptosis of promastigotes using 100 µg/ml of aqueous and alcoholic extracts of S. mirzayanii was 5.81% and 5.39%, respectively, while apoptosis induced at 200 µg/ml were 5.09% and 70.71%, respectively. Lesion size was significantly decreased in in vivo experiments, and the survival rate of the treated mice improved in contrast to the control group. Given the efficacy of aqueous and alcoholic extracts of S. mirzayanii on promastigotes both in vitro and in vivo condition, the plant could be considered as a candidate source for the treatment of leishmaniosis.

Immune checkpoints and cancer development: Therapeutic implications and future directions.

Over the past few decades, different inhibitory receptors have been identified, which have played prominent roles in reducing anti-tumor immune responses. The role of immune checkpoint inhibitors in cancer was revealed by critical blockade of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) checkpoints. Immune checkpoint inhibitors, including anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (Atezolizumab, avelumab, and duravulumab), and anti-CTLA-4 (ipilimumab, tremelimumab), are currently FDA-approved treatment options for a broad range of cancer types. However, regarding immunotherapy advances in recent years, most studies have been focused on finding the antibodies against other inhibitory immune checkpoints in the tumor microenvironment such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin, and mucin domain 3 (TIM-3), B7-homolog 3 (B7-H3), V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA), diacylglycerol kinase-α (DGK-α), T cell immunoglobulin and ITIM domain (TIGIT), and B and T lymphocyte attenuator (BTLA). This immune checkpoint exerts differential inhibitory impacts on various types of lymphocytes. The suppression of immune responses demonstrates a surprising synergy with PD-1. Therefore, most antibodies against these immune checkpoints are undertaking clinical trials for cancer immunotherapy of advanced solid tumors and hematologic malignancies. In this review, we will summarize recent findings of immune checkpoint and the role of monoclonal antibodies in cancer immunotherapy targeting these receptors.

Functional significance of lymphocytes in pregnancy and lymphocyte immunotherapy in infertility: A comprehensive review and update.

During pregnancy, the fetal-maternal interface underlies several dynamic alterations to permit the fetus to be cultivated and developed in the uterus, in spite of being identifies by the maternal immune system. A large variety of decidual leukocyte populations, including natural killer cells, NKT cells, innate lymphoid cells, dendritic cells, B cells, T cells, subpopulations of helper T cells play a vital role in controlling the trophoblast invasion, angiogenesis as well as vascular remodeling. In contrast, several regulatory immunosuppressive mechanisms, including regulatory T cells, regulatory B cells, several cytokines and mediators are involved in maintain the homeostasis of immune system in the fetal-maternal interface. Nonetheless, aberrant alterations in the balance of immune inflammatory or immunosuppressive arms have been associated with various pregnancy losses and infertilities. As a result, numerous strategies have been developed to revers dysregulated balance of immune players to increase the chance of successful pregnancy. Lymphocyte immunotherapy has been developed through utilization of peripheral white blood cells of the husband or others and administered into the mother to confer an immune tolerance for embryo's antigens. However, the results have not always been promising, implying to further investigations to improve the approach. This review attempts to clarify the involvement of lymphocytes in contributing to the pregnancy outcome and the potential of lymphocyte immunotherapy in treatment of infertilities with dysregulated immune system basis.