Combination of IFN-gamma with STING agonist and PD-1 immune checkpoint blockade: a potential immunotherapy for gastric cancer.

Suppression of the cGAS-STING pathway is an immune escape mechanism in cancer cells. The critical role of this pathway in gastric cancer (GC) is not fully understood. Herein, we evaluated the effect of the interferon-gamma (IFN-gamma), STING agonist, PD-1 immune checkpoint blockade, and their combination on the cGAS-STING pathway in GC. Expression of cGAS and STING in tumor tissue samples and adjacent normal tissue (ANT) biopsies of fifty new GC patients was evaluated by quantitative real-time PCR (qRT-PCR). Moreover, cGAS and STING expression levels were examined in Peripheral Blood Mononuclear Cells (PBMC) samples of forty GC patients and twenty-five healthy subjects. The apoptosis rate of cancer cells was analyzed by Annexin V-FITC/PI. Cell proliferation was measured by the BrdU assay. Also, IFN-ß levels were evaluated in the supernatants of the treated groups. The cGAS expression was decreased in patients with distant metastasis. Co-cultures treated with IFN-gamma showed an elevated level of cGAS and STING expressions in PBMC and cancer cells. The rate of apoptosis increased in all the treatment groups. In addition, the rate of proliferation in PBMCs increased in different treated groups. The main role of PBMCs in cytotoxicity was determined by a comparative analysis of the viability of cells treated with all treatments, both with and without PBMCs. The production of IFN-ß was elevated in all treated groups. The current study suggests that a combination therapy using IFN-gamma, STING agonist, and anti-PD-1 antibody can provide a promising approach to the treatment of GC.

The role of genetics and gender specific differences in neurodegenerative disorders: Insights from molecular and immune landscape.

Neurodegenerative disorders (NDDs) are the most common neurological disorders with high prevalence and have significant socioeconomic implications. Understanding the underlying cellular and molecular mechanisms associated with the immune system can be effective in disease etiology, leading to more effective therapeutic approaches for both females and males. The central nervous system (CNS) actively participates in immune responses, both within and outside the CNS. Immune system activation is a common feature in NDDs. Gender-specific factors play a significant role in the prevalence, progression, and manifestation of NDDs. Neuroinflammation, in both inflammatory neurological and neurodegenerative conditions, is defined by the triggering of microglia and astrocyte cell activation. This results in the secretion of pro-inflammatory cytokines and chemokines. Numerous studies have documented the role of neuroinflammation in neurological diseases, highlighting the involvement of immune signaling pathways in disease development. Converging evidence support immune system involvement during neurodegeneration in NDDs. In this review, we summarize emerging evidence that reveals gender-dependent differences in immune responses related to NDDs. Also, we highlight sex differences in immune responses and discuss how these sex-specific influences can increase the risk of NDDs. Understanding the role of gender-specific factors can aid in developing targeted therapeutic strategies and improving patient outcomes. Ultimately, the better understanding of these mechanisms contributed to sex-dependent immune response in NDDs, can be critically usful in targeting of immune signaling cascades in such disorders. In this regard, sex-related immune responses in NDDs may be promising and effective targets in therapeutic strategies.

Imipenem resistance associated with amino acid alterations of the OprD porin in Pseudomonas aeruginosa clinical isolates.

Globally, the spread of carbapenem-resistant strains has limited treatment options for multidrug-resistant (MDR) Pseudomonas aeruginosa infections. This study aimed to determine the role of point mutations as well as the expression level of the oprD gene in the emergence of imipenem-resistant P. aeruginosa strains isolated from patients referred to Ardabil hospitals. A total of 48 imipenem-resistant clinical isolates of P. aeruginosa collected between June 2019 and January 2022 were used in this study. Detection of the oprD gene and its amino acid alterations was performed using the polymerase chain reaction (PCR) and DNA sequencing techniques. The expression level of the oprD gene in imipenem-resistant strains was determined using the real-time quantitative reverse transcription PCR (RT-PCR) method. All imipenem-resistant P. aeruginosa strains were positive for the oprD gene based on the PCR results, and also five selected isolates indicated one or more amino acid alterations. Detected amino acid alterations in the OprD porin were Ala210Ile, Gln202Glu, Ala189Val, Ala186Pro, Leu170Phe, Leu127Val, Thr115Lys, and Ser103Thr. Based on the RT-PCR results, the oprD gene was downregulated in 79.1% of imipenem-resistant P. aeruginosa strains. However, 20.9% of strains showed overexpression of the oprD gene. Probably, resistance to imipenem in these strains is associated with the presence of carbapenemases, AmpC cephalosporinase, or efflux pumps. Owing to the high prevalence of imipenem-resistant P. aeruginosa strains due to various resistance mechanisms in Ardabil hospitals, the implementation of surveillance programs to reduce the spread of these resistant microorganisms along with rational selection and prescription of antibiotics is recommended.

Current understanding of epigenetics role in melanoma treatment and resistance.

Melanoma is the most aggressive form of skin cancer resulting from genetic mutations in melanocytes. Several factors have been considered to be involved in melanoma progression, including genetic alteration, processes of damaged DNA repair, and changes in mechanisms of cell growth and proliferation. Epigenetics is the other factor with a crucial role in melanoma development. Epigenetic changes have become novel targets for treating patients suffering from melanoma. These changes can alter the expression of microRNAs and their interaction with target genes, which involves cell growth, differentiation, or even death. Given these circumstances, we conducted the present review to discuss the melanoma risk factors and represent the current knowledge about the factors related to its etiopathogenesis. Moreover, various epigenetic pathways, which are involved in melanoma progression, treatment, and chemo-resistance, as well as employed epigenetic factors as a solution to the problems, will be discussed in detail.

Oncolytic virotherapy as promising immunotherapy against cancer: mechanisms of resistance to oncolytic viruses.

Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.

Lay abstract Using viruses in the treatment of cancer goes back to the early 20th century. One of the promising fields in cancer virotherapy is viruses' ability to preferentially lysis tumor cells, either naturally or genetically engineered cells; these viruses are termed 'oncolytic viruses.' As with other therapeutic strategies, resistance to the oncolytic viruses is the main challenge in their application in clinical trials. This review summarizes the mechanisms of resistance to oncolytic viruses and the strategies that have been used to overcome these challenges.

Innate immune response in systemic autoimmune diseases: a potential target of therapy.

Innate immunity refers to defense mechanisms that are always present, ready to combat microbes and other offending agents. Innate immunity acts as a first-line defense and activates the conventional immune responses; however, it has been speculated that the importance of innate immunity in initiation and development of some disorders is more than just the "first line of defense". Autoimmune diseases, caused by immune system overactivation, are among the most challenging scientific and clinical problems, and there is still much to be learned about their pathogenesis. We aimed to provide a comprehensive overview of available documents about the role of innate immunity in systemic autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, polymyositis, and systemic sclerosis. This study highlights the innate immunity pathways or molecules that are under investigation for therapy of these diseases.

Neopterin serum level does not reflect the disease activity in rheumatoid arthritis: A systematic review and meta-analysis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by established chronic inflammation. Neopterin levels have extensively been considered as a marker of immune activation during inflammation. In this study, we performed a systematic evaluation and meta-analysis to elucidate the overall relationship between neopterin concentration and RA disease activity. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a systematic review was conducted using PubMed, Google Scholar, Web of Science, and Scopus from 2000 to August 2020. The Newcastle-Ottawa scale was used to assess the quality of eligible studies. The effect size (ES) and corresponding 95% confidence intervals (CIs) were calculated to evaluate this association. A total of 15 studies out of 98 met our inclusion criteria. The pooled analysis found that patients with RA had high level of neopterin; however, no statistically significant association was found between neopterin levels with high, intermediate, and low diseases activity score (DAS)-28 (ES =11.18, 95% CI: 6.02 to 16.34, and I2 = 91.8%; and ES = 8.57, 95% CI: 6.41 to 10.37, and I2 = 99.5%; and ES =12.45, 95% CI: -1.68 to 26.58, and I2 = 99.0%, respectively). Our results indicated that the neopterin concentration does not seem to have any substantial impact on the RA disease activity.

Interaction of CpG-oligodeoxynucleotides with Toll like receptor 9 induces apoptosis and modulates metaloproteinase-2 activity in human intestinal epithelium.

Recent reports have indicated different effects of immunostimulatory sequences containing CpG-Oligodeoxynucleotides (ODN) on various immune cells. However, the exact role of CpG-ODN in the human gut is unclear. In the present study, we assessed potential effects of CpG-ODN on non lymphoid cell (intestinal epithelial cell line HT-29) on a dose-response and time-course basis. Intestinal epithelial cell line HT-29 was treated with CpG-ODN (CpG 2006) and lipopolysaccharide (LPS) at 5, 10, 25, 50 microg/ ml and 1, 5, 10 microg/ ml concentrations, respectively. Following treatments, dose- response and time-course cytotoxicity using a colorimetric method, Metaloproteinase-2 (MMP-2) activity (using gelatin zymography) and apoptosis (using annexin-v flowcytometry method) assays were performed. Chloroquine treatment was also used for its inhibitory effect on endosomal acidification process to verify specific CpG-ODN and Toll Like Receptor 9 (TLR9) interactions. Cytotoxicity analysis of CpG-ODN showed that CpG-ODN increased significantly the proliferation of CpG-ODN treated cells, as compared to untreated cells, at concentrations of 10-25 microg/ml (p < 0.05). Overall MMP-2 activity analysis showed significant differences between treated and untreated cells. However, minimal changes were observed when MMP-2 activity was assessed per cell. Moreover, CpG-ODN treated cells demonstrated an increasing apoptosis rate of 0.8 %, 6.46 % and 14.21% at concentrations of 5, 10, 25 microg/ml, respectively. Collectively, our data indicated that intestinal epithelial cell line HT-29 is highly responsive to CpG effect in vitro and exhibits modified activities. The direct CpG-ODN and TLR-9 interactions in HT-29 cells could provide new approaches in malignant tumor therapeutic strategies.