SARS-CoV-2 NSP5 antagonizes MHC II expression by subverting histone deacetylase 2.

SARS-CoV-2 interferes with antigen presentation by downregulating major histocompatibility complex (MHC) II on antigen-presenting cells, but the mechanism mediating this process is unelucidated. Herein, analysis of protein and gene expression in human antigen-presenting cells reveals that MHC II is downregulated by the SARS-CoV-2 main protease, NSP5. This suppression of MHC II expression occurs via decreased expression of the MHC II regulatory protein CIITA. CIITA downregulation is independent of the proteolytic activity of NSP5, and rather, NSP5 delivers HDAC2 to the transcription factor IRF3 at an IRF-binding site within the CIITA promoter. Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a mechanism by which SARS-CoV-2 limits MHC II expression, thereby delaying or weakening the subsequent adaptive immune response.

Suppression of academics and school training in Iran during the "Woman, Life, Freedom" revolution.

For the past 6 months, there has been an ongoing revolution in Iran after the brutal death of Zhina (Mahsa) Amini in morality police custody. Iranian universities' professors and students have been on the frontline of this revolution and have been fired or sentenced. On the other hand, Iranian high schools and primary schools have been under suspected toxic gas attack. In the current article, the latest status of oppression of the university students and professors and toxic gas attack on primary and high schools in Iran has been evaluated.

From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy.

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

Vascular mimicry: changing the therapeutic paradigms in cancer.

Cancer is a major problem in the health system, and despite many efforts to effectively treat it, none has yet been fully successful. Angiogenesis and metastasis are considered as major challenges in the treatment of various cancers. Researchers have struggled to succeed with anti-angiogenesis drugs for the effective treatment of cancer, although new challenges have emerged in the treatment with the emergence of resistance to anti-angiogenesis and anti-metastatic drugs. Numerous studies have shown that different cancers can resist anti-angiogenesis drugs in a new process called vascular mimicry (VM). The studies have revealed that cells resistant to anti-angiogenesis cancer therapies are more capable of forming VMs in the in vivo and in vitro environment, although there is a link between the presence of VM and poor clinical outcomes. Given the importance of the VM in the challenges facing cancer treatment, researchers are trying to identify factors that prevent the formation of these structures. In this review article, it is attempted to provide a comprehensive overview of the molecules and main signaling pathways involved in VM phenomena, as well as the agents currently being identified as anti-VM and the role of VM in response to treatment and prognosis of cancer patients.

Association of IL-10, IL-18, and IL-33 genetic polymorphisms with recurrent pregnancy loss risk in Iranian women.

Recurrent pregnancy loss (RPL) is a heterogeneous disease with three or more consecutive abortions before 20 weeks of pregnancy. Recently, inflammatory factors such as interleukins (IL) have been found to be a significant factor in the RPL. The objective of this study was to investigate the association between RPL and IL-10 (rs1800896), IL-18 (rs1946518) and IL-33 (rs1929992) genes polymorphisms in Iranian women. The study participants consisted of 300 women with RPL and the control group comprised of 300 healthy women with successful delivery. Genomic DNA was extracted from peripheral blood, and genotyping was performed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). There were no significant differences in the frequencies of genotype and allele in IL-10 gene polymorphism (rs1800896) between patients and control group (p > .005). In contrast, there were significant differences in the frequencies of CC genotype in IL-18 gene polymorphism (rs1946518) between patients and the control groups (p = .004; OR =0.990; 95% CI: 0.320-8.855). Also, there were significant differences in the frequencies of GA genotype in IL-33 gene polymorphism (rs1929992) between patients and the control groups (p = .001; OR =0.955; 95% CI: 0.239-9.807). Present study showed that the rs1800896 polymorphism (IL-10) might not play role in RPL in the Iranian population; whereas rs1946518 (IL-18) and rs1929992 (IL-33) polymorphisms may be associated with the risk of RPL in the Iranian women.

In vivo and in vitro impact of miR-31 and miR-143 on the suppression of metastasis and invasion in breast cancer.

PURPOSE: The microRNA (miR)-31 and miR-143 are pleiotropic anti-metastatic miRs, with an expression that decreases significantly in metastatic breast cancer cells. The aim of this study was to investigate the effect of miR-31 and miR-143 inhibition on metastasis and invasion in both MDA-MB231, MDA-MB468 as well as the MCF-7 breast cancer cell lines and 5-week old female mice. METHODS: Following the cloning of miR-31 and miR-143 into vectors, their expressions were determined before treatment with constructs of miR-31 and miR-143 in cancer cell lines and normal breast cells. Then miR-31 and miR-143 were transfected to the cell lines and the expression was assessed after 48 hrs. Moreover, the levels of migration and invasion were determined in cell lines. These experiments were performed in 5-week old female mice. RESULTS: The results showed that miR-31 expression before the transfection of miR-31 construct was decreased 4, 70 and 100 times in MCF-7, MDA-MB468 and MDA-MB231 cell lines, respectively, in comparison to normal breast cells; but after the transfection of miR-31 construct, the expression of miR-31 increased 80 times. Additionally, invasion and migration decreased by 15 and 10 times in MDAMB-468. All of the modifications in miR-143 were low in comparison to miR-31. The results of the in vivo experiments were approximately the same as in the in vitro experiments. CONCLUSIONS: It appears that the use of miR-31 is highly efficient than miR-143 in the inhibition of invasion and metastasis in breast cancer. Our study improved our conception about miR-31 and miR-143 and their roles in the identification and therapy of breast cancer.

Methods for Quantitative Efferocytosis Assays.

Efferocytosis, the phagocytic removal of apoptotic cells, is a dynamic process requiring recruitment of numerous regulatory proteins to mediate the uptake, engulfment, and degradation of apoptotic cells. Herein, we describe microscopy-based methods for the enumeration of efferocytic events and characterization of the spatiotemporal dynamics of signaling molecule recruitment during efferocytosis using genetically encoded probes and immunofluorescent labeling. While these methods are illustrated using macrophages, they are applicable to any efferocytic cell type.

The Effects of Statins on Respiratory Symptoms and Pulmonary Fibrosis in COVID-19 Patients with Diabetes Mellitus: A Longitudinal Multicenter Study.

The aim of this prospective cohort study was to explore the effect of statins on long-term respiratory symptoms and pulmonary fibrosis in coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM). Patients were recruited from three tertiary hospitals, categorized into Statin or Non-statin groups, and assessed on days 0, 28, and 90 after symptoms onset to record the duration of symptoms. Pulmonary fibrosis was scored at baseline and follow-up time points by high-resolution computed tomography scans. Each group comprised 176 patients after propensity score matching. Data analysis revealed that the odds of having cough and dyspnea were significantly higher in the Non-statin group compared to the Statin group during the follow-up period. Overall, there was no significant difference in the change in pulmonary fibrosis score between groups. However, Non-statin patients with > 5 years of DM were more likely to exhibit a significantly higher fibrosis score during the follow-up period as compared to their peers in the Statin group. Our results suggest that the use of statins is associated with a lower risk of developing chronic cough and dyspnea in diabetic patients with COVID-19, and may reduce pulmonary fibrosis associated with COVID-19 in patients with long-term (> 5 years) DM.

Cancer immunotherapy: Challenges and limitations.

Although cancer immunotherapy has taken center stage in mainstream oncology inducing complete and long-lasting tumor regression, only a subset of patients receiving treatment respond and others relapse after an initial response. Different tumor types respond differently, and even in cancer types that respond (hot tumors), we still observe tumors that are unresponsive (cold tumors), suggesting the presence of resistance. Hence, the development of intrinsic or acquired resistance is a big challenge for the cancer immunotherapy field. Resistance to immunotherapy, including checkpoint inhibitors, CAR-T cell therapy, oncolytic viruses, and recombinant cytokines arises due to cancer cells employing several mechanisms to evade immunosurveillance.

The Regulatory Role of Pivotal MicroRNAs in the AKT Signaling Pathway in Breast Cancer.

Breast cancer is the most prevalent type of cancer among women, and it remains the main challenge despite improved treatments. MicroRNAs (miRNAs) are a small non-coding family of RNAs that play an indispensable role in regulating major physiological processes, including differentiation, proliferation, invasion, migration, cell cycle regulation, stem cell maintenance apoptosis, and organ development. The dysregulation of these tiny molecules is associated with various human malignancies. More than 50% of these non-coding RNA sequences estimated have been placed on genomic regions or fragile sites linked to cancer. Following the discovery of the first signatures of specific miRNA in breast cancer, numerous researches focused on involving these tiny RNAs in breast cancer physiopathology as a new therapeutic approach or as reliable prognostic biomarkers. In the current review, we focus on recent findings related to the involvement of miRNAs in breast cancer via the AKT signaling pathway related to their clinical implications.

Rab GTPases in the differential processing of phagocytosed pathogens versus efferocytosed apoptotic cells.

Phagocytosis is an important feature of innate immunity in which invading microorganisms are engulfed, killed and degraded - and in some immune cells, their antigens presented to adaptive immune system. A closely related process, efferocytosis, removes apoptotic cells, and is essential for the maintenance of homeostasis. Both phagocytosis and efferocytosis are tightly regulated processes that involve target recognition and uptake through specific receptors, followed by endolysosomal trafficking and processing of the internalized target. Central to the uptake and trafficking of these targets are the Rab family of small GTPases, which coordinate the engulfment and trafficking of both phagocytosed and efferocytosed materials through the endolysosomal system. Because of this regulatory function, Rab GTPases are often targeted by pathogens to escape phagocytosis. In this review, we will discuss the shared and differential roles of Rab GTPases in phagocytosis and efferocytosis.

The pivotal role of MicroRNAs in glucose metabolism in cancer.

Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.

The role of tumor suppressor short non-coding RNAs on breast cancer.

Characterized by remarkable levels of aggression and malignancy, BC remains one of the leading causes of death in females world wide. Accordingly, significant efforts have been made to develop early diagnostic tools, increase treatment efficacy, and improve patient prognosis. Hopefully, many of the molecular mechanisms underlying BC have been detected and show promising targeting potential. In particular, short and long non-coding RNAs (ncRNAs) are a class of endogenous BC controllers and include a number of different species including microRNAs, Piwi-interacting RNAs, small nucleolar RNA, short interfering RNAs, and tRNA-derivatives. In this review, we discuss the tumor suppressing roles of ncRNAs in the context of BC, and the mechanisms by which ncRNAs target tumor hallmarks, including apoptosis, proliferation, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis, and cell cycle progression, in addition to their diagnostic and prognostic significance in cancer treatment.

Mechanisms of Dysregulated Humoral and Cellular Immunity by SARS-CoV-2.

The current coronavirus disease 2019 (COVID-19) pandemic, a disease caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), was first identified in December 2019 in China, and has led to thousands of mortalities globally each day. While the innate immune response serves as the first line of defense, viral clearance requires activation of adaptive immunity, which employs B and T cells to provide sanitizing immunity. SARS-CoV-2 has a potent arsenal of mechanisms used to counter this adaptive immune response through processes, such as T cells depletion and T cell exhaustion. These phenomena are most often observed in severe SARS-CoV-2 patients, pointing towards a link between T cell function and disease severity. Moreover, neutralizing antibody titers and memory B cell responses may be short lived in many SARS-CoV-2 patients, potentially exposing these patients to re-infection. In this review, we discuss our current understanding of B and T cells immune responses and activity in SARS-CoV-2 pathogenesis.

Covid-19: Perspectives on Innate Immune Evasion.

The ongoing outbreak of Coronavirus disease 2019 infection achieved pandemic status on March 11, 2020. As of September 8, 2020 it has caused over 890,000 mortalities world-wide. Coronaviral infections are enabled by potent immunoevasory mechanisms that target multiple aspects of innate immunity, with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) able to induce a cytokine storm, impair interferon responses, and suppress antigen presentation on both MHC class I and class II. Understanding the immune responses to SARS-CoV-2 and its immunoevasion approaches will improve our understanding of pathogenesis, virus clearance, and contribute toward vaccine and immunotherepeutic design and evaluation. This review discusses the known host innate immune response and immune evasion mechanisms driving SARS-CoV-2 infection and pathophysiology.

Promising approaches in cancer immunotherapy.

Immunotherapy is a promising field, which enhances and harnesses the powers of the host immune system against cancer and in recent years, has become a major application of the fundamental research of cancer immunology. Cancer immunotherapy is often more targeted than non-specific therapy approaches, including radiotherapy or chemotherapy, as the immune system can be trained to remember cancer cells, highlighting a durable approach that can be maintained after the treatment completion. Immunotherapy functions by directing the immune system to attack the tumour cells via targeting tumour antigens, also enhancing the existing anti-tumour immune responses. Current strategies include non-specific immunotherapy, cancer vaccines, oncolytic virus therapy, monoclonal antibodies, immune checkpoints and T cell therapy. The combination of effective approaches can increase the immunotherapy efficacy, leading to durable anti-tumour immune responses. This review will discuss the immunotherapy approaches, particularly immune checkpoints and T cell therapy, which are the most common clinical applications in cancer immunotherapy.

Egr2 regulation in T cells is mediated through IFNγ/STAT1 and IL-6/STAT3 signalling pathway.

The immune system is a host defence system to protect the body against foreign invaders. T cells are one of the major components of the immune cells and they are essential for immune responses. Early growth response gene (Egr2) in T cells is important for maintaining immune functions of T cells by promoting adaptive immune responses while controlling inflammation and preventing the development of autoimmune diseases. A study by our group demonstrated the function of Egr2 as a checkpoint regulator controlling the proliferation and differentiation of the T cells. In association, Egr2 and 3 play indispensable role in T cell immune response, but the mechanism regulating Egr2 expression in T cells is still unclear. In this study, we analysed the Egr2 expression mechanism in CD4 T cells under antigen stimulation. We found that Egr2 expression is regulated by different cytokines including IL-2 and IL-4, which increased Egr2 induction in activated T cells. However, inflammatory cytokines, including INFγ and IL-6, suppressed Egr2 expression through STAT1 and STAT3 signalling pathway respectively, highlighting a mechanism for tolergenic immune response on T cells.

Regulatory role of microRNAs in cancer through Hippo signaling pathway.

Cancer is the major cause of death worldwide in countries of all income levels. The Hippo signaling pathway is a Drosophila kinase gene that was identified to regulate organ size, cell regeneration, and contribute to tumorigenesis. A huge variety of extrinsic and intrinsic signals regulate the Hippo signaling pathway. The Hippo signaling pathway consists of a wide array of components that merge numerous signals such as mechanical signals to address apoptosis resistance, cell proliferation, cellular outputs of growth, cell death and survival at cellular and tissue level. Recent studies have shed new light on the regulatory role of microRNAs in Hippo signaling and how they contribute to cancer progression. MicroRNAs influence various cancer-related processes such as, apoptosis, proliferation, migration, cell cycle and metabolism. Inhibition and overexpression of miRNAs via miRNA mimics and miRNA inhibitors, respectively, can uncover a hopeful and reliable insight for treatment and early diagnosis of cancer patients. In this review we will discuss our current understanding of regulatory role of miRNAs in Hippo signaling pathway.

Association of rs1946518 C/A Polymorphism in Promoter Region of Interleukin 18 Gene and Breast Cancer Risk in Iranian Women: A Case-control Study.

Breast cancer (BC) is the most frequently diagnosed cancer among women in the world. Genetic polymorphisms in Interleukin (IL) genes are one of the most important risk factors in BC. The aim of this study was to investigate the association of rs1946518 C/A polymorphism in the promoter region of the IL-18 gene and BC risk in Iranian women. In this case-control study, we recruited 140 women with BC as a case group and 140 age and ethnically matched women as healthy controls from East Azerbaijan, Tabriz in Iran. The genomic DNA was extracted using a salting-out method from peripheral blood leukocytes. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotype distribution in BC patients was 37.86% CC, 47.14% CA, and 15.00% AA, whereas in healthy controls these were 40.72% CC, 42.85% CA, and 16.43% AA. Statistical analysis showed that the genotype and allele frequencies of IL-18 rs1946518 C/A polymorphism were not significantly different between BC patients and healthy controls (p>0.05). The only significant difference between cases and controls was related to family history (p=0.023). In conclusion, our study indicated that IL-18 rs1946518 C/A polymorphism was not associated with BC in the Iranian women population. However, more studies on different races and geographic areas are required to determine the exact role of rs1946518 C/A polymorphism in prognosis, diagnosis, and risk of BC.

Reciprocal role of hBD2 and hBD3 on the adaptive immune response by measuring T lymphocyte proliferation in terms of CD4 and CCR6 expression.

Background Human ß-defensins (hBD2 and hBD3) are small cationic antimicrobial peptides of innate immune system which can act as a barrier against the majority of pathogens, contributing to the host immune defence. Objective The aim of study is to determine whether hBD2 and hBD3 play a role in development and proliferation of human effector CD4 T cells or not. Furthermore, if enhanced proliferation is observed in the presence of hBD2 and hBD3, these data will demonstrate whether chemokine receptor type 6 (CCR6) is required to be present for this activity to occur. Methods In this study, we examined the effect of hBD2 and hBD3 on CD4+ T cell proliferation in CCR6+ and CCR6- T cells through co-culture of peripheral blood mononuclear cells with anti-CD3 and anti-CD28 stimulation in the presence or absence of hBD2 and hBD3. Proliferation was assessed using flow cytometry. Results It was demonstrated that, co-culture with hBD2 and hBD3 led to up-regulation of CD4+ T cell proliferation after 72 h whereas, CD4+ T cell proliferation was suppressed after 96 h. On the other hand, CCR6- and CCR6+ T cell proliferation was up-regulated after 72 h. But, CCR6+ only was down-regulated in the second cycle in the presence of hBD3. In contrast, after 96 h CCR6+ and CCR6- T cell proliferation was decreased. Conclusion Collectively, our data indicated that hBD2 and hBD3 play a positive and negative regulatory role in development and proliferation of human effector CD4+ T cells which is essential for optimal adaptive immune responses and the control of immunopathology.