Current and future immunotherapeutic approaches in pancreatic cancer treatment.

Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.

Vitamin D and reproductive disorders: a comprehensive review with a focus on endometriosis.

Vitamin D is a fat-soluble steroid hormone that was initially known only for regulating calcium and phosphorus levels and maintaining bone health. However, it was later discovered that many organs express vitamin D metabolizing enzymes and have a ligand for vitamin D, which regulates the expression of an extensive assortment of genes. As a result, vitamin D is indispensable for the proper function of organs, and its deficiency is believed to be a critical factor in symptoms and disorders such as cardiovascular diseases, autoimmune diseases, and cancers. The significance of vitamin D in reproductive tissues was recognized later, and studies have revealed its crucial role in male and female fertility, as well as proper reproductive function during pregnancy. Vitamin D deficiency has been identified as a risk factor for infertility, gonadal cancers, pregnancy complications, polycystic ovary syndrome, and endometriosis. However, data investigating the association between vitamin D levels and reproductive disorders, including endometriosis, have encountered inconsistencies. Therefore, the present study aims to review existing research on the effect of vitamin D on proper reproductive function, and the role of deficiency in reproductive diseases and specifically focuses on endometriosis.

Unraveling the potential of CD8, CD68, and VISTA as diagnostic and prognostic markers in patients with pancreatic ductal adenocarcinoma.

Introduction: Pancreatic cancer is a truculent disease with limited treatment options and a grim prognosis. Immunotherapy has shown promise in treating various types of cancer, but its effectiveness in pancreatic cancer has been lacking. As a result, it is crucial to identify markers associated with immunological pathways in order to improve the treatment outcomes for this deadly cancer. The purpose of this study was to investigate the diagnostic and prognostic significance of three markers, CD8, CD68, and VISTA, in pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer. Methods: We analyzed gene expression data from Gene Expression Omnibus (GEO) database using bioinformatics tools. We also utilized the STRING online tool and Funrich software to study the protein-protein interactions and transcription factors associated with CD8, CD68, and VISTA. In addition, tissue microarray (TMA) and immunohistochemistry (IHC) staining were performed on 228 samples of PDAC tissue and 10 samples of normal pancreatic tissue to assess the expression levels of the markers. We then correlated these expression levels with the clinicopathological characteristics of the patients and evaluated their survival rates. Results: The analysis of the GEO data revealed slightly elevated levels of VISTA in PDAC samples compared to normal tissues. However, there was a significant increase in CD68 expression and a notable reduction in CD8A expression in pancreatic cancer. Further investigation identified potential protein-protein interactions and transcription factors associated with these markers. The IHC staining of PDAC tissue samples showed an increased expression of VISTA, CD68, and CD8A in pancreatic cancer tissues. Moreover, we found correlations between the expression levels of these markers and certain clinicopathological features of the patients. Additionally, the survival analysis revealed that high expression of CD8 was associated with better disease-specific survival and progression-free survival in PDAC patients. Conclusion: These findings highlight the potential of CD8, CD68, and VISTA as diagnostic and prognostic indicators in PDAC.

Ellagic acid effects on disease severity, levels of cytokines and T-bet, RORγt, and GATA3 genes expression in multiple sclerosis patients: a multicentral-triple blind randomized clinical trial.

Background: Multiple sclerosis (MS) is a chronic autoimmune disease. Ellagic acid is a natural polyphenol and affects the fate of neurons through its anti-inflammatory and antioxidant properties. The present study aimed to investigate ellagic acid effects on disease severity, the expression of involved genes in the pathogenesis of MS, and the levels of related cytokines. Methods: The present study was a triple-blind clinical trial. Eligible patients were randomly assigned to two groups: Ellagic acid (25 subjects) for 12 weeks, receiving 180 mg of Ellagic acid (Axenic, Australia) and the control group (25 subjects) receiving a placebo, before the main meals. Before and after the study, the data including general information, foods intake, physical activity, anthropometric data, expanded disability status scale (EDSS), general health questionnaire (GHQ) and pain rating index (PRI), fatigue severity scale (FSS) were assessed, as well as serum levels of interferon-gamma (IFNγ), interleukin-17 (IL-17), interleukin-4 (IL-4) and transforming growth factor-beta (TGF-ß), nitric-oxide (NO) using enzyme-linked immunoassay (ELISA) method and expression of T-box transcription factor (Tbet), GATA Binding Protein 3 (GATA3), retinoic acid-related orphan receptor-γt (RORγt) and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes were determined using Real-Time Quantitative Reverse Transcription PCR (RT-qPCR) method. Findings: Ellagic acid supplementation led to a reduction in IFNγ, IL-17, NO and increased IL-4 in the ellagic acid group, however in the placebo group no such changes were observed (-24.52 ± 3.79 vs. -0.05 ± 0.02, p < 0.01; -5.37 ± 0.92 vs. 2.03 ± 1.03, p < 0.01; -18.03 ± 1.02 vs. -0.06 ± 0.05, p < 0.01, 14.69 ± 0.47 vs. -0.09 ± 0.14, p < 0.01, respectively). Ellagic acid supplementation had no effect on TGF-ß in any of the study groups (p > 0.05). Also, the Tbet and RORγt genes expression decreased, and the GATA3 gene expression in the group receiving ellagic acid compared to control group significantly increased (0.52 ± 0.29 vs. 1.51 ± 0.18, p < 0.01, 0.49 ± 0.18 vs. 1.38 ± 0.14, p < 0.01, 1.71 ± 0.39 vs. 0.27 ± 0.10, p < 0.01). Also, ellagic acid supplementation led to significant decrease in EDSS, FSS and GHQ scores (p < 0.05), and no significant changes observed in PRI score (p > 0.05). Conclusion: Ellagic acid supplementation can improve the health status of MS patients by reduction of the inflammatory cytokines and Tbet and RORγt gene expression, and increment of anti-inflammatory cytokines and GATA3 gene expression.Clinical trial registration: (https://en.irct.ir/trial/53020), IRCT20120415009472N22.

The effects of Ellagic acid supplementation on neurotrophic, inflammation, and oxidative stress factors, and indoleamine 2, 3-dioxygenase gene expression in multiple sclerosis patients with mild to moderate depressive symptoms: A randomized, triple-blind, placebo-controlled trial.

BACKGROUND: Depression is one of the most common psychological disorders among multiple sclerosis (MS) patients that characterized as the first symptoms. Ellagic acid is a natural polyphenol that may have neuroprotective properties through antioxidant, anti-inflammatory, and immunomodulatory effects. PURPOSE: The aim of the present study was to investigate the effects of Ellagic acid on circulating levels of brain derived neurotrophic factor (BDNF), interferon-γ (IFN-Æ´), nitric oxide (NO), nuclear factor erythroid-2-related factor 2 (Nrf2), cortisol, serotonergic system, and indoleamine 2, 3-dioxygenase (IDO) gene expression in MS patients with mild to moderate depressive symptoms. STUDY DESIGN: A randomized triple-blind clinical trial. METHODS: The eligible patients according to the inclusion criteria were randomly divided into two groups: either 180 mg Ellagic acid (Axenic company) (n = 25) or 180 mg maltodextrin (n = 25) group for 12 weeks. The Ellagic acid supplement were identical to placebo in shape, color and odor. Serum BDNF, NO, Nrf2, cortisol, serotonin, and IFN-Æ´ were measured by ELISA kit in the baseline and end of the study. Also, demographic characteristics, anthropometric measurements, physical activity, food intake, Beck Depression Inventory-II (BDI-II) and expanding disability status scale (EDSS) questionnaires, as well as IDO gene expression were assessed. SPSS software version 24 was used for statistical analysis. RESULTS: Fifty patients were evaluated, and a significant decrease in BDI-II (p = 0.001), IFN-Æ´ (p = 0.001), NO (p = 0.004), cortisol (p = 0.015), IDO gene expression (p = 0.001) and as well as increased the level of BDNF (p = 0.006) and serotonin (p = 0.019) was observed among those who received 90 mg Ellagic acid twice a day for 12 weeks versus control group. However, there were no significant differences between groups for Nrf2 levels (p>0.05) at the end of study. CONCLUSION: The current study indicates that Ellagic acid intervention has a favorable effect on depression in MS patients. This is achieved by reducing BDI-II scores, as well as levels of NO, cortisol, IFN-Æ´, and IDO gene expression. Furthermore, we found a significant elevation in circulating levels of BDNF and serotonin.

Bispecific antibodies targeting CTLA-4: game-changer troopers in cancer immunotherapy.

Antibody-based cancer immunotherapy has become a powerful asset in the arsenal against malignancies. In this regard, bispecific antibodies (BsAbs) are a ground-breaking novel approach in the therapy of cancers. Recently, BsAbs have represented a significant advancement in improving clinical outcomes. BsAbs are designed to target two different antigens specifically. Over a hundred various BsAb forms currently exist, and more are constantly being manufactured. An antagonistic regulator of T cell activation is cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or CD152, a second counter-receptor for the B7 family of co-stimulatory molecules was introduced in 1996 by Professor James P. Allison and colleagues. Contrary to the explosive success of dual immune checkpoint blockade for treating cancers, a major hurdle still yet persist is that immune-related adverse events (irAEs) observed by combining immune checkpoint inhibitors (ICIs) or monoclonal antibodies such as ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). A promising strategy to overcome this hurdle is using BsAbs. This article will summarize BsAbs targeting CTLA-4, their applications in cancer immunotherapy, and relevant clinical trial advances. We will also discuss the pre-clinical rationale for using these BsAbs, and provide the current landscape of the field.

SLAM-family receptors come of age as a potential molecular target in cancer immunotherapy.

The signaling lymphocytic activation molecule (SLAM) family receptors were discovered in immune cells for the first time. The SLAM-family receptors are a significant player in cytotoxicity, humoral immune responses, autoimmune diseases, lymphocyte development, cell survival, and cell adhesion. There is growing evidence that SLAM-family receptors have been involved in cancer progression and heralded as a novel immune checkpoint on T cells. Previous studies have reported the role of SLAMs in tumor immunity in various cancers, including chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, hepatocellular carcinoma, head and neck squamous cell carcinoma, pancreas, lung, and melanoma. Evidence has deciphered that the SLAM-family receptors may be targeted for cancer immunotherapy. However, our understanding in this regard is not complete. This review will discuss the role of SLAM-family receptors in cancer immunotherapy. It will also provide an update on recent advances in SLAM-based targeted immunotherapies.

The association between CD3+ and CD8+tumor-infiltrating lymphocytes (TILs) and prognosis in patients with pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC), with more than 250,000 deaths each year, is the eighth leading cause of death worldwide, with a five-year survival of less than 5% and a median recurrence time between 5 and 23 months. The association between PDAC and CD3+/CD8+ tumor-infiltrating lymphocytes (TILs) and the extent of tumor spread and clinical outcomes has been recently shown. This study aimed to determine and compare the density of TILs and their association with disease prognosis in patients with PDAC. MATERIALS AND METHODS: In this study, we collected PDAC tissues and corresponding adjacent normal tissues from 64 patients with TIL-positive PDAC. The immunohistochemistry method was used for the detection of the expression levels of CD3+ and CD8+ TILs in PDAC tissues. Also, the completed follow-up history was evaluated for at least five years. RESULTS: The frequency of intratumoral and peritumoral TILs was 20 (31.2%) and 44 (68.8%), respectively. The mean density of CD3+ TILs and CD8+ TILs was 67.73%±20.17% and 69.45%±17.82%, respectively. The density of CD3+ TILs and CD8+ TILs was not associated with overall survival nor metastasis-free survival of the patients and tumor grade. However, the density of TILs was significantly lower in those patients who experienced tumor recurrence than those without this recurrence. CONCLUSION: TILs density was high in patients with PDAC. The density of both CD3+ and CD8+ TILs was significantly lower in patients who experienced tumor recurrence. Thus, this study suggests that tracking and determining the density of CD3+ and CD8+ TILs might be effective in predicting PDAC recurrence.

Tumor-promoting myeloid cells in the pathogenesis of human oncoviruses: potential targets for immunotherapy.

Oncoviruses, known as cancer-causing viruses, are typically involved in cancer progression by inhibiting tumor suppressor pathways and uncontrolled cell division. Myeloid cells are the most frequent populations recruited to the tumor microenvironment (TME) and play a critical role in cancer development and metastasis of malignant tumors. Tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumor-associated dendritic cells (TADCs), and tumor-associated neutrophils (TANs) exert different states from anti-tumorigenic to pro-tumorigenic phenotypes in TME. Although their role in the anti-tumorigenic state is well introduced, their opposing roles, pro-tumorigenic activities, such as anti-inflammatory cytokine and reactive oxygen species (ROS) production, should not be ignored since they result in inflammation, tumor progression, angiogenesis, and evasion. Since the blockade of these cells had promising results against cancer progression, their inhibition might be helpful in various cancer immunotherapies. This review highlights the promoting role of tumor-associated myeloid cells (TAMCs) in the pathophysiology of human virus tumorigenesis.

Advances in therapeutic targeting of immune checkpoints receptors within the CD96-TIGIT axis: clinical implications and future perspectives.

INTRODUCTION: The development of therapeutic antibodies targeting immune checkpoint molecules (ICMs) that induce long-term remissions in cancer patients has revolutionized cancer immunotherapy. However, a major drawback is that relapse after an initial response may be attributed to innate and acquired resistance. Additionally, these treatments are not beneficial to all patients. Therefore, the discovery and targeting of novel ICMs and their combination with other immunotherapeutics are urgently needed. AREAS COVERED: There has been increasing evidence of the CD96-TIGIT axis as ICMs in cancer immunotherapy in the last five years. This review will highlight and discuss the current knowledge about the role of CD96 and TIGIT in hematological and solid tumor immunotherapy in the context of empirical studies and clinical trials, and provide a comprehensive list of ongoing cancer clinical trials on the blockade of these ICMs, as well as the rationale behind combinational therapies with anti-PD-1/PD-L1 agents, chemotherapy drugs, and radiotherapy. Moreover, we share our perspectives on anti-CD96/TIGIT-related combination therapies. EXPERT OPINION: CD96-TIGIT axis regulates anti-tumor immune responses. Thus, the receptors within this axis are the potential candidates for cancer immunotherapy. Combining the inhibition of CD96-TIGIT with anti-PD-1/PD-L1 mAbs and chemotherapy drugs has shown relatively effective results in the context of preclinical studies and tumor models.

Recent advances in passive immunotherapies for COVID-19: The Evidence-Based approaches and clinical trials.

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, causing a global pandemic called COVID-19. Currently, there is no definitive treatment for this emerging disease. Global efforts resulted in developing multiple platforms of COVID-19 vaccines, but their efficacy in humans should be wholly investigated in the long-term clinical and epidemiological follow-ups. Despite the international efforts, COVID-19 vaccination accompanies challenges, including financial and political obstacles, serious adverse effects (AEs), the impossibility of using vaccines in certain groups of people in the community, and viral evasion due to emerging novel variants of SARS-CoV-2 in many countries. For these reasons, passive immunotherapy has been considered a complementary remedy and a promising way to manage COVID-19. These approaches arebased on reduced inflammation due to inhibiting cytokine storm phenomena, immunomodulation,preventing acute respiratory distress syndrome (ARDS), viral neutralization, anddecreased viral load. This article highlights passive immunotherapy and immunomodulation approaches in managing and treating COVID-19 patients and discusses relevant clinical trials (CTs).

The molecular mechanisms and therapeutic potential of EZH2 in breast cancer.

Due to its high occurrence and mortality rate, breast cancer has been studied from various aspects as one of the cancer field's hot topics in the last decade. Epigenetic alterations are spoused to be highly effective in breast cancer development. Enhancer of zeste homolog 2 (EZH2) is an enzymatic epi-protein that takes part in most vital cell functions by its different action modes. EZH2 is suggested to be dysregulated in specific breast cancer types, particularly in advanced stages. Mounting evidence revealed that EZH2 overexpression or dysfunction affects the pathophysiology of breast cancer. In this review, we discuss biological aspects of the EZH2 molecule with a focus on its newly identified action mechanisms. We also highlight how EZH2 plays an essential role in breast cancer initiation, progression, metastasis, and invasion, which emerged as a worthy target for treating breast cancer in different approaches.

Potential Antiviral Immune Response Against COVID-19: Lessons Learned from SARS-CoV.

Virus and host innate immune system interaction plays a significant role in forming the outcome of viral diseases. Host innate immunity initially recognizes the viral invasion and induces a rapid inflammatory response, and this recognition activates signaling cascades that trigger the release of antiviral mediators. This chapter aims to explore the mechanisms by which newly emerged coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activates the host immune system. Since SARS-CoV-2 shares similarities with SARS-CoV that caused the epidemic of SARS in 2003, the pathogenesis of both viruses could be at least very similar. For this, this chapter provides a synthesis of literature concerning antiviral immunity in SARS-CoV and SARS-CoV-2. It includes the presentation of epitopes linked to SARS-CoV-2 as well as the ability of SARS-CoV-2 to cause proteolytic activation and interact with angiotensin-converting enzyme 2 (ACE2) via molecular mimicry. This chapter characterizes various mechanisms that this virus may engage in escaping the host immunity, ended by a discussion of humoral immune responses against SARS-CoV-2.

Death due to COVID-19 in a patient with diabetes, epilepsy, and gout comorbidities.

There is evidence of increased incidence, rapid progression, and poor prognosis of COVID-19 in patients with underlying comorbidities such as diabetes and epilepsy. Developing effective treatment regimens for COVID-19 patients with multiple comorbidities is crucial, as patients' past medical history is an essential contributor to possible organ injuries in COVID-19 patients. Herein, we report a confirmed case of COVID-19 patient with a history of multiple underlying diseases, including diabetes, epilepsy, and gout. The patient developed multiple organ failure and died a week after intensive care unit (ICU) admission. Multiple organ failure is the most common cause of death in COVID-19 patients.