Competing endogenous RNA networks and ferroptosis in cancer: novel therapeutic targets.

As a newly identified regulated cell death, ferroptosis is a metabolically driven process that relies on iron and is associated with polyunsaturated fatty acyl peroxidation, elevated levels of reactive oxygen species (ROS), and mitochondrial damage. This distinct regulated cell death is dysregulated in various cancers; activating ferroptosis in malignant cells increases cancer immunotherapy and chemoradiotherapy responses across different malignancies. Over the last decade, accumulating research has provided evidence of cross-talk between non-coding RNAs (ncRNAs) and competing endogenous RNA (ceRNA) networks and highlighted their significance in developing and progressing malignancies. Aside from pharmaceutical agents to regulate ferroptosis, recent studies have shed light on the potential of restoring dysregulated ferroptosis-related ceRNA networks in cancer treatment. The present study provides a comprehensive and up-to-date review of the ferroptosis significance, ferroptosis pathways, the role of ferroptosis in cancer immunotherapy and chemoradiotherapy, ceRNA biogenesis, and ferroptosis-regulating ceRNA networks in different cancers. The provided insights can offer the authorship with state-of-the-art findings and future perspectives regarding the ferroptosis and ferroptosis-related ceRNA networks and their implication in the treatment and determining the prognosis of affected patients.

hsa-miR-34a-5p enhances temozolomide anti-tumoral effects on glioblastoma: in-silico and in-vitro study.

Glioblastoma multiform (GBM) is a commonly diagnosed brain neoplasm with a poor prognosis. Accumulating evidence has highlighted the significance of microRNA (miR) dysregulation in tumor development and progression. This study investigated the effect of hsa-miR-34a-5p and its combination with temozolomide on GBM, the related molecular mechanisms, and the signaling pathway using in-silico and in-vitro approaches. The in-silico tumor bulk and single-cell RNA sequencing analyses were done on TCGA-GTEx, CGGA, GSE13276, GSE90603, and GSE182109 datasets. After selecting the A172 cell line, hsa-miR-34a-5p mimics were transfected, and the cell viability, migration, cell cycle, clonogenicity, and apoptosis of studied groups were studied using MTT, scratch, flow cytometry, colony formation, and Annexin V/PI assays. The mRNA expression of CASP9, CASP3, CASP8, MMP2, CD44, CDK6, CDK4, CCND1, RAF1, MAP2K1, MET, SRC, and CD274 was studied using qRT-PCR method. hsa-miR-34a-5p downregulated RAF1 expression, as the signaling factor of the MAPK pathway. The combined treatment significantly downregulated the expression of MET, SRC, and MAP2K1, leading to the inhibition of the MET/MAPK pathway compared to temozolomide. Besides exerting anti-tumoral effects on the cell viability, migration, cell cycle, apoptosis, and clonogenicity of A172 cells, its combination with temozolomide enhanced temozolomide anti-tumoral effect. Compared to temozolomide, the combined treatment significantly decreased CDK4, CDK6, CCND1, and MMP2 expression. hsa-miR-34a-5p targets RAF1, as the signaling factor of the MAPK pathway, and potentiates the temozolomide anti-tumoral effect on A172 cells.

CD133 significance in glioblastoma development: in silico and in vitro study.

BACKGROUND: Glioblastoma multiform (GBM) is among the commonly diagnosed brain malignancies with poor prognosis. CD133 has been introduced as an oncogene in various cancers, like GBM. This study aimed to investigate the significance of CD133 in GBM development using in silico and in vitro techniques. METHOD: The TCGA-GBM database was analyzed for the correlational and comparative studies. After selecting the U87MG cell line, CD133-siRNA was transfected into U87MG cells and treated with temozolomide. The cell viability, cell cycle, migration, clonogenicity, and apoptosis of groups were investigated using MTT, flow cytometry, wound-healing, colony formation, and annexin V/PI assays. Using qRT-PCR method, the mRNA expression levels of MMP16, SOX2, RAF1, MAP2K1, MAPK3, PIK3CA, AKT3, mTOR, CDK4, and BCL2 were studied. RESULTS: CD133 silencing improves apoptosis rate, arrests the cell cycle at the sub-G1 phase, suppresses the clonogenicity of U87MG cells, and inhibits the PI3K/Akt and MAPK pathways via downregulating the RAF1, MAP2K1, MAPK3, PIK3CA, AKT3, and mTOR expression. Besides, combining CD133 silencing with temozolomide treatment considerably inhibits the migration of U87MG cells compared to temozolomide monotherapy. CONCLUSION: CD133 can regulate the PI3K/Akt and MAPK pathways and modulate the clonogenicity, apoptosis, and cell cycle of GBM. Combining CD133 silencing with temozolomide treatment considerably increases apoptosis, arrests the cell cycle at the sub-G1, and suppresses migration of U87MG cells compared to temozolomide monotherapy.

Tumor-infiltrating CD8+ sub-populations in primary and recurrent glioblastoma: An in-silico study.

Background: Glioblastoma multiforme (GBM) remains an incurable primary brain tumor. CD8+ tumor-infiltrating lymphocytes (TILs) can target malignant cells; however, their anti-tumoral immune responses mostly do not lead to GBM rejection in GBM patients. We profiled the sub-populations of tumor-infiltrating CD8+ T-cells, i.e., naïve, cytotoxic, and exhausted cells, in primary and recurrent GBM tissues and provided a blueprint for future precision-based GBM immunotherapy. Method: We re-analyzed the raw data of single-cell RNA sequencing on the cells residing in the GBM microenvironment and leveraged tumor bulk RNA analyses to study the significance of CD8+ TILs sub-populations in primary and recurrent GBM. We investigated cell-cell interaction between exhausted CD8+ TILs and other immune cells residing in the primary and recurrent GBM microenvironments and profiled the expression changes following CD8+ TILs' transition from primary GBM to recurrent GBM. Results: Exhausted CD8+ TILs are the majority of CD8+ TILs sub-populations in primary and recurrent GBM, and cytotoxic CD8+ TILs display decreased expression of inhibitory immune checkpoint (IC) molecules in the primary and recurrent GBM. In the primary and recurrent GBM microenvironment, exhausted CD8+ TILs interact most with tumor-infiltrating dendritic cells. Conclusion: This study demonstrates the profiles of CD8+ TILs sub-populations in primary and recurrent GBM and provides a proof-of-concept for future precision-based GBM immunotherapy.

Mature cystic ovarian teratoma with squamous cell carcinoma transformation: a case report and literature review.

OBJECTIVES: Cancerous transformation in mature cystic ovarian teratoma is rare. Herein, we reported a case of squamous cell carcinoma transformation in mature cystic ovarian teratoma and performed an in-depth literature review to highlight the risk factors, prognosis, and suggested treatment for these patients. CASE PRESENTATION: We report a 66-years old postmenopausal woman diagnosed with a 120×90 (mm) mass at the left adnexa compatible with mature cystic ovarian teratoma. Following resection, the histopathological investigations showed malignant transformation in her mature cystic ovarian teratoma, and the immunohistochemistry for cytokeratin (CK) 5/6 and tumor protein 63 (P63) indicated squamous cell carcinoma transformation. She has been observed for her stage IA tumor and has been cancer-free for 6 months. CONCLUSIONS: Although malignant transformation in mature cystic ovarian teratoma is rare, it should be suspected if certain risk factors, e.g., elderly and high tumor size, exist. Stage IA patients' prognosis is favorable, and chemotherapy is not recommended.

HSV1 microRNAs in glioblastoma development: an in silico study.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor. Recent findings highlighted the significance of viral microRNAs (miRs) in regulating post-transcriptional mRNA expression in various human conditions. Although HSV1 encodes viral miRs and affects the central nervous system, no study investigated the roles of HSV1-encoding miRs in GBM development. This study applied in silico approaches to investigate whether HSV1-encoding miRs are involved in GBM development and, if so, how they regulate tumor-suppressive/oncogenes expression in GBM. This study leveraged bioinformatics approaches to identify the potential effect of HSV1 miRs in GBM development. The GSE158284, GSE153679, and GSE182109 datasets were analyzed to identify differentially expressed genes in GBM tissues and cell lines using the limma package in the R software. The GSE182109 dataset was analyzed to determine gene expression at the single-cell levels using the Seurat package in the R software. The TCGA-GTEX, GDSC, CTRP, immunogenetic, and enrichment analyses were performed to study the impact of identified viral HSV1 miRs targets in GBM development. hsv1-miR-H6-3p is upregulated in GBM and can be responsible for EPB41L1 and SH3PXD2A downregulation in GBM tissues. Also, hsv1-miR-H1-5p is upregulated in GBM and can decrease the expression of MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC in GBM development. The single-cell RNA sequencing analyses have demonstrated that MELK, FZD2, NOVA1, TMEM97, PTPRZ1, and PDGFC are expressed in astrocytes residing in the GBM microenvironment. This study provides novel insights into the potential roles of HSV1 miRs in GBM pathogenesis and offers a reference for further studies on the significance of HSV1 miRs in GBM development.

MiR-146a Restoration Suppresses Triple-Negative Breast Cancer Cell Migration: A Bioinformatic and In Vitro Study.

Purpose: Breast cancer is one of the most commonly diagnosed types of cancer worldwide. This cancer is treated with various methods like mastectomy, chemotherapy, hormone therapy, and radiotherapy. Among them, targeted therapy, like microRNA (miRNA) replacement therapy, is considered a new approach to treating breast cancer. Methods: Data analysis from TCGA datasets were used to investigate the expression of hsa-miR-146a-5p in breast cancer. MTT assay was used to evaluate the viability of MDA-MB-231 cells after hsa-miR-146a-5p ectopic expression. A wound-healing assay was used to observe migration in the MDA-MB-231 cell line and the effect of the hsa-miR-146a-5p ectopic expression on migration. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used as a method to determine the effect of the hsa-miR-146a-5p ectopic expression on the expression of CXCR4, ß-catenin, MMP2, MMP9, and Vimentin genes known to be involved in invasion and migration of MDA-MB-231 cells. Results: Our results indicated that hsa-miR-146a-5p is not involved in apoptosis in the MDAMB-231 cells, while it is highly effective in migration inhibition. MMP9, MMP2, CXCR4, and Vimentin expressions were suppressed by hsa-miR-146a-5p induction; however, it induced the expression of ß-catenin. Conclusion: Some non-coding RNAs, such as hsa-miR-146a-5p, are effective in breast cancer targeted therapy. As cancer is a complicated disorder, therefore the combination of therapies might lead to novel therapeutic strategies.

Regulation of NLRP3 inflammasome by zinc supplementation in Behçet's disease patients: A double-blind, randomized placebo-controlled clinical trial.

BACKGROUND: Overproduction of NLRP3 inflammasome complex is one of the causes of Behcet's disease's (BD) auto-inflammatory nature. The aim of current study was to examine the effect of zinc supplementation on NLRP3 inflammasome expression; as well as clinical manifestations of BD. METHODS: In this double-blind parallel placebo-controlled randomized clinical trial, 50 BD patients were randomly allocated into either zinc gluconate (30 mg/day elemental zinc) or placebo groups for 12 weeks. The mRNA expression of NLRP3 and caspase-1 in the leukocytes, serum level of zinc and IL-1ß, anthropometric measures, and clinical manifestations of patients were collected at pre- and post-intervention phase. The Iranian Behçet's disease dynamic activity measure (IBDDAM) was scored to measure the treatment effect using the calculation of number needed to treat (NNT). Analysis of covariance was performed to obtain the corresponding effect sizes. RESULTS: Zinc gluconate led to a significant improvement in genital ulcer (P = 0.019). Zinc supplementation decreased NLRP3 and caspase-1 genes expression compared with placebo group (baseline-adjusted P-value = 0.046 for NLRP3 and P-value = 0.003 for caspase-1), even after adjustment for the effect of confounding factors (baseline- and confounders-adjusted P-value = 0.032 for NLRP3 and P-value = 0.004 for caspase-1). Baseline and confounders adjusted effect size demonstrated that zinc was effective in reducing the serum level of IL-1ß (P = 0.046). The NNT [95 %CI] for the rate of IBDDAM improvement was 3 [1.7-8.5]. CONCLUSIONS: Zinc gluconate supplementation (30 mg/day) for a 3-month period can be considered as an adjuvant therapy in alleviating inflammation and genital ulcer among BD patients.

Identification of Common and Distinct Pathways in Inflammatory Bowel Disease and Colorectal Cancer: A Hypothesis Based on Weighted Gene Co-Expression Network Analysis.

Patients with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, are at higher risk to develop colorectal cancer (CRC). However, the underlying mechanisms of this predisposition remain elusive. We performed in-depth comparative computational analyses to gain new insights, including weighted gene co-expression network analysis (WGCNA) and gene ontology and pathway enrichment analyses, using gene expression datasets from IBD and CRC patients. When individually comparing IBD and CRC to normal control samples, we identified clusters of highly correlated genes, differentially expressed genes, and module-trait associations specific for each disease. When comparing IBD to CRC, we identified common hub genes and commonly enriched pathways. Most notably, IBD and CRC share significantly increased expression of five genes (MMP10, LCN2, REG1A, REG3A, and DUOX2), enriched inflammatory and neutrophil activation pathways and, most notably, highly significant enrichment of IL-4 and IL-13 signaling. Thus, our work expands our knowledge about the intricate relationship between IBD and CRC development and provides new rationales for developing novel therapeutic strategies.

The expression pattern of VISTA in the PBMCs of relapsing-remitting multiple sclerosis patients: A single-cell RNA sequencing-based study.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Dysregulated immune responses have been implicated in MS development. Growing evidence has indicated that inhibitory immune checkpoint molecules can substantially regulate immune responses and maintain immune tolerance. V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune checkpoint molecule that can suppress immune responses; however, its expression pattern in the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) has not thoroughly been studied. Herein, we evaluated Vsir expression in PBMCs of RRMS patients and characterized the expression pattern of the Vsir in the PBMCs of MS patients. Besides, we investigated the effect of fingolimod, IFNß-1α, glatiramer acetate (GA), and dimethyl fumarate (DMF) on Vsir expression in PBMCs of RRMS patients. Our results have shown that Vsir expression is significantly downregulated in the PBMCs of patients with RRMS. Besides, the single-cell RNA sequencing results have demonstrated that Vsir expression is downregulated in classical monocyte, intermediate monocytes, non-classical monocytes, myeloid DCs (mDC), Plasmacytoid dendritic cells (pDCs), and naive B-cells of PBMCs of MS patients compared to the control. In addition, DMF, IFNß-1α, and GA have significantly upregulated Vsir expression in the PBMCs of RRMS patients. Collectively, the current study has shed light on Vsir expression in the PBMCs of MS patients; however, further studies are needed to elucidate the significance of VISTA in the mentioned immune cells.

B7 immune checkpoint family members as putative therapeutics in autoimmune disease: An updated overview.

Autoimmune diseases, especially among young people in the US, are one of the leading causes of morbidity and death. The immune responses are the fundamental pathogenicity of autoimmune disorders. The equilibrium between stimulatory and inhibitory signals is critical for the stimulation, migration, survival, and T cell-related immune responses. The B7 family can substantially regulate T cell-mediated immune responses. Nevertheless, recent breakthroughs in immune checkpoint blockade in cancer immunotherapy have facilitated autoimmune diseases, especially among the prone populations. In the current study, we tried to concisely review the role of the B7 family in regulating immune reactions and the influence of immune checkpoint inhibitors on autoimmunity development.

Alpha-lipoic acid preconditioning plus ischemic postconditioning provides additional protection against myocardial reperfusion injury of diabetic rats: modulation of autophagy and mitochondrial function.

BACKGROUND: Investigating the interaction of diabetes with ischemic postconditioning (IPostC)-associated cardioprotection in myocardial ischemia/reperfusion (I/R) damage is of great clinical importance. The present work was designed to determine the possible synergistic effects of alpha-lipoic acid (LA) preconditioning and IPostC on myocardial I/R damage in type-II diabetic rats through modulating autophagy, and the involvement of mitochondrial function. METHODS: High-fat diet/low dose of streptozotocin-induced type-II diabetic model with duration of 12 weeks was used in this study. LA (100 mg/kg/day) was administered orally in diabetic rats for 5 weeks before I/R. Myocardial I/R was established on Langendorff apparatus through the ligation of left anterior descending coronary artery for 35 min, then reperfusion for 60 min. IPostC was carried out immediately at the beginning of the reperfusion. At the end of the experiment, myocardial infarct size (IS), autophagy markers at both gene and protein levels, and mitochondrial ROS production and membrane potential were assessed. RESULTS: Combined conditioning with LA and ischemia significantly decreased the IS of diabetic hearts (P < 0.05), however, single therapies had no significant effects. LA in combination with IPostC more significantly decreased LC3 and p62 mRNA levels (P < 0.01), and LC3II/LC3I and p62 protein levels (P < 0.01). Also, this combined therapy decreased mitochondrial ROS generation and membrane depolarization (P < 0.01). CONCLUSIONS: Pretreatment with LA in diabetic rats notably restored cardioprotection by IPostC via modulating autophagy and restoring mitochondrial function. This combined conditioning might be an effective strategy to diminish I/R damage in diabetic hearts.

The Role of Hemoglobin Subunit Delta in the Immunopathy of Multiple Sclerosis: Mitochondria Matters.

Background: Although the exact pathophysiology of MS has not been identified, mitochondrial stress can be one of the culprits in MS development. Herein, we have applied microarray analysis, single-cell sequencing analysis, and ex vivo study to elucidate the role of mitochondrial stress in PBMCs of MS patients. Methods: For this purpose, we analyzed the GSE21942 and GSE138266 datasets to identify the DEGs and hub genes in the PBMCS of MS patients and describe the expression of shared genes in the different immune cells. The GO pathway analysis of DEGs and turquoise module genes were conducted to shed light on their biological significance. To validate the obtained results, the gene expression of HBD, as the most remarkable DEG in the PBMCS of affected patients, was measured in the PBMCS of healthy donors, treatment-naïve MS patients, and MS patients treated with GA, fingolimod, DMF, and IFNß-1α. Results: Based on WGCNA and DEGs analysis, HBD, HBM, SLC4A1, LILRA5, SLC25A37, SELENBP1, ALYREF, SNRNP40, and HINT3 are the identified common genes in the PMBCS. Using single-cell sequencing analysis on PBMCS, we have characterized various cell populations in MS and illustrated the common gene expression on the different immune cells. Furthermore, GO pathway analysis of DEGs, and turquoise module genes have indicated that these genes are involved in immune responses, myeloid cell activation, leukocyte activation, oxygen carrier activity, and replication fork processing bicarbonate transport pathways. Our ex vivo investigation has shown that HBD expression in the treatment-naïve RRMS patients is significantly increased compared to healthy donors. Of interest, immunomodulatory therapies with fingolimod, DMF, and IFNß-1α have significantly decreased HBD expression. Conclusion: HBD is one of the remarkably up-regulated genes in the PBMCS of MS patients. HBD is substantially up-regulated in treatment-naïve MS patients, and immunomodulatory therapies with fingolimod, DMF, and IFNß-1α can remarkably down-regulate HBD expression. Based on the currently available evidence, the cytoprotective nature of HBD against oxidative stress can be the underlying reason for HBD up-regulation in MS. Nevertheless, further investigations are needed to shed light on the molecular mechanisms of HBD in the oxidative stress of MS patients.

The Prognostic Value of CD133 in Predicting the Relapse and Recurrence Pattern of High-Grade Gliomas on MRI: A Meta-Analysis.

BACKGROUND: Cancer stem cells have been implicated in tumor relapse, tumor invasion, and cancer therapy resistance in high-grade gliomas; thus, characterizing cancer stem cell-related markers can help determine the prognosis of affected patients. Preclinical studies have reported that CD133 is implicated in tumor recurrence and cancer therapy resistance in high-grade gliomas; however, clinical studies have reported inconclusive results regarding its prognostic value in patients with high-grade gliomas. METHODS: We systematically searched the PubMed, Scopus, Web of Science, and Embase databases to obtain peer-reviewed studies published before March 10, 2021. Then, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. By applying the random-effect model, the effect size of studies investigating the progression-free survival (PFS), time to local recurrence (TTL), and time to distant recurrence (TTD) were calculated using RevMan version 5.4. The heterogeneity between the included studies was studied by the I2 index and Cochran's Q test. Egger test was performed on funnel plots to investigate the potential asymmetry and publication bias among the included studies using CMA version 2. RESULTS: With the 10% cut-off, CD133 protein overexpression is associated with the inferior PFS of patients with high-grade gliomas. Increased CD133 protein expression is associated with sooner distant tumor recurrence on MRI in glioblastoma patients and patients with high-grade gliomas and improved TTL on MRI in glioblastoma patients. CONCLUSION: Based on the current evidence from 1086 patients with high-grade gliomas, CD133 overexpression is a valuable marker to predict tumor relapse and tumor recurrence patterns in patients with high-grade gliomas.

A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead.

As a unique population of tumor bulk, cancer stem cells have been implicated in tumor relapse and chemoresistance in triple-negative breast cancer (TNBC). Therefore, understanding the phenotype of cancer stem cells can pave the way for introducing novel molecular targeted therapies for treating TNBC patients. Preclinical studies have identified CD44+CD24-/low as a cancer stem cell phenotype; however, clinical studies have reported seemingly controversial results regarding the prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients. To critically review the clinicopathological significance and prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients, the Scopus, Embase, PubMed, and Web of Science databases were systematically searched to obtain the relevant records published before 20 October 2020. Based on nine included studies, CD44 and CD44+CD24-/low phenotype are associated with inferior prognosis in TNBC patients. Moreover, these cancer stem cell markers have been associated with advanced tumor stage, tumor size, higher tumor grade, tumor metastasis, and lymphatic involvement in TNBC patients. Our evidence has also indicated that, unlike the treatment-naïve TNBC patients, the tumoral cells of chemoradiotherapy-treated TNBC patients can upregulate the CD44+CD24-/low phenotype and establish an inverse association with androgen receptor (AR), leading to the inferior prognosis of affected patients. In summary, CD44 and CD44+CD24-/low phenotype can be utilized to determine TNBC patients' prognosis in the pathology department as a routine practice, and targeting these phenotypes can substantially improve the prognosis of TNBC patients.

The role of CD44 in cancer chemoresistance: A concise review.

CD44 is a cell surface adhesion molecule, which is overexpressed on cancer stem cells. The interaction of CD44 with hyaluronan is responsible for tumor development, metastasis, and expression of the chemoresistant phenotype. The overexpression of CD44 impedes the cytotoxic effect of chemotherapy medications in various cancers. Therefore, the high expression of CD44 is associated with a poor prognosis in affected patients. This high expression of CD44 in various cancers has provided an ample opportunity for the treatment of patients with chemoresistant malignancy. This review aims to demonstrate the various cross-talk between CD44 and intracellular and extracellular factors and highlight its role in developing chemoresistant tumors in some troublesome cancers.

Interleukin-1 in obesity-related low-grade inflammation: From molecular mechanisms to therapeutic strategies.

Since adipose tissue (AT) can upregulate pro-inflammatory interleukins (ILs) via storing extra lipids in obesity, obesity is considered the leading cause of chronic low-grade inflammation. These ILs can pave the way for the infiltration of immune cells into the AT, ultimately resulting in low-grade inflammation and dysregulation of adipocytes. IL-1, which is divided into two subclasses, i.e., IL-1α and IL-1ß, is a critical pro-inflammatory factor. In obesity, IL-1α and IL-1ß can promote insulin resistance via impairing the function of adipocytes and promoting inflammation. The current study aims to review the detailed molecular mechanisms and the roles of IL-1α and IL-1ß and their antagonist, interleukin-1 receptor antagonist(IL-1Ra), in developing obesity-related inflammatory complications, i.e., type II diabetes (T2D), non-alcoholic steatohepatitis (NASH), atherosclerosis, and cognitive disorders. Besides, the current study discusses the recent advances in natural drugs, synthetic agents, and gene therapy approaches to treat obesity-related inflammatory complications via suppressing IL-1.

PD-L1 silencing inhibits triple-negative breast cancer development and upregulates T-cell-induced pro-inflammatory cytokines.

Triple-negative breast cancer (TNBC) is an invasive tumor with a high incidence of distant metastasis and poor prognosis. In TNBC cells, high PD-L1 expression can induce an immunosuppressive tumor microenvironment, repressing the anti-tumoral immune responses. Although FDA-approved agents targeting the PD-1/PD-L1 axis are potent to eliminate tumoral cells, their immune-related adverse events have become worrisome. As the regulator of gene expression, siRNAs can directly target PD-L1 in breast cancer cells. The gene modification of tumoral PD-L1 can reduce our reliance on the current method of targeting the PD-L1/PD-1 axis. We initiated the study with bioinformatics analysis; the results indicated that TNBC and the MDA-MB-231 cells significantly overexpressed PD-L1 compared to other breast cancer subtypes and cell lines. Our results demonstrated that PD-L1 silencing substantially reduced PD-L1 expression at mRNA and protein levels in MDA-MB-231 cells. Moreover, our results demonstrated that PD-L1 knockdown reduced cancer cell proliferation and induced apoptosis via intrinsic and extrinsic apoptosis pathways. We observed that PD-L1 silencing effectively inhibited the migration of TNBC cells. Further investigation also displayed that silencing of PD-L1 in breast cancer cells induced T-cell cytotoxic function by upregulating the gene expression of pro-inflammatory cytokines, i.e., IL-2, IFN-γ, and TNF-α, and downregulating the gene expression of anti-inflammatory cytokines, i.e., IL-10, and TGF-ß, in a co-culture system.

A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine.

Background: Programmed cell death protein 1 (PD-1) can attenuate chimeric antigen receptor-T (CAR-T) cell-mediated anti-tumoral immune responses. In this regard, co-administration of anti-PD-1 with CAR-T cells and PD-1 gene-editing of CAR-T cells have been suggested to disrupt this inhibitory axis. Herein, we aim to investigate the advantages and disadvantages of these two approaches and propose a novel strategy to ameliorate the prognosis of glioma patients. Methods: Scopus, Embase, and Web of Science were systematically searched to obtain relevant peer-reviewed studies published before March 7, 2021. Then, the current study was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. The random-effect model was applied to evaluate the effect size of administrated agents on the survival of animal models bearing gliomas using RevMan version 5.4. The Cochran Q test and I2 were performed to assess the possible between-study heterogeneity. Egger's and Begg and Mazumdar's tests were performed to objectively assess potential asymmetry and publication bias using CMA version 2. Results: Anti-PD-1 can substantially increase the survival of animal models on second-generation CAR-T cells. Also, PD-1 knockdown can remarkably prolong the survival of animal models on third-generation CAR-T cells. Regardless of the CAR-T generations, PD-1 gene-edited CAR-T cells can considerably enhance the survival of animal-bearing gliomas compared to the conventional CAR-T cells. Conclusions: The single-cell sequencing of tumoral cells and cells residing in the tumor microenvironment can provide valuable insights into the patient-derived neoantigens and the expression profile of inhibitory immune checkpoint molecules in tumor bulk. Thus, single-cell sequencing-guided fourth-generation CAR-T cells can cover patient-derived neoantigens expressed in various subpopulations of tumoral cells and inhibit related inhibitory immune checkpoint molecules. The proposed approach can improve anti-tumoral immune responses, decrease the risk of immune-related adverse events, reduce the risk of glioma relapse, and address the vast inter-and intra-heterogeneity of gliomas.

Recent developments of RNA-based vaccines in cancer immunotherapy.

INTRODUCTION: Cancer immunotherapy is more dependent on monoclonal antibodies, proteins, and cells, as therapeutic agents, to attain prominent outcomes. However, cancer immunotherapy's clinical benefits need to be enhanced, as many patients still do not respond well to existing treatments, or their diseases may relapse after temporary control. RNA-based approaches have provided new options for advancing cancer immunotherapy. Moreover, considerable efforts have been made to utilize RNA for vaccine production. RNA vaccines, which encode tumor-associated or specific epitopes, stimulate adaptive immunity. This adaptive immune response is capable of elimination or reduction of tumor burden. It is crucial to develop effective RNA transfer technologies that penetrate the lipid bilayer to reach the cytoplasm for translation into functional proteins. Two important delivery methods include the loading of mRNA into dendritic cells ex vivo; and direct injection of naked RNA with or without a carrier. AREAS COVERED: The latest results of pre-clinical and clinical studies with RNA vaccines in cancer immunotherapy are summarized in this review. EXPERT OPINION: RNA vaccines are now in early clinical development with promising safety and efficacy outcomes. Also, the translation capacity and durability of these vaccines can be increased with chemical modifications and sequence engineering.