Epigenetic tuning of tumour-associated macrophages (TAMs): a potential approach in hepatocellular carcinoma (HCC) immunotherapy.

Recent development in immunotherapy for cancer treatment has substantiated to be more effective than most of the other treatments. Immunity is the first line of defence of the body; nevertheless, cancerous cells can manipulate immunity compartments to play several roles in tumour progression. Tumour-associated macrophages (TAMs), one of the most dominant components in the tumour microenvironment, are recognized as anti-tumour suppressors. Unfortunately, the complete behaviour of TAMs is still unclear and understudied. TAM density is directly correlated with the progression and poor prognosis of hepatocellular carcinoma (HCC), therefore studying TAMs from different points of view passing by all the factors that may affect its existence, polarization, functions and repolarization are of great importance. Different epigenetic regulations were reported to have a direct relation with both HCC and TAMs. Here, this review discusses different epigenetic regulations that can affect TAMs in HCC whether positively or negatively.

When less is more: The association between the expression of polymorphic CYPs and AFB1-induced HCC.

BACKGROUND: An individual's genetic fingerprint is emerging as a pivotal predictor of numerous disease- and treatment-related factors. Single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes play key roles in an individual's exposure to a malignancy-associated risk, such as Aflatoxin B1 (AFB1)-induced hepatocellular carcinoma (HCC). AIM: This study aimed at reviewing literature on the polymorphisms that exist in CYP enzymes and their possible link with susceptibility to AFB1-induced HCC. MATERIALS & METHODS: A set of keywords associated with the study subject of interest was used to search the Google Scholar and the PubMed database. The last ten years' worth of research projects were included in the results filter. The research involved HCC patients and any connection between polymorphic forms of CYP enzymes and their susceptibility to AFB1-induced HCC, including older but significant data. RESULTS: Variations in CYP1A2 and CYP3A4 were reported to impact the rate and magnitude of AFB1 bio-activation, thus influencing an individual's vulnerability to develop HCC. In HCC patients, the activity of CYP isoforms varies, where increased activity has been reported with CYP2C9, CYP2D6, and CYP2E1, while CYP1A2, CYP2C8, and CYP2C19 exhibit decreased activity. CYP2D6*10 frequency has been discovered to differ considerably in HCC patients. Rs2740574 (an upstream polymorphism in CYP3A4 as detected in CYP3A4*1B) and rs776746 (which affects CYP3A5 RNA splicing), both of which influence CYP3A expression, thus impacting the variability of AFB1-epoxide adducts in HCC patients. DISCUSSION: CYP1A2 is the primary enzyme accountable for the formation of harmful AFBO globally. CYP3A4, CYP3A5, CYP3A7, CYP2B7, and CYP3A3 are also implicated in the bio-activation of AFB1 to mutagenic metabolites. It is thought that CYP3A4 is the protein that interacts with AFB1 metabolism the most. CONCLUSION: Polymorphic variants of CYP enzymes have a functional impact on the susceptibility to AFB1-induced HCC. Outlining such variation and their implications may provide deeper insights into approaching HCC in a more personalized manner for guiding future risk-assessment, diagnosis, and treatment.

Inflammasomes in breast cancer: the ignition spark of progression and resistance?

Inflammation and immune evasion are major key players in breast cancer (BC) progression. Recently, the FDA approved the use of anti-programmed death-ligand 1 antibody (anti-PD-L1) and phosphoinositide 3-kinase (PI3K) inhibitors against aggressive BC. Despite the paradigm shift in BC treatments, patients still suffer from resistance, recurrence and serious immune-related adverse events. These obstacles require unravelling of the hidden molecular contributors for such therapy failure hence yielding therapeutics that are at least as efficient yet safer. Inflammasome pathway is activated when the pattern recognition receptor senses danger signals (danger-associated molecular patterns) from damagedRdying cells or pathogen-associated molecular patterns found in microbes, leading to secretion of the active pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). It has been shown throughout numerous studies that inflammasome pathway enhanced invasion, metastasis, provoked BC progression and therapy resistance. Additionally, inflammasomes upregulated the proliferative index ki67 and enhanced PD-L1 expression leading to immunotherapy resistance. IL-1ß contributed to significant decrease in oestrogen receptor levels and promoted BC chemo-resistance. High levels of IL-18 in sera of BC patients were associated with worst prognosis. Stimulation of purinergic receptors and modulation of adipokines in obese subjects activated inflammasomes that evoked radiotherapy resistance and BC progression. The micro RNA miR-223-3p attenuated the inflammasome over-expression leading to lowered tumour volume and lessened angiogenesis in BC. This review sheds the light on the molecular pathways of inflammasomes and their impacts in distinct BC subtypes. In addition, it highlights novel strategies in treatment and prevention of BC.

Thymoquinone, a Novel Multi-Strike Inhibitor of Pro-Tumorigenic Breast Cancer (BC) Markers: CALR, NLRP3 Pathway and sPD-L1 in PBMCs of HR+ and TNBC Patients.

Breast cancer (BC) is not only a mass of malignant cells but also a systemic inflammatory disease. BC pro-tumorigenic inflammation has been shown to promote immune evasion and provoke BC progression. The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is activated when pattern recognition receptors (PRRs) sense danger signals such as calreticulin (CALR) from damaged/dying cells, leading to the secretion of interleukin-1ß (IL-1ß). CALR is a novel BC biological marker, and its high levels are associated with advanced tumors. NLRP3 expression is strongly correlated with an elevated proliferative index Ki67, BC progression, metastasis, and recurrence in patients with hormone receptor-positive (HR+) and triple-negative BC (TNBC). Tumor-associated macrophages (TAMs) secrete high levels of IL-1ß promoting endocrine resistance in HR+ BC. Recently, an immunosuppressive soluble form of programmed death ligand 1 (sPD-L1) has been identified as a novel prognostic biomarker in triple-negative breast cancer (TNBC) patients. Interestingly, IL-1ß induces sPD-L1 release. BC Patients with elevated IL-1ß and sPD-L1 levels show significantly short progression-free survival. For the first time, this study aims to investigate the inhibitory impact of thymoquinone (TQ) on CALR, the NLRP3 pathway and sPD-L1 in HR+ and TNBC. Blood samples were collected from 45 patients with BC. The effect of differing TQ concentrations for different durations on the expression of CALR, NLRP3 complex components and IL-1ß as well as the protein levels of sPD-L1 and IL-1ß were investigated in the peripheral blood mononuclear cells (PBMCs) and TAMs of TNBC and HR+ BC patients, respectively. The findings showed that TQ significantly downregulated the expression of CALR, NLRP3 components and IL-1ß together with the protein levels of secreted IL-1ß and sPD-L1. The current findings demonstrated novel immunomodulatory effects of TQ, highlighting its potential role not only as an excellent adjuvant but also as a possible immunotherapeutic agent in HR+ and TNBC patients.

Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges.

According to data provided by World Health Organization, hepatocellular carcinoma (HCC) is the sixth most common cause of deaths due to cancer worldwide. Tremendous progress has been achieved over the last 10 years developing novel agents for HCC treatment, including small-molecule kinase inhibitors. Several small molecule inhibitors currently form the core of HCC treatment due to their versatility since they would be more easily absorbed and have higher oral bioavailability, thus easier to formulate and administer to patients. In addition, they can be altered structurally to have greater volumes of distribution, allowing them to block extravascular molecular targets and to accumulate in a high concentration in the tumor microenvironment. Moreover, they can be designed to have shortened half-lives to control for immune-related adverse events. Most importantly, they would spare patients, healthcare institutions, and society as a whole from the burden of high drug costs. The present review provides an overview of the pharmaceutical compounds that are licensed for HCC treatment and other emerging compounds that are still investigated in preclinical and clinical trials. These molecules are targeting different molecular targets and pathways that are proven to be involved in the pathogenesis of the disease.

The impact of metformin use on the outcomes of relapse-remitting multiple sclerosis patients receiving interferon beta 1a: an exploratory prospective phase II open-label randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disorder. Elevated levels of pro-inflammatory mediators and some oxidative stress parameters can accelerate the demyelination process. We aimed to investigate the efficacy and safety of metformin as an adjuvant therapy to interferon beta 1a (IFNß-1a) in relapsing-remitting multiple sclerosis (RRMS) patients. METHOD: Eighty RRMS patients were equally divided into 2 groups: the intervention group receiving IFNß-1a plus 2 gm of metformin once daily and the control group receiving IFNß-1a alone. Interleukin 17 (IL17), interleukin 22 (IL22), malondialdehyde (MDA), T2 lesions in magnetic resonance imaging (MRI) and expanded disability status scale (EDSS) were assessed at the baseline and then after 6 months. RESULTS: At baseline, there were no statistically significant differences between the two groups (p > 0.05). After 6 months, the change in the median (interquartile range) of the results for both the intervention and control group were; IL17 (- 1.39 (4.19) vs - 0.93 (5.48), p = 0.48), IL22 (- 0.14 (0.48) vs - 0.09 (0.6), p = 0.53), and EDSS (0 vs 0, p = 1), respectively. The mean (standard deviation) change in MDA for the intervention and control group was - 0.93 (2.2) vs - 0.5 (2.53), p = 0.038, respectively. For MRI results, 21 patients had stationary and regressive course and 1 patient had a progressive course in the intervention arm vs 12 patients had stationary and regressive course and 4 had a progressive course in the control arm, p = 0.14. CONCLUSION: Adding metformin to IFNß-1a demonstrated a potential effect on an oxidative stress marker (MDA). However, there is no statistically significant effect on immunological, MRI and clinical outcomes. We recommend larger scale studies to confirm or negate these findings. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT05298670, 28/3/2022.

More gain, less pain: How resistance training affects immune system functioning in multiple sclerosis patients: A review.

Multiple sclerosis (MS) is characterized by a complex etiology that is mirrored by the perplexing and inconsistent treatment responses observed across different patients. Although epigenetic research has garnered rightful interest in its efforts towards demystifying and understanding aberrant responses to treatment, the interim undoubtedly requires alternative non-pharmacological approaches towards attaining more effective management strategies. Of particular interest in this review is resistance training (RT) as a non-pharmacological exercise-based interventional strategy and its potential role as a disease-modifying tool. RT has been reported across literature to positively influence numerous aspects in the quality of life (QoL) and functional capacity of MS patients, and one of the attributes of these benefits may be a shift in the immune system of these individuals. RT has also been proven to affect different immune system key players associated with MS pathology. Ultimately, this brief review aims to provide a potential yet crucial link between RT, alterations in the expression profile of the immune system, and finally an imminent improvement in the overall well-being and QoL of MS patients, suggesting that utilizing RT as an interventional exercise modality may be an effective strategy that would aid in managing such a complex and debilitating disease.

MicroRNA­155 modulation of CD8+ T­cell activity personalizes response to disease­modifying therapies of patients with relapsing­remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease where activated immune cells can attack oligodendrocytes causing damage to the myelin sheath. Several molecular mechanisms are responsible for the auto-activation of immune cells such as RNA interference (RNAi) through microRNAs (miRNAs or miRs). In the present study, the role of miR-155 in regulating CD8+ T-cell activity in patients with relapsing-remitting multiple sclerosis (RRMS) was investigated, in terms of its migratory functions with regard to intracellular adhesion molecule-1 (ICAM1) and integrin subunit ß2 (ITGB2), and its cytotoxic proteins, perforin and granzyme B. Gene expression of miR-155, ICAM1, ITGB2, perforin and granzyme B was evaluated following epigenetic modulations using reverse transcription-quantitative polymerase chain reaction in CD8+ T-cells isolated from blood samples of patients with RRMS and compared to healthy controls. The ectopic expression of miR-155 resulted in a persistent downregulation in all genes of interest related to CD8+ T-cell activation that were positively correlated with the Expanded Disability Status Scale of patients. The present study revealed the interplay between miR-155, ICAM1, and ITGB2, shedding light on their beneficial use as possible therapeutic regulators and diagnostic biomarkers of disease. Moreover, epigenetic modulations enhancing the efficacy of disease-modifying therapies (DMTs) may be employed as personalized therapy, to decrease the side effects of DMTs and improve the outcomes of patients.

What's your cup of tea? The role of herbal compounds in the management of multiple sclerosis.

Multiple Sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease that is characterized by a complex etiology. Efforts towards the management of MS have long been directed towards symptomatic relief, as well as the use of immune-modulatory, disease modifying therapies; however, inconsistent treatment responses still prevail, increasing the risk for disease progression. While a great deal of research attempted to unravel the complexity of treatment responses in light of epigenetic variability, parallel efforts in the direction of alternative medicine may be as paramount. Herbal compounds have long been regarded as safe and versatile options for aiding in various disorders, including neurodegenerative conditions like MS. Numerous studies have taken interest in a myriad of herbal plants for their potential benefit in alleviating some of the most common MS symptoms such as spasticity and fatigue, delaying the progression of the disease, as well as influencing the overall quality of life for MS patients. This review aims to provide a comprehensive overview of recent clinical studies examining the effects of various herbal plants on different aspects of MS, in an attempt to shed light on an important tool for aiding in the management of this complex and multifactorial disease.

Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as Anti-Hepatocellular Carcinoma Agents.

Blockade of the programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint pathway is an efficient immunotherapeutic modality that provided significant advances in cancer treatment especially in solid tumors highly resistant to traditional therapy. Monoclonal antibodies (mAbs) and small-molecule inhibitors are the two main strategies used to block this axis with mAbs suffering from many limitations. Accordingly, the current alternative is the development of small-molecule PD-1/PD-L1 inhibitors. Here, we present a sequential virtual screening (VS) protocol involving pharmacophore screening followed by molecular docking for the discovery of novel PD-L1 inhibitors. The VS protocol resulted in the discovery of eight novel compounds. A 100 ns MD simulation showed two compounds, H4 and H6, exhibiting a stable binding mode at the PD-L1 dimer interface. Upon evaluation of their immunological activities, the two compounds induced higher cytokines levels (IL-2, IL-6, and INF-γ) relative to BMS-202, 72 h post treatment of PBMCs of HCC patients. Thus, the discovered hits represent potential leads for the development of novel classes targeting the PD-L1 receptor as anti-hepatocellular carcinoma agents.

Rs205764 and rs547311 in linc00513 may influence treatment responses in multiple sclerosis patients: A pharmacogenomics Egyptian study.

Background: Multiple sclerosis (MS) is characterized by a complex etiology that is reflected in the lack of consistently predictable treatment responses across patients of seemingly similar characteristics. Approaches to demystify the underlying predictors of aberrant treatment responses have made use of genome-wide association studies (GWAS), with imminent progress made in identifying single nucleotide polymorphisms (SNPs) associated with MS risk, disease progression, and treatment response. Ultimately, such pharmacogenomic studies aim to utilize the approach of personalized medicine to maximize patient benefit and minimize rate of disease progression. Objective: Very limited research is available around the long intergenic non-coding RNA (linc)00513, recently being reported as a novel positive regulator of the type-1 interferon (IFN) pathway, following its overexpression in the presence of two polymorphisms: rs205764 and rs547311 in the promoter region of this gene. We attempt to provide data on the prevalence of genetic variations at rs205764 and rs547311 in Egyptian MS patients, and correlate these polymorphisms with the patients' responses to disease-modifying treatments. Methods: Genomic DNA from 144 RRMS patients was isolated and analyzed for genotypes at the positions of interest on linc00513 using RT-qPCR. Genotype groups were compared with regards to their response to treatment; additional secondary clinical parameters including the estimated disability status score (EDSS), and onset of the disease were examined in relation to these polymorphisms. Results: Polymorphisms at rs205764 were associated with a significantly higher response to fingolimod and a significantly lower response to dimethylfumarate. Moreover, the average EDSS of patients carrying polymorphisms at rs547311 was significantly higher, whereas no correlation appeared to exist with the onset of MS. Conclusion: Understanding the complex interplay of factors influencing treatment response is pivotal in MS. One of the factors contributing to a patient's response to treatment, as well as disease disability, may be polymorphisms on non-coding genetic material, such as rs205764 and rs547311 on linc00513. Through this work, we propose that genetic polymorphisms may partially drive disease disability and inconsistent responses to treatment in MS; we also aim to draw attention towards genetic approaches, such as screening for specific polymorphisms, to possibly direct treatment choices in such a complex disease.

The Monocyte, a Maestro in the Tumor Microenvironment (TME) of Breast Cancer.

Breast cancer (BC) is well-known for being a leading cause of death worldwide. It is classified molecularly into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These subtypes differ in their prognosis; thus, understanding the tumor microenvironment (TME) makes new treatment strategies possible. The TME contains populations that exhibit anti-tumorigenic actions such as tumor-associated eosinophils. Moreover, it contains pro-tumorigenic populations such as tumor-associated neutrophils (TANs), or monocyte-derived populations. The monocyte-derived populations are tumor-associated macrophages (TAMs) and MDSCs. Thus, a monocyte can be considered a maestro within the TME. Moreover, the expansion of monocytes in the TME depends on many factors such as the BC stage, the presence of macrophage colony-stimulating factor (M-CSF), and the presence of some chemoattractants. After expansion, monocytes can differentiate into pro-inflammatory populations such as M1 macrophages or anti-inflammatory populations such as M2 macrophages according to the nature of cytokines present in the TME. Differentiation to TAMs depends on various factors such as the BC subtype, the presence of anti-inflammatory cytokines, and epigenetic factors. Furthermore, TAMs and MDSCs not only have a role in tumor progression but also are key players in metastasis. Thus, understanding the monocytes further can introduce new target therapies.

A cutting-edge immunomodulatory interlinkage between HOTAIR and MALAT1 in tumor-associated macrophages in breast cancer: A personalized immunotherapeutic approach.

Breast cancer (BC) is one of the most common cancers, accounting for 2.3 million cases worldwide. BC can be molecularly subclassified into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These molecular subtypes differ in their prognosis and treatment strategies; thus, understanding the tumor microenvironment (TME) of BC could lead to new potential treatment strategies. The TME hosts a population of cells that act as antitumorigenic such as tumor-associated eosinophils or pro-tumorigenic such as cancer-associated fibroblasts (CAFs), tumor-associated neutrophils (TANs), monocytic-derived populations such as MDSCs, or most importantly "tumor-associated macrophages (TAMs)," which are derived from CD14+ monocytes. TAMs are reported to have the pro-inflammatory phenotype M1, which is found only in the very early stages of tumor and is not correlated with progression; however, the M2 phenotype is anti-inflammatory that is correlated with tumor progression and metastasis. The current study focused on controlling the anti-inflammatory activity in TAMs of hormonal, HER2+, and TNBC by epigenetic fine-tuning of two immunomodulatory proteins, namely, CD80 and mesothelin (MSLN), which are known to be overexpressed in BC with pro-tumorigenic activity. Long non-coding RNAs are crucial key players in tumor progression whether acting as oncogenic or tumor suppressors. We focused on the regulatory role of MALAT1 and HOTAIR lncRNAs and their role in controlling the tumorigenic activity of TAMs. This study observed the impact of manipulation of MALAT1 and HOTAIR on the expression of both CD80 and MSLN in TAMs of BC. Moreover, we analyzed the interlinkage between HOTAIR and MALAT1 as regulators to one another in TAMs of BC. The current study reported an upstream regulatory effect of HOTAIR on MALAT1. Moreover, our results showed a promising use of MALAT1 and HOTAIR in regulating oncogenic immune-modulatory proteins MSLN and CD80 in TAMs of HER2+ and TNBC. The downregulation of MALAT1 and HOTAIR resulted in the upregulation of CD80 and MSLN, which indicates that they might have a cell-specific activity in TAMs. These data shed light on novel key players affecting the anti-inflammatory activity of TAMs as a possible therapeutic target in HER2+ and TNBC.

CXCR2 Small-Molecule Antagonist Combats Chemoresistance and Enhances Immunotherapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer as the absence of cell surface receptors renders it more difficult to be therapeutically targeted. Chemokine receptor 2 (CXCR2) has been suggested not only to promote therapy resistance and suppress immunotherapy but it also to possess a positive cross-talk with the multifunctional cytokine transforming growth factor beta (TGF-ß). Here, we showed that CXCR2 and TGF-ß signaling were both upregulated in human TNBC biopsies. CXCR2 inhibition abrogated doxorubicin-mediated TGF-ß upregulation in 3D in vitro TNBC coculture with PBMCs and eliminated drug resistance in TNBC mammospheres, suggesting a vital role for CXCR2 in TNBC doxorubicin-resistance via TGF-ß signaling regulation. Moreover, CXCR2 inhibition improved the efficacy of the immunotherapeutic drug "atezolizumab" where the combined inhibition of CXCR2 and PDL1 in TNBC in vitro coculture showed an additive effect in cytotoxicity. Altogether, the current study suggests CXCR2 inhibitors as a promising approach to improve TNBC treatment if used in combination with chemotherapy and/or immunotherapy.

NEAT1: Culprit lncRNA linking PIG-C, MSLN, and CD80 in triple-negative breast cancer.

BACKGROUND: Breast cancer (BC) is the most common cancer in women. Despite the effectiveness of conventional therapies, they cause detrimental side effects. Glycosyl-Phosphatidyl-Inositol (GPI) pathway is a conserved pathway that culminates in the generation of GPI anchored proteins (GPI-AP). Phosphatidyl-Inositol-Glycan Biosynthesis Class C (PIG-C) is the first step in GPI pathway and upon its overexpression, Mesothelin (MSLN); an oncogenic GPI-AP, expression is induced. Therefore, blocking GPI pathway is a potential therapy through which multiple pathways can be rectified. Recombinant GPI-CD80 proved to be a potent immunostimulatory protein and currently being evaluated as tumor vaccine. In fact, CD80 is a unique immunomodulator that binds to CD28, CTLA-4 and PD-L1. Furthermore, research advancement showed that non-coding RNAs (ncRNAs) are key epigenetic modulators. Therefore, epigenetic tuning of GPI-APs remains an unexplored area. This study aims at investigating the potential role of ncRNAs in regulating MSLN, PIG-C and CD80 in BC. METHODS: Potential ncRNAs were filtered by bioinformatics algorithms. MDA-MB-231 cells were transfected with RNA oligonucleotides. Surface CD80 and MSLN were assessed by FACS and immunofluorescence. Gene expression was tested by q-PCR. RESULTS: PIG-C gene was overexpressed in TNBC and its manipulation altered MSLN surface level. Aligning with bioinformatics analysis, miR-2355 manipulated PIG-C and MSLN expression, while miR-455 manipulated CD80 expression. NEAT1 sponged both miRNAs. Paradoxically, NEAT1 lowered PIG-C gene expression while increased MSLN gene expression. CONCLUSION: This study unravels novel immunotherapeutic targets for TNBC. NEAT1 is potential immunomodulator by sponging several miRNAs. Finally, this study highlights GPI pathway applications, therefore integrating epigenetics, post-translational modifications and immunomodulation.

Scavenging the hidden impacts of non-coding RNAs in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that causes severe neurological dysfunction leading to disabilities in patients. The prevalence of the disease has been increasing gradually worldwide, and the specific etiology behind the disease is not yet fully understood. Therapies aimed against treating MS patients have been growing lately, intending to delay the disease progression and increase the patients' quality of life. Various pathways play crucial roles in developing the disease, and several therapeutic approaches have been tackling those pathways. However, these strategies have shown several side effects and inconsistent efficacy. MicroRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) have been shown to act as key players in various disease pathogenesis and development. Several proinflammatory and anti-inflammatory miRNAs have been reported to participate in the development of MS. Hence, the review assesses the role of miRNAs, lncRNAs, and circRNAs in regulating immune cell functions better to understand their impact on the molecular mechanics of MS.

Long non-coding RNAs XIST and MALAT1 hijack the PD-L1 regulatory signaling pathway in breast cancer subtypes.

Long non-coding RNAs (lncRNAs) have attracted widespread attention as potential biological and pathological regulators. lncRNAs are involved in several biological processes in cancer. Triple negative breast cancer (TNBC) is characterized by strong heterogeneity and aggressiveness. At present, the implication of microRNAs (miRs) and lncRNAs in immunotherapy has been poorly studied. Nevertheless, the blockade of immune checkpoints, particularly that of the programmed cell-death protein-1/programmed cell-death ligand-1 (PD-L1) axis, is considered as a principle approach in breast cancer (BC) therapy. The present study aimed to investigate the interaction between immune-modulatory upstream signaling pathways of the PD-L1 transcript that could enhance personalized targeted therapy. MDA-MB-231 cells were transfected with miR-182-5p mimics followed by RNA extraction and cDNA synthesis using a reverse transcription kit, and the expression levels of the target genes were assessed by reverse transcription-quantitative PCR. Furthermore, the expression levels of target genes were measured in tissues derived from 41 patients with BC, including patients with luminal BC and TNBC, as well as their adjacent lymph nodes. The results revealed that the expression levels of miR-182-5p, PD-L1 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were upregulated in MDA-MB-231 cells and BC tissues. However, X-inactive specific transcript (XIST) expression was downregulated in cancer tissues and TNBC cells. Following co-transfection of cells with small interfering RNAs specific for each target gene and miR-182-5p antagomirs, the effect of miR-182-5p was abolished in the presence of lncRNAs. Therefore, the results of the present study indicated that although miR-182-5p exhibited an oncogenic effect, XIST exerted a dominant effect on the regulation of the PD-L1 signaling pathway via the inhibition of the oncogenic function of MALAT1.

Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.

miR-155 and functional proteins of CD8+ T cells as potential prognostic biomarkers for relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that results in neurological deficits in patients leading to disabilities which are evaluated on a scale known as the Expanded Disability Status Scale (EDSS). The most prevalent subtype of the disease is Relapsing-Remitting Multiple sclerosis (RRMS). One of the key players in MS pathogenesis is CD8+ T cells present in abundance in MS lesions expressing surface receptors, intracellular adhesion molecule (ICAM1) and integrin Subunit Beta 2 (ITGB2). These proteins are crucial for migration through the blood-brain barrier (BBB) and secondary stimulatory signal, along with the cytotoxic proteins perforin and granzymeB that attack oligodendrocytes. MicroRNAs (miRNAs) are small non-coding RNAs that play a substantial regulatory role in various disease pathogeneses through post-transcriptional modifications, and miR-155 shows potential for its use as a biomarker of the disease. The study aims at investigating the expression of miR-155, ICAM1, ITGB2, perforin and GranzymeB in CD8+ T cells of RRMS patients receiving different treatment regimens and how these genes correlate with patients' EDSS and miR-155 expression. METHODS: Gene expression of miR-155, ICAM1, ITGB2, perforin and granzymeB was evaluated using RT-qPCR in CD8+ T cells isolated from blood samples of RRMS patients and compared to healthy controls. RESULTS: Results showed downregulation of miR-155 and upregulation of surface receptors and cytotoxic proteins in CD8+T cells with significant correlation with each other and patients' EDSS. CONCLUSION: This study helps pave the road for the discussed genes for their use as potential biomarkers of disease disability and future investigations on their regulatory roles in disease pathogenesis.

Thymoquinone: A Tie-Breaker in SARS-CoV2-Infected Cancer Patients?

Since the beginning of the SARS-CoV-2(severe acute respiratory syndrome-coronavirus-2) pandemic, arace to develop a vaccine has been initiated, considering the massive and rather significant economic and healthcare hits that this virus has caused. The pathophysiology occurring following COVID-19(coronavirus disease-2019) infection has givenhints regarding the supportive and symptomatic treatments to establish for patients, as no specific anti-SARS-CoV-2 is available yet. Patient symptoms vary greatly and range from mild symptoms to severe fatal complications. Supportive treatments include antipyretics, antiviral therapies, different combinations of broad-spectrum antibiotics, hydroxychloroquine and plasma transfusion. Unfortunately, cancer patients are at higher risk of viral infection and more likely to develop serious complications due to their immunocompromised state, the fact that they are already administering multiple medications, as well as combined comorbidity compared to the general population. It may seem impossible to find a drug that possesses both potent antiviral and anticancer effects specifically against COVID-19 infection and its complications and the existing malignancy, respectively. Thymoquinone (TQ) is the most pharmacologically active ingredient in Nigella sativa seeds (black seeds); it is reported to have anticancer, anti-inflammatory and antioxidant effects in various settings. In this review, we will discuss the multiple effects of TQ specifically against COVID-19, its beneficial effects against COVID-19 pathophysiology and multiple-organ complications, its use as an adjuvant for supportive COVID-19 therapy and cancer therapy, and finally, its anticancer effects.