Vitamin D and Microbiome: Molecular Interaction in Inflammatory Bowel Disease Pathogenesis.

Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency, leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. This review examines the role of the gut microbiome in IBD and discusses how vitamin D-vitamin D receptor (VDR)-associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function. The present data demonstrate that vitamin D promotes the proper function of the innate immune system by acting as an immunomodulator, exerting anti-inflammatory effects, and critically contributing to the maintenance of gut barrier integrity and modulation of the gut microbiota, mechanisms that may influence the IBD development and progression. VDR regulates the biological effects of vitamin D and is related to environmental, genetic, immunologic, and microbial aspects of IBD. Vitamin D influences the distribution of the fecal microbiota, with high vitamin D levels associated with increased levels of beneficial bacterial species and lower levels of pathogenic bacteria. Understanding the cellular functions of vitamin D-VDR signaling in intestinal epithelial cells may pave the way for the development of new treatment strategies for the therapeutic armamentarium of IBD in the near future.

Adrenal insufficiency in liver diseases - pathophysiology and underlying mechanisms.

Relative adrenal insufficiency (RAI) is common in critically ill patients with cirrhosis, but it has been also documented in non-critically ill patients. Its pathophysiology is complex and not well understood yet. In this review, we aimed to present potential mechanisms and causal pathways implicated in the pathogenesis of RAI in cirrhosis. There is accumulating evidence supporting a suboptimal baseline adrenal function in cirrhosis mainly due to decreased cortisol synthesis and metabolism rates from the adrenal gland. Apart from this peripheral impairment, more recent studies suggest that there is a greater defect in the central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis (hypothalamus/pituitary gland). Pro-inflammatory mediators, which are elevated in cirrhosis, have been also implicated through suppression of the HPA axis, decrease in cortisol synthesis and tissue glucocorticoid resistance. All abovementioned support the hepatoadrenal syndrome hypothesis that during episodes of acute decompensation there is suboptimal adrenocortical response that leads to worse outcomes. In conclusion, the complex pathophysiology of adrenal dysfunction in cirrhosis has not been fully elucidated yet and further research is needed in order to better understand this rather common entity in cirrhosis.

The role of gut barrier dysfunction in postoperative complications in liver transplantation: pathophysiological and therapeutic considerations.

PURPOSE: Gut barrier dysfunction is a pivotal pathophysiological alteration in cirrhosis and end-stage liver disease, which is further aggravated during and after the operational procedures for liver transplantation (LT). In this review, we analyze the multifactorial disruption of all major levels of defense of the gut barrier (biological, mechanical, and immunological) and correlate with clinical implications. METHODS: A narrative review of the literature was performed using PubMed, PubMed Central and Google from inception until November 29th, 2023. RESULTS: Systemic translocation of indigenous bacteria through this dysfunctional barrier contributes to the early post-LT infectious complications, while endotoxin translocation, through activation of the systemic inflammatory response, is implicated in non-infectious complications including renal dysfunction and graft rejection. Bacterial infections are the main cause of early in-hospital mortality of LT patients and unraveling the pathophysiology of gut barrier failure is of outmost importance. CONCLUSION: A pathophysiology-based approach to prophylactic or therapeutic interventions may lead to enhancement of gut barrier function eliminating its detrimental consequences and leading to better outcomes for LT patients.

Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?

Hepatocellular carcinoma (HCC) remains a global health challenge that urgently calls for innovative therapeutic strategies. Chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising avenue for HCC treatment. However, the therapeutic efficacy of CAR T immunotherapy in HCC patients is significantly compromised by some major issues including the immunosuppressive environment within the tumor, antigen heterogeneity, CAR T cell exhaustion, and the advanced risk for on-target/off-tumor toxicity. To overcome these challenges, many ongoing preclinical and clinical trials are underway focusing on the identification of optimal target antigens and the decryption of the immunosuppressive milieu of HCC. Moreover, limited tumor infiltration constitutes a significant obstacle of CAR T cell therapy that should be addressed. The continuous effort to design molecular targets for CAR cells highlights the importance for a more practical approach for CAR-modified cell manufacturing. This review critically examines the current landscape of CAR T cell therapy for HCC, shedding light on the changes in innate and adaptive immune responses in the context of HCC, identifying potential CAR T cell targets, and exploring approaches to overcome inherent challenges. Ongoing advancements in scientific research and convergence of diverse treatment modalities offer the potential to greatly enhance HCC patients' care in the future.

Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.

Myelin Oligodendrocyte Glycoprotein (MOG)35-55 Mannan Conjugate Induces Human T-Cell Tolerance and Can Be Used as a Personalized Therapy for Multiple Sclerosis.

We have previously performed preclinical studies with the oxidized mannan-conjugated peptide MOG35-55 (OM-MOG35-55) in vivo (EAE mouse model) and in vitro (human peripheral blood) and demonstrated that OM-MOG35-55 suppresses antigen-specific T cell responses associated with autoimmune demyelination. Based on these results, we developed different types of dendritic cells (DCs) from the peripheral blood monocytes of patients with multiple sclerosis (MS) or healthy controls presenting OM-MOG35-55 or MOG-35-55 to autologous T cells to investigate the tolerogenic potential of OM-MOG35-55 for its possible use in MS therapy. To this end, monocytes were differentiated into different DC types in the presence of IL-4+GM-CSF ± dexamethasone (DEXA) ± vitamin D3 (VITD3). At the end of their differentiation, the DCs were loaded with peptides and co-cultured with T cells +IL-2 for 4 antigen presentation cycles. The phenotypes of the DC and T cell populations were analyzed using flow cytometry and the secreted cytokines using flow cytometry or ELISA. On day 8, the monocytes had converted into DCs expressing the typical markers of mature or immature phenotypes. Co-culture of T cells with all DC types for 4 antigen presentation cycles resulted in an increase in memory CD4+ T cells compared to memory CD8+ T cells and a suppressive shift in secreted cytokines, mainly due to increased TGF-ß1 levels. The best tolerogenic effect was obtained when patient CD4+ T cells were co-cultured with VITD3-DCs presenting OM-MOG35-55, resulting in the highest levels of CD4+PD-1+ T cells and CD4+CD25+Foxp3+ Τ cells. In conclusion, the tolerance induction protocols presented in this work demonstrate that OM-MOG35-55 could form the basis for the development of personalized therapeutic vaccines or immunomodulatory treatments for MS.

Diagnostic and Prognostic Ability of Pancreatic Stone Protein: A Scoping Review.

Pancreatic stone protein (PSP) is an acute-phase reactant mainly produced in response to stress. Its diagnostic and prognostic accuracy for several types of infection has been studied in several clinical settings. The aim of the current review was to assess all studies examining a possible connection of pancreatic stone protein levels with the severity and possible complications of patients diagnosed with infection. We performed a systematic search in PubMed, Scopus, the Cochrane Library and Clinicaltrials.gov to identify original clinical studies assessing the role of pancreatic stone protein in the diagnosis and prognosis of infectious diseases. We identified 22 eligible studies. Ten of them provided diagnostic aspects, ten studies provided prognostic aspects, and another two studies provided both diagnostic and prognostic information. The majority of the studies were performed in an intensive care unit (ICU) setting, five studies were on patients who visited the emergency department (ED), and three studies were on burn-injury patients. According to the literature, pancreatic stone protein has been utilized in patients with different sites of infection, including pneumonia, soft tissue infections, intra-abdominal infections, urinary tract infections, and sepsis. In conclusion, PSP appears to be a useful point-of-care biomarker for the ED and ICU due to its ability to recognize bacterial infections and sepsis early. Further studies are required to examine PSP's kinetics and utility in specific populations and conditions.

miRNA Molecules-Late Breaking Treatment for Inflammatory Bowel Diseases?

MicroRNAs (miRNAs) are a group of non-coding RNAs that play a critical role in regulating epigenetic mechanisms in inflammation-related diseases. Inflammatory bowel diseases (IBDs), which primarily include ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic recurrent inflammation of intestinal tissues. Due to the multifactorial etiology of these diseases, the development of innovative treatment strategies that can effectively maintain remission and alleviate disease symptoms is a major challenge. In recent years, evidence for the regulatory role of miRNAs in the pathogenetic mechanisms of various diseases, including IBD, has been accumulating. In light of these findings, miRNAs represent potential innovative candidates for therapeutic application in IBD. In this review, we discuss recent findings on the role of miRNAs in regulating inflammatory responses, maintaining intestinal barrier integrity, and developing fibrosis in clinical and experimental IBD. The focus is on the existing literature, indicating potential therapeutic application of miRNAs in both preclinical experimental IBD models and translational data in the context of clinical IBD. To date, a large and diverse data set, which is growing rapidly, supports the potential use of miRNA-based therapies in clinical practice, although many questions remain unanswered.

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder.

The Influence of Single Nucleotide Polymorphisms on Vitamin D Receptor Protein Levels and Function in Chronic Liver Disease.

Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been associated with chronic liver disease. We investigated the role of VDR SNPs on VDR protein levels and function in patients with chronic liver disease. VDR expression levels were determined in peripheral T lymphocytes (CD3+VDR+), monocytes (CD14+VDR+), and plasma from patients (n = 66) and healthy controls (n = 38). Genotyping of SNPs and the determination of expression of VDR/vitamin D-related genes were performed by using qPCR. The effect of FokI SNP on vitamin D-binding to VDR was investigated by molecular dynamics simulations. CD14+VDR+ cells were correlated with the MELD score. The ApaI SNP was associated with decreased CD3+VDR+ levels in cirrhotic patients and with higher liver stiffness in HCV patients. The BsmI and TaqI SNPs were associated with increased VDR plasma concentrations in cirrhotic patients and decreased CD14+VDR+ levels in HCV patients. The FokI SNP was associated with increased CD3+VDR+ levels in cirrhotic patients and controls. VDR polymorphisms were significantly related to the expression of genes critical for normal hepatocyte function and immune homeostasis. VDR expression levels were related to the clinical severity of liver disease. VDR SNPs may be related to the progression of chronic liver disease by affecting VDR expression levels.

Low Urinary Free Cortisol as a Risk Factor for Patients with Variceal Bleeding.

Background and Objectives: Specificity and reliability issues of the current cortisol assessment methods lead to limitations on the accurate assessment of relative adrenal insufficiency. Although free cortisol provides a more accurate evaluation of adrenal cortisol production, the expense and time-consuming nature of these assays make them impractical for routine use. Research has, thus, focused on alternative methods, such as indirectly measuring free cortisol using Coolens' equation or directly assessing salivary cortisol concentration, which is considered a more favorable approach despite associated challenges like sampling issues and infection risks. The aim of this study was to explore correlations between 24 h urinary free cortisol (UFC), free plasma cortisol, serum total cortisol, and salivary cortisol as potential reliable indices of free cortisol in the setting of variceal bleeding. Additionally, we assessed the predictive value of UFC for 6-week mortality and 5-day treatment failure in patients with liver cirrhosis and variceal bleeding. Materials and Methods: A total of 40 outpatients with liver cirrhosis and variceal bleeding were enrolled. Free cortisol levels in serum, saliva, and urine were assessed using the electrochemiluminescence immunoassay method. For the measurement of plasma-free cortisol, a single quadrupole mass spectrometer was employed. The quantification of free cortisol was fulfilled by analyzing the signal response in the negative ESI-MS mode. Results: UFC was significantly correlated to free plasma cortisol. Negative correlations were demonstrated between UFC, the Child-Pugh (CP) score, and C reactive protein (CRP) levels. In the multivariate analysis, CP stage C was associated with 6-week mortality risk and portal vein thrombosis with 5-day treatment failure using Cox regression and binary logistic regression analyses, respectively. Patients who experienced rebleeding, infection, or death (or any combination of these events) presented with lower levels of UFC. Conclusions: This study suggests that low levels of UFC may impose a risk factor for patients with liver cirrhosis and variceal bleeding. The use of UFC as an index of adrenal cortisol production in variceal bleeding warrants further investigation.

Vitamin D-VDR Novel Anti-Inflammatory Molecules-New Insights into Their Effects on Liver Diseases.

There is consistent evidence that vitamin D deficiency is strongly associated with liver dysfunction, disease severity, and poor prognosis in patients with liver disease. Vitamin D and its receptor (VDR) contribute to the regulation of innate and adaptive immune responses. The presence of genetic variants of vitamin D- and VDR-associated genes has been associated with liver disease progression. In our recent work, we summarized the progress in understanding the molecular mechanisms involved in vitamin D-VDR signaling and discussed the functional significance of VDR signaling in specific cell populations in liver disease. The current review focuses on the complex interaction between immune and liver cells in the maintenance of liver homeostasis and the development of liver injury, the interplay of vitamin D and VDR in the development and outcome of liver disease, the role of vitamin D- and VDR-associated genetic variants in modulating the occurrence and severity of liver disease, and the therapeutic value of vitamin D supplementation in various liver diseases. The association of the vitamin D-VDR complex with liver dysfunction shows great potential for clinical application and supports its use as a prognostic index and diagnostic tool.

Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease.

Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical regulators of inflammatory disorders. The IL-33/ST2 axis is involved in the maintenance of intestinal homeostasis; on the basis of their role as pro- or anti-inflammatory mediators of first-line innate immunity, their expression is of great importance in regard to mucosal defenses. Mucosal immunity commonly presents an imbalance in inflammatory bowel disease (IBD). This review summarizes the main cellular and molecular aspects of IL-33 and ST2, mainly focusing on the current evidence of the pro- and anti-inflammatory effects of the IL-33/ST2 axis in the course of ulcerative colitis and Crohn's disease, as well as the molecular mechanisms underlying the association of IL-33/ST2 signaling in IBD pathogenesis. Although IL-33 modulates and impacts the development, course, and recurrence of the inflammatory response, the exact role of this molecule is elusive, and it seems to be associated with the subtype of the disease or the disease stage. Unraveling of IL-33/ST2-mediated mechanisms involved in IBD pathology shows great potential for clinical application as therapeutic targets in IBD treatment.

The Role of Leptin in Childhood Immune Thrombocytopenia (ITP): An Anti-Inflammatory Agent?

To investigate the effect of leptin in childhood ITP, we measured plasma leptin in 39 children with acute ITP, after treatment and in remission, and in 33 healthy age/BMI-matched controls. We also cultured ITP and control peripheral blood mononuclear cells (PBMCs) with recombinant leptin to assess its direct effect on pro/anti-inflammatory cytokine gene expression. A significant increase in leptin was observed in children with active disease compared to controls. A significant inverse correlation of leptin with platelet count was also observed in children with acute ITP. Leptin remained high after treatment with IVIg, whereas steroid treatment lowered leptin below control levels. In remission, leptin was in the control range. Cytokine gene expression was significantly increased in children with acute ITP compared with controls, with highest expression for IFN-γ and IL-10. IVIg/steroid treatment significantly decreased IFN-γ and IL-10 expression. In remission, IFN-γ and IL-10 expression remained low. Addition of leptin to PBMCs isolated from patients in remission resulted in a significant increase in IL-10 gene expression compared to controls. Further experiments with purified T-cells and monocytes identified monocytes as the source of leptin-induced IL-10. We suggest that leptin acts as an active anti-inflammatory agent in childhood ITP by promoting IL-10 secretion by monocytes.

Transcription factor Ets-2 regulates the expression of key lymphotropic factors.

Transcription factor Ets-2 downregulates the expression of cytokine genes and HIV-1 in resting T-cells. Herein, we studied whether Ets-2 regulates the expression of lymphotropic factors (LFs) NFAT2, NF-κΒ/p65, c-Jun, c-Fos, which regulate the activation/differentiation of T-cells, and kinase CDK10, which controls Ets-2 degradation and repression activity. In silico analysis revealed Ets-2 binding sites on the promoters of NFAT2, c-Jun, c-Fos. The T-cell lines Jurkat (models T-cell signaling/activation) and H938 (contains the HIV-1-LTR) were transfected with an Ets-2 overexpressing vector, in the presence/absence of mitogens. mRNA and protein levels were assessed by qPCR and Western immunoblotting, respectively. Ets-2 overexpression in unstimulated Jurkat increased NFAT2 and c-Jun mRNA/protein, c-Fos mRNA and NF-κΒ/p65 protein, and decreased CDK10 protein. In unstimulated H938, Ets-2 upregulated NFAT2, c-Jun and CDK10 mRNA/protein and NF-κΒ/p65 protein. In stimulated Jurkat, Ets-2 increased NFAT2, c-Jun and c-Fos mRNA/protein and decreased CDK10 mRNA/protein. In stimulated H938 Ets-2 increased NFAT2, c-Jun and c-Fos protein and reduced CDK10 protein levels. Furthermore, Ets-2 overexpression modulated the expression of pro- and anti-apoptotic genes in both cell lines. Ets-2 upregulates the expression of key LFs involved in the activation of cytokine genes or HIV-1 in T-cells, either through its physical interaction with gene promoters or through its involvement in signaling pathways that directly impact their expression. The effect of Ets-2 on CDK10 expression in H938 vs Jurkat cells dictates that, additionally to Ets-2 degradation, CDK10 may facilitate Ets-2 repression activity in cells carrying the HIV-1-LTR, contributing thus to the regulation of HIV latency in virus-infected T-cells.

The role of the gut microbiota in the treatment of inflammatory bowel diseases.

The human intestinal microbiota coevolves with its host through a symbiotic relationship and exerts great influence on substantial functions including aspects of physiology, metabolism, nutrition and regulation of immune responses leading to physiological homeostasis. Over the last years, several studies have been conducted toward the assessment of the host-gut microbiota interaction, aiming to elucidate the mechanisms underlying the pathogenesis of several diseases. A defect on the microbiota-host crosstalk and the concomitant dysregulation of immune responses combined with genetic and environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). To this end, novel therapeutic options based on the gut microbiota modulation have been an area of extensive research interest. In this review we present the recent findings on the association of dysbiosis with IBD pathogenesis, we focus on the role of gut microbiota on the treatment of IBD and discuss the novel and currently available therapeutic strategies in manipulating the composition and function of gut microbiota in IBD patients. Applicable and emerging microbiota treatment modalities, such as the use of antibiotics, prebiotics, probiotics, postbiotics, synbiotics and fecal microbiota transplantation (FMT) constitute promising therapeutic options. However, the therapeutic potential of the aforementioned approaches is a topic of investigation and further studies are needed to elucidate their position in the present treatment algorithms of IBD.

Response to hepatitis B vaccination in patients with liver cirrhosis.

Hepatitis B vaccination is strongly recommended for all infants and children but also for adults who are at risk of HBV infection. Attempts to immunize patients with liver cirrhosis have been proven relatively ineffective, and several strategies have already been used to improve the immune response in this group. The primary aim of this review is to examine, discuss, and summarize the immunogenicity of hepatitis B vaccination in patients with liver cirrhosis. MEDLINE search identified 11 studies (n = 961). The dose of the vaccine and the schedule of the vaccination varied. The response rates to the HBV vaccination ranged from 16% to 87% among patients with cirrhosis regardless of the number and vaccine dose. In particular, patients who received the standard dose of vaccination achieved seroprotection rates ranged from 16% to 79% (mean response rate 38%) and those who received a double dose achieved relatively better seroprotection rates (range: 26%-87%; mean response rate 53%). The overall mean response rate to the HBV vaccination was 47%. In conclusion, cirrhotic patients achieve lower seroprotection rates after the completion of HBV vaccination series. Several strategies have tried to improve the immunogenicity; however, there is a great need for additional studies to further explore (1) the immune response in relation to poor vaccination responsiveness confounding factors, (2) novel strategies to improve immunogenicity, and (3) the immune mechanism underlying the differences in response rates to HBV vaccination.

Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes.

IL-2 is the first cytokine produced when naive T helper (Th) cells are activated and differentiate into dividing pre-Th0 proliferating precursors. IL-2 expression is blocked in naive, but not activated or memory, Th cells by the transcription factor Ets-2 that binds to the antigen receptor response element (ARRE)-2 of the proximal IL-2 promoter. Ets-2 acts as an independent preinduction repressor in naive Th cells and does not interact physically with the transcription factor NFAT (nuclear factor of activated T-cells) that binds to the ARRE-2 in activated Th cells. In naive Th cells, Ets-2 mRNA expression, Ets-2 protein levels, and Ets-2 binding to ARRE-2 decrease upon cell activation followed by the concomitant expression of IL-2. Cyclosporine A stabilizes Ets-2 mRNA and protein when the cells are activated. Ets-2 silences directly constitutive or induced IL-2 expression through the ARRE-2. Conversely, Ets-2 silencing allows for constitutive IL-2 expression in unstimulated cells. Ets-2 binding to ARRE-2 in chromatin is stronger in naive compared with activated or memory Th cells; in the latter, Ets-2 participates in a change of the IL-2 promoter architecture, possibly to facilitate a quick response when the cells re-encounter antigen. We propose that Ets-2 expression and protein binding to the ARRE-2 of the IL-2 promoter are part of a strictly regulated process that results in a physiological transition of naive Th cells to Th0 cells upon antigenic stimulation. Malfunction of such a repression mechanism at the molecular level could lead to a disturbance of later events in Th cell plasticity, leading to autoimmune diseases or other pathological conditions.

Evaluation of PAGE-B Score for Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients: Reliability, Validity, and Responsiveness.

Chronic hepatitis B (CHB) constitutes a major global public health issue, affecting millions of individuals. Despite the implementation of robust vaccination programs, the hepatitis B virus (HBV) significantly influences morbidity and mortality rates. CHB emerges as one of the leading causes of hepatocellular carcinoma (HCC), introducing a major challenge in the effective management of CHB patients. Therefore, it is of utmost clinical importance to diligently monitor individuals with CHB who are at high risk of HCC development. While various prognostic scores have been developed for surveillance and screening purposes, their accuracy in predicting HCC risk may be limited, particularly in patients under treatment with nucleos(t)ide analogues. The PAGE-B model, incorporating age, gender, and platelet count, has exhibited remarkable accuracy, validity, and reliability in predicting HCC occurrence among CHB patients receiving HBV treatment. Its predictive performance stands out, whether considered independently or in comparison to alternative HCC risk scoring systems. Furthermore, the introduction of targeted adjustments to the calculation of the PAGE-B score might have the potential to further improve its predictive accuracy. This review aims to evaluate the efficacy of the PAGE-B score as a dependable tool for accurate prediction of the development of HCC in CHB patients. The evidence discussed aims to provide valuable insights for guiding recommendations on HCC surveillance within this specific population.