Exploring the Role of GITR/GITRL Signaling: From Liver Disease to Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.

PD-L1 Expression in Neoplastic and Immune Cells of Thymic Epithelial Tumors: Correlations with Disease Characteristics and HDAC Expression.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression in neoplastic and immune cells of the tumor microenvironment determines the efficacy of antitumor immunity, while it can be regulated at the epigenetic level by various factors, including HDACs. In this study, we aim to evaluate the expression patterns of PD-L1 in thymic epithelial tumors (TETs), while we attempt the first correlation analysis between PD-L1 and histone deacetylases (HDACs) expression. METHODS: Immunohistochemistry was used to evaluate the expression of PD-L1 in tumor and immune cells of 91 TETs with SP263 and SP142 antibody clones, as well as the expressions of HDCA1, -2, -3, -4, -5, and -6. RESULTS: The PD-L1 tumor proportion score (TPS) was higher, while the immune cell score (IC-score) was lower in the more aggressive TET subtypes and in more advanced Masaoka-Koga stages. A positive correlation between PD-L1 and HDAC-3, -4, and -5 cytoplasmic expression was identified. CONCLUSIONS: Higher PD-L1 expression in neoplastic cells and lower PD-L1 expression in immune cells of TETs characterizes more aggressive and advanced neoplasms. Correlations between PD-L1 and HDAC expression unravel the impact of epigenetic regulation on the expression of immune checkpoint molecules in TETs, with possible future applications in combined therapeutic targeting.

Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications.

Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential.

Pathophysiology and Clinical Management of Dyslipidemia in People Living with HIV: Sailing through Rough Seas.

Infections with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst HAART regimens, darunavir and atazanavir, tenofovir disoproxil fumarate, nevirapine, rilpivirine, and especially integrase inhibitors have demonstrated the most favorable lipid profile, emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates, or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies.

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell-cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell-cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.

Metformin in Esophageal Carcinoma: Exploring Molecular Mechanisms and Therapeutic Insights.

Esophageal cancer (EC) remains a formidable malignancy with limited treatment options and high mortality rates, necessitating the exploration of innovative therapeutic avenues. Through a systematic analysis of a multitude of studies, we synthesize the diverse findings related to metformin's influence on EC. This review comprehensively elucidates the intricate metabolic pathways and molecular mechanisms through which metformin may exert its anti-cancer effects. Key focus areas include its impact on insulin signaling, AMP-activated protein kinase (AMPK) activation, and the mTOR pathway, which collectively contribute to its role in mitigating esophageal cancer progression. This review critically examines the body of clinical and preclinical evidence surrounding the potential role of metformin, a widely prescribed anti-diabetic medication, in EC management. Our examination extends to the modulation of inflammation, oxidative stress and angiogenesis, revealing metformin's potential as a metabolic intervention in esophageal cancer pathogenesis. By consolidating epidemiological and clinical data, we assess the evidence that supports metformin's candidacy as an adjuvant therapy for esophageal cancer. By summarizing clinical and preclinical findings, our review aims to enhance our understanding of metformin's role in EC management, potentially improving patient care and outcomes.

γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy.

Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and a poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest in exploring novel approaches to combat HCC. One such approach involves the unique and versatile subset of T cells known as γδ T cells. γδ T cells represent a distinct subset of T lymphocytes that differ from conventional αß T cells in terms of antigen recognition and effector functions. They play a crucial role in immunosurveillance against various malignancies, including HCC. Recent studies have demonstrated that γδ T cells can directly recognize and target HCC cells, making them an attractive candidate for immunotherapy. In this article, we aimed to explore the role exerted by γδ T cells in the context of HCC. We investigate strategies designed to maximize the therapeutic effectiveness of these cells and examine the challenges and opportunities inherent in applying these research findings to clinical practice. The potential to bring about a revolutionary shift in HCC immunotherapy by capitalizing on the unique attributes of γδ T cells offers considerable promise for enhancing patient outcomes, warranting further investigation.

Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies.

Inflammasomes are multimeric protein complexes, sensors of intracellular danger signals, and crucial components of the innate immune system, with the NLRP3 inflammasome being the best characterized among them. The increasing scientific interest in the mechanisms interconnecting inflammation and tumorigenesis has led to the study of the NLRP3 inflammasome in the setting of various neoplasms. Despite a plethora of data regarding solid tumors, NLRP3 inflammasome's implication in the pathogenesis of hematological malignancies only recently gained attention. In this review, we investigate its role in normal lymphopoiesis and lymphomagenesis. Considering that lymphomas comprise a heterogeneous group of hematologic neoplasms, both tumor-promoting and tumor-suppressing properties were attributed to the NLRP3 inflammasome, affecting neoplastic cells and immune cells in the tumor microenvironment. NLRP3 inflammasome-related proteins were associated with disease characteristics, response to treatment, and prognosis. Few studies assess the efficacy of NLRP3 inflammasome therapeutic targeting with encouraging results, though most are still at the preclinical level. Further understanding of the mechanisms regulating NLRP3 inflammasome activation during lymphoma development and progression can contribute to the investigation of novel treatment approaches to cover unmet needs in lymphoma therapeutics.

Management of type 2 diabetes in patients with compensated liver cirrhosis: Short of evidence, plenty of potential.

BACKGROUND AND AIMS: Treatment of type 2 diabetes (T2D) in patients with compensated cirrhosis is challenging due to hypoglycemic risk, altered pharmacokinetics, and the lack of robust evidence on the risk/benefit ratio of various drugs. Suboptimal glycemic control accelerates the progression of cirrhosis, while the frequent coexistence of nonalcoholic fatty liver disease (NAFLD) with T2D highlights the need for a multifactorial therapeutic approach. METHODS: A literature search was performed in Medline, Google Scholar and Scopus databases till July 2023, using relevant keywords to extract studies regarding the management of T2D in patients with compensated cirrhosis. RESULTS: Metformin, sodium-glucose co-transporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are promising treatment options for patients with T2D and compensated liver cirrhosis, offering good glycemic control with minimal risk of hypoglycemia, while their pleiotropic actions confer benefits on NAFLD and body weight, and decrease cardiorenal risk. Sulfonylureas cause hypoglycemia, thus should be avoided, while in specific studies, dipeptidyl peptidase-4 inhibitors have been correlated with increased risk of decompensation and variceal bleeding. Despite the benefits of thiazolidinediones in nonalcoholic steatohepatitis, concerns about edema and weight gain limit their use in compensated cirrhosis. Insulin does not exert hepatotoxic effects and can be administered safely in combination with other drugs; however, the risk of hypoglycemia should be considered. CONCLUSIONS: The introduction of new hepatoprotective diabetes drugs into clinical practice, including tirzepatide, SGLT2i, and GLP-1 RA, sets the stage for future trials to investigate the ideal therapeutic regimen for people with T2D and compensated cirrhosis.

The Clinical Impact of Death Domain-Associated Protein and Holliday Junction Recognition Protein Expression in Cancer: Unmasking the Driving Forces of Neoplasia.

Death domain-associated protein (DAXX) and Holliday junction recognition protein (HJURP) act as chaperones of H3 histone variants H3.3 and centromere protein A (CENPA), respectively, and are implicated in many physiological processes, including aging and epigenetic regulation, by controlling various genes' transcription and subsequently protein expression. Research has highlighted both these biomolecules as participants in key procedures of tumorigenesis, including cell proliferation, chromosome instability, and oncogene expression. As cancer continues to exert a heavy impact on patients' well-being and bears substantial socioeconomic ramifications, the discovery of novel biomarkers for timely disease detection, estimation of prognosis, and therapy monitoring remains of utmost importance. In the present review, we present data reported from studies investigating DAXX and HJURP expression, either on mRNA or protein level, in human tissue samples from various types of neoplasia. Of note, the expression of DAXX and HJURP has been associated with a multitude of clinicopathological parameters, including disease stage, tumor grade, patients' overall and disease-free survival, as well as lymphovascular invasion. The data reveal the tumor-promoting properties of DAXX and HJURP in a number of organs as well as their potential use as diagnostic biomarkers and underline the important association between aberrations in their expression and patients' prognosis, rendering them as possible targets of future, personalized and precise therapeutic interventions.

Unusual Presentation of an Uncommon Malignancy: A 74-Year-Old Woman with Aggressive Fibromatosis of the Large Intestine Presenting as a Liver Mass and the Therapeutic Management.

BACKGROUND Desmoid tumors are a fibroblastic proliferation of soft tissues, with an extreme inclination for local dissemination and recurrence. Surgical excision is the usual treatment choice, with data regarding pharmaceutical treatment being scarce. CASE REPORT A 74-year-old female patient was admitted to "Laikon" General Hospital of Athens, Greece presenting with acute kidney injury secondary to diarrhea. The ultrasound, CT, and abdominal MRI performed showed a 12×6×10 cm tumorous liver lesion. Biopsy of the lesion revealed loosely organized, mesenchymal tissue with spindle cells, and myxoid stroma. Immunochemistry was positive for SMA and b-catenin. Right hemicolectomy was performed with tumor-free surgical margins (R0 resection) and tamoxifen was initiated. Six months after the last MRI (3 months after the use of tamoxifen), a follow-up MRI was performed. The tumor had increased to 14.2×11×12.3 cm, and at the next follow-up it had grown to 20.3×19 cm maximal dimensions; no new metastases were found. The patient received sorafenib and pazopanib. Our patient had PFS with sorafenib for more than 2 years and remained in a good performance status (ECOG 1). For Pazopanid, the median PFS for this treatment option was 6.5 months. CONCLUSIONS The results were good and show a promising method for the treatment of this rare but severe malignancy.

Meeting at the Crossroad between Obesity and Hepatic Carcinogenesis: Unique Pathophysiological Pathways Raise Expectations for Innovative Therapeutic Approaches.

The escalating global prevalence of obesity and its intricate association with the development of hepatocellular carcinoma (HCC) pose a substantial challenge to public health. Obesity, acknowledged as a pervasive epidemic, is linked to an array of chronic diseases, including HCC, catalyzing the need for a comprehensive understanding of its molecular underpinnings. Notably, HCC has emerged as a leading malignancy with rising incidence and mortality. The transition from viral etiologies to the prominence of metabolic dysfunction-associated fatty liver disease (MAFLD)-related HCC underscores the urgent need to explore the intricate molecular pathways linking obesity and hepatic carcinogenesis. This review delves into the interwoven landscape of molecular carcinogenesis in the context of obesity-driven HCC while also navigating using the current therapeutic strategies and future prospects for combating obesity-related HCC. We underscore the pivotal role of obesity as a risk factor and propose an integrated approach encompassing lifestyle interventions, pharmacotherapy, and the exploration of emerging targeted therapies. As the obesity-HCC nexus continues to challenge healthcare systems globally, a comprehensive understanding of the intricate molecular mechanisms and innovative therapeutic strategies is imperative to alleviate the rising burden of this dual menace.

Interplay of Extracellular Vesicles and TLR4 Signaling in Hepatocellular Carcinoma Pathophysiology and Therapeutics.

Hepatocellular carcinoma (HCC) stands as a significant contributor to global cancer-related mortality. Chronic inflammation, often arising from diverse sources such as viral hepatitis, alcohol misuse, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), profoundly influences HCC development. Within this context, the interplay of extracellular vesicles (EVs) gains prominence. EVs, encompassing exosomes and microvesicles, mediate cell-to-cell communication and cargo transfer, impacting various biological processes, including inflammation and cancer progression. Toll-like receptor 4 (TLR4), a key sentinel of the innate immune system, recognizes both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thereby triggering diverse signaling cascades and pro-inflammatory cytokine release. The intricate involvement of the TLR4 signaling pathway in chronic liver disease and HCC pathogenesis is discussed in this study. Moreover, we delve into the therapeutic potential of modulating the TLR4 pathway using EVs as novel therapeutic agents for HCC. This review underscores the multifaceted role of EVs in the context of HCC and proposes innovative avenues for targeted interventions against this formidable disease.

Unveiling the Yin-Yang Balance of M1 and M2 Macrophages in Hepatocellular Carcinoma: Role of Exosomes in Tumor Microenvironment and Immune Modulation.

Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate and limited treatment options. Recent research has brought attention to the significant importance of intercellular communication in the progression of HCC, wherein exosomes have been identified as critical agents facilitating cell-to-cell signaling. In this article, we investigate the impact of macrophages as both sources and targets of exosomes in HCC, shedding light on the intricate interplay between exosome-mediated communication and macrophage involvement in HCC pathogenesis. It investigates how exosomes derived from HCC cells and other cell types within the tumor microenvironment (TME) can influence macrophage behavior, polarization, and recruitment. Furthermore, the section explores the reciprocal interactions between macrophage-derived exosomes and HCC cells, stromal cells, and other immune cells, elucidating their role in tumor growth, angiogenesis, metastasis, and immune evasion. The findings presented here contribute to a better understanding of the role of macrophage-derived exosomes in HCC progression and offer new avenues for targeted interventions and improved patient outcomes.

EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets.

Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary.

Unraveling the Significance of EPH/Ephrin Signaling in Liver Cancer: Insights into Tumor Progression and Therapeutic Implications.

Liver cancer is a complex and challenging disease with limited treatment options and dismal prognosis. Understanding the underlying molecular mechanisms driving liver cancer progression and metastasis is crucial for developing effective therapeutic strategies. The EPH/ephrin system, which comprises a family of cell surface receptors and their corresponding ligands, has been implicated in the pathogenesis of HCC. This review paper aims to provide an overview of the current understanding of the role of the EPH/ephrin system in HCC. Specifically, we discuss the dysregulation of EPH/ephrin signaling in HCC and its impact on various cellular processes, including cell proliferation, migration, and invasion. Overall, the EPH/ephrin signaling system emerges as a compelling and multifaceted player in liver cancer biology. Elucidating its precise mechanisms and understanding its implications in disease progression and therapeutic responses may pave the way for novel targeted therapies and personalized treatment approaches for liver cancer patients. Further research is warranted to unravel the full potential of the EPH/ephrin system in liver cancer and its clinical translation.

Clinical and Oncological Impact of the Toll-like Receptor-3 and -4 in Esophageal and Gastro-esophageal Junction Adenocarcinoma.

BACKGROUND/AIM: Esophageal and gastro-esophageal junction cancer is a major cause of cancer-related mortality, with poor prognosis. Toll-like receptors (TLRs) play a significant role in the innate immune system; their increased expression has been associated with esophageal adenocarcinoma. This study aimed to determine the association between TLR-3 and TLR-4 expression with clinical and oncological outcomes of patients that underwent esophagectomy for cancer. PATIENTS AND METHODS: This is a retrospective analysis of prospectively collected data from consecutive patients within a 2-year period. Primary endpoints of the study were the assessment of the expression of TLR-3 and TLR-4 in primary tumors as well as in metastatic lymph nodes. Secondary endpoints were the correlation of TLR-3 and TLR-4 values with the clinical, pathological, and oncological outcomes. RESULTS: A significantly higher expression of TLR-3 and TLR-4 in primary tumors and metastatic-lymph nodes was observed. There was a significant association between TLR-3 expression and T-stage, as well as TLR-4 expression and grade of differentiation in the primary site. Additionally, metastatic-lymph node TLR-4 expression was significantly correlated with N-stage. A strong correlation between TLR-4 expression and overall or progression-free survival rates was detected. CONCLUSION: This study found a significantly increased TLR expression in malignant tissue/metastatic lymph nodes, as well as a significant positive correlation between TLRs and worse clinical outcomes. TLRs have a pivotal role in the inflammation pathway in the esophagus and during esophageal carcinogenesis. This study highlights the need for further investigation into TLR-mediated signaling pathways and their potential role as diagnostic and therapeutic targets.

The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.

The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.