MicroRNA-206 as a promising epigenetic approach to modulate tumor-associated macrophages in hepatocellular carcinoma

This letter comments on the recently published manuscript by Huang et al in the World Journal of Gastroenterology,which focused on the immunomodulatory effect of Calculus bovis on hepatocellular carcinoma(HCC)tumor microenvironments(TME)by inhibiting M2-tumor-associated macrophage(M2-TAM)polarization via Wnt/β-catenin pathway modulation.Recent research highlights the crucial role of TAMs and their polarization towards the M2 phenotype in promoting HCC progression.Epigenetic regulation,particularly through microRNAs(miR),has emerged as a key factor in modulating immune responses and TAM polarization in the TME,influencing treatment responses and tumor progression.This editorial focuses on miR-206,which has been found to inhibit HCC cell proliferation and migration and promote apoptosis.Moreover,miR-206 enhances anti-tumor immune responses by promoting M1-polarization of Kupffer cells,facilitating CD8+T cell recruitment and suppressing liver cancer stem cell expansion.However,challenges remain in understanding the precise mechanisms regulating miR-206 and its potential as a therapeutic agent.Targeting epigenetic mechanisms and improving strategies,whether through pharmacological or genetic approaches,offer promising avenues to sensitize tumor cells to chemotherapy.Understanding the intricate interactions between cancer and non-coding RNA regulation opens new avenues for developing targeted therapies,potentially improving HCC prognosis.

Navigating the autophagic landscape:Epigenetic modulation in gastrointestinal cancer

This editorial comments on the manuscript by Chang et al,focusing on the still elusive interplay between epigenetic regulation and autophagy in gastrointestinal diseases,particularly cancer.Autophagy,essential for cellular homeostasis,exhibits diverse functions ranging from cell survival to death,and is particularly implicated in physiological gastrointestinal cell functions.However,its role in pathological backgrounds remains intricate and context-dependent.Studies underscore the dual nature of autophagy in cancer,where its early suppressive effects in early stages are juxtaposed with its later promotion,contributing to chemoresistance.This discrepancy is attributed to the dysregulation of autophagy-related genes and their intricate involvement in cellular processes.Epigenetic modifications and regulations of gene expression,including non-coding RNAs(ncRNAs),emerge as critical players in exerting regulatory control over autophagy flux,influencing treatment responses and tumor progression.Targeting epigenetic mechanisms and improving strategies involving the inhibition or induction of autophagy through pharmacological or genetic means present potential avenues to sensitize tumor cells to chemotherapy.Additionally,nanocarrier-based delivery of ncRNAs offers innovative therapeutic approaches.Understanding the intricate interaction between autophagy and ncRNA regula-tion opens avenues for the development of targeted therapies,thereby improving the prognosis of gastrointestinal malignancies with poor outcomes.

Inflammation as a cause of acute myocardial infarction in patients with myeloproliferative neoplasm

Myeloproliferative neoplasms(MPN)are a group of diseases characterized by the clonal proliferation of hematopoietic progenitor or stem cells.They are clinically classifiable into four main diseases:chronic myeloid leukemia,essential thrombocythemia,polycythemia vera,and primary myelofibrosis.These pathologies are closely related to cardio-and cerebrovascular diseases due to the increased risk of arterial thrombosis,the most common underlying cause of acute myocardial infarction.Recent evidence shows that the classical Virchow triad(hypercoagulability,blood stasis,endothelial injury)might offer an explanation for such association.Indeed,patients with MPN might have a higher number and more reactive circulating platelets and leukocytes,a tendency toward blood stasis because of a high number of circulating red blood cells,endothelial injury or overactivation as a consequence of sustained inflammation caused by the neoplastic clonal cell.These abnormal cancer cells,especially when associated with the JAK2V617F mutation,tend to proliferate and secrete several inflammatory cytokines.This sustains a pro-inflammatory state throughout the body.The direct consequence is the induction of a pro-thrombotic state that acts as a determinant in favoring both venous and arterial thrombus formation.Clinically,MPN patients need to be carefully evaluated to be treated not only with cytoreductive treatments but also with cardiovascular protective strategies.

Ultrasound unveiling:Decoding venous congestion in heart failure for precision management of fluid status

This editorial discusses the manuscript by Di Maria et al,published in the recent issue of the World Journal of Cardiology.We here focus on the still elusive pathophysiological mechanisms underlying cardio-renal syndrome(CRS),despite its high prevalence and the substantial worsening of both kidney function and heart failure.While the measure of right atrial pressure through right cardiac catheterization remains the most accurate albeit invasive and costly procedure,integrating bedside ultrasound into diagnostic protocols may substantially enhance the staging of venous congestion and guide therapeutic decisions.In particular,with the assessment of Doppler patterns across multiple venous districts,the Venous Excess Ultrasound(VExUS)score improves the management of fluid overload and provides insight into the underlying factors contributing to cardio-renal interactions.Integrating specific echocardiographic parameters,particularly those concerning the right heart,may thus improve the VExUS score sensitivity,offering perspective into the nuanced comprehension of cardio-renal dynamics.A multidisciplinary approach that consistently incorporates the use of ultrasound is emerging as a promising advance in the understanding and management of CRS.

Facing ethical concerns in the age of precise gene therapy:Outlook on inherited arrhythmias

This editorial,comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology.We here provide an outlook on potential ethical concerns related to the future application of gene therapy in the field of inherited arrhythmias.As monogenic diseases with no or few therapeutic options available through standard care,inherited arrhythmias are ideal candidates to gene therapy in their treatment.Patients with inherited arrhythmias typically have a poor quality of life,especially young people engaged in agonistic sports.While genome editing for treatment of inherited arrhythmias still has theoretical application,advances in CRISPR/Cas9 technology now allows the generation of knock-in animal models of the disease.However,clinical translation is somehow expected soon and this make consistent discussing about ethical concerns related to gene editing in inherited arrhythmias.Genomic off-target activity is a known technical issue,but its relationship with ethnical and individual genetical diversity raises concerns about an equitable accessibility.Meanwhile,the costeffectiveness may further limit an equal distribution of gene therapies.The economic burden of gene therapies on healthcare systems is is increasingly recognized as a pressing concern.A growing body of studies are reporting uncertainty in payback periods with intuitive short-term effects for insurance-based healthcare systems,but potential concerns for universal healthcare systems in the long term as well.Altogether,those aspects strongly indicate a need of regulatory entities to manage those issues.

Role of cytokines and chemokines in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.

Autoantibodies to apolipoprotein A-1 as a biomarker of cardiovascular autoimmunity

Immune-driven inflammation plays an important part inatherogenesis and is therefore believed to be key to thedevelopment of cardiovascular disease(CVD), whichis currently the leading cause of death in the Westernworld. By fulfilling some of the Koch postulates, athero-genesis has even been proposed to be considered as anautoimmune disease, raising the hope that CVD couldbe prevented by immunomodulation. Nevertheless,the role of the immune system and autoimmune reac-tions in atherosclerosis appear to be a double edged-sword, with both pro-atherogenic and anti-atherogenicattributes. Hence, if immunomodulation is to becomea therapeutic option for atherosclerosis and CVD, it willbe crucial to correctly identify patients who might ben-efit from targeted suppression of deleterious autoim-mune responses. This could be achieved, for example, by the detection of disease-associated autoantibodies. In this work, we will review the currently available clini-cal, in vitro, and animal studies dedicated to autoan-tibodies against apolipoprotein A-1(anti-apoA-1 IgG), the major proteic fraction of high density lipoprotein. Current clinical studies indicate that high levels of anti-apoA-1 IgG are associated with a worse cardiovascular prognosis. In addition, in vitro and animal studies indi-cate a pro-inflammatory and pro-atherogenic role, sup-porting the hypothesis that these autoantibodies may play a direct causal role in CVD, and furthermore that they could potentially represent a therapeutic target for CVD in the future.

Potential pathophysiological role for the vitamin D deficiency in essential hypertension

Vitamin D deficiency has been indicated as a pandemicemerging public health problem. In addition to the well-known role on calcium-phosphorus homeostasis in thebone, vitamin D-mediated processes have been recentlyinvestigated on other diseases, such as infections, can-cer and cardiovascular diseases. Recently, both the dis-covery of paracrine actions of vitamin D(recognized as"local vitamin D system") and the link of vitamin D with renin-angiotensin-aldosterone system and the fibroblast growth factor 23/klotho pathways highlighted its ac-tive cardiovascular activity. Focusing on hypertension, this review summarizes the more recent experimental evidence involving the vitamin D system and deficiency in the cardiovascular pathophysiology. In particular, we updated the vascular synthesis/catabolism of vitamin D and its complex interactions between the various endocrine networks involved in the regulation of blood pressure in humans. On the other hand, the conflicting results emerged from the comparison between obser-vational and interventional studies emphasize the frag-mentary nature of our knowledge in the field of vitamin D and hypertension, strongly suggesting the need of further researches in this field.

Sofosbuvir/velpatasvir: A promising combination

Hepatitis C virus(HCV) affects 3% of the world population. It represents the main cause of chronic liver disease and is responsible for extra-hepatic complications, such as type 2 diabetes and cardiovascular diseases. HCV includes 7 genotypes differing in the nucleotide sequence variability, the geographic distribution, the rates of viral clearance, the risk of progression to liver fibrosis and to hepatocellular carcinoma, and the response to therapy. Last years have seen remarkable advances in the field of HCV infection with the approval of direct antiviral agents(DAAs) targeting key viral proteins involved in the HCV replication. Several oral regimens combining DAAs from different families have been developed and these regimens showed increased and sustained virological response rates to above 90% reducing the treatment duration to 12 wk or less. In particular, sofosbuvir, a nucleotide analogue nonstructural(NS)5B polymerase inhibitor, and velpatasvir, a NS5 A inhibitor, have been tested in two phase 3 trials, the ASTRAL-2(against HCV genotype 2) and the ASTRAL-3(against HCV genotype 3), demonstrating to be effective, safe, and well tolerated in patients who were 18 years of age or older and had at least a 6-mo history of HCV infection with a compensated liver disease.

Left atrial thrombosis in an anticoagulated patient after bioprosthetic valve replacement:Report of a case

We present the case of a 74 year old woman suffering from severe mitral valve incompetence and rapid atrial fibrillation. After an appropriate vitamin K antagonist(VKA) therapy, the patient underwent mitral valve replacement by bioprosthesis. Then, the patient was rehospitalized for jaundice. Suspecting hepatotoxicity, VKA was discontinued and fondaparinux was started. During this treatment, the patient developed a symptomatic atrial thrombus. After exclusion of a hepatic disease, VKA was re-established with hemodynamic and liver enzymes normalization and atrial thrombus resolution. Caution has to be used when considering fondaparinux as an alternative strategy to VKA in patients with multiple thrombotic risk factors.

Matrix metalloproteinase-9:A deleterious link between hepatic ischemia-reperfusion and colorectal cancer

Despite the advent of improved surgical techniques and the development of cytotoxic chemotherapeutic agents useful for the treatment of colorectal cancer,the primary clinical challenge remains that of preventing and combating metastatic spread.Surgical resection is the best treatment for colorectal metastases isolated to the liver.However,in rodent models,the hepatic ischemia-reperfusion(I/R) applied during the surgery accelerates the outgrowth of implanted tumors.Among the adverse effects of I/R on cellular function,several studies have demonstrated an over expression of the matrix metalloproteinase-9(MMP-9) in the ischemic liver.Since several studies showed high local levels of expression and activity of this proteolytic enzyme in the primary colorectal adenocarcinoma,the role of MMP-9 might be considered as a potential common mediator,favoring both growth of local tumor and the dissemination of colorectal carcinoma metastases.

Alpha-fetoprotein:A controversial prognostic biomarker for small hepatocellular carcinoma

The assessment of the prognosis in patients with early hepatocellular carcinoma represents a hot-topic issue that requires further improvements and clarifications. The life expectancy of the patients has been shown to depend on several clinical and histological parameters (such as patient's general conditions,macroscopic tumor morphology and histopathology).Recently,the prognostic role of some biomarkers[i.e.,alpha-fetoprotein(AFP)] has been also investigated with controversial findings mainly on the assessment of patient survival.The study by Giannini et al failed to show a prognostic value of AFP on survival of patients with well-compensated cirrhosis and small hepatocellular carcinoma.Since the study presents some limitations,a larger clinical trial is needed to clarify the potential prognostic role of serum AFP levels in these patients.

T-cells in myocardial infarction:Culprit instigators or mere effectors?

Immune system activation and dysfunction characterize the early phase of reperfusion after a myocardial infarction(MI). Despite initially neglected, adaptive immunity has been recently showed to play an important role in this setting. In fact, the immune system can recognize sequestered antigens released by the necrotic tissue, initiating a deleterious autoimmune vicious circle leading to worse outcome. In their recent work, Angelini et al shed the light on a new feature of post-MI which involves two "old players" of post-ischemic myocardial injury: CD31 and matrix metalloproteinase(MMP)-9. Specifically, the authors showed that an enhancement of MMP-9 release could determine the cleavage of inhibitory CD31 from CD4+ T-cells surface in patients with Acute Coronary Syndromes(ACS). These findings open the room for new studies investigating the role of MMP9 in other pathological processes associated with a reduction of CD31 functionality, such as plaque instability and rupture. Of interest, in the case of a causative role for CD31 shedding in ACS would be confirmed, there might be a potential role for the administration of CD31 protein or analogue compounds to blunt post-ischemic cardiac inflammation and improve ACS outcome.

Coronary stenting:A matter of revascularization

In the last few decades, the recommended treatment for coronary artery disease has been dramatically improved by percutaneous coronary intervention(PCI) and the use of balloon catheters, bare metal stents(BMSs), and drug-eluting stents(DESs). Catheter balloons were burdened by acute vessel occlusion or target-lesion restenosis. BMSs greatly reduced those problems holding up the vessel structure, but showed high rates of instent re-stenosis, which is characterized by neo-intimal hyperplasia and vessel remodeling leading to a renarrowing of the vessel diameter. This challenge was overtaken by first-generation DESs, which reduced restenosis rates to nearly 5%, but demonstrated delayed arterial healing and risk for late in-stent thrombosis, with inflammatory cells playing a pivotal role. Finally, new-generation DESs, characterized by innovations in design, metal composition, surface polymers, and antiproliferative drugs, finally reduced the risk for stent thrombosis and greatly improved revascularization outcomes. New advances include bioresorbable stents potentially changing the future of revascularization techniques as the concept bases upon the degradation of the stent scaffold to inert particles after its function expired, thus theoretically eliminating risks linked with both stent thrombosis and re-stenosis. Talking about DESs also dictates to consider dual antiplatelet therapy(DAPT), which is a fundamental moment in view of the good outcome duration, but also deals with bleeding complications. The better management of patients undergoing PCI should include the use of DESs and a DAPT finely tailored in consideration of the potentially developing bleeding risk in accordance with the indications from last updated guidelines.