Comprehensive analysis of differentially expressed miRNAs in hepatocellular carcinoma: Prognostic, predictive significance and pathway insights

Robust prognostic and predictive factors for hepatocellular carcinoma, a leading cause of cancer-related deaths worldwide, have not yet been identified. Previous studies have identified potential HCC determinants such as genetic mutations, epigenetic alterations, and pathway dysregulation. However, the clinical significance of these molecular alterations remains elusive. MicroRNAs are major regulators of protein expression. MiRNA functions are frequently altered in cancer. In this study, we aimed to explore the prognostic value of differentially expressed miRNAs in HCC, to elucidate their associated pathways and their impact on treatment response. To this aim, bioinformatics techniques and clinical dataset analyses were employed to identify differentially expressed miRNAs in HCC compared to normal hepatic tissue. We validated known associations and identified a novel miRNA signature with potential prognostic significance. Our comprehensive analysis identified new miRNA-targeted pathways and showed that some of these protein coding genes predict HCC patients’ response to the tyrosine kinase inhibitor sorafenib

Repeated SARS-CoV-2 vaccination in cancer patients treated with immune checkpoint inhibitors: induction of high-avidity anti-RBD neutralizing antibodies

BackgroundCancer patients are more vulnerable to COVID-19 and are thus given high priority in vaccination campaigns. In solid cancer patients treated with checkpoint inhibitors, we evaluated the amount of anti-RBD and neutralizing antibodies and antibody avidity after two or three doses of the vaccine.MethodsThirty-eight solid cancer patients, 15 untreated hematological patients and 21 healthy subjects were enrolled in the study. Blood was collected before the first dose (T0), 21 days after the second (T2) and in 18 solid cancer patients also 15 days after the third dose of vaccine (T3). IgG, IgM and IgA anti-RBD antibodies were detected by ELISA. Neutralizing antibodies were measured testing the inhibition of RBD binding to ACE2. Antibody avidity was evaluated in 18 patients by a urea avidity ELISA.ResultsIgG anti-RBD antibodies were produced in 65.8% of the cancer patients at T2, and in 60% of hematological patients at levels lower than healthy controls. IgM and IgA anti-RBD antibodies were also produced in 5.3% and 21% cancer patients, respectively. At T3, a significant increase in anti-RBD IgG levels was observed. Neutralizing antibodies were produced in 68.4% of cancer patients as compared with 93% of untreated hematological patients and 100% of controls, at titers lower than in healthy subjects. At T3, neutralizing antibodies and avidity of IgG anti-RBD increased; 6/18 patients negative at T2 developed neutralizing antibodies at T3.ConclusionThe data indicate that in cancer patients mRNA vaccine induces high avidity anti-RBD antibodies and neutralizing antibodies that increase after the third dose. The process of induction and selection of high-affinity antibodies is apparently unaffected by the treatment with anti-PD-1 or anti-PD-L1 antibodies

Persistent Inflammation Alters the Function of the Endogenous Brain Stem Cell Compartment

Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation of non-migratory neuroblasts within the SVZ germinal niche. In parallel, we demonstrate a quantitative reduction of the putative brain stem cells proliferation in the SVZ during persistent brain inflammation, which is completely reversed after in vitro culture of the isolated NPCs. Together, these data indicate that the inflamed brain microenvironment sustains a non cell-autonomous dysfunction of the endogenous CNS stem cell compartment and challenge the potential efficacy of proposed therapies aimed at mobilizing endogenous precursors in chronic inflammatory brain disorders

Primary Tumor Resection for Metastatic Colorectal, Gastric and Pancreatic Cancer Patients: In Search of Scientific Evidence to Inform Clinical Practice

The management of the primary tumor in metastatic colorectal, gastric and pancreatic cancer patients may be challenging. Indeed, primary tumor progression could be associated with severe symptoms, compromising the quality of life and the feasibility of effective systemic therapy, and might result in life-threatening complications. While retrospective series have suggested that surgery on the primary tumor may confer a survival advantage even in asymptomatic patients, randomized trials seem not to definitively support this hypothesis. We discuss the evidence for and against primary tumor resection for patients with metastatic gastrointestinal (colorectal, gastric and pancreatic) cancers treated with systemic therapies and put in context the pros and cons of the onco-surgical approach in the time of precision oncology. We also evaluate current ongoing trials on this topic, anticipating how these will influence both research and everyday practice

Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment

Alzheimer’s disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the ε4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1β, Tumor necrosis factor-alpha (TNFα), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFβ), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEε4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti-inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression

Predictive significance of circulating histones in hepatocellular carcinoma patients treated with sorafenib

Background: Predictive biomarkers for advanced hepatocellular carcinoma are lacking. EZH2 drives sorafenib resistance through H3K27me3 and is counteracted by SETD2, which catalyzes H3K36me3. The authors tested the predictive power of circulating H3K27me3 and H3K36me3 in advanced hepatocellular carcinoma patients treated with sorafenib. Methods: A total of 80 plasma samples were tested for histone variants by ELISA. Changes from baseline to best response or progressive disease were correlated with patient survival. Results: A higher EZH2/SETD2 ratio predicted worse prognosis in this setting. H3K27me3 and H3K36me3 decreased from baseline to best response. The H3K27me3/H3K36me3 ratio increased from baseline to progressive disease. Higher ratios at best response were associated with shorter progression-free survival. Conclusion: The authors suggest that circulating H3K27me3/H3K36me3 ratio level acts as a predictive biomarker for sorafenib treatment outcomes in patients with advanced hepatocellular carcinoma

High serum levels of transforming growth factor β1 are associated with increased cortical thickness in cingulate and right frontal areas in healthy subjects

ABSTRACT

Endothelin-1 Inhibits Prolyl Hydroxylase Domain 2 to Activate Hypoxia-Inducible Factor-1α in Melanoma Cells

The endothelin B receptor (ET(B)R) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1alpha is essential for melanomagenesis and progression, and is controlled by site-specific hydroxylation carried out by HIF-prolyl hydroxylase domain (PHD) and subsequent proteosomal degradation.Here we found that in melanoma cells ET-1, ET-2, and ET-3 through ET(B)R, enhance the expression and activity of HIF-1alpha and HIF-2alpha that in turn regulate the expression of vascular endothelial growth factor (VEGF) in response to ETs or hypoxia. Under normoxic conditions, ET-1 controls HIF-alpha stability by inhibiting its degradation, as determined by impaired degradation of a reporter gene containing the HIF-1alpha oxygen-dependent degradation domain encompassing the PHD-targeted prolines. In particular, ETs through ET(B)R markedly decrease PHD2 mRNA and protein levels and promoter activity. In addition, activation of phosphatidylinositol 3-kinase (PI3K)-dependent integrin linked kinase (ILK)-AKT-mammalian target of rapamycin (mTOR) pathway is required for ET(B)R-mediated PHD2 inhibition, HIF-1alpha, HIF-2alpha, and VEGF expression. At functional level, PHD2 knockdown does not further increase ETs-induced in vitro tube formation of endothelial cells and melanoma cell invasiveness, demonstrating that these processes are regulated in a PHD2-dependent manner. In human primary and metastatic melanoma tissues as well as in cell lines, that express high levels of HIF-1alpha, ET(B)R expression is associated with low PHD2 levels. In melanoma xenografts, ET(B)R blockade by ET(B)R antagonist results in a concomitant reduction of tumor growth, angiogenesis, HIF-1alpha, and HIF-2alpha expression, and an increase in PHD2 levels.In this study we identified the underlying mechanism by which ET-1, through the regulation of PHD2, controls HIF-1alpha stability and thereby regulates angiogenesis and melanoma cell invasion. These results further indicate that targeting ET(B)R may represent a potential therapeutic treatment of melanoma by impairing HIF-1alpha stability

Mutations in DCHS1 Cause Mitral Valve Prolapse

SUMMARY Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals1–3. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery4,5. Despite a clear heritable component, the genetic etiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds) that segregates with MVP in the family. Morpholino knockdown of the zebrafish homolog dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 mRNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells, and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1+/− mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs as well as in Dchs1+/− mouse MVICs result in altered migration and cellular patterning, supporting these processes as etiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease

Epidemia da N. meningitidis gruppo C in Toscana: caratteristiche epidemiologiche, cliniche ed approcci terapeutici

Nonostante in Italia, come in Europa, le Malattie Meningococciche Invasive siano rare, nel biennio 2015-2016 la Regione Toscana è stata interessata da un outbreak epidemico di infezioni da Neisseria meningitidis sierogruppo C genotipo ST-11, come precedentemente avvenuto in Francia, Germania e Norvegia. Tale epidemia si è caratterizzata per una elevata letalità (22%) e ha avuto un forte impatto sull'opinione pubblica e sull'ambito sanitario. Il presente studio analizza in modo retrospettivo la caratteristiche epidemiologiche, cliniche, laboratoristiche e microbiologiche di 32 casi toscani (per problemi burocratici non è stato possibile descrivere l'intera epidemiologia costituita di 50 casi) e li confronta, attraverso un'analisi statistica comparativa, con un campione napoletano costituito dai 35 casi di Malattie Meningococciche Invasive registrati nello stesso biennio presso l'Ospedale Cotugno di Napoli, centro di riferimento per le emergenze-urgenze infettivologiche. Il caso toscano si distingue per la maggior proporzione di sierogruppi C fra i meningococchi isolati, di pazienti che hanno presentato sepsi o porpora fulminante, di utilizzo in terapia di metodiche di clearence della sepsi (quali Coupled Plasma Filtration Adsorption) e per l'età media inusualmente elevata della popolazione colpita. \par Tutte queste variabili, a meno dell'utilizzo della CPFA, risultano effettivamente associate a una letalità maggiore; sono inoltre confermate quali fattori di rischio per un outcome negativo le variabili già note in letteratura che descrivono la maggior gravità del quadro clinico (porpora fulminante, shock settico, lattati elevati, Multi Organ Failure, valori elevati di procalcitonina). Il dato sulla letalità è contrastante: nel setting delle porpore fulminanti va dallo 0% di alcune aree al 100% di altre. Tuttavia poiché non sono state individuate lacune nell'approccio terapeutico, sia empirico che mirato, la misura più efficace per limitare la mortalità dell'infezione resta la vaccinazione