Search

Following the practice-changing results observed in several hematological and solid tumors, immunotherapy with immune checkpoint inhibitors (ICIs) has been tested in cholangiocarcinoma (CCA) patients. However, ICI monotherapy has had disappointing results in CCA, and phase I–III clinical trials have assessed whether combinatorial strategies including immunotherapy plus other anticancer agents may have a synergistic activity. The TOPAZ-1 trial has recently highlighted improved survival in CCA patients receiving first-line durvalumab plus gemcitabine–cisplatin compared with gemcitabine plus cisplatin alone, and several guidelines consider adding durvalumab to the reference doublet as standard of care. This article provides an overview of durvalumab pharmacology, safety and efficacy in CCA, highlighting current and future research directions in this setting.

Expression of LPAR1-5 mRNA levels in peritumoral and HCC cell lines (S1); Cell cycle analysis of LPAR6-knocked-down cells versus controls (S2); Absence of apoptosis in stably LPAR6-knocked-down cells (S3); LPAR6 knockdown impairs HCC migration and actin organization but not cells adhesion (S4); Ectopic expression of LPAR6 in human hepatocarcinoma cell line HLE (S5); LPAR6 knockdown affects the gene expression profile in HCC cells (S6); The PIM3 inhibitor, SGI-1776 decreases tumor growth in vivo and in vitro (S7).

List of genes up-regulated in LPAR6 knocked down cells.

Description of additional methods and procedures used in the study.

Legends for Supplementary Tables S1-S3 and Supplementary Figures S1-S7.

List of genes down-regulated in LPAR6 knocked down cells.

IntroductionPaclitaxel (PTX) interferes with microtubule architecture by binding to β-tubulin, thereby blocking progression at the G2/M phase and inducing apoptosis. This study aimed to investigate molecular processes underlying PTX-mediated resistance in gastric cancer (GC) cells. MethodsPTX-mediated resistance involves many processes, and in this work some of the factors involved in the resistance mechanism were identified by comparing two GC lines with PTX induced resistance to their sensitive counterparts. ResultsThus, the key feature of PTX-resistant cells was the overexpression of pro-angiogenic factors such as VEGFA, VEGFC, and Ang2, known to support tumor cell growth. A second relevant change detected in PTX-resistant lines was the elevated level of TUBβIII, a tubulin isoform that opposes microtubule stabilization. A third identified factor contributing to PTX-resistance was P-glycoprotein (P-gp), a transporter responsible for chemotherapy efflux from the cells, highly expressed in PTX-resistant lines.Discussion These findings were in line with a greater sensitivity of resistant cells to treatment with both Ramucirumab and Elacridar. Ramucirumab significantly reduced the expression of angiogenic molecules and TUBβIII, while Elacridar restored the access of chemotherapy, recovering its anti-mitotic and pro-apoptotic effects. Finally, this study highlighted the role played by exosomes in spreading factors responsible for resistance in the tumor microenvironment.

Hypothesis Solid lipid nanoparticles (SLNs), co-encapsulating superparamagnetic iron oxide nanoparticles and sorafenib, have been exploited for magnetic-guided drug delivery to the liver. Two different magnetic configurations, both comprising two small magnets, were under-skin implanted to investigate the effect of the magnetic field topology on the magnetic SLNP accumulation in liver tissues. A preliminary simulation analysis was performed to predict the magnetic field topography for each tested configuration. Experiments SLNs were prepared using a hot homogenization approach and characterized using complementary techniques. Their in vitro biological behavior was assessed in HepG-2 liver cancer cells; wild-type mice were used for the in vivo study. The magnet configuration that resulted in a higher magnetic targeting efficiency was investigated by evaluating the iron content in homogenated murine liver tissues. Findings SLNs, characterized by an average size smaller than 200 nm, retained their superparamagnetic behavior and relevant molecular resonance imaging properties as negative contrast agents. The evaluation of iron accumulation in the liver tissues was consistent with the magnetic induction profile of each magnet configuration, concurring with the results predicted by simulation analysis and obtained by measurements in living mice.

BackgroundAge is a leading contributor to the liver fibrosis rate and a gradual deterioration of optical function, but this association in older populations is still under-explored. The present study aimed to explore the link between vascular and neural retinal characteristics and the risk of liver fibrosis in 731 older adults from the population-based Salus in Apulia study.MethodsRetinal features were obtained using optical coherence tomography (OCT) and OCT-angiography (OCT-A). Liver fibrosis risk was taken as the fibrosis-4 (FIB-4) score. Generalized linear models (logistic regression) were used to estimate the association effect between each unit increase of OCT and OCT-A parameters as independent variables and a FIB-4 ≥ 2.67 score as an outcome. Generalized additive models were used to assess the non-linear association between OCT-A features and the linear FIB-4 score.ResultsIncreased gangliar cell complex (GCC) thickness was inversely associated with a FIB-4 score above the cut-off in both the raw model (OR: 0.98; 95% CI: 0.96–0.99; SE: 0.01) and after adjustment for age, sex, education, hypertension, diabetes, total cholesterol, and triglycerides (OR: 0.98; 95% CI: 0.97–0.99; SE: 0.01).ConclusionOur findings add to the growing volume of scientific literature demonstrating that liver fibrosis is associated with retinal neurodegeneration. This study raises a number of new questions, including whether OCT-A may be used to track the progression of metabolic abnormalities and define exact thresholds for predicting and classifying liver disease.

Introduction: The majority of the money spent on possible new medications’ clinical trials is accounted for by the innovative pharmaceutical sector, which also stimulates the economy of a nation. The objective of this study was to evaluate the impact of pharmaceutical industry-sponsored clinical trials (ISCTs) in inflammatory bowel diseases (IBDs) towards the national health service (NHS) in terms of avoided costs and leverage effect.Methodology: The research was conducted at National Institute of Gastroenterology, “Saverio De Bellis”, Castellana Grotte (Apulia, Italy) collecting data from profit ISCTs of pharmaceutical products conducted over the time period 2018-2020 with focus on inflammatory bowel diseases. After the quantification of health services and drug costs from the latter studies, avoided costs and leverage effects were then estimated.Results: The results on the avoided costs for healthcare facilities deriving from the conduct of clinical studies show that, in relation to the sample of five drug companies participating in our 2018-2020 analysis, out of a total of 235,102.46 €, identified as direct investment, 628,158.21 € of avoided costs for the NHS were measured, with an additional saving (leverage effect) for the NHS of 3.67 € for each € invested by the companies promoting clinical trials.Conclusion: Conducting profit clinical trials has practical benefits and a favourable macroeconomic impact that, by completing its limited resources, helps to sustain one country NHS thanks to the avoided costs while also contributing to locational and industrial policy while guaranteeing novel therapeutics and health services for the patients enrolled.

Background Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor characterized by an intensive desmoplastic reaction due to the exaggerated presence of the extracellular (ECM) matrix components. Liver fibroblasts close to the tumor, activated by transforming growth factor (TGF)-β1 and expressing high levels of α-smooth muscle actin (α-SMA), become cancer-associated fibroblasts (CAFs). CAFs are deputed to produce and secrete ECM components and crosstalk with cancer cells favoring tumor progression and resistance to therapy. Overexpression of Notch signaling is implicated in CCA development and growth. The study aimed to determine the effectiveness of the Notch inhibitor, Crenigacestat, on the surrounding microenvironment of iCCA. Methods We investigated Crenigacestat’s effectiveness in a PDX model of iCCA and human primary culture of CAFs isolated from patients with iCCA. Results In silico analysis of transcriptomic profiling from PDX iCCA tissues treated with Crenigacestat highlighted “liver fibrosis” as one of the most modulated pathways. In the iCCA PDX model, Crenigacestat treatment significantly (p p p p p Conclusions Notch signaling inhibition reduces the peritumoral desmoplastic reaction in iCCA, blocking the TGF-β1 canonical pathway.

Since irritable bowel syndrome (IBS)—a common gastrointestinal (GI) disorder—still lacks effective therapy, a nutritional approach may represent a practical alternative. Different reports demonstrated that a low-fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) diet (LFD) reduces symptoms in IBS with diarrhea (IBS-D) patients, also inducing beneficial pathophysiological and biochemical modifications. More recently, diets with alternative cereals having a different gluten composition, such as tritordeum, have also been considered (TBD). We investigated the impact of TBD and LFD on the fecal metabolome composition in 38 IBS-D patients randomly allocated to the two diets for 12 weeks. Summarily, at baseline, the profile of fecal volatile organic compounds (VOCs) of IBS-D patients was not significantly different in the two groups. After treatment, significant changes were observed in the two groups regarding the VOCs content since some of them increased in the TBD group (namely, decanoic acid), whereas others (i.e., nonanal and ethanol) increased in the LFD one. Further, at baseline, short-chain fatty acids were positively related to inflammation and showed a significant decreasing trend after both diets compared to baseline values (namely, acetic and propanoic acid). Preliminary results from this pilot study suggest a potential positive intervention of TBD and LFD affecting the fecal metabolome composition in IBS-D patients.

SLC15A4/PHT1 is an endolysosome-resident carrier of oligopeptides and histidine recently come into view as a key path marker of immune/autoimmune/inflammatory pathways in immune cells. Yet, its emerging role in inflammatory processes directly targeting the gastrointestinal epithelial layer, as in the multifactorial pathophysiology of inflammatory bowel disease (IBD), is poorly investigated. Here, the first identification of

The immunoproteasome is a multi-catalytic protein complex expressed in hematopoietic cells. Increased expression of immuno-subunits followed by increased proteasome activities is associated with the pathogenesis of IBD. Therefore, the identification of molecules that could inhibit the activities of this complex has been widely studied. microRNAs are small molecules of non-coding RNA that regulate the expression of target genes. Our purpose was to demonstrate that miR-369-3p is able to reduce the expression of the PSMB9 subunit and consequently modulate the catalytic activities of immunoproteasome. After bioinformatics prediction of the gene target of miR-369-3p, we validated its modulation on PSMB9 expression in the RAW264.7 cell line in vitro. We also found that miR-369-3p indirectly reduced the expression of other immunoproteasome subunits and that this regulation reduced the catalytic functions of the immunoproteasome. Increased levels of PSMB9 were observed in colon samples of acute IBD patients compared to the remission IBD group and control group. Our data suggest that miR-369-3p may be a future alternative therapeutic approach to several compounds currently used for the treatment of inflammatory disorders including IBD.

Hepatic fibrosis (HF) is a major cause of liver-related disorders and together with cancer-associated fibroblasts can favor liver cancer development by modulating the tumor microenvironment. Advanced HF, characterized by an excess of extracellular matrix (ECM), is mediated by TGF- β1, that activates hepatic stellate cells (HSCs) and fibroblasts. A TGF-β1 receptor inhibitor, LY2157299 or Galunisertib (GLY), has shown promising results against chronic liver progression in animal models, and we show that it can be further improved by enhancing GLYs bioavailability through encapsulation in polymeric polygalacturonic-polyacrylic acid nanomicelles (GLY-NMs). GLY-NMs reduced HF in an in vivo rat model of liver fibrosis induced by intraperitoneal injection of CCl

Introduction In subjects with nonalcoholic fatty liver disease (NAFLD), advanced fibrosis (AF) carries the highest risk of adverse liver-related events. To reduce the number of unnecessary biopsies, several noninvasive tools (NITs) for the risk stratification of fibrosis have been developed. We conducted this meta-analysis to assess the performance of the fibrosis-4 index (FIB-4) and NAFLD fibrosis scores (NFS), the 2 most common NITs, for the appropriate selection of subjects with AF for biopsy. Methods Four databases were searched until December 2020 (CRD42021224766). Original articles reporting data on the performance of FIB-4 and NFS, interpreted according to standard cutoffs in subjects with biopsy-proven NAFLD, were included. Separate data extractions were performed according to the lower cutoff, the higher cutoff, and the dual threshold approach. The numbers of subjects classified as true-negative, true-positive, false-negative, and false-positive were extracted. Summary operating points were estimated using a random-effects model. Results Eighteen studies evaluating 12,604 subjects were included. Participants were adult outpatients with biopsy-proven NAFLD or nonalcoholic steatohepatitis. Overall, a weak-to-moderate performance was found for both scores. The head-to-head comparison showed FIB-4 to be associated with a higher performance in ruling in and NFS in ruling out AF in the single threshold approach, whereas, with the dual threshold approach, a lower prevalence of indeterminate findings was found for FIB-4. Discussion This meta-analysis suggested that currently available NITs have a limited performance in identifying AF among subjects with NAFLD. Further studies are needed to optimize existing thresholds or develop new NITs.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the entire planet. The objectives of our study were to compare responses to the vaccine (Pfizer-Biontech COMIRNATY) in a population of patients with intestinal bowel syndrome undergoing different biological therapies or conventional therapy. The study recruited 390 patients who received the first vaccination dose during the dedicated vaccination campaign for inflammatory bowel disease (IBD) patients. The inclusion criteria were a diagnosis of CD or UC and complete vaccination with the Pfizer–BioNTech COVID-19 (Comirnaty) vaccine. The exclusion criteria were other significant diseases or important therapies under way or contraindications to vaccination according to the European drug surveillance recommendations. Linear rank models were run to assess the association between the different therapies and S1/S2 antibodies at three different times. The models showed that in patients with IBD receiving Vedolizumab a significant increase in mean IgG levels was observed, independently of other therapies and confounding factors (β: 57.45, 95% CI 19.62 to 19.00). This study confirmed the complete antibody response to vaccination against COVID-19 in patients with IBD undergoing biological therapy—particularly Vedolizumab treatment—but also a reduced immune response due to concomitant steroid therapy.

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.

Most female patients with irritable bowel syndrome (IBS) complain of abdominal bloating rather than abdominal pain and diarrhea. The higher incidence in women could be due to the so-called dysfunctional gas handling. Since diet seems the most effective and durable strategy for managing IBS symptoms, we aimed to evaluate the effects of a 12 week diet based on a relatively new cereal, Tritordeum (TBD), on gastrointestinal (GI) symptoms, anthropometric and bioelectrical impedance parameters, and psychological profiles in 18 diarrhea-predominant IBS (IBS-D) female patients with abdominal bloating as the dominant symptom. The IBS Severity Scoring System (IBS-SSS), the Symptom Checklist-90 Revised, the Italian version of the 36-Item Short-Form Health Survey, and the IBS-Quality of Life questionnaire were administered. The TBD reduces the IBS-SSS “Intensity of abdominal bloating” with a concomitant improvement in the anthropometric profile. No correlation was found between “Intensity of abdominal bloating” and “Abdominal circumference”. Anxiety, depression, somatization, interpersonal sensitivity, and phobic and avoidance manifestations were significantly reduced after TBD. Lastly, anxiety was correlated with “Intensity of abdominal bloating”. Overall, these results suggest the possibility of lowering abdominal bloating and improving the psychological profile of female IBS-D patients using a diet based on an alternative grain such as Tritordeum.

The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10–20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients’ survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.

Consistency among population-based studies investigating the relationship between diet and cognition in older inhabitants in the Mediterranean area is poor. The present study investigated whether diet changes over 12 years were associated with cognitive function in older people in Southern-Italy.From the 'Salus in Apulia Study', that includes the MICOL and GreatAGE Studies, 584 participants were selected, firstly enrolled in MICOL3 (M3) and later in the GreatAGE Study (MICOL4, M4). Foods and micronutrients intake were recorded in both studies, and global cognitive function in M4, assessed with the Mini Mental State Examination.Plant-based foods, particularly coffee and vegetables, as well as vitamin A sources, were inversely associated to age-related cognitive impairment. Alcohol consumption showed a detrimental role on cognition, while red meat appeared to be beneficial in the present study, although its role is traditionally considered harmful for cognitive function.Our study confirmed that a traditional Mediterranean dietary pattern based on agricultural products and low alcohol consumption may help to prevent/delay age-related cognitive impairment.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition that affects 25% of the world’s population. There is a clear difference in both geographical distribution and sex in childbearing age. These differences are reduced when women become older and senescence begins. The factors that affect the likelihood of developing NAFLD in a premenopausal woman are an imbalance of sex hormones (especially in estradiol and androgen), microbiome dysregulation, insulin resistance, early menarche, the length of time that the woman breastfeeds for and polycystic ovarian syndrome (PCOS). The aim of this review is to identify various physical ailments that may not appear to be serious to young women but that then affect the onset of NAFLD in perimenopause and can degenerate into NASH. These conditions should also be considered in future clinical management, as well as in research opportunities, in order to customize the monitoring and treatment of NAFLD, considering gender medicine for those women who had early metabolic symptoms that were not considered to be significant at the time.

The male/female ratio of patients with hepatocellular carcinoma (HCC) is often unbalanced towards the male sex, indicating a sex predisposition for HCC development. A possible explanation may be attributed to different hormonal statuses, including the pro-inflammatory action of androgens in men and the protective effects of oestrogen against excessive inflammation in women. Although several studies have studied gene expression in patients with HCC, very few have attempted to identify features that could be distinctive between male and female patients. The present study aimed to identify distinctive signalling mechanisms between men and women that may be associated with HCC progression. The present study analysed a detailed microarray database that was obtained from the prospective study of 78 patients with HCC to study gene expression according to sex. In addition, the present study aimed to evaluate whether the differentially expressed genes were known oestrogen targets. Moreover, RNAs from the HCC cohort were evaluated for microRNA (miRNA/miR) expression, and a relationship between miRNA and gene expression according to sex was investigated. One gene, sineoculis homeobox homolog 1 (SIX1), which is known to be an oestrogen target gene, was revealed to be highly upregulated in hepatitis virus C (HCV)-positive female patients with HCC but not in HCV-positive male patients. In addition, SIX1 upregulation had a significant relationship with tumour growth speed (assessed as tumour doubling time in two CTs performed 6 weeks apart) and survival (P=0.009 and P=0.042, respectively) in female patients only. Furthermore, SIX1 upregulation was related with miR-421 and miR-9-5p only in male patients; however, in female patients, SIX1 upregulation had a direct relationship with miR-181b, miR-503-5p and miR-125b (miRNAs with potential oncogenic capacity), and an inverse correlation with miR139-5p, miR-26b, let7c-3p and let7c-5p (putatively oncosuppressive microRNAs). These data suggested a distinctive model for liver carcinogenesis in HCV-positive women, with downregulation of protective mechanisms against tumour progression and the activation of potential oncogenes, in relation to the oestrogen target gene SIX1. (IRB10/08_CE_UniRer; ClinicalTrials ID: NCT01657695).

The combination of paclitaxel and ramucirumab is the second-line therapy of choice in the treatment of advanced gastric cancer. To date, no biomarkers are available in gastric cancer to predict the outcome of antiangiogenic therapy. The present prospective study included 35 patients undergoing second-line therapy with ramucirumab and paclitaxel. Serum samples were systematically collected from the beginning of therapy and at each cycle until disease progression. Multiplex analysis of a panel of angiogenic factors identified markers for which the changes at defined time intervals were significantly different in patients with progression-free survival ≤3 (Rapid Progression Group) compared to those with progression-free survival >3 (Control Disease Group). Comparative analysis revealed significantly different results in the two groups of patients for VEGFC and Angiopoietin-2, both involved in angiogenesis and lymphangiogenesis. VEGFC increased in the progressive-disease group, while it decreased in the control-disease group. This decrease persisted beyond the third cycle, and it was statistically significant compared to the basal level in patients with longer progression-free survival. Angiopoietin-2 decreased significantly after 2 months of therapy. At progression time, there was a significant increase in VEGFC and Angiopoietin-2, suggesting the activation pathways counteracting the blockade of VEGFR2 by ramucirumab. Overall results showed that a greater change in VEGFC and Angiopoietin-2 levels measured at the beginning of the third cycle of therapy corresponded to a lower risk of progression and thus to longer progression-free survival.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, and its prevalence worldwide is increasing. Several studies support the pathophysiological role of the gut–liver axis, where specific signal pathways are finely tuned by intestinal microbiota both in the onset and progression of NAFLD. In the present study, we investigate the impact of different lifestyle interventions on the gut microbiota composition in 109 NAFLD patients randomly allocated to six lifestyle intervention groups: Low Glycemic Index Mediterranean Diet (LGIMD), aerobic activity program (ATFIS_1), combined activity program (ATFIS_2), LGIMD plus ATFIS_1 or ATFIS2 and Control Diet based on CREA-AN (INRAN). The relative abundances of microbial taxa at all taxonomic levels were explored in all the intervention groups and used to cluster samples based on a statistical approach, relying both on the discriminant analysis of principal components (DAPCs) and on a linear regression model. Our analyses reveal important differences when physical activity and the Mediterranean diet are merged as treatment and allow us to identify the most statistically significant taxa linked with liver protection. These findings agree with the decreased ‘controlled attenuation parameter’ (CAP) detected in the LGIMD-ATFIS_1 group, measured using FibroScan®. In conclusion, our study demonstrates the synergistic effect of lifestyle interventions (diet and/or physical activity programs) on the gut microbiota composition in NAFLD patients.

Grape pomace (GP), a major byproduct obtained from the winemaking process, is characterized by a high amount of phenolic compounds and secondary plant metabolites, with potential beneficial effects on human health. Therefore, GP is a source of bioactive compounds with antioxidant, antimicrobial, and anti-inflammatory activity. As people are paying more attention to sustainability, in this work, we evaluate two different extractions (aqueous and hydroalcoholic) of GP bioactive compounds. In vitro simulated gastrointestinal digestion of the GP extracts was performed to improve the bioavailability and bioaccessibility of polyphenols. The antioxidant activity (ABTS and DPPH assays) and the phenolic characterization of the extracts by UHPLC-DAD were evaluated. The antimicrobial effects of GP antioxidants in combination with a probiotic (Lactiplantibacillus plantarum) on the growth of pathogenic microorganisms (Escherichia coli, Bacillus megaterium, and Listeria monocytogenes) were evaluated. As a result, an increase of antioxidant activity of aqueous GP extracts during the gastrointestinal digestion, and a contextual decrease of hydroalcoholic extracts, were detected. The main compounds assessed by UHPLC-DAD were anthocyanins, phenolic acids, flavonoids, and stilbenes. Despite lower antioxidant activity, due to the presence of antimicrobial active compounds, the aqueous extracts inhibited the growth of pathogens.

Background the possible relationship between dietary habits and the incidence of late-onset depression (LOD), defined as first depression onset at later age, is unclear. Objective to investigate the relationship between consumption of different food groups and incident LOD. Design longitudinal population-based study with a 12-year follow-up. Setting Castellana Grotte, Bari, Italy. Subjects five hundred and forty-six older subjects from the Salus in Apulia Study. Methods baseline data were recorded in 2003–06, and diagnostic data were recorded in 2013–18 at follow-up. Dietary intake was assessed with a food frequency questionnaire. Depressive disorders were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders. Subjects who already suffered from depression or other psychiatric disorders at baseline were excluded from the analysis. The association between LOD and single dietary determinants was examined by Cox regression analysis and then applying the hazard ratio (HR). Results subjects with incident LOD (n = 34) had lower global cognition and total cholesterol levels and a higher body mass index (BMI) at baseline. Only processed meat significantly increased the risk of incident LOD of about 10% by 5 g/day intake (HR adjusted for age, sex, education, multimorbidity and BMI: 1.13, 95% confidence intervals: 1.04–1.22). A similar relationship was found for single foods in the processed meat food group such as sausages, salami and mortadella and baked ham, but not for raw ham. Conclusions in midlife, a higher intake of processed meat was not only associated with an increased risk of cardiovascular- and metabolic-related chronic diseases in older age but also with an increased risk of developing LOD.

Background Age-related hearing loss (ARHL) and retinal vessel changes have both been associated to neurodegeneration/dementia, suggesting a possible link between these 2 conditions in older age. We aimed to determine whether superficial and deep vascular density (SVD and DVD) of the capillary plexi of macular vasculature can be associated with peripheral ARHL and age-related central auditory central processing (CAPD). Method We analyzed data on 886 older participants (65 years+, age range: 65–92 years) in the cross-sectional population-based Salus in Apulia Study. Optical coherence tomography angiography was used to measure SVD and DVD of the capillary plexi of the macula at the 3-mm circle area centered on the fovea (whole retina), the parafoveal quadrant, and foveal quadrant. Disabling peripheral ARHL was defined as >40 dB hearing level of pure tone average on the frequencies from 0.5, 1, 2, and 4 KHz in the better ear, and age-related CAPD as Results DVD at the whole retina and at the parafoveal quadrant were inversely associated only with age-related CAPD (odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.88–0.96 and OR: 0.94, 95 CI: 0.90–0.99, respectively). No further associations with peripheral ARHL were evident. Conclusions Retinal vasculature is associated with central auditory processing pathology, possibly playing an important role in early detection and intervention. The association of retinal vascular density with age-related CAPD may bring us a further step forward in understanding the biological mechanisms underlying the links between neurodegeneration/dementia and ARHL.

Microbiota might be considered as a pool for environmental epigenetic factors. Evidence is accumulating that environmental exposures – including microbes, diet, drugs – play a role in the pathogenesis of many neuropsychiatric disorders. Underlying mechanisms are complex, involving the sensitive interplay of genetics with epigenetics, neuroinflammation and the innate immune system. Modifications of microbiota affect neurogenesis and the maturation of microglia, influencing social behavior, stress-related responses and fear learning mechanisms. The excitatory neurons in the medial prefrontal cortex appear to play a key role. The mechanisms through which antibiotics administration may modulate microbiota and, therefore, behavior and neuropsychiatric disorders, may be influenced by several variables such as pre-existing gastrointestinal inflammation, the baseline microbiota composition, diet and stress perception. Probiotics, individualized diet, antibiotics and fecal transplantation could positively modulate the effects of epigenetic factors on neuropsychiatric disorders.

Group B Coxsackieviruses (CVB) include six serotypes (B1-6) responsible for a wide range of clinical diseases. Since no recent seroepidemiologic data are available in Italy, the study aim was to investigate CVB seroprevalence in a wide Italian population. The study retrospectively included 2459 subjects referring to a large academic hospital in Rome (Italy) in the period 2004-2016. Seroprevalence rates and neutralizing antibodies (nAb) titers were evaluated in relation to years of observation and subjects' characteristics. Positivity for at least one serotype was detected in 69.1% of individuals. Overall, the prevalent serotype was B4, followed by B3 (33.3%), B5 (26.2%), B1 (12.7%), B2 (11.0%), and B6 (1.7%). For B2, a significant decrease in seroprevalence over years was observed. Positivity to at least one virus was 25.2% in children aged 0 to 2 years, but significantly increased in preschool (3-5 years) (50.3%) and school (6-10 years) children (70.4%). Higher nAb responses for B3 and B4 were observed in children aged 3 to 5 years. A high overall CVB prevalence was found. Type-specific variations in prevalence over time probably reflect the fluctuations in circulation typical of Enteroviruses. Children are at greater risk for CVB infection given the high number of seronegative subjects aged 0 to 10 years.

Celiac disease (CD) is an inflammatory autoimmune disorder triggered by the ingestion of gluten from wheat and other cereals. Nowadays, its positive diagnosis is based on invasive approaches such as the histological examination of intestinal biopsies and positive serology screening of antibodies. After proven diagnosis, the only admissible treatment for CD individuals is strict life-long adherence to gluten-free diet (GFD), although it is not a conclusive therapy. Acting by different mechanisms and with different etiologies, both CD and GFD have a great impact on gut microbiota that result in a different taxa composition. Altered production of specific metabolites reflects these microbiota changes. In this light, the currently available literature reports some suggestions about the possible use of specific metabolites, detected by meta-omics analyses, as potential biomarkers for a CD non-invasive diagnosis. To highlight insights about metabolomics application in CD study, we conducted a narrative dissertation of selected original articles published in the last decade. By applying a systematic search, it clearly emerged how the metabolomic signature appears to be contradictory, as well as poorly investigated.

Background Intrahepatic Cholangiocarcinoma (iCCA) is characterized by a strong stromal reaction playing a role in tumor progression. Thymus cell antigen 1 (THY1), also called Cluster of Differentiation 90 (CD90), is a key regulator of cell–cell and cell–matrix interaction. In iCCA, CD90 has been reported to be associated with a poor prognosis. In an iCCA PDX model, we recently found that CD90 was downregulated in mice treated with the Notch γ-secretase inhibitor Crenigacestat. The study aims to investigate the role of CD90 in relation to the NOTCH pathway. Methods THY1/CD90 gene and protein expression was evaluated in human iCCA tissues and xenograft models by qRT-PCR, immunohistochemistry, and immunofluorescence. Notch1 inhibition was achieved by siRNA. THY1/CD90 functions were investigated in xenograft models built with HuCCT1 and KKU-M213 cell lines, engineered to overexpress or knockdown THY1, respectively. Results CD90 co-localized with EPCAM, showing its epithelial origin. In vitro, NOTCH1 silencing triggered HES1 and THY1 down-regulation. RBPJ, a critical transcriptional regulator of NOTCH signaling, exhibited putative binding sites on the THY1 promoter and bound to the latter, implying CD90 as a downstream NOTCH pathway effector. In vivo, Crenigacestat suppressed iCCA growth and reduced CD90 expression in the PDX model. In the xenograft model, Crenigacestat inhibited tumor growth of HuCCT1 cells transfected to overexpress CD90 and KKU-M213 cells constitutively expressing high levels of CD90, while not affecting the growth of HuCCT1 control cells and KKU-M213 depleted of CD90. In an iCCA cohort, patients with higher expression levels of NOTCH1/HES1/THY1 displayed a significantly shorter survival. Conclusions iCCA patients with higher NOTCH1/HES1/THY1 expression have the worst prognosis, but they are more likely to benefit from Notch signaling inhibition. These findings represent the scientific rationale for testing NOTCH1 inhibitors in clinical trials, taking the first step toward precision medicine for iCCA.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition characterized from hypertriglyceridemia and hepatic fat accumulation, in the absence of alcohol intake. NAFLD starts as steatosis (NAFL), and the continued injury relative to the toxic fat induces inflammation, steatohepatitis (NASH), and HCC. One of the factors determining liver degeneration during the evolution of NAFLD is a modification of Wnt/Frizzled (FZD) signaling. In particular, an inhibition of Wnt signaling and an overexpression of a specific FZD receptor protein, namely, the FZD7, have been observed in NAFLD. Actually, the prognosis and the follow-up of NAFLD is not easy, and the liver biopsy is the gold standard for an accurate detection of liver fibrosis. In this study, the modulation of the FZD7 expression levels in plasma-derived exosomes of NAFLD-affected patients, before and after specific lifestyle interventions, were experimentally evaluated by Western blotting analysis. The experimental data were analyzed by an accurate statistical study that indicated, in the exosomes derived from plasma of NAFLD patients with moderate or severe steatosis, an average expression level of FZD7 that was significantly higher than healthy subjects at baseline; conversely, the values were normalized after 90 days of specific lifestyle interventions. The overall results suggested that the FZD7 delivered by exosomes represents a good candidate as a new and effective biomarker for diagnosis and prognosis of NAFLD.

Contains fulltext : 252162.pdf (Publisher’s version ) (Closed access)

Hepatocellular carcinoma (HCC) is a malignancy marked by heterogeneity. This study aimed to discover target molecules for potential therapeutic efficacy that may encompass HCC heterogeneity. In silico analysis using published datasets identified 16 proto-oncogenes as potential pharmacological targets. We used an immortalized hepatocyte (IHH) and five HCC cell lines under two subtypes: S1/TGFβ-Wnt-activated (HLE, HLF, and JHH6) and the S2/progenitor subtype (HepG2 and Huh7). Three treatment modalities, 5 µM 5-Azacytidine, 50 µM Sorafenib, and 20 nM PD-L1 gene silencing, were evaluated in vitro. The effect of treatments on the proto-oncogene targets was assessed by gene expression and Western blot analysis. Our results showed that 10/16 targets were upregulated in HCC cells, where cells belonging to the S2/progenitor subtype had more upregulated targets compared to the S1/TGFβ-Wnt-activated subtype (81% vs. 62%, respectively). Among the targets, FGR was consistently down-regulated in the cell lines following the three different treatments. Sorafenib was effective to down-regulate targets in S2/progenitor subtype while PD-L1 silencing was able to decrease targets in all HCC subtypes, suggesting that this treatment strategy may comprise cellular heterogeneity. This study strengthens the relevance of liver cancer cellular heterogeneity in response to cancer therapies.

Colorectal cancer (CRC) carcinogenesis is generally the result of the sequential mutation and deletion of various genes; this is known as the normal mucosa–adenoma–carcinoma sequence. The aim of this study was to develop a predictor-classifier during the “adenoma-carcinoma” sequence using microarray gene expression profiles of primary CRC, adenoma, and normal colon epithelial tissues. Four gene expression profiles from the Gene Expression Omnibus database, containing 465 samples (105 normal, 155 adenoma, and 205 CRC), were preprocessed to identify differentially expressed genes (DEGs) between adenoma tissue and primary CRC. The feature selection procedure, using the sequential Boruta algorithm and Stepwise Regression, determined 56 highly important genes. K-Means methods showed that, using the selected 56 DEGs, the three groups were clearly separate. The classification was performed with machine learning algorithms such as Linear Model (LM), Random Forest (RF), k-Nearest Neighbors (k-NN), and Artificial Neural Network (ANN). The best classification method in terms of accuracy (88.06 ± 0.70) and AUC (92.04 ± 0.47) was k-NN. To confirm the relevance of the predictive models, we applied the four models on a validation cohort: the k-NN model remained the best model in terms of performance, with 91.11% accuracy. Among the 56 DEGs, we identified 17 genes with an ascending or descending trend through the normal mucosa–adenoma–carcinoma sequence. Moreover, using the survival information of the TCGA database, we selected six DEGs related to patient prognosis (SCARA5, PKIB, CWH43, TEX11, METTL7A, and VEGFA). The six-gene-based classifier described in the current study could be used as a potential biomarker for the early diagnosis of CRC.

BackgroundDiet and social determinants influence the state of human health. In older adults, the presence of social, physical and psychological barriers increases the probability of deprivation. This study investigated the relationship between social deprivation and eating habits in non-institutionalized older adults from Southern Italy, and identified foods and dietary habits associated with social deprivation.MethodsWe recruited 1,002 subjects, mean age 74 years, from the large population based Salus in Apulia Study. In this cross-sectional study, eating habits and the level of deprivation were assessed with FFQ and DiPCare-Q, respectively.ResultsDeprived subjects (n = 441) included slightly more females, who were slightly older and with a lower level of education. They consumed less fish (23 vs. 26 g), fruiting vegetables (87 vs. 102 g), nuts (6 vs. 9 g) and less “ready to eat” dishes (29 vs. 33 g). A Random Forest (RF) model was used to identify a dietary pattern associated with social deprivation. This pattern included an increased consumption of low-fat dairy products and white meat, and a decreased consumption of wine, leafy vegetables, seafood/shellfish, processed meat, red meat, dairy products, and eggs.ConclusionThe present study showed that social factors also define diet and eating habits. Subjects with higher levels of deprivation consume cheaper and more readily available food.

Background: Aging is the main negative prognostic factor for various chronic diseases, such as liver fibrosis, and clinical disorders such as hearing loss. This study aimed to investigate the association between age-related hearing loss (ARHL) and age-related central auditory processing disorder (CAPD), and the risk for liver fibrosis in a cross-sectional study on an aging population. Methods: Liver fibrosis risk was judged on the fibrosis-4 (FIB-4) score. Peripheral ARHL was evaluated with pure tone audiometry using a calibrated audiometer. The pure tone average (PTA), calculated as a threshold ≤ 40 dB (HL) in the better ear, was measured at the frequencies 0.5–4 kHz. For age-related CAPD assessment, we employed the Synthetic Sentence Identification with an Ipsilateral Competitive Message test (SSI-ICM). General linear Logistic regression models were used to estimate the association. Results: The increase in the PTA 0.5–2 kHz (coefficient: 0.02, SE: 0.01, CI 95%: 0.01 to 0.03) was directly associated with a higher risk of liver fibrosis (FIB-4 ≥ 2.67). Moreover, the reduction in SSI (coefficient: −0.02, SE: 0.01, CI 95%: −0.03 to −0.01) was inversely associated with FIB-4 values < 2.67. Conclusion: Our results show an association between liver fibrosis and both ARHL and CAPD, linked by the typical consequence of aging. We also assume a role of inflammatory responses and oxidative stress.

Hepatic fibrosis (HF) is a major cause of liver-related disorders and together with cancer-associated fibroblasts can favor liver cancer development by modulating the tumor microenvironment. Advanced HF, characterized by an excess of extracellular matrix (ECM), is mediated by TGF- β1, that activates hepatic stellate cells (HSCs) and fibroblasts. A TGF-β1 receptor inhibitor, LY2157299 or Galunisertib (GLY), has shown promising results against chronic liver progression in animal models, and we show that it can be further improved by enhancing GLYs bioavailability through encapsulation in polymeric polygalacturonic-polyacrylic acid nanomicelles (GLY-NMs). GLY-NMs reduced HF in an in vivo rat model of liver fibrosis induced by intraperitoneal injection of CCl4 as shown by the morphological, biochemical, and molecular biology parameters of normal and fibrotic livers. Moreover, GLY-NM was able to induce recovery from HF better than free GLY. Indeed, the encapsulated drug reduces collagen deposition, hepatic stellate cells (HSCs) activation, prevents fatty degeneration and restores the correct lobular architecture of the liver as well as normalizes the serum parameters and expression of the genes involved in the onset of HF. In summary, GLY-NM improved the pharmacological activity of the free TGF- β1 inhibitor in the in vivo HF treatment and thus is a candidate as a novel therapeutic strategy.

Malabsorptive disorders are closely associated with micronutrient deficiencies. In inflammatory bowel disease (IBD), trace element deficiencies pose a clinical burden from disease onset throughout its course, contributing to morbidity and poor quality of life. We aimed to conduct a systematic review and meta-analysis of the prevalence of zinc deficiency in IBD. Literature screening was performed on six electronic databases until 1 May 2022. Two independent investigators assessed the 152 retrieved articles for inclusion criteria, met by only nine, that included 17 prevalence entries for Crohn’s disease (CD) (n = 9) and ulcerative colitis (UC) (n = 8). No exclusion criteria were applied to language, deficiency cut-offs, population age, general health status, country, or study setting (cohort or cross-sectional). The prevalence of zinc deficiency in blood was scored positive if due to a single disease, not cumulative factors. Zinc deficiency prevalence across selected studies showed higher values in CD than in UC. Pooled analyses by the IBD subgroup showed a total population of 1677 with CD, for an overall mean zinc deficiency prevalence of 54% and 95% confidence intervals (CI) ranging from 0.51 to 0.56, versus 41% (95%CI 0.38–0.45) in the UC population (n = 806). The overall prevalence at meta-analysis was estimated at 50% (95%CI 0.48–0.52), but with high heterogeneity, I2 = 96%. The funnel plot analysis failed to show any evidence of publication bias. The risk of bias across selected studies was moderate to low. In IBD contexts, one of two patients suffers from zinc deficiency. Mismanagement of micronutrient deficiencies plays a role in inflammation trajectories and related cross-pathways. Clinicians in the field are advised to list zinc among trace elements to be monitored in serum.

The liver contribution to the biological network underlying physical frailty in aging is underestimated. How best to measure this contribution magnitude and impact on health risk trajectories in frail individuals is not yet entirely clear. We analyzed the association of a novel liver frailty phenotype with the risk of death in older participants of the Salus in Apulia Study cohort. Clinical and physical examination, routine biomarkers, medical history, and anthropometry were analyzed in 1929 older adults (65 +). Physical frailty was classified by Cardiovascular Health Study criteria, and liver fibrosis risk by fibrosis-4 (FIB-4). The liver frailty phenotype was defined as physical frailty plus high-risk liver fibrosis (score > 2.67). Physical frailty, high-risk liver fibrosis, and liver frailty subjects were compared to subjects without these conditions (non-frail). Proportional Cox regression tested the adjusted association between liver frailty and all-cause mortality for each category. The liver frailty prevalence was relatively low (3.8%), but higher in men (58.1%). Compared to non-frail older subjects, liver frailty subjects were significantly older (effect size (ES) − 1.11, 95% confidence interval (CI) − 1.35 to − 0.87), with a lower education (ES 0.48, 95%CI 0.24 to 0.71) and higher multimorbidity (ES 15.81, 95%CI 4.20 to 27.41). Cox multivariate analyses showed a two-fold increased risk of overall mortality (hazard ratio 2.09, 95%CI 1.16–3.74) even after the adjustment for age, sex, education, and alcohol consumption. The liver frailty phenotype runs twice the risk of overall mortality compared with the non-frail population. This clinical tool, validated in a Southern Italian population, is based on simple sets of measures that can conveniently be assessed also in the primary care setting. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00434-x.