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BACKGROUND: Variations in faecal volatile organic metabolites (VOMs) are increasingly thought to be indicative of digestive disorders. There are no studies in the literature that evaluated VOMs for inflammatory bowel disease (IBD) treatment response prediction. The assessment of the VOMs' capacity to predict clinical response after a year of adalimumab or vedolizumab therapy was the main goal of our investigation. VOM and IBD clinical characteristic correlations were among the secondary outcomes. METHODS: We sequentially included IBD patients who had indications for biologic treatment as part of a prospective research. RESULTS: We collected fifty IBD patients, and we used gas chromatography/mass spectrometry (GC/MS) to study their feces. Adalimumab was used to treat 31 patients, while vedolizumab was used to treat 19 individuals. After a year of treatment, pre-biologics methyl butyrate could predict clinical response (AUC = 0.68, 95%CI = 0.53-0.81, P=0.02). Age, the length of the disease, gender, or smoking habit had no effect on VOMs. Two VOMs, octenol and, specifically, methyl indole, correlated with greater levels of inflammation markers (CRP and calprotectin, respectively) and were able to differentiate between ulcerative colitis (UC) and Crohn's disease (CD) (AUC = 0.72 and 0.85, respectively). On the other hand, methylbutanal was associated with CD and specifically with ileal location (P=0.01). With an accuracy at least comparable to calprotectin, methyl butanoate could differentiate between active clinical illness and remission (AUC = 0.69 and 0.62, respectively). CONCLUSIONS: Using VOMs to characterize the intestinal metabolome appears to be a viable way to better understand IBD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an abnormal prothrombin produced by hepatocytes following impaired vitamin K-dependent carboxylase activity. Several studies showed that PIVKA-II could be useful for prognosis prediction in patients with hepatocellular carcinoma (HCC). We aimed to investigate the analytical and clinical performance of a novel enzyme-linked immunosorbent assay (ELISA) for the assessment of PIVKA-II in serum of patients with HCC as compared to a consolidated chemiluminescence enzyme immunoassay (CLEAI) as reference test. METHODS: A total of 103 patients with viral related-HCC (median age: 65 years; males: 74.8%) were retrospectively enrolled. Patients were classified according to Barcelona Clinic Liver Cancer (BCLC) staging system; 67 patients had a diagnosis of early HCC (BCLC 0/A), while 36 had a diagnosis of advanced tumor (BCLC B/C). After HCC diagnosis, patients were followed for a median of 16.8 (7.7-49.2) months. We measured PIVKA-II in serum samples by ELISA (AssayGenie, Dublin, Ireland) and by CLEIA (Fujirebio Inc., Tokyo, Japan) and we investigated the association between PIVKA-II results and overall survival (OS). RESULTS: Overall, the 103 patients examined showed median serum PIVKA-II values of 118 ng/mL and 197 mAU/mL by ELISA and CLEIA, respectively. We observed that PIVKA-II values significantly increased according to BCLC stage (P<0.001) and results from the two methods had a satisfactory correlation (rs=0.84, P<0.001). At multivariate analysis corrected for BCLC stage, both ELISA and CLEIA PIVKA-II resulted significantly and independently associated to OS (HR=2.93, 95% CI: 1.38-6.21, P=0.005 and HR=2.22, 95% CI: 1.15-4.27, P=0.017, respectively). CONCLUSIONS: ELISA and CLEIA PIVKA-II showed good analytical correlation and comparable clinical performance. The new AssayGenie ELISA test could be a valid and cost-effective alternative to CLEIA for measuring serum PIVKA-II in serum of patients with HCC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chronic hepatitis D virus (HDV) infection causes the most severe form of viral hepatitis. While HDV usually dominates over hepatitis B virus (HBV), several evidence support HBV role in determining HDV pathogenicity. We investigated the clinical value of novel HBV biomarkers for the prediction of long-term outcomes in patients with chronic hepatitis D (CHD). METHODS: Serum samples from CHD patients (N.=82; median age 51, 43-59 years; males, N.=58 [70.7%]) were retrospectively evaluated at baseline for hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and quantitative antibodies to hepatitis B core antigen (anti-HBc IgG) class IgG (Lumipulse® G600II; Fujirebio, Tokyo, Japan). An in-house RT-qPCR assay was used to quantify HDV RNA. RESULTS: Median patients' follow-up (FU) was 8 (4-13) years. At baseline, HDV RNA was detectable in 72 (87.8%), with a median value of 5.28 (3.62-6.02) Log IU/mL. Median serum HBsAg, HBcrAg, and anti-HBc IgG values were 3.76 (3.13-4.01) Log IU/mL, 3.7 (2.8-4.6) Log U/mL, and 2.59 (2.18-3.02) Log IU/mL, respectively. During the FU, liver related events (LREs) occurred in 42 (51.2%) patients; 24 (29.3%) patients developed hepatocellular carcinoma (HCC) while 18 (22.0%) developed ascites. A total of 22 (26.8%) patients underwent liver transplant, while 13 (15.9%) died. HBcrAg was associated to mortality (adjusted hazard ratio [aHR]=1.62, P=0.032), while HBcrAg/anti-HBc IgG ratio resulted associated to an increased risk of HCC (aHR=2.75, P=0.007), LREs (aHR=2.01, P=0.013), and mortality (aHR=3.82, P=0.005). CONCLUSIONS: The measurement of HBcrAg and quantitative anti-HBc IgG may represent a valuable tool for risk stratification in patients with CHD. [ABSTRACT FROM AUTHOR]

Background/Objectives: Vitamin D (VD) has immunoregulatory properties, generating interest in its potential to influence therapeutic outcomes in inflammatory bowel disease (IBD), other than affecting the expression of genes encoding enzymes and transporters involved in drug metabolism and transport. This study investigated VD-related single nucleotide polymorphisms (SNPs) as predictors of clinical responses in patients with Crohn's disease (CD) and ulcerative colitis (UC) treated with vedolizumab (VDZ) or ustekinumab (UST) after 3 (T3) and 12 months (T12), as well as the achievement of fecal calprotectin (FC) levels < 250 mg/kg, a marker of mucosal healing. Methods: In this prospective study, 103 patients (67 CD, 36 UC) were enrolled, 40 receiving VDZ and 63 receiving UST. SNPs in the genes CYP24A1, GC, CYP27B1, and VD receptor (VDR) were analyzed via polymerase chain reaction (PCR) and associated with clinical and laboratory outcomes. Results: UST therapy demonstrated a higher clinical response rate at T12 compared to VDZ (p = 0.03). A correlation was found between response at T3 and T12 (p = 0.0002). GC 1296 AC polymorphism negatively predicted response at T12, with 63.6% of non-responders carrying this genotype. CYP24A1 8620 AG was a negative predictor for achieving FC < 250 mg/kg (p = 0.045). CYP24A1 22776 CT and VDR Cdx2 GG increased the likelihood of presenting CD over UC (OR 3.40, p = 0.009 and OR 3.74, p = 0.047, respectively). Additionally, CYP27B1 −1260 GT and +2838 CT increased the likelihood of non-ileal CD (OR 3.13, p = 0.054; OR 7.02, p = 0.01). Conclusions: This study reveals associations between VD-SNPs, clinical response to VDZ and UST, and IBD phenotype and localization, supporting the development of personalized IBD treatment and warranting further validation. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions Patients with hepatitis C virus (HCV)‐related cirrhosis with sustained virological response (SVR) to direct‐acting antivirals (DAA) remain at risk of developing hepatocellular carcinoma (HCC). Recently, serum protein induced by vitamin K absence or antagonist‐II (PIVKA‐II) has shown promising results as an HCC‐predictive biomarker. We aimed to develop and validate a PIVKA‐II‐based model for HCC risk stratification in cirrhotic patients with SVR to DAA.A total of 1220 consecutive patients (Turin, n = 531; Pisa, n = 335; Milan, n = 354) with HCV‐related cirrhosis treated with DAA were included in the study. Patients were retrospectively allocated to the training cohort (Turin+Pisa; median follow‐up [FU] 39, 22–55 months; incident HCC: 93 [10.7%]) and validation cohort (Milan; median FU 49.0, 35.0–52.0 months; incident HCC: 19 [5.4%]). Serum PIVKA‐II levels were measured using the LumipulseG system (Fujirebio, Japan) at SVR12 (Turin and Pisa cohorts) or the end of treatment (Milan cohort).Using Cox regression analysis, a model including PIVKA‐II combined with age, sex, ALT, AST, γGT, platelet count, albumin and total bilirubin was derived from the training cohort (C‐index = 0.72). In the validation cohort, the model showed a C‐index of 0.71 with an area under the curve of 0.84 for identifying patients who developed HCC during the first 12 months of FU. When patients were grouped into three risk categories, the cumulative incidence of HCC was 2.7%, 4.0% and 14.3% in the low‐, medium‐ and high‐risk groups, respectively (p < 0.001). Notably, no HCC occurred within 3 years of FU in the low‐risk group.Our PIVKA‐II‐based model showed satisfactory accuracy for HCC risk stratification and may represent a valuable tool for implementing risk‐based surveillance protocols in patients with HCV‐related cirrhosis with SVR to DAA. [ABSTRACT FROM AUTHOR]

Micro‐RNAs (miRNAs) are involved in the modulation of viral replication and host immune antiviral response. Using next‐generation sequencing, we investigated the miRNome profile of circulating extracellular vesicles in 20 patients with chronic hepatitis D virus (HDV) infection undergoing pegylated interferon alpha (Peg‐IFNα) treatment. Circulating miRNAs' expression was analysed according to virologic response (i.e., HDV RNA clearance maintained at least 6 months after the end of therapy). Overall, 8 patients (40%) achieved a virologic response to Peg‐IFNα treatment. At baseline, 14 miRNAs were differentially expressed between responders and non‐responders; after 6 months of Peg‐IFNα treatment, 7 miRNAs (miR‐155‐5p, miR‐1246, miR‐423‐3p, miR‐760, miR‐744‐5p, miR‐1307‐3p and miR‐146a‐5p) were consistently de‐regulated. Among de‐regulated miRNAs, miR‐155‐5p showed an inverse correlation with HDV RNA (at baseline: rs = −0.39, p = 0.092; at 6 months: rs = −0.53, p = 0.016) and hepatitis B surface antigen (HBsAg) (at baseline: rs = −0.49, p = 0.028; at 6 months: rs−0.71, p < 0.001). At logistic regression analysis, both miR‐155‐5p (at baseline: OR = 4.52, p = 0.022; at 6 months: OR = 5.30, p = 0.029) and HDV RNA (at baseline: OR = 0.19, p = 0.022; at 6 months: OR = 0.38, p = 0.018) resulted significantly associated to virologic response. Considering that Peg‐IFNα still has a relevant role in the treatment of patients with chronic hepatitis D infection, the assessment of EV miR‐155‐5p may represent an additional valuable tool for the management of HDV patients undergoing Peg‐IFNα treatment. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) includes patients affected by Crohn's disease or ulcerative colitis. IBD is thought to be a chronic immune-mediated disease, but its origin remains elusive, and this limits new therapeutic approaches. Human endogenous retroviruses (HERVs) originate from ancestral infections and represent 8% of the human genome. HERVs are no longer infectious, but some retroviral sequences can be activated, and their aberrant expressions have been implicated in inflammatory and autoimmune disorders. HERV transcription is regulated by TRIM28 and SETDB1, which are also directly involved in epigenetic processes and modulation of the immune response. Using a PCR real-time Taqman amplification assay, we assessed, for the first time, the transcription levels of pol genes of HERV-H, -K, and -W families of env genes of syncytin 1 (SYN1), SYN2, and HERV-W, as well as of TRIM28 and SETDB1 in the whole blood of 48 patients with Crohn's disease (CD), 20 with ulcerative colitis (UC), and in healthy controls (HC) of comparable age. The transcriptional levels of HERV-H-pol (p = 0.0003) and HERV-K-pol (p = 0.001) were significantly higher in IBD patients compared with HC, with no differences between patients with CD and UC. No significant differences were found for the remaining HERVs between IBD patients and HC. The transcript levels of TRIM28 were significantly downregulated in IBD patients (p < 0.001), without differences between CD and UC, while the SETDB1 levels were preserved. The enhanced transcription of HERV-H-pol and HERV-K-pol, as well as the impaired activation of TRIM28, were not influenced by clinical disease activity and type of treatment. The overexpression of HERVs and impaired transcription of TRIM28 in patients affected by CD or UC suggest that they might be the main actors in the pathophysiology of IBD, opening the way to innovative targeted interventions. [ABSTRACT FROM AUTHOR]

The relationship between serum 25-hydroxyvitamin D (25(OH)D) levels, genomic response to vitamin D (Vit.D), and positivity to SARS-CoV-2 remains understudied. In this pilot study, during the follow-up of patients with Inflammatory Bowel Disease (IBD) and COVID-19, we investigated this issue by analyzing the molecular contents of serum extracellular vesicles (EVs) from six groups of IBD patients (n = 32), classified according to anti-SARS-CoV-2 status, 25(OH)D level, and Vit.D supplementation, by small RNA-seq. This analysis revealed differentially expressed miRNAs, PIWI-RNA, transfer RNA, small nucleolar RNAs, and protein-coding RNAs in the EVs obtained from these cohorts of IBD patients. Experimental validation evidenced a statistically significant increase in miR30d-5p, miR150-5p, Let-7f-5p, and Let-7a-5p in the anti-SARS-CoV-2-positive and low 25(OH)D and Vit.D supplemented groups with respect to the non-Vit.D supplemented group, indicating their responsiveness to Vit.D treatment. Bioinformatics analysis highlighted the regulation of these validated miRNAs by oxidative stress and inflammation, hallmarks of IBD and COVID-19. Our study reports an unprecedented panel of circulating EV-enclosed inflammation- and oxidative stress-related miRNAs, the potentiality of which, as biomarkers for Vit.D responsivity in IBD patients, needs to be explored in future studies on larger cohorts in order to allow clinicians to optimize current treatment strategies upon viral infection. [ABSTRACT FROM AUTHOR]

Plant-based diets (PBDs) are gaining attention as a sustainable and health-conscious alternative for managing various chronic conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD). In the absence of pharmacological treatments, exploring the potential of lifestyle modifications to improve biochemical and pathological outcomes becomes crucial. The adoption of PBDs has demonstrated beneficial effects such as weight control, increased metabolic health and improved coexisting diseases. Nonetheless, challenges persist, including adherence difficulties, ensuring nutritional adequacy, and addressing potential deficiencies. The aim of this review is to provide a comprehensive overview of the impact of PBDs on MASLD, emphasizing the need for tailored dietary interventions with professional support to optimize their effectiveness in preventing and treating metabolic diseases. [ABSTRACT FROM AUTHOR]