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Individuals with Inflammatory Bowel Disease (IBD) are more susceptible to experiencing severe complications of COVID-19 if infected. Nevertheless, sub-optimal immunization rates have been reported among these patients. Our study aims to assess COVID-19 VH among a global population of patients with IBD and to investigate the role of healthcare professionals, particularly gastroenterologists, in promoting immunization. Twenty-six studies were systematically selected from scientific articles in the MEDLINE/PubMed, WoK, and Scopus databases from January 1, 2020, to September 15, 2023. The pooled prevalence of COVID-19 VH was 27.2% (95%CI = 20.6-34.2%). A significant relationship was evidenced between COVID-19 vaccine compliance and receiving advice from gastroenterologists or healthcare providers (OR = 2.77; 95%CI = 1.79-4.30). By leveraging their knowledge of IBD, familiarity with patient histories, and trusted patient-doctor relationships, gastroenterologists are pivotal in promoting vaccination. This patient-centered care is crucial in increasing vaccine acceptance among individuals with IBD, contributing to better public health outcomes.

Studies conducted in the last few years have suggested a connection between clinical outcomes and the time of immune checkpoint inhibitors (ICIs) infusion. However, few data are available regarding the differences between early and late time-of-day (ToD) administration in metastatic renal cell carcinoma (mRCC) patients receiving immunotherapy and immune-based combinations. In this meta-analysis, we aimed to fully investigate the influence of timing of administration on the efficacy of mRCC immunotherapy, by comparing early ToD versus late ToD dosing in this setting. The present systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Overall Survival (OS) was measured as Hazard Ratios (HRs) and 95% confidence intervals (CIs). Our search resulted in the identification of 1429 potentially relevant reports, which were subsequently restricted to four following independent evaluation of three authors. The pooled HR for OS in RCC patients receiving early ToD versus late ToD dosing was 0.62 (95% Confidence Interval, 0.50-0.72; p < 0.001). According to our findings, a statistically significant improvement in terms of OS for mRCC patients receiving early ToD administration compared with late ToD dosing was observed, with a reduction of death by 38%. Well-designed, randomized clinical and translational trials are required to clarify this issue and to establish recommendations for personalized treatments according to ToD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The condition of cellular senescence has specific features, including an altered lipid metabolism. Delta-9 desaturase (Δ9) catalyzes the conversion of saturated fatty acids, such as palmitic acid and stearic acid, into their monounsaturated forms, palmitoleic and oleic acid, respectively. Δ9 activity is important for most lipid functions, such as membrane fluidity, lipoprotein metabolism and energy storage. The present study aimed to investigate differences in the expression of Δ9 in senescence-induced pancreatic (MIA-PaCa-2 and PANC-1) and hepatic (Hepa-RG and HLF) cancer cell lines. Cellular senescence was induced by growing cells in the presence of the chemotherapic drug doxorubicin. Senescence status was determined by the senescence-associated beta-galactosidase activity assay kit combined with the p21 and senescence associated secretory phenotype protein assay. Δ9 was downregulated in all senescence-induced cell lines compared to control cells, in both the lipidomic analysis and when measuring protein levels via western blotting. Hence, our findings demonstrate that the study of membrane lipid composition and the expression levels of Δ9 could potentially form the basis for future applications investigating the state of cellular senescence., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Steatotic liver disease associated with metabolic dysfunction (MASLD) affects up to about 30% of the general adult population and is closely related to obesity and the metabolic syndrome. Cortisol, a stress-related hormone contributing to hepatic fat accumulation and insulin resistance, also promotes progression of the disease. The study aims to investigate the impact of lifestyle modifications on cortisol levels and hepatic steatosis in patients with MASLD. Methods: In a 16-week three-arm randomized trial, 42 patients were randomly assigned to three groups who received dietary advice (CG), dietary advice combined with aerobic exercise (AE + DA), or dietary advice with high-intensity interval training (HIIT + DA). Before the start, after 2 months of intervention, and at the end of the project, medical evaluations, routine biochemical assessments, and psychological questionnaires were analyzed. At baseline and at the end of 4 months, hepatic steatosis was evaluated by Fibroscan ® . Results: In the study population, severe hepatic steatosis (74%) and obesity (98%) were prevalent at the beginning of the study. A statistically significant ( p -value = 0.001) reduction in circulating cortisol levels was observed over time in the two groups doing exercise, especially in HIIT + DA ( p -value = 0.006). Hepatic steatosis, assessed by Fibroscan ® , disappeared in 10 participants (CAP value < 248, p -value = 0.003). CAP values and waist circumference decreased in all groups, statistically significantly in the AE + DA group ( p -value = 0.005; p -value = 0.04, respectively). Conclusions: The study emphasizes the benefits of combining diet and exercise in managing MASLD. HIIT + DA significantly decreased cortisol levels, while AE + DA was the most potent intervention for reducing hepatic steatosis.

NOD-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) implicated in the innate immune sensing of pathogens and damage signals. NLRs act as sensors in multi-protein complexes called inflammasomes. Inflammasome activity is necessary for the maintenance of intestinal homeostasis, although their aberrant activation contributes to the pathogenesis of several gastrointestinal diseases. In this review, we summarize the main features of the predominant types of inflammasomes involved in gastrointestinal immune responses and their implications in intestinal disease, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), celiac disease, and Colorectal Cancer (CRC). In addition, we report therapeutic discoveries that target the inflammasome pathway, highlighting promising novel therapeutic strategies in the treatment of intestinal diseases. Collectively, our understanding of the mechanisms of intestinal inflammasome activation and their interactions with other immune pathways appear to be not fully elucidated. Moreover, the clinical relevance of the efficacy of inflammasome inhibitors has not been evaluated. Despite these limitations, a greater understanding of the effectiveness, specificity, and reliability of pharmacological and natural inhibitors that target inflammasome components could be an opportunity to develop new therapeutic options for the treatment of intestinal disease.

Background. Very low-calorie ketogenic diets (VLCKD) are an effective weight-loss strategy for obese individuals, reducing risks of liver conditions such as non-alcoholic steatohepatitis and fibrosis. Small extracellular vesicles (sEVs) are implicated in liver fibrosis by influencing hepatic cell phenotypes and contributing to liver damage. This study investigates sEVs derived from serum of 60 obese adults categorized into low fibrosis risk (LR) and intermediate/high fibrosis risk (IHR) groups based on FibroScan elastography (FIB E scores, limit value 8 kPa) and all participants underwent an 8-week VLCKD intervention. Methods. The study examines the impact of these sEVs on fibrosis markers, inflammation, and autophagy in a hepatocyte cell line (HEPA-RG) using bioinformatics, RNA sequencing, lipidomics, RT-PCR, and Western blotting before (T0) and after (T1) VLCKD. Results. sEVs from LR patients post-VLCKD reduced fibrosis related gene expression (e.g., ACTA2) and enhanced proteins associated with regeneration and inflammation (e.g., HDAC6). Conversely, sEVs from IHR patients increased fibrosis and inflammation related gene expression (PIK3CB, AKT1, ACTA2) in hepatocytes, raising concerns about VLCKD suitability for IHR patients. IHR sEVs also decreased expression of HDAC10, HDAC6, HDAC3, MMP19, and MMP2, while increasing modulation of p-AKT, α-SMA, and VIM. Conclusion. These findings underscore the critical role of sEVs in regulating inflammation, remodeling, and hepatic stress responses, particularly in IHR patients, and suggest sEVs could complement instrumental evaluations like FibroScan in fibrosis assessment.

Background: Irritable bowel syndrome (IBS) and obesity are associated with intestinal barrier alterations that result in low-grade inflammation. Zonulin and intestinal fatty acid-binding protein (I-FABP) assess gut barrier health, while urinary indican concentrations reflect dysbiosis in the small intestine. Physical activity, such as Fitwalking, aids weight management and improves intestinal permeability. This study assesses the impact of a 12-week Fitwalking program on intestinal barrier health in IBS patients categorized by body mass index (BMI). Methods: Fifty-seven mild IBS patients were categorized as obese (OB = 18), overweight (OW = 24), or normal weight (NW = 15) and assigned to a walking group. Participants walked thrice weekly at moderate intensity for 60 min per session, using the specific Fitwalking technique, supervised by staff. Results: No significant changes in biochemical or anthropometric variables were observed. However, Fitwalking improved the Global Physical Capacity Score (GPCS) by 46%, 48%, and 24% in the NW, OW, and OB groups. Post-intervention, serum zonulin levels notably decreased in OB individuals, suggesting reduced inflammation. OW patients unexpectedly showed increased fecal zonulin levels. OB participants experienced decreased urinary indican levels. Zonulin levels positively correlated with BMI and inversely with GPCS. Conclusions: Regular exercise benefits the intestinal barrier, especially in obese IBS patients. Monitoring zonulin and I-FABP may offer insights into gut barrier integrity and GI injury severity. Future studies should explore longer intervention durations, larger populations, and advanced diagnostic tools to validate findings and investigate the mechanisms behind exercise-induced changes in intestinal permeability and gut health markers.

Introduction: Recently, immunotherapy has offered new hope for treating biliary tract cancer (BTC). However, several issues are to be considered, including the lack of validated predictive biomarkers that could help to identify patient groups which are most likely to benefit from such therapeutic approaches., Areas Covered: In the current article, we will provide an overview of recent results and ongoing and future research directions of immunotherapy in BTC, with a special focus on recently published, practice-changing data, and ongoing active and recruiting clinical trials., Expert Opinion: At this moment, dozens of clinical trials in phases I to III are evaluating the role of cancer immunotherapy in this setting, with the hope of adding more therapeutic options for BTC patients. Future research must focus on the development of novel agents and combinations, but the validation of biomarkers remains an urgent need. As more research results emerge, novel combinatorial strategies are destined to further transform the treatment paradigm for this heterogeneous and aggressive tumor type.

Objective: This study aims to explore the association between liver steatosis and fibrosis, as assessed by Fibroscan, and the onset of type 2 diabetes in overweight, medication-free men and women., Methods: We analyzed data from 164 participants with overweight or obesity (41.4 % male), including 39 individuals (23.8 %) with type 2 diabetes. All participants underwent Fibroscan to evaluate liver steatosis (CAP > 275 dBm) and fibrosis (liver stiffness > 8.2 kPa). Diabetes was diagnosed using fasting glucose, 2-hour glucose tolerance test (OGTT), and HbA1c levels., Results: Liver steatosis was significantly more prevalent in individuals with diabetes (89.7 % vs 52 %, P < 0.001). Liver fibrosis was observed in 35.9 % of subjects with diabetes (vs 13.6 %, P = 0.002). Mean CAP (P < 0.001) and kPA (P = 0.006) values were significantly higher in the group with diabetes. Significant associations between CAP (MD: 30.87, P = 0.009) and liver stiffness (MD: 2.454, P = 0.006) with diabetes were found, independent of other variables. Additionally, liver steatosis was independently associated with elevated HOMA-IR levels (P = 0.001)., Conclusion: Elevated liver steatosis and fibrosis are both linked to type 2 diabetes, independent of traditional risk factors. These findings support screening for diabetes in individuals with significant steatosis and fibrosis and vice versa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although early-stage gastric cancer is a candidate for curative surgical resection, the absence of specific early symptoms results in a late diagnosis and consequently most patients present advanced or metastatic disease. Identifying noveland tumor-specific biomarkers is needed to increase early detection and match patients to the appropriate treatment. The present study focused on the possible prognostic role of Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2)/Autotaxin (ATX) and lysophosphatidic acid (LPA) in Gastro-Esophageal Adenocarcinoma (GEA). High levels of ATX/LPA are associated with several malignancies including gastrointestinal tumors., Methods: Using a bioinformatics analysis, the incidence of ENPP2 mutations together with its expression in the tumor tissues and the correlation between the presence of mutations and the survival rate were examined in databases of GEA patients. Furthermore, circulating levels of ATX and LPA were studied retrospectively and longitudinally both in patients receiving frontal surgery and in patients receiving preoperative chemotherapy., Results: Overall findings suggested that although ENPP2 mutations occur at low incidence, their presence was associated with a particular poor Overall Survival (OS). Furthermore, removal of the tumour by surgery resulted in a decrease in serum ATX and LPA levels within five days, regardless of any previous chemotherapy. Basal circulating ATX were associated with the aggressive diffuse GEA and could be considered of negative prognostic value, mainly in combination models with circulating Carcino-Embryonic Antigen (CEA)., Conclusions: Based on these observations, clinical trials with ATX-targeted drugs and standard chemotherapy regimens may benefit from selecting GEA patients based on their levels of ATX, LPA and CEA., Competing Interests: Declaration of Competing Interest Dr Michael Lahn is Chief Medical Officer at iOnctura SA and holds stocks in the company; Dr Gianluigi Giannelli is an Editorial Member for Journal Experimental Clinical Cancer Research and was not involved in the editorial review or the decision to publish this article. Dr Rosalba D’Alessandro is Guest Editor for Cancers and was not involved in the editorial review or the decision to publish this article. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available., Materials and Methods: The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based sequence of three treatment lines in patients with RAS/BRAF V600E wild-type (WT) mCRC, as determined by the local laboratory. Before first-line therapy, CGP is carried out with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively., Results: For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF ≥ 10%) was detected among 140/205 (68.3%) patients. One thousand and thirteen genomic variants were identified. F1L CDx found KRAS, NRAS, or BRAF V600E alterations in 19 patients, whose tumors were classified as RAS/BRAF V600E WT by the local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. A concordance of 61.4% between the two tests was observed. The concordance increased to 72.7% for F1L CDx with TF ≥ 10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥ 10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including six cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT)., Conclusion: Baseline liquid biopsy-based CGP is feasible, has high concordance with tumor tissue-based CGP, could better recapitulate tumor heterogeneity, and is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAF V600E WT mCRC patients., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background/Objectives: Biliary tract cancers (BTCs) are aggressive neoplasms with limited therapeutic options. The amount of prospective evidence is poor, and limited data are available on the impact of treatment sequencing on survival. Here we report a real-world experience of patients with advanced BTC treated with at least three lines of therapy. We evaluated the impact of sequential treatments, and we further compared the efficacy of Gemcitabine/Cisplatin (GemCis) and mFOLFOX to other first- and second-line chemotherapy regimens, respectively. Methods : Data on 60 patients with locally advanced or metastatic BTC under the care of a single Italian referral hospital and treated with at least three lines of chemotherapy were retrospectively collected. Data from 56 patients were included in the analysis. Survival analyses were performed using R software (v1.2.5042). Results : We compared the outcomes of patients treated according to the "standard" pre-immunotherapy sequence (GemCis and mFOLFOX in the first and second lines, respectively) versus those treated with all other combinations ("control" group). Our analysis did not show significant survival differences between the two groups. However, it should be noted that we selected long-survival patients by including only those who received at least three or more lines of chemotherapy. Focusing on the first-line setting, no significant differences in both mPFS and mOS emerged by comparing GemCis versus other doublets (mainly Gemcitabine/Oxaliplatin). Similarly, mPFS and mOS from second-line treatment did not statistically differ between patients treated with mFOLFOX versus those treated with other regimens (71% chemotherapy doublets). Conclusions: Our series provides real-world outcomes of patients with advanced BTC before the approval of immunotherapy. Even considering the monocentric and retrospective design, our study represents one of the first analyses on the impact of sequential treatment strategies in patients with BTC.

Background: More than half of patients with Crohn's disease develop intestinal fibrosis induced intestinal obstruction with debilitating symptoms throughout their disease course. The incidence of stricture formation in CD has remained unchanged over the last several decades. Factors promoting intestinal fibrosis are currently unclear, but diet may represent an underestimated risk factor for intestinal fibrosis by modification of both the host immune response and intestinal microbial composition. Evaluating the impact of diet on the course of IBD is very complex. Sarcopenia is a common problem in IBD patients and correlates with an increased rate of disease. Skeletal muscle index (SMI) is an important parameter to measure sarcopenia and is an easily accessible tool for evaluating the likelihood of complications in individuals with CD., Methods: Using a randomized and controlled pilot design, we aimed to investigate the efficacy of 12 months of short-term dietary intervention based on essential amino acid (EAA) and sodium butyrate (NaB) supplementation in the management of stricturing Crohn's disease patients., Results: After the treatment in the diet EAA/NaB group, we revealed a statistically significant improvement of muscle mass (61.49 ± 5.47 vs. control 86 ± 10.70, p = 0.01) and SMI index (9.97 ± 1.79 vs. control 7.60 ± 2.29, p = 0.02). In addition, the measurement of skeletal muscle mass in CD patients has been suggested to be crucial for predicting the disease course. Indeed, after one year, surgery was required in 4/10 control group patients (40%) and 1/10 study group (10%) patients, underlining the importance of body composition alterations and adequate dietary intake in the management of these patients., Conclusions: Further prospective studies are needed to confirm these results; nonetheless this nutritional approach could become an integral part in the treatment of stricturing CD patients to improve disease outcomes and increase the quality of life in these patients.

Purpose: To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS / BRAF wild-type (wt) metastatic colorectal cancer (mCRC)., Patients and Methods: IMPROVE (ClinicalTrials.gov identifier: NCT04425239) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS / BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test., Results: Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B., Conclusion: Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.

Background : Celiac disease (CD) is associated with an increased risk of cardiovascular (CV) events, especially inflammatory heart diseases. We aimed to gather evidence on the association between CD and inflammatory CV diseases, including pericarditis and myocarditis, and the underlying pathophysiological mechanisms. Methods : The PubMed, Scopus, and Google Scholar databases were searched for studies assessing the prevalence and the long-term outcomes of patients with CD and inflammatory CV diseases. Result : Ten studies (nine case series/reports and one prospective observational study) covering a total of 22 patients, including 9 women (41%) and 13 men (59%), were evaluated. The median age was 23 (IQR, 12-41) years. A total of 6 patients had recurrent pericarditis, while 16 patients had celiac-related myocarditis (11 patients presented with heart failure and 5 with arrhythmia). A strict gluten-free diet (GFD) alone was effective in 87.5% of cases (4/6 for pericarditis and 10/16 for myocarditis). All patients with pericarditis achieved complete resolution of symptoms. Conversely, heart function was restored in 81% of patients with myocarditis. Only one patient died. Conclusions : Myocarditis and/or pericarditis, especially if recurrent, may complicate CD in pediatric and adult subjects due to an autoimmune reaction involving the pericardium/myocardium and the small intestine.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) induce body weight loss, but their effect on skeletal muscle mass (SMM) and strength needs to be better elucidated., Objectives: This study aimed to evaluate the effects of SGLT2i on SMM in a real-life population setting of patients with type 2 diabetes (T2D). Secondary outcomes included changes in liver steatosis and in anthropometric and glucometabolic parameters., Methods: Seventy-one patients were treated with SGLT2is as an add-on to metformin for 52 consecutive weeks. Visits were scheduled at baseline (T0) and after 6 (T6) and 12 months of therapy (T12) and included the checking of laboratory tests, measurement of anthropometric parameters, bioimpedance analysis of body composition, and abdominal ultrasound (US)., Results: Fat mass (FM) and visceral adipose tissue (VAT) progressively decreased compared to the baseline (FM: -2.9 ± 0.6 kg at T6; -2.8 ± 0.6 kg at T12; VAT: -0.3 ± 0.1 L at T6; -0.4 ± 0.1 L at T12; all p < 0.01). Changes in SMM were less pronounced (-0.4 ± 0.3 kg at T6, ns; -0.7 ± 0.4 kg at T12, p < 0.05), yielding a beneficial increase in the SMM/FM ratio (+0.3 ± 0.05 at T6 and +0.2 ± 0.05 at T12, all p < 0.01). No significant changes in sarcopenia, sarcopenic obesity, fat-free mass, muscle strength, and water compartments were observed at the end of the follow-up period. Anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and biometric indices and US grading of hepatic steatosis improved throughout this study., Conclusions: In a real-life setting, SGLT2i therapy is associated with weight loss attributable to FM rather than SMM loss without any relevant deterioration in muscle strength. In addition, SGLT2is proved to have beneficial effects on steatotic liver disease.

Background: Irritable Bowel Syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder characterized by abdominal pain, altered bowel habits, and bloating, affecting approximately 10.1% of the global population. While current treatments emphasize dietary modifications and symptom management, emerging evidence suggests that physical activity (PA) may help alleviate IBS symptoms. This study evaluated the effects of a structured walking program, "StepFit-18K", on IBS symptom relief. Methods: A total of 106 participants (68 females and 38 males) completed the 12-week intervention, which consisted of 18,000 additional steps per week (6000 extra steps on three days per week) tracked via fitness devices. The program emphasized step count, ease of adoption, and social support through walking groups. Results: As assessed by validated questionnaires, significant reductions in GI symptoms were observed. The IBS Symptom Severity Score (IBS-SSS) decreased from 118.30 ± 98.73 to 74.46 ± 74.93, with a delta score of -43.84%, highlighting bloating as the most improved symptom. No clinically significant changes were observed in anthropometric or biochemical markers. Conclusions: StepFit-18K is a simple, accessible, and effective form of physical activity that has demonstrated therapeutic benefits for IBS symptoms. This offers an additional application beyond its well-established role in preventing cardiovascular diseases.

Hepatocellular carcinoma (HCC) represents a major public health concern and ranks among the leading cancer-related mortalities globally. Due to the frequent late-stage diagnosis of HCC, therapeutic options remain limited. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) in the regulation of Aurora kinase A (AURKA), one of the key hub genes involved in several key cancer pathways. Indeed, the dysregulated interaction between ncRNAs and AURKA contributes to tumor development, progression, and therapeutic resistance. This review delves into the interplay between ncRNAs and AURKA and their role in hepatocarcinogenesis. Recent findings underscore the involvement of the ncRNAs and AURKA axis in tumor development and progression. Furthermore, this review also discusses the clinical significance of targeting ncRNA-AURKA axes, offering new perspectives that could lead to innovative therapeutic strategies aimed at improving outcomes for HCC patients.

Drug resistance is a significant challenge in oncology and is driven by various mechanisms, among which a crucial role is played by enhanced DNA repair. Thus, targeting DNA damage response (DDR) factors with specific inhibitors is emerging as a promising therapeutic strategy. An important process involved in the modulation of DNA repair pathways, and hence in drug resistance, is post-translational modification (PTM). PTMs such as methylation affect protein function and are critical in cancer biology. Methylation is catalyzed by specific enzymes called protein methyltransferases. In recent years, the SET domain-containing N-lysine methyltransferase SMYD3 has emerged as a significant oncogenic driver. It is overexpressed in several tumor types and plays a signal-dependent role in promoting gastrointestinal cancer formation and development. Recent evidence indicates that SMYD3 is involved in the maintenance of cancer genome integrity and contributes to drug resistance in response to genotoxic stress by regulating DDR mechanisms. Several potential SMYD3 interactors implicated in DNA repair, especially in the homologous recombination and non-homologous end-joining pathways, have been identified by in silico analyses and confirmed by experimental validation, showing that SMYD3 promotes DDR protein interactions and enzymatic activity, thereby sustaining cancer cell survival. Targeting SMYD3, in combination with standard or targeted therapy, shows promise in overcoming drug resistance in colorectal, gastric, pancreatic, breast, endometrial, and lung cancer models, supporting the integration of SMYD3 inhibition into cancer treatment regimens. In this review, we describe the role played by SMYD3 in drug resistance and analyze its potential as a molecular target to sensitize cancer cells to treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. The increasingly sedentary lifestyle in recent years may have accelerated the development of NAFLD, independent of the level of physical activity., Objective: The purpose of this cross-sectional study was to determine the association between leisure-time physical activity (LTPA) and time spent sitting (TSS) and the likelihood of developing NAFLD in a sample of men and women aged 18-64 years, from southern Italy., Design: The study is based on two cohort studies, a randomized clinical trial and an observational cost-benefit study., Participants: A total of 1269 participants (51.5% women) drawn from 3992 eligible subjects were enrolled in this study., Exposures: Leisure-time physical activity (LTPA) and time spent sitting (TSS) were assessed using the Italian long form of the International Physical Activity Questionnaire (IPAQ-LF), designed for administration to adults aged 18 to 65 years., Main Measures: The association of exposures with the probability of belonging to a certain NAFLD degree of severity., Key Results: The probability of having mild, moderate, and severe NAFLD tends to decrease with increasing LTPA and decreasing TSS levels. We selected a combination of participants aged 50 years and older stratified by gender. Men had a statistically significant difference in the probability of developing moderate NAFLD if they spent 70 h per week sitting and had low LTPA, while among women there was a statistically significant difference in the probability of developing mild or moderate NAFLD if they had moderate LPTA and spent 35-70 h/week sitting., Conclusions: The study thus showed that the amount of LTPA and the amount of TSS are associated with development and progression of NAFLD, but this relationship is not a linear one-especially in women aged ≥ 50 years old., (© 2024. The Author(s).)

Background : Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. Methods : A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes ( APC , BMPR1A , MUTYH , PTEN , SMAD4 , and STK11 ) in order to identify germline genetic variants. Results : In the screened index cases, we found 14 pathogenic variants involving APC , MUTYH , SMAD4 , and STK11 and 6 variants of uncertain significance involving APC , BMPR1A , and SMAD4 . In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. Conclusions : Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients' clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most recent definition for steatotic liver disease associated with metabolic syndrome. The results of recent metabolic and observational studies suggest a potential beneficial effect of food-derived flavonoids in some chronic diseases, including MASLD. The study aims to evaluate the protective role of diet flavonoids in subjects with and without MASLD belonging to a cohort living in the South of Italy., Methods: The study cohort comprised 1297 participants assessed in the NUTRIHEP cohort (2015-2018), divided into two groups, based on presence or absence of MASLD., Results: The results indicated statistically significant flavonoid consumption, showing a protective role against MASLD, at an optimal concentration of 165 mg/day, with an OR value of 0.63, ( p = 0.001, 95% C.I.: 0.47; 0.83 t). The OR remained almost unchanged when the intake increased from 165 mg per day to 185 mg per day., Conclusions: In conclusion, our study results show a protective role of flavonoids against MASLD. Consuming only 165 mg of flavonoids daily can activate this protective function, reducing the risk of MASLD.

Competing Interests: C.B. served as a consultant for AbbVie, Celtrion, Ferring, Galapagos, Janssen, MSD, and Takeda. E.V.S. has served as speaker for AbbVie, Agave, AG Pharma, Alfasigma, Aurora Pharma, Cadigroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; has served as a consultant for AbbVie, Agave, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Diadema Farmaceutici, Dr Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlé, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas, Takeda, and Unifarco; and has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, and Zeta Farmaceutici. M.M. has received lecture fees and has been an Advisory Board member for Takeda, Galapagos, Biogen, Aurora Pharma, and AbbVie. F.A.C. served as consultant and advisory board member for Mundipharma, AbbVie, MS&D, Takeda, Janssen, Roche, and Celgene; has received lecture fees from AbbVie, Amgen, Ferring, Takeda, and Allergy Therapeutics; and has received unrestricted research grants from Giuliani, Sofar, MSD, Takeda, and AbbVie. G.B. served as speaker for AbbVie, Takeda, Galapagos, Lilly, and Janssen. A.V. has received lecture fees from and has been an advisory board member for Janssen-Cilag, Takeda, Pfizer, Ferring, MSD, Zambon, AbbVie, and Celltrion. F.S. has served as a lecturer for Sanofi. F.F. received consulting fees from Amgen, AbbVie, and Galapagos and lecture fees from Janssen and Pfizer; has served as an advisory board member; and/or received lecture grants from AbbVie, Biogen, Galapagos, Janssen, MSD, Pfizer, Takeda Pharmaceuticals. E.C. served as advisory board member for Takeda and AbbVie; and received lecture fees from AbbVie, Janssen, Galapagos, Ferring, Takeda. M.B.P. served as advisory board member and received lecture fee from MSD, AbbVie, Janssen, Pfizer, and Takeda. A.A. has been an advisory board member for Galapagos and consultant for AbbVie, Galapagos, Pfizer, Takeda, and Janssen. M.C. served as a speaker or advisory board member for Takeda, MSD, AbbVie, Shire, Fresenius, and Janssen. B.B. has served as a speaker for AbbVie, Agave, Alfasigma, AG Pharma, Janssen, MSD, Procise, Sofar, Takeda, and Unifarco. S.S. has received consultancy and lecture fees and has been an advisory board member for AbbVie, Arena, Ferring, Galapagos, Gilead, Janssen, MSD, Pfizer, and Takeda. P.B. has participated on advisory boards for Janssen and Takeda. A.A. has received consulting and/or advisory board fees from AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, and Takeda; has received lecture and speaker bureau fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mitsubishi Tanabe, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, and TiGenix; and has received research grants from Biogen, MSD, Pfizer, and Takeda. L.B. has received lecture fees, consultancy fees, or advisory board honoraria from Abbvie, Aliveda, Janssen, Noos, Pfizer, Pharmanutra, Takeda, and Zambon. S.D. received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor. G.F., M.M., G.B., A.M., C.C., M.C., L.C., V.C., A.S., and F.S.C. declare no conflict of interest.

Background/objectives: This study investigates the association between extra virgin olive oil (EVOO) consumption and mortality risk in a cohort of Italian adults adhering to the Mediterranean diet., Methods: In a 17-year follow-up study involving participants from Castellana Grotte, Italy (2005-2023), we analyzed dietary intake and mortality data. Participants were categorized into three EVOO consumption groups: <30 g/day, 30-50 g/day, and >50 g/day. Mortality Hazard Ratios (HR) and Subdistribution Hazard Ratios (SHR) were calculated to assess the relationship between EVOO intake and all-cause and cancer mortality., Results: Higher EVOO consumption was associated with significantly reduced cancer and all-cause mortality. Specifically, the daily intake of 30-50 g of EVOO was linked to a 24% lower risk of all-cause mortality (HR 0.77; 95% CI 0.63-0.93), while the consumption of more than 50 g/day was associated with a 20% reduction (HR 0.80; 95% CI 0.65-0.98). The most pronounced benefit was observed for gastrointestinal cancers, with a 60% lower mortality risk for those consuming over 50 g/day (SHR 0.39; 95% CI 0.21-0.73). A 50% reduction in mortality risk from other cancers was also noted for the highest consumption category (SHR 0.50; 95% CI 0.31-0.81)., Conclusions: The findings support the beneficial role of EVOO in reducing cancer mortality, particularly with higher consumption levels. The results underscore EVOO's potential as a dietary intervention for cancer prevention, aligning with the Mediterranean diet's overall health benefits. Further research is needed to confirm these findings and explore the underlying mechanisms.

Background/Objectives : We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods : This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results : The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS- patients. By the end, 78.9% had died, with nTS- patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS- to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions : The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management.

Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients.

Background/objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is currently the most common cause of chronic liver disease. Systemic inflammatory status and peripheral metabolic symptoms in the clinical picture have an impact on gut commensal bacteria., Methods: Our designed clinical trial was based on a cohort of patients with MAFLD whose diet included the daily consumption of 400 g of "Navelina" oranges for 28 days, compared with a control group of patients with the same pathologic conditions whose diet did not include the consumption of oranges and other foods containing similar nutrients/micronutrients. We used 16S metataxonomics and GC/MS analyses to identify taxa and urine/fecal VOCs, respectively., Results: A set of micronutrients from the diet were inspected, and some specific fatty acids were identified as the main contributors in terms of cluster sample separation. Metataxonomics and metabolomics profiles were obtained, and a stringent statistical approach allowed for the identification of significant taxa/VOCs, which emerged from pairwise group comparisons in both fecal and urine samples., Conclusions: In conclusion, a set of taxa/VOCs can be directly referred to as a marker of dysbiosis status and other comorbidities that, together, make up the pathologic burden associated with MAFLD. The investigated variables can be a target of therapeutic strategies.

Background: Cancer-associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely have a role in tumor aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor, namely Crenigacestat, may affect cancer progression., Methods: We used different in vitro models in 2D and established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. The results were confirmed in a xenograft model, and explanted tumoral tissues underwent transcriptomic and bioinformatic analysis., Results: hCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grew larger than homo-spheroids, formed by only iCCA cells. Crenigacestat significantly reduced the invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumors grew significantly larger than KKU-M213 tumors, but were significantly reduced in volume by Crenigacestat treatment, which also significantly decreased the fibrotic reaction. Ingenuity pathway analysis revealed that genes of hCAFs/KKU-M213 but not of KKU-M213 tumors increased tumor lesions, and that Crenigacestat treatment inhibited the modulated canonical pathways. Cell cycle checkpoints were the most notably modulated pathway and Crenigacestat reduced CCNE2 gene expression, consequently inducing cell cycle arrest. In hetero-spheroids, the number of cells increased in the G2/M cell cycle phase, while Crenigacestat significantly decreased cell numbers in the G2/M phase in hetero but not in homo-spheroids., Conclusions: The hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat., (© 2024. The Author(s).)

One of the most essential procedures for individuals with biliopancreatic disorders is endoscopic retrograde cholangiopancreatography (ERCP). It is based on the combination of endoscopy and radiology to study the biliopancreatic ducts and apply therapeutic solutions. ERCP is currently used to treat choledocholithiasis with or without cholangitis, as well as pancreatic duct stones, benign bile, and pancreatic leaks. On the other hand, ERCP is an unpleasant procedure that must be conducted under anesthetic (moderate sedation, deep sedation, or general anesthesia). With procedures becoming more challenging, the role of anesthesia in ERCP has become even more relevant, and the use of general anesthesia has become better defined. In the last decades, many drugs have been used and some new drugs, like dexmedetomidine, have been recently introduced for sedation or anesthesia during ERCP. Moreover, the scientific community is still divided on the level of sedation to be applied, as well as on appropriate airway management. We therefore performed a narrative review of the literature to assess currently available anesthetic medications for elective ERCP and evidence supporting their effectiveness.

BTC overall incidence is globally increasing. CCA, including its subtypes, is a form of BTC. MetS, obesity, MASLD, and diabetes are all linked to CCA in interconnected ways. The link between obesity and CCA is less well-defined in Eastern countries as compared to Western. Although more research is needed to determine the relationship between MASLD and extrahepatic CCA (eCCA), MASLD may be a concurrent risk factor for intrahepatic CCA, particularly in populations with established or unidentified underlying liver disease. Interestingly, the risk of biliary tract cancer (BTC) seemed to be higher in patients with shorter diabetes durations who were not treated with insulin. Therefore, early detection and prevention of chronic liver disease, as well as additional intervention studies, will undoubtedly be required to determine whether improvements to MetS, weight loss, and diabetes therapy can reduce the risk and progression of BTC. However, further studies are needed to understand how reproductive hormones are involved in causing BTC and to develop consistent treatment for patients. Finally, it is critical to carefully assess the cardiological risk in BTC patients due to their increased intrinsic cardiovascular risk, putting them at risk for thrombotic complications, cardiovascular death, cardiac metastasis, and nonbacterial thrombotic endocarditis. This review aimed to provide an updated summary of the relation between the abovementioned cardio-metabolic conditions and BTC.

Recently, volatile organic compound (VOC) determination in exhaled breath has seen growing interest due to its promising potential in early diagnosis of several pathological conditions, including chronic kidney disease (CKD). Therefore, this study aimed to identify the breath VOC pattern providing an accurate, reproducible and fast CKD diagnosis at early stages of disease. A cross-sectional observational study was carried out, enrolling a total of 30 subjects matched for age and gender. More specifically, the breath samples were collected from (a) 10 patients with end-stage kidney disease (ESKD) before undergoing hemodialysis treatment (DIAL); (b) 10 patients with mild-moderate CKD (G) including 3 patients in stage G2 with mild albuminuria, and 7 patients in stage G3 and (c) 10 healthy controls (CTRL). For each volunteer, an end-tidal exhaled breath sample and an ambient air sample (AA) were collected at the same time on two sorbent tubes by an automated sampling system and analyzed by Thermal Desorption-Gas Chromatography-Mass Spectrometry. A total of 110 VOCs were detected in breath samples but only 42 showed significatively different levels with respect to AA. Nonparametric tests, such as Wilcoxon/Kruskal-Wallis tests, allowed us to identify the most weighting variables able to discriminate between AA, DIAL, G and CTRL breath samples. A promising multivariate data mining approach incorporating only selected variables (showing p -values lower than 0.05), such as nonanal, pentane, acetophenone, pentanone, undecane, butanedione, ethyl hexanol and benzene, was developed and cross-validated, providing a prediction accuracy equal to 87% and 100% in identifying patients with both mild-moderate CKD (G) and ESKD (DIAL), respectively.

Background & Aims: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA., Methods: We used data from the Italian RECAPITULATE (N = 441) and the IBER-PBC (N = 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS) or also after 6 months of treatment (ORS+). Multivariable Cox regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (alkaline phosphatase [ALP]/upper limit of normal [ULN]<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or normal range criteria (NR: normal ALP, alanine aminotransferase [ALT], and bilirubin) up to 24 months., Results: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN, and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were 0.75, 0.78, and 0.72 for POISE, ALP/ULN<1.67, and NR response, which raised to 0.83, 0.88, and 0.81 with ORS+, respectively. The respective performances in validation were 0.70, 0.72, and 0.71 for ORS and 0.80, 0.84, and 0.78 for ORS+. Results were consistent across groups with mild/severe disease., Conclusions: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Colorectal cancer (CRC) is characterized by a pro-inflammatory microenvironment and features high-energy-supply molecules that assure tumor growth. A still less studied macromolecule is inorganic polyphosphate (iPolyP), a high-energy linear polymer that is ubiquitous in all forms of life. Made up of hundreds of repeated orthophosphate units, iPolyP is essential for a wide variety of functions in mammalian cells, including the regulation of proliferative signaling pathways. Some evidence has suggested its involvement in carcinogenesis, although more studies need to be pursued. Moreover, iPolyP regulates several homeostatic processes in animals, spanning from energy metabolism to blood coagulation and tissue regeneration., Results: In this study, we tested the role of iPolyP on CRC proliferation, using in vitro and ex vivo approaches, in order to evaluate its effect on tumor growth. We found that iPolyP is significantly increased in tumor tissues, derived from affected individuals enrolled in this study, compared to the corresponding peritumoral counterparts. In addition, iPolyP signaling occurs through the TRPM8 receptor, a well-characterized Na + and Ca 2+ ion channel often overexpressed in CRC and linked with poor prognosis, thus promoting CRC cell proliferation. The pharmacological inhibition of TRPM8 or RNA interference experiments performed in established CRC cell lines, such as Caco-2 and SW620, showed that the involvement of TRPM8 is essential, greater than that of the other two known iPolyP receptors, P2Y1 and RAGE. The presence of iPolyP drives cancer cells towards the mitotic phase of the cell cycle by enhancing the expression of ccnb1 , which encodes the Cyclin B protein. In vitro 2D and 3D data reflected the ex vivo results, obtained by the generation of CRC-derived organoids, which increased in size., Conclusions: These results indicate that iPolyP may be considered a novel and unexpected early biomarker supporting colorectal cancer cell proliferation.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. One way to resolve this reversible condition is by making dietary changes. Extra virgin olive oil (EVOO) is often associated with an improvement in this disease. The aim of this study was to explore the protective role of EVOO on NAFLD conditions, stratified by gender., Methods: The study cohort included 1426 participants assessed in the second recall of the NUTRIHEP cohort (2014-2018), subdivided by gender and dividing the EVOO intake into quartiles of daily gram intake., Results: The results indicated a protective role of the last quartile of EVOO only for female subjects, OR = 0.43, p = 0.02, 0.21 to 0.85 at 95% C.I., whereas in the male sub-cohort, the effect was not statistically significant., Conclusions: The protective role of EVOO is different between genders. This difference has not been explored in the literature, so we conclude that this is one of the few papers in the literature to evaluate a gender difference in the intestinal absorption of humans based on an epidemiological study.

Background : Consumption of flavonoid-rich orange juice has been shown to reduce adiposity and liver steatosis in murine models of diet-induced obesity. However, little is known about the effects of whole orange intake, independent of body weight changes, on liver function and steatosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). The goal is to understand the direct impact of orange consumption on metabolic health. Methods : Sixty-two men and women aged 30-65 with MASLD (Controlled Attenuation Parameter, (CAP) > 275 dB/m) were randomly assigned to consume either 400 g of whole oranges or non-citrus fruits daily for 4 weeks. Baseline evaluations included medical assessments, blood tests, and body composition. Liver health was assessed using transient elastography (FibroScan ® ) for steatosis and fibrosis, conducted by blinded personnel. This clinical trial was registered at ClinicalTrials.gov (NCT05558592). Results : After 4 weeks of orange supplementation, liver steatosis decreased in the treatment group, with 70.9% showing steatosis compared to 100% in controls ( p < 0.004), indicating a 30% reduction in liver disease prevalence. There were no significant changes in fibrosis or plasma liver enzymes, though plasma gamma glutaril transferase (GGT) levels decreased significantly. Body weight, waist circumference, body composition, lipid profile, fasting glucose, insulin, and C-reactive protein levels remained unchanged. Dietary analysis revealed no change in caloric intake, but vitamins C, A, thiamine, and riboflavin increased in the orange group. Conclusions : Our findings suggest that phytochemical-rich foods, especially whole fruits like oranges, may enhance liver function as an adjunct treatment for MASLD. The notable reduction in liver steatosis prevalence occurred independently of body weight changes. Further studies are needed to investigate the long-term effects of orange supplementation on steatosis and fibrosis progression and to identify the specific bioactive compounds and mechanisms involved.

(1) Background: Metabolic dysfunction-associated liver disease (MASLD) is one of the most important causes of liver disease worldwide. Meat consumption is a growing trend and white meat has been shown to have beneficial effects on cardiometabolic risk factors. The aim of this study was to investigate the dose-response relationship between white meat intake and MASLD at survey level in a Southern Italy setting. (2) Methods: This cross-sectional study encompassed 1192 subjects (509 males, 42.7%) without missing data from the second wave of the NUTRIHEP cohort (2014-2016). Adjusted dose-response modeling was employed for statistical analysis; (3) Results: There were 587 subjects with MASLD (49.2%), i.e., 278 males (54.6%) and 309 females (45.2%). By increasing the intake, an unfavorable influence of white meat on MASLD was significantly revealed in females, whereas a protective effect of white meat was detectable in males. Male sex was shown to be involved in other associations in this study, such as influencing the preference for specific foods such as poultry and chicken skin. (4) Conclusions: Our data suggest that white meat does not have a clear-cut independent dose-response effect on MASLD, but sex may be a trigger moderator for age and BMI, with an increasing unfavorable effect of white meat in women, and a favorable effect in men.

This study, employing an interim analysis, investigates the effects of the Dermamecum protocol, a structured educational and tailored approach that stratifies ostomy patients into risk paths (green, yellow, red) based on pre-operative and post-operative characteristics. The green path indicates a low risk of peristomal skin complications (PSCs), focusing on sustaining healthy behaviours and basic stoma care. The yellow path represents a moderate risk, emphasizing the need for patients to self-monitor and recognize early signs of complications. The red path corresponds to high risk, requiring stringent monitoring and immediate access to healthcare support. The study aims to reduce PSCs and improve patient outcomes. Methods include the stratification of 226 patients, with significant differences in gender distribution, BMI categories, and stoma types across the paths. Results show an occurrence rate of PSCs of 5.9% in all risk paths (5.7% green path, 4.7% yellow path, and 7.9% red path, p = 0.685), significantly lower than the median rate of 35% reported in the literature. Multiple correspondence analysis validated the stratification, with distinct clusters for each path. Poisson regression models in the exploratory framework of an interim analysis identified male gender as the only significant predictor of PSCs, indicating the need for gender-specific interventions. The findings suggest that the Dermamecum protocol effectively reduces early PSCs, providing a foundation for further research.

Background: Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA., Methods: Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids., Results: Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells., Conclusions: The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis., (© 2024. The Author(s).)

Background: The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. Methods: rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. Results: Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., p = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., p = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (β = 0.10, -0.003 to 0.12 95% C.I., p = 0.04) on diabetes, but only in TT genotypes. Conclusions: The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD.

Background: Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients., Methods: This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers., Results: The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS., Conclusion: The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum., Gov Identifier: NCT03387592., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background/Objectives : Constrictive pericarditis very rarely causes protein-losing enteropathy (PLE) induced by secondary intestinal lymphangiectasia. This study thoroughly reviewed the literature to shed light on the clinical management of PLE provoked by intestinal lymphangiectasia following constrictive pericarditis. Methods : We performed a PubMed search using the keywords enteropathy, protein-losing enteropathy, pericarditis, acute pericarditis, pericardial effusion, recurrent pericarditis, constrictive pericarditis, noninfectious pericarditis, idiopathic pericarditis, and infective pericarditis, with only English-language publications included. Results : Although constrictive pericarditis is primarily idiopathic, less common causes include infectious etiologies, connective/autoimmune tissue disorders, previous cardiac surgery, congenital syndromes, and cancer. On the one hand, PLE secondary to intestinal lymphangiectasia may cause a severe cellular immune deficiency that could raise infection hazards due to lymphocytopenia and hypogammaglobulinemia. On the other hand, lymphocytopenia may cause anergy and mask an underlying tuberculous etiology of constrictive pericarditis. Cardiac catheterization is the most useful diagnostic tool for constrictive pericarditis, though it may be misdiagnosed in rare cases. The videocapsule endoscopy and double-balloon enteroscopy techniques can detect small bowel lymphangiectasias distal to the Treitz ligament. MRI or a CT scan helps confirm constrictive pericarditis, visualize lymphangiectasias, and reveal features specific to the underlying etiology of PLE. Radioisotopic techniques may ensure PLE diagnosis in challenging cases, whereas fecal alpha1-antitrypsin can estimate gastrointestinal protein loss. Conclusions : Constrictive pericarditis is rarely associated with PLE. The cardio-intestinal abnormalities of PLE caused by constrictive pericarditis are frequently reversed following a complete pericardiectomy, though its ability to invert severe hypoalbuminemia is currently unknown.