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Background: The role of metabolic dysfunction-associated steatotic liver disease (MASLD) in sleeve gastrectomy (SG)-related outcomes remains uncertain. In this study, we aimed to assess the influence of preoperative biopsy-proven MASLD and its stages on weight loss after SG., Methods: One hundred sixty-three patients with obesity undergoing SG with concomitant intraoperative liver biopsy were followed up for 1 year. Fifty-eight participants were categorized as no MASLD, thirty-eight as metabolic dysfunction-associated steatotic liver (MASL), and sixty-seven as metabolic dysfunction-associated steatohepatitis (MASH). Percentage total weight loss (%TWL) and percentage excess weight loss (%EWL) 1 year after SG were calculated for the different groups. We also evaluated the association between preoperative MASLD (and its stages) and weight loss, after adjusting for potential confounders., Results: Significant differences among groups were detected in %EWL ( p = 0.004, ANOVA test), but not in %TWL ( p = 0.079). However, significant differences in %TWL were found when MASH and no MASH (i.e., participants with MASL and participants without MASLD) groups were compared (27.3 ± 9.9 vs. 30.7 ± 9, respectively, p = 0.025). In the linear regression model for predicting %EWL 1 year after SG, the presence of MASH was independently associated with a lower %EWL, after adjusting for age, sex, baseline body mass index (BMI), and baseline glycated hemoglobin (HbA1c) (Beta -7.1; 95% CI -13.6, -0.5; p = 0.035). The presence of MASLD, liver fibrosis, or advanced liver fibrosis (≥F2) was also associated with lower %EWL after SG in crude models, although they did not remain significant after adjusting for these confounders. The presence of MASH was inversely related to %TWL, although the association did not remain significant after adjustment (Beta -2.7; 95% CI -5.7, 0.2; p = 0.069)., Conclusions: MASH may be independently associated with lower %EWL 1 year after SG in patients with obesity.

Background: Colorectal cancer (CRC) continues to be a major health concern in today's world. Despite conflictive findings, evidence supports systemic inflammation's impact on CRC patients' survival rates. Therefore, this study aims to assess the prognostic role of the innate immune system in patients with CRC., Method: A total of 449 patients were included, with a 5-year follow-up period, and absolute neutrophil counts and their related ratios were measured., Results: The non-survival group had increased levels of white blood cells, neutrophils (both p <0.001), and monocytes (p=0.038), compared to the survival group, along with other neutrophil-related ratios. We observed increased mortality risk in patients in the highest tertile of white blood cells [HR=1.85 (1.09-3.13), p<0.05], neutrophils [HR=1.78 (95% CI: 1.07-2.96), p<0.05], and monocytes [HR=2.11 (95% CI: 1.22-3.63)], compared to the lowest tertile, after adjusting for all clinicopathological variables. Random forest analysis identified neutrophils as the most crucial variable in predicting survival rates, having an AUC of 0.712, considering all clinicopathological variables. A positive relationship between neutrophil counts and metastasis was observed when neutrophil counts are considered continuous (β=0.92 (0.41), p<0.05) and tumor size (width) when neutrophils were considered as logistic variable (T1 vs T3) [OR=1.42, (95% CI: 1.05-1.98), p<0.05]., Conclusion: This study offers comprehensive insights into the immune factors that impact the prognosis of CRC, emphasizing the need for personalized prognostic tools., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Garcia-Flores, Dawid De Vera, Pilo, Rego, Gomez-Casado, Arranz-Salas, Hierro Martín, Alcaide, Torres, Ortega-Gomez, Boughanem and Macias-Gonzalez.)

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem due to the increased obesity rates, among other factors. In its more severe stage (NASH), inflammation, hepatocellular ballooning and fibrosis are present in the liver, which can further evolve to total liver dysfunction or even hepatocarcinoma. As a metabolic disease, is associated to environmental factors such as diet and lifestyle conditions, which in turn can influence the epigenetic landscape of the cells, affecting to the gene expression profile and chromatin organization. In this study we performed ATAC-sequencing and RNA-sequencing to interrogate the chromatin status of liver biopsies in subjects with and without NASH and its effects on RNA transcription and NASH etiology. NASH subjects showed transcriptional downregulation for lipid and glucose metabolic pathways (e.g., ABC transporters, AMPK, FoxO or insulin pathways). A total of 229 genes were differentially enriched (ATAC and mRNA) in NASH, which were mainly related to lipid transport activity, nuclear receptor-binding, dicarboxylic acid transporter, and PPARA lipid regulation. Interpolation of ATAC data with known liver enhancer regions showed differential openness at 8 enhancers, some linked to genes involved in lipid metabolism, (i.e., FASN) and glucose homeostasis (i.e., GCGR). In conclusion, the chromatin landscape is altered in NASH patients compared to patients without this liver condition. This alteration might cause mRNA changes explaining, at least partially, the etiology and pathophysiology of the disease., 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 Masson SAS.)

Background/aim: Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate gut microbiota composition and functionality in patients with morbid obesity with different degrees of MAFLD, as assessed by biopsy., Subjects/methods: 110 patients with morbid obesity were evaluated by biopsy obtained during bariatric surgery for MAFLD. Stool samples were collected prior to surgery for microbiota analysis., Results: Gut microbiota from patients with steatosis and non-alcoholic steatohepatitis (NASH) were characterized by an enrichment in Enterobacteriaceae (an ethanol-producing bacteria), Acidaminococcus and Megasphaera and the depletion of Eggerthellaceae and Ruminococcaceae (SCFA-producing bacteria). MAFLD was also associated with enrichment of pathways related to proteinogenic amino acid degradation, succinate production, menaquinol-7 (K2-vitamin) biosynthesis, and saccharolytic and proteolytic fermentation. Basic histological hepatic alterations (steatosis, necroinflammatory activity, or fibrosis) were associated with specific changes in microbiota patterns. Overall, the core microbiome related to basic histological alterations in MAFLD showed an increase in Enterobacteriaceae and a decrease in Ruminococcaceae. Specifically, Escherichia coli was associated with steatosis and necroinflammatory activity, whilst Escherichia-shigella was associated with fibrosis and necroinflammatory activity., Conclusions: We established a link between gut microbiota alterations and histological injury in liver diagnosis using biopsy. Harmful products such as ethanol or succinate may be involved in the pathogenesis and progression of MAFLD. Thus, these alterations in gut microbiota patterns and their possible metabolic pathways could add information to the classical predictors of MAFLD severity and suggest novel metabolic targets., (© 2024. The Author(s).)

In the last decade, the role of the microbiota-gut-brain axis has been gaining momentum in the context of many neurodegenerative and metabolic disorders, including Alzheimer's disease (AD) and diabetes, respectively. Notably, a balanced gut microbiota contributes to the epithelial intestinal barrier maintenance, modulates the host immune system, and releases neurotransmitters and/or neuroprotective short-chain fatty acids. However, dysbiosis may provoke immune dysregulation, impacting neuroinflammation through peripheral-central immune communication. Moreover, lipopolysaccharide or detrimental microbial end-products can cross the blood-brain barrier and induce or at least potentiate the neuropathological progression of AD. Thus, after repeated failure to find a cure for this dementia, a necessary paradigmatic shift towards considering AD as a systemic disorder has occurred. Here, we present an overview of the use of germ-free and/or transgenic animal models as valid tools to unravel the connection between dysbiosis, metabolic diseases, and AD, and to investigate novel therapeutical targets. Given the high impact of dietary habits, not only on the microbiota but also on other well-established AD risk factors such as diabetes or obesity, consistent changes of lifestyle along with microbiome-based therapies should be considered as complementary approaches.

DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)-a DNA repair enzyme-may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants ( p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients ( p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients ( p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.

Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury (DILI) could share molecular mechanisms involving the immune system. We aimed to identify activation immunological biomarkers in invariant natural killer T (iNKT) and CD4/CD8+ T cells in NAFLD and DILI., Methods: We analyzed the activation profile (CD69, CD25, and HLA-DR) and natural killer group 2 member D (NKG2D) on iNKT cells, and CD4/CD8 T cells in peripheral blood mononuclear cells from NAFLD, with or without significant liver fibrosis, and DILI patients., Results: There was an increase in iNKT cells in NAFLD patients compared to DILI or control subjects. Regarding the cellular activation profile, NAFLD with significant liver fibrosis (F ≥ 2) displayed higher levels of CD69+iNKT cells compared to NAFLD with none or mild liver fibrosis (F ≤ 1) and control patients. CD69+iNKT positively correlated with insulin resistance, aspartate aminotransferase (AST) level, liver fibrosis-4 index (FIB4) and AST to Platelet Ratio Index (APRI). DILI patients showed an increase in CD69+ and HLA-DR+ in both CD4+ and CD8+ T cells, detecting the most relevant difference in the case of CD69+CD8+ T cells., Conclusions: CD69+iNKT may be a biomarker to assess liver fibrosis progression in NAFLD. CD69+CD8+ T cells were identified as a potential distinctive biomarker for distinguishing DILI from NAFLD.

Introduction: Vitamin D has been widely associated with colorectal cancer (CRC) through different insights. This study aims to explore the association between serum 25-hydroxyvitamin D (25(OH)D) and the global DNA methylation in tumor from CRC patients., Methods and Results: A genome-wide DNA methylation analysis is conducted in 20 CRC patients under categorical (10 patients have 25(OH)D <30 ng mL -1 ; 10 patients with 25(OH)D ≥30 ng mL -1 ) and continuous models of 25(OH)D. A total of 95 differentially methylated CpGs (DMCpGs) are detected under the categorical model (false discovery rate (FDR) < 0.05), while 16 DMCpGs are found under the continuous model. Regional analysis showed eight vitamin D-associated differentially methylated regions (DMR). Between them, a DMR is the most significant at cAMP-Dependent Protein Kinase Inhibitor Alpha (PKIA) locus. Furthermore, seven genes, including PKIA gene, have more or equal than two significant DMCpGs. The protein networking analysis found pathways implicated in cell adhesion and extracellular matrix, as well as signaling transduction., Conclusions: This study identifies novel epigenetic loci associated with serum 25(OH)D status. Interestingly, also, a positive association between vitamin D and DNA methylation in the CRC context is found, suggesting a role in CRC. Further studies are warranted to clarify and replicate these results., (© 2021 Wiley-VCH GmbH.)

Gastric cancer (GC) is one of the leading causes of cancer-related death. The combination of new molecular classifications with clinicopathological data could contribute to the individualization of patients and to the development of new therapeutic strategies. We examined the various associations in two molecular types of GC: HER2-positive (human epidermal growth factor receptor 2) and microsatellite instability (MSI), assessing their influence on treatment and prognosis. A retrospective study of 142 GC patients was performed with molecular characterization through HER2 overexpression and DNA repair protein expression for MSI. The percentage of HER2-positive tumors was 13.4%, predominantly in men. Correlations were found with intestinal type, metastases, advanced stages and chemotherapy. Almost 75% of HER2-positive patients died. MSI occurred in 16.2%, associated with advanced age, female sex, distal location and intestinal type. These patients had few metastases and low stages. The percentage of deaths was higher among MSI patients who received perioperative chemotherapy. The determination of HER2 and MSI status in GC is important for their association with specific clinicopathological features and for their prognostic and predictive value.

Recent studies suggest that long-interspersed nucleotide element-1 ( LINE-1 ) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of LINE-1 methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect LINE-1 methylation. Thus, the aim of this study was to assess the prognostic value of tumor LINE-1 methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor LINE-1 methylation, as well as pathological and oncological variables. We also studied the association between LINE-1 methylation and pathological features, and finally, we assessed the overall and disease-free survival of LINE1 methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. LINE-1 was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area ( p < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, LINE-1 methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated LINE-1 tumors than those with normal LINE-1 methylation ( p = 0.004 and 0.0049, respectively). Indeed, LINE-1 was hypermethylated more in the treated patients than in the non-treated patients ( p < 0.05). The present study showed that tumor LINE-1 hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor LINE-1 methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.

We operated on a 23-year-old black Nigerian man with a 4-year history of a tumour on the left cheek associated with IgE hypergammaglobulinaemia and peripheral eosinophilia. The lesion recurred.

Background: Porokeratosis (PK) is a group of cutaneous entities characterized by disordered epidermal keratinization and by a predisposition to develop malignant transformation. The molecular mechanism of this carcinogenesis remains unclear, but p53 has been proposed as a mediator of this process. p53 overexpression, detected by immunohistochemistry, has frequently been reported in PK, and p53 mutations are direct results of ultraviolet (UV) skin exposure and are directly involved in most common skin cancers., Methods: Eleven cases of Mibelli-type PK, one of them associated with a squamous cell carcinoma, were reviewed. Formalin-fixed, paraffin-embedded archival tissue from these cases was immunostained for p53 and used for DNA extraction for the analysis of p53 mutations by polymerase chain reaction and single-strand conformation polymorphism., Results: Increased p53 expression was confirmed in all cases. Most of them showed a discontinuous labeling, often stronger at the base of the cornoid lamella. No relation with sun exposure was observed. Finally, no p53 mutations were found at the gene levels more frequently damaged in human cancers called "hot spots"., Conclusions: p53 alterations can be involved in the pathogenesis of the PK and the carcinogenesis arising in some of the lesions. Since p53 gene inactivation in human cancer is related to mutation and/or loss, the absence of genetic damage could indicate that p53 alterations are only at the protein level, leading to an abnormal cell-cycle control. UV exposure does not seem to play a main role in the process.