Maikel Petrus Peppelenbosch

Objectives: To evaluate the roles of intracellular acid phosphatase 1 (ACP1) and ACP3 expression as biomarkers of prostate cancer progression through a systematic review and meta‐analysis assessing associations with disease presence, tumour aggressiveness, and patient prognosis. Patients and Methods: A systematic review and meta‐analysis were conducted to assess the associations between ACP1 and ACP3 expression and clinical outcomes, including disease presence, Gleason grade, tumour stage, lymph node involvement, and patient survival in prostate cancer. Results: Prostate cancer tissues showed reduced ACP3 expression (odds ratio [OR] 0.30, P = 0.006), and low intracellular ACP3 expression was associated with higher Gleason grade (OR 0.44, P = 0.031), advanced tumour stage, lymph node involvement, and poorer survival. In contrast, preliminary evidence from a limited number of studies indicated that patients more frequently showed elevated ACP1 expression (hazard ratio [HR] 2.24, P < 0.001), which correlated with aggressive pathological features, including high Gleason grade (HR 3.75, P < 0.001), advanced stage, lymph node metastasis, and poor patient survival. Conclusion: Acid phosphatase 3 functions as a favourable prognostic biomarker, whereas ACP1 acts as a potential negative prognostic indicator in prostate cancer. Further research is warranted to elucidate their divergent roles and support their utility in biomarker‐driven risk stratification and precision oncology.

Background: Esophageal submucosal glands (SMGs) contribute to mucosal defense through bicarbonate, mucin, and reparative-factor secretion. Chronic reflux may impair these functions and remodel the glandular compartment, potentially linking SMG injury to reflux esophagitis, Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC). Objective: To map the human, animal, and in vitro literature on the physiological and pathological roles of esophageal SMGs and to identify evidence gaps relevant to reflux injury, BE, EAC, and endoscopic therapy. Methods: This scoping review was reported in accordance with PRISMA-ScR. Embase, Web of Science, PubMed, and Google Scholar were searched from inception to 15 January 2025. Two reviewers independently screened records against prespecified eligibility criteria. The protocol was not registered. Results: The review included 97 full-text publications and 7 conference abstracts. The full-text set comprised 89 original studies and 8 reviews; review articles were used for context and citation tracing rather than counted as independent primary evidence. The mapped literature supports secretory and reparative functions of SMGs and documents injury-associated remodeling, including loss of mucinous acini and expansion of atrophic, oncocytic, or duct-like phenotypes. Marker expression, spatial continuity, and clonal observations are compatible with glandular participation in repair and Barrett-associated biology, but do not establish a unique cell of origin and lineage relationships remain unresolved. Conclusions: Esophageal SMGs occupy a plausible interface between mucosal protection and pathological plasticity. The most consequential gaps are the lack of longitudinal human evidence, source-resolved lineage information, standardized reporting of glandular phenotypes, and human models that reproduce reflux exposure and the stromal niche.

Background/Objectives: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease frequently requiring liver transplantation (LTx). The gut–liver axis, host genetics, and microbial dysbiosis are thought to contribute to disease progression and post-transplant outcomes. The FUT2 rs601338 polymorphism influences mucosal fucosylation, host–microbial interactions, and susceptibility to infection. This study aimed to investigate the association between FUT2 genotype, colonic mucosal microbiome composition, post-transplant bacteremia, and all-cause mortality in a retrospective single-center PSC cohort. Methods: This retrospective cohort study included PSC patients who underwent LTx at Erasmus MC University Medical Center (Rotterdam, The Netherlands) between 1987 and 2015. Pre-transplant archival formalin-fixed paraffin-embedded (FFPE) colonic biopsy specimens were available for microbiome analysis. Of 169 transplanted patients, FFPE tissue was available for 98 individuals, and FUT2 rs601338 genotyping was successfully performed in 87 patients. Patients were classified as FUT2 non-secretors (AA, n = 28) and secretors (GA/GG, n = 59). Post-transplant bacteremia was assessed based on clinically indicated blood cultures during follow-up. Colonic mucosal microbiome composition was analyzed using 16S rRNA gene sequencing. Results: FUT2 non-secretors showed a distinct colonic mucosal microbiome profile compared with secretors, characterized by differential abundance of selected taxa within Proteobacteria, Firmicutes, and Bacteroidetes. Post-transplant bacteremia occurred in 30 patients and was more frequent among non-secretors (43%) compared with secretors (15%). Both FUT2 non-secretor status and post-transplant bacteremia were associated with reduced all-cause post-transplant survival in Kaplan–Meier analysis and remained associated with mortality in multivariable regression models. Specific microbial taxa were also showed associations with bacteremia, mortality, and established prognostic scores, including the Amsterdam–Oxford Model and Mayo Risk Score. Conclusions: FUT2 genotype is associated with alterations in colonic mucosal microbiome composition, post-transplant bacteremia, and all-cause mortality in PSC patients undergoing liver transplantation. These findings suggest a potential interplay between host genetics, intestinal microbiota, and infectious complications after transplantation. Given the retrospective design, limited sample size, and use of archival FFPE tissue, all findings should be interpreted as exploratory and hypothesis-generating. Prospective multicenter studies using standardized sampling and high-resolution metagenomic approaches are warranted for validation.

Helicobacter pylori ( H. pylori ) infects the gastric epithelium of approximately half of the global population, and is a well-known risk factor for developing gastric cancer. Despite the clinical significance of H. pylori infection, many genetic factors that contribute to susceptibility remain unidentified. While it is well-established that H. pylori infection can result in gastritis and peptic ulcers, which may progress to gastric cancer, its causal link to other diseases remains unclear. We performed the genome-wide association study (GWAS) for anti- H. pylori IgG antibody titers, which were validated as a surrogate marker for H. pylori infection by the correlation with clinical traits, followed by gene-based and pathway analyses, involving up to 140,863 individuals. This included 56,967 in the discovery phase, and 68,211 in the replication phase from Japanese cohorts, and an additional 15,685 from European populations in a cross-ancestry meta-analysis. We reveal significant associations between H. pylori infection and polymorphisms in the Human Leukocyte Antigen (HLA) class II region within the Major Histocompatibility Complex (MHC), as well as genes related to innate immunity, including CCDC80 , NFKBIZ , TIFA , PSCA , and TRAF3 . Mendelian randomization (MR) analysis revealed that genetic liability to H. pylori infection has both positive and negative causal relationships with a variety of diseases, including autoimmune-related diseases such as Type 1 diabetes, Hashimoto’s disease, atopic dermatitis, as well as traits like body height and weight. These genetic findings strongly support the notion that genetic liability to H. pylori infection influences not only gastrointestinal diseases, but also a broader spectrum of health issues, thereby providing valuable insights for public health strategies and personalized medicine approaches.

RNF43 is best known for removing the Wnt-receptor complex from the cell surface, thereby maintaining Wnt-signaling at minimal essential levels. Recent studies reported that RNF43-mutant colorectal cancers carrying the common BRAFV600E mutation, respond more effectively to combined BRAF/EGFR inhibition. To determine whether RNF43 directly regulates EGFR or BRAF protein abundance, multiple pancreatic and colorectal cancer cell line models were generated in which RNF43 was knocked out, repaired, or stably overexpressed. Total and cell surface EGFR levels, as well as endogenous BRAF expression, were quantified. Across all models, no consistent evidence emerges that RNF43 modulates endogenous EGFR or BRAF levels. R-spondins likewise fail to alter EGFR levels or internalization. Notably, elevated EGFR expression observed in a subset of RNF43 knockout clones is induced by unintended CRISPR/Cas9 vector integration rather than the absence of RNF43 itself, highlighting a previously underappreciated artefact that can confound interpretations of EGFR regulation in genome edited lines. Overall, the data argue against a direct and general role for RNF43 in controlling EGFR or BRAF protein abundance, contradicting recent reports that propose degradation of these targets. Further studies are required to resolve these discrepancies and clarify the mechanistic basis underlying these conflicting observations.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the intra- and extrahepatic bile ducts, and is often associated with inflammatory bowel disease (IBD)