Dementia with Lewy bodies (DLB) shares substantial clinical and molecular features with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD), complicating the identification of disease-specific molecular alterations. This study aimed to characterize transcriptomic differences among these disorders and to integrate expression findings with published Lewy body dementia (LBD) genetic evidence. Gene-level expression profiles from 42 postmortem prefrontal cortex samples in GSE150696, including controls, AD, DLB, and PDD, were analyzed using age- and sex-adjusted empirical-Bayes models with false discovery rate (FDR) correction, followed by sensitivity analyses, post hoc exploratory candidate selection, and integration with an external LBD multi-omics gene-prioritization dataset. No gene reached FDR < 0.05 in the DLB-versus-AD comparison. In contrast, SLC19A2, VAMP1, and COX5B were lower in DLB than in PDD and were FDR-supported in the primary age- and sex-adjusted model, although their statistical significance was partly model-dependent. A post hoc cross-disease analysis identified 60 exploratory candidates, of which SYT11 was the only gene overlapping with the published LBD-prioritized gene set. The overall 60-gene set was not significantly enriched for LBD-associated genes. These findings did not demonstrate broad robust disease-disease differences and are consistent with substantial molecular overlap, while remaining compatible with limited statistical power. A limited number of transcriptomic candidates, including the exploratory SYT11 overlap, warrant independent validation.
Desmoid tumors (DTs) may be sporadic or associated with familial polyposis syndromes, including familial adenomatous polyposis (FAP) and its variant, Gardner syndrome (GS). DTs are pathogenetically linked to activation of the Wnt/beta-catenin signaling pathway. In sporadic DT, CTNNB1 is most frequently implicated, with exon 3 somatic mutations (T41A, S45F and S45P) being the most commonly reported. APC is implicated in FAP/GS-associated DTs and occasionally in sporadic DT, most often through alterations involving the exon 15 mutation cluster region. In this study of five sporadic intra-abdominal DTs, we identified uncommon somatic missense mutations in three cases involving APC (exons 2 and 13), LRP6 (exon 3) and TCF7L2 (exons 3, 6, 8 and 10). One case harbored the canonical activating CTNNB1 exon 3 p.S45P mutation, whereas another one case showed no detectable genomic alterations. Multi-algorithm in silico assessment using AlphaMissense, REVEL, CADD, SIFT and PolyPhen-2 provided supportive computational evidence for potential functional effects of several variants, particularly TCF7L2 p.P113L, p.R243W and p.C337Y, and CTNNB1 p.S45P, while predictions were variable for other variants. All five tumors arose intra-abdominally and presented as abdominal emergencies requiring surgical intervention. During a median follow-up of 24 months (range, 18-68 months), four patients remained recurrence-free, whereas one case developed multifocal intra-abdominal recurrence approximately five years after the initial resection and underwent repeat surgery. These findings broaden the spectrum of Wnt/beta-catenin pathway alterations observed in intra-abdominal DTs, although the functional consequences of the uncommon variants require experimental validation.
Purine metabolism and oxidative stress are increasingly recognized as important contributors to ischemic brain injury following acute ischemic stroke (AIS). Although uric acid has been extensively investigated because of its dual antioxidant and pro-oxidant properties, comparatively limited data exist regarding the prognostic relevance of upstream purine metabolites such as xanthine and hypoxanthine. The present study aimed to evaluate the association between serum uric acid, xanthine, and hypoxanthine concentrations and neurological severity and functional outcome following AIS. We performed a prospective observational cohort study including 143 consecutive patients admitted with acute ischemic stroke in a tertiary neurological center. Neurological severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), while functional outcome was evaluated using the modified Rankin Scale (mRS) at discharge and at 3-month follow-up. Plasma xanthine and hypoxanthine concentrations were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology. Distribution normality was assessed using Shapiro-Wilk and Kolmogorov-Smirnov testing. Comparative analyses were performed using Student's t-test, the Mann-Whitney U test, and the Kruskal-Wallis test, according to the distribution and measurement scale of the variables. Correlations were assessed using Spearman's rank correlation coefficient and visualized using a heatmap. Receiver operating characteristic (ROC) curve analysis and multivariable logistic regression models were additionally performed in order to evaluate the predictive performance of purine metabolism biomarkers for unfavorable functional outcome. Numerically lower serum uric acid concentrations were observed in patients with poorer functional outcomes at discharge and at 3 months, although these differences were not statistically significant. Hypoxanthine concentrations varied significantly according to admission NIHSS severity categories (p = 0.022), with lower values observed among patients presenting severe neurological deficits. Plasma xanthine concentrations demonstrated significant association with unfavorable long-term functional outcome (p = 0.033) and exhibited the highest predictive performance in ROC analysis (AUC = 0.614). In the adjusted multivariable logistic regression model, admission NIHSS remained the main independent predictor of unfavorable 3-month functional outcome, whereas xanthine and the other purine biomarkers did not retain statistically significant independent associations. Purine metabolism biomarkers showed exploratory associations with neurological severity and functional outcome, but the underlying biological mechanisms were not directly assessed. Simultaneous assessment of uric acid together with xanthine and hypoxanthine may provide additional insight into stroke severity and neurological recovery, supporting the potential role of purine metabolism profiling as a complementary biomarker approach in acute ischemic stroke.
Enterotoxigenic Bacteroides fragilis (ETBF) secretes Bacteroides fragilis toxin (BFT), a metalloprotease that disrupts intestinal epithelial integrity and activates pro-inflammatory signaling. Although E-cadherin cleavage is a well-established response to BFT, the involvement of other membrane receptors in BFT-induced signaling remains poorly defined. In this study, we examined whether HER2 undergoes proteolytic processing following BFT exposure and whether HER2 contributes to BFT-induced ERK activation. In HT29/c1 and MCF-7 epithelial cells, BFT induced the loss of full-length 185 kDa HER2 and the generation of a membrane-tethered similar to 95 kDa fragment. This truncated HER2 underwent gamma-secretase-dependent intramembrane processing and subsequent proteasomal degradation. Knockdown of MMP-7 or ADAM10 did not prevent HER2 cleavage, indicating that neither protease is required for this process. In addition, BFT-induced ERK phosphorylation was observed in HER2-expressing cells but was abolished in HER2-deficient HT29/c1 clones, whereas E-cadherin cleavage and IL-8 secretion remained detectable. These findings identify HER2 as a previously unrecognized target of BFT-induced proteolytic remodeling and support a contribution of HER2 to BFT-induced ERK activation.
Carnivorous plants, such as Nepenthes (Nepenthaceae), possess a unique feature: the external digestion of animal-origin food. Nepenthes & times; ventrata pitchers are filled with digestive fluid containing: enzymes, small regulatory compounds and reactive oxygen species (ROS), which also act as signalling molecules. The aim of this study was to investigate the pattern of ROS content and to characterise enzymatic and non-enzymatic ROS modulators in the digestive fluid of N. & times; ventrata at various developmental stages of the pitcher. Significant changes were observed in the levels of hydrogen peroxide (H2O2) and hydroxyl radical (center dot OH) throughout trap development. The highest concentration of H2O2 was found in aged pitchers, while the highest level of center dot OH was recorded in freshly opened immature traps. These findings corresponded with superoxide dismutase and class III peroxidase activities. After maturation of the trap, there was an increase in the activity of diamine and polyamine oxidases. We suggest that the production of ROS in the digestive fluid of pitcher plants at different stages of trap development is controlled by the redox modulatory system. These findings provide a basis for further research into how the regulation of ROS content supports trap development and digestive functions.
