👤 Nathan Joyce

Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4-1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM-SNAC (1:33 w/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, p < 0.05) and depleted primary fermenters in Muribaculaceae (-62%) and Bacteroidaceae (-77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (-77% SNAC, -75% SEM-SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked Muribaculaceae and Bacteroidaceae loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery. Show less

Over 10 million patients undergoing non-cardiac surgery each year face major cardiovascular complications within 30 days, many due to destabilized atherosclerotic plaques. Reverse cholesterol transport (RCT), driven by HDL and Apoa1, protects against plaque progression, but the effects of surgical inflammation on this pathway remain unclear. Using an abdominal laparotomy model in ApoE Show less

The prognostic impact of PICALM::MLLT10 status in childhood leukaemia is not well described. Ten International Berlin Frankfurt Münster-affiliated study groups and the Children's Oncology Group collaborated in this multicentre retrospective study. The presence of the PICALM::MLLT10 fusion gene was confirmed by fluorescence in situ hybridization and/or RNA sequencing at participating sites. Ninety-eight children met the study criteria. T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML) predominated 55 (56%) and 39 (40%) patients, respectively. Most patients received a chemotherapy regimen per their disease phenotype: 58% received an ALL regimen, 40% an AML regimen and 1% a hybrid regimen. Outcomes for children with PICALM::MLLT10 ALL were reasonable: 5-year event-free survival (EFS) 67% and 5-year overall survival (OS) 76%, but children with PICALM::MLLT10 AML had poor outcomes: 5-year EFS 22% and 5-year OS 26%. Haematopoietic stem cell transplant (HSCT) did not result in a significant improvement in outcomes for PICALM::MLLT10 AML: 5-year EFS 20% for those who received HSCT versus 23% for those who did not (p = 0.6) and 5-year OS 37% versus 36% (p = 0.7). In summary, this study confirms that PICALM::MLLT10 AML is associated with a dismal prognosis and patients cannot be salvaged with HSCT; exploration of novel therapeutic options is warranted. Show less

The generation of a functional, self-tolerant T cell receptor (TCR) repertoire depends on interactions between developing thymocytes and antigen-presenting thymic epithelial cells (TECs). Cortical TECs (cTECs) rely on unique antigen-processing machinery to generate self-peptides specialized for T cell positive selection. In our current study, we focus on the lipid kinase Vps34, which has been implicated in autophagy and endocytic vesicle trafficking. We show that loss of Vps34 in TECs causes profound defects in the positive selection of the CD4 T cell lineage but not the CD8 T cell lineage. Utilizing TCR sequencing, we show that T cell selection in conditional mutants causes altered repertoire properties including reduced clonal sharing. cTECs from mutant mice display an increased abundance of invariant chain intermediates bound to surface MHC class II molecules, indicating altered antigen processing. Collectively, these studies identify lipid kinase Vps34 as an important contributor to the repertoire of selecting ligands processed and presented by TECs to developing CD4 T cells. Show less