Background: The newly onset debate surrounding the risk of gastric cancer (GC) in autoimmune gastritis (AIG) and pernicious anaemia has intensified. It is necessary to supplement higher level research evidences to settle this issue.
Methods: Two-sample Mendelian randomization (MR) analysis using inverse variance weighted method was conducted to reveal the causal relationship between pernicious anaemia and GC. Because of the absence of available summary statistics for AIG at present, we used pernicious anaemia as a proxy exposure, as it was frequently used interchangeably. The multi-omics characteristics of AIG and pernicious anaemia were further explored through proteome-wide MR, colocalization, and transcriptome sequencing analysis.
Results: MR analysis found pernicious anaemia was causally associated with a higher risk of GC (odds ratio: 1.16, 95% confidence interval [1.03, 1.31], p = .018). Sensitivity analyses confirmed the stability of the results. The up-regulation of genes involved in gastric dysplasia and carcinogenesis, including receptor activity-modifying protein 3, fibroblast growth factor 3, transforming growth factor beta-2 and tumour-associated calcium signal transducer 2, suggested potential mechanisms underlying the risk of GC in AIG.
Conclusions: These results emphasized the independent link fromAIG and pernicious anaemia to GC. Therefore, endoscopy follow-up for GC screening in AIG is still appealed.
The heterodimeric complex of S100 calcium binding proteins A8 and A9 (S100A8/A9, also known as Calprotectin) is constitutively expressed in myeloid neutrophils and monocytes and plays a role in the modulation of the inflammatory response and cytoskeleton rearrangement. Recently, S100A8/A9 complex has garnered significant attention as a critical alarmin involved in regulating the pathogenesis of various inflammatory cardiovascular diseases, particularly nonischaemic cardiomyopathy (NICM). Furthermore, S100A8/A9 is reportedly associated with the pathophysiological processes of myocardial ischaemia‒reperfusion injury and has also been recognised as a predictor and a potentialmediator of heart failure caused by acutemyocardial infarction. Recent studies have attempted to provide a comprehensive and detailed overview of the involvement of the S100A8/A9 protein in NICM, covering topics such as hypertrophicmyocardial remodelling, septic and dilated cardiomyopathy,myocarditis, chemotherapeutic cardiotoxicity, senescent cardiac dysfunction and cardiac allograft rejection. Ultimately, we aimed to evaluate the application of S100A8/A9 as promising biomarkers and therapeutic strategies for the prediction, prevention and treatment of NICM.
Retinoic acid receptors (RARs), including RARα, RARβ and RARγ, serve as essential nuclear receptors that act as transcription factors activated by ligands. They predominantly regulate gene expression and affect various biological processes, including differentiation. Their dysregulation is implicated in various cancers and other diseases, notably acute promyelocytic leukaemia (APL), where the promyelocytic leukemia (PML)–RARα fusion protein disrupts normal granulocyte maturation. All-trans retinoic acid, which promotes the degradation of this fusion protein is a key therapeutic agent for APL and is also involved in the treatment of other diseases. Recently, various selective RAR modulators targeting specific RAR subtypes have been developed, which show promise in treating cancer and other diseases. The structural biology of RARs reveals how ligand binding induces conformational changes that facilitate co-activator recruitment, thereby modulating transcription. This review explores the crystal structures of RARs in various activation states, detailing RARs’ interactions with retinoid X receptors, ligands, DNA and co-regulators, and emphasises the importance of understanding these mechanisms for the rational design of new RAR-targeted therapies. The potential for developing selective RARmodulators is highlighted, along with the need for comprehensive structural data to enhance our understanding of RAR functions in disease contexts. Future research directions include utilising advanced imaging techniques and artificial intelligence-driven predictions to elucidate the dynamics of RAR complexes, ultimately aiming to translate structural insights into clinical applications for various diseases.
Background: Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by distinct French–American–British (FAB) classifications and molecularmutations.Understanding how these biologicalmarkers relate to drug responses is crucial for refining therapeutic approaches.
Methods: We examined drug sensitivity patterns in 186 AML patients using selective Drug Sensitivity Scores (sDSS), analysing data from 515 commercially available chemotherapeutic and targeted oncology agents. Drug sensitivity was analysed across various FAB subtypes (M0, M1, M2, M4, M4 eos, M4/M5, and M5) and important mutations (NPM1, FLT3, FLT3-ITD, FLT3-TKD and KIT).
Results: Navitoclax showed greater effectiveness in M0, M1, and M2 subtypes. NPM1 mutations were linked to increased sensitivity to multiple therapeutic agents. FLT3-ITD mutations were associated with significant responsiveness to PI3K/mTOR inhibitors. Analysis of drug combinations revealed complexities in using multiple therapeutic agents, often leading to reduced effectiveness but providing insights into successful drug pairings.
Conclusions: The findings underscore the necessity for personalised therapeutic strategies inAML, advocating for treatment protocols that integrate individual mutation profiles and FAB classifications to enhance patient care and improve clinical outcomes.