Primary sclerosing cholangitis
Related Articles
Regulatory T cells-related gene in primary sclerosing cholangitis: evidence from Mendelian randomization and transcriptome data
The present study utilized large-scale genome-wide association studies (GWAS) summary data (731 immune cell subtypes and three primary sclerosing cholangitis (PSC) GWAS datasets), meta-analysis, and two PSC transcriptome data to elucidate the pivotal role of Tregs proportion imbalance in the occurrence of PSC. Then, we employed weighted gene co-expression network analysis (WGCNA), differential analysis, and 107 combinations of 12 machine-learning algorithms to construct and validate an artificial intelligence-derived diagnostic model (Tregs classifier) according to the average area under curve (AUC) (0.959) in two cohorts. Quantitative real-time polymerase chain reaction (qRT-PCR) verified that compared to control, Akap10, Basp1, Dennd3, Plxnc1, and Tmco3 were significantly up-regulated in the PSC mice model yet the expression level of Klf13, and Scap was significantly lower. Furthermore, immune cell infiltration and functional enrichment analysis revealed significant associations of the hub Tregs-related gene with M2 macrophage, neutrophils, megakaryocyte-erythroid progenitor (MEP), natural killer T cell (NKT), and enrichment scores of the autophagic cell death, complement and coagulation cascades, metabolic disturbance, Fc gamma R-mediated phagocytosis, mitochondrial dysfunction, potentially mediating PSC onset. XGBoost algorithm and SHapley Additive exPlanations (SHAP) identified AKAP10 and KLF13 as optimal genes, which may be an important target for PSC.
Microbiome-based interventions to modulate gut ecology and the immune system
The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.
DNA repair and disease: insights from the human DNA glycosylase NEIL family
The base excision repair pathway protects DNA from base damage via oxidation, deamination, alkylation and methylation. DNA glycosylases are key enzymes that recognize damaged bases in a lesion-specific manner and initiate the base excision repair process. Among these, the endonuclease VIII-like 1–3 (NEIL1–3) family, which is found in mammalian genomes, is a homolog of bacterial DNA glycosylases known as Fpg/Nei. NEIL enzymes have similar structures and substrates but with slight differences. When repair proteins are impaired, the accumulation of damaged bases can lead to increased genomic instability, which is implicated in various pathologies, including cancer and neurodegeneration. Notably, mutations in these proteins also influence a range of other diseases and inflammation. This review focuses on the influence of the NEIL family on human health across different organ systems. Investigating the relationship between NEIL mutations and diseases can improve our understanding of how these enzymes affect the human body. This information is crucial for understanding the basic mechanisms of DNA repair and enabling the development of novel inhibitors or gene therapies that target only these enzymes. Understanding the role of the NEIL family provides insights into novel therapies and improves our ability to combat genetic diseases.
Efficacy and tolerability of neoadjuvant therapy with Talimogene laherparepvec in cutaneous basal cell carcinoma: a phase II trial (NeoBCC trial)
We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks), become resectable without the need for plastic reconstructive surgery, was already achieved after stage I (9 of 18 patients; 50.0%); thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Secondary end points included safety, relapse-free survival and overall survival, time to occurrence of new basal cell carcinomas and biological read outs. Only mild adverse events occurred. The 6-month relapse-free survival and overall survival rates were 100%. In two patients a new basal cell carcinoma was diagnosed. T-VEC led to a significant increase in cytotoxic T cells (P = 0.0092), B cells (P = 0.0004) and myeloid cells (P = 0.0042) and a decrease in regulatory T cells (P = 0.0290) within the tumor microenvironment. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect basal cell carcinomas (EudraCT no. 2018-002165-19).
Responses