Trends in molecular medicine最新文献

A growing number of diseases are now treated with immunotherapies, which consist of interventions that suppress or stimulate the patient's immune system. Because individual humans express a unique repertoire of adaptive immune receptors, the efficacy of immunotherapies typically varies from person to person. Next generation sequencing of adaptive immune receptor repertoires, combined with machine learning or statistical analysis, has emerged as a sensitive means of stratifying patients based on their immune status, particularly in the fields of cancer and autoimmune disease therapy. The sensitivity and specificity of these approaches rely heavily on the methods of deriving features from each individual repertoire. Here, we review recent trends in stratification methods and highlight their limitations, including the need for data standardization and sharing.

Single cell RNA sequencing (scRNA-seq) has revolutionized the field of biology and become the most powerful tool for evaluating transcriptional profiles of a biological sample. Given its power, it is widely utilized across multiple disciplines, including chimeric antigen receptor (CAR)-T cell therapy. In this review, we provide a comprehensive summary of published studies that have used scRNA-seq to analyze clinical CAR-T cells, focusing on T cell exhaustion, cytotoxicity, memory, expansion, clonal diversity, and cytokines. We also highlight findings on activation, CD4+/CD8+ ratios, proliferation, regulatory T cells (Tregs) and metabolism, and their relevance to patient response across diseases. Finally, we discuss the limitations and future directions of scRNA-seq in CAR-T cell research, providing key insights for clinicians and researchers.

The liver has a unique microarchitecture, with hepatic sinusoids receiving blood from the portal vein and hepatic artery and draining into the central vein. This flow establishes an oxygen gradient along the sinusoids critical for defining the liver zonation. In metabolic dysfunction-associated steatotic liver disease (MASLD), fat accumulation and fibrosis disrupt this architecture, contributing to localised hypoxia. Mounting evidence implicates hypoxia in MASLD, including the activation of canonical hypoxia sensors such as hypoxia-inducible factors. Moreover, chronic intermittent hypoxia, characteristic of obstructive sleep apnoea (OSA), is epidemiologically and mechanistically associated with MASLD progression. This review examines the intrahepatic oxygen dynamics, the interplay between OSA and MASLD, and molecular responses to hypoxia, proposing intrahepatic hypoxia as a spatial determinant of liver injury.

Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare genetic disease caused by progerin, a broadly expressed mutant variant of lamin A protein that accelerates aging and leads to premature death typically in adolescence. Progerin affects many organs and reproduces many characteristics of physiological aging, with the main cause of death in HGPS being atherosclerotic cardiovascular disease (CVD). Due to the rarity of HGPS, advances in understanding the disease and progress toward new therapeutic approaches are crucially dependent on preclinical models. We discuss recent research developments from a variety of HGPS experimental systems, with a special focus on in vivo studies of the role of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that are key players in atherosclerosis.

Chronic pain affects millions of people worldwide and represents a crucial public health issue. A growing body of preclinical evidence suggests that adeno-associated virus (AAV) vectors are a powerful gene therapy tool for chronic pain management. We systematically summarize how AAV vectors, by targeting molecular pain pathways in neuronal and non-neuronal cells, may offer precise and sustained pain relief. We provide an overview of the latest findings and emerging concepts in this area, and discuss preclinical innovations in neuropathic, inflammatory and cancer-related pain. We also present clinical data on pain modulation by AAV in osteoarthritis (OA) patients. Finally, we provide a thorough analysis of key concerns about AAV therapy, including potential immune responses, toxicity, and adverse effects.

Bhatt et al. have identified two RNAome-based skeletal muscle subtypes in cancer cachexia. The first subtype is cachexia associated with weight and muscle loss, fiber atrophy, and shortened survival. Furthermore, this subtype has dysregulated post-transcriptional networks involving hub long noncoding (lnc)RNAs, neuronal, immune, and metabolic pathways. The study highlights new biomarkers and network-targeted interventions.

Systemic lupus erythematosus (SLE, lupus) remains an enigmatic diagnosis with a poor prognosis. SLE is characterised by complex biology and heterogeneous clinical manifestations that create a major hurdle to the approval of new medicines and contribute to multiple trial failures. While the pace of research has accelerated, drugs currently in development target a limited spectrum of mechanisms, tempering hope that any will be a panacea. The pace of translation lags behind advances in basic science, and this continues to cost patients dearly. The unacceptable metabolic adverse effects of glucocorticoids have rightly driven treatment guidelines towards ever more stringent dose-reduction targets, and new research is ongoing to develop a safe and reliable glucocorticoid replacement that will be active across a breadth of inflammatory pathways.

The initiation of labour in humans remains poorly understood, although there is mounting evidence for a role for decidual macrophages. These may trigger labour by promoting a proinflammatory state, thereby modulating progesterone signalling and weakening fetal membranes. Preclinical work targeting macrophages therapeutically shows promise in preventing preterm labour, underscoring their significance in this process.