Clinical and translational discovery最新文献

The persistent threat of tuberculosis (TB) on a global scale hasprompted a reevaluation of preventive strategies, with a particular focus onthe Bacille Calmette-Guérin (BCG) vaccine's role in revaccination. Theresurgence underscores an urgent need for enhanced measures, prompting acritical examination of BCG revaccination strategies. Drawing from the researchof Paulo Cesar Pereira dos Santos and a synthesis of randomized controlledtrials (RCTs), this review identifies key considerations for refining BCGrevaccination's efficacy against Mycobacterium tuberculosis (MTB) andTB. The main body of this review integrates four principal domains essentialfor optimizing BCG revaccination: the timing of revaccination, the assessmentof various BCG strains, the evaluation of the vaccine's effectiveness on MTBand non-tuberculous mycobacteria (NTM) strains, and the enhancement of RCTmethodologies. Determining the optimal revaccination timing is paramount forbolstering immunity, especially in regions with high TB prevalence. Theanalysis of different BCG strains provides insights into strain-specificimmunogenicity, informing vaccine deployment strategies. Additionally,understanding the vaccine's impact on a range of mycobacterial infections iscrucial for its broader application in various microbial contexts. The reviewemphasizes the refinement of RCT designs to ensure robust and consistentoutcomes, facilitating the reproducibility of results in diverse settings. Itproposes a strategy that not only suggests modifications to revaccinationpractices to increase global TB prevention effectiveness but also calls forcontinuous research to improve BCG revaccination methodologies. The paperadvocates for a standardized, evidence-driven approach to global TB preventionthat takes into account regional epidemiological differences. In conclusion,this review significantly contributes to the discourse on TB prevention,advocating for evidence-based, standardized approaches that could potentiallytransform the role of BCG revaccination in global TB prevention efforts. Thefindings support current initiatives aimed at developing policies based onsolid evidence, ensuring the scientific integrity and practical relevance ofBCG revaccination strategies.

The spatiotemporal heterogeneity of neurons, circuits and regulators is being uncovered at a single-cell level, from the single-cell gene expression to functional regulations. The classifications, architectonics and functional communications amongst neural cells and circuits within the brain can be clearly delineated using single-cell multiomics and transomics. This Editorial highlights the spatiotemporal heterogeneity of neurons and circuits as well as regulators, initiates the translation of neuronal diversity and spatial organisation at single-cell levels into clinical considerations, and enables the discovery and development of new therapies for neurological diseases. It is predicted that single-cell and spatial multiomics will be integrated with metabolomic profiles and corresponding gene epigenetic modifications. The interactions amongst DNAs, RNAs and proteins in a cell provide details of intracellular functional regulations and new opportunities for the translation of temporospatial diversity of neural cell subtypes/states into clinical practice. The application of single-cell multiomics with four-dimensional genome to the human pathological brain will lead us to a new milestone of the diagnosis and treatment.

Genome-wide association studies (GWAS) have been instrumental in elucidating the genetic architecture of various traits and diseases. Despite the success of GWAS, inherent limitations such as identifying rare and ultra-rare variants, the potential for spurious associations and pinpointing causative agents can undermine diagnostic capabilities. This review provides an overview of GWAS and highlights recent advances in genetics that employ a range of methodologies, including whole-genome sequencing (WGS), Mendelian randomisation (MR), the Pangenome's high-quality Telomere-to-Telomere (T2T)-CHM13 panel and the Human BioMolecular Atlas Program (HuBMAP), as potential enablers of current and future GWAS research. The state of the literature demonstrates the capabilities of these techniques to enhance the statistical power of GWAS. WGS, with its comprehensive approach, captures the entire genome, surpassing the capabilities of the traditional GWAS technique focused on predefined single nucleotide polymorphism sites. The Pangenome's T2T-CHM13 panel, with its holistic approach, aids in the analysis of regions with high sequence identity, such as segmental duplications. MR has advanced causative inference, improving clinical diagnostics and facilitating definitive conclusions. Furthermore, spatial biology techniques such as HuBMAP enable 3D molecular mapping of tissues at single-cell resolution, offering insights into pathology of complex traits. This study aimed to elucidate and advocate for the increased application of these technologies, highlighting their potential to shape the future of GWAS research.

Amino acids are necessary for all life forms, which play various roles. Disorder of amino acid metabolism is now considered an important driving mechanism in diverse pulmonary conditions, particularly chronic lung diseases like chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and lung cancer. Glutamate actively participates in multiple vital biological processes, while the intricate glutamate metabolism, glutamate receptors and glutamate transporters assume crucial regulatory functions in the development of chronic lung diseases. This review aims to discuss the relationship between glutamate dysfunction and chronic lung diseases. By discussing the physiological and pathological function of glutamate, we probe the potential drug targets for chronic lung diseases in the glutamate pathway.

KRAS is one of the most frequently mutated oncogenes in cancer.¹ Codon 12, 13 and 61 mutations are frequently observed as the hot spot mutations in various cancers. Normally, KRAS protein functions as a molecular switch downstream of cell surface receptors, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor, etc., shuttling GTP-bound active state and GDP-bound inactive state, which turns on and off the growth factors’ signals that activate MAPK, PI3K/AKT/mTOR and other signalling pathways fundamental for cell proliferation, differentiation and survival. The oncogenic mutations lock the KRAS at the active state, resulting in contributing to tumorigenesis. Genetically engineered mouse models containing tissue-specific Kras codon 12 mutation have developed clinically relevant cancers in the corresponding tissues, which indicates the central driver role of KRAS mutation in cancer formation and progression.2

Therefore, targeting the mutated KRAS is considered an ideal therapeutic strategy in the KRAS-mutated cancers. Especially, KRAS codon 12 mutation is detected in 90% of pancreatic cancer,1 which suggests the tumour addiction to the mutated KRAS in the most deadly cancer with a 5-year survival of still around 10%. However, KRAS has been undruggable for more than 40 years, because of its relatively smooth protein structure and lack of approachable binding pocket.1

Recently, KRAS G12C-specific covalent inhibitors, sotorasib and adagrasib, that lock KRAS to a GDP-bound inactive state, were developed and clinically approved for the treatment of cancers with KRAS G12C mutation,3^,4 with significant therapeutic efficacy, especially in non-small cell lung cancer (NSCLC). It was a breakthrough in the field: Now, KRAS is druggable. Following them, other KRAS G12C inhibitors, as well as inhibitors specific for other KRAS mutations, have been on the line of development with growing expectations in the improvement of clinical practice.

Subsequent to the success of the KRAS G12C inhibitor, acquired resistance to the inhibitor has become a clinical problem and the underlying mechanisms have been explored.5 Compared to NSCLC, colorectal cancer with KRAS G12C mutation showed a limited objective response to the KRAS G12C inhibitors, indicating resistance to the therapy. To overcome the resistance, combinatorial therapeutics have been investigated with the KRAS G12C inhibitors. Recently, a couple of studies demonstrated the feasibility and possible efficacy of the combination of the KRAS G12C inhibitors with EGFR inhibitors in advanced colorectal cancer.6^-8 Among them, the CodeBreaK 300, a phase 3, multicenter, open-label, randomized trial (NCT05198934) showed that a KRAS G12C-specific inhibitor sotorasib, in combination with EGFR inhibitor panitumu

Understanding the interplay between immune cells and the bone marrow microenvironment is crucial for elucidating age-related musculoskeletal changes. In this commentary manuscript, we summarized that studies have shown that proinflammatory immune cells in the bone marrow, such as macrophages and neutrophils, can inhibit bone formation by secreting grancalcin. Research on skeletal stem cells (SSCs) in aged mice reveals a shift towards pro-inflammatory gene expression, affecting their osteogenic potential, while another study maps age-related changes in cranial SSC niches, emphasizing the role of the CXCL12–CXCR4 axis in stem cell-immune cell communication, Additionally, the immune system influences hematopoietic stem cells (HSCs); Niche ageing and accumulation of mutations with age lead to HSC exhaustion and a bias towards myeloid differentiation, with toll-like receptors playing a key role in maintaining hematopoiesis and bone metabolism balance.

Melanoma is one of the most prevalent cancers in the United States, accounting for 5% of all new cancer cases, and has been increasing worldwide.¹ Melanoma arises from the malignant proliferation of melanocytes, cells that produce melanin that provides skin pigmentation. The high metastatic potential of melanoma drastically affects the prognosis of patients diagnosed at later stages. In particular, 50%–75% of melanoma cases metastasize to the brain, accounting for 54% of all melanoma-related deaths.^{2, 3} It is thus critical to diagnose melanoma at earlier stages to limit metastasis and more widespread invasion, allowing for complete surgical removal of the tumour.

While excision of early-stage melanoma results in a favourable prognosis, recurrence can occur in many of these patients, being responsible for a large proportion of melanoma-related deaths. The mechanisms underlying melanoma recurrence remain incompletely understood. Recent evidence points toward the critical influence of the tumour microenvironment (TME) on melanoma recurrence. The TME is composed of the extracellular matrix, immune cells, mesenchymal cells, and blood vessels that surround the tumour cells, communicating their behaviour and response to treatment. Dissecting the melanoma TME therefore may give rise to diagnostic markers and mechanistic insights into its recurrence patterns, opening avenues for the development of targeted therapies that can lower the risk of melanoma recurrence.

Recent development in artificial intelligence (AI)-driven histopathology introduces important tools that can be leveraged to investigate the spatial organization and molecular markers in the TME. The application of AI technology has been proven to objectively and consistently produce valuable clinical information that provides molecular markers and predicts cancer outcomes. The utilization of AI in cancer histopathology is not just limited to its predictive and prognostic usage. This technology can be used to profile and map tumour immune cell networks and dissect molecular pathways within the TME, revealing critical mechanistic insights into response to treatments, recurrence patterns, and metastatic potential.

In a recent study, Szadai et al.⁴ employed AI-powered histopathology and spatial proteomics to explore and compare the tumour cells and TME interplay between recurrent and non-recurrent primary melanoma samples. This AI-driven methodology proved to be effective in distinguishing normal tissue from stromal and tumour regions across both groups. Notably, these authors integrated laser-microdissection technology and quantitative proteomic analysis with digital pathology readouts. This unique approach produced critical spatial proteomics data that sheds light on the molecular interplay between mitochondrial functions and immune response in the tumour and stromal components of recurrent melanoma.