Clinical and translational discovery最新文献

The management of papillary thyroid cancer (PTC), a malignancy accounting for over 80% of thyroid cancers, has long relied on standardized surgical and radioiodine therapies.^1-3 Yet, a critical unmet challenge persists: the unpredictable progression of lymph node metastasis (LNM), which correlates with increased recurrence and mortality. Current risk stratification systems, based on clinicopathological features, fail to explain the molecular mechanisms underlying aggressive LNM in subsets of patients. A study by Xiao et al. published in Clinical and Translational Medicine, titled “Single-cell RNA-sequencing and spatial transcriptomic analysis reveal a distinct population of APOE⁻ cells yielding pathological lymph node metastasis in papillary thyroid cancer”, provides groundbreaking insights into this issue.⁴ By integrating single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the authors identify a previously unrecognized APOE⁻ cell subpopulation that drives metastatic dissemination, offering a paradigm shift in understanding PTC progression. This work not only advances molecular oncology but also underscores both the transformative potential and inherent complexities of high-resolution spatial genomics in clinical translation.

In PTC, as with many solid tumors, the process of metastasis is multifaceted and involves intricate interactions between cancer cells, stromal components, and the immune system.^{5, 6} scRNA-seq and spatial transcriptomics have emerged as powerful tools to dissect the heterogeneity that exists within a tumor, enabling researchers to profile the transcriptome of individual cells and to map gene expression patterns within the tumor microenvironment with high spatial resolution.^{7, 8} The study in question utilized these cutting-edge technologies to interrogate the cellular composition of PTC tumors and lymph node metastases. First, scRNA-seq was performed on tumor samples from PTC patients with aggressive LNM, revealing remarkable intratumoral heterogeneity. A subset of cells exhibiting downregulated APOE expression, a gene traditionally associated with lipid metabolism and immune modulation, was identified as a hallmark of metastatic propensity. Spatial transcriptomic analysis further localized these APOE⁻ cells to invasive tumor margins, where they interacted with immunosuppressive macrophages and fibroblasts. This spatial resolution confirmed that APOE⁻ cells serve as “metastatic hubs,” orchestrating a microenvironment conducive to lymphatic invasion. The identification of APOE⁻ cells as key drivers of PTC metastasis thus represents a novel and intriguing finding.

The promise of this study lies in its potential to revolutionize the management of PTC patients. By identifying APOE⁻ cells as a biomarker for lymph node metastasis

This study was focused to formulate and optimize transferosomes encapsulating ketoconazole (KTZ) for its repurposed use as a hair growth promoting agent. Ketoconazole exerts trichogenic effect in patients with androgenic alopecia androgen by acting on receptors present in keratinocytes and sebocytes of the scalp. This necessitates the penetration of ketoconazole into deep epidermal and dermal layers for exerting trichogenic effect. Transferosomes have been reported to improve drug penetration owing to their deformable vesicular structure. Thus, in the present work, transferosomal gel loaded with ketoconazole was developed with the intention to enhance drug permeation and improved hair proliferation activity. Solvent evaporation method has been adopted for the formulation of transferosomes and then optimized by quality by design approach. KTZ-TF (ketoconazole-transferosomes) were assessed for particle size, entrapment efficiency (%EE), surface charge, and morphology. The optimized KTZ-TF formulation demonstrated particle size of 151.22 ± 1.3 nm, PDI index of 0.191 ± 0.034, and ζ potential of –33.05 ± 01.3 mV, respectively. The developed formulation was further added into gel and compared with commercially available product. It was concluded that KTZ-TF gels showed control drug release (89.1 ± 2.12%) for 9 h. The in vivo skin irritation test demonstrated that the gel formulation caused minimal irritation and was well accepted by the scalp. In vivo qualitative hair growth activity demonstrated improved hair growth with the developed formulation in comparison to marketed KTZ. Histopathological studies also corroborated the findings through demonstrating increase in number of hair follicles. Hence, this study concluded that ketoconazole-loaded transferosomes are efficacious in hair growth activity.

Lung cancer is the malignant tumour with the highest global morbidity and mortality rates, and a substantial proportion of lung cancers are driven by EGFR mutations.^{1, 2} EGFR tyrosine kinase inhibitors (EGFR-TKIs) can specifically bind to mutated EGFR proteins, blocking the carcinogenic process, and have thus become the preferred treatment for patients with EGFR-mutation-positive lung cancer.³

However, despite the remarkable efficacy of EGFR-TKIs in the initial treatment phase, patients often experience tumour progression due to drug resistance after 10–20 months.⁴ This highlights the importance of identifying new therapeutic targets to enhance the efficacy of EGFR-TKIs. Currently, the combination of immune checkpoint inhibitors or traditional chemotherapy with EGFR-TKIs offers limited benefits for patients' long-term survival, underscoring the urgent need to explore new therapeutic targets.³

The strategy for cancer treatment has shifted from solely targeting tumour cells to also focusing on modulating the tumour microenvironment. Cancer-associated fibroblasts (CAFs), one of the most abundant stromal components in the tumour microenvironment, have been observed to infiltrate and invade the areas where lung cancer cells retreat in the cancer nest during EGFR-TKI treatment, surrounding the residual lung cancer cells. This suggests that CAFs may play a crucial role in EGFR-TKI resistance.^{5, 6}

In terms of cellular origin, CAFs are a complex collection of multiple cell subsets, mainly including normal tissue fibroblasts induced and activated in the tumour microenvironment (TME), bone marrow-derived fibroblasts and mesenchymal stem cells recruited and migrated to the TME, and stromal cells (such as epithelial cells, endothelial cells, and smooth muscle cells) that can undergo transdifferentiation under specific conditions.^{7, 8} The diversity of cellular origins and the intricate interactions between CAFs and tumour cells, as well as other non-tumour cells, contribute to the wide range of phenotypic and functional heterogeneity exhibited by CAFs.^{9, 10}

The research by Xu et al. significantly advanced our understanding of lung cancer by identifying a unique CAFs subset marked by the co-expression of CXCL14 and POSTN (CXCL14 + POSTN + CAFs).¹¹ The authors further demonstrated that CXCL14 + POSTN + CAFs promote metastasis through epithelial-mesenchymal transition (EMT) and angiogenesis and have a specific association with EGFR-TKI resistance. This subset-specific resistance may stem from paracrine signalling (CXCL14 secreted by CAFs activates STAT3 in cancer cells through CXCR4, bypassing EGFR blockade) and the matrix barrier (the extracellular matrix rich in POSTN may physically impede drug penetration).

In addition, Xu et al.’s identif

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 RAR modulators 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.

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 potential mediator of heart failure caused by acute myocardial 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 hypertrophic myocardial 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.