Clinical and translational discovery最新文献

{"title":"scICB: A pan-cancer database of human temporal immune checkpoint blockade therapy at single-cell transcriptomic resolution","authors":"Fansen Ji, Weitong Bi, Jiawei Zhang, Bingjun Tang, Ying Xiao, Huan Li, Hao Liu, Boyang Wu, Fei Yu, Shizhong Yang, Gang Xu, Jiahong Dong","doi":"10.1002/ctd2.70044","DOIUrl":"https://doi.org/10.1002/ctd2.70044","url":null,"abstract":"<p>Dear Editor,</p><p>We developed a pan-cancer scRNA-seq database under the treatment of Immune checkpoint blockade (ICB): scICB. The detailed biopsy timepoint relative to the ICB and clinical efficacy assessment information after the treatment have been identified to help clinicians to analyse different aspects of immunotherapy responsive biomarkers (Figure 1). The database is freely accessible at http://www.scimmnue.com/.</p><p>Herein, we collected scRNA-seq datasets related to ICB treatment and corresponding clinical information from multiple sources (Table 1). scICB includes 807 samples from 338 patients treated by ICB or ICB combination therapy across 13 cancer types (Figure 2a, Tables S1–S3). A total of 3 686 385 single cells covering NSCLC, CRC, RCC, HNSCC, BLCA, BCC, SCC, HCC, BRCA, SKCM, ESCC, GC and UCEC. For response status level, there are 174 patients defined as responders (R) while 170 patients labelled as nonresponders (NR) (Figure 2b). For biopsy timepoint level, a total of 23 patients only has pre ICB treatment scRNA-seq data, while a total of 68 patients only has post ICB treatment data and a total of 247 patients has matched pre and post treatment scRNA-seq data (Figure 2c), which facilitate us to trace the dynamic TME changes during the intervention of ICB. After annotating the major cell type and removing mitochondrial or ribosome genes enriched cells, we have annotated the cell types for each cell (Figure 2d). BRCA, HNSCC, CRC, SKCM and NSCLC rank top 5 both in terms of both patient and sample number in scICB, implying the high level of clinical translational research activity for ICB in these cancer types over the past few years.</p><p>scICB provides mainly four functionalities for users. In Browse module, users can browse information like Cancer Type, Dataset ID, Tissue Type, Patient ID, Sample ID, Cell Type, Timepoint, Response and ICB Drug. Besides, the logFC value expression table for each cell type, TNSE, UMAP, marker gene heatmap plots, cell type annotation and relative proportion for each patient, patient/response status/biopsy timepoint/tissue type can also be browsed (Figure S1). In Pre VS Post module, users could select an interested cancer type and dataset to see the dynamic changes before and after the ICB for a certain tissue type and cell type and the relevant volcano plot, differential genes and enrichment analysis will be returned (Figure S2). In R VS NR module, users can compare the DEGs between R and NR for a certain cell type after selecting a certain cancer type and dataset ID, helping to uncover the underlying mechanisms or biomarkers of immune response to ICB (Figure S3). In GeneSet module, we provide functionality for users to upload custom gene sets or specific signalling pathway genes for analysis using our curated datasets. After selecting the cancer type, dataset, tissue type, and cell type, and uploading their gene sets, users will receive a boxplot illustrating gene set activity across differen","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A vital step toward targeting lymph node metastasis: Identifying APOE− cells as prognostic drivers in papillary thyroid carcinoma","authors":"Ling Xiao, Hui Luo","doi":"10.1002/ctd2.70052","DOIUrl":"https://doi.org/10.1002/ctd2.70052","url":null,"abstract":"<p>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.<span><sup>1-3</sup></span> 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 <b><i>Clinical and Translational Medicine</i></b>, titled “Single-cell RNA-sequencing and spatial transcriptomic analysis reveal a distinct population of APOE<sup>−</sup> cells yielding pathological lymph node metastasis in papillary thyroid cancer”, provides groundbreaking insights into this issue.<span><sup>4</sup></span> By integrating single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the authors identify a previously unrecognized APOE<sup>−</sup> 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.</p><p>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.<span><sup>5, 6</sup></span> 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.<span><sup>7, 8</sup></span> 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<sup>−</sup> cells to invasive tumor margins, where they interacted with immunosuppressive macrophages and fibroblasts. This spatial resolution confirmed that APOE<sup>−</sup> cells serve as “metastatic hubs,” orchestrating a microenvironment conducive to lymphatic invasion. The identification of APOE<sup>−</sup> cells as key drivers of PTC metastasis thus represents a novel and intriguing finding.</p><p>The promise of this study lies in its potential to revolutionize the management of PTC patients. By identifying APOE<sup>−</sup> cells as a biomarker for lymph node metastasis","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formulation and evaluation of repurposed ketoconazole-loaded transferosomal gel for enhanced trichogenic effects","authors":"Madhvi Mishra,&nbsp;Gopal Thakur,&nbsp;Pallavi Bassi,&nbsp;Gurpreet Kaur,&nbsp;Thakur Gurjeet Singh,&nbsp;Narinderpal Kaur,&nbsp;Ling Shing Wong,&nbsp;Satyanarayana Reddy,&nbsp;Gowtham Kuppusamy,&nbsp;Vinoth Kumarasamy,&nbsp;Gaurav Gupta,&nbsp;Vetriselvan Subramaniyan","doi":"10.1002/ctd2.70037","DOIUrl":"https://doi.org/10.1002/ctd2.70037","url":null,"abstract":"<p>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.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143801872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring new frontiers in lung cancer treatment: The role of cancer-associated fibroblasts (CAFs) and EGFR-TKI resistance","authors":"Jiaqi Liang,&nbsp;Yidu Hu,&nbsp;Cheng Zhan","doi":"10.1002/ctd2.70047","DOIUrl":"https://doi.org/10.1002/ctd2.70047","url":null,"abstract":"&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;9, 10&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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).&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; 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).&lt;/p&gt;&lt;p&gt;In addition, Xu et al.’s identif","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Sensitivity patterns across FAB subtypes and molecular mutations in AML: A comprehensive analysis for precision medicine","authors":"Mobina Shrestha,&nbsp;Bishwas Mandal,&nbsp;Vishal Mandal,&nbsp;Sabin Karki,&nbsp;Reshu Thapa","doi":"10.1002/ctd2.70046","DOIUrl":"https://doi.org/10.1002/ctd2.70046","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by distinct French–American–British (FAB) classifications and molecular mutations. Understanding how these biological markers relate to drug responses is crucial for refining therapeutic approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The findings underscore the necessity for personalised therapeutic strategies in AML, advocating for treatment protocols that integrate individual mutation profiles and FAB classifications to enhance patient care and improve clinical outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of gastric cancer in autoimmune gastritis and pernicious anaemia: Insights from Mendelian randomization and multi-omics analysis","authors":"Shengan Zhang,&nbsp;Ziqi Zhang,&nbsp;Liang Dai,&nbsp;Wenjun Zhou,&nbsp;Yanqi Dang,&nbsp;Wendong Huang,&nbsp;Guang Ji","doi":"10.1002/ctd2.70036","DOIUrl":"https://doi.org/10.1002/ctd2.70036","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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], <i>p</i> = .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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results emphasized the independent link from AIG and pernicious anaemia to GC. Therefore, endoscopy follow-up for GC screening in AIG is still appealed.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into retinoic acid receptor activation and selective modulators","authors":"Yining Song,&nbsp;Wenrui Zhao,&nbsp;Xuan Huang,&nbsp;Lai Wei,&nbsp;Jingyi Han,&nbsp;Jiayun Hou,&nbsp;Min Li,&nbsp;Xin Cao","doi":"10.1002/ctd2.70043","DOIUrl":"https://doi.org/10.1002/ctd2.70043","url":null,"abstract":"<p>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.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards a one-time cure for Fabry disease: Lentivirus-mediated haematopoietic stem and progenitor cell gene therapy","authors":"Rina Kansal","doi":"10.1002/ctd2.70042","DOIUrl":"https://doi.org/10.1002/ctd2.70042","url":null,"abstract":"&lt;p&gt;Fabry disease, also known as Anderson‒Fabry disease, is an X-linked systemic disease first described independently in Germany and England over 125 years ago, in 1898, in patients presenting with small, reddish purple telangiectatic cutaneous papules called &lt;i&gt;angiokeratoma corporis diffusum&lt;/i&gt;.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Five decades later, in 1947, the concept of a lipid storage disease emerged following postmortem studies, and the abnormal lipid was identified as trihexosyl ceramide in 1963.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Subsequently, the underlying deficiency of the lysosomal enzyme α-galactosidase, which cleaves galactose from the neutral glycosphingolipid, globotriaosylceramide (Gb&lt;sub&gt;3&lt;/sub&gt;) or trihexosyl ceramide, in the normal cellular degradation pathway, was identified.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The enzyme activity was near-completely deficient in leukocytes in affected males and reduced in female carriers of the disease compared to normal leukocytes.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In 1978, the α-galactosidase A (&lt;i&gt;GLA)&lt;/i&gt; gene, which encodes the enzyme, was found to be located in the Xq22 chromosomal region, and the gene's nucleotide sequence was identified in 1986. Gene mutations in &lt;i&gt;GLA&lt;/i&gt; that do not allow enzyme expression were recognised as the fundamental cause of Fabry disease.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Although the clinical features of this inherited disease, including neurologic pain in the extremities, cutaneous angiokeratomas, hypohidrosis, and corneal opacities, are evident in childhood, the diagnosis of classic Fabry disease is often missed and delayed, with an average age of 29 years at diagnosis.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; The disease worsens in untreated adults due to the progressive accumulation of glycosphingolipids in various cells across multiple organ systems, leading to cardiovascular, cerebrovascular, and renal damage that shortens lifespan. Females exhibit variability in disease severity and may be asymptomatic or experience complications like affected males. Until 2001, no treatment was available to halt disease progression, when enzyme replacement therapy (ERT) was approved for treating Fabry disease in Europe, followed by approval in the United States in 2003.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Nonetheless, ERT is very expensive, requires biweekly infusions for life, and its efficacy may be reduced if the patient develops an antibody response. Migalastat, a pharmacologic chaperone therapy approved for adults with Fabry disease since 2016, is only applicable for 30%–50% of patients who have &lt;i&gt;GLA&lt;/i&gt; mutations that are amenable to increase the activity of the deficient enzyme with the drug; furthermore, the in vitro determinations of amenability do not translate to in vivo drug efficacy.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Medin et al. began their gene therapy efforts more than two decades ago with the vision of developing a one-time cure for Fabry disease.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; In an accompanying article in thi","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell therapy based on stem cells or their extracellular vesicles during kidney graft preservation: Current state of the art and novelties","authors":"Nessma Chenaf-Benabdelmoumene,&nbsp;Thierry Hauet,&nbsp;Clara Steichen","doi":"10.1002/ctd2.70040","DOIUrl":"https://doi.org/10.1002/ctd2.70040","url":null,"abstract":"&lt;p&gt;Transplantation often remains the best therapeutic option in terms of life quality and disease prognosis improvement to treat chronic or even acute organ failure. According to a report published by the World Health Organization in 2023,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; less than 10% of the world's organ needs are covered. Focusing on the kidney, which is now the most transplanted organ in the world, the latest report of the Global Observatory on Donation and Transplantation published in 2023 (based on 2022 data)&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; pointed out the gap between supply and demand: there are currently more patients on the active waiting list than there are grafts available for them worldwide. Kidney grafts can come from two main different sources: living donors, which represent a minority of donations, and deceased donors. Nevertheless, the organ shortage, which has been worsening year after year, has led to extend donation criteria over the years. This means, for example, the use of deceased donors not only after brainstem death but also after unpredictable irreversible circulatory arrest with immediate cardiopulmonary resuscitation attempted by trained providers (according to the Maastricht classification, second category) and after circulatory arrest occurring based on a decision to withhold or withdraw life-sustaining treatment (according to the Maastricht classification, third category). These death circumstances are usually associated with intensive donor reanimation processes consisting in noradrenaline administration, in massive vascular filling to prevent reanimation complications such as inflammation, haemodynamic instability or acute kidney failure. Extended criteria donors also include older donors aged over 65 years and donors with comorbidities such as arterial hypertension, cardiopathy, diabetes and even chronic kidney failure. The growing need for organs may also result in organs being transported from more distant regions. In all these situations kidney grafts are more susceptible to be affected by ischaemia‒reperfusion (IR) injuries.&lt;/p&gt;&lt;p&gt;IR is a pathophysiological phenomenon taking place from the donor's reanimation to the recipient's transplantation. Ischaemia is induced by the sudden arrest of oxygen and nutrients supply during the organ retrieval step, which may be prolonged during organ preservation sequence depending on its modalities. Reperfusion occurs when anastomoses are performed between the graft and the recipient and refers to the massive oxygen supply in a medium, which was previously deprived of oxygen.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; On a microscopic scale, this phenomenon is associated with shifts in mitochondrial metabolism and function, by a release of reactive oxidative species causing cytoskeleton destruction, complement system activation and recruitment of innate and adaptative immune cells.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Faced with these perturbations, the cell eventually dies by necrosis, phagocytosis or apoptosis. On a ","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of S100A8 and S100A9 in nonischaemic cardiomyopathy","authors":"Qiu-Yue Lin,&nbsp;Wen-Xi Jiang,&nbsp;Hui-Hua Li","doi":"10.1002/ctd2.70039","DOIUrl":"https://doi.org/10.1002/ctd2.70039","url":null,"abstract":"<p>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.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}