Clinical and translational discovery最新文献

{"title":"Current advances in the role of classical non-homologous end joining in hematologic malignancies","authors":"Pengcheng Liu,&nbsp;Zizhen Xu","doi":"10.1002/ctd2.70053","DOIUrl":"https://doi.org/10.1002/ctd2.70053","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Double-strand breaks (DSBs) are universally acknowledged as the most detrimental type of DNA damage, and their effective repair primarily depends on the non-homologous end joining (NHEJ) pathway. Such DSBs, which require NHEJ for resolution, can arise from intrinsic and extrinsic DNA-damaging factors or emerge naturally during essential biological processes like V(D)J recombination and antibody class switch recombination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Body</h3>\u0000 \u0000 <p>Failure to properly repair DSBs may lead to genomic instability, disruption of cellular functions, and immunodeficiency, thereby promoting the development of hematologic malignancies. Conversely, overexpression of NHEJ-related genes can enhance resistance to DNA-damaging therapies in these cancers. Analyzing mutations in key classical NHEJ (cNHEJ) components and understanding their mechanisms could provide valuable biomarkers for predicting therapeutic outcomes and guiding treatment decisions. Consequently, defects in cNHEJ may offer insights into the development of novel drugs targeting DNA repair pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We focus on genetic changes and alterations in gene regulation, while also providing an overview of cNHEJ.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171618","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 snapshot of the role of estrogen-regulated divergent non-coding transcripts","authors":"Barbara Yang,&nbsp;Melina J. Sedano,&nbsp;Kimberly Diwa,&nbsp;Johnathan Dominguez,&nbsp;Gabriela Boisselier,&nbsp;Alana L. Harrison,&nbsp;Victoria A. Reid,&nbsp;Enrique I. Ramos,&nbsp;Maria V. Jimenez,&nbsp;Laura A. Sanchez-Michael,&nbsp;Shreya Kolli,&nbsp;Jai Patel,&nbsp;Debra Lee,&nbsp;Mahalakshmi Vijayaraghavan,&nbsp;Jessica Chacon,&nbsp;Subramanian Dhandayuthapani,&nbsp;Shrikanth S. Gadad","doi":"10.1002/ctd2.70055","DOIUrl":"https://doi.org/10.1002/ctd2.70055","url":null,"abstract":"<p>Recent high-throughput sequencing technologies have discovered various polymerase II transcribed transcripts. The majority of them are non-protein-coding, understudied and poorly conserved. Non-coding transcripts are categorised based on their location in the genome and the direction in which they are transcribed; these categories classify a non-coding transcript as either antisense, intergenic or divergent. The RNAs belonging to divergent classes consist of two transcripts, transcribed in sense and antisense direction, generated from the same promoter or locus. Multiple environmental and genetic cues can determine the regulation of these transcripts. One of the well-known signalling molecules, estrogen, has been shown to play a vital role in the activation and regulation of divergent transcripts by mediating effects through the estrogen receptors. Emerging studies have shown a strong causative effect between estrogen-regulated divergent transcripts and diseases such as cancer. However, few, viz., <i>lncRNA67</i>, <i>CUPID1</i> and <i>CUPID2</i>, show a causal relationship with estrogen-dependent biology. This mini-review summarises their role in estrogen-dependent processes that may drive the research to identify novel estrogen-signalling regulators.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135553","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":"Friend or foe: The paradoxical roles of cancer-associated fibroblasts in tumour immunotherapy","authors":"Minying Xiong,&nbsp;Aimin Jiang,&nbsp;Zhengrui Li,&nbsp;Hank Z. H. Wong,&nbsp;Jian Zhang,&nbsp;Anqi Lin,&nbsp;Suyin Feng,&nbsp;Peng Luo","doi":"10.1002/ctd2.70056","DOIUrl":"https://doi.org/10.1002/ctd2.70056","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs) represent critical cellular components of the tumor microenvironment and have garnered widespread attention in the field of tumor immunology. However, given the pronounced heterogeneity of CAFs, research investigating their impact on tumor immunity has yielded diverse and often contradictory results. Therefore, in this review, we have systematically summarized previous studies to comprehensively elucidate the role of CAFs in the tumor immune microenvironment and have explored the bidirectional regulatory effects of CAFs on immune cells and immune molecules within this complex niche. We highlight the multifaceted role of CAFs in cancer immunotherapy, focusing on their impact on immunotherapeutic efficacy, as well as the synergistic effects between CAF-targeted therapies and immunotherapies in anti-cancer treatment. Addressing the heterogeneity of CAFs, we also critically analyze controversies surrounding these cells in the field of tumor immunology and propose strategic directions for future investigations targeting this cell population. Our comprehensive analysis provides a strategic framework for future research directions and clinical translation of CAF-targeted strategies, ultimately facilitating the development of more effective and personalized cancer immunotherapeutic approaches.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085040","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":"Senescence as a pathogenic driver in chronic kidney disease: From cellular fate to clinical stratification","authors":"Samuel Chauvin,&nbsp;Ariane Coutrot,&nbsp;Camille Cohen","doi":"10.1002/ctd2.70059","DOIUrl":"https://doi.org/10.1002/ctd2.70059","url":null,"abstract":"&lt;p&gt;Chronic kidney disease (CKD) is increasingly viewed through the lens of premature ageing.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Among the many cellular processes implicated in CKD progression, senescence—defined as a stable cell cycle arrest in metabolically active cells—has gained prominence in recent years.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Initially studied in the context of ageing, senescence has now been implicated in a range of chronic conditions, including cardiovascular disease, pulmonary fibrosis, and more recently, renal pathology.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Within the kidney, senescence has been observed both in aging and in disease states across species, including human and murine models.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; While the full spectrum of mechanisms driving lesion development remains unclear, growing evidence suggests that the senescence-associated secretory phenotype (SASP)—a complex network of pro-inflammatory cytokines, chemokines and proteases—plays a key role. The SASP may mediate its effects locally (cell-autonomous) or by influencing the surrounding microenvironment (non-autonomous), promoting inflammation, fibrosis and tubular atrophy.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Experimental studies have demonstrated that SASP components can drive tissue damage in both the tubulo-interstitial compartment&lt;span&gt;&lt;sup&gt;4, 7&lt;/sup&gt;&lt;/span&gt; and the glomerulus.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, SASP molecules are not exclusive to senescent cells; they can also be produced by other cell types in response to injury. As such, establishing the direct contribution of senescence to kidney damage remains a challenge.&lt;/p&gt;&lt;p&gt;The advent of omics technologies, coupled with the availability of large-scale public datasets, has opened new avenues to study SASP in the context of human disease. Proteomic profiling and transcriptomic analyses now enable us to identify signatures of senescence beyond histology, and potentially, without the need for invasive tissue sampling.&lt;/p&gt;&lt;p&gt;The recent article by McLarnon et al. represents a significant advance in this field.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Leveraging multi-omic approaches, including plasma proteomics, kidney biopsy transcriptomics and injury-induced kidney organoid models, the authors propose a novel stratification method for CKD patients based on senescence profiles.&lt;/p&gt;&lt;p&gt;Using proximity extension assays, they identified a 16-protein panel enriched in senescence-associated markers, which could reliably cluster CKD patients into two major groups—or &lt;b&gt;‘&lt;/b&gt;sendotypes&lt;b&gt;’&lt;/b&gt;—corresponding to disease severity. These sendotypes correlated with current and future measures of renal function, such as estimated Glomerular Filtration Rate (eGFR) and serum creatinine, validating their potential as prognostic indicators.&lt;/p&gt;&lt;p&gt;Among the most differentially expressed proteins were TNFR1, EFNA4, N2DL2 and TNFRSF14, all implicated in inflammatory signalling and previously linked to senescence. Importantly, transcriptomic analyses from huma","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091814","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":"Complex, cell-type-specific role of EEPD1: Bridging TNF-α, inflammation and apoptosis in endothelial cells","authors":"Rong Li,&nbsp;Cindy Xinyu Zhang,&nbsp;Gaohui Zhu,&nbsp;Da-Wei Zhang","doi":"10.1002/ctd2.70057","DOIUrl":"https://doi.org/10.1002/ctd2.70057","url":null,"abstract":"&lt;p&gt;Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of mortality and morbidity worldwide. Plasma low-density lipoprotein (LDL) cholesterol levels are positively correlated with the risk of ASCVD. Current lipid-lowering medications, such as statins and PCSK9 inhibitors, can effectively reduce plasma LDL cholesterol levels and lower ASCVD risk.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; However, the residual risk remains high.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Therefore, there is an urgent need to develop alternative therapeutic strategies for patients who do not respond to existing treatments.&lt;/p&gt;&lt;p&gt;Atherosclerosis is the hardening and narrowing of arteries, accompanied by chronic inflammation. The development and progression of atherosclerosis involve the dysfunction and activation of multiple cell types and signalling pathways within the arteries. Emerging evidence demonstrates that vascular endothelial cells play a critical role in this process, highlighting their potential as a therapeutic target for preventing and treating ASCVD.&lt;/p&gt;&lt;p&gt;Endothelial cells line the inner surface of blood vessels and are essential for regulating vascular tone and structure. They control the permeability of blood vessels, preventing the entry of lipoproteins and leukocytes and thereby reducing the development of atherosclerosis. Additionally, endothelial cells have antiplatelet, anticoagulant and fibrinolytic functions. However, when endothelial cells become activated and dysfunctional, they promote atherosclerosis progression and contribute to cardiovascular events, such as plaque erosion. Activated endothelial cells express adhesive molecules and inflammatory mediators, which stimulate inflammation. Dysfunctional endothelial cells compromise vascular integrity and increase the permeability of lipoprotein particles, leading to lipid accumulation in the intima.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Therefore, targeting endothelial cells presents a promising therapeutic approach for the treatment of ASCVD. However, achieving this requires a comprehensive understanding of the pathophysiology and underlying mechanisms of endothelial cells in atherogenesis, areas that remain elusive.&lt;/p&gt;&lt;p&gt;In a recent publication in &lt;i&gt;Clinical and Translational Medicine&lt;/i&gt;, Yu et al. reported that Endonuclease/Exonuclease/Phosphatase Family Domain Containing 1 (EEPD1) is a crucial regulator of inflammation and apoptosis in endothelial cells during atherogenesis, acting through the Kruppel-like factor 4 (KLF4)–EEPD1–extracellular signal-regulated kinase (ERK) signalling axis (Figure 1).&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; EEPD1, an endonuclease, plays a vital role in DNA repair and maintaining genome stability.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; The authors reported that EEPD1 expression was elevated in both human and murine atherosclerotic plaques. They demonstrated that knockout of &lt;i&gt;Eepd1&lt;/i&gt; in &lt;i&gt;ApoE&lt;/i&gt;-deficient mice provided significant vascular protection, reducing macrophage infiltration, endothelial ce","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074324","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":"scICB: A pan-cancer database of human temporal immune checkpoint blockade therapy at single-cell transcriptomic resolution","authors":"Fansen Ji,&nbsp;Weitong Bi,&nbsp;Jiawei Zhang,&nbsp;Bingjun Tang,&nbsp;Ying Xiao,&nbsp;Huan Li,&nbsp;Hao Liu,&nbsp;Boyang Wu,&nbsp;Fei Yu,&nbsp;Shizhong Yang,&nbsp;Gang Xu,&nbsp;Jiahong Dong","doi":"10.1002/ctd2.70044","DOIUrl":"https://doi.org/10.1002/ctd2.70044","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;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/.&lt;/p&gt;&lt;p&gt;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.&lt;/p&gt;&lt;p&gt;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,&nbsp;Hui Luo","doi":"10.1002/ctd2.70052","DOIUrl":"https://doi.org/10.1002/ctd2.70052","url":null,"abstract":"&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; 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 &lt;b&gt;&lt;i&gt;Clinical and Translational Medicine&lt;/i&gt;&lt;/b&gt;, titled “Single-cell RNA-sequencing and spatial transcriptomic analysis reveal a distinct population of APOE&lt;sup&gt;−&lt;/sup&gt; cells yielding pathological lymph node metastasis in papillary thyroid cancer”, provides groundbreaking insights into this issue.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; By integrating single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the authors identify a previously unrecognized APOE&lt;sup&gt;−&lt;/sup&gt; 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.&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; 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&lt;sup&gt;−&lt;/sup&gt; cells to invasive tumor margins, where they interacted with immunosuppressive macrophages and fibroblasts. This spatial resolution confirmed that APOE&lt;sup&gt;−&lt;/sup&gt; cells serve as “metastatic hubs,” orchestrating a microenvironment conducive to lymphatic invasion. The identification of APOE&lt;sup&gt;−&lt;/sup&gt; cells as key drivers of PTC metastasis thus represents a novel and intriguing finding.&lt;/p&gt;&lt;p&gt;The promise of this study lies in its potential to revolutionize the management of PTC patients. By identifying APOE&lt;sup&gt;−&lt;/sup&gt; 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}