Clinical and translational discovery最新文献

{"title":"A novel mechanism for maintaining spindle normality in mammalian oocytes","authors":"Zhi-Xia Yang,&nbsp;Zi-Fu Wang,&nbsp;Dong Zhang","doi":"10.1002/ctd2.70089","DOIUrl":"https://doi.org/10.1002/ctd2.70089","url":null,"abstract":"<p>Mammalian oocyte meiosis holds distinct features from mitosis in many aspects. For example, the organisation of the spindle poles, the separation processes of the chromosomes, the way microtubules (MTs) are nucleated and so forth.<span>¹</span> Many issues about oocyte meiosis are still to be addressed. Moreover, in the past decade, researchers found that oocyte meiosis in primates, including humans, employed some specific proteins or structures, making the mechanical study of mammalian oocyte meiosis more complicated.<span>^2-4</span> Among these primate-specific proteins, TUBB8 is the most conspicuous since the Tubb8 mutation in humans accounts for about 30% or more of abnormal clinical cases in MI arrest, fertilisation failure, and early embryo development arrest.<span>^{5, 6}</span> However, there are still many unaddressed questions about TUBB8. For example, what's the exact mechanism by which TUBB8 function to organise and stabilise spindle MTs? Are there effective and easy strategies to rescue all sorts of spindle defects caused by different TUBB8 mutations? Recently, a work by Hui Luo et al has made significant progress on both questions.<span>⁷</span></p><p>For the first question, through a combination of multiple cell biological &amp; molecular biology, and biochemistry techniques, they found that TUBB8-D417N expression significantly disrupted its interaction with EB1, a fundamental MT nucleator and polymerizer, and thereby dis-localised EB1; meanwhile, the EB1 protein level didn't change, suggesting that TUBB8 help the correct localisation of EB1. EB1 mislocalisation in turn seriously disrupted the distribution of several other MT nucleators, including CKAP5 and TACC, but didn't affect their protein levels (Figure 1). In addition, TUBB8-D417N expression also broke up the localisation of several critical MT polymerisers and stabilisers, including TPX2, Ran-GTP and KIF11. All these suggest that TUBB8 is fundamentally important for MT nucleation &amp; polymerisation and the maintenance of spindle bipolarity.</p><p>Nonetheless, it's this study that incites the upper issues, and many others. Therefore, it is a very important and enlightening work. It would be exciting to expect further related investigations. Figure 1</p><p>Zhi-Xia Yang wrote the manuscript and made the graphic abstract image. Dong Zhang and Zi-Fu Wang proofread and gave advice. All authors read and approved the final manuscript.</p><p>The authors declare no conflict of interest.</p><p>Not applicable.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145272168","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":"Advances in epilepsy associated with 16p11.2 microdeletion syndrome","authors":"Qikai Zhao,&nbsp;Shuqi Liang,&nbsp;Xiao Wu,&nbsp;Xiaohui Min,&nbsp;Nooraynee Bibi Needah Ginowree,&nbsp;Gang Zhang","doi":"10.1002/ctd2.70088","DOIUrl":"https://doi.org/10.1002/ctd2.70088","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>16p11.2 microdeletion syndrome is a genetic disorder with a population prevalence of approximately 2.84.3 per 100,000 individuals. Epilepsy is one of its core symptoms, significantly impacting neurodevelopment and quality of life. Current treatment strategies are shifting from empirical antiepileptic drug use toward mechanism-based precision therapy. Epilepsy in this syndrome typically presents in infancy, with focal seizures as the most common type.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Electroencephalogram findings often include focal or multifocal epileptiform discharges. Genomic deletions affecting key genes such as PRRT2, KCTD13, TAOK2, QPRT, and SEZ6L2 contribute to neurodevelopmental abnormalities, synaptic dysfunction, and excitatory-inhibitory imbalance through dysregulated molecular pathways including RhoA signaling, microtubule dynamics, and quinolinic acid metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Clinically, levetiracetam shows limited efficacy in PRRT2-related epilepsy, whereas valproate, oxcarbazepine, and topiramate are often effective. Emerging therapeutic strategies target specific molecular mechanisms, such as RhoA inhibition or modulation of the kynurenine pathway. The integration of genetic diagnosis with pathway-specific interventions offers promising avenues for improving seizure control and neurodevelopmental outcomes in patients with 16p11.2 microdeletion syndrome. In this article, we review the clinical features.molecular mechanisms and therapeutic strategies of 16p11.2 microdeletion.associated epilepsy to provide a theoretical basis for precision diagnosis and treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146513","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 comprehensive atlas of pediatric immune checkpoint inhibitors-related adverse events: From real-world pharmacovigilance data to mechanistic insights","authors":"Anqi Lin,&nbsp;Junyi Shen,&nbsp;Zhenyu Xie,&nbsp;Quan Cheng,&nbsp;Jian Zhang,&nbsp;Peng Luo","doi":"10.1002/ctd2.70086","DOIUrl":"https://doi.org/10.1002/ctd2.70086","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immune checkpoint inhibitors (ICIs) are widely used in childhood cancer, posing challenges with associated ICIs-related adverse events (irAEs). This study focuses on pediatric irAEs and explores underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data on ICI-related adverse reactions were gathered from two sources: VigiBase database (1967–2023) and the FDA Adverse Event Reporting System (FAERS) database (2013–2022). Disproportionality analysis (Reporting odds ratio, proportional reporting ratio, information component) compared pediatric and adult cancer patients using ICIs. Integration with the Gene Expression Omnibus (GEO) database explored potential biological mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified four categories of pediatric irAEs in the VigiBase and FAERS databases, including cytokine release syndrome (ROR_VigiBase = 17.05; ROR_FAERS = 14.17), acute respiratory distress syndrome (ROR_VigiBase = 10.26; ROR_FAERS = 12.39), seizure (ROR_VigiBase = 7.18; ROR_FAERS = 10.63), and febrile neutropenia (FN) (ROR_VigiBase = 3.01; ROR_FAERS = 4.84). The development of irAEs in pediatric patients potentially involves various pathways: immune activation, inflammatory imbalance, pathogen recognition systems, decreased inhibitory synapses, altered E/I ratios, and CNS abnormalities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study explores pediatric irAEs, revealing potential mechanisms and stressing tailored prevention for young cancer patients on ICIs, providing theoretical insights for better management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146733","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":"Intravital microscopy contribution to cancer: From preclinical to human studies","authors":"Diogo Moniz-Garcia,&nbsp;Wan-Hsin Lin,&nbsp;Loizos Michaelides,&nbsp;Anthony Quagliano,&nbsp;Emmanuel Gabriel,&nbsp;Alfredo Quinones-Hinojosa","doi":"10.1002/ctd2.70051","DOIUrl":"https://doi.org/10.1002/ctd2.70051","url":null,"abstract":"<p>Intravital microscopy enables dynamic and real-time visualisation of microscopic structures in living tissues without the need for fixation, with real-life applicability being illustrated by several first-in-human studies in different cancers. Its use in preclinical models has yielded important observations of the microvasculature of both healthy and diseased tissues. It has further enabled the observation of the interactions between important components of the tissue microenvironment such as immune cells and neighbouring microvessels. Important recent technological advances, however, have enabled the translation of this technology to human use. Here, we review the main advances in intravital microscopy and some of the most recent uses in different human disease settings.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110721","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":"Translational values of tissue-resident memory T cells in chronic inflammation and cancer","authors":"Wanxin Duan,&nbsp;Xiangdong Wang","doi":"10.1002/ctd2.70078","DOIUrl":"https://doi.org/10.1002/ctd2.70078","url":null,"abstract":"&lt;p&gt;T cells are central orchestrators of adaptive immunity and play important and complex roles in chronic inflammation, despite that their roles remain even paradoxical. The dysregulations of T cells occur in chronic diseases, such as inflammation and cancer, from being protectors to potent drivers of tissue pathology.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; Of those, the pro-inflammatory tissue-resident memory (TRM) T cells accumulate within the tissue, perpetuating a cycle of inflammation. Subsets of TRM T cells, including those producing the highly inflammatory cytokine interleukin-17 (IL-17), are directly implicated in tissue damage, to form the ectopic lymphoid tissues, remodel the microenvironment, and amplify the local response in inflammation and cancer.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Reformed lymphoid alter local gradients of inflammatory mediators to trap and retain more lymphocytes and exacerbate the microenvironmental bioecology. The pre-activated TRM-like T cells harboured in lungs of smokers as the pre-existing state of a tissue can create an immune pressure that reprograms subsequent tumour evolution and response to therapy and profoundly influences disease progression.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The deep understanding of TRM T-cell phenomes and bio-behaviours provides new insights for the identification of diagnostic biomarkers and therapeutic targets. The TRM T cells as a special type of memory T cells are categorised on basis of the locations (e.g., gut-TRM, lung-TRM, brain-TRM), cell surface antigens (e.g., CD8&lt;sup&gt;+&lt;/sup&gt; TRM, CD4&lt;sup&gt;+&lt;/sup&gt; TRM) or cell identity gene markers measured by single-cell RNA sequencing (scRNA-seq).&lt;span&gt;&lt;sup&gt;7-9&lt;/sup&gt;&lt;/span&gt; One of biological characteristics is their long-term residence in specific tissue to take an immediate action in the initiation of immune responses to invaded pathogens and reduction infectious spreads, faster than circulating memory T cells. Of those, CD8&lt;sup&gt;+&lt;/sup&gt; TRM T cells are the majority responsible for antiviral and anti-tumour immunity and can directly terminate infected cells and pathogen replication by releasing inflammatory mediators and enzymes. CD4&lt;sup&gt;+&lt;/sup&gt; TRM can support other immune cells (such as B cells for antibody production, macrophages for activation) and regulate local immune responses to infectious and autoimmune diseases by enhancing the synergistic effects of the immune networks. In addition, TRM T cells play critical roles in the tissue repair by controlling microenvironmental contents of inflammatory mediators and recognising abnormal cells such as infected cells or cancer cells to reduce the risk of tissue damage and maintain microenvironmental immune bioecology. The molecular processes of reservable immune memory in TRM T cells can provide a number of alternatives for vaccination and immunotherapy.&lt;/p&gt;&lt;p&gt;Recent redefinition of redefining T-cell behaviour in inflamed or tumour microenvironment are largely driven by high-resolution techniques such as scRN","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101917","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":"Genetic insights into congenital heart disease: Prevalence, aetiology and clinical implications","authors":"Yuan Yuan,&nbsp;Yi Jia,&nbsp;Shasha Peng,&nbsp;Shuru Zhao,&nbsp;Kang Dong,&nbsp;Yuruo Hu,&nbsp;Zicheng Zhao,&nbsp;Xiaofei Jiang,&nbsp;Zhe Zhang","doi":"10.1002/ctd2.70087","DOIUrl":"https://doi.org/10.1002/ctd2.70087","url":null,"abstract":"<p>Congenital heart disease (CHDs) pose a significant public health burden, impacting nearly 1% of newborns each year. This review focuses on the genetic aspects of CHDs, examining their prevalence, causes and the significant advancements in genetic technologies used for their diagnosis and management. We cover the wide range of CHDs, from minor septal defects to critical conditions like hypoplastic left heart syndrome, and underscore the complex interaction among genetic and environmental influences contributing to these defects. The review stresses the importance of understanding genetic inheritance patterns, especially in families with a history of CHDs, and the essential role of genetic counselling in evaluating familial risk and informing reproductive choices. We also explore the latest developments in genetic technologies, such as genome-wide association studies, single-nucleotide variations and copy number variants, which have greatly improved our ability to pinpoint genetic risk factors for CHDs. These genetic discoveries have important clinical applications, including their use in tailoring treatment plans and enhancing prenatal diagnosis. This review aims to elucidate the genetic architecture of CHDs by integrating findings from recent research, with the goal of enhancing the lives of those affected and their families.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101202","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":"Beyond the paradox: Cardiac-specific miR-106a delivery as a translational turning point for heart failure?","authors":"Wei-Wen Lim","doi":"10.1002/ctd2.70084","DOIUrl":"https://doi.org/10.1002/ctd2.70084","url":null,"abstract":"&lt;p&gt;Heart failure (HF) remains a global health burden and a leading cause of death and disability. In Asia, HF prevalence is projected to reach 74.5 million by 2050, a 127.6% increase from 2025,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; driven by rising cardiometabolic disease across the region. While current therapies target haemodynamic impairment and pathological neurohormonal hyperactivation, they offer limited benefit against progressive myocardial decline and cardiovascular mortality. Novel therapeutics are urgently needed to overcome challenges of poor tissue specificity, limited intracellular delivery and suboptimal pharmacokinetics.&lt;/p&gt;&lt;p&gt;MicroRNAs (miRNAs) are small non-coding RNAs, typically 20–24 nucleotides long, that regulate key post-transcriptional gene expression by binding to complementary sequences in messenger RNAs (mRNAs), leading to mRNA degradation or inhibition of translation. MiRNAs have recently emerged as promising biomarkers and potential therapeutic targets in HF. Their clinical translation, however, hinges on precise delivery to minimize off-target effects and enhancing biodistribution. In this context, Lu et al. recently reported a cardiac targeting peptide (CTP; 12-amino acid sequence APWHLSSQYSRT) conjugated to miR-106a (CTP–miR-106a), which reversed cardiac hypertrophy and dysfunction in an angiotensin II/isoproterenol-induced mouse model of HF.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This study builds on prior in vitro evidence demonstrating that CTP–miR-106a selectively attenuates phenylephrine- and angiotensin II-induced cardiomyocyte hypertrophy, with preferential uptake over the human embryonic kidney 293 cell line, cardiac fibroblasts and endothelial cells.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Following intravenous administration of 10 mg/kg of the dual-reporter construct Cy5.5–CTP–miR-106a–Cy3, which is linked via a disulphide bond cleavable by endogenous reductases to release Cy5.5–CTP and miR-106a–Cy3, cardiac expression of miR-106a peaked at 30 min post-injection.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This was accompanied by tissue-level expression of the miR-106a–Cy3 reporter. The Cy5.5–CTP moiety was subsequently expelled from the myocardium within 3.5 h and cleared via hepatic and renal pathways. In contrast, miR-106a–Cy3 remained upregulated in cardiac tissue at 3.5 h, and elevated miR-106a mRNA levels persisted up to 7 days. Importantly, neither miR-106a–Cy3 nor miR-106a gene expression was detected in the liver, kidney or lung, suggesting cardiac-specific uptake. However, this observation contrasts with earlier studies by the same group, in which mice injected with 10 mg/kg of Cy5.5–CTP alone (without miR-106a moiety) exhibited robust and peak uptake in the liver and kidney as early as 15 min post-injection.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; This uptake paralleled the observations in the heart but declined more slowly, indicating delayed clearance.&lt;/p&gt;&lt;p&gt;Despite these findings, the precise mechanisms underlying CTP's cardiac specificity remain unclear. It i","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022225","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":"The role of tertiary lymphoid structures in renal cell carcinoma: From predictive biomarker to therapeutic target","authors":"Chongxiang Gao,&nbsp;Du Cai,&nbsp;Jianguang Qiu,&nbsp;Feng Gao","doi":"10.1002/ctd2.70085","DOIUrl":"https://doi.org/10.1002/ctd2.70085","url":null,"abstract":"&lt;p&gt;In the evolving landscape of cancer immunotherapy, tertiary lymphoid structures (TLS) have rapidly transitioned from a histological curiosity to a central mediator of anti-tumour immunity.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; A growing body of evidence, particularly within renal cell carcinoma (RCC), has established a strong association between the presence of dense, mature TLS in the tumour microenvironment (TME) and significant clinical benefit from immune checkpoint inhibitor (ICI) therapy. A recent meta-analysis provided high-level evidence for this, confirming that high TLS density correlates with superior objective response rates and prolonged progression-free survival across solid tumours, including RCC.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This consensus is not only reshaping our understanding of the TME but also charting new paths for therapeutic innovation.&lt;/p&gt;&lt;p&gt;The significance of TLS lies in their function as fully equipped, in situ immune factories. Groundbreaking work using spatial transcriptomics has beautifully elucidated that within the TLS of RCC, a complete B cell maturation process occurs — from B cell recruitment and germinal centre reactions to the generation of antibody-producing plasma cells.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; These locally produced IgG antibodies can directly bind to and mark tumour cells for apoptosis. This elegant mechanism provides a compelling explanation for why TLS signatures are a key immunogenomic determinant for ‘exceptional responders’ to combination immunotherapy in RCC.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;However, the clinical utility of TLS is not a simple binary question; its value is deeply rooted in its heterogeneity. First, location and maturity are paramount. Studies indicate that it is the intratumoral and mature (i.e. secondary follicle-like) TLS that are most strongly associated with favourable outcomes and ICI efficacy.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Second, the value of TLS is highly context-dependent on the surrounding immune milieu. A pivotal study proposed a more refined paradigm: optimal response to PD-1 blockade in RCC requires the combination of high TLS density with a low abundance of tissue-resident exhausted CD8&lt;sup&gt;+&lt;/sup&gt; T cells.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; This suggests that even a potent ‘immune factory’ is of limited use if the effector T cells are already terminally dysfunctional. This complex interplay may explain paradoxical reports of TLS correlating with poor prognosis in some RCC cohorts.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;These deepening insights are paving the way for clinical translation and future therapeutic strategies. To overcome the challenges of invasive biopsies, developing non-invasive surrogates is critical. An important clinical study has linked the baseline level of circulating unswitched memory B cells with the presence of intratumoral TLS and improved survival in patients with RCC treated with nivolumab, presenting a promising avenue for a liquid biopsy approach.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; This ","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022226","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":"Computational modeling and simulation in oncology","authors":"Christian Baumgartner","doi":"10.1002/ctd2.70082","DOIUrl":"https://doi.org/10.1002/ctd2.70082","url":null,"abstract":"<p>Computational modeling and simulation are playing an increasingly important role in oncology, bridging biological research, data science and clinical practice to better understand cancer complexity and inform therapeutic development. This special issue presents recent advances in multiscale modeling, artificial intelligence-driven systems, digital twins, and in silico trials, illustrating the evolving potential of computational tools to support innovation from bench to bedside. Together, these contributions outline a future in which precision medicine, adaptive therapies and personalized diagnostics are guided by integrative and predictive modelling approaches.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998752","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":"The SLC39A1-DRP1 axis: A paradigm shift in targeting mitochondrial dynamics for HCC therapy","authors":"Jing Zhao,&nbsp;Dengke Bao","doi":"10.1002/ctd2.70074","DOIUrl":"https://doi.org/10.1002/ctd2.70074","url":null,"abstract":"&lt;p&gt;No abstract available&lt;/p&gt;&lt;p&gt;Hepatocellular carcinoma (HCC) remains a formidable global health challenge, with recurrence rates exceeding 70% post-resection due to elusive molecular drivers.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The groundbreaking study by Li et al. (CTM2-2024-12-4200) unveils the SLC39A1-DRP1 interaction as a linchpin in HCC recurrence, bridging mitochondrial dysfunction to therapeutic innovation.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Here, we distil the study's transformative insights and their implications for precision oncology.&lt;/p&gt;&lt;p&gt;SLC39A1, traditionally known for zinc transport, emerges as an oncogenic disruptor of mitochondrial quality control. Li et al. demonstrate that SLC39A1 hyperactivates DRP1, triggering aberrant fission, mitophagy, and ROS suppression—key survival mechanisms for residual HCC cells. Strikingly, this effect is zinc—independent, challenging dogma and revealing a moonlighting role for SLC39A1 in mitochondrial dynamics. The study's multi-omics rigor—spanning clinical cohorts (&lt;i&gt;n&lt;/i&gt; = 27), TCGA validation, and genetically engineered mice—solidifies SLC39A1 as a prognostic biomarker and actionable target.&lt;/p&gt;&lt;p&gt;The study's crowning achievement is a rationally designed peptide that disrupts SLC39A1-DRP1 binding, restoring mitochondrial homeostasis and inducing apoptosis in preclinical models. This approach outshines broad-spectrum inhibitors by precision-targeting a nodal interaction, minimizing off-target effects. The peptide's efficacy in xenografts underscores its potential as an adjuvant therapy to curb post-surgical recurrence—a critical unmet need.&lt;/p&gt;&lt;p&gt;Previous work by Bao et al.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; established that DRP1-mediated mitochondrial fission promotes cancer metastasis through cytosolic mtDNA release and TLR9/NF-κB pathway activation, a mechanism that aligns with and strengthens Li et al.’s observations of DRP1's pro-tumorigenic role in HCC. While SLC39A1 has been primarily characterized as a zinc transporter involved in maintaining cellular zinc homeostasis,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; this study uncovered a zinc-independent oncogenic mechanism, significantly expanding our understanding of its functional diversity in cancer progression. However, several key controversies and knowledge gaps emerge when situating these findings within the larger literature. The role of autophagy in cancer remains particularly contentious—while previous study demonstrated tumour-suppressive effects through p62/SQSTM1-mediated pathways,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Li et al.’s data suggest SLC39A1-induced autophagy promotes HCC recurrence, potentially indicating stage- or context-dependent functionality. This paradox is further complicated by tissue-specific differences in SLC39A1 activity. Notably, in prostate cancer models, SLC39A1 exhibits tumour-suppressive properties by inhibiting NF-κB signalling,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; starkly contrasting with its pro-tumorigenic role in HCC. These discrepancies underscore the critical","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"5 5","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923754","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}