Clinical and translational discovery最新文献

{"title":"Milk exosomes: Harnessing nature's duality for cancer therapy","authors":"Asmit Das,&nbsp;Swarup Sonar,&nbsp;Ketki Kalele,&nbsp;Vetriselvan Subramaniyan","doi":"10.1002/ctd2.349","DOIUrl":"https://doi.org/10.1002/ctd2.349","url":null,"abstract":"<p>Milk exosomes, extracellular nanovesicles that are naturally present in milk, have gained significant attention in cancer research for their potential to revolutionize cancer treatment strategies. They possess a specific set of characteristics that make them promising nanoscale vehicles for targeted drug delivery systems. Their inherent biocompatibility, coupled with their ability to effectively encapsulate and transport therapeutic agents directly into tumor cells, suggests the possibility of developing novel cancer therapies, potentially minimizing side effects associated with conventional therapies. However, recent studies have shown that milk exosomes have a dual nature, which is not entirely positive. Although they show potential in delivering anticancer therapeutics, evidence suggests they may also, under certain conditions, contribute to cancer progression. This paradoxical nature necessitates a better understanding of how they interact and work in different stages of cancer. Further investigation is crucial to understand the factors influencing their behaviour and to develop strategies that can maximize their therapeutic prospects while mitigating potential risks associated with their use in cancer treatment.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.349","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732551","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":"Novel insights into the pathological features of COPD: Focus on oxidative stress and mitophagy","authors":"Jiameng Gao,&nbsp;Yao Shen,&nbsp;Zhihong Chen","doi":"10.1002/ctd2.343","DOIUrl":"https://doi.org/10.1002/ctd2.343","url":null,"abstract":"<p>Chronic airway obstructive pulmonary disease (COPD) is a preventable and curable disease characterised by persistent airflow limitation. It is characterised by chronic bronchitis and/or emphysema, and its aetiology is related to various factors such as smoking and infectious factors, and so forth. The pathogenesis is complex and prone to frequent exacerbations, and the prognosis of acute exacerbations of COPD is often poor. As a crucial component of the innate immune system, lung macrophages significantly influence the onset and progression of COPD. When macrophage mitochondria become dysfunctional, many macrophage functions (e.g., phagocytosis, cytokine secretion, chemotaxis, etc.) change. The aim of this paper is to describe the three major pathological features of COPD (oxidative stress imbalance, macrophage polarisation and mitochondrial membrane potential [MMP] production and mitochondrial autophagy), to describe in detail the mechanism of mitochondrial autophagy pathway and its association with oxidative stress and macrophage polarisation and to emphasise the role of macrophage mitochondrial reactive oxygen species (mROS) in COPD, with the aim of providing ideas and directions for subsequent studies.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.343","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732550","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":"Tracking down metabolic vulnerabilities in CDK12-mutant prostate cancer","authors":"Wei-Ling Tu,&nbsp;Mu-En Wang,&nbsp;Ming Chen","doi":"10.1002/ctd2.345","DOIUrl":"https://doi.org/10.1002/ctd2.345","url":null,"abstract":"<p><i>CDK12</i> is among the most frequently mutated cyclin-dependent kinases (CDKs) in various cancers, including prostate, ovarian, breast, esophageal, bladder, and colon cancers.<span>¹</span> Specifically, biallelic aberrations of <i>CDK12</i> occur in 3%–7% of metastatic castration-resistant prostate cancer (mCRPC) cases and correlate with poor prognosis.<span>¹</span> One of the most well-studied functions of CDK12 is its orchestration of transcription initiation and elongation through cyclin K-dependent Ser2 phosphorylation of RNA polymerase II,<span>²</span> and therefore CDK12 is important in regulating the expression of long genes or genes with high exon numbers, especially DNA damage response (DDR)-related genes such as <i>BRCA1</i>, <i>ATR</i>, <i>FANCI</i>, and <i>FANCD21</i>.<span>³</span> As a result, <i>CDK12</i>-deficient cancers are commonly characterized by focal tandem duplications (FTDs) and various features of genome instability.<span>^{4, 5}</span> Because FTDs often generate a large amount of neoantigens, it has been suggested that <i>CDK12</i>-deficient tumours may be more sensitive to immunotherapy.<span>⁵</span> However, studies of immune checkpoint blockade therapy have shown only limited effects in mCRPC patients harbouring <i>CDK12</i> mutations.<span>⁶</span> Likewise, despite the observed sensitization of <i>CDK12</i>-deficient ovarian cancer cells to PARP inhibitors (PARPi) due to impaired DDR functionality,<span>⁷</span> clinical trials of PARPi have produced unsatisfactory results in prostate cancer patients with <i>CDK12</i> mutations.<span>⁶</span> Therefore, there is an urgent need to identify exploitable vulnerabilities in <i>CDK12</i>-deficient prostate cancer.</p><p>In a recent study, Zhang et al. investigated the impact of <i>CDK12</i> deficiency on cell metabolism and tumour progression in prostate cancer.<span>⁸</span> By analyzing public datasets, they confirmed an association between <i>CDK12</i> deficiency and poor prognosis in mCRPC, while noting higher levels of <i>CDK12</i> mutations in Chinese patients (15.4%–27.2%) than in the global populations (4.7%). To further delineate how <i>CDK12</i> deficiency promotes mCRPC, they generated <i>CDK12</i>-knockout prostate cancer cell lines using CRISPR-Cas9 technology and conducted metabolomic and transcriptomic analyses. The resulting data showed that <i>CDK12</i> deficiency reprogrammed energy metabolisms in prostate cancer cells; specifically, <i>CDK12</i> knockout cells exhibited higher levels of metabolites related to glycolysis, glutaminolysis, and the tricarboxylic acid cycle, but lower levels of metabolites related to β-oxidation. Further, the associated RNA-seq data showed enrichment of mitochondrial electron transport chain (ETC) and oxidative phosphorylation-related pathways in <i>CDK12</i>-deficient prostate cancers, suggesting that <i>CD","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732552","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":"Clinical signature of exosomal tetraspanin proteins in cancer","authors":"Asmit Das,&nbsp;Priyanka Saha,&nbsp;Ketki Kalele,&nbsp;Swarup Sonar","doi":"10.1002/ctd2.341","DOIUrl":"https://doi.org/10.1002/ctd2.341","url":null,"abstract":"<p>Exosomes are nano-scale vesicles involved in intercellular communication and have a significant role in cancer progression. Tetraspanins, are transmembrane proteins enriched in exosomes. These proteins have significant role in exosome biogenesis, cargo sorting,and target-cell interactions, influencing tumor development and therapeutic response. Exosomal tetraspanins, including CD9, CD63, CD81, and Tspan8, contribute to tumor cell proliferation, angiogenesis, extracellular matrix remodelling, immune evasion, and promote metastasis. Their ability to prepare distant organ sites for colonization highlights their role in establishing the premetastatic niche. Expression profiling of exosomal tetraspanin proteins in cancer become a promising diagnostic and prognostic biomarker. Exosomal tetraspanin proteins also be an effective therapeutic target in cancer.This article highlighted impactful role ofexosomal tetraspanin Proteins in Cancer.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639518","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":"Clinical and translational research on cancer of the stomach and gastroesophageal junction: A pathologist's view","authors":"Christoph Röcken","doi":"10.1002/ctd2.332","DOIUrl":"https://doi.org/10.1002/ctd2.332","url":null,"abstract":"<p>Adenocarcinomas of the stomach and gastroesophageal junction remain one of the most common malignant tumours in humans worldwide, often with a poor prognosis. Particularly in countries without upper gastrointestinal tract screening endoscopy, tumours that have been asymptomatic for a long time are only diagnosed at an advanced stage. This limits the therapeutic options. Often only palliative therapy concepts are available. Great progress has been made in the last two decades. The genetic basis of adenocarcinomas of the stomach and gastroesophageal junction has been deciphered and new targeted drugs have been developed. Cell and tissue-based predictive diagnostics are becoming increasingly important in therapy planning. Here, surgical pathology forms an important link between basic research, clinical trials, and translation into clinical application. This review article summarizes the experiences made in translational tumour research, which point to the problems of spatial and temporal intratumoral heterogeneity of adenocarcinomas of the stomach and gastroesophageal, the development and continuous re-assessment of therapeutically relevant cut-off values, resistance mechanisms, tumour microenvironment, sexual dimorphism and the pitfalls molecular tumour boards may face.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.332","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141608091","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":"Gastric cancer detection based on cell-free DNA in blood: A systematic review and meta-analysis","authors":"Mona Wang,&nbsp;Xiaohan Fan,&nbsp;Boyang Huang,&nbsp;Kaifeng Pan,&nbsp;Markus Gerhard,&nbsp;Raquel Mejías-Luque,&nbsp;Yang Zhang","doi":"10.1002/ctd2.329","DOIUrl":"https://doi.org/10.1002/ctd2.329","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Screening and early diagnosis of gastric cancer (GC) are crucial for improved prognosis. However, gastroscopic screening is not feasible in large populations due to its high cost and invasive nature. The detection of circulating cell-free DNA (cfDNA) provides an attractive minimally-invasive alternative for screening of GC. In this systematic review and meta-analysis, we evaluate the diagnostic value of cfDNA-based markers for GC, including the detection of total concentration, mutations, and methylation alterations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a systematic search of four literature databases (PubMed, Embase, Web of Science, and Cochrane Library) for articles published before November 2022. The revised tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to evaluate the quality of included studies. PROSPERO registration number: CRD42021210830.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 15 original articles involving 2849 individuals were included in this meta-analysis, comprising five studies on concentration, nine studies on methylation alterations, and one study on mutation biomarkers of cfDNA. Among these studies, seven selected early-stage GC subjects. For the diagnoses of overall stages and early-stage GC, the pooled sensitivities with 95% confidence interval were 0.74 (0.66–0.82) and 0.64 (0.51–0.76), and the pooled specificities were 0.92 (0.84–0.96) and 0.94 (0.87–0.98) with summary areas under the curve (SAUCs) of 0.89 (0.86–0.91) and 0.86 (0.83–0.89), respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This meta-analysis suggests that cfDNA-based biomarkers show diagnostic value for GC early detection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.329","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597086","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":"Plant-derived exosomes: A new frontier in nano-medicine for cancer and microbial infection therapy","authors":"Swastika Maitra,&nbsp;Subham Sarkar,&nbsp;Bikram Dhara","doi":"10.1002/ctd2.342","DOIUrl":"https://doi.org/10.1002/ctd2.342","url":null,"abstract":"<p>Exosomes, small extracellular vesicles secreted by cells, have emerged as pivotal players in cell-to-cell communication. Plant-derived exosomes, in particular, are gaining attention for their potential therapeutic applications in nano-medicine. These vesicles are naturally occurring nanoparticles that carry bioactive molecules such as proteins, lipids, and nucleic acids. Due to their biocompatibility, low toxicity, and ability to traverse biological barriers, plant-derived exosomes present a promising alternative to synthetic nanoparticles for drug delivery, especially in cancer and microbial infection therapy. Exosomes are secreted by almost every cell and are profusely present in all living organisms, making them excellent candidates for a large spectrum of research and applications. This paper describes the highly organized and regulated biosynthesis of exosomes and the prospects of their application in cancer therapy and treatment of microbial infections.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.342","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141583913","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":"Targeting autophagy: A promising approach for the treatment of breast cancer brain metastases","authors":"Steffan T. Nawrocki,&nbsp;Claudia M. Espitia,&nbsp;Maria Janina Carrera Espinoza,&nbsp;Madison E. Gamble,&nbsp;Sruthi Sureshkumar,&nbsp;Mengyang Chang,&nbsp;Wei Wang,&nbsp;Jennifer S. Carew","doi":"10.1002/ctd2.340","DOIUrl":"https://doi.org/10.1002/ctd2.340","url":null,"abstract":"<p>Patients with breast tumours that metastasise to the brain have limited treatment options and a very poor prognosis. More effective therapeutic strategies are desperately needed for this patient population. Recent evidence demonstrates that brain metastases arising from breast tumours display altered energy production that results in enhanced autophagy. Preclinical studies have shown that genetically or pharmacologically disrupting the autophagy pathway significantly decreases the brain metastatic burden, resulting in improved animal survival and increased sensitivity to lapatinib. These findings pave the way for the development of novel strategies targeting autophagy for breast cancer patients with brain metastatic disease.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141556623","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":"PROteolysis Targeting Chimeras: A new cutting-edge nanomedicine for colorectal cancer","authors":"Swastika Maitra,&nbsp;Nobendu Mukerjee,&nbsp;Dattatreya Mukherjee,&nbsp;Arabinda Ghosh,&nbsp;Athanasios T. Alexiou","doi":"10.1002/ctd2.337","DOIUrl":"https://doi.org/10.1002/ctd2.337","url":null,"abstract":"<p>Colorectal cancer (CRC) is a prevalent malignancy with a high mortality rate, necessitating innovative treatment strategies. PROTACs (PROteolysis Targeting Chimeras) represent a promising therapeutic approach by targeting and degrading oncogenic proteins via the ubiquitin-proteasome pathway. This study explores the potential of using exosomes as delivery vehicles for PROTACs to enhance treatment efficacy. Exosomes, due to their biocompatibility and inherent targeting capabilities, offer a precise method for delivering PROTACs to CRC cells, potentially overcoming challenges associated with traditional therapies such as drug resistance and off-target effects. By harnessing the advantages of both exosome-based delivery and PROTAC technology, this approach aims to improve targeted protein degradation and therapeutic outcomes in CRC treatment. Further research is required to optimize exosome engineering, ensure efficient PROTAC loading, and validate the safety and efficacy of this novel therapeutic strategy through preclinical and clinical trials.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.337","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536626","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":"Modified plant-derived exosomes: Precision medicine in cancer treatment","authors":"Swastika Maitra,&nbsp;Subham Sarkar,&nbsp;Bikram Dhara","doi":"10.1002/ctd2.338","DOIUrl":"https://doi.org/10.1002/ctd2.338","url":null,"abstract":"<p>Plant-derived exosomes (PDEs) are extracellular vesicles (EVs) occurring naturally,which have propitious applications in the development of cost-effective and fruitful cancer therapy with minimum aftereffects and ramifications. Recent advancements in research based on PDEs demonstrate their extraordinary advantages in cancer therapy. The components of PDEs exhibit accomplished cancer prevention activity and having insignificant or negligible toxicity. The conventional methods to deliver drugs to the target have various problems, several of which can be solved by using PDEs for drug delivery. The main constituents of PDEs are proteins, lipids, DNA and RNA. PDEs are believed to revolutionize cancer therapy due to their magnificent attributes, but only a few clinical trials on PDEs are in progress. The mechanisms and regulations by which PDEs execute anticancer properties are yet not completely understood. Hence, research are conducted worldwide to understand the mechanisms of action of cancer antagonist PDEs more comprehensively and perspicuously. Modified PDEs have prospect in evolution of precision medicine which can bring a new dimension in the treatment of cancer.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536904","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}