Huai Yi Chen, Chia Rou Por, Yong Kai Hong, Eason Qi Zheng Kong, Vetriselvan Subramaniyan
This review explores the mechanisms underlying alcohol-induced oesophageal carcinogenesis, including DNA damage, oxidative stress, and nutritional deficiencies. Alcohol metabolism primarily involves alcohol dehydrogenase (ADH) converting ethanol to acetaldehyde, which can cause DNA damage, inhibit repair mechanisms, and form DNA adducts thus inhibiting DNA replication. Plus, it delves into the epidemiological evidence, genetic susceptibility, epigenetic modifications, biomarkers, and preventive strategies associated with alcohol-related oesophageal cancers. Consumption of alcohol increases the risk of gastroesophageal reflux disease thus compromising mucosal integrity of the oesophagus as dysregulation of cytokines such as IL-18, TNFA, GATA3, TLR4, and CD68 expands the intercellular spaces of epithelial cells. Genetic variants, such as ADH1B rs1229984 and ALDH2 rs671, significantly influence susceptibility to alcohol-related oesophageal cancers, with these variations affecting acetaldehyde metabolism and cancer risk. Understanding these factors is crucial for early detection, effective treatment, and the development of targeted prevention strategies. Biomarkers, such as miRNA and metabolite markers, offer non-invasive methods for early detection, while advanced endoscopic techniques provide better diagnostic accuracy. Pharmacological interventions, such as statins and proton pump inhibitors, also show potential for reducing cancer progression in high-risk individuals. Despite advances, late-stage oesophageal cancer diagnoses are still common, highlighting the need for better screening and prevention. Further research, including this study, should aim to improve early detection, personalise prevention, and explore new treatments to reduce cases and enhance outcomes in alcohol-related oesophageal cancers.
{"title":"Molecular mechanisms underlying oesophageal cancer development triggered by chronic alcohol consumption","authors":"Huai Yi Chen, Chia Rou Por, Yong Kai Hong, Eason Qi Zheng Kong, Vetriselvan Subramaniyan","doi":"10.1002/ctd2.70021","DOIUrl":"https://doi.org/10.1002/ctd2.70021","url":null,"abstract":"<p>This review explores the mechanisms underlying alcohol-induced oesophageal carcinogenesis, including DNA damage, oxidative stress, and nutritional deficiencies. Alcohol metabolism primarily involves alcohol dehydrogenase (ADH) converting ethanol to acetaldehyde, which can cause DNA damage, inhibit repair mechanisms, and form DNA adducts thus inhibiting DNA replication. Plus, it delves into the epidemiological evidence, genetic susceptibility, epigenetic modifications, biomarkers, and preventive strategies associated with alcohol-related oesophageal cancers. Consumption of alcohol increases the risk of gastroesophageal reflux disease thus compromising mucosal integrity of the oesophagus as dysregulation of cytokines such as IL-18, TNFA, GATA3, TLR4, and CD68 expands the intercellular spaces of epithelial cells. Genetic variants, such as ADH1B rs1229984 and ALDH2 rs671, significantly influence susceptibility to alcohol-related oesophageal cancers, with these variations affecting acetaldehyde metabolism and cancer risk. Understanding these factors is crucial for early detection, effective treatment, and the development of targeted prevention strategies. Biomarkers, such as miRNA and metabolite markers, offer non-invasive methods for early detection, while advanced endoscopic techniques provide better diagnostic accuracy. Pharmacological interventions, such as statins and proton pump inhibitors, also show potential for reducing cancer progression in high-risk individuals. Despite advances, late-stage oesophageal cancer diagnoses are still common, highlighting the need for better screening and prevention. Further research, including this study, should aim to improve early detection, personalise prevention, and explore new treatments to reduce cases and enhance outcomes in alcohol-related oesophageal cancers.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142860041","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}
Xuchao Gu, Xiaojun Wang, Yijing Yang, Kangwei Guan, Hung-Chen Chang, Dehua Liu, Wenhao Wang, Tao Wu, Peiqing He, Jiaofeng Wang, Jie Chen, Zhijun Bao
Introduction
As global population ages, frailty has surfaced as a major public health challenge. Given the heterogeneity of frailty in the clinical presentation, it is imperative to develop personalised diagnostic and treatment strategies. The traditional Chinese medicine (TCM) constitution offers notable advantages in discerning individual differences. This study aims to elucidate the association between TCM constitutions and frailty, providing insights into the application of TCM for the frailty management.
Methods
An observational study was conducted at Huadong hospital from July 2022 to November 2023. A total of 241 older patients were recruited. Each patient underwent assessments for the TCM constitution and frailty status. Comprehensive data collection encompassed medical history, biochemical indicators, bone mineral density (BMD), body composition and physical performance metrics. Plasma samples were also collected to detect levels of inflammatory factors and lymphogenesis-related factors, including IL-1β, TNF-α, VEGF-C, ANGPTL4 and ACV-A. Multi-level statistical analysis was used to establish the relationship of TCM constitutions with frailty.
Results
Amongst all participants, 54 individuals were classified as non-frail, 90 individuals as pre-frail and 97 individuals as frail. Regression analysis indicated that frailty was closely associated with four imbalanced TCM constitutions: Qi deficiency, phlegm dampness, blood stasis and Qi depression. Subsequent analysis demonstrated that Qi deficiency was associated with decreased BMD, phlegm dampness with elevated high-density lipoprotein levels, Blood stasis with elevated blood glucose levels, and Qi depression with both decreased BMD and elevated low-density lipoprotein levels. Furthermore, individuals characterised by imbalanced TCM constitutions exhibited inferior handgrip strength, walking pace, lower limb strength and higher levels of inflammatory factors and lymphogenesis-related factors compared to those with balanced TCM constitution.
Conclusion
Frailty is independently associated with Qi deficiency, phlegm dampness, blood stasis and Qi depression. Personalised diagnostic approaches based on the TCM constitution may offer valuable insights for directing treatment for older patients with frailty.
{"title":"An auxiliary diagnostic approach based on traditional Chinese medicine constitutions for older patients with frailty","authors":"Xuchao Gu, Xiaojun Wang, Yijing Yang, Kangwei Guan, Hung-Chen Chang, Dehua Liu, Wenhao Wang, Tao Wu, Peiqing He, Jiaofeng Wang, Jie Chen, Zhijun Bao","doi":"10.1002/ctd2.70019","DOIUrl":"https://doi.org/10.1002/ctd2.70019","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>As global population ages, frailty has surfaced as a major public health challenge. Given the heterogeneity of frailty in the clinical presentation, it is imperative to develop personalised diagnostic and treatment strategies. The traditional Chinese medicine (TCM) constitution offers notable advantages in discerning individual differences. This study aims to elucidate the association between TCM constitutions and frailty, providing insights into the application of TCM for the frailty management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An observational study was conducted at Huadong hospital from July 2022 to November 2023. A total of 241 older patients were recruited. Each patient underwent assessments for the TCM constitution and frailty status. Comprehensive data collection encompassed medical history, biochemical indicators, bone mineral density (BMD), body composition and physical performance metrics. Plasma samples were also collected to detect levels of inflammatory factors and lymphogenesis-related factors, including IL-1β, TNF-α, VEGF-C, ANGPTL4 and ACV-A. Multi-level statistical analysis was used to establish the relationship of TCM constitutions with frailty.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Amongst all participants, 54 individuals were classified as non-frail, 90 individuals as pre-frail and 97 individuals as frail. Regression analysis indicated that frailty was closely associated with four imbalanced TCM constitutions: Qi deficiency, phlegm dampness, blood stasis and Qi depression. Subsequent analysis demonstrated that Qi deficiency was associated with decreased BMD, phlegm dampness with elevated high-density lipoprotein levels, Blood stasis with elevated blood glucose levels, and Qi depression with both decreased BMD and elevated low-density lipoprotein levels. Furthermore, individuals characterised by imbalanced TCM constitutions exhibited inferior handgrip strength, walking pace, lower limb strength and higher levels of inflammatory factors and lymphogenesis-related factors compared to those with balanced TCM constitution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Frailty is independently associated with Qi deficiency, phlegm dampness, blood stasis and Qi depression. Personalised diagnostic approaches based on the TCM constitution may offer valuable insights for directing treatment for older patients with frailty.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708345","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}
<p>Heart failure (HF) is a major public health challenge, with fluid management being one of the most critical aspects of treatment. Fluid management is particularly a complex and challenging issue in critically ill patients, especially when cardiac pump function fails to meet the body's needs.<span><sup>1-3</sup></span> Clinicians often face multiple challenges when formulating fluid management strategies, including significant individual variations, complex dynamic changes, and diverse monitoring indicators. Most current intervention studies targeting fixed fluid management in HF patients have reported negative outcomes,<span><sup>4, 5</sup></span> reflecting the heterogeneity of severe HF patients and highlighting the urgent need for precision medicine. Therefore, our study aims to identify distinct characteristics of critically ill HF patients through retrospective analyses and develop targeted treatment strategies based on the optimal fluid balance ranges identified by longitudinal infusion data for each patient phenotype (Figure 1).<span><sup>6</sup></span></p><p>The advancement of artificial intelligence and machine learning (ML) technology offers innovative solutions to these challenges. Unsupervised ML has emerged as a powerful tool in medical research, capable of identifying patterns in complex, high-dimensional data without explicit labelling. The patient data were extracted from two intensive care unit databases, integrating both numerical and categorical variables to maintain comprehensive clinical characteristics. The K-Prototypes algorithm was selected for its ability to effectively combine the principles of K-Means and K-Modes principles, thereby enhancing clustering quality by considering the differential contributions of various variable types to the total distance between samples.<span><sup>7</sup></span> Furthermore, fluid management is a dynamic process, where daily interventions and test results can affect subsequent outcomes. To address this, we analyzed 7-day fluid balance records using the G-formula parameter.<span><sup>8</sup></span> a sophisticated statistical approach to eliminate confounding effects between time-varying exposures and outcomes, thus providing more reliable clinical guidance.</p><p>Our analysis identified four distinct phenotypes of HF patients, each exhibiting significant differences in clinical characteristics and prognosis. The optimal fluid balance ranges for each phenotype aligned closely with their distinct clinical features. Phenotype A, characterized by severe inflammation and aggressive interventions including high rates of vasoactive drug use and mechanical ventilation, showed optimal outcomes with a moderate fluid balance of between –1000 and 500 mL per day. This finding indicates that a positive fluid balance is associated with adverse effects on mechanical ventilation duration and mortality. Phenotype C, despite having milder clinical parameters but combined with advanced age and multiple c
心力衰竭（HF）是一项重大的公共卫生挑战，而体液管理是治疗中最关键的环节之一。1-3 临床医生在制定液体管理策略时往往面临多重挑战，包括显著的个体差异、复杂的动态变化和多样的监测指标。目前大多数针对高血压患者固定液体管理的干预研究都报告了负面结果，4、5 反映了严重高血压患者的异质性，并突出了对精准医疗的迫切需求。因此，我们的研究旨在通过回顾性分析确定重症 HF 患者的不同特征，并根据纵向输液数据为每种患者表型确定的最佳液体平衡范围（图 1）制定有针对性的治疗策略6。6 人工智能和机器学习（ML）技术的发展为这些挑战提供了创新性的解决方案。无监督 ML 已成为医学研究的强大工具，它能够在没有明确标签的情况下识别复杂的高维数据中的模式。患者数据是从两个重症监护室数据库中提取的，整合了数字变量和分类变量，以保持全面的临床特征。之所以选择 K-Prototypes 算法，是因为该算法能够有效结合 K-Means 和 K-Modes 原理，从而通过考虑各种变量类型对样本间总距离的不同贡献来提高聚类质量。我们的分析确定了四种不同的高血压患者表型，每种表型在临床特征和预后方面都有显著差异。每种表型的最佳体液平衡范围与其不同的临床特征密切相关。表型 A 以严重炎症和积极干预（包括大量使用血管活性药物和机械通气）为特征，其最佳预后为每天-1000 至 500 毫升的中度体液平衡。这一发现表明，正的体液平衡与机械通气持续时间和死亡率的不利影响相关。表型 C 虽然临床指标较轻，但合并高龄和多种并发症，死亡率较高，需要严格限制液体摄入（每天-1500 至 500 毫升），这突出表明了年龄和体弱对高频预后的重要影响。为了便于临床应用，我们开发了一种简化的分类方法，使用通过特征筛选确定的九个临床指标：年龄、血尿素氮、血细胞比容、血管活性药物使用、肾脏疾病、肌酐、舒张压、机械通气状态和阴离子间隙。XGBoost 模型在内部和外部验证中均表现出良好的预测效果，曲线下面积值分别为 0.918 至 0.943 和 0.802 至 0.907。我们开发了一种基于网络的分型工具，以方便床旁快速识别表型，从而为液体管理的及时决策提供支持。虽然我们目前的研究结果显示出了良好的前景，但仍有必要在几个关键领域开展进一步的研究和技术进步。首先，前瞻性验证研究至关重要，应包括不同的患者群体和医疗环境，以确保研究结果的广泛适用性。其次，新型生物标记物的整合为提高表型分类的准确性提供了机会。除了传统的临床参数外，新型分子标记物、遗传特征和复杂的成像指标可以让人们更深入地了解疾病机制和治疗反应。从技术角度来看，不断完善预测模型仍然至关重要。应用先进的 ML 架构，包括深度学习和集合方法，有可能提高预测的准确性和模型的稳健性。
{"title":"Application of machine learning-based phenotyping in individualized fluid management in critically ill patients with heart failure","authors":"Chengjian Guan, Bing Xiao","doi":"10.1002/ctd2.70020","DOIUrl":"https://doi.org/10.1002/ctd2.70020","url":null,"abstract":"<p>Heart failure (HF) is a major public health challenge, with fluid management being one of the most critical aspects of treatment. Fluid management is particularly a complex and challenging issue in critically ill patients, especially when cardiac pump function fails to meet the body's needs.<span><sup>1-3</sup></span> Clinicians often face multiple challenges when formulating fluid management strategies, including significant individual variations, complex dynamic changes, and diverse monitoring indicators. Most current intervention studies targeting fixed fluid management in HF patients have reported negative outcomes,<span><sup>4, 5</sup></span> reflecting the heterogeneity of severe HF patients and highlighting the urgent need for precision medicine. Therefore, our study aims to identify distinct characteristics of critically ill HF patients through retrospective analyses and develop targeted treatment strategies based on the optimal fluid balance ranges identified by longitudinal infusion data for each patient phenotype (Figure 1).<span><sup>6</sup></span></p><p>The advancement of artificial intelligence and machine learning (ML) technology offers innovative solutions to these challenges. Unsupervised ML has emerged as a powerful tool in medical research, capable of identifying patterns in complex, high-dimensional data without explicit labelling. The patient data were extracted from two intensive care unit databases, integrating both numerical and categorical variables to maintain comprehensive clinical characteristics. The K-Prototypes algorithm was selected for its ability to effectively combine the principles of K-Means and K-Modes principles, thereby enhancing clustering quality by considering the differential contributions of various variable types to the total distance between samples.<span><sup>7</sup></span> Furthermore, fluid management is a dynamic process, where daily interventions and test results can affect subsequent outcomes. To address this, we analyzed 7-day fluid balance records using the G-formula parameter.<span><sup>8</sup></span> a sophisticated statistical approach to eliminate confounding effects between time-varying exposures and outcomes, thus providing more reliable clinical guidance.</p><p>Our analysis identified four distinct phenotypes of HF patients, each exhibiting significant differences in clinical characteristics and prognosis. The optimal fluid balance ranges for each phenotype aligned closely with their distinct clinical features. Phenotype A, characterized by severe inflammation and aggressive interventions including high rates of vasoactive drug use and mechanical ventilation, showed optimal outcomes with a moderate fluid balance of between –1000 and 500 mL per day. This finding indicates that a positive fluid balance is associated with adverse effects on mechanical ventilation duration and mortality. Phenotype C, despite having milder clinical parameters but combined with advanced age and multiple c","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708343","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}
Abha Somesh, Jackson Catalano, Andrew Underhill, Jessica Hocking, Evan Symons, Biswadev Mitra
<p>We read with interest the manuscript on the topic of cervical collars for the management of spinal cord injuries.<span><sup>1</sup></span> Kolli et al. provide compelling evidence on the low levels of evidence for cervical collars to restrict movement and prevent worsening injury. On the contrary, evidence towards delayed recovery and worse pain profiles suggest adverse effects from collar use.<span><sup>1</sup></span></p><p>The association of long-term collar use with poorer quality of life was highlighted.<span><sup>1</sup></span> especially in older adults.<span><sup>2, 3</sup></span> However, patient experiences of wearing cervical collars for shorter times in an emergency department (ED) setting have not been previously evaluated. The current standard of care in Victoria, Australia is the use of rigid foam cervical collars for spinal immobilisation in a patient with suspected cervical spine injury.<span><sup>4</sup></span></p><p>We conducted a pilot prospective cohort study at an adult major trauma centre in Australia which records approximately 10 000 trauma presentations a year. The aim of this study was to evaluate patients’ experiences in a short-term cervical collar and the purpose of the study was to generate a hypothesis of harm. Short-term was defined as the period between application of the collar and until being cleared of any cervical spine injuries, which is less than 12 h.</p><p>A total of 20 participants enrolled by convenience sampling who were managed in cervical collars awaiting clearance with a Glasgow Coma Scale rating of 15, and who could converse in English formed the exposure group. A non-exposure group of 20 participants included adult patients not in cervical collars awaiting the results of investigations in the ED. All 40 participants were admitted to the short-stay unit in the ED with an aim to be discharged home in 24 h which suggests they all had low disease severity. The groups were matched for age (± 2 years) and gender. All 40 participants were assessed at a single time point using the Patient Evaluation of Emotional Comfort Experience (PEECE) questionnaire.<span><sup>5</sup></span> This tool evaluates positive mental well-being elements like emotional comfort rather than negative health outcomes.</p><p>Each component of the PEECE score and the total were summarised using medians (inter-quartile range) and differences were compared using the Wilcoxon Rank Sum test. A <i>p</i>-value of <.05 was defined to be statistically significant. All analyses were conducted using Stata v18.0.</p><p>The total PEECE score among patients with a collar was 30.5 (interquartile range [IQR] 21–39.5), significantly lower than patients without a collar (total score 38.5; IQR 32–41.5, <i>p</i> = .016) (Figure 1). With a collar in place, patients reported significantly lower scores for positive emotions of being at ease, relaxed or wanting to smile. In addition, they also scored significantly lower perceptions of being valued, f
{"title":"Use of short-term cervical collars is associated with emotional discomfort","authors":"Abha Somesh, Jackson Catalano, Andrew Underhill, Jessica Hocking, Evan Symons, Biswadev Mitra","doi":"10.1002/ctd2.70016","DOIUrl":"https://doi.org/10.1002/ctd2.70016","url":null,"abstract":"<p>We read with interest the manuscript on the topic of cervical collars for the management of spinal cord injuries.<span><sup>1</sup></span> Kolli et al. provide compelling evidence on the low levels of evidence for cervical collars to restrict movement and prevent worsening injury. On the contrary, evidence towards delayed recovery and worse pain profiles suggest adverse effects from collar use.<span><sup>1</sup></span></p><p>The association of long-term collar use with poorer quality of life was highlighted.<span><sup>1</sup></span> especially in older adults.<span><sup>2, 3</sup></span> However, patient experiences of wearing cervical collars for shorter times in an emergency department (ED) setting have not been previously evaluated. The current standard of care in Victoria, Australia is the use of rigid foam cervical collars for spinal immobilisation in a patient with suspected cervical spine injury.<span><sup>4</sup></span></p><p>We conducted a pilot prospective cohort study at an adult major trauma centre in Australia which records approximately 10 000 trauma presentations a year. The aim of this study was to evaluate patients’ experiences in a short-term cervical collar and the purpose of the study was to generate a hypothesis of harm. Short-term was defined as the period between application of the collar and until being cleared of any cervical spine injuries, which is less than 12 h.</p><p>A total of 20 participants enrolled by convenience sampling who were managed in cervical collars awaiting clearance with a Glasgow Coma Scale rating of 15, and who could converse in English formed the exposure group. A non-exposure group of 20 participants included adult patients not in cervical collars awaiting the results of investigations in the ED. All 40 participants were admitted to the short-stay unit in the ED with an aim to be discharged home in 24 h which suggests they all had low disease severity. The groups were matched for age (± 2 years) and gender. All 40 participants were assessed at a single time point using the Patient Evaluation of Emotional Comfort Experience (PEECE) questionnaire.<span><sup>5</sup></span> This tool evaluates positive mental well-being elements like emotional comfort rather than negative health outcomes.</p><p>Each component of the PEECE score and the total were summarised using medians (inter-quartile range) and differences were compared using the Wilcoxon Rank Sum test. A <i>p</i>-value of <.05 was defined to be statistically significant. All analyses were conducted using Stata v18.0.</p><p>The total PEECE score among patients with a collar was 30.5 (interquartile range [IQR] 21–39.5), significantly lower than patients without a collar (total score 38.5; IQR 32–41.5, <i>p</i> = .016) (Figure 1). With a collar in place, patients reported significantly lower scores for positive emotions of being at ease, relaxed or wanting to smile. In addition, they also scored significantly lower perceptions of being valued, f","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641392","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}
Immuno-checkpoint therapy (ICT) significantly alters the clinical course of cancer patients, providing long-lasting clinical benefits and offering the potential for cure to some patients. However, response rates for different tumour types vary, and predictive biomarkers are needed to enhance patient selection for the purpose of optimising effectiveness and reducing toxicity. This has driven efforts to decipher the immune and non-immune factors that regulate ICT response.
Main Content
This review offers a thorough examination of the advantages and future challenges of immune checkpoint inhibitors in cancer therapy. Additionally, we explore ongoing efforts to address current challenges, such as guiding subsequent clinical trials, developing ICT combination therapy strategies and utilising epigenetics to enhance clinical efficacy.
Conclusion and Perspectives
Despite significant progress, ICT faces challenges including immune-related adverse events (irAEs) and resistance mechanisms. Ongoing research focuses on developing novel biomarkers, combination therapies, and epigenetic strategies to improve the efficacy and safety of ICT for cancer patients worldwide. Future studies are required to validate these findings across different tumor types and treatment settings.
{"title":"Challenges and advances of immune checkpoint therapy","authors":"Lingyu Li, Yingli Sun","doi":"10.1002/ctd2.70001","DOIUrl":"https://doi.org/10.1002/ctd2.70001","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Objectives</h3>\u0000 \u0000 <p>Immuno-checkpoint therapy (ICT) significantly alters the clinical course of cancer patients, providing long-lasting clinical benefits and offering the potential for cure to some patients. However, response rates for different tumour types vary, and predictive biomarkers are needed to enhance patient selection for the purpose of optimising effectiveness and reducing toxicity. This has driven efforts to decipher the immune and non-immune factors that regulate ICT response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Content</h3>\u0000 \u0000 <p>This review offers a thorough examination of the advantages and future challenges of immune checkpoint inhibitors in cancer therapy. Additionally, we explore ongoing efforts to address current challenges, such as guiding subsequent clinical trials, developing ICT combination therapy strategies and utilising epigenetics to enhance clinical efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Perspectives</h3>\u0000 \u0000 <p>Despite significant progress, ICT faces challenges including immune-related adverse events (irAEs) and resistance mechanisms. Ongoing research focuses on developing novel biomarkers, combination therapies, and epigenetic strategies to improve the efficacy and safety of ICT for cancer patients worldwide. Future studies are required to validate these findings across different tumor types and treatment settings.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142587927","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}
<p>Intrahepatic cholangiocarcinoma (iCCA) is an epithelial malignancy arising from intrahepatic biliary tract, characterised by a dismal prognosis with limited therapeutic alternatives.<span><sup>1</sup></span> The standard first-line treatment for patients with unresectable iCCA includes gemcitabine-based chemotherapy and immunotherapy. However, the objective response rate (ORR) of first-line treatment is below 30%, and there is currently insufficient evidence to support the use of second-line chemotherapy.<span><sup>2, 3</sup></span> This underscores an urgent need to identify novel therapeutic targets and effective drugs for iCCA.</p><p>Our previous research has demonstrated that phosphatase and tension homolog (PTEN), a tumour suppressor which counteracts phosphatidylinositol 3-kinase (PI3K)–AKT signalling, is frequently mutated or deleted in iCCA.<span><sup>4</sup></span> We established a spontaneous iCCA model in mice through liver-specific PTEN disruption and Kras activation, highlighting the crucial role of PTEN in iCCA tumourigenesis.<span><sup>5</sup></span> Importantly, we identified PTEN as a pivotal regulator of both the lysosomal and proteasomal systems, which are essential for maintaining cellular proteostasis in CCA cells. PTEN drives lysosome biogenesis and acidification through its protein phosphatase activity, which dephosphorylates transcription factor EB (TFEB) at Ser211, thereby regulating exosome secretion and iCCA metastasis.<span><sup>6</sup></span> Simultaneously, PTEN inhibits proteasomal transcription via its lipid phosphatase activity in a BACH1/MAFF-dependent manner.<span><sup>7</sup></span> Consequently, PTEN deficiency enhances protein synthesis and proteasomal activity, creating a dependency on the proteasome for iCCA cell growth and survival. Therefore, targeting the proteasome machinery by inhibitor bortezomib induces more apoptosis in PTEN-deficient iCCA cells.</p><p>We subsequently conducted a clinical trial (NCT03345303) to assess whether PTEN-deficient iCCA patients could benefit from bortezomib treatment after failure of first-line chemotherapy, investigating PTEN as a potential biomarker for proteasome inhibition. This open-label, single-arm, phase II clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital, Shanghai. A total of 130 advanced iCCA patients were screened for PTEN expression and 16 were enrolled and treated with single-agent bortezomib. Among the intent-to-treat cohort (<i>n</i> = 16), the ORR was 18.75% (three out of 16), and the disease control rate (DCR) was 43.75% (seven out of 16). Notably, three patients did not undergo efficacy assessment, resulting in more favourable outcomes in the per-protocol (PP) cohort (<i>n</i> = 13), which demonstrated an ORR of 23.08% and a DCR of 53.85%. The median progression-free survival (PFS) was 3.6 months, and median overall survival (OS) was 9.6 months in the PP cohort. To our knowledge, the primary efficacy endpoint of our trail, the
{"title":"Drug repurposing: Bortezomib in the treatment of PTEN-deficient iCCA","authors":"Shi-jia Dai, Tian-yi Jiang, Zhen-gang Yuan","doi":"10.1002/ctd2.70004","DOIUrl":"https://doi.org/10.1002/ctd2.70004","url":null,"abstract":"<p>Intrahepatic cholangiocarcinoma (iCCA) is an epithelial malignancy arising from intrahepatic biliary tract, characterised by a dismal prognosis with limited therapeutic alternatives.<span><sup>1</sup></span> The standard first-line treatment for patients with unresectable iCCA includes gemcitabine-based chemotherapy and immunotherapy. However, the objective response rate (ORR) of first-line treatment is below 30%, and there is currently insufficient evidence to support the use of second-line chemotherapy.<span><sup>2, 3</sup></span> This underscores an urgent need to identify novel therapeutic targets and effective drugs for iCCA.</p><p>Our previous research has demonstrated that phosphatase and tension homolog (PTEN), a tumour suppressor which counteracts phosphatidylinositol 3-kinase (PI3K)–AKT signalling, is frequently mutated or deleted in iCCA.<span><sup>4</sup></span> We established a spontaneous iCCA model in mice through liver-specific PTEN disruption and Kras activation, highlighting the crucial role of PTEN in iCCA tumourigenesis.<span><sup>5</sup></span> Importantly, we identified PTEN as a pivotal regulator of both the lysosomal and proteasomal systems, which are essential for maintaining cellular proteostasis in CCA cells. PTEN drives lysosome biogenesis and acidification through its protein phosphatase activity, which dephosphorylates transcription factor EB (TFEB) at Ser211, thereby regulating exosome secretion and iCCA metastasis.<span><sup>6</sup></span> Simultaneously, PTEN inhibits proteasomal transcription via its lipid phosphatase activity in a BACH1/MAFF-dependent manner.<span><sup>7</sup></span> Consequently, PTEN deficiency enhances protein synthesis and proteasomal activity, creating a dependency on the proteasome for iCCA cell growth and survival. Therefore, targeting the proteasome machinery by inhibitor bortezomib induces more apoptosis in PTEN-deficient iCCA cells.</p><p>We subsequently conducted a clinical trial (NCT03345303) to assess whether PTEN-deficient iCCA patients could benefit from bortezomib treatment after failure of first-line chemotherapy, investigating PTEN as a potential biomarker for proteasome inhibition. This open-label, single-arm, phase II clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital, Shanghai. A total of 130 advanced iCCA patients were screened for PTEN expression and 16 were enrolled and treated with single-agent bortezomib. Among the intent-to-treat cohort (<i>n</i> = 16), the ORR was 18.75% (three out of 16), and the disease control rate (DCR) was 43.75% (seven out of 16). Notably, three patients did not undergo efficacy assessment, resulting in more favourable outcomes in the per-protocol (PP) cohort (<i>n</i> = 13), which demonstrated an ORR of 23.08% and a DCR of 53.85%. The median progression-free survival (PFS) was 3.6 months, and median overall survival (OS) was 9.6 months in the PP cohort. To our knowledge, the primary efficacy endpoint of our trail, the","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555491","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}
Xinyue Liang, Fang Fang, Xiaoqing Wang, Ming Jiang, Jing Cang
Background and Aims
Microglia are the innate immune cells of central nervous system which play critical roles in brain homeostasis. Recently, the effects of general anesthetic agents (GAAs) on microglia and their potential neurotoxicity in neurodevelopment have attracted the attention of anesthesiologists and neuroscientists.
Methods
Here, we review the physiology of microglia in neurodevelopment, the potential mechanisms of GAAs on microglia and the consequent changes in microglial function.
Outcomes
Microglia-mediated neuroinflammation is a key mechanism of neurocognitive deficits during neurodevelopment. In addition, microglia could be primed by active inflammatory processes and have innate immune memory, both of which make them a potential candidate responsible of long-term neural deficits.
Conclusion
This review aims in summarizing the in vivo and in vitro studies associating microglia with general anesthesia and describing how GAAs induce neurocognitive deficits via microglia to further explore the effects of GAAs on neurodevelopment.
{"title":"The role of microglia in neurocognitive deficits induced by general anaesthetic agents during neurodevelopment","authors":"Xinyue Liang, Fang Fang, Xiaoqing Wang, Ming Jiang, Jing Cang","doi":"10.1002/ctd2.70012","DOIUrl":"https://doi.org/10.1002/ctd2.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Microglia are the innate immune cells of central nervous system which play critical roles in brain homeostasis. Recently, the effects of general anesthetic agents (GAAs) on microglia and their potential neurotoxicity in neurodevelopment have attracted the attention of anesthesiologists and neuroscientists.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we review the physiology of microglia in neurodevelopment, the potential mechanisms of GAAs on microglia and the consequent changes in microglial function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Outcomes</h3>\u0000 \u0000 <p>Microglia-mediated neuroinflammation is a key mechanism of neurocognitive deficits during neurodevelopment. In addition, microglia could be primed by active inflammatory processes and have innate immune memory, both of which make them a potential candidate responsible of long-term neural deficits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review aims in summarizing the in vivo and in vitro studies associating microglia with general anesthesia and describing how GAAs induce neurocognitive deficits via microglia to further explore the effects of GAAs on neurodevelopment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541074","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}
<p>Dear Editor,</p><p>Pancreatic cystic lesions pose a diagnostic challenge. The accuracy of distinguishing low-grade from high-grade dysplasia is suboptimal, with the progression risk varying based on the types of cysts (simple retention cysts, pseudocysts and cystic neoplasms).<span><sup>1</sup></span> Traditional imaging-based radiological approaches (computed tomography [CT] and magnetic resonance imaging [MRI]), endoscopic ultrasound (EUS)-guided fine needle aspiration, including analysis of cystic fluid components such as amylase, glucose, carcinoembryonic antigen (CEA) levels, liquid-based cytology and more recently molecular markers can enhance the diagnosis of pancreatic cystic lesions.<span><sup>2</sup></span> Even though, there is a pressing need for a stable and accurate model that allows in-depth analysis of cell components of cystic lesions and reflects their behaviour. Organoids as 3D multicellular structures resemble features of their original tissue individually for self-organization and self-renewal.<span><sup>3, 4</sup></span> Organoid-based longitudinal testing aids in monitoring translational diagnosis, disease progression, treatment response and adapting therapies. To enhance precision in diagnosing pancreatic cystic lesions, we collected cystic fluids for organoid culture, evaluating their growth phenotypes and molecular markers. The cell context of successfully constructed organoids was further validated by single-cell RNA sequencing (scRNA-Seq) (Figure 1A).</p><p>A comprehensive explanation of the methods is in the Supporting Information. A 34-year-old female (patient #<i>X</i>) complained of epigastric pain persisting for 5 years with recurrent pancreatitis. The CT data showed a pancreatic cystic lesion measuring 5 cm in diameter within the pancreatic body, raising suspicion of a pancreatic pseudocyst (Figure 1B). Subsequent enhanced MRI and contrast EUS suggested the lesion as a mucinous cystic neoplasm with enhanced mural nodules (Figure 1C). An EUS-guided fine needle aspiration was conducted and approximately 40 mL of cystic fluid was aspirated. The cystic fluid revealed amylase at a level of 165 328 U/L (>250 U/mL suggests the possibility of pancreatic pseudocyst), CEA level of 261.98 ng/mL (>192 ng/mL indicates the possibility of pancreatic mucinous cystic neoplasm) and glucose level of 9 mg/dL (<50 mg/dL suggests the possibility of pancreatic mucinous cystic neoplasm). Meanwhile, a small volume of cyst fluid (∼3 mL) from the puncture was performed for organoid culture (Figure 1D). Notably, organoids derived from this case exhibited robust growth. Haematoxylin and eosin staining highlighted abnormal structures in cell nuclei (Figure 1E). Immunohistochemical staining for CEA, TP53 and MIK67, as well as immunostaining for MUC5AC, all yielded positive results (Figure 1F,G). These staining data may confirm the diagnosis of this patient with high-grade intraepithelial neoplasia.</p><p>The patient eventually unde
{"title":"Organoid-driven diagrammatic devolution: Elevating precision in pancreatic cystic lesions diagnosis","authors":"Fei Jiang, Dongyan Cao, Gengming Niu, Hui Jiang, Zhendong Jin, Yingbin Liu, Dongxi Xiang","doi":"10.1002/ctd2.70008","DOIUrl":"https://doi.org/10.1002/ctd2.70008","url":null,"abstract":"<p>Dear Editor,</p><p>Pancreatic cystic lesions pose a diagnostic challenge. The accuracy of distinguishing low-grade from high-grade dysplasia is suboptimal, with the progression risk varying based on the types of cysts (simple retention cysts, pseudocysts and cystic neoplasms).<span><sup>1</sup></span> Traditional imaging-based radiological approaches (computed tomography [CT] and magnetic resonance imaging [MRI]), endoscopic ultrasound (EUS)-guided fine needle aspiration, including analysis of cystic fluid components such as amylase, glucose, carcinoembryonic antigen (CEA) levels, liquid-based cytology and more recently molecular markers can enhance the diagnosis of pancreatic cystic lesions.<span><sup>2</sup></span> Even though, there is a pressing need for a stable and accurate model that allows in-depth analysis of cell components of cystic lesions and reflects their behaviour. Organoids as 3D multicellular structures resemble features of their original tissue individually for self-organization and self-renewal.<span><sup>3, 4</sup></span> Organoid-based longitudinal testing aids in monitoring translational diagnosis, disease progression, treatment response and adapting therapies. To enhance precision in diagnosing pancreatic cystic lesions, we collected cystic fluids for organoid culture, evaluating their growth phenotypes and molecular markers. The cell context of successfully constructed organoids was further validated by single-cell RNA sequencing (scRNA-Seq) (Figure 1A).</p><p>A comprehensive explanation of the methods is in the Supporting Information. A 34-year-old female (patient #<i>X</i>) complained of epigastric pain persisting for 5 years with recurrent pancreatitis. The CT data showed a pancreatic cystic lesion measuring 5 cm in diameter within the pancreatic body, raising suspicion of a pancreatic pseudocyst (Figure 1B). Subsequent enhanced MRI and contrast EUS suggested the lesion as a mucinous cystic neoplasm with enhanced mural nodules (Figure 1C). An EUS-guided fine needle aspiration was conducted and approximately 40 mL of cystic fluid was aspirated. The cystic fluid revealed amylase at a level of 165 328 U/L (>250 U/mL suggests the possibility of pancreatic pseudocyst), CEA level of 261.98 ng/mL (>192 ng/mL indicates the possibility of pancreatic mucinous cystic neoplasm) and glucose level of 9 mg/dL (<50 mg/dL suggests the possibility of pancreatic mucinous cystic neoplasm). Meanwhile, a small volume of cyst fluid (∼3 mL) from the puncture was performed for organoid culture (Figure 1D). Notably, organoids derived from this case exhibited robust growth. Haematoxylin and eosin staining highlighted abnormal structures in cell nuclei (Figure 1E). Immunohistochemical staining for CEA, TP53 and MIK67, as well as immunostaining for MUC5AC, all yielded positive results (Figure 1F,G). These staining data may confirm the diagnosis of this patient with high-grade intraepithelial neoplasia.</p><p>The patient eventually unde","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142540906","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}
Lung cancer represents a significant public health concern worldwide. Lung cancer typically receives a diagnosis at a late stage, leading to a generally unfavourable prognosis. Additionally, traditional treatments frequently fail in cases of metastatic lung cancer. However, targeted therapy has advanced considerably in the management of lung cancer, and overcoming drug resistance has emerged as a significant hurdle in achieving optimal treatment outcomes. As a result, there has been a new trend toward precision therapy for lung cancer based on changes at the molecular and genetic levels. On the other hand, for lung cancer, early diagnosis plays a crucial role in treatment and prognosis. Based on existing knowledge, we strongly believe that it is imperative to promptly identify innovative biomarkers. The emergence of microRNAs (miRNAs) provides new ideas. The expression profiles of miRNAs have been investigated using noninvasive blood samples to explore the regulatory mechanisms played by miRNAs during the progression and targeted therapy resistance of lung cancer. Due to the complexity of miRNA profiles, they may play the role of tumour suppressors or oncogenes. However, specific regulatory mechanisms are still a huge topic to be explored. In this Review, we summarize the latest research that has shed light on the potential regulatory mechanisms of miRNAs in driving lung cancer progression, their value for clinical application as biomarkers and their role in targeted therapy resistance.
{"title":"Effects of microRNA on the growth and targeted therapy response on lung cancer","authors":"Mengchen Zhu, Yi Jiang, Lingshuang Liu","doi":"10.1002/ctd2.70011","DOIUrl":"https://doi.org/10.1002/ctd2.70011","url":null,"abstract":"<p>Lung cancer represents a significant public health concern worldwide. Lung cancer typically receives a diagnosis at a late stage, leading to a generally unfavourable prognosis. Additionally, traditional treatments frequently fail in cases of metastatic lung cancer. However, targeted therapy has advanced considerably in the management of lung cancer, and overcoming drug resistance has emerged as a significant hurdle in achieving optimal treatment outcomes. As a result, there has been a new trend toward precision therapy for lung cancer based on changes at the molecular and genetic levels. On the other hand, for lung cancer, early diagnosis plays a crucial role in treatment and prognosis. Based on existing knowledge, we strongly believe that it is imperative to promptly identify innovative biomarkers. The emergence of microRNAs (miRNAs) provides new ideas. The expression profiles of miRNAs have been investigated using noninvasive blood samples to explore the regulatory mechanisms played by miRNAs during the progression and targeted therapy resistance of lung cancer. Due to the complexity of miRNA profiles, they may play the role of tumour suppressors or oncogenes. However, specific regulatory mechanisms are still a huge topic to be explored. In this Review, we summarize the latest research that has shed light on the potential regulatory mechanisms of miRNAs in driving lung cancer progression, their value for clinical application as biomarkers and their role in targeted therapy resistance.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142540847","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}
<p>Immune responses in the gut need to be tightly controlled in order to maintain mucosal immune tolerance and proper interactions with intestinal microbiota. Disruptions of these immune-microbiota circuits presumably underlie different immune-mediated disorders including inflammatory bowel disease (IBD). Distinct genetic traits that alter the expression and/or function of molecules and consequently the immune signalling networks they are embedded in can disrupt immune-microbiota interactions and microbe recognition and thus, promote mucosal inflammation. However, the molecular mechanisms and cellular circuits underlying the pathogenesis of IBD are only incompletely understood. Du and colleagues investigated the influence of posttranslational modifications on the complex signalling network in the gut in an experimental colitis model and in patients with ulcerative colitis.<span><sup>1</sup></span></p><p>The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an intracellular pattern recognition receptor which contributes to intestinal homeostasis through the regulation of epithelial cell functions and innate and adaptive immune responses. Hematopoietic cells of both myeloid and lymphoid origin as well as intestinal epithelial cells and Paneth cells express NOD2.<span><sup>2</sup></span> NOD2 senses intracellular muramyl dipeptide (MDP), a peptidoglycan component conserved in Gram-positive and Gram-negative bacteria. Following engagement by MDP, NOD2 undergoes oligomerization and subsequently attracts and activates receptor interaction protein 2 (RIPK2) through homotypic interactions, followed by transforming growth factor-beta-activated kinase 1 recruitment and activation which engages nuclear factor kappa-beta (NFκB) and mitogen-activated protein kinase pathways for pro-inflammatory cytokine production.<span><sup>3</sup></span></p><p>Allelic variations of the gene encoding NOD2 have been associated with IBD. The three most common risk variants of the more than 2400 NOD2 variant genes reported to date are typically present in a heterozygous state and account for more than 80% of the NOD2 variations.<span><sup>4</sup></span> These allelic risk variants are predicted to encode loss-of-function mutations that impair NFκB activation in response to MDP and to promote the onset and progression of IBD by altering the interaction with and the composition of intestinal microbiota.<span><sup>5, 6</sup></span> Along with this assumption, MDP administration protects from experimental colitis and this protective effect of MDP is lost when NOD2 signalling is defective,<span><sup>7, 8</sup></span> Thus, proper NOD2 signalling is pivotal for the maintenance of intestinal immune tolerance and the restriction of inflammatory insults.</p><p>Next to genetic NOD2 mutations, the versatile and complex signalling network NOD2 is embedded in as well as various posttranslational modifications regulate NOD2 function and thus, influence the outcome of d
{"title":"Otubain 2 promotes muramyl dipeptide-mediated anti-colitogenic effects due to de-ubiquitination of receptor interaction protein 2","authors":"Jochen Mattner","doi":"10.1002/ctd2.70014","DOIUrl":"https://doi.org/10.1002/ctd2.70014","url":null,"abstract":"<p>Immune responses in the gut need to be tightly controlled in order to maintain mucosal immune tolerance and proper interactions with intestinal microbiota. Disruptions of these immune-microbiota circuits presumably underlie different immune-mediated disorders including inflammatory bowel disease (IBD). Distinct genetic traits that alter the expression and/or function of molecules and consequently the immune signalling networks they are embedded in can disrupt immune-microbiota interactions and microbe recognition and thus, promote mucosal inflammation. However, the molecular mechanisms and cellular circuits underlying the pathogenesis of IBD are only incompletely understood. Du and colleagues investigated the influence of posttranslational modifications on the complex signalling network in the gut in an experimental colitis model and in patients with ulcerative colitis.<span><sup>1</sup></span></p><p>The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an intracellular pattern recognition receptor which contributes to intestinal homeostasis through the regulation of epithelial cell functions and innate and adaptive immune responses. Hematopoietic cells of both myeloid and lymphoid origin as well as intestinal epithelial cells and Paneth cells express NOD2.<span><sup>2</sup></span> NOD2 senses intracellular muramyl dipeptide (MDP), a peptidoglycan component conserved in Gram-positive and Gram-negative bacteria. Following engagement by MDP, NOD2 undergoes oligomerization and subsequently attracts and activates receptor interaction protein 2 (RIPK2) through homotypic interactions, followed by transforming growth factor-beta-activated kinase 1 recruitment and activation which engages nuclear factor kappa-beta (NFκB) and mitogen-activated protein kinase pathways for pro-inflammatory cytokine production.<span><sup>3</sup></span></p><p>Allelic variations of the gene encoding NOD2 have been associated with IBD. The three most common risk variants of the more than 2400 NOD2 variant genes reported to date are typically present in a heterozygous state and account for more than 80% of the NOD2 variations.<span><sup>4</sup></span> These allelic risk variants are predicted to encode loss-of-function mutations that impair NFκB activation in response to MDP and to promote the onset and progression of IBD by altering the interaction with and the composition of intestinal microbiota.<span><sup>5, 6</sup></span> Along with this assumption, MDP administration protects from experimental colitis and this protective effect of MDP is lost when NOD2 signalling is defective,<span><sup>7, 8</sup></span> Thus, proper NOD2 signalling is pivotal for the maintenance of intestinal immune tolerance and the restriction of inflammatory insults.</p><p>Next to genetic NOD2 mutations, the versatile and complex signalling network NOD2 is embedded in as well as various posttranslational modifications regulate NOD2 function and thus, influence the outcome of d","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142524933","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}
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