Clinical and translational discovery最新文献

{"title":"An auxiliary diagnostic approach based on traditional Chinese medicine constitutions for older patients with frailty","authors":"Xuchao Gu,&nbsp;Xiaojun Wang,&nbsp;Yijing Yang,&nbsp;Kangwei Guan,&nbsp;Hung-Chen Chang,&nbsp;Dehua Liu,&nbsp;Wenhao Wang,&nbsp;Tao Wu,&nbsp;Peiqing He,&nbsp;Jiaofeng Wang,&nbsp;Jie Chen,&nbsp;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}

{"title":"Application of machine learning-based phenotyping in individualized fluid management in critically ill patients with heart failure","authors":"Chengjian Guan,&nbsp;Bing Xiao","doi":"10.1002/ctd2.70020","DOIUrl":"https://doi.org/10.1002/ctd2.70020","url":null,"abstract":"&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; 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,&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; 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).&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; a sophisticated statistical approach to eliminate confounding effects between time-varying exposures and outcomes, thus providing more reliable clinical guidance.&lt;/p&gt;&lt;p&gt;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}

{"title":"Use of short-term cervical collars is associated with emotional discomfort","authors":"Abha Somesh,&nbsp;Jackson Catalano,&nbsp;Andrew Underhill,&nbsp;Jessica Hocking,&nbsp;Evan Symons,&nbsp;Biswadev Mitra","doi":"10.1002/ctd2.70016","DOIUrl":"https://doi.org/10.1002/ctd2.70016","url":null,"abstract":"&lt;p&gt;We read with interest the manuscript on the topic of cervical collars for the management of spinal cord injuries.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The association of long-term collar use with poorer quality of life was highlighted.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; especially in older adults.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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.&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; This tool evaluates positive mental well-being elements like emotional comfort rather than negative health outcomes.&lt;/p&gt;&lt;p&gt;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 &lt;i&gt;p&lt;/i&gt;-value of &lt;.05 was defined to be statistically significant. All analyses were conducted using Stata v18.0.&lt;/p&gt;&lt;p&gt;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, &lt;i&gt;p&lt;/i&gt; = .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}

{"title":"Challenges and advances of immune checkpoint therapy","authors":"Lingyu Li,&nbsp;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}

{"title":"Drug repurposing: Bortezomib in the treatment of PTEN-deficient iCCA","authors":"Shi-jia Dai,&nbsp;Tian-yi Jiang,&nbsp;Zhen-gang Yuan","doi":"10.1002/ctd2.70004","DOIUrl":"https://doi.org/10.1002/ctd2.70004","url":null,"abstract":"&lt;p&gt;Intrahepatic cholangiocarcinoma (iCCA) is an epithelial malignancy arising from intrahepatic biliary tract, characterised by a dismal prognosis with limited therapeutic alternatives.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; This underscores an urgent need to identify novel therapeutic targets and effective drugs for iCCA.&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Simultaneously, PTEN inhibits proteasomal transcription via its lipid phosphatase activity in a BACH1/MAFF-dependent manner.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; 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.&lt;/p&gt;&lt;p&gt;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 (&lt;i&gt;n&lt;/i&gt; = 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 (&lt;i&gt;n&lt;/i&gt; = 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}

{"title":"The role of microglia in neurocognitive deficits induced by general anaesthetic agents during neurodevelopment","authors":"Xinyue Liang,&nbsp;Fang Fang,&nbsp;Xiaoqing Wang,&nbsp;Ming Jiang,&nbsp;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}

{"title":"Organoid-driven diagrammatic devolution: Elevating precision in pancreatic cystic lesions diagnosis","authors":"Fei Jiang,&nbsp;Dongyan Cao,&nbsp;Gengming Niu,&nbsp;Hui Jiang,&nbsp;Zhendong Jin,&nbsp;Yingbin Liu,&nbsp;Dongxi Xiang","doi":"10.1002/ctd2.70008","DOIUrl":"https://doi.org/10.1002/ctd2.70008","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;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).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; 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).&lt;/p&gt;&lt;p&gt;A comprehensive explanation of the methods is in the Supporting Information. A 34-year-old female (patient #&lt;i&gt;X&lt;/i&gt;) 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 (&gt;250 U/mL suggests the possibility of pancreatic pseudocyst), CEA level of 261.98 ng/mL (&gt;192 ng/mL indicates the possibility of pancreatic mucinous cystic neoplasm) and glucose level of 9 mg/dL (&lt;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.&lt;/p&gt;&lt;p&gt;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}

{"title":"Effects of microRNA on the growth and targeted therapy response on lung cancer","authors":"Mengchen Zhu,&nbsp;Yi Jiang,&nbsp;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}

{"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":"&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; 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.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; Along with this assumption, MDP administration protects from experimental colitis and this protective effect of MDP is lost when NOD2 signalling is defective,&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; Thus, proper NOD2 signalling is pivotal for the maintenance of intestinal immune tolerance and the restriction of inflammatory insults.&lt;/p&gt;&lt;p&gt;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}

{"title":"EccDNA, STING activation, and their potential roles in DLBCL prognosis and therapy","authors":"Xi-Bo Hu,&nbsp;Wei-Ying Wang,&nbsp;Xiao-Jian Sun,&nbsp;Qun-Ling Zhang","doi":"10.1002/ctd2.70013","DOIUrl":"https://doi.org/10.1002/ctd2.70013","url":null,"abstract":"&lt;p&gt;Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adults, poses a significant clinical challenge due to its marked heterogeneity and high incidence of patients suffering relapse or becoming refractory after the first-line immunochemotherapy. DLBCL cells may originate from different stages of lymphoid differentiation, and thus their gene expression profiling can delineate two distinct molecular subtypes of DLBCL: germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes, with a minority of cases remaining unclassifiable. Alternatively, immunohistochemistry-based algorithms can also dichotomize DLBCL into GCB and non-GCB subtypes. In addition to these classifications related to cell-of-origin, recent in-depth genomic analyses have also revealed recurrent genomic aberrations, prompting the proposal of new classification systems for DLBCL.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; However, as yet the correlation between prognosis and molecular subtypes remains elusive.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; As an effort to further explore the heterogeneity of DLBCL, in an article recently published in &lt;i&gt;Clinical and Translational Medicine&lt;/i&gt;, Wu et al. reported the first profiling of extrachromosomal circular DNA (eccDNA) in DLBCL cells and identified the oncogenic role and prognostic significance of the eccDNAs in DLBCL. Meanwhile, their multi-omic and mechanistic studies uncovered an activation of the stimulator of interferon genes (STING) signalling pathway by eccDNAs in DLBCL cells, thus suggesting a potential therapeutic approach combining chemotherapy with STING inhibition (Figure 1).&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;EccDNAs are circular double-strand DNA molecules that are originally derived from, but physically independent of, chromosomal DNA. They are heterogeneous in size ranging from a few hundred to millions of base pairs and appear to be derived from either repetitive sequences or unique genomic sequences, and many eccDNAs can be self-replicated. While the biogenesis and functions of eccDNAs remain to be fully understood, an increase in eccDNA has been observed in several types of human cancers. Importantly, because the eccDNAs provide a significant source of oncogene amplification and can be segregated unequally to daughter cells, they are believed to contribute enormously to tumour evolution and intratumor heterogeneity,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and the presence of eccDNAs in patient tumour samples has been found to be associated with poor outcomes across many types of cancers.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Furthermore, studies have shown that eccDNAs can function as potent innate immunostimulants, which require the STING signalling pathways to serve as intracellular DNA sensors.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;By integrating circular DNA sequencing (circle-seq), atomic force microscopy, whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq) techniques, Wu et al. performed a comprehensive eccDNA profiling of 18 DLBC","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/ctd2.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142524934","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}