Le Li, Li Li, Qiuyue Zhao, Xiao Liu, Yaohui Liu, Kailin Guo, Dongsu Zhang, Chang Hu, Bo Hu
Magnesium imbalances commonly exist in septic patients. However, the association of serum magnesium levels with mortality in septic patients remains uncertain. Herein, we elucidated the association between serum magnesium and all-cause mortality in septic patients from American and Chinese cohorts by analyzing data from 9099 patients in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and 1727 patients from a university-affiliated hospital’ intensive care unit in China. Patients in both cohorts were categorized into five groups based on serum magnesium quintiles from the MIMIC-IV dataset. Patients with higher serum magnesium levels exhibited an increased risk of 28-day mortality in both cohorts. The restricted cubic spline (RCS) curves revealed a progressively elevated risk of 28-day mortality with increasing serum magnesium in MIMIC-IV cohort, while a J-shaped correlation was observed in institutional cohort. Our findings have validated the association between high serum magnesium and high mortality in sepsis across different races and medical conditions. Serum magnesium levels might be useful in identifying septic patients at higher mortality risk.
{"title":"High serum magnesium level is associated with increased mortality in patients with sepsis: an international, multicenter retrospective study","authors":"Le Li, Li Li, Qiuyue Zhao, Xiao Liu, Yaohui Liu, Kailin Guo, Dongsu Zhang, Chang Hu, Bo Hu","doi":"10.1002/mco2.713","DOIUrl":"https://doi.org/10.1002/mco2.713","url":null,"abstract":"<p>Magnesium imbalances commonly exist in septic patients. However, the association of serum magnesium levels with mortality in septic patients remains uncertain. Herein, we elucidated the association between serum magnesium and all-cause mortality in septic patients from American and Chinese cohorts by analyzing data from 9099 patients in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and 1727 patients from a university-affiliated hospital’ intensive care unit in China. Patients in both cohorts were categorized into five groups based on serum magnesium quintiles from the MIMIC-IV dataset. Patients with higher serum magnesium levels exhibited an increased risk of 28-day mortality in both cohorts. The restricted cubic spline (RCS) curves revealed a progressively elevated risk of 28-day mortality with increasing serum magnesium in MIMIC-IV cohort, while a J-shaped correlation was observed in institutional cohort. Our findings have validated the association between high serum magnesium and high mortality in sepsis across different races and medical conditions. Serum magnesium levels might be useful in identifying septic patients at higher mortality risk.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.713","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244544","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}
Liver cirrhosis is the end-stage of chronic liver disease, characterized by inflammation, necrosis, advanced fibrosis, and regenerative nodule formation. Long-term inflammation can cause continuous damage to liver tissues and hepatocytes, along with increased vascular tone and portal hypertension. Among them, fibrosis is the necessary stage and essential feature of liver cirrhosis, and effective antifibrosis strategies are commonly considered the key to treating liver cirrhosis. Although different therapeutic strategies aimed at reversing or preventing fibrosis have been developed, the effects have not be more satisfactory. In this review, we discussed abnormal changes in the liver microenvironment that contribute to the progression of liver cirrhosis and highlighted the importance of recent therapeutic strategies, including lifestyle improvement, small molecular agents, traditional Chinese medicine, stem cells, extracellular vesicles, and gut remediation, that regulate liver fibrosis and liver cirrhosis. Meanwhile, therapeutic strategies for nanoparticles are discussed, as are their possible underlying broad application and prospects for ameliorating liver cirrhosis. Finally, we also reviewed the major challenges and opportunities of nanomedicine‒biological environment interactions. We hope this review will provide insights into the pathogenesis and molecular mechanisms of liver cirrhosis, thus facilitating new methods, drug discovery, and better treatment of liver cirrhosis.
{"title":"Liver cirrhosis: molecular mechanisms and therapeutic interventions","authors":"Zihe Dong, Yeying Wang, Weilin Jin","doi":"10.1002/mco2.721","DOIUrl":"https://doi.org/10.1002/mco2.721","url":null,"abstract":"<p>Liver cirrhosis is the end-stage of chronic liver disease, characterized by inflammation, necrosis, advanced fibrosis, and regenerative nodule formation. Long-term inflammation can cause continuous damage to liver tissues and hepatocytes, along with increased vascular tone and portal hypertension. Among them, fibrosis is the necessary stage and essential feature of liver cirrhosis, and effective antifibrosis strategies are commonly considered the key to treating liver cirrhosis. Although different therapeutic strategies aimed at reversing or preventing fibrosis have been developed, the effects have not be more satisfactory. In this review, we discussed abnormal changes in the liver microenvironment that contribute to the progression of liver cirrhosis and highlighted the importance of recent therapeutic strategies, including lifestyle improvement, small molecular agents, traditional Chinese medicine, stem cells, extracellular vesicles, and gut remediation, that regulate liver fibrosis and liver cirrhosis. Meanwhile, therapeutic strategies for nanoparticles are discussed, as are their possible underlying broad application and prospects for ameliorating liver cirrhosis. Finally, we also reviewed the major challenges and opportunities of nanomedicine‒biological environment interactions. We hope this review will provide insights into the pathogenesis and molecular mechanisms of liver cirrhosis, thus facilitating new methods, drug discovery, and better treatment of liver cirrhosis.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.721","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244543","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>Messenger RNA (mRNA) has undergone significant evolution, emerging as a robust platform for diverse therapeutic applications such as vaccines, protein replacement, and adoptive cell therapy across infectious, cancer, and immunological diseases. In vitro transcribed mRNA offers distinct advantages, including cytoplasmic transient expression, devoid of the risk of genomic integration. Nucleotide modifications, such as pseudouridine (Ψ), N1-methylpseudouridine (m1Ψ), and 5-methylcytidine (m5C), play pivotal roles in mRNA immunogenicity, stability, and translational efficiency. Notably, standing out as a state-of-the-art modification, global m1Ψ modification has been performed in the two approved mRNA vaccines against severe acute respiratory syndrome coronavirus 2, mRNA-1273, and BNT162b2. The in vivo stability and translational duration of synthesized mRNA are partially restricted by its immunogenicity. Recognition of foreign RNA by toll-like receptor 3 (TLR3), TLR7, TLR8, and retinoic acid-inducible gene I (RIG-I)-like receptors triggers innate immunity, leading to RNA degradation.<span><sup>1, 2</sup></span> The therapeutic application of mRNA necessitates a delicate balance between immune activation and protein expression. For infectious disease vaccines, chemical modifications can minimize inflammatory responses while ensuring effective mRNA translation. Conversely, cancer vaccines require adequate innate immune stimulation for anti-tumor immunity. Thus far, most studies have investigated alternative m1Ψ modification individually or combined with others. However, it is unknown whether m1Ψ modification ratio in mRNA has an impact on the delicate balance between immunogenicity, stability, and translational efficiency.</p><p>Therefore, we synthesized mRNA encoding enhanced green fluorescent protein (mEGFP) with different m1Ψ modification ratios (5%, 10%, 20%, 50%, 75%, and 100%) through in vitro transcription. HEK-293T cells were transfected with unmodified mEGFP or m1Ψ-modified m1ΨEGFP (m1ΨEGFP-5%, m1ΨEGFP-10%, m1ΨEGFP-20%, m1ΨEGFP-50%, m1ΨEGFP-75%, and m1ΨEGFP-100%). The expression and duration of EGFP were assessed using flow cytometry over a 6-day period. As depicted in Figure 1A (upper part), m1ΨEGFP-5%, m1ΨEGFP-10%, and m1ΨEGFP-20% group exhibited a higher percentage of EGFP-positive cells (EGFP<sup>+</sup>cells %) and mean fluorescence intensity (MFI) compared to mEGFP group. Conversely, m1ΨEGFP-50%, m1ΨEGFP-75%, and m1ΨEGFP-100% group had lower EGFP<sup>+</sup>cells % and MFI. Notably, the EGFP<sup>+</sup>cells % and MFI of cells transfected with m1ΨEGFP-50%, m1ΨEGFP-75%, and m1ΨEGFP-100% were barely undetectable on day 6. EGFP expression detected by Western Blot on days 3, 4, and 5 was consistent with the flow cytometry (Figure 1A, bottom part, and Figure S1A). In summary, our finding indicates that the m1Ψ modification ratio might impact both mRNA translational ability and duration in HEK-293T cells.</p><p>To valida
{"title":"N1-methylpseudouridine modification level correlates with protein expression, immunogenicity, and stability of mRNA","authors":"Shaoyi Chen, Zheng Liu, Jingsheng Cai, Haoran Li, Mantang Qiu","doi":"10.1002/mco2.691","DOIUrl":"https://doi.org/10.1002/mco2.691","url":null,"abstract":"<p>Dear Editor,</p><p>Messenger RNA (mRNA) has undergone significant evolution, emerging as a robust platform for diverse therapeutic applications such as vaccines, protein replacement, and adoptive cell therapy across infectious, cancer, and immunological diseases. In vitro transcribed mRNA offers distinct advantages, including cytoplasmic transient expression, devoid of the risk of genomic integration. Nucleotide modifications, such as pseudouridine (Ψ), N1-methylpseudouridine (m1Ψ), and 5-methylcytidine (m5C), play pivotal roles in mRNA immunogenicity, stability, and translational efficiency. Notably, standing out as a state-of-the-art modification, global m1Ψ modification has been performed in the two approved mRNA vaccines against severe acute respiratory syndrome coronavirus 2, mRNA-1273, and BNT162b2. The in vivo stability and translational duration of synthesized mRNA are partially restricted by its immunogenicity. Recognition of foreign RNA by toll-like receptor 3 (TLR3), TLR7, TLR8, and retinoic acid-inducible gene I (RIG-I)-like receptors triggers innate immunity, leading to RNA degradation.<span><sup>1, 2</sup></span> The therapeutic application of mRNA necessitates a delicate balance between immune activation and protein expression. For infectious disease vaccines, chemical modifications can minimize inflammatory responses while ensuring effective mRNA translation. Conversely, cancer vaccines require adequate innate immune stimulation for anti-tumor immunity. Thus far, most studies have investigated alternative m1Ψ modification individually or combined with others. However, it is unknown whether m1Ψ modification ratio in mRNA has an impact on the delicate balance between immunogenicity, stability, and translational efficiency.</p><p>Therefore, we synthesized mRNA encoding enhanced green fluorescent protein (mEGFP) with different m1Ψ modification ratios (5%, 10%, 20%, 50%, 75%, and 100%) through in vitro transcription. HEK-293T cells were transfected with unmodified mEGFP or m1Ψ-modified m1ΨEGFP (m1ΨEGFP-5%, m1ΨEGFP-10%, m1ΨEGFP-20%, m1ΨEGFP-50%, m1ΨEGFP-75%, and m1ΨEGFP-100%). The expression and duration of EGFP were assessed using flow cytometry over a 6-day period. As depicted in Figure 1A (upper part), m1ΨEGFP-5%, m1ΨEGFP-10%, and m1ΨEGFP-20% group exhibited a higher percentage of EGFP-positive cells (EGFP<sup>+</sup>cells %) and mean fluorescence intensity (MFI) compared to mEGFP group. Conversely, m1ΨEGFP-50%, m1ΨEGFP-75%, and m1ΨEGFP-100% group had lower EGFP<sup>+</sup>cells % and MFI. Notably, the EGFP<sup>+</sup>cells % and MFI of cells transfected with m1ΨEGFP-50%, m1ΨEGFP-75%, and m1ΨEGFP-100% were barely undetectable on day 6. EGFP expression detected by Western Blot on days 3, 4, and 5 was consistent with the flow cytometry (Figure 1A, bottom part, and Figure S1A). In summary, our finding indicates that the m1Ψ modification ratio might impact both mRNA translational ability and duration in HEK-293T cells.</p><p>To valida","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.691","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245013","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}
Yunuo Yang, Jiaxuan Wu, Lisheng Wang, Guang Ji, Yanqi Dang
Copper is a vital trace element in human physiology, essential for the synthesis of numerous crucial metabolic enzymes and facilitation of various biological processes. Regulation of copper levels within a narrow range is imperative for maintaining metabolic homeostasis. Numerous studies have demonstrated the significant roles of copper homeostasis and cuproptosis in health and disease pathogenesis. However, a comprehensive and up-to-date systematic review in this domain remains absent. This review aims to consolidate recent advancements in understanding the roles of cuproptosis and copper homeostasis in health and disease, focusing on the underlying mechanisms and potential therapeutic interventions. Dysregulation of copper homeostasis, manifesting as either copper excess or deficiency, is implicated in the etiology of various diseases. Cuproptosis, a recently identified form of cell death, is characterized by intracellular copper overload. This phenomenon mediates a diverse array of evolutionary processes in organisms, spanning from health to disease, and is implicated in genetic disorders, liver diseases, neurodegenerative disorders, and various cancers. This review provides a comprehensive summary of the pathogenic mechanisms underlying cuproptosis and copper homeostasis, along with associated targeted therapeutic agents. Furthermore, it explores future research directions with the potential to yield significant advancements in disease treatment, health management, and disease prevention.
{"title":"Copper homeostasis and cuproptosis in health and disease","authors":"Yunuo Yang, Jiaxuan Wu, Lisheng Wang, Guang Ji, Yanqi Dang","doi":"10.1002/mco2.724","DOIUrl":"https://doi.org/10.1002/mco2.724","url":null,"abstract":"<p>Copper is a vital trace element in human physiology, essential for the synthesis of numerous crucial metabolic enzymes and facilitation of various biological processes. Regulation of copper levels within a narrow range is imperative for maintaining metabolic homeostasis. Numerous studies have demonstrated the significant roles of copper homeostasis and cuproptosis in health and disease pathogenesis. However, a comprehensive and up-to-date systematic review in this domain remains absent. This review aims to consolidate recent advancements in understanding the roles of cuproptosis and copper homeostasis in health and disease, focusing on the underlying mechanisms and potential therapeutic interventions. Dysregulation of copper homeostasis, manifesting as either copper excess or deficiency, is implicated in the etiology of various diseases. Cuproptosis, a recently identified form of cell death, is characterized by intracellular copper overload. This phenomenon mediates a diverse array of evolutionary processes in organisms, spanning from health to disease, and is implicated in genetic disorders, liver diseases, neurodegenerative disorders, and various cancers. This review provides a comprehensive summary of the pathogenic mechanisms underlying cuproptosis and copper homeostasis, along with associated targeted therapeutic agents. Furthermore, it explores future research directions with the potential to yield significant advancements in disease treatment, health management, and disease prevention.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.724","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244542","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}
Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real-world study aimed to compare patient-reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate-/high-risk premenopausal hormone receptor (HR)-positive breast cancer. The primary endpoint was PROs, assessed using SF-36 and EQ-5D-5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical (p = 0.034) and mental health (p = 0.009) dimensions of SF-36 and lower anxiety/depression (AD) scores (p = 0.038) in EQ-5D-5L compared to AI group. The estimated 5- and 8-year disease-free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% (p = 0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening (p < 0.001) and a lower occurrence of morning stiffness (p < 0.001) in the toremifene compared to the AI group. Premenopausal HR-positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles.
{"title":"Patient-reported outcome and survival in premenopausal hormone receptor-positive breast cancer patients at moderate to high risk: comparing toremifene with aromatase inhibitor in a real-world study","authors":"Yaping Yang, Fengxia Gan, Ting Luo, Qun Lin, Wenqian Yang, Lili Chen, Wei Zhang, Qiang Liu, Chang Gong","doi":"10.1002/mco2.698","DOIUrl":"https://doi.org/10.1002/mco2.698","url":null,"abstract":"<p>Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real-world study aimed to compare patient-reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate-/high-risk premenopausal hormone receptor (HR)-positive breast cancer. The primary endpoint was PROs, assessed using SF-36 and EQ-5D-5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical (<i>p</i> = 0.034) and mental health (<i>p </i>= 0.009) dimensions of SF-36 and lower anxiety/depression (AD) scores (<i>p </i>= 0.038) in EQ-5D-5L compared to AI group. The estimated 5- and 8-year disease-free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% (<i>p </i>= 0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening (<i>p </i>< 0.001) and a lower occurrence of morning stiffness (<i>p </i>< 0.001) in the toremifene compared to the AI group. Premenopausal HR-positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.698","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233998","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}
Qian Ding, Jianghong Cai, Li Jin, Wei Hu, Wu Song, Peter Rose, Zhiyuan Tang, Yangyang Zhan, Leilei Bao, Wei Lei, Yi Zhun Zhu
SMYD3 (SET and MYND domain-containing 3) is a histone lysine methyltransferase highly expressed in different types of cancer(s) and is a promising epigenetic target for developing novel antitumor therapeutics. No selective inhibitors for this protein have been developed for cancer treatment. Therefore, the current study describes developing and characterizing a novel small molecule ZYZ384 screened and synthesized based on SMYD3 structure. Virtual screening was initially used to identify a lead compound and followed up by modification to get the novel molecules. Several technologies were used to facilitate compound screening about these novel molecules' binding affinities and inhibition activities with SMYD3 protein; the antitumor activity has been assessed in vitro using various cancer cell lines. In addition, a tumor-bearing nude mice model was established, and the activity of the selected molecule was determined in vivo. Both RNA-seq and chip-seq were performed to explore the antitumor mechanism. This work identified a novel small molecule ZYZ384 targeting SMYD3 with antitumor activity and impaired hepatocellular carcinoma tumor growth by reducing H3K4 trimethylation of the Rac1 promoter triggering the tumor cell cycle arrest through the AKT pathway.
SMYD3(含 SET 和 MYND 结构域的 3)是一种组蛋白赖氨酸甲基转移酶,在不同类型的癌症中高度表达,是开发新型抗肿瘤疗法的一个有前景的表观遗传学靶点。目前尚未开发出治疗癌症的该蛋白选择性抑制剂。因此,本研究介绍了根据 SMYD3 结构筛选和合成的新型小分子 ZYZ384 的开发和表征情况。虚拟筛选最初用于确定先导化合物,随后通过修饰得到新型分子。研究人员利用多种技术对这些新型分子与 SMYD3 蛋白的结合亲和力和抑制活性进行了化合物筛选;并利用多种癌症细胞系对其抗肿瘤活性进行了体外评估。此外,还建立了肿瘤裸鼠模型,并在体内测定了所选分子的活性。为探索抗肿瘤机制,还进行了 RNA-seq 和芯片-seq 研究。这项研究发现了一种靶向SMYD3的新型小分子ZYZ384,它具有抗肿瘤活性,通过减少Rac1启动子的H3K4三甲基化,通过AKT通路引发肿瘤细胞周期停滞,从而抑制肝细胞癌肿瘤的生长。
{"title":"A novel small molecule ZYZ384 targeting SMYD3 for hepatocellular carcinoma via reducing H3K4 trimethylation of the Rac1 promoter","authors":"Qian Ding, Jianghong Cai, Li Jin, Wei Hu, Wu Song, Peter Rose, Zhiyuan Tang, Yangyang Zhan, Leilei Bao, Wei Lei, Yi Zhun Zhu","doi":"10.1002/mco2.711","DOIUrl":"https://doi.org/10.1002/mco2.711","url":null,"abstract":"<p>SMYD3 (SET and MYND domain-containing 3) is a histone lysine methyltransferase highly expressed in different types of cancer(s) and is a promising epigenetic target for developing novel antitumor therapeutics. No selective inhibitors for this protein have been developed for cancer treatment. Therefore, the current study describes developing and characterizing a novel small molecule ZYZ384 screened and synthesized based on SMYD3 structure. Virtual screening was initially used to identify a lead compound and followed up by modification to get the novel molecules. Several technologies were used to facilitate compound screening about these novel molecules' binding affinities and inhibition activities with SMYD3 protein; the antitumor activity has been assessed in vitro using various cancer cell lines. In addition, a tumor-bearing nude mice model was established, and the activity of the selected molecule was determined in vivo. Both RNA-seq and chip-seq were performed to explore the antitumor mechanism. This work identified a novel small molecule ZYZ384 targeting SMYD3 with antitumor activity and impaired hepatocellular carcinoma tumor growth by reducing H3K4 trimethylation of the Rac1 promoter triggering the tumor cell cycle arrest through the AKT pathway.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.711","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233999","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>Recently, a novel transcriptome and genome profiling study published in the <i>Journal of Nature Genetics</i>, expanded the prognosis-related molecular classification coverage of pediatric acute myeloid leukemia (pAML) from 68.5% (as defined by the WHO 5th edition) to 91.4%.<span><sup>1</sup></span> This framework was strongly associated with clinical outcomes, potentially shaping future classifications and treatment of pediatric AML.</p><p>Differences in molecular profiles between pediatric and adult AML restrict the use of risk stratification tools designed for adults when applied to pediatric patients. For instance, while the TP53 mutation, present in about 8% of adult AML cases and linked to poor outcomes, is emphasized in the European LeukemiaNet (ELN) 2022 guidelines,<span><sup>2</sup></span> it is infrequently observed in pediatric AML. Furthermore, numerous driver alterations that are specific to pediatric cases are not adequately represented in the existing classification schemas, and risk stratification for pediatric AML is still evolving. This prompted Umeda and colleagues to comprehensively explore the increasingly intricate genomic landscape within the framework of the latest hematological malignancy classification systems and to create a categorization system uniquely designed for pediatric AML.</p><p>In their study, RNA sequencing (RNA-seq) data of 887 pAML patients were assessed, complemented by DNA sequencing data, allowing for a comprehensive examination of genetic features, including internal or partial tandem duplications (ITD/PTD), copy-number variations, single nucleotide mutations, fusions, and insertions and deletions (indels). It was revealed that while WHO 5th identified 68.5% of pAML cases with specified genetic alterations, the new pAML classification system, which incorporates 12 additional molecular categories, captures 91.4% of cases. The discovery of these new major entities such as UBTF tandem duplications, GLIS family rearrangements, and BCL11B structural variants and outlier expression will lead to greater attention and analysis of these patients’ biological and clinical features.</p><p>Further clinicopathological association analysis revealed that pAML morphological features are defined by the identified driver alterations and developmental stages. Given that numerous category-defining alterations are either cytogenetically obscure or involve somatic mutations, this underscores the necessity for sequencing techniques to achieve precise molecular diagnosis of pAML. As for gene expression, molecular categories with favorable prognosis (such as CBFB::MYH11, CEBPA, RUNX1::RUNX1T1) typically exhibited high granulocyte–monocyte progenitor scores. Conversely, KMT2Ar, associated with poor prognosis, had low stemness-related scores and variable differentiation-related scores. The differences in the aforementioned prognosis or drug–response-related patterns reflect that molecular categories are associated with unique
{"title":"Unlocking fresh perspectives: molecular breakthroughs in pediatric acute myeloid leukemia classification and prognosis","authors":"Yu Tao, Li Wei, Hua You","doi":"10.1002/mco2.750","DOIUrl":"https://doi.org/10.1002/mco2.750","url":null,"abstract":"<p>Recently, a novel transcriptome and genome profiling study published in the <i>Journal of Nature Genetics</i>, expanded the prognosis-related molecular classification coverage of pediatric acute myeloid leukemia (pAML) from 68.5% (as defined by the WHO 5th edition) to 91.4%.<span><sup>1</sup></span> This framework was strongly associated with clinical outcomes, potentially shaping future classifications and treatment of pediatric AML.</p><p>Differences in molecular profiles between pediatric and adult AML restrict the use of risk stratification tools designed for adults when applied to pediatric patients. For instance, while the TP53 mutation, present in about 8% of adult AML cases and linked to poor outcomes, is emphasized in the European LeukemiaNet (ELN) 2022 guidelines,<span><sup>2</sup></span> it is infrequently observed in pediatric AML. Furthermore, numerous driver alterations that are specific to pediatric cases are not adequately represented in the existing classification schemas, and risk stratification for pediatric AML is still evolving. This prompted Umeda and colleagues to comprehensively explore the increasingly intricate genomic landscape within the framework of the latest hematological malignancy classification systems and to create a categorization system uniquely designed for pediatric AML.</p><p>In their study, RNA sequencing (RNA-seq) data of 887 pAML patients were assessed, complemented by DNA sequencing data, allowing for a comprehensive examination of genetic features, including internal or partial tandem duplications (ITD/PTD), copy-number variations, single nucleotide mutations, fusions, and insertions and deletions (indels). It was revealed that while WHO 5th identified 68.5% of pAML cases with specified genetic alterations, the new pAML classification system, which incorporates 12 additional molecular categories, captures 91.4% of cases. The discovery of these new major entities such as UBTF tandem duplications, GLIS family rearrangements, and BCL11B structural variants and outlier expression will lead to greater attention and analysis of these patients’ biological and clinical features.</p><p>Further clinicopathological association analysis revealed that pAML morphological features are defined by the identified driver alterations and developmental stages. Given that numerous category-defining alterations are either cytogenetically obscure or involve somatic mutations, this underscores the necessity for sequencing techniques to achieve precise molecular diagnosis of pAML. As for gene expression, molecular categories with favorable prognosis (such as CBFB::MYH11, CEBPA, RUNX1::RUNX1T1) typically exhibited high granulocyte–monocyte progenitor scores. Conversely, KMT2Ar, associated with poor prognosis, had low stemness-related scores and variable differentiation-related scores. The differences in the aforementioned prognosis or drug–response-related patterns reflect that molecular categories are associated with unique ","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.750","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233996","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>A recent study by Chi and colleagues in <i>Science</i> identified skin type 2 innate lymphoid cells (ILC2s) as crucial for maintaining skin dendritic cell (DC) network homeostasis through cytokine production.<span><sup>1</sup></span> Their findings reveal that the interplay between sex hormones and the microbiota shapes tissue immune set points and DC network strength, with hormones influencing local immunity and the microbiota modulating its intensity.</p><p>Differences in the immune systems of females and males contribute to observed sexual dimorphisms in susceptibility to a range of diseases, including cancers, autoimmune diseases, allergies, and infectious diseases, including coronavirus disease 2019, particularly in barrier tissues which are primary sites for infections and are regulated by a complex microbial community. Laffont et al. first identified the role of androgen signaling in regulating ILC2 responses, showing that females have more ILC2s than males.<span><sup>2</sup></span> This disparity arises not from estrogen enhancement in females but from androgen inhibition of ILC2 maintenance and local expansion in males.<span><sup>2</sup></span> Building on this observation, Chi et al. examined the impact of androgen-mediated regulation of ILC2s on the skin DC network and its subsequent effects on adaptive immune responses.<span><sup>1</sup></span></p><p>Acting as nuclear regulators, sex hormone receptors play a pivotal role in fine-tuning immune responses at the transcriptional level, which in turn influences disease outcomes. In the domain of cancer immunology, these receptors oversee specific pathways in both the innate and adaptive immune systems, providing potential avenues for therapeutic interventions in reproductive cancers. Specifically, androgen receptor (AR) signaling has been linked to the suppression of CD8<sup>+</sup> T cell function within the tumor microenvironment.<span><sup>3</sup></span> Meanwhile, testosterone, the primary male hormone governing sex differentiation and the development of male sex characteristics, interacts with cytosolic or membrane-bound ARs to modulate gene transcription either directly or indirectly. ARs are expressed across a variety of cells, including many in developmental stages and some mature immune cells. Further studies across infectious diseases, autoimmunity, and cancer highlight testosterone's direct influence on immune cell development and function, typically leading to immunosuppressive effects.<span><sup>3</sup></span> Additionally, gender disparities in the immune system render males more susceptible to microbial infections and less effective in viral clearance, albeit affording greater protection against autoimmune diseases.<span><sup>1</sup></span> Barrier tissues serve as primary sites for infections and injury and are perpetually inhabited by a diverse microbial community that modulates host defense mechanisms. Despite this, the immune differences specific to each sex in these
Chi 及其同事最近在《科学》(Science)杂志上发表的一项研究发现,皮肤 2 型先天性淋巴细胞(ILC2s)对通过细胞因子的产生维持皮肤树突状细胞(DC)网络的平衡至关重要。他们的研究结果表明,性激素和微生物群之间的相互作用塑造了组织免疫设定点和DC网络的强度,激素影响局部免疫,微生物群调节免疫强度。女性和男性免疫系统的差异导致了对一系列疾病易感性的性双态性,这些疾病包括癌症、自身免疫性疾病、过敏和传染病,包括2019年冠状病毒疾病,尤其是在屏障组织中,因为屏障组织是感染的主要场所,并受到复杂微生物群落的调控。拉丰等人首次发现了雄激素信号在调节 ILC2 反应中的作用,表明女性的 ILC2 数量多于男性2 。基于这一观察结果,Chi 等人研究了雄激素介导的 ILC2 对皮肤 DC 网络的调控及其对适应性免疫反应的影响。在癌症免疫学领域,这些受体监督着先天性免疫系统和适应性免疫系统的特定途径,为生殖系统癌症的治疗干预提供了潜在的途径。雄激素受体(AR)信号传导与肿瘤微环境中 CD8+ T 细胞功能的抑制有关。3 同时,睾酮是控制性别分化和男性性征发育的主要雄性激素,它与细胞膜或膜结合的 ARs 相互作用,直接或间接地调节基因转录。ARs 在多种细胞中表达,包括许多处于发育阶段的细胞和一些成熟的免疫细胞。3 此外,免疫系统中的性别差异使男性更容易受到微生物感染,清除病毒的能力也更弱,但却能更好地抵御自身免疫性疾病的侵袭。尽管如此,这些组织中男女特有的免疫差异以及微生物群对它们的调节作用还没有得到很好的描述。Chi 等人的研究表明,性别差异会影响对微生物群的免疫反应,特别是影响 T 辅助细胞 17(Th17)和 T 细胞对感染的反应1 。这表现在雌性小鼠肺部和皮肤中的主要经典 T 细胞亚群(包括 Th1 细胞、Th17 细胞和产生白细胞介素-17 的 CD8+ T 细胞)数量都比雄性多。有趣的是,虽然研究发现无菌小鼠皮肤中的T细胞存在性别特异性差异,但肺中却没有这种差异,这表明性别对皮肤免疫力的影响与微生物无关。此外,Chi 等人的研究涉及用表皮葡萄球菌对成年无菌小鼠进行常规化处理,该研究加剧了性别差异,尤其是在 17 型细胞和 Treg 细胞反应方面。研究结果表明,微生物群可能在形成雌性小鼠对 17 型和 Treg 细胞免疫的性别特异性偏向方面发挥作用。在青春期前期,性激素水平较低,雌性和雄性淋巴细胞的差异很小。然而,随着性成熟的开始和雄性性激素的激增,这些差异变得更加明显。切除性腺的实验表明,雄性激素主要调节观察到的表型。值得注意的是,阉割雄性小鼠可使 T 细胞的组成和表型恢复到与雌性小鼠相似的水平,这凸显了雄性激素在决定淋巴细胞偏向中的关键作用。
{"title":"Androgen-type 2 innate lymphoid cells-dendritic cell axis modulates sex-associated differences in skin immune responses","authors":"Shi-Jun He, Jian-Ping Zuo, Ze-Min Lin","doi":"10.1002/mco2.732","DOIUrl":"https://doi.org/10.1002/mco2.732","url":null,"abstract":"<p>A recent study by Chi and colleagues in <i>Science</i> identified skin type 2 innate lymphoid cells (ILC2s) as crucial for maintaining skin dendritic cell (DC) network homeostasis through cytokine production.<span><sup>1</sup></span> Their findings reveal that the interplay between sex hormones and the microbiota shapes tissue immune set points and DC network strength, with hormones influencing local immunity and the microbiota modulating its intensity.</p><p>Differences in the immune systems of females and males contribute to observed sexual dimorphisms in susceptibility to a range of diseases, including cancers, autoimmune diseases, allergies, and infectious diseases, including coronavirus disease 2019, particularly in barrier tissues which are primary sites for infections and are regulated by a complex microbial community. Laffont et al. first identified the role of androgen signaling in regulating ILC2 responses, showing that females have more ILC2s than males.<span><sup>2</sup></span> This disparity arises not from estrogen enhancement in females but from androgen inhibition of ILC2 maintenance and local expansion in males.<span><sup>2</sup></span> Building on this observation, Chi et al. examined the impact of androgen-mediated regulation of ILC2s on the skin DC network and its subsequent effects on adaptive immune responses.<span><sup>1</sup></span></p><p>Acting as nuclear regulators, sex hormone receptors play a pivotal role in fine-tuning immune responses at the transcriptional level, which in turn influences disease outcomes. In the domain of cancer immunology, these receptors oversee specific pathways in both the innate and adaptive immune systems, providing potential avenues for therapeutic interventions in reproductive cancers. Specifically, androgen receptor (AR) signaling has been linked to the suppression of CD8<sup>+</sup> T cell function within the tumor microenvironment.<span><sup>3</sup></span> Meanwhile, testosterone, the primary male hormone governing sex differentiation and the development of male sex characteristics, interacts with cytosolic or membrane-bound ARs to modulate gene transcription either directly or indirectly. ARs are expressed across a variety of cells, including many in developmental stages and some mature immune cells. Further studies across infectious diseases, autoimmunity, and cancer highlight testosterone's direct influence on immune cell development and function, typically leading to immunosuppressive effects.<span><sup>3</sup></span> Additionally, gender disparities in the immune system render males more susceptible to microbial infections and less effective in viral clearance, albeit affording greater protection against autoimmune diseases.<span><sup>1</sup></span> Barrier tissues serve as primary sites for infections and injury and are perpetually inhabited by a diverse microbial community that modulates host defense mechanisms. Despite this, the immune differences specific to each sex in these ","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.732","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234000","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}
The innate immune system serves as the body's first line of defense, utilizing pattern recognition receptors like Toll-like receptors to detect pathogens and initiate rapid response mechanisms. Following this initial response, adaptive immunity provides highly specific and sustained killing of pathogens via B cells, T cells, and antibodies. Traditionally, it has been assumed that innate immunity activates adaptive immunity; however, recent studies have revealed more complex interactions. This review provides a detailed dissection of the composition and function of the innate and adaptive immune systems, emphasizing their synergistic roles in physiological and pathological contexts, providing new insights into the link between these two forms of immunity. Precise regulation of both immune systems at the same time is more beneficial in the fight against immune-related diseases, for example, the cGAS–STING pathway has been found to play an important role in infections and cancers. In addition, this paper summarizes the challenges and future directions in the field of immunity, including the latest single-cell sequencing technologies, CAR-T cell therapy, and immune checkpoint inhibitors. By summarizing these developments, this review aims to enhance our understanding of the complexity interactions between innate and adaptive immunity and provides new perspectives in understanding the immune system.
先天性免疫系统是人体的第一道防线,它利用模式识别受体(如 Toll 样受体)来检测病原体并启动快速反应机制。在最初的反应之后,适应性免疫系统通过 B 细胞、T 细胞和抗体对病原体进行高度特异性和持续性的杀灭。传统上,人们认为先天性免疫激活了适应性免疫;然而,最近的研究揭示了更为复杂的相互作用。本综述详细剖析了先天性免疫系统和适应性免疫系统的组成和功能,强调了它们在生理和病理环境中的协同作用,为人们了解这两种免疫形式之间的联系提供了新的视角。同时对两种免疫系统进行精确调控更有利于对抗免疫相关疾病,例如,研究发现 cGAS-STING 通路在感染和癌症中发挥着重要作用。此外,本文还总结了免疫领域的挑战和未来发展方向,包括最新的单细胞测序技术、CAR-T 细胞疗法和免疫检查点抑制剂。通过总结这些发展,本综述旨在加深我们对先天性免疫和适应性免疫之间复杂互动的理解,并为理解免疫系统提供新的视角。
{"title":"The interaction of innate immune and adaptive immune system","authors":"Ruyuan Wang, Caini Lan, Kamel Benlagha, Niels Olsen Saraiva Camara, Heather Miller, Masato Kubo, Steffen Heegaard, Pamela Lee, Lu Yang, Huamei Forsman, Xingrui Li, Zhimin Zhai, Chaohong Liu","doi":"10.1002/mco2.714","DOIUrl":"https://doi.org/10.1002/mco2.714","url":null,"abstract":"<p>The innate immune system serves as the body's first line of defense, utilizing pattern recognition receptors like Toll-like receptors to detect pathogens and initiate rapid response mechanisms. Following this initial response, adaptive immunity provides highly specific and sustained killing of pathogens via B cells, T cells, and antibodies. Traditionally, it has been assumed that innate immunity activates adaptive immunity; however, recent studies have revealed more complex interactions. This review provides a detailed dissection of the composition and function of the innate and adaptive immune systems, emphasizing their synergistic roles in physiological and pathological contexts, providing new insights into the link between these two forms of immunity. Precise regulation of both immune systems at the same time is more beneficial in the fight against immune-related diseases, for example, the cGAS–STING pathway has been found to play an important role in infections and cancers. In addition, this paper summarizes the challenges and future directions in the field of immunity, including the latest single-cell sequencing technologies, CAR-T cell therapy, and immune checkpoint inhibitors. By summarizing these developments, this review aims to enhance our understanding of the complexity interactions between innate and adaptive immunity and provides new perspectives in understanding the immune system.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.714","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233994","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}
Jie Mei, Xue-Yao Jiang, Hui-Xiang Tian, Ding-Chao Rong, Jia-Nan Song, Luozixian Wang, Yuan-Shen Chen, Raymond C. B. Wong, Cheng-Xian Guo, Lian-Sheng Wang, Lei-Yun Wang, Peng-Yuan Wang, Ji-Ye Yin
The extracellular matrix (ECM) governs a wide spectrum of cellular fate processes, with a particular emphasis on anoikis, an integrin-dependent form of cell death. Currently, anoikis is defined as an intrinsic apoptosis. In contrast to traditional apoptosis and necroptosis, integrin correlates ECM signaling with intracellular signaling cascades, describing the full process of anoikis. However, anoikis is frequently overlooked in physiological and pathological processes as well as traditional in vitro research models. In this review, we summarized the role of anoikis in physiological and pathological processes, spanning embryonic development, organ development, tissue repair, inflammatory responses, cardiovascular diseases, tumor metastasis, and so on. Similarly, in the realm of stem cell research focused on the functional evolution of cells, anoikis offers a potential solution to various challenges, including in vitro cell culture models, stem cell therapy, cell transplantation, and engineering applications, which are largely based on the regulation of cell fate by anoikis. More importantly, the regulatory mechanisms of anoikis based on molecular processes and ECM signaling will provide new strategies for therapeutic interventions (drug therapy and cell-based therapy) in disease. In summary, this review provides a systematic elaboration of anoikis, thus shedding light on its future research.
{"title":"Anoikis in cell fate, physiopathology, and therapeutic interventions","authors":"Jie Mei, Xue-Yao Jiang, Hui-Xiang Tian, Ding-Chao Rong, Jia-Nan Song, Luozixian Wang, Yuan-Shen Chen, Raymond C. B. Wong, Cheng-Xian Guo, Lian-Sheng Wang, Lei-Yun Wang, Peng-Yuan Wang, Ji-Ye Yin","doi":"10.1002/mco2.718","DOIUrl":"https://doi.org/10.1002/mco2.718","url":null,"abstract":"<p>The extracellular matrix (ECM) governs a wide spectrum of cellular fate processes, with a particular emphasis on anoikis, an integrin-dependent form of cell death. Currently, anoikis is defined as an intrinsic apoptosis. In contrast to traditional apoptosis and necroptosis, integrin correlates ECM signaling with intracellular signaling cascades, describing the full process of anoikis. However, anoikis is frequently overlooked in physiological and pathological processes as well as traditional in vitro research models. In this review, we summarized the role of anoikis in physiological and pathological processes, spanning embryonic development, organ development, tissue repair, inflammatory responses, cardiovascular diseases, tumor metastasis, and so on. Similarly, in the realm of stem cell research focused on the functional evolution of cells, anoikis offers a potential solution to various challenges, including in vitro cell culture models, stem cell therapy, cell transplantation, and engineering applications, which are largely based on the regulation of cell fate by anoikis. More importantly, the regulatory mechanisms of anoikis based on molecular processes and ECM signaling will provide new strategies for therapeutic interventions (drug therapy and cell-based therapy) in disease. In summary, this review provides a systematic elaboration of anoikis, thus shedding light on its future research.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":null,"pages":null},"PeriodicalIF":10.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.718","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233995","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}