Pub Date : 2024-06-12DOI: 10.1038/s41392-024-01859-4
Yun Yang, Qingya Liu, Meng Wang, Lang Li, Yan Yu, Meng Pan, Danrong Hu, Bingyang Chu, Ying Qu, Zhiyong Qian
Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK2), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.
{"title":"Genetically programmable cell membrane-camouflaged nanoparticles for targeted combination therapy of colorectal cancer.","authors":"Yun Yang, Qingya Liu, Meng Wang, Lang Li, Yan Yu, Meng Pan, Danrong Hu, Bingyang Chu, Ying Qu, Zhiyong Qian","doi":"10.1038/s41392-024-01859-4","DOIUrl":"10.1038/s41392-024-01859-4","url":null,"abstract":"<p><p>Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK<sub>2</sub>), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-12DOI: 10.1038/s41392-024-01878-1
Daniel Noerenberg, Frederik Damm
{"title":"Beyond the code: the role of histone methylation in cancer resistance and therapy","authors":"Daniel Noerenberg, Frederik Damm","doi":"10.1038/s41392-024-01878-1","DOIUrl":"https://doi.org/10.1038/s41392-024-01878-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.
呼吸道合胞病毒(RSV)是导致幼儿和老年人支气管炎和肺炎的主要原因。目前还没有获得批准的 RSV 特异性治疗小分子药物。通过高通量抗病毒筛选,我们发现了一种口服药物--前酰化抑制剂lonafarnib,它对RSV的融合过程有很强的抑制作用。Lonafarnib 对 RSV A 和 B 基因型都具有抗病毒活性,并且在 HEp-2 和人类原发性支气管上皮细胞(HBEC)中显示出较低的细胞毒性。添加时间和伪病毒试验表明,lonafarnib 可抑制 RSV 进入,但其抗病毒效力不依赖于法尼基转移酶。冷冻电镜显示,lonafarnib与RSV F可蜕变融合前构象中央空腔内的三重对称口袋结合。与诺那法尼相互作用的RSV F位点突变体对诺那法尼表现出抗药性,但对中和单克隆抗体帕利珠单抗仍完全敏感。此外,诺那法尼还能剂量依赖性地减少 RSV 在 BALB/c 小鼠体内的复制。总之,lonafarnib可能是一种潜在的RSV感染融合抑制剂。
{"title":"Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.","authors":"Qi Yang, Bao Xue, Fengjiang Liu, Yongzhi Lu, Jielin Tang, Mengrong Yan, Qiong Wu, Ruyi Chen, Anqi Zhou, Lijie Liu, Junjun Liu, Changbin Qu, Qingxin Wu, Muqing Fu, Jiayi Zhong, Jianwei Dong, Sijie Chen, Fan Wang, Yuan Zhou, Jie Zheng, Wei Peng, Jinsai Shang, Xinwen Chen","doi":"10.1038/s41392-024-01858-5","DOIUrl":"10.1038/s41392-024-01858-5","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-08DOI: 10.1038/s41392-024-01845-w
Bo Cao, Qixuan Xu, Yajiao Shi, Ruiyang Zhao, Hanghang Li, Jie Zheng, Fengyu Liu, You Wan, Bo Wei
Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.
{"title":"Pathology of pain and its implications for therapeutic interventions","authors":"Bo Cao, Qixuan Xu, Yajiao Shi, Ruiyang Zhao, Hanghang Li, Jie Zheng, Fengyu Liu, You Wan, Bo Wei","doi":"10.1038/s41392-024-01845-w","DOIUrl":"https://doi.org/10.1038/s41392-024-01845-w","url":null,"abstract":"<p>Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141292672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-08DOI: 10.1038/s41392-024-01883-4
Chunling Wang, Junchao Xu, Xiaoyu Cheng, Ge Sun, Fenfen Li, Guangjun Nie, Yinlong Zhang
{"title":"Correction: Anti-lymphangiogenesis for boosting drug accumulation in tumors.","authors":"Chunling Wang, Junchao Xu, Xiaoyu Cheng, Ge Sun, Fenfen Li, Guangjun Nie, Yinlong Zhang","doi":"10.1038/s41392-024-01883-4","DOIUrl":"10.1038/s41392-024-01883-4","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11162444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-08DOI: 10.1038/s41392-024-01864-7
Imke Atreya, Markus F. Neurath
{"title":"Linking IL-10 signaling with lipid metabolic programs in macrophages: dysregulated ceramide homeostasis drives colitis","authors":"Imke Atreya, Markus F. Neurath","doi":"10.1038/s41392-024-01864-7","DOIUrl":"https://doi.org/10.1038/s41392-024-01864-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141292710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-07DOI: 10.1038/s41392-024-01857-6
Huizi Sha, Fan Tong, Jiayao Ni, Yi Sun, Yahui Zhu, Liang Qi, Xiaoqin Li, Wei Li, Yan Yang, Qing Gu, Xing Zhang, Xiaoxuan Wang, Chan Zhu, Dongsheng Chen, Baorui Liu, Juan Du
Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine (PAAG) in patients with first-line mPC (NCT05493995). The primary endpoints included the objective response rate (ORR) and disease control rate (DCR), while secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and safety. In 66 patients analysed for efficacy, the best response, indicated by the ORR, was recorded at 50.0% (33/66) (95% CI, 37.4-62.6%), with 33 patients achieving partial response (PR). Notably, the DCR was 95.5% (63/66, 95% CI, 87.3-99.1%). The median PFS (mPFS) and OS (mOS) were 8.8 (95% CI, 8.1-11.6), and 13.7 (95% CI, 12.4 to not reached) months, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 39.4% of patients (26/66). In prespecified exploratory analysis, patients with altered SWI/SNF complex had a poorer PFS. Additionally, low serum CA724 level, high T-cell recruitment, low Th17 cell recruitment, and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy. In conclusion, PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC. The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.
转移性胰腺癌(mPC)的预后很差。在此,我们开展了一项前瞻性、多中心、单臂 II 期试验,评估了 Penpulimab 和安罗替尼联合纳布-紫杉醇/吉西他滨(PAAG)治疗一线 mPC 患者的有效性和安全性(NCT05493995)。主要终点包括客观反应率(ORR)和疾病控制率(DCR),次要终点包括无进展生存期(PFS)、总生存期(OS)和安全性。在接受疗效分析的 66 例患者中,以 ORR 表示的最佳反应率为 50.0%(33/66)(95% CI,37.4-62.6%),33 例患者获得部分反应(PR)。值得注意的是,DCR 为 95.5%(63/66,95% CI,87.3-99.1%)。中位PFS(mPFS)和OS(mOS)分别为8.8个月(95% CI,8.1-11.6)和13.7个月(95% CI,12.4-未达)。39.4%的患者(26/66)报告了3/4级治疗相关不良事件(TRAEs)。在预设的探索性分析中,SWI/SNF复合物改变的患者PFS较差。此外,基线时的低血清 CA724 水平、高 T 细胞招募、低 Th17 细胞招募和高 NK CD56dim 细胞评分是更有利疗效的潜在预测性生物标志物。总之,PAAG作为一线疗法对mPC具有耐受性和良好的临床疗效。本研究中发现的生物分子发现有望指导三联疗法的精确临床应用。
{"title":"First-line penpulimab (an anti-PD1 antibody) and anlotinib (an angiogenesis inhibitor) with nab-paclitaxel/gemcitabine (PAAG) in metastatic pancreatic cancer: a prospective, multicentre, biomolecular exploratory, phase II trial.","authors":"Huizi Sha, Fan Tong, Jiayao Ni, Yi Sun, Yahui Zhu, Liang Qi, Xiaoqin Li, Wei Li, Yan Yang, Qing Gu, Xing Zhang, Xiaoxuan Wang, Chan Zhu, Dongsheng Chen, Baorui Liu, Juan Du","doi":"10.1038/s41392-024-01857-6","DOIUrl":"10.1038/s41392-024-01857-6","url":null,"abstract":"<p><p>Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine (PAAG) in patients with first-line mPC (NCT05493995). The primary endpoints included the objective response rate (ORR) and disease control rate (DCR), while secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and safety. In 66 patients analysed for efficacy, the best response, indicated by the ORR, was recorded at 50.0% (33/66) (95% CI, 37.4-62.6%), with 33 patients achieving partial response (PR). Notably, the DCR was 95.5% (63/66, 95% CI, 87.3-99.1%). The median PFS (mPFS) and OS (mOS) were 8.8 (95% CI, 8.1-11.6), and 13.7 (95% CI, 12.4 to not reached) months, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 39.4% of patients (26/66). In prespecified exploratory analysis, patients with altered SWI/SNF complex had a poorer PFS. Additionally, low serum CA724 level, high T-cell recruitment, low Th17 cell recruitment, and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy. In conclusion, PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC. The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":40.8,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11156675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-06DOI: 10.1038/s41392-024-01854-9
Sihui Luo, Xueying Zheng, Wei Bao, Sheng Nie, Yu Ding, Tong Yue, Yilun Zhou, Ying Hu, Hua Li, Qiongqiong Yang, Qijun Wan, Bicheng Liu, Hong Xu, Guisen Li, Gang Xu, Chunbo Chen, Huafeng Liu, Yongjun Shi, Yan Zha, Yaozhong Kong, Guobin Su, Ying Tang, Mengchun Gong, Linong Ji, Fan Fan Hou, Jianping Weng
Early insulin therapy is capable to achieve glycemic control and restore β-cell function in newly diagnosed type 2 diabetes (T2D), but its effect on cardiovascular outcomes in these patients remains unclear. In this nationwide real-world study, we analyzed electronic health record data from 19 medical centers across China between 1 January 2000, and 26 May 2022. We included 5424 eligible patients (mean age 56 years, 2176 women/3248 men) who were diagnosed T2D within six months and did not have prior cardiovascular disease. Multivariable Cox regression models were used to estimate the associations of early insulin therapy (defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients) with the incidence of major cardiovascular events including coronary heart disease (CHD), stroke, and hospitalization for heart failure (HF). During 17,158 persons years of observation, we documented 834 incident CHD cases, 719 stroke cases, and 230 hospitalized cases for HF. Newly diagnosed T2D patients who received early insulin therapy, compared with those who did not receive such treatment, had 31% lower risk of incident stroke, and 28% lower risk of hospitalization for HF. No significant difference in the risk of CHD was observed. We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models. These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.
{"title":"Real-world effectiveness of early insulin therapy on the incidence of cardiovascular events in newly diagnosed type 2 diabetes","authors":"Sihui Luo, Xueying Zheng, Wei Bao, Sheng Nie, Yu Ding, Tong Yue, Yilun Zhou, Ying Hu, Hua Li, Qiongqiong Yang, Qijun Wan, Bicheng Liu, Hong Xu, Guisen Li, Gang Xu, Chunbo Chen, Huafeng Liu, Yongjun Shi, Yan Zha, Yaozhong Kong, Guobin Su, Ying Tang, Mengchun Gong, Linong Ji, Fan Fan Hou, Jianping Weng","doi":"10.1038/s41392-024-01854-9","DOIUrl":"https://doi.org/10.1038/s41392-024-01854-9","url":null,"abstract":"<p>Early insulin therapy is capable to achieve glycemic control and restore β-cell function in newly diagnosed type 2 diabetes (T2D), but its effect on cardiovascular outcomes in these patients remains unclear. In this nationwide real-world study, we analyzed electronic health record data from 19 medical centers across China between 1 January 2000, and 26 May 2022. We included 5424 eligible patients (mean age 56 years, 2176 women/3248 men) who were diagnosed T2D within six months and did not have prior cardiovascular disease. Multivariable Cox regression models were used to estimate the associations of early insulin therapy (defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients) with the incidence of major cardiovascular events including coronary heart disease (CHD), stroke, and hospitalization for heart failure (HF). During 17,158 persons years of observation, we documented 834 incident CHD cases, 719 stroke cases, and 230 hospitalized cases for HF. Newly diagnosed T2D patients who received early insulin therapy, compared with those who did not receive such treatment, had 31% lower risk of incident stroke, and 28% lower risk of hospitalization for HF. No significant difference in the risk of CHD was observed. We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models. These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141264860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.
{"title":"Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade.","authors":"Liang Zhao, Yizhen Pang, Yangfan Zhou, Jianhao Chen, Hao Fu, Wei Guo, Weizhi Xu, Xin Xue, Guoqiang Su, Long Sun, Hua Wu, Jingjing Zhang, Zhanxiang Wang, Qin Lin, Xiaoyuan Chen, Haojun Chen","doi":"10.1038/s41392-024-01853-w","DOIUrl":"10.1038/s41392-024-01853-w","url":null,"abstract":"<p><p>Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that <sup>68</sup>Ga/<sup>177</sup>Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with <sup>177</sup>Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of <sup>177</sup>Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8<sup>+</sup> T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that <sup>177</sup>Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with <sup>177</sup>Lu-LNC1004 for cancer patients with FAP-positive tumors.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11144707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.
{"title":"Macrophages in cardiovascular diseases: molecular mechanisms and therapeutic targets.","authors":"Runkai Chen, Hongrui Zhang, Botao Tang, Yukun Luo, Yufei Yang, Xin Zhong, Sifei Chen, Xinjie Xu, Shengkang Huang, Canzhao Liu","doi":"10.1038/s41392-024-01840-1","DOIUrl":"10.1038/s41392-024-01840-1","url":null,"abstract":"<p><p>The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}