Pub Date : 2024-08-20DOI: 10.1016/j.xcrm.2024.101700
Dennis S Metselaar, Michaël H Meel, Joshua R Goulding, Aimeé du Chatinier, Leyla Rigamonti, Piotr Waranecki, Neal Geisemeyer, Mark C de Gooijer, Marjolein Breur, Jan Koster, Sophie E M Veldhuijzen van Zanten, Marianna Bugiani, Niels E Franke, Alyssa Reddy, Pieter Wesseling, Gertjan J L Kaspers, Esther Hulleman
Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the sonic hedgehog (SHH) signaling activator GLI2, explaining the observed additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival and yielded long-term survivors in two independent patient-derived xenograft models. These findings demonstrate that ATRTs are highly sensitive to gemcitabine treatment and may form part of a future multimodal treatment strategy for ATRTs.
{"title":"Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.","authors":"Dennis S Metselaar, Michaël H Meel, Joshua R Goulding, Aimeé du Chatinier, Leyla Rigamonti, Piotr Waranecki, Neal Geisemeyer, Mark C de Gooijer, Marjolein Breur, Jan Koster, Sophie E M Veldhuijzen van Zanten, Marianna Bugiani, Niels E Franke, Alyssa Reddy, Pieter Wesseling, Gertjan J L Kaspers, Esther Hulleman","doi":"10.1016/j.xcrm.2024.101700","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101700","url":null,"abstract":"<p><p>Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the sonic hedgehog (SHH) signaling activator GLI2, explaining the observed additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of ATRT xenograft-bearing mice with gemcitabine resulted in a >30% increase in median survival and yielded long-term survivors in two independent patient-derived xenograft models. These findings demonstrate that ATRTs are highly sensitive to gemcitabine treatment and may form part of a future multimodal treatment strategy for ATRTs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104785","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 : 2024-08-20DOI: 10.1016/j.xcrm.2024.101694
Qianmin Gao, Yingying Jiang, Dongyang Zhou, Guangfeng Li, Yafei Han, Jingzhi Yang, Ke Xu, Yingying Jing, Long Bai, Zhen Geng, Hao Zhang, Guangyin Zhou, Mengru Zhu, Ning Ji, Ruina Han, Yuanwei Zhang, Zuhao Li, Chuandong Wang, Yan Hu, Hao Shen, Guangchao Wang, Zhongmin Shi, Qinglin Han, Xiao Chen, Jiacan Su
Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.
{"title":"Advanced glycation end products mediate biomineralization disorder in diabetic bone disease.","authors":"Qianmin Gao, Yingying Jiang, Dongyang Zhou, Guangfeng Li, Yafei Han, Jingzhi Yang, Ke Xu, Yingying Jing, Long Bai, Zhen Geng, Hao Zhang, Guangyin Zhou, Mengru Zhu, Ning Ji, Ruina Han, Yuanwei Zhang, Zuhao Li, Chuandong Wang, Yan Hu, Hao Shen, Guangchao Wang, Zhongmin Shi, Qinglin Han, Xiao Chen, Jiacan Su","doi":"10.1016/j.xcrm.2024.101694","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101694","url":null,"abstract":"<p><p>Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035286","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}
The potential of serum extracellular vesicles (EVs) as non-invasive biomarkers for diagnosing colorectal cancer (CRC) remains elusive. We employed an in-depth 4D-DIA proteomics and machine learning (ML) pipeline to identify key proteins, PF4 and AACT, for CRC diagnosis in serum EV samples from a discovery cohort of 37 cases. PF4 and AACT outperform traditional biomarkers, CEA and CA19-9, detected by ELISA in 912 individuals. Furthermore, we developed an EV-related random forest (RF) model with the highest diagnostic efficiency, achieving AUC values of 0.960 and 0.963 in the train and test sets, respectively. Notably, this model demonstrated reliable diagnostic performance for early-stage CRC and distinguishing CRC from benign colorectal diseases. Additionally, multi-omics approaches were employed to predict the functions and potential sources of serum EV-derived proteins. Collectively, our study identified the crucial proteomic signatures in serum EVs and established a promising EV-related RF model for CRC diagnosis in the clinic.
血清细胞外囊泡(EVs)作为诊断结直肠癌(CRC)的非侵入性生物标记物的潜力仍然难以捉摸。我们采用了深入的4D-DIA蛋白质组学和机器学习(ML)管道,从37个病例的发现队列的血清EV样本中鉴定出了用于诊断CRC的关键蛋白质PF4和AACT。在912例患者中,PF4和AACT的表现优于ELISA检测的传统生物标记物CEA和CA19-9。此外,我们还开发了一种与 EV 相关的随机森林(RF)模型,其诊断效率最高,在训练集和测试集中的 AUC 值分别达到了 0.960 和 0.963。值得注意的是,该模型对早期 CRC 和区分 CRC 与良性结直肠疾病具有可靠的诊断性能。此外,我们还采用了多组学方法来预测血清 EV 衍生蛋白的功能和潜在来源。总之,我们的研究确定了血清 EV 中关键的蛋白质组特征,并为临床诊断 CRC 建立了一个前景良好的 EV 相关 RF 模型。
{"title":"Machine learning-based analysis identifies and validates serum exosomal proteomic signatures for the diagnosis of colorectal cancer.","authors":"Haofan Yin, Jinye Xie, Shan Xing, Xiaofang Lu, Yu Yu, Yong Ren, Jian Tao, Guirong He, Lijun Zhang, Xiaopeng Yuan, Zheng Yang, Zhijian Huang","doi":"10.1016/j.xcrm.2024.101689","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101689","url":null,"abstract":"<p><p>The potential of serum extracellular vesicles (EVs) as non-invasive biomarkers for diagnosing colorectal cancer (CRC) remains elusive. We employed an in-depth 4D-DIA proteomics and machine learning (ML) pipeline to identify key proteins, PF4 and AACT, for CRC diagnosis in serum EV samples from a discovery cohort of 37 cases. PF4 and AACT outperform traditional biomarkers, CEA and CA19-9, detected by ELISA in 912 individuals. Furthermore, we developed an EV-related random forest (RF) model with the highest diagnostic efficiency, achieving AUC values of 0.960 and 0.963 in the train and test sets, respectively. Notably, this model demonstrated reliable diagnostic performance for early-stage CRC and distinguishing CRC from benign colorectal diseases. Additionally, multi-omics approaches were employed to predict the functions and potential sources of serum EV-derived proteins. Collectively, our study identified the crucial proteomic signatures in serum EVs and established a promising EV-related RF model for CRC diagnosis in the clinic.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016491","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 : 2024-08-20DOI: 10.1016/j.xcrm.2024.101685
Giulia Grisendi, Massimiliano Dall'Ora, Giulia Casari, Giliola Spattini, Moein Farshchian, Aurora Melandri, Valentina Masicale, Fabio Lepore, Federico Banchelli, Riccardo Cuoghi Costantini, Angela D'Esposito, Chiara Chiavelli, Carlotta Spano, Andrea Spallanzani, Tiziana Petrachi, Elena Veronesi, Manuela Ferracin, Roberta Roncarati, Jonathan Vinet, Paolo Magistri, Barbara Catellani, Olivia Candini, Caterina Marra, Albino Eccher, Luca Reggiani Bonetti, Edwin M Horwtiz, Fabrizio Di Benedetto, Massimo Dominici
Pancreatic ductal adenocarcinoma (PDAC) still has a poor response to therapies, partly due to their cancer-associated fibroblasts (CAFs). Here, we investigate the synergistic impact of a combinatory approach between a known chemotherapy agent, such as gemcitabine (GEM), and gene-modified human mesenchymal stromal/stem cells (MSCs) secreting the pro-apoptotic soluble (s)TRAIL (sTRAIL MSCs) on both PDAC cells and CAFs. The combo significantly impacts on PDAC survival in 2D and 3D models. In orthotopic xenograft models, GEM and sTRAIL MSCs induce tumor architecture shredding with a reduction of CK7- and CK8/18-positive cancer cells and the abrogation of spleen metastases. A cytotoxic effect on primary human CAFs is also observed along with an alteration of their transcriptome and a reduction of the related desmoplasia. Collectively, we demonstrate a promising therapeutic profile of combining GEM and sTRAIL MSCs to target both tumoral and stromal compartments in PDAC.
{"title":"Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma.","authors":"Giulia Grisendi, Massimiliano Dall'Ora, Giulia Casari, Giliola Spattini, Moein Farshchian, Aurora Melandri, Valentina Masicale, Fabio Lepore, Federico Banchelli, Riccardo Cuoghi Costantini, Angela D'Esposito, Chiara Chiavelli, Carlotta Spano, Andrea Spallanzani, Tiziana Petrachi, Elena Veronesi, Manuela Ferracin, Roberta Roncarati, Jonathan Vinet, Paolo Magistri, Barbara Catellani, Olivia Candini, Caterina Marra, Albino Eccher, Luca Reggiani Bonetti, Edwin M Horwtiz, Fabrizio Di Benedetto, Massimo Dominici","doi":"10.1016/j.xcrm.2024.101685","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101685","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) still has a poor response to therapies, partly due to their cancer-associated fibroblasts (CAFs). Here, we investigate the synergistic impact of a combinatory approach between a known chemotherapy agent, such as gemcitabine (GEM), and gene-modified human mesenchymal stromal/stem cells (MSCs) secreting the pro-apoptotic soluble (s)TRAIL (sTRAIL MSCs) on both PDAC cells and CAFs. The combo significantly impacts on PDAC survival in 2D and 3D models. In orthotopic xenograft models, GEM and sTRAIL MSCs induce tumor architecture shredding with a reduction of CK7- and CK8/18-positive cancer cells and the abrogation of spleen metastases. A cytotoxic effect on primary human CAFs is also observed along with an alteration of their transcriptome and a reduction of the related desmoplasia. Collectively, we demonstrate a promising therapeutic profile of combining GEM and sTRAIL MSCs to target both tumoral and stromal compartments in PDAC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016489","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 : 2024-08-20DOI: 10.1016/j.xcrm.2024.101644
Nima Sharifi, Arun A Azad, Mona Patel, Jason W D Hearn, Michele Wozniak, Fabian Zohren, Jennifer Sugg, Gabriel P Haas, Arnulf Stenzl, Andrew J Armstrong
HSD3B1 encodes 3β-hydroxysteroid dehydrogenase-1, which converts adrenal dehydroepiandrosterone to 5α-dihydrotestosterone and is inherited in adrenal-permissive (AP) or adrenal-restrictive forms. The AP allele is linked to castration resistance, mainly in low-volume tumors. Here, we investigate the association of HSD3B1 alleles with outcomes in ARCHES, a multinational, double-blind, randomized, placebo-controlled phase 3 trial that demonstrated clinical benefit with enzalutamide plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to those treated with placebo plus ADT. There are no significant differences between genotypes for clinical efficacy endpoints. Enzalutamide significantly improves radiographic progression-free survival and overall survival vs. placebo irrespective of HSD3B1 status. Men with the AP genotype have higher post-progression mortality and treatment-emergent adverse events, including hypertension, cardiovascular events, and gynecomastia, but a lower fracture rate. Overall, enzalutamide is beneficial in men with mHSPC independent of the HSD3B1 genotype. Inherited polymorphisms of HSD3B1 may account for differential toxicities.
{"title":"HSD3B1 genotype and outcomes in metastatic hormone-sensitive prostate cancer with androgen deprivation therapy and enzalutamide: ARCHES.","authors":"Nima Sharifi, Arun A Azad, Mona Patel, Jason W D Hearn, Michele Wozniak, Fabian Zohren, Jennifer Sugg, Gabriel P Haas, Arnulf Stenzl, Andrew J Armstrong","doi":"10.1016/j.xcrm.2024.101644","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101644","url":null,"abstract":"<p><p>HSD3B1 encodes 3β-hydroxysteroid dehydrogenase-1, which converts adrenal dehydroepiandrosterone to 5α-dihydrotestosterone and is inherited in adrenal-permissive (AP) or adrenal-restrictive forms. The AP allele is linked to castration resistance, mainly in low-volume tumors. Here, we investigate the association of HSD3B1 alleles with outcomes in ARCHES, a multinational, double-blind, randomized, placebo-controlled phase 3 trial that demonstrated clinical benefit with enzalutamide plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to those treated with placebo plus ADT. There are no significant differences between genotypes for clinical efficacy endpoints. Enzalutamide significantly improves radiographic progression-free survival and overall survival vs. placebo irrespective of HSD3B1 status. Men with the AP genotype have higher post-progression mortality and treatment-emergent adverse events, including hypertension, cardiovascular events, and gynecomastia, but a lower fracture rate. Overall, enzalutamide is beneficial in men with mHSPC independent of the HSD3B1 genotype. Inherited polymorphisms of HSD3B1 may account for differential toxicities.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016490","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 : 2024-08-20Epub Date: 2024-07-25DOI: 10.1016/j.xcrm.2024.101660
Zhuangyuan Tang, Shuo Wang, Xi Li, Chengbin Hu, Qiangrong Zhai, Jing Wang, Qingshi Ye, Jinnan Liu, Guohong Zhang, Yuanyuan Guo, Fengxia Su, Huikun Liu, Lingyao Guan, Chang Jiang, Jiayu Chen, Min Li, Fangyi Ren, Yu Zhang, Minjuan Huang, Lingguo Li, Haiqiang Zhang, Guixue Hou, Xin Jin, Fang Chen, Huanhuan Zhu, Linxuan Li, Jingyu Zeng, Han Xiao, Aifen Zhou, Lingyan Feng, Ya Gao, Gongshu Liu
Gestational diabetes mellitus (GDM) presents varied manifestations throughout pregnancy and poses a complex clinical challenge. High-depth cell-free DNA (cfDNA) sequencing analysis holds promise in advancing our understanding of GDM pathogenesis and prediction. In 299 women with GDM and 299 matched healthy pregnant women, distinct cfDNA fragment characteristics associated with GDM are identified throughout pregnancy. Integrating cfDNA profiles with lipidomic and single-cell transcriptomic data elucidates functional changes linked to altered lipid metabolism processes in GDM. Transcription start site (TSS) scores in 50 feature genes are used as the cfDNA signature to distinguish GDM cases from controls effectively. Notably, differential coverage of the islet acinar marker gene PRSS1 emerges as a valuable biomarker for GDM. A specialized neural network model is developed, predicting GDM occurrence and validated across two independent cohorts. This research underscores the high-depth cfDNA early prediction and characterization of GDM, offering insights into its molecular underpinnings and potential clinical applications.
{"title":"Longitudinal integrative cell-free DNA analysis in gestational diabetes mellitus.","authors":"Zhuangyuan Tang, Shuo Wang, Xi Li, Chengbin Hu, Qiangrong Zhai, Jing Wang, Qingshi Ye, Jinnan Liu, Guohong Zhang, Yuanyuan Guo, Fengxia Su, Huikun Liu, Lingyao Guan, Chang Jiang, Jiayu Chen, Min Li, Fangyi Ren, Yu Zhang, Minjuan Huang, Lingguo Li, Haiqiang Zhang, Guixue Hou, Xin Jin, Fang Chen, Huanhuan Zhu, Linxuan Li, Jingyu Zeng, Han Xiao, Aifen Zhou, Lingyan Feng, Ya Gao, Gongshu Liu","doi":"10.1016/j.xcrm.2024.101660","DOIUrl":"10.1016/j.xcrm.2024.101660","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM) presents varied manifestations throughout pregnancy and poses a complex clinical challenge. High-depth cell-free DNA (cfDNA) sequencing analysis holds promise in advancing our understanding of GDM pathogenesis and prediction. In 299 women with GDM and 299 matched healthy pregnant women, distinct cfDNA fragment characteristics associated with GDM are identified throughout pregnancy. Integrating cfDNA profiles with lipidomic and single-cell transcriptomic data elucidates functional changes linked to altered lipid metabolism processes in GDM. Transcription start site (TSS) scores in 50 feature genes are used as the cfDNA signature to distinguish GDM cases from controls effectively. Notably, differential coverage of the islet acinar marker gene PRSS1 emerges as a valuable biomarker for GDM. A specialized neural network model is developed, predicting GDM occurrence and validated across two independent cohorts. This research underscores the high-depth cfDNA early prediction and characterization of GDM, offering insights into its molecular underpinnings and potential clinical applications.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765657","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 : 2024-08-20DOI: 10.1016/j.xcrm.2024.101682
Anne-Laure Agrinier, Arianne Morissette, Laurence Daoust, Théo Gignac, Julie Marois, Thibault V Varin, Geneviève Pilon, Éric Larose, Claudia Gagnon, Yves Desjardins, Fernando F Anhê, Anne-Marie Carreau, Marie-Claude Vohl, André Marette
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population with no effective drug treatments available. Previous animal studies reported that a polyphenol-rich extract from the Amazonian berry camu-camu (CC) prevented hepatic steatosis in a mouse model of diet-induced obesity. This study aims to determine the impact of CC on hepatic steatosis (primary outcome) and evaluate changes in metabolic and gut microbiota profiles (exploratory outcomes). A randomized, double-blind, placebo-controlled crossover trial is conducted on 30 adults with overweight and hypertriglyceridemia, who consume 1.5 g of CC capsules or placebo daily for 12 weeks. CC treatment decreases liver fat by 7.43%, while it increases by 8.42% during the placebo intervention, showing a significant difference of 15.85%. CC decreases plasma aspartate and alanine aminotransferases levels and promotes changes in gut microbiota composition. These findings support that polyphenol-rich prebiotic may reduce liver fat in adults with overweight, reducing the risk of developing NAFLD.
{"title":"Camu-camu decreases hepatic steatosis and liver injury markers in overweight, hypertriglyceridemic individuals: A randomized crossover trial.","authors":"Anne-Laure Agrinier, Arianne Morissette, Laurence Daoust, Théo Gignac, Julie Marois, Thibault V Varin, Geneviève Pilon, Éric Larose, Claudia Gagnon, Yves Desjardins, Fernando F Anhê, Anne-Marie Carreau, Marie-Claude Vohl, André Marette","doi":"10.1016/j.xcrm.2024.101682","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101682","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population with no effective drug treatments available. Previous animal studies reported that a polyphenol-rich extract from the Amazonian berry camu-camu (CC) prevented hepatic steatosis in a mouse model of diet-induced obesity. This study aims to determine the impact of CC on hepatic steatosis (primary outcome) and evaluate changes in metabolic and gut microbiota profiles (exploratory outcomes). A randomized, double-blind, placebo-controlled crossover trial is conducted on 30 adults with overweight and hypertriglyceridemia, who consume 1.5 g of CC capsules or placebo daily for 12 weeks. CC treatment decreases liver fat by 7.43%, while it increases by 8.42% during the placebo intervention, showing a significant difference of 15.85%. CC decreases plasma aspartate and alanine aminotransferases levels and promotes changes in gut microbiota composition. These findings support that polyphenol-rich prebiotic may reduce liver fat in adults with overweight, reducing the risk of developing NAFLD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016488","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 : 2024-08-20Epub Date: 2024-08-09DOI: 10.1016/j.xcrm.2024.101669
Yona Levites, Eric B Dammer, Yong Ran, Wangchen Tsering, Duc Duong, Measho Abreha, Joshna Gadhavi, Kiara Lolo, Jorge Trejo-Lopez, Jennifer Phillips, Andrea Iturbe, Aya Erquizi, Brenda D Moore, Danny Ryu, Aditya Natu, Kristy Dillon, Jose Torrellas, Corey Moran, Thomas Ladd, Farhana Afroz, Tariful Islam, Jaishree Jagirdar, Cory C Funk, Max Robinson, Srikant Rangaraju, David R Borchelt, Nilüfer Ertekin-Taner, Jeffrey W Kelly, Frank L Heppner, Erik C B Johnson, Karen McFarland, Allan I Levey, Stefan Prokop, Nicholas T Seyfried, Todd E Golde
Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.
{"title":"Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer's disease.","authors":"Yona Levites, Eric B Dammer, Yong Ran, Wangchen Tsering, Duc Duong, Measho Abreha, Joshna Gadhavi, Kiara Lolo, Jorge Trejo-Lopez, Jennifer Phillips, Andrea Iturbe, Aya Erquizi, Brenda D Moore, Danny Ryu, Aditya Natu, Kristy Dillon, Jose Torrellas, Corey Moran, Thomas Ladd, Farhana Afroz, Tariful Islam, Jaishree Jagirdar, Cory C Funk, Max Robinson, Srikant Rangaraju, David R Borchelt, Nilüfer Ertekin-Taner, Jeffrey W Kelly, Frank L Heppner, Erik C B Johnson, Karen McFarland, Allan I Levey, Stefan Prokop, Nicholas T Seyfried, Todd E Golde","doi":"10.1016/j.xcrm.2024.101669","DOIUrl":"10.1016/j.xcrm.2024.101669","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912017","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}
Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8+ T cell response to PD-1 blockade through carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Moreover, the ADAM10 inhibitor GI254023X, which blocks sTim-3 production, reduces tumor progression in Tim-3 humanized mice and reverses anti-PD-1 resistance in human tumor-infiltrating lymphocytes (TILs). Overall, human sTim-3 holds great predictive and therapeutic potential in onco-immunotherapy.
{"title":"Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8<sup>+</sup> T cell exhaustion and anti-PD-1 resistance.","authors":"Chaojia Chen, Fangcheng Zhao, Jiali Peng, Di Zhao, Liyun Xu, Huayu Li, Shuaiya Ma, Xueqi Peng, Xue Sheng, Yang Sun, Tixiao Wang, Haoqing Dong, Yuming Ding, Zhuanchang Wu, Xiaohong Liang, Lifen Gao, Hongyan Wang, Chunhong Ma, Chunyang Li","doi":"10.1016/j.xcrm.2024.101686","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101686","url":null,"abstract":"<p><p>Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8<sup>+</sup> T cell response to PD-1 blockade through carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Moreover, the ADAM10 inhibitor GI254023X, which blocks sTim-3 production, reduces tumor progression in Tim-3 humanized mice and reverses anti-PD-1 resistance in human tumor-infiltrating lymphocytes (TILs). Overall, human sTim-3 holds great predictive and therapeutic potential in onco-immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016493","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}
Mesenchymal stromal cell (MSC) senescence is a key factor in skeletal aging, affecting the potential of MSC applications. Identifying targets to prevent MSC and skeletal senescence is crucial. Here, we report increased miR-29 expression in bone tissues of aged mice, osteoporotic patients, and senescent MSCs. Genetic overexpression of miR-29 in Prx1-positive MSCs significantly accelerates skeletal senescence, reducing cortical bone thickness and trabecular bone mass, while increasing femur cross-sectional area, bone marrow adiposity, p53, and senescence-associated secretory phenotype (SASP) levels. Mechanistically, miR-29 promotes senescence by upregulating p53 via targeting Kindlin-2 mRNA. miR-29 knockdown in BMSCs impedes skeletal senescence, enhances bone mass, and accelerates calvarial defect regeneration, also reducing lipopolysaccharide (LPS)-induced organ injuries and mortality. Thus, our findings underscore miR-29 as a promising therapeutic target for senescence-related skeletal diseases and acute inflammation-induced organ damage.
{"title":"Targeting miR-29 mitigates skeletal senescence and bolsters therapeutic potential of mesenchymal stromal cells.","authors":"Zhen Ding, Guixing Ma, Bo Zhou, Siyuan Cheng, Wanze Tang, Yingying Han, Litong Chen, Wei Pang, Yangshan Chen, Dazhi Yang, Huiling Cao","doi":"10.1016/j.xcrm.2024.101665","DOIUrl":"10.1016/j.xcrm.2024.101665","url":null,"abstract":"<p><p>Mesenchymal stromal cell (MSC) senescence is a key factor in skeletal aging, affecting the potential of MSC applications. Identifying targets to prevent MSC and skeletal senescence is crucial. Here, we report increased miR-29 expression in bone tissues of aged mice, osteoporotic patients, and senescent MSCs. Genetic overexpression of miR-29 in Prx1-positive MSCs significantly accelerates skeletal senescence, reducing cortical bone thickness and trabecular bone mass, while increasing femur cross-sectional area, bone marrow adiposity, p53, and senescence-associated secretory phenotype (SASP) levels. Mechanistically, miR-29 promotes senescence by upregulating p53 via targeting Kindlin-2 mRNA. miR-29 knockdown in BMSCs impedes skeletal senescence, enhances bone mass, and accelerates calvarial defect regeneration, also reducing lipopolysaccharide (LPS)-induced organ injuries and mortality. Thus, our findings underscore miR-29 as a promising therapeutic target for senescence-related skeletal diseases and acute inflammation-induced organ damage.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016494","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}