Pub Date : 2024-08-01Epub Date: 2024-07-12DOI: 10.1016/j.ebiom.2024.105233
Marcus C B Tan, Chelsea A Isom, Yangzi Liu, David-Alexandre Trégouët, Lang Wu, Dan Zhou, Eric R Gamazon
Background: Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE).
Methods: In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls).
Findings: Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e-7). No evidence of a causal effect of PDAC on VTE was found.
Interpretation: These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC.
{"title":"Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism.","authors":"Marcus C B Tan, Chelsea A Isom, Yangzi Liu, David-Alexandre Trégouët, Lang Wu, Dan Zhou, Eric R Gamazon","doi":"10.1016/j.ebiom.2024.105233","DOIUrl":"10.1016/j.ebiom.2024.105233","url":null,"abstract":"<p><strong>Background: </strong>Two important questions regarding the genetics of pancreatic adenocarcinoma (PDAC) are 1. Which germline genetic variants influence the incidence of this cancer; and 2. Whether PDAC causally predisposes to associated non-malignant phenotypes, such as type 2 diabetes (T2D) and venous thromboembolism (VTE).</p><p><strong>Methods: </strong>In this study of 8803 patients with PDAC and 67,523 controls, we first performed a large-scale transcriptome-wide association study to investigate the association between genetically determined gene expression in normal pancreas tissue and PDAC risk. Secondly, we used Mendelian Randomization (MR) to analyse the causal relationships among PDAC, T2D (74,124 cases and 824,006 controls) and VTE (30,234 cases and 172,122 controls).</p><p><strong>Findings: </strong>Sixteen genes showed an association with PDAC risk (FDR <0.10), including six genes not yet reported for PDAC risk (PPIP5K2, TFR2, HNF4G, LRRC10B, PRC1 and FBXL20) and ten previously reported genes (INHBA, SMC2, ABO, PDX1, MTMR6, ACOT2, PGAP3, STARD3, GSDMB, ADAM33). MR provided support for a causal effect of PDAC on T2D using genetic instruments in the HNF4G and PDX1 loci, and unidirectional causality of VTE on PDAC involving the ABO locus (OR 2.12, P < 1e<sup>-7</sup>). No evidence of a causal effect of PDAC on VTE was found.</p><p><strong>Interpretation: </strong>These analyses identified candidate susceptibility genes and disease relationships for PDAC that warrant further investigation. HNF4G and PDX1 may induce PDAC-associated diabetes, whereas ABO may induce the causative effect of VTE on PDAC.</p><p><strong>Funding: </strong>National Institutes of Health (USA).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603462","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 : 2024-08-01Epub Date: 2024-07-16DOI: 10.1016/j.ebiom.2024.105220
Sandro Pasquali, Viviana Vallacchi, Luca Lalli, Paola Collini, Marta Barisella, Cleofe Romagosa, Silvia Bague, Jean Michel Coindre, Angelo Paolo Dei Tos, Emanuela Palmerini, Vittorio Quagliuolo, Javier Martin-Broto, Antonio Lopez-Pousa, Giovanni Grignani, Jean-Yves Blay, Robert Diaz Beveridge, Elena Casiraghi, Silvia Brich, Salvatore Lorenzo Renne, Laura Bergamaschi, Barbara Vergani, Marta Sbaraglia, Paolo Giovanni Casali, Licia Rivoltini, Silvia Stacchiotti, Alessandro Gronchi
Background: Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis.
Methods: The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS).
Findings: Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI.
Interpretation: The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS.
Funding: Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds-2016, Italian Ministry of Health; AIRC Grant [ID#28546].
{"title":"Spatial distribution of tumour immune infiltrate predicts outcomes of patients with high-risk soft tissue sarcomas after neoadjuvant chemotherapy.","authors":"Sandro Pasquali, Viviana Vallacchi, Luca Lalli, Paola Collini, Marta Barisella, Cleofe Romagosa, Silvia Bague, Jean Michel Coindre, Angelo Paolo Dei Tos, Emanuela Palmerini, Vittorio Quagliuolo, Javier Martin-Broto, Antonio Lopez-Pousa, Giovanni Grignani, Jean-Yves Blay, Robert Diaz Beveridge, Elena Casiraghi, Silvia Brich, Salvatore Lorenzo Renne, Laura Bergamaschi, Barbara Vergani, Marta Sbaraglia, Paolo Giovanni Casali, Licia Rivoltini, Silvia Stacchiotti, Alessandro Gronchi","doi":"10.1016/j.ebiom.2024.105220","DOIUrl":"10.1016/j.ebiom.2024.105220","url":null,"abstract":"<p><strong>Background: </strong>Anthracycline-based neoadjuvant chemotherapy (NAC) may modify tumour immune infiltrate. This study characterized immune infiltrate spatial distribution after NAC in primary high-risk soft tissue sarcomas (STS) and investigate association with prognosis.</p><p><strong>Methods: </strong>The ISG-STS 1001 trial randomized STS patients to anthracycline plus ifosfamide (AI) or a histology-tailored (HT) NAC. Four areas of tumour specimens were sampled: the area showing the highest lymphocyte infiltrate (HI) at H&E; the area with lack of post-treatment changes (highest grade, HG); the area with post-treatment changes (lowest grade, LG); and the tumour edge (TE). CD3, CD8, PD-1, CD20, FOXP3, and CD163 were analyzed at immunohistochemistry and digital pathology. A machine learning method was used to generate sarcoma immune index scores (SIS) that predict patient disease-free and overall survival (DFS and OS).</p><p><strong>Findings: </strong>Tumour infiltrating lymphocytes and PD-1+ cells together with CD163+ cells were more represented in STS histologies with complex compared to simple karyotype, while CD20+ B-cells were detected in both these histology groups. PD-1+ cells exerted a negative prognostic value irrespectively of their spatial distribution. Enrichment in CD20+ B-cells at HI and TE areas was associated with better patient outcomes. We generated a prognostic SIS for each tumour area, having the HI-SIS the best performance. Such prognostic value was driven by treatment with AI.</p><p><strong>Interpretation: </strong>The different spatial distribution of immune populations and their different association with prognosis support NAC as a modifier of tumour immune infiltrate in STS.</p><p><strong>Funding: </strong>Pharmamar; Italian Ministry of Health [RF-2019-12370923; GR-2016-02362609]; 5 × 1000 Funds-2016, Italian Ministry of Health; AIRC Grant [ID#28546].</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633033","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 : 2024-08-01Epub Date: 2024-07-16DOI: 10.1016/j.ebiom.2024.105248
Tingting Geng, Duomeng Yang, Tao Lin, Andrew G Harrison, Binsheng Wang, Ziming Cao, Blake Torrance, Zhichao Fan, Kepeng Wang, Yanlin Wang, Long Yang, Laura Haynes, Gong Cheng, Anthony T Vella, Richard A Flavell, Joao P Pereira, Erol Fikrig, Penghua Wang
Background: The ubiquitin regulatory X (UBX) domain-containing proteins (UBXNs) are putative adaptors for ubiquitin ligases and valosin-containing protein; however, their in vivo physiological functions remain poorly characterised. We recently showed that UBXN3B is essential for activating innate immunity to DNA viruses and controlling DNA/RNA virus infection. Herein, we investigate its role in adaptive immunity.
Methods: We evaluated the antibody responses to multiple viruses and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza in tamoxifen-inducible global and constitutive B cell-specific Ubxn3b knockout mice; quantified various immune populations, B lineage progenitors/precursors, B cell receptor (BCR) signalling and apoptosis by flow cytometry, immunoblotting and immunofluorescence microscopy. We also performed bone marrow transfer, single-cell and bulk RNA sequencing.
Findings: Both global and B cell-specific Ubxn3b knockout mice present a marked reduction in small precursor B-II (>60%), immature (>70%) and mature B (>95%) cell numbers. Transfer of wildtype bone marrow to irradiated global Ubxn3b knockouts restores normal B lymphopoiesis, while reverse transplantation does not. The mature B population shrinks rapidly with apoptosis and higher pro and activated caspase-3 protein levels were observed following induction of Ubxn3b knockout. Mechanistically, Ubxn3b deficiency leads to impaired pre-BCR signalling and cell cycle arrest. Ubxn3b knockout mice are highly vulnerable to respiratory viruses, with increased viral loads and prolonged immunopathology in the lung, and reduced production of virus-specific IgM/IgG.
Interpretation: UBXN3B is essential for B lymphopoiesis by maintaining constitutive pre-BCR signalling and cell survival in a cell-intrinsic manner.
Funding: United States National Institutes of Health grants, R01AI132526 and R21AI155820.
背景:含泛素调控X(UBX)结构域的蛋白(UBXNs)是泛素连接酶和含缬氨酸蛋白的假定适配体;然而,它们在体内的生理功能仍鲜为人知。我们最近发现,UBXN3B 对激活 DNA 病毒的先天免疫和控制 DNA/RNA 病毒感染至关重要。在此,我们研究了它在适应性免疫中的作用:我们评估了他莫昔芬诱导的全局性和组成型 B 细胞特异性 Ubxn3b 基因敲除小鼠对多种病毒的抗体反应以及严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)和流感的发病机制;通过流式细胞术、免疫印迹法和免疫荧光显微镜对各种免疫群体、B 系祖细胞/前体、B 细胞受体(BCR)信号传导和细胞凋亡进行了量化。我们还进行了骨髓移植、单细胞和大量 RNA 测序:研究结果:整体和B细胞特异性Ubxn3b基因敲除小鼠的小前体B-II细胞(>60%)、未成熟细胞(>70%)和成熟B细胞(>95%)数量均明显减少。将野生型骨髓移植到经过辐照的全局性 Ubxn3b 基因敲除小鼠体内可恢复正常的 B 淋巴造血,而反向移植则不能。在诱导 Ubxn3b 基因敲除后,成熟的 B 群体随着细胞凋亡而迅速缩小,并观察到较高的促活化 Caspase-3 蛋白水平。从机理上讲,Ubxn3b 缺乏会导致前 BCR 信号受损和细胞周期停滞。Ubxn3b 基因敲除小鼠极易感染呼吸道病毒,病毒载量增加,肺部免疫病理过程延长,病毒特异性 IgM/IgG 的产生减少:UBXN3B对B淋巴细胞生成至关重要,它以细胞内在方式维持构成性前BCR信号传导和细胞存活:美国国立卫生研究院资助:R01AI132526和R21AI155820。
{"title":"UBXN3B is crucial for B lymphopoiesis.","authors":"Tingting Geng, Duomeng Yang, Tao Lin, Andrew G Harrison, Binsheng Wang, Ziming Cao, Blake Torrance, Zhichao Fan, Kepeng Wang, Yanlin Wang, Long Yang, Laura Haynes, Gong Cheng, Anthony T Vella, Richard A Flavell, Joao P Pereira, Erol Fikrig, Penghua Wang","doi":"10.1016/j.ebiom.2024.105248","DOIUrl":"10.1016/j.ebiom.2024.105248","url":null,"abstract":"<p><strong>Background: </strong>The ubiquitin regulatory X (UBX) domain-containing proteins (UBXNs) are putative adaptors for ubiquitin ligases and valosin-containing protein; however, their in vivo physiological functions remain poorly characterised. We recently showed that UBXN3B is essential for activating innate immunity to DNA viruses and controlling DNA/RNA virus infection. Herein, we investigate its role in adaptive immunity.</p><p><strong>Methods: </strong>We evaluated the antibody responses to multiple viruses and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza in tamoxifen-inducible global and constitutive B cell-specific Ubxn3b knockout mice; quantified various immune populations, B lineage progenitors/precursors, B cell receptor (BCR) signalling and apoptosis by flow cytometry, immunoblotting and immunofluorescence microscopy. We also performed bone marrow transfer, single-cell and bulk RNA sequencing.</p><p><strong>Findings: </strong>Both global and B cell-specific Ubxn3b knockout mice present a marked reduction in small precursor B-II (>60%), immature (>70%) and mature B (>95%) cell numbers. Transfer of wildtype bone marrow to irradiated global Ubxn3b knockouts restores normal B lymphopoiesis, while reverse transplantation does not. The mature B population shrinks rapidly with apoptosis and higher pro and activated caspase-3 protein levels were observed following induction of Ubxn3b knockout. Mechanistically, Ubxn3b deficiency leads to impaired pre-BCR signalling and cell cycle arrest. Ubxn3b knockout mice are highly vulnerable to respiratory viruses, with increased viral loads and prolonged immunopathology in the lung, and reduced production of virus-specific IgM/IgG.</p><p><strong>Interpretation: </strong>UBXN3B is essential for B lymphopoiesis by maintaining constitutive pre-BCR signalling and cell survival in a cell-intrinsic manner.</p><p><strong>Funding: </strong>United States National Institutes of Health grants, R01AI132526 and R21AI155820.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633034","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 : 2024-08-01DOI: 10.1016/j.ebiom.2024.105266
Thuy Anh Bui, Haoqi Mei, Rui Sang, David Gallego Ortega, Wei Deng
The Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a ground-breaking immunotherapeutic approach in cancer treatment. To overcome the complexity and high manufacturing cost associated with current ex vivo CAR T cell therapy products, alternative strategies to produce CAR T cells directly in the body have been developed in recent years. These strategies involve the direct infusion of CAR genes via engineered nanocarriers or viral vectors to generate CAR T cells in situ. This review offers a comprehensive overview of recent advancements in the development of T cell-targeted CAR generation in situ. Additionally, it identifies the challenges associated with in vivo CAR T method and potential strategies to overcome these issues.
嵌合抗原受体(CAR)T 细胞疗法已成为治疗癌症的一种突破性免疫疗法。为了克服目前体外 CAR T 细胞疗法产品的复杂性和高制造成本,近年来开发出了直接在体内制造 CAR T 细胞的替代策略。这些策略包括通过工程纳米载体或病毒载体直接注入 CAR 基因,在原位生成 CAR T 细胞。本综述全面概述了原位生成 T 细胞靶向 CAR 的最新进展。此外,它还指出了与体内 CAR T 方法相关的挑战以及克服这些问题的潜在策略。
{"title":"Advancements and challenges in developing in vivo CAR T cell therapies for cancer treatment.","authors":"Thuy Anh Bui, Haoqi Mei, Rui Sang, David Gallego Ortega, Wei Deng","doi":"10.1016/j.ebiom.2024.105266","DOIUrl":"10.1016/j.ebiom.2024.105266","url":null,"abstract":"<p><p>The Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a ground-breaking immunotherapeutic approach in cancer treatment. To overcome the complexity and high manufacturing cost associated with current ex vivo CAR T cell therapy products, alternative strategies to produce CAR T cells directly in the body have been developed in recent years. These strategies involve the direct infusion of CAR genes via engineered nanocarriers or viral vectors to generate CAR T cells in situ. This review offers a comprehensive overview of recent advancements in the development of T cell-targeted CAR generation in situ. Additionally, it identifies the challenges associated with in vivo CAR T method and potential strategies to overcome these issues.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11345408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878510","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 : 2024-08-01Epub Date: 2024-07-13DOI: 10.1016/j.ebiom.2024.105239
Ana F David, Andreas Heinzel, Michael Kammer, Constantin Aschauer, Roman Reindl-Schwaighofer, Karin Hu, Hao-Shan Chen, Moritz Muckenhuber, Anna Kubetz, Anna Marianne Weijler, Nina Worel, Matthias Edinger, Gabriela Berlakovich, Thomas Lion, Megan Sykes, Thomas Wekerle, Rainer Oberbauer
Background: Induction of donor-specific tolerance is a promising approach to achieve long-term graft patency in transplantation with little to no maintenance immunosuppression. Changes to the recipient's T cell receptor (TCR) repertoire are understood to play a pivotal role in the establishment of a robust state of tolerance in chimerism-based transplantation protocols.
Methods: We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression.
Findings: Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4+ T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4+ and CD8+ TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity.
Interpretation: Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression.
Funding: This study was funded by the Vienna Science and Technology Fund (WWTF).
{"title":"Combination cell therapy leads to clonal deletion of donor-specific T cells in kidney transplant recipients.","authors":"Ana F David, Andreas Heinzel, Michael Kammer, Constantin Aschauer, Roman Reindl-Schwaighofer, Karin Hu, Hao-Shan Chen, Moritz Muckenhuber, Anna Kubetz, Anna Marianne Weijler, Nina Worel, Matthias Edinger, Gabriela Berlakovich, Thomas Lion, Megan Sykes, Thomas Wekerle, Rainer Oberbauer","doi":"10.1016/j.ebiom.2024.105239","DOIUrl":"10.1016/j.ebiom.2024.105239","url":null,"abstract":"<p><strong>Background: </strong>Induction of donor-specific tolerance is a promising approach to achieve long-term graft patency in transplantation with little to no maintenance immunosuppression. Changes to the recipient's T cell receptor (TCR) repertoire are understood to play a pivotal role in the establishment of a robust state of tolerance in chimerism-based transplantation protocols.</p><p><strong>Methods: </strong>We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression.</p><p><strong>Findings: </strong>Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4<sup>+</sup> T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4<sup>+</sup> and CD8<sup>+</sup> TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity.</p><p><strong>Interpretation: </strong>Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression.</p><p><strong>Funding: </strong>This study was funded by the Vienna Science and Technology Fund (WWTF).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598922","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 : 2024-08-01Epub Date: 2024-07-13DOI: 10.1016/j.ebiom.2024.105242
Luise Müller, Anne Hoffmann, Stephan H Bernhart, Adhideb Ghosh, Jiawei Zhong, Tobias Hagemann, Wenfei Sun, Hua Dong, Falko Noé, Christian Wolfrum, Arne Dietrich, Michael Stumvoll, Lucas Massier, Matthias Blüher, Peter Kovacs, Rima Chakaroun, Maria Keller
Background: Studies on DNA methylation following bariatric surgery have primarily focused on blood cells, while it is unclear to which extend it may reflect DNA methylation profiles in specific metabolically relevant organs such as adipose tissue. Here, we investigated whether adipose tissue depots specific methylation changes after bariatric surgery are mirrored in blood.
Methods: Using Illumina 850K EPIC technology, we analysed genome-wide DNA methylation in paired blood, subcutaneous and omental visceral AT (SAT/OVAT) samples from nine individuals (N = 6 female) with severe obesity pre- and post-surgery.
Findings: The numbers and effect sizes of differentially methylated regions (DMRs) post-bariatric surgery were more pronounced in AT (SAT: 12,865 DMRs from -11.5 to 10.8%; OVAT: 14,632 DMRs from -13.7 to 12.8%) than in blood (9267 DMRs from -8.8 to 7.7%). Cross-tissue DMRs implicated immune-related genes. Among them, 49 regions could be validated with similar methylation changes in blood from independent individuals. Fourteen DMRs correlated with differentially expressed genes in AT post bariatric surgery, including downregulation of PIK3AP1 in both SAT and OVAT. DNA methylation age acceleration was significantly higher in AT compared to blood, but remained unaffected after surgery.
Interpretation: Concurrent methylation pattern changes in blood and AT, particularly in immune-related genes, suggest blood DNA methylation mirrors AT's inflammatory state post-bariatric surgery.
Funding: The funding sources are listed in the Acknowledgments section.
{"title":"Blood methylation pattern reflects epigenetic remodelling in adipose tissue after bariatric surgery.","authors":"Luise Müller, Anne Hoffmann, Stephan H Bernhart, Adhideb Ghosh, Jiawei Zhong, Tobias Hagemann, Wenfei Sun, Hua Dong, Falko Noé, Christian Wolfrum, Arne Dietrich, Michael Stumvoll, Lucas Massier, Matthias Blüher, Peter Kovacs, Rima Chakaroun, Maria Keller","doi":"10.1016/j.ebiom.2024.105242","DOIUrl":"10.1016/j.ebiom.2024.105242","url":null,"abstract":"<p><strong>Background: </strong>Studies on DNA methylation following bariatric surgery have primarily focused on blood cells, while it is unclear to which extend it may reflect DNA methylation profiles in specific metabolically relevant organs such as adipose tissue. Here, we investigated whether adipose tissue depots specific methylation changes after bariatric surgery are mirrored in blood.</p><p><strong>Methods: </strong>Using Illumina 850K EPIC technology, we analysed genome-wide DNA methylation in paired blood, subcutaneous and omental visceral AT (SAT/OVAT) samples from nine individuals (N = 6 female) with severe obesity pre- and post-surgery.</p><p><strong>Findings: </strong>The numbers and effect sizes of differentially methylated regions (DMRs) post-bariatric surgery were more pronounced in AT (SAT: 12,865 DMRs from -11.5 to 10.8%; OVAT: 14,632 DMRs from -13.7 to 12.8%) than in blood (9267 DMRs from -8.8 to 7.7%). Cross-tissue DMRs implicated immune-related genes. Among them, 49 regions could be validated with similar methylation changes in blood from independent individuals. Fourteen DMRs correlated with differentially expressed genes in AT post bariatric surgery, including downregulation of PIK3AP1 in both SAT and OVAT. DNA methylation age acceleration was significantly higher in AT compared to blood, but remained unaffected after surgery.</p><p><strong>Interpretation: </strong>Concurrent methylation pattern changes in blood and AT, particularly in immune-related genes, suggest blood DNA methylation mirrors AT's inflammatory state post-bariatric surgery.</p><p><strong>Funding: </strong>The funding sources are listed in the Acknowledgments section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603460","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 : 2024-08-01Epub Date: 2024-07-29DOI: 10.1016/j.ebiom.2024.105261
Yuting Xie, Shujun Fan, Yana Luo, Jiaxin Li, Yidan Zhang, Lixin Hu, Huiling Qiu, Ganglong Zhou, Joachim Heinrich, Tianyu Zhao, Zhengtu Li, Li Li, Aimin Xu, John S Ji, Zhoubin Zhang, Yuanzhong Zhou, Sam S S Lau, Xiaoguang Zou, Guanghui Dong, Payam Dadvand, Boyi Yang
Background: Green space is an important part of the human living environment, with many epidemiological studies estimating its impact on human health. However, no study has quantitatively assessed the credibility of the existing evidence, impeding their translations into policy decisions and hindering researchers from identifying new research gaps. This overview aims to evaluate and rank such evidence credibility.
Methods: Following the PRISMA guideline, we systematically searched PubMed, Web of Science, and Embase databases for systematic reviews with meta-analyses concerning green spaces and health outcomes published up to January 15, 2024. We categorized the credibility of meta-analytical evidence from interventional studies into four levels (i.e., high, moderate, low, and very low) using the Grading of Recommendation, Assessment, Development and Evaluations framework, based on five domains including risk of bias, inconsistency, indirectness, imprecision, and publication bias. Further, we recalculated all the meta-analyses from observational studies and classified evidence into five levels (i.e., convincing, highly suggestive, suggestive, weak, and non-significant) by considering stringent thresholds for P-values, sample size, robustness, heterogeneity, and testing for biases.
Findings: In total, 154 meta-analysed associations (interventional = 44, observational = 110) between green spaces and health outcomes were graded. Among meta-analyses from interventional studies, zero, four (wellbeing, systolic blood pressure, negative affect, and positive affect), 20, and 20 associations between green spaces and health outcomes were graded as high, moderate, low, and very low credibility evidence, respectively. Among meta-analyses from observational studies, one (cardiovascular disease mortality), four (prevalence/incidence of diabetes mellitus, preterm birth, and small for gestational age infant, and all-cause mortality), 12, 22, and 71 associations were categorized as convincing, highly suggestive, suggestive, weak, and non-significant evidence, respectively.
Interpretation: The current evidence largely confirms beneficial associations between green spaces and human health. However, only a small subset of these associations can be deemed to have a high or convincing credibility. Hence, future better designed primary studies and meta-analyses are still needed to provide higher quality evidence for informing health promotion strategies.
Funding: The National Natural Science Foundation of China of China; the Guangzhou Science and Technology Program; the Guangdong Medical Science and Technology Research Fund; the Research Grant Council of the Hong Kong SAR; and Sino-German mobility program.
{"title":"Credibility of the evidence on green space and human health: an overview of meta-analyses using evidence grading approaches.","authors":"Yuting Xie, Shujun Fan, Yana Luo, Jiaxin Li, Yidan Zhang, Lixin Hu, Huiling Qiu, Ganglong Zhou, Joachim Heinrich, Tianyu Zhao, Zhengtu Li, Li Li, Aimin Xu, John S Ji, Zhoubin Zhang, Yuanzhong Zhou, Sam S S Lau, Xiaoguang Zou, Guanghui Dong, Payam Dadvand, Boyi Yang","doi":"10.1016/j.ebiom.2024.105261","DOIUrl":"10.1016/j.ebiom.2024.105261","url":null,"abstract":"<p><strong>Background: </strong>Green space is an important part of the human living environment, with many epidemiological studies estimating its impact on human health. However, no study has quantitatively assessed the credibility of the existing evidence, impeding their translations into policy decisions and hindering researchers from identifying new research gaps. This overview aims to evaluate and rank such evidence credibility.</p><p><strong>Methods: </strong>Following the PRISMA guideline, we systematically searched PubMed, Web of Science, and Embase databases for systematic reviews with meta-analyses concerning green spaces and health outcomes published up to January 15, 2024. We categorized the credibility of meta-analytical evidence from interventional studies into four levels (i.e., high, moderate, low, and very low) using the Grading of Recommendation, Assessment, Development and Evaluations framework, based on five domains including risk of bias, inconsistency, indirectness, imprecision, and publication bias. Further, we recalculated all the meta-analyses from observational studies and classified evidence into five levels (i.e., convincing, highly suggestive, suggestive, weak, and non-significant) by considering stringent thresholds for P-values, sample size, robustness, heterogeneity, and testing for biases.</p><p><strong>Findings: </strong>In total, 154 meta-analysed associations (interventional = 44, observational = 110) between green spaces and health outcomes were graded. Among meta-analyses from interventional studies, zero, four (wellbeing, systolic blood pressure, negative affect, and positive affect), 20, and 20 associations between green spaces and health outcomes were graded as high, moderate, low, and very low credibility evidence, respectively. Among meta-analyses from observational studies, one (cardiovascular disease mortality), four (prevalence/incidence of diabetes mellitus, preterm birth, and small for gestational age infant, and all-cause mortality), 12, 22, and 71 associations were categorized as convincing, highly suggestive, suggestive, weak, and non-significant evidence, respectively.</p><p><strong>Interpretation: </strong>The current evidence largely confirms beneficial associations between green spaces and human health. However, only a small subset of these associations can be deemed to have a high or convincing credibility. Hence, future better designed primary studies and meta-analyses are still needed to provide higher quality evidence for informing health promotion strategies.</p><p><strong>Funding: </strong>The National Natural Science Foundation of China of China; the Guangzhou Science and Technology Program; the Guangdong Medical Science and Technology Research Fund; the Research Grant Council of the Hong Kong SAR; and Sino-German mobility program.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855190","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 : 2024-08-01Epub Date: 2024-07-05DOI: 10.1016/j.ebiom.2024.105229
Sara A Lewis, Andrew Ruttenberg, Tuğçe Iyiyol, Nahyun Kong, Sheng Chih Jin, Michael C Kruer
Cerebral palsy (CP) has historically been attributed to acquired insults, but emerging research suggests that genetic variations are also important causes of CP. While microarray and whole-exome sequencing based studies have been the primary methods for establishing new CP-gene relationships and providing a genetic etiology for individual patients, the cause of their condition remains unknown for many patients with CP. Recent advancements in genomic technologies offer additional opportunities to uncover variations in human genomes, transcriptomes, and epigenomes that have previously escaped detection. In this review, we outline the use of these state-of-the-art technologies to address the molecular diagnostic challenges experienced by individuals with CP. We also explore the importance of identifying a molecular etiology whenever possible, given the potential for genomic medicine to provide opportunities to treat patients with CP in new and more precise ways.
{"title":"Potential clinical applications of advanced genomic analysis in cerebral palsy.","authors":"Sara A Lewis, Andrew Ruttenberg, Tuğçe Iyiyol, Nahyun Kong, Sheng Chih Jin, Michael C Kruer","doi":"10.1016/j.ebiom.2024.105229","DOIUrl":"10.1016/j.ebiom.2024.105229","url":null,"abstract":"<p><p>Cerebral palsy (CP) has historically been attributed to acquired insults, but emerging research suggests that genetic variations are also important causes of CP. While microarray and whole-exome sequencing based studies have been the primary methods for establishing new CP-gene relationships and providing a genetic etiology for individual patients, the cause of their condition remains unknown for many patients with CP. Recent advancements in genomic technologies offer additional opportunities to uncover variations in human genomes, transcriptomes, and epigenomes that have previously escaped detection. In this review, we outline the use of these state-of-the-art technologies to address the molecular diagnostic challenges experienced by individuals with CP. We also explore the importance of identifying a molecular etiology whenever possible, given the potential for genomic medicine to provide opportunities to treat patients with CP in new and more precise ways.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544640","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 : 2024-08-01Epub Date: 2024-07-16DOI: 10.1016/j.ebiom.2024.105228
Enric Domingo, Sanjay Rathee, Andrew Blake, Leslie Samuel, Graeme Murray, David Sebag-Montefiore, Simon Gollins, Nicholas West, Rubina Begum, Susan Richman, Phil Quirke, Keara Redmond, Aikaterini Chatzipli, Alessandro Barberis, Sylvana Hassanieh, Umair Mahmood, Michael Youdell, Ultan McDermott, Viktor Koelzer, Simon Leedham, Ian Tomlinson, Philip Dunne, Francesca M Buffa, Timothy S Maughan
Background: It is uncertain which biological features underpin the response of rectal cancer (RC) to radiotherapy. No biomarker is currently in clinical use to select patients for treatment modifications.
Methods: We identified two cohorts of patients (total N = 249) with RC treated with neoadjuvant radiotherapy (45Gy/25) plus fluoropyrimidine. This discovery set included 57 cases with pathological complete response (pCR) to chemoradiotherapy (23%). Pre-treatment cancer biopsies were assessed using transcriptome-wide mRNA expression and targeted DNA sequencing for copy number and driver mutations. Biological candidate and machine learning (ML) approaches were used to identify predictors of pCR to radiotherapy independent of tumour stage. Findings were assessed in 107 cases from an independent validation set (GSE87211).
Findings: Three gene expression sets showed significant independent associations with pCR: Fibroblast-TGFβ Response Signature (F-TBRS) with radioresistance; and cytotoxic lymphocyte (CL) expression signature and consensus molecular subtype CMS1 with radiosensitivity. These associations were replicated in the validation cohort. In parallel, a gradient boosting machine model comprising the expression of 33 genes generated in the discovery cohort showed high performance in GSE87211 with 90% sensitivity, 86% specificity. Biological and ML signatures indicated similar mechanisms underlying radiation response, and showed better AUC and p-values than published transcriptomic signatures of radiation response in RC.
Interpretation: RCs responding completely to chemoradiotherapy (CRT) have biological characteristics of immune response and absence of immune inhibitory TGFβ signalling. These tumours may be identified with a potential biomarker based on a 33 gene expression signature. This could help select patients likely to respond to treatment with a primary radiotherapy approach as for anal cancer. Conversely, those with predicted radioresistance may be candidates for clinical trials evaluating addition of immune-oncology agents and stromal TGFβ signalling inhibition.
Funding: The Stratification in Colorectal Cancer Consortium (S:CORT) was funded by the Medical Research Council and Cancer Research UK (MR/M016587/1).
背景:直肠癌(RC)对放疗反应的生物学特征尚不确定。目前临床上还没有生物标志物可用于选择患者进行治疗调整:我们发现了两组接受新辅助放疗(45Gy/25)加氟嘧啶治疗的 RC 患者(总人数 = 249)。该发现组包括57例对化疗放疗有病理完全反应(pCR)的患者(23%)。治疗前的癌症活检采用全转录组 mRNA 表达和靶向 DNA 测序评估拷贝数和驱动突变。生物候选方法和机器学习(ML)方法被用来识别放化疗pCR的预测因子,而与肿瘤分期无关。对独立验证集(GSE87211)中的 107 个病例进行了评估:三个基因表达集显示出与pCR显著的独立关联:成纤维细胞-TGFβ反应特征(F-TBRS)与放射抵抗有关;细胞毒性淋巴细胞(CL)表达特征和共识分子亚型CMS1与放射敏感性有关。这些关联在验证队列中得到了复制。与此同时,由发现队列中产生的 33 个基因表达组成的梯度提升机模型在 GSE87211 中表现出很高的灵敏度和特异性,灵敏度为 90%,特异性为 86%。生物特征和 ML 特征显示了类似的辐射反应机制,其 AUC 和 p 值优于已发表的 RC 辐射反应转录组特征:对化疗放疗(CRT)完全应答的RC具有免疫应答和缺乏免疫抑制TGFβ信号的生物学特征。这些肿瘤可通过基于 33 个基因表达特征的潜在生物标记物来识别。这有助于选择可能对肛门癌的原发性放疗方法产生反应的患者。相反,那些预测具有放射抗性的患者可能成为临床试验的候选者,这些临床试验将评估添加免疫肿瘤学药物和基质 TGFβ 信号抑制剂的效果:结直肠癌分层研究联合会(S:CORT)由英国医学研究委员会(MR/M016587/1)和英国癌症研究中心(MR/M016587/1)资助。
{"title":"Identification and validation of a machine learning model of complete response to radiation in rectal cancer reveals immune infiltrate and TGFβ as key predictors.","authors":"Enric Domingo, Sanjay Rathee, Andrew Blake, Leslie Samuel, Graeme Murray, David Sebag-Montefiore, Simon Gollins, Nicholas West, Rubina Begum, Susan Richman, Phil Quirke, Keara Redmond, Aikaterini Chatzipli, Alessandro Barberis, Sylvana Hassanieh, Umair Mahmood, Michael Youdell, Ultan McDermott, Viktor Koelzer, Simon Leedham, Ian Tomlinson, Philip Dunne, Francesca M Buffa, Timothy S Maughan","doi":"10.1016/j.ebiom.2024.105228","DOIUrl":"10.1016/j.ebiom.2024.105228","url":null,"abstract":"<p><strong>Background: </strong>It is uncertain which biological features underpin the response of rectal cancer (RC) to radiotherapy. No biomarker is currently in clinical use to select patients for treatment modifications.</p><p><strong>Methods: </strong>We identified two cohorts of patients (total N = 249) with RC treated with neoadjuvant radiotherapy (45Gy/25) plus fluoropyrimidine. This discovery set included 57 cases with pathological complete response (pCR) to chemoradiotherapy (23%). Pre-treatment cancer biopsies were assessed using transcriptome-wide mRNA expression and targeted DNA sequencing for copy number and driver mutations. Biological candidate and machine learning (ML) approaches were used to identify predictors of pCR to radiotherapy independent of tumour stage. Findings were assessed in 107 cases from an independent validation set (GSE87211).</p><p><strong>Findings: </strong>Three gene expression sets showed significant independent associations with pCR: Fibroblast-TGFβ Response Signature (F-TBRS) with radioresistance; and cytotoxic lymphocyte (CL) expression signature and consensus molecular subtype CMS1 with radiosensitivity. These associations were replicated in the validation cohort. In parallel, a gradient boosting machine model comprising the expression of 33 genes generated in the discovery cohort showed high performance in GSE87211 with 90% sensitivity, 86% specificity. Biological and ML signatures indicated similar mechanisms underlying radiation response, and showed better AUC and p-values than published transcriptomic signatures of radiation response in RC.</p><p><strong>Interpretation: </strong>RCs responding completely to chemoradiotherapy (CRT) have biological characteristics of immune response and absence of immune inhibitory TGFβ signalling. These tumours may be identified with a potential biomarker based on a 33 gene expression signature. This could help select patients likely to respond to treatment with a primary radiotherapy approach as for anal cancer. Conversely, those with predicted radioresistance may be candidates for clinical trials evaluating addition of immune-oncology agents and stromal TGFβ signalling inhibition.</p><p><strong>Funding: </strong>The Stratification in Colorectal Cancer Consortium (S:CORT) was funded by the Medical Research Council and Cancer Research UK (MR/M016587/1).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626307","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}