Pub Date : 2024-10-30DOI: 10.1126/scitranslmed.abo1997
Biqing Zhu, Jae-Min Park, Sarah R. Coffey, Anthony Russo, I-Uen Hsu, Jiawei Wang, Chang Su, Rui Chang, TuKiet T. Lam, Pallavi P. Gopal, Stephen D. Ginsberg, Hongyu Zhao, David A. Hafler, Sreeganga S. Chandra, Le Zhang
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.
{"title":"Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains","authors":"Biqing Zhu, Jae-Min Park, Sarah R. Coffey, Anthony Russo, I-Uen Hsu, Jiawei Wang, Chang Su, Rui Chang, TuKiet T. Lam, Pallavi P. Gopal, Stephen D. Ginsberg, Hongyu Zhao, David A. Hafler, Sreeganga S. Chandra, Le Zhang","doi":"10.1126/scitranslmed.abo1997","DOIUrl":"10.1126/scitranslmed.abo1997","url":null,"abstract":"<div >Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 771","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547169","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 : 2024-10-30DOI: 10.1126/scitranslmed.adl5514
Valentina Villani, Camille Nicolas Frank, Paolo Cravedi, Xiaogang Hou, Sofia Bin, Anna Kamitakahara, Cristiani Barbati, Roberta Buono, Stefano Da Sacco, Kevin V. Lemley, Roger E. De Filippo, Silvia Lai, Alessandro Laviano, Valter D. Longo, Laura Perin
Cycles of a fasting-mimicking diet (FMD) promote regeneration and reduce damage in the pancreases, blood, guts, and nervous systems of mice, but their effect on kidney disease is unknown. In addition, a FMD has not been tested in rats. Here, we show that cycles of a newly developed low-salt FMD (LS-FMD) restored normal proteinuria and nephron structure and function in rats with puromycin-induced nephrosis compared with that in animals with renal damage that did not receive the dietary intervention. LS-FMD induced modulation of a nephrogenic gene program, resembling renal developmental processes in multiple kidney structures. LS-FMD also activated podocyte-lineage reprogramming pathways and promoted a quiescent state in mature podocytes in the rat kidney damage model. In a pilot clinical study in patients with chronic kidney disease, FMD cycles of 5 days each month for 3 months promoted renoprotection, including reduction of proteinuria and improved endothelial function, compared with that in patients who did not receive the FMD cycles. These results show that FMD cycles, which promote the reprogramming of multiple renal cell types and lead to glomerular damage reversal in rats, should be tested further for the treatment of progressive kidney diseases.
{"title":"A kidney-specific fasting-mimicking diet induces podocyte reprogramming and restores renal function in glomerulopathy","authors":"Valentina Villani, Camille Nicolas Frank, Paolo Cravedi, Xiaogang Hou, Sofia Bin, Anna Kamitakahara, Cristiani Barbati, Roberta Buono, Stefano Da Sacco, Kevin V. Lemley, Roger E. De Filippo, Silvia Lai, Alessandro Laviano, Valter D. Longo, Laura Perin","doi":"10.1126/scitranslmed.adl5514","DOIUrl":"10.1126/scitranslmed.adl5514","url":null,"abstract":"<div >Cycles of a fasting-mimicking diet (FMD) promote regeneration and reduce damage in the pancreases, blood, guts, and nervous systems of mice, but their effect on kidney disease is unknown. In addition, a FMD has not been tested in rats. Here, we show that cycles of a newly developed low-salt FMD (LS-FMD) restored normal proteinuria and nephron structure and function in rats with puromycin-induced nephrosis compared with that in animals with renal damage that did not receive the dietary intervention. LS-FMD induced modulation of a nephrogenic gene program, resembling renal developmental processes in multiple kidney structures. LS-FMD also activated podocyte-lineage reprogramming pathways and promoted a quiescent state in mature podocytes in the rat kidney damage model. In a pilot clinical study in patients with chronic kidney disease, FMD cycles of 5 days each month for 3 months promoted renoprotection, including reduction of proteinuria and improved endothelial function, compared with that in patients who did not receive the FMD cycles. These results show that FMD cycles, which promote the reprogramming of multiple renal cell types and lead to glomerular damage reversal in rats, should be tested further for the treatment of progressive kidney diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 771","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547164","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 : 2024-10-30DOI: 10.1126/scitranslmed.adi9004
Bairu Zhang, Lukasz Magiera, Juliana Candido, Olga Muraeva, Jane Coates Ulrichsen, Jim Eyles, Elena Galvani, Natasha A. Karp
In anticancer research, tumor growth measured in mouse models is important for assessing treatment efficacy for a treatment to progress to human clinical trials. Statistical analysis of time-to-event tumor volume data is complex because of heterogeneity in response and welfare-related data loss. Traditional statistical methods of testing the mean difference between groups are not robust because they assume common responses across a population. Heterogeneity in response is also seen in the clinic, and consequently, the assessment of the treatment considers the diversity through classification of the individual’s response using the RECIST (Response Evaluation Criteria in Solid Tumors). To provide a comparable and translatable assessment of in vivo tumor response, we developed a statistical method called INSPECT (IN vivo reSPonsE Classification of Tumors) for analyzing heterogeneous responses through Bayesian modeling. This method can classify individual tumor behaviors into the categories of nonresponder, modest responder, stable responder, and regressing responder. Using both published and simulated data, we show that INSPECT methodology is more accurate and sensitive than existing methods with respect to balancing false-negative and false-positive rates. A case study demonstrates the value of INSPECT in drug projects for supporting the translation of drug efficacy from the preclinical phase into clinical trials. We also provide a package, “INSPECTumours,” that launches a web interface to enable users to conduct the analysis and generate reports.
{"title":"Bayesian modeling for analyzing heterogeneous response in preclinical mouse tumor models","authors":"Bairu Zhang, Lukasz Magiera, Juliana Candido, Olga Muraeva, Jane Coates Ulrichsen, Jim Eyles, Elena Galvani, Natasha A. Karp","doi":"10.1126/scitranslmed.adi9004","DOIUrl":"10.1126/scitranslmed.adi9004","url":null,"abstract":"<div >In anticancer research, tumor growth measured in mouse models is important for assessing treatment efficacy for a treatment to progress to human clinical trials. Statistical analysis of time-to-event tumor volume data is complex because of heterogeneity in response and welfare-related data loss. Traditional statistical methods of testing the mean difference between groups are not robust because they assume common responses across a population. Heterogeneity in response is also seen in the clinic, and consequently, the assessment of the treatment considers the diversity through classification of the individual’s response using the RECIST (Response Evaluation Criteria in Solid Tumors). To provide a comparable and translatable assessment of in vivo tumor response, we developed a statistical method called INSPECT (IN vivo reSPonsE Classification of Tumors) for analyzing heterogeneous responses through Bayesian modeling. This method can classify individual tumor behaviors into the categories of nonresponder, modest responder, stable responder, and regressing responder. Using both published and simulated data, we show that INSPECT methodology is more accurate and sensitive than existing methods with respect to balancing false-negative and false-positive rates. A case study demonstrates the value of INSPECT in drug projects for supporting the translation of drug efficacy from the preclinical phase into clinical trials. We also provide a package, “INSPECTumours,” that launches a web interface to enable users to conduct the analysis and generate reports.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 771","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547165","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 : 2024-10-30DOI: 10.1126/scitranslmed.adk1168
Valeria Governa, Kelin Gonçalves de Oliveira, Anna Bång-Rudenstam, Svenja Offer, Myriam Cerezo-Magaña, Jiaxin Li, Sarah Beyer, Maria C. Johansson, Ann-Sofie Månsson, Charlotte Edvardsson, Faris Durmo, Emma Gustafsson, Axel Boukredine, Pauline Jeannot, Katja Schmidt, Emelie Gezelius, Julien A. Menard, Raquel Garza, Johan Jakobsson, Therese de Neergaard, Pia C. Sundgren, Aliisa M. Tiihonen, Hannu Haapasalo, Kirsi J. Rautajoki, Pontus Nordenfelt, Anna Darabi, Karin Forsberg-Nilsson, Alexander Pietras, Hugo Talbot, Johan Bengzon, Mattias Belting
Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet–loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol O-acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.
{"title":"Protumoral lipid droplet–loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted","authors":"Valeria Governa, Kelin Gonçalves de Oliveira, Anna Bång-Rudenstam, Svenja Offer, Myriam Cerezo-Magaña, Jiaxin Li, Sarah Beyer, Maria C. Johansson, Ann-Sofie Månsson, Charlotte Edvardsson, Faris Durmo, Emma Gustafsson, Axel Boukredine, Pauline Jeannot, Katja Schmidt, Emelie Gezelius, Julien A. Menard, Raquel Garza, Johan Jakobsson, Therese de Neergaard, Pia C. Sundgren, Aliisa M. Tiihonen, Hannu Haapasalo, Kirsi J. Rautajoki, Pontus Nordenfelt, Anna Darabi, Karin Forsberg-Nilsson, Alexander Pietras, Hugo Talbot, Johan Bengzon, Mattias Belting","doi":"10.1126/scitranslmed.adk1168","DOIUrl":"10.1126/scitranslmed.adk1168","url":null,"abstract":"<div >Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet–loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol <i>O</i>-acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 771","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547168","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 : 2024-10-30DOI: 10.1126/scitranslmed.ado2084
Emily P. English, Rachel N. Swingler, Simran Patwa, Mehmet Tosun, James F. Howard Jr., Miloš D. Miljković, Christopher M. Jewell
Chimeric antigen receptor–T cell (CAR-T) therapy has transformed the management of refractory hematological malignancies. Now that targeting pathogenic cells of interest with antigen-directed cytotoxic T lymphocytes is possible, the field is expanding the reach of CAR-T therapy beyond oncology. Recently, breakthrough progress has been made in the application of CAR-T technology to autoimmune diseases, exploiting the same validated targets that were used by pioneering CAR-T therapies in hematology. Here, we discuss recent advances and outcomes that are paving the way for extension to new therapeutic areas, including autoimmunity.
嵌合抗原受体-T 细胞（CAR-T）疗法改变了难治性血液恶性肿瘤的治疗方法。现在，利用抗原导向的细胞毒性 T 淋巴细胞靶向相关致病细胞已成为可能，CAR-T疗法的应用领域正扩展到肿瘤学以外。最近，CAR-T 技术在自身免疫性疾病中的应用取得了突破性进展，它利用了血液学领域先驱 CAR-T 疗法所使用的相同验证靶点。在这里，我们将讨论最近的进展和成果，这些进展和成果为扩展到包括自身免疫在内的新治疗领域铺平了道路。
{"title":"Engineering CAR-T therapies for autoimmune disease and beyond","authors":"Emily P. English, Rachel N. Swingler, Simran Patwa, Mehmet Tosun, James F. Howard Jr., Miloš D. Miljković, Christopher M. Jewell","doi":"10.1126/scitranslmed.ado2084","DOIUrl":"10.1126/scitranslmed.ado2084","url":null,"abstract":"<div >Chimeric antigen receptor–T cell (CAR-T) therapy has transformed the management of refractory hematological malignancies. Now that targeting pathogenic cells of interest with antigen-directed cytotoxic T lymphocytes is possible, the field is expanding the reach of CAR-T therapy beyond oncology. Recently, breakthrough progress has been made in the application of CAR-T technology to autoimmune diseases, exploiting the same validated targets that were used by pioneering CAR-T therapies in hematology. Here, we discuss recent advances and outcomes that are paving the way for extension to new therapeutic areas, including autoimmunity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 771","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado2084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547166","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 : 2024-10-30DOI: 10.1126/scitranslmed.adf5128
Marta J. Koper, Sebastiaan Moonen, Alicja Ronisz, Simona Ospitalieri, Zsuzsanna Callaerts-Vegh, Dries T’Syen, Sabine Rabe, Matthias Staufenbiel, Bart De Strooper, Sriram Balusu, Dietmar Rudolf Thal
Necroptosis is a regulated form of cell death that has been observed in Alzheimer’s disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)–Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as “GVD-necroptosis” may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD.
坏死是细胞死亡的一种调节形式，在阿尔茨海默病（AD）中，除了淀粉样蛋白斑块和 Tau 神经纤维缠结等经典病理标志性病变外，还可观察到坏死。为了了解阿尔茨海默病的神经退行性过程，我们研究了坏死细胞在小鼠模型和原代小鼠神经元中的作用。利用免疫组化技术，我们在出现 Tau 病理变化的转基因小鼠体内以及淀粉样前体蛋白（APP）-Tau 双转基因小鼠的原代神经元中发现了活化的坏死相关蛋白，而在只表现出 β 淀粉样蛋白沉积的 APP 转基因小鼠体内则没有发现。颗粒细胞变性（GVD）体中的坏死蛋白与小鼠脑区的神经元损失有关，而已知人类AD脑区也容易发生GVD。在转基因小鼠和原代小鼠神经元中，坏死抑制剂降低了出现GVD的神经元比例，减少了神经元丢失。这表明，GVD 相关的坏死形式（我们称之为 "GVD-坏死"）可能代表了 AD 中坏死的延迟形式。我们建议，抑制坏死凋亡可以挽救这种类型的 AD 神经元死亡。
{"title":"Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models","authors":"Marta J. Koper, Sebastiaan Moonen, Alicja Ronisz, Simona Ospitalieri, Zsuzsanna Callaerts-Vegh, Dries T’Syen, Sabine Rabe, Matthias Staufenbiel, Bart De Strooper, Sriram Balusu, Dietmar Rudolf Thal","doi":"10.1126/scitranslmed.adf5128","DOIUrl":"10.1126/scitranslmed.adf5128","url":null,"abstract":"<div >Necroptosis is a regulated form of cell death that has been observed in Alzheimer’s disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)–Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as “GVD-necroptosis” may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 771","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547167","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 : 2024-10-23DOI: 10.1126/scitranslmed.adm8631
Nicola Caldwell, Caroline Peet, Peter Miller, Beatrice L. Colon, Malcolm G. Taylor, Mattia Cocco, Alice Dawson, Iva Lukac, Jose E. Teixeira, Lee Robinson, Laura Frame, Simona Seizova, Sebastian Damerow, Fabio Tamaki, John Post, Jennifer Riley, Nicole Mutter, Jack C. Hanna, Liam Ferguson, Xiao Hu, Michele Tinti, Barbara Forte, Neil R. Norcross, Peter S. Campbell, Nina Svensen, Flora C. Caldwell, Chimed Jansen, Vincent Postis, Kevin D. Read, Christopher D. Huston, Ian H. Gilbert, Beatriz Baragaña, Mattie C. Pawlowic
Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.
{"title":"Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy","authors":"Nicola Caldwell, Caroline Peet, Peter Miller, Beatrice L. Colon, Malcolm G. Taylor, Mattia Cocco, Alice Dawson, Iva Lukac, Jose E. Teixeira, Lee Robinson, Laura Frame, Simona Seizova, Sebastian Damerow, Fabio Tamaki, John Post, Jennifer Riley, Nicole Mutter, Jack C. Hanna, Liam Ferguson, Xiao Hu, Michele Tinti, Barbara Forte, Neil R. Norcross, Peter S. Campbell, Nina Svensen, Flora C. Caldwell, Chimed Jansen, Vincent Postis, Kevin D. Read, Christopher D. Huston, Ian H. Gilbert, Beatriz Baragaña, Mattie C. Pawlowic","doi":"10.1126/scitranslmed.adm8631","DOIUrl":"10.1126/scitranslmed.adm8631","url":null,"abstract":"<div >Cryptosporidiosis is a diarrheal disease caused by infection with <i>Cryptosporidium</i> spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 770","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487822","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 : 2024-10-23DOI: 10.1126/scitranslmed.adp8920
Ninaad Lasrado, Marjorie Rowe, Katherine McMahan, Nicole P. Hachmann, Jessica Miller, Catherine Jacob-Dolan, Jinyan Liu, Brookelynne Verrette, Kristin A. Gotthardt, Darren M. Ty, Juliana Pereira, Camille R. Mazurek, Amelia Hoyt, Ai-ris Y. Collier, Dan H. Barouch
Current COVID-19 vaccines provide robust protection against severe disease but minimal protection against acquisition of infection. Intramuscularly administered COVID-19 vaccines induce robust serum neutralizing antibodies (NAbs), but their ability to boost mucosal immune responses remains to be determined. In this study, we show that the XBB.1.5 messenger RNA (mRNA) boosters result in increased serum neutralization to multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in humans, including the dominant circulating variant JN.1. In contrast, we found that the XBB.1.5 mRNA booster did not augment mucosal NAbs or mucosal IgA responses, although acute SARS-CoV-2 XBB infection substantially increased mucosal antibody responses. These data demonstrate that current XBB.1.5 mRNA boosters substantially enhance peripheral antibody responses but do not robustly increase mucosal antibody responses. Our data highlight a separation between the peripheral and mucosal immune systems in humans and emphasize the importance of developing next-generation vaccines to augment mucosal immunity to protect against respiratory virus infections.
{"title":"SARS-CoV-2 XBB.1.5 mRNA booster vaccination elicits limited mucosal immunity","authors":"Ninaad Lasrado, Marjorie Rowe, Katherine McMahan, Nicole P. Hachmann, Jessica Miller, Catherine Jacob-Dolan, Jinyan Liu, Brookelynne Verrette, Kristin A. Gotthardt, Darren M. Ty, Juliana Pereira, Camille R. Mazurek, Amelia Hoyt, Ai-ris Y. Collier, Dan H. Barouch","doi":"10.1126/scitranslmed.adp8920","DOIUrl":"10.1126/scitranslmed.adp8920","url":null,"abstract":"<div >Current COVID-19 vaccines provide robust protection against severe disease but minimal protection against acquisition of infection. Intramuscularly administered COVID-19 vaccines induce robust serum neutralizing antibodies (NAbs), but their ability to boost mucosal immune responses remains to be determined. In this study, we show that the XBB.1.5 messenger RNA (mRNA) boosters result in increased serum neutralization to multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in humans, including the dominant circulating variant JN.1. In contrast, we found that the XBB.1.5 mRNA booster did not augment mucosal NAbs or mucosal IgA responses, although acute SARS-CoV-2 XBB infection substantially increased mucosal antibody responses. These data demonstrate that current XBB.1.5 mRNA boosters substantially enhance peripheral antibody responses but do not robustly increase mucosal antibody responses. Our data highlight a separation between the peripheral and mucosal immune systems in humans and emphasize the importance of developing next-generation vaccines to augment mucosal immunity to protect against respiratory virus infections.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 770","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487799","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 : 2024-10-23DOI: 10.1126/scitranslmed.ado5108
Masumi Ueda Oshima, Jacob Higgins, Isaac Jenkins, Timothy Randolph, Thomas Smith, Charles Valentine III, Jesse Salk, Cecilia Yeung, Lan Beppu, Judy Campbell, Paul A. Carpenter, Stephanie J. Lee, Mary E. Flowers, Jerald P. Radich, Rainer Storb
After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.
{"title":"Characterization of clonal dynamics using duplex sequencing in donor-recipient pairs decades after hematopoietic cell transplantation","authors":"Masumi Ueda Oshima, Jacob Higgins, Isaac Jenkins, Timothy Randolph, Thomas Smith, Charles Valentine III, Jesse Salk, Cecilia Yeung, Lan Beppu, Judy Campbell, Paul A. Carpenter, Stephanie J. Lee, Mary E. Flowers, Jerald P. Radich, Rainer Storb","doi":"10.1126/scitranslmed.ado5108","DOIUrl":"10.1126/scitranslmed.ado5108","url":null,"abstract":"<div >After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 770","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado5108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487830","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 : 2024-10-23DOI: 10.1126/scitranslmed.ado2402
Xiuting Liu, John M. Baer, Meredith L. Stone, Brett L. Knolhoff, Graham D. Hogg, Madeleine C. Turner, Yu-Lan Kao, Alyssa G. Weinstein, Faiz Ahmad, Jie Chen, Andrew D. Schmidt, Jeffrey A. Klomp, Heather Coho, Kayjana S. Coho, Silvia Coma, Jonathan A. Pachter, Kirsten L. Bryant, Liang-I Kang, Kian-Huat Lim, Gregory L. Beatty, David G. DeNardo
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance. However, the unique PDAC TME may also be a driver of resistance. We found that long-term focal adhesion kinase (FAK) inhibitor treatment led to hyperactivation of the RAS/MAPK pathway in PDAC cells in mouse models and tissues from patients with PDAC. Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. In the TME, cancer-associated fibroblasts (CAFs) impaired the down-regulation of MYC by RAF-MEK inhibition in PDAC cells, resulting in resistance. By contrast, FAK inhibition reprogramed CAFs to suppress the production of FGF1, which can drive resistance to RAF-MEK inhibition. The addition of chemotherapy to combined FAK and RAF-MEK inhibition led to tumor regression, a decrease in liver metastasis, and improved survival in KRAS-driven PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.
{"title":"Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy","authors":"Xiuting Liu, John M. Baer, Meredith L. Stone, Brett L. Knolhoff, Graham D. Hogg, Madeleine C. Turner, Yu-Lan Kao, Alyssa G. Weinstein, Faiz Ahmad, Jie Chen, Andrew D. Schmidt, Jeffrey A. Klomp, Heather Coho, Kayjana S. Coho, Silvia Coma, Jonathan A. Pachter, Kirsten L. Bryant, Liang-I Kang, Kian-Huat Lim, Gregory L. Beatty, David G. DeNardo","doi":"10.1126/scitranslmed.ado2402","DOIUrl":"10.1126/scitranslmed.ado2402","url":null,"abstract":"<div >Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in <i>KRAS</i> have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance. However, the unique PDAC TME may also be a driver of resistance. We found that long-term focal adhesion kinase (FAK) inhibitor treatment led to hyperactivation of the RAS/MAPK pathway in PDAC cells in mouse models and tissues from patients with PDAC. Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. In the TME, cancer-associated fibroblasts (CAFs) impaired the down-regulation of MYC by RAF-MEK inhibition in PDAC cells, resulting in resistance. By contrast, FAK inhibition reprogramed CAFs to suppress the production of FGF1, which can drive resistance to RAF-MEK inhibition. The addition of chemotherapy to combined FAK and RAF-MEK inhibition led to tumor regression, a decrease in liver metastasis, and improved survival in KRAS-driven PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 770","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487818","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}
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