Honglin Jiang, Ryan K Muir, Ryan L Gonciarz, Adam B Olshen, Iwei Yeh, Byron C Hann, Ning Zhao, Yung-Hua Wang, Spencer C Behr, James E Korkola, Michael J Evans, Eric A Collisson, Adam R Renslo
{"title":"Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors.","authors":"Honglin Jiang, Ryan K Muir, Ryan L Gonciarz, Adam B Olshen, Iwei Yeh, Byron C Hann, Ning Zhao, Yung-Hua Wang, Spencer C Behr, James E Korkola, Michael J Evans, Eric A Collisson, Adam R Renslo","doi":"10.1084/jem.20210739","DOIUrl":"10.1084/jem.20210739","url":null,"abstract":"<p><p>KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8916116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83369557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna Maria Sole Giordano, Marco Luciani, Francesca Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia Della Volpe, Alessandro Migliara, Sara Valsoni, Marco Genua, Monika Dzieciatkowska, Giacomo Frati, Julie Tahraoui-Bories, Silvia Clara Giliani, Simona Orcesi, Elisa Fazzi, Renato Ostuni, Angelo D'Alessandro, Raffaella Di Micco, Ivan Merelli, Angelo Lombardo, Martin A M Reijns, Natalia Gromak, Angela Gritti, Anna Kajaste-Rudnitski
{"title":"DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.","authors":"Anna Maria Sole Giordano, Marco Luciani, Francesca Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia Della Volpe, Alessandro Migliara, Sara Valsoni, Marco Genua, Monika Dzieciatkowska, Giacomo Frati, Julie Tahraoui-Bories, Silvia Clara Giliani, Simona Orcesi, Elisa Fazzi, Renato Ostuni, Angelo D'Alessandro, Raffaella Di Micco, Ivan Merelli, Angelo Lombardo, Martin A M Reijns, Natalia Gromak, Angela Gritti, Anna Kajaste-Rudnitski","doi":"10.1084/jem.20211121","DOIUrl":"10.1084/jem.20211121","url":null,"abstract":"<p><p>Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"209 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8916121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73038358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yawen Chen, Xianwei Wang, Xiaolei Hao, Bin Li, Wanyin Tao, Shu Zhu, K. Qu, Haiming Wei, R. Sun, Hui Peng, Z. Tian
{"title":"Ly49E separates liver ILC1s into embryo-derived and postnatal subsets with different functions","authors":"Yawen Chen, Xianwei Wang, Xiaolei Hao, Bin Li, Wanyin Tao, Shu Zhu, K. Qu, Haiming Wei, R. Sun, Hui Peng, Z. Tian","doi":"10.1084/jem.20211805","DOIUrl":"https://doi.org/10.1084/jem.20211805","url":null,"abstract":"Chen et al. uncovered the transcriptional, developmental, and functional heterogeneity of ILC1s and demonstrated the dynamic changes that occur in ILC1 subsets from different origins during ontogeny, which correspond to their different functional roles, facilitating adaptation to age-related immune demands.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86345734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chihiro Kurematsu, Masato Sawada, M. Ohmuraya, Motoki Tanaka, Kazuya Kuboyama, Takashi Ogino, M. Matsumoto, Hisashi Oishi, H. Inada, Yuri Ishido, Yukina Sakakibara, Huy Bang Nguyen, T. Q. Thai, S. Kohsaka, N. Ohno, M. Yamada, Masato Asai, M. Sokabe, J. Nabekura, K. Asano, Masato Tanaka, K. Sawamoto
{"title":"Synaptic pruning of murine adult-born neurons by microglia depends on phosphatidylserine","authors":"Chihiro Kurematsu, Masato Sawada, M. Ohmuraya, Motoki Tanaka, Kazuya Kuboyama, Takashi Ogino, M. Matsumoto, Hisashi Oishi, H. Inada, Yuri Ishido, Yukina Sakakibara, Huy Bang Nguyen, T. Q. Thai, S. Kohsaka, N. Ohno, M. Yamada, Masato Asai, M. Sokabe, J. Nabekura, K. Asano, Masato Tanaka, K. Sawamoto","doi":"10.1084/jem.20202304","DOIUrl":"https://doi.org/10.1084/jem.20202304","url":null,"abstract":"Mechanisms for synaptic pruning of adult-born neurons remain unknown. In this study, Kurematsu et al. demonstrate that phosphatidylserine is involved in microglial spine pruning and functional maturation of adult-born neurons in the olfactory bulb and hippocampus.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88354777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Allo-reactive tissue-resident T cells causing damage: An inside job","authors":"R. V. van Lier, P. Hombrink","doi":"10.1084/jem.20220121","DOIUrl":"https://doi.org/10.1084/jem.20220121","url":null,"abstract":"Using single-cell RNA and TCR sequencing, Snyder et al. show that during acute cellular rejection there is an allograft-specific clonal expansion of cytotoxic recipient-derived tissue resident memory T cells that are reprogrammed but persist despite high-dose glucocorticoid therapy.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78150230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen","authors":"Mingyu Liu, Chong Wu, Shufeng Luo, Qiaomin Hua, Hai-Tian Chen, Yulan Weng, Junyu Xu, Huiling Lin, Lu Wang, Jinheng Li, Lan Zhu, Zhenhong Guo, Shi‐Mei Zhuang, Tiebang Kang, Limin Zheng","doi":"10.1084/jem.20211498","DOIUrl":"https://doi.org/10.1084/jem.20211498","url":null,"abstract":"Liu et al. demonstrate that the PERK-triggered HSPC preconditioning in the spleen is essential for their myeloid descendant cells to become immune suppressors in response to subsequent tumor microenvironmental stimulation. A spleen-targeted PERK blockade could be an effective strategy of immunotherapy.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73964867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Martín-Fernández, S. Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, F. Vuillier, Lina Franklin, F. Ailal, Alice Muglia Amancio, L. Malle, C. Gruber, I. Benhsaien, J. Altman, J. Taft, C. Deswarte, Manon Roynard, A. Nieto-Patlán, K. Moriya, J. Rosain, N. Boddaert, A. Bousfiha, Y. Crow, Dragana Jankovic, A. Sher, J. Casanova, S. Pellegrini, J. Bustamante, D. Bogunovic
{"title":"A partial form of inherited human USP18 deficiency underlies infection and inflammation","authors":"M. Martín-Fernández, S. Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, F. Vuillier, Lina Franklin, F. Ailal, Alice Muglia Amancio, L. Malle, C. Gruber, I. Benhsaien, J. Altman, J. Taft, C. Deswarte, Manon Roynard, A. Nieto-Patlán, K. Moriya, J. Rosain, N. Boddaert, A. Bousfiha, Y. Crow, Dragana Jankovic, A. Sher, J. Casanova, S. Pellegrini, J. Bustamante, D. Bogunovic","doi":"10.1084/jem.20211273","DOIUrl":"https://doi.org/10.1084/jem.20211273","url":null,"abstract":"Martin-Fernandez et al. describe patients with partial USP18 deficiency, which underlies both type I interferonopathy and Mendelian susceptibility to mycobacterial disease (MSMD). This work delineates the lack of negative regulation of the IFN-I signaling pathway leading to depression of the IFN-γ–IL12 loop as a cause of MSMD.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81002460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Z. Fang, Yi Zhang, Zhaoqin Zhu, Cong Wang, Yao Hu, Xiuhua Peng, Dandan Zhang, Jun Zhao, Bisheng Shi, Zhongliang Shen, Min Wu, Chunhua Xu, Jieliang Chen, Xiaohui Zhou, Youhua Xie, Hui Yu, Xiaonan Zhang, Jianhua Li, Yun-wen Hu, M. Kozlowski, A. Bertoletti, Zhenghong Yuan
{"title":"Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV","authors":"Z. Fang, Yi Zhang, Zhaoqin Zhu, Cong Wang, Yao Hu, Xiuhua Peng, Dandan Zhang, Jun Zhao, Bisheng Shi, Zhongliang Shen, Min Wu, Chunhua Xu, Jieliang Chen, Xiaohui Zhou, Youhua Xie, Hui Yu, Xiaonan Zhang, Jianhua Li, Yun-wen Hu, M. Kozlowski, A. Bertoletti, Zhenghong Yuan","doi":"10.1084/jem.20211838","DOIUrl":"https://doi.org/10.1084/jem.20211838","url":null,"abstract":"HBV exposure in children usually causes chronic infection, and HBsAg-specific CD8+ T cells are rarely detected in this situation. We find that mMDSCs, cross-presenting HBsAg, migrate to the thymus and eliminate HBsAg-specific CD8+ thymocytes, resulting in a specific tolerance to HBV.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82016902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maxence Cornille, Stéphanie Moriceau, R. Khonsari, Y. Heuzé, L. Loisay, Valérie Boitez, A. Morice, Éric Arnaud, C. Collet, M. Bensidhoum, N. Kaci, N. Boddaert, G. Paternoster, T. Rauschendorfer, Sabine Werner, S. Mansour, F. Di Rocco, F. Oury, L. Legeai-Mallet
{"title":"FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model","authors":"Maxence Cornille, Stéphanie Moriceau, R. Khonsari, Y. Heuzé, L. Loisay, Valérie Boitez, A. Morice, Éric Arnaud, C. Collet, M. Bensidhoum, N. Kaci, N. Boddaert, G. Paternoster, T. Rauschendorfer, Sabine Werner, S. Mansour, F. Di Rocco, F. Oury, L. Legeai-Mallet","doi":"10.1084/jem.20201879","DOIUrl":"https://doi.org/10.1084/jem.20201879","url":null,"abstract":"FGFR3 gain-of-function mutation leads to learning and memory impairments independently of skull abnormalities. Cornille et al. suggest that modulation of the FGFR3 signaling pathway might be of value for treating the neurological and cognitive impairments observed in craniosynostosis.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86358329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Lorin, Ignacio Fernández, Guillemette Masse-Ranson, M. Bouvin-Pley, Luis M Molinos-Albert, C. Planchais, Thierry Hieu, G. Péhau-Arnaudet, D. Hrebík, Giulia Girelli-Zubani, O. Fiquet, F. Guivel-Benhassine, R. Sanders, B. Walker, O. Schwartz, J. Scheid, J. Dimitrov, P. Plevka, M. Braibant, M. Seaman, F. Bontems, J. D. Di Santo, F. Rey, H. Mouquet
{"title":"Epitope convergence of broadly HIV-1 neutralizing IgA and IgG antibody lineages in a viremic controller","authors":"V. Lorin, Ignacio Fernández, Guillemette Masse-Ranson, M. Bouvin-Pley, Luis M Molinos-Albert, C. Planchais, Thierry Hieu, G. Péhau-Arnaudet, D. Hrebík, Giulia Girelli-Zubani, O. Fiquet, F. Guivel-Benhassine, R. Sanders, B. Walker, O. Schwartz, J. Scheid, J. Dimitrov, P. Plevka, M. Braibant, M. Seaman, F. Bontems, J. D. Di Santo, F. Rey, H. Mouquet","doi":"10.1084/jem.20212045","DOIUrl":"https://doi.org/10.1084/jem.20212045","url":null,"abstract":"This study identifies a trio of broadly HIV-1 neutralizing IgA and IgG antibody lineages in a HIV-1 viremic controller that all target a unique viral site of vulnerability.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87226904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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