Pub Date : 2022-04-04Epub Date: 2022-03-09DOI: 10.1084/jem.20210739
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
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.
{"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}
Yawen Chen, Xianwei Wang, Xiaolei Hao, Bin Li, Wanyin Tao, Shu Zhu, K. Qu, Haiming Wei, R. Sun, Hui Peng, Z. Tian
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.
{"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
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.
{"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}
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.
{"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}
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.
{"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}
A. Giordano, M. Luciani, F. Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia Della Volpe, A. Migliara, Sara Valsoni, M. Genua, M. Dzieciatkowska, Giacomo Frati, Julie Tahraoui-Bories, S. Giliani, S. Orcesi, E. Fazzi, Renato Ostuni, Angelo D’Alessandro, Raffaella Di Micco, I. Merelli, A. Lombardo, Martin A. M. Reijns, N. Gromak, A. Gritti, A. Kajaste-Rudnitski
Giordano et al. establish human AGS iPSC-based models of TREX1 or RNASEH2B deficiencies. They uncover DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes that can be uncoupled from aberrant type I IFN responses and identify novel targets to curtail AGS neuroinflammation.
{"title":"DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes","authors":"A. Giordano, M. Luciani, F. Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia Della Volpe, A. Migliara, Sara Valsoni, M. Genua, M. Dzieciatkowska, Giacomo Frati, Julie Tahraoui-Bories, S. Giliani, S. Orcesi, E. Fazzi, Renato Ostuni, Angelo D’Alessandro, Raffaella Di Micco, I. Merelli, A. Lombardo, Martin A. M. Reijns, N. Gromak, A. Gritti, A. Kajaste-Rudnitski","doi":"10.1084/jem.20211121","DOIUrl":"https://doi.org/10.1084/jem.20211121","url":null,"abstract":"Giordano et al. establish human AGS iPSC-based models of TREX1 or RNASEH2B deficiencies. They uncover DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes that can be uncoupled from aberrant type I IFN responses and identify novel targets to curtail AGS neuroinflammation.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"209 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73038358","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
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.
Martin-Fernandez等人描述了部分USP18缺乏的患者，这是I型干扰素病和分枝杆菌病(MSMD)孟德尔易感性的基础。这项工作描述了缺乏IFN- i信号通路的负调控，导致IFN-γ - il - 12环路的抑制，这是MSMD的原因之一。
{"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
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.
{"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
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.
{"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
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.
{"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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