Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-04DOI: 10.1016/j.xcrm.2024.101845
Kadi Vaher, Manuel Blesa Cabez, Paula Lusarreta Parga, Justyna Binkowska, Gina J van Beveren, Mari-Lee Odendaal, Gemma Sullivan, David Q Stoye, Amy Corrigan, Alan J Quigley, Michael J Thrippleton, Mark E Bastin, Debby Bogaert, James P Boardman
{"title":"The neonatal gut microbiota: A role in the encephalopathy of prematurity.","authors":"Kadi Vaher, Manuel Blesa Cabez, Paula Lusarreta Parga, Justyna Binkowska, Gina J van Beveren, Mari-Lee Odendaal, Gemma Sullivan, David Q Stoye, Amy Corrigan, Alan J Quigley, Michael J Thrippleton, Mark E Bastin, Debby Bogaert, James P Boardman","doi":"10.1016/j.xcrm.2024.101845","DOIUrl":"10.1016/j.xcrm.2024.101845","url":null,"abstract":"<p><p>Preterm birth correlates with brain dysmaturation and neurocognitive impairment. The gut microbiome associates with behavioral outcomes in typical development, but its relationship with neurodevelopment in preterm infants is unknown. We characterize fecal microbiome in a cohort of 147 neonates enriched for very preterm birth using 16S-based and shotgun metagenomic sequencing. Delivery mode strongly correlates with the preterm microbiome shortly after birth. Low birth gestational age, infant sex assigned at birth, and antibiotics associate with microbiome composition at neonatal intensive care unit discharge. We integrate these data with term-equivalent structural and diffusion brain MRI. Bacterial community composition associates with MRI features of encephalopathy of prematurity. Particularly, abundances of Escherichia coli and Klebsiella spp. correlate with microstructural parameters in deep and cortical gray matter. Metagenome functional capacity analyses suggest that these bacteria may interact with brain microstructure via tryptophan and propionate metabolism. This study indicates that the gut microbiome associates with brain development following preterm birth.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101845"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784264","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-04DOI: 10.1016/j.xcrm.2024.101844
Shuchang Zhou, Weiwei Lin, Xiong Jin, Rui Niu, Zheng Yuan, Tianran Chai, Qi Zhang, Meixia Guo, Sung Soo Kim, Meichen Liu, Yilin Deng, Jong Bae Park, Sun Il Choi, Bingyang Shi, Jinlong Yin
{"title":"CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells.","authors":"Shuchang Zhou, Weiwei Lin, Xiong Jin, Rui Niu, Zheng Yuan, Tianran Chai, Qi Zhang, Meixia Guo, Sung Soo Kim, Meichen Liu, Yilin Deng, Jong Bae Park, Sun Il Choi, Bingyang Shi, Jinlong Yin","doi":"10.1016/j.xcrm.2024.101844","DOIUrl":"10.1016/j.xcrm.2024.101844","url":null,"abstract":"<p><p>Glioblastoma (GBM) stem cells (GSCs) contribute to poor prognosis in patients with GBM. Identifying molecular markers is crucial for developing targeted therapies. Here, we identify cluster of differentiation 97 (CD97) as an optimal GSC surface antigen for potential targeting by chimeric antigen receptor (CAR) T cell therapy through in vitro antibody screening. CD97 is consistently expressed in all validated patient-derived GSCs and positively correlated with known intracellular GSC markers. Silencing CD97 reduces GSC tumorigenicity-related activities, including self-renewal, proliferation, and tumor progression. Transcriptome analysis reveals that CD97 activates mTORC2, leading to AKT S473 phosphorylation and enhanced expression of the downstream genes ARHGAP1, BZW1, and BZW2. Inhibiting mTORC2 with JR-AB2-011 suppresses GSC tumorigenicity and downstream gene expression. We develop CD97-CAR T helper (Th) 9 cells, which exhibit potent cytotoxic effects in vitro and extend survival in mice. These findings suggest that CD97 is a promising GSC-enriched antigen and that targeting it with CAR Th9 cells offers a potential therapeutic strategy for GBM.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101844"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784258","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-11-29DOI: 10.1016/j.xcrm.2024.101839
Yukihiro Shiga, Aline Giselle Rangel Olguin, Sana El Hajji, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Luis Alarcon-Martinez, Arjun Krishnaswamy, Adriana Di Polo
{"title":"Endoplasmic reticulum stress-related deficits in calcium clearance promote neuronal dysfunction that is prevented by SERCA2 gene augmentation.","authors":"Yukihiro Shiga, Aline Giselle Rangel Olguin, Sana El Hajji, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Luis Alarcon-Martinez, Arjun Krishnaswamy, Adriana Di Polo","doi":"10.1016/j.xcrm.2024.101839","DOIUrl":"10.1016/j.xcrm.2024.101839","url":null,"abstract":"<p><p>Disruption of calcium (Ca<sup>2+</sup>) homeostasis in neurons is a hallmark of neurodegenerative diseases. Here, we investigate the mechanisms leading to Ca<sup>2+</sup> dysregulation and ask whether altered Ca<sup>2+</sup> dynamics impinge on neuronal stress and circuit dysfunction. Using two-photon microscopy, we show that ocular hypertension, a major risk factor in glaucoma, and optic nerve crush injury disrupt the capacity of retinal neurons to clear cytosolic Ca<sup>2+</sup> leading to impaired light-evoked responses. Gene- and protein expression analysis reveal the loss of the sarco-endoplasmic reticulum (ER) Ca<sup>2+</sup>-ATPase2 pump (SERCA2/ATP2A2) in injured retinal neurons from mice and patients with primary open-angle glaucoma. Pharmacological activation or neuron-specific gene delivery of SERCA2 is sufficient to rescue single-cell Ca<sup>2+</sup> dynamics and promote robust survival of damaged neurons. Furthermore, SERCA2 gene supplementation reduces ER stress, reestablishes circuit balance, and restores visual behaviors. Our findings reveal that enhancing the Ca<sup>2+</sup> clearance capacity of vulnerable neurons alleviates organelle stress and promotes neurorecovery.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101839"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766761","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-02DOI: 10.1016/j.xcrm.2024.101840
Jiangnan Zhang, Yunhan Jiang, Dongmei Fan, Zhiqiang Qiu, Xinlian He, Song Liu, Linjie Li, Zhengyi Dai, Lidan Zhang, Ziyi Shu, Lili Li, Hu Zhang, Tao Yang, Youfu Luo
{"title":"Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4<sup>+</sup> T cell for inflammatory bowel diseases treatment.","authors":"Jiangnan Zhang, Yunhan Jiang, Dongmei Fan, Zhiqiang Qiu, Xinlian He, Song Liu, Linjie Li, Zhengyi Dai, Lidan Zhang, Ziyi Shu, Lili Li, Hu Zhang, Tao Yang, Youfu Luo","doi":"10.1016/j.xcrm.2024.101840","DOIUrl":"10.1016/j.xcrm.2024.101840","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is an autoimmune disorder, and despite the availability of multiple Food and Drug Administration (FDA)-approved therapies, current clinical needs remain unmet. In this study, we find that caseinolytic protease P (ClpP) expression is markedly upregulated in colonic tissues from IBD patients and preclinical colitis models, particularly in CD4<sup>+</sup> T cells. Subsequently, a small molecule, namely NCA029, is identified, and its therapeutic efficacy and mechanism of action are investigated both in vitro and in vivo. Oral administration of NCA029 significantly alleviates symptoms associated with dextran sulfate sodium (DSS)-induced acute and interleukin (IL)-10-deficient chronic colitis. The effects of NCA029 are largely dependent on its selective binding to ClpP in CD4<sup>+</sup> T cells, thereby mitigating inflammation and restoring intestinal barrier function. Furthermore, NCA029 activates ClpP to promote oxidative phosphorylation (OXPHOS) inhibition and concomitantly modulate the Th17/Treg balance. In conclusion, our study develops a therapeutic strategy for treating IBD through the chemical activation of ClpP.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101840"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766773","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-09DOI: 10.1016/j.xcrm.2024.101849
Kylie A Alexander, Hsu-Wen Tseng, Hong Wa Lao, Dorothée Girard, Valérie Barbier, Jacobus P J Ungerer, Brett C McWhinney, Selwin G Samuel, Whitney Fleming, Ingrid G Winkler, Marjorie Salga, François Genêt, Sébastien Banzet, Marc J Ruitenberg, Jean-Pierre Lévesque
{"title":"A glucocorticoid spike derails muscle repair to heterotopic ossification after spinal cord injury.","authors":"Kylie A Alexander, Hsu-Wen Tseng, Hong Wa Lao, Dorothée Girard, Valérie Barbier, Jacobus P J Ungerer, Brett C McWhinney, Selwin G Samuel, Whitney Fleming, Ingrid G Winkler, Marjorie Salga, François Genêt, Sébastien Banzet, Marc J Ruitenberg, Jean-Pierre Lévesque","doi":"10.1016/j.xcrm.2024.101849","DOIUrl":"10.1016/j.xcrm.2024.101849","url":null,"abstract":"<p><p>Why severe injury to the central nervous system (CNS) triggers the development of large neurogenic heterotopic ossifications (NHOs) within periarticular muscles remains unknown. We report that spinal cord injury (SCI) triggers a rapid corticosterone spike in mice, which is causal for NHO development because treatments with corticosterone or the synthetic glucocorticoid (GC) receptor (GR) agonist dexamethasone are sufficient to trigger heterotopic ossification and upregulate the expression of osteoinductive and osteogenic differentiation genes in injured muscles even without SCI. The central role for GR signaling in causing NHO is further demonstrated in mice deleted for the GR gene (Nr3c1), which no longer develop NHO after SCI. Furthermore, administration of clinical GR antagonists inhibits NHO development in mice with SCI. This study identifies endogenous GC as causing pathological NHO after CNS injury and suggests that GR antagonists may be of prophylactic use to prevent NHO development in victims of severe CNS injuries.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101849"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805779","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-09DOI: 10.1016/j.xcrm.2024.101868
Ilya S Senatorov, Joel Bowman, Keith H Jansson, Aian Neil Alilin, Brian J Capaldo, Ross Lake, Morgan Riba, Yasmine C Abbey, Crystal Mcknight, Xiaohu Zhang, Sonam Raj, Michael L Beshiri, Paul Shinn, Holly Nguyen, Craig J Thomas, Eva Corey, Kathleen Kelly
{"title":"Castrate-resistant prostate cancer response to taxane is determined by an HNF1-dependent apoptosis resistance circuit.","authors":"Ilya S Senatorov, Joel Bowman, Keith H Jansson, Aian Neil Alilin, Brian J Capaldo, Ross Lake, Morgan Riba, Yasmine C Abbey, Crystal Mcknight, Xiaohu Zhang, Sonam Raj, Michael L Beshiri, Paul Shinn, Holly Nguyen, Craig J Thomas, Eva Corey, Kathleen Kelly","doi":"10.1016/j.xcrm.2024.101868","DOIUrl":"10.1016/j.xcrm.2024.101868","url":null,"abstract":"<p><p>Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We perform a high-throughput screen across a cohort of 30 diverse patient-derived castrate-resistant prostate cancer (CRPC) organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrates that HNF1 homeobox A (HNF1A) drives a transcriptional program of taxane resistance, commonly dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 is sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel. These data may be useful in future clinical trial designs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101868"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805821","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-02DOI: 10.1016/j.xcrm.2024.101835
Win Min Han, Hossain M S Sazzad, Mark Bloch, David A Baker, Norman Roth, Ellen Bowden-Reid, Don E Smith, Jennifer F Hoy, Ian Woolley, Robert Finlayson, David J Templeton, Gail V Matthews, Jane Costello, Mark A Dawson, Sarah-Jane Dawson, Mark N Polizzotto, Kathy Petoumenos, Paul Yeh, Nila J Dharan
{"title":"Age-related clonal hematopoiesis and HIV infection are associated with geriatric outcomes: The ARCHIVE study.","authors":"Win Min Han, Hossain M S Sazzad, Mark Bloch, David A Baker, Norman Roth, Ellen Bowden-Reid, Don E Smith, Jennifer F Hoy, Ian Woolley, Robert Finlayson, David J Templeton, Gail V Matthews, Jane Costello, Mark A Dawson, Sarah-Jane Dawson, Mark N Polizzotto, Kathy Petoumenos, Paul Yeh, Nila J Dharan","doi":"10.1016/j.xcrm.2024.101835","DOIUrl":"10.1016/j.xcrm.2024.101835","url":null,"abstract":"<p><p>While HIV infection and clonal hematopoiesis (CH) have been linked with inflammatory dysregulation and an increased risk of aging-related comorbidities, their relationship with clinical geriatric syndromes has not been well defined. In the Age-related Clonal Haematopoiesis in an HIV Evaluation Cohort (ARCHIVE) study (NCT04641013), we measure associations between HIV and CH and geriatric syndromes. Of 345 participants (176 with HIV and 169 without HIV), 23% had at least one mutation associated with CH: 27% with HIV and 18% without HIV (p = 0.048). In adjusted analyses, HIV infection is independently associated with increased phenotypic age acceleration (coefficient 1.73, 95% confidence interval [CI] 0.3, 3.16) and CH is independently associated with being frail (vs. pre-frail/robust; odds ratio 2.38, 95% CI 1.01, 5.67) and with having reduced quality of life (coefficient -2.18, 95% CI -3.92, -0.44). Our findings suggest that HIV is associated with increased biological age and that CH may be used as a biomarker for adverse geriatric outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101835"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766703","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}
{"title":"Interpretable multi-modal artificial intelligence model for predicting gastric cancer response to neoadjuvant chemotherapy.","authors":"Peng Gao, Qiong Xiao, Hui Tan, Jiangdian Song, Yu Fu, Jingao Xu, Junhua Zhao, Yuan Miao, Xiaoyan Li, Yi Jing, Yingying Feng, Zitong Wang, Yingjie Zhang, Enbo Yao, Tongjia Xu, Jipeng Mei, Hanyu Chen, Xue Jiang, Yuchong Yang, Zhengyang Wang, Xianchun Gao, Minwen Zheng, Liying Zhang, Min Jiang, Yuying Long, Lijie He, Jinghua Sun, Yanhong Deng, Bin Wang, Yan Zhao, Yi Ba, Guan Wang, Yong Zhang, Ting Deng, Dinggang Shen, Zhenning Wang","doi":"10.1016/j.xcrm.2024.101848","DOIUrl":"10.1016/j.xcrm.2024.101848","url":null,"abstract":"<p><p>Neoadjuvant chemotherapy assessment is imperative for prognostication and clinical management of locally advanced gastric cancer. We propose an incremental supervised contrastive learning model (iSCLM), an interpretable artificial intelligence framework integrating pretreatment CT scans and H&E-stained biopsy images, for improved decision-making regarding neoadjuvant chemotherapy. We have constructed and tested iSCLM using retrospective data from 2,387 patients across 10 medical centers and evaluated its discriminative ability in a prospective cohort (132 patients; ChiCTR2300068917). iSCLM achieves areas under receiver operating characteristic curves of 0.846-0.876 across different test cohorts. Computed tomography (CT) and pathological attention heatmaps from Shapley additive explanations and global sort pooling illustrate additional benefits for capturing morphological features through supervised contrastive learning. Specifically, pathological top-ranked tiles exhibit decreased distances to tumor-invasive borders and increased inflammatory cell infiltration in responders compared with non-responders. Moreover, CD11c expression is elevated in responders. The developed interpretable model at the molecular pathology level accurately predicts chemotherapy efficacy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101848"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784260","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-11-26DOI: 10.1016/j.xcrm.2024.101830
Anna C Beielstein, Elena Izquierdo, Stuart Blakemore, Nadine Nickel, Michael Michalik, Samruddhi Chawan, Reinhild Brinker, Hans-Henrik Bartel, Daniela Vorholt, Lukas Albert, Janica L Nolte, Rebecca Linke, Carolina Raíssa Costa Picossi, Jorge Sáiz, Felix Picard, Alexandra Florin, Jörn Meinel, Reinhard Büttner, Paul Diefenhardt, Sebastian Brähler, Alma Villaseñor, Holger Winkels, Michael Hallek, Marcus Krüger, Coral Barbas, Christian P Pallasch
{"title":"Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition.","authors":"Anna C Beielstein, Elena Izquierdo, Stuart Blakemore, Nadine Nickel, Michael Michalik, Samruddhi Chawan, Reinhild Brinker, Hans-Henrik Bartel, Daniela Vorholt, Lukas Albert, Janica L Nolte, Rebecca Linke, Carolina Raíssa Costa Picossi, Jorge Sáiz, Felix Picard, Alexandra Florin, Jörn Meinel, Reinhard Büttner, Paul Diefenhardt, Sebastian Brähler, Alma Villaseñor, Holger Winkels, Michael Hallek, Marcus Krüger, Coral Barbas, Christian P Pallasch","doi":"10.1016/j.xcrm.2024.101830","DOIUrl":"10.1016/j.xcrm.2024.101830","url":null,"abstract":"<p><p>Macrophages in the B cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition induces increased phagocytic lymphoma cell clearance by macrophages in vitro, in primary human chronic lymphocytic leukemia (CLL) patient co-cultures, and in mouse models. Addition of the PPP inhibitor S3 to antibody therapy achieves significantly prolonged overall survival in an aggressive B cell lymphoma mouse model. PPP inhibition induces metabolic activation and pro-inflammatory polarization of macrophages while it decreases macrophages' support for survival of lymphoma cells empowering anti-lymphoma function. As a mechanism of macrophage repolarization, the link between PPP and immune regulation was identified. PPP inhibition causes decreased glycogen level and subsequent modulation of the immune modulatory uridine diphosphate glucose (UDPG)-Stat1-Irg1-itaconate axis. Thus, we hypothesize the PPP as a key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies and prolong survival.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101830"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738486","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}
Cell Reports MedicinePub Date : 2024-12-17Epub Date: 2024-12-09DOI: 10.1016/j.xcrm.2024.101871
Andrew S Perry, Niran Hadad, Emeli Chatterjee, Maria Jimenez-Ramos, Eric Farber-Eger, Rashedeh Roshani, Lindsey K Stolze, Michael J Betti, Shilin Zhao, Shi Huang, Liesbet Martens, Timothy J Kendall, Tinne Thone, Kaushik Amancherla, Samuel Bailin, Curtis L Gabriel, John Koethe, J Jeffrey Carr, James Greg Terry, Nataraja Sarma Vaitinadin, Jane E Freedman, Kahraman Tanriverdi, Eric Alsop, Kendall Van Keuren-Jensen, John F K Sauld, Gautam Mahajan, Sadiya S Khan, Laura Colangelo, Matthew Nayor, Susan Fisher-Hoch, Joseph B McCormick, Kari E North, Jennifer E Below, Quinn S Wells, E Dale Abel, Ravi Kalhan, Charlotte Scott, Martin Guilliams, Eric R Gamazon, Jonathan A Fallowfield, Nicholas E Banovich, Saumya Das, Ravi Shah
{"title":"A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.","authors":"Andrew S Perry, Niran Hadad, Emeli Chatterjee, Maria Jimenez-Ramos, Eric Farber-Eger, Rashedeh Roshani, Lindsey K Stolze, Michael J Betti, Shilin Zhao, Shi Huang, Liesbet Martens, Timothy J Kendall, Tinne Thone, Kaushik Amancherla, Samuel Bailin, Curtis L Gabriel, John Koethe, J Jeffrey Carr, James Greg Terry, Nataraja Sarma Vaitinadin, Jane E Freedman, Kahraman Tanriverdi, Eric Alsop, Kendall Van Keuren-Jensen, John F K Sauld, Gautam Mahajan, Sadiya S Khan, Laura Colangelo, Matthew Nayor, Susan Fisher-Hoch, Joseph B McCormick, Kari E North, Jennifer E Below, Quinn S Wells, E Dale Abel, Ravi Kalhan, Charlotte Scott, Martin Guilliams, Eric R Gamazon, Jonathan A Fallowfield, Nicholas E Banovich, Saumya Das, Ravi Shah","doi":"10.1016/j.xcrm.2024.101871","DOIUrl":"10.1016/j.xcrm.2024.101871","url":null,"abstract":"<p><p>Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized \"liver-on-a-chip\" model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic \"liquid biopsy\" of human liver, relevant to biomarker discovery and mechanistic research applications.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101871"},"PeriodicalIF":11.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11722105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805908","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}
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