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Abstract
Periodontal disease, a bacterial infection affecting a large percentage of the world's population, is an important risk factor for several systemic diseases and is significantly worsened by diabetes. To investigate how diabetes exacerbates the inflammatory response to bacteria in this disease, we combined insights from murine and human studies. Through single-cell RNA sequencing, we identified a compelling hyperglycemia-driven molecular pathway: the upregulation of CD137L in dendritic cells and increased expression of its receptor, CD137, in γδ T-cells. The CD137L-CD137 axis emerged as a pivotal mediator of diabetes-induced inflammatory tissue destruction. Antibody-mediated inhibition of CD137L markedly reduced the diabetes-driven bone loss, neutrophil recruitment, expansion of γδ T-cells, and excessive infiltration by IL17A+ cells. In vitro studies further validated these findings and established that high glucose-mediated dysregulation of dendritic cells dramatically altered γδ T-cell activity in co-culture systems via CD137L. The essential role of dendritic cells as CD137L producers in vivo was definitively established through lineage-specific Akt1 deletion, which abrogated CD137L expression in these cells and reversed the adverse effects of hyperglycemia on leukocyte responses to bacterial pathogens in vivo. Conversely, activation of CD137 with an agonist in normal animals recapitulated diabetes-induced abnormalities in the inflammatory response and accelerated bone loss. These findings elucidate a key mechanism underlying diabetes-induced immune dysregulation and inflammatory damage, and point to the CD137L-CD137 pathway as a promising therapeutic target, offering potential insights into mitigating other diabetes-associated complications linked to inflammatory changes.
Authors
Xin Huang, Min Liu, Michael V. Gonzalez, Rahul Debnath, Hamideh Afzali, Yongwon Choi, Su Ah Kim, Kang I. Ko, Dana T. Graves
Abstract
KRAS mutations serve as key oncogenic drivers in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Despite the advancement of KRAS inhibitors like MRTX1133 for PDAC treatment, intrinsic and acquired resistance remain major barriers to their clinical efficacy. This study underscored the role of histone deacetylase 5 (HDAC5) loss in mediating intrinsic resistance to KRASG12D inhibitors. Mechanistically, HDAC5 promoted c-Myc degradation by deacetylating K148, thereby facilitating NEDD4-mediated ubiquitination at this site. The loss of HDAC5 resulted in hyperacetylation of c-Myc at K148, impeding the ubiquitination and subsequent degradation process of c-Myc following deacetylation. Consequently, c-Myc stability and transcriptional activity were sustained even under KRAS-MEK-ERK pathway inhibition, reinforcing MAPK signaling and promoting cell survival despite KRAS suppression. Our data further demonstrated that pharmacological or genetic inhibition of c-Myc effectively reversed the resistance phenotype mediated by HDAC5 loss, suggesting a therapeutic strategy centered on "KRAS-MYC dual-node blockade." Furthermore, the expression levels of HDAC5 and the acetylation status of c-Myc may serve as potential biomarkers for predicting the therapeutic response to MRTX1133. These findings provide insights into overcoming resistance to KRASG12D inhibitors and offer potential biomarkers and combinatorial therapeutic strategies for precision treatment of PDAC.
Authors
Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou
Abstract
BACKGROUND. Among antiretroviral therapy (ART)-suppressed people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the broader effect of sex on the inflammatory proteome, and whether these differences are modified by age, remains unclear. METHODS. 363 plasma inflammatory protein levels (Olink Inflammation Explore) were assessed in ART-suppressed PWH sampled from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). The relationship between sex and 363 plasma proteins – including 22 in the interferon-α response pathway – was assessed with linear regression models adjusting for confounders, assessing interactions by age. FINDINGS. Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age impacted the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 (P = 0.024), but higher in women in those > 47 (P = 0.005, p-interaction < 0.001). Among the 131 proteins associated with mortality risk (q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women . Women had decreased mortality than men ≤47 (P < 0.001) but had similar mortality > 47 (P = 0.84). INTERPRETATION. The menopausal transition appears to have a dramatic effect on systemic Type I interferon responses and the broader inflammatory proteome in women with HIV. Among older PWH, women have greater inflammation than men, including the majority of proteins linked with mortality risk.
Authors
Rebecca A. Abelman, Samuel R. Schnittman, Natalia Faraj Murad, Adam Olshen, Gabriele B. Beck-Engeser, Noah Aquino, Gabrielle C. Ambayec, Edward R. Cachay, Joseph J. Eron, Michael Saag, Robin M. Nance, Joseph A. Delaney, Stephanie A. Ruderman, Richard D. Moore, Kenneth H. Mayer, Jeffrey M. Jacobson, Heidi M. Crane, Peter W. Hunt
Abstract
Autoimmune factor XIII (FXIII) deficiency is a rare hemorrhagic disease characterized by severe bleeding and a high mortality rate. However, the pathogenesis of this disease remains unclear. Currently, FXIII consumption caused by infections is becoming increasingly common. Our clinical investigation, combined with in vivo experiments, revealed that patients and mice with autoimmune FXIII deficiency displayed complement dysfunction, and that pathogenic infection and autoantibody generation were positively correlated. Further analysis revealed the presence of combined FXIII-C3 autoantibodies in patients with autoimmune FXIII deficiency. These combined autoantibodies neutralize FXIII, causing excessive bleeding, and form a complex with C3, inhibiting complement activation and complement-mediated adaptive immune responses. Therefore, compromised immune responses increase host susceptibility to pathogenic Candida albicans infections. Consequently, uncontrolled exogenous fungal infections further activate platelets and cause platelet-related CD40 ligand (CD40L) release. By interacting with the CD40 on the B cell surface, the released CD40L further promotes auto-reactive B cell activation to produce more autoantibodies, thereby forming a self-amplification loop for the progressive consumption of FXIII. We believe that this study provides a perspective on disease pathogenesis and therapeutic guidance for better treatment of autoimmune FXIII deficiency.
Authors
Shanshan Luo, Jun Deng, Yue Liu, Lv Xiong, Wanting Wang, Chaofan Wang, Yaohua Cai, Yajie Ding, Bahgat Fayed, Zhipeng Cheng, Lu Zhang, Min Zhang, Jun Fang, Gensheng Zhang, Rui Zhu, Haiqiang Jiang, Yunlun Li, Kun Huang, Xiang Cheng, Liang V. Tang, Chunyan Sun, Heng Mei, Peter F. Zipfel, Huafang Wang, Yadan Wang, Desheng Hu, Yu Hu
Abstract
The role of the tumor immune microenvironment (TIME) in modulating responses to antiestrogen therapy in hormone receptor-positive (HR+) breast cancers remains unclear. We analyzed pre- and on-treatment biopsies from patients with HR+ breast cancer treated with letrozole to induce estrogen deprivation (ED). Stromal tumor-infiltrating lymphocytes, assessed by H&E-staining, and immune-related gene sets, including IFNɣ signaling, measured by RNA sequencing, were increased in ED-resistant tumors. Cyclic immunofluorescence and spatial transcriptomics revealed an abundance of CD8+ T cells and enhanced antigen processing and immune gene signatures in ED-resistant tumors. In this group, the expression of CXCL9, CXCL10, and CXCL11 — chemokine genes involved in CD8+ T cell recruitment — and the CXCR3 receptor were upregulated both before and after letrozole. CXCL11 levels were higher in conditioned media from HR+ breast cancer cells co-cultured with CD8+ T cells. Both recombinant CXCL11 and co-culture with CD8+ T cells promoted MCF7 and T47D cell growth in estrogen-free conditions. Finally, deletion combined with silencing of the CXCL11 receptors CXCR3 and CXCR7 in MCF7 cells impaired proliferation in response to exogenous CXCL11 and to co-culture with CD8+ T cells in estrogen-free conditions. These findings suggest that CD8+ T cell-associated CXCL11 in the TIME modulates the response of HR+ breast cancer cells to estrogen suppression.
Authors
Fabiana Napolitano, Yunguan Wang, Dhivya R. Sudhan, Paula I. Gonzalez-Ericsson, Luigi Formisano, Nisha Unni, Shahbano Shakeel, James Z. Zhu, Khushi Ahuja, Lei Guo, María Rosario Chica-Parrado, Yuki Matsunaga, Pamela Luna, Chang-Ching A. Lin, Yasuaki Uemoto, Kyung-Min Lee, Hongli Ma, Nathaniel J. Evans, Alberto Servetto, Saurabh Mendiratta, Spencer D. Barnes, Roberto Bianco, Yisheng V. Fang, Lin Xu, Jeon Lee, Tao Wang, Justin M. Balko, Gordon B. Mills, Marilyne Labrie, Ariella B. Hanker, Carlos L. Arteaga
Abstract
Adoptive cell therapy (ACT) relies on durable and functional T cells to mediate tumor clearance. Th9 cells are a metabolically fit CD4+ T cell subset with strong persistence but limited cytotoxicity. Here, we identified endomelipeptide A (EpA), a cyclic peptide isolated from Ganoderma lucidum–associated endophytic fungi, as a potent enhancer of Th9 differentiation. EpA promoted a cytotoxic Th9 phenotype with enhanced mitochondrial function and metabolic fitness. Mechanistically, EpA dually targeted ZAP70 and SREBP1, coupling T cell receptor (TCR) signaling activation with lipid metabolism suppression. EpA-treated Th9 cells mediated robust, CD8+ T cell–dependent tumor control and enhanced the efficacy of human Th9 CAR-T therapy in vivo. These findings establish EpA as a distinct cyclic peptide that reprograms Th9 cells and provides a potential approach to boost ACT efficacy.
Authors
Wenli Zhao, Yang Zhou, Yuyang Chen, Yicheng Sun, Jiaxin Tang, Yihan Zhu, Jie Ren, Tianxu Du, Handuo Wang, Yuan Gao, Yu Hu, Ling Jiang, Tomohiko Ohwada, Qi Luo, Enguang Bi
Abstract
Vinculin (VCL), a linker between cells and their environment, has rarely been linked to disease. This study examines the role of VCL in the development of the enteric nervous system (ENS) and its relationship to Hirschsprung disease (HSCR). Using whole-genome sequencing and in vitro assays, we identified four VCL mutations associated with HSCR, most causing loss of function. Neural crest-specific Vcl knock-out mice (Vcl cKO) displayed ENS defects resembling short-segment HSCR, including partial colonic aganglionosis and abnormal gut musculature. Single-cell transcriptomics revealed dysregulation of genes involved in neuronal differentiation and MAPK signaling. Spatial RNA sequencing revealed reduced ENS-mesenchyme interactions in Vcl cKO mice, accompanied by significant disruption of the Pleiotrophin (PTN) pathway; Ptn knock-out mice exhibited phenotypes similar to those of Vcl cKO mice, underscoring the importance of ENS-mesenchyme crosstalk. VCL works as a hub gene crucial for cell connection and signaling pathways essential for ENS formation. VCL deficiency subtly impacts various developmental stages and neighboring cells, cumulatively leading to a phenotype similar to short-segment HSCR. This research highlights the role of VCL in maintaining cellular interactions and signaling pathways, such as MAPK and PTN, which are crucial for ENS development and may inform therapeutic targets for ENS disorders.
Authors
Lifang Liu, Xixin Wang, Mingxuan Liang, Peiting Li, Cindy Yifei Yan, Patrick Ho-Yu Chung, Kenneth Kak-Yuen Wong, Asif Javed, Maria-Mercedes Garcia-Barcelo, Elly Sau-Wai Ngan
Abstract
EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist Osimertinib (Osi) eventually relapse owing in part to the emergence of drug tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intra-tumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-to-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell lines in which drug naive (DN) cells were rendered OR by chronic exposure to escalating doses of Osi. Co-cultured in vitro or co-injected into mice, paracrine signals from OR cells enhanced the growth and metastatic properties of DN cells. EMT and senescence activated non-overlapping secretomes, and OR cells governed DN cells by undergoing EMT but not senescence. Mechanistically, Osi rapidly increased TGFβ2 levels to initiate EMT, which triggered a Golgi remodeling process that accelerated the biogenesis and anterograde trafficking of secretory vesicles. The pro-tumorigenic activity of OR cells was diminished by depletion of EMT-dependent secreted proteins or the EMT-activating transcription factor ZEB1. These findings identify paracrine mechanisms by which OR cells drive LUAD progression.
Authors
Madhurima Ghosh, Chao Wu, Abhishek Kumar, Monique B. Nilsson, John V. Heymach, Weina Zhao, Jiang Yu, Xin Liu, Na Ding, Shike Wang, Guan-Yu Xiao, Angelo Chen, Kate V. Grimley, William K. Russell, Chad J. Creighton, Xiaochao Tan, Jonathan M. Kurie
Abstract
Androgen deprivation therapy is the primary treatment for advanced prostate tumors. While initially effective, tumor progression to the therapy-resistant stage is inevitable. Paradoxically, UDP-glucuronosyltransferase 2B17 (UGT2B17), the key enzyme responsible for androgen catabolism in prostate tumor cells, is upregulated in therapy-resistant tumors, though its role in tumor progression remains unclear. Here, we demonstrate that UGT2B17 possesses multiple oncogenic functions independent of androgen catabolism. It modulates protein-folding pathways, allowing tumor cells to endure therapy-induced stress. UGT2B17 also regulates transcription associated with cell division and the DNA damage response, enabling unchecked cell proliferation. Targeting the newly identified UGT2B17 functions using a combination of inhibitors reduces tumor growth in therapy-resistant tumor models, highlighting a promising therapeutic strategy. Collectively, these findings reveal a mechanism by which prostate tumors exploit UGT2B17 to evade therapy and highlight its potential as a therapeutic target in advanced prostate cancer.
Authors
Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong
Abstract
BACKGROUND. Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study. METHODS. We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI). RESULTS. Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort. CONCLUSIONS. Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness. FUNDING. This work is the result of NIH funding.
Authors
Narges Alipanah-Lechner, Lucile Neyton, Pratik Sinha, Carolyn Leroux, Kim Bardillon, Sidney A. Carrillo, Suzanna Chak, Olivia Chao, Taarini Hariharan, Carolyn Hendrickson, Kirsten Kangelaris, Charles R. Langelier, Deanna Lee, Chelsea Lin, Kathleen Liu, Liam Magee, Angelika Ringor, Aartik Sarma, Emma Schmiege, Natasha Spottiswoode, Kathryn Sullivan, Melanie F. Weingart, Andrew Willmore, Hanjing Zhuo, Angela J. Rogers, Kathleen A. Stringer, Michael A. Matthay, Carolyn S. Calfee
Abstract
GATA6 is a master regulator of differentiation in the pancreas and its expression levels determine the two main molecular subtypes of pancreatic cancer. High GATA6 contributes to the “classical” pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why GATA6 expression varies across pancreatic cancers and what regulate GATA6 expression remain elusive. Here we report that the oncogenic KRAS-activated ERK signaling suppresses GATA6 transcription in pancreatic cancers. GATA6 mRNA levels inversely correlated with KRAS/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a GATA6-EGFP reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for GATA6. Active ERK stabilizes JUNB protein while KRAS/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of GATA6. Up-regulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells and KRAS/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS/ERK signaling suppresses GATA6 to cause dedifferentiation in pancreatic cancer. Combining KRAS/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.
Authors
Zheng Zhong, Xinang Cao, Pei-Ju Liao, Raman Sethi, Jeffrey A. Klomp, Clint A. Stalnecker, Jinmiao Chen, Yue Wan, Channing J. Der, David M. Virshup
Abstract
During vascular injury, platelets are essential for halting bleeding and recruiting neutrophils to prevent microbial invasion. However, in antibody-mediated autoimmune diseases occurring without vascular damage, neutrophils infiltrate tissues and contribute to pathology. Here, we investigated whether the dependence of neutrophils on platelets is conserved in the context of antibody-driven inflammation. Using human cells from individuals with rheumatoid arthritis and a microfluidic system mimicking physiological shear over IgG-containing immune complexes, we demonstrate that despite expressing Fc receptors, neutrophils require platelets to stably adhere to immune complexes under flow. Platelet FcγRIIA binding was critical for resisting shear stress, while neutrophils used FcγRIIA and FcγRIIIB for immune complex recognition. Platelet P-selectin binding to neutrophil PSGL-1 was essential for recruitment, whereas Mac-1 was dispensable. In a mouse model of autoantibody-mediated arthritis, intravital imaging confirmed that neutrophil recruitment critically relies on PSGL-1. Importantly, expression of FcyRIIA aggravated arthritis, and blockade of PSGL-1 in these mice, but not of Mac-1, abrogated both the platelet and neutrophil interactions and disease. These findings identify key molecular interactions in platelet–neutrophil cooperation and reveal that platelets are essential enablers of FcR-mediated neutrophil adhesion in antibody-driven inflammation.
Authors
Marie Bellio, Isabelle Allaeys, Etienne Doré, Myriam Vaillancourt, Tania Lévesque, Mélina Monteil, Nicolas Vallières, Philippe Desaulniers, Nicolas Bertrand, Valance A. Washington, Yotis Senis, Steve Lacroix, Paul Fortin, Clémence Belleannée, Eric Boilard
Abstract
The role of CARD9 in the pathogenesis of various chronic fungal infections has been established; however, the precise mechanisms underlying the pathobiology of these infections remain unclear. We aimed to investigate the specific cellular mechanisms by which CARD9 deficiency contributes to the pathogenesis of chronic fungal infections. Using single-cell RNA sequencing (scRNA-seq), we analyzed the immune cell profiles in skin lesions from both murine and human samples. We focused on macrophage differentiation and signaling pathways influenced by CARD9 deficiency. We found that CARD9 deficiency promotes the differentiation of TREM2high macrophages following fungal stimulation, impairing their antifungal functions and inducing exhaustion-like T helper 1 (Th1) cells. Mechanistically, the NF-κB pathway activation was restricted in CARD9-deficient macrophages, leading to enhanced CREB activation, which in turn exerted a positive regulatory effect on Trem2 expression by activating C/EBPβ. Notably, targeting TREM2 enhanced the antifungal immune response in vivo and in vitro, thereby alleviating the severity of CARD9-deficient subcutaneous dematiaceous fungal infection. Our findings highlight the important role of CARD9 in regulating cutaneous antifungal immunity and identify potential targets for immunotherapy in chronic dematiaceous fungal infections.
Authors
Lu Zhang, Zhichun Tang, Yi Zhang, Wenjie Liu, Haitao Jiang, Li Yu, Kexin Lei, Yubo Ma, Yang-xin Fu, Ruoyu Li, Wenyan Wang, Fan Bai, Xiaowen Wang
Abstract
Emerging evidence demonstrates that chronic stress alters immunological, neurochemical and endocrinological functions, thereby promoting tumor progression. However, the underlying metabolic mechanism of chronic stress in tumor progression is still elusive. Using multi-omics analysis, we found that aminopeptidase N (ANPEP) was upregulated in tumors with chronic restraint, associating with the reprogramming of amino acid metabolism. Functional assays revealed that ANPEP promoted liver cancer growth and metastasis. Knockdown of ANPEP blocked chronic stress-induced liver cancer progression. Chronic stress-induced glucocorticoids promoted nuclear receptor subfamily 3 group C member 1 (NR3C1) nuclear translocation to activate ANPEP transcription by directly binding to its promoter. Furthermore, ANPEP promotes glutathione synthesis, subsequently inhibiting reactive oxygen species (ROS)-induced ferroptosis. Mechanistically, ANPEP interacted with solute carrier family 3 member 2 (SLC3A2) to block membrane associated ring-CH-type finger 8-mediated (MARCH8-mediated) lysosome-dependent degradation of SLC3A2, promoting intracellular L-cystine transport, thereby increasing glutathione synthesis. The combination of ANPEP silencing and sorafenib treatment showed a synergistic effect in inhibiting liver cancer progression. Finally, clinical data and mouse models demonstrated that chronic stress drove liver tumor progression via ANPEP-regulated SLC3A2. These findings reveal unanticipated communication between chronic stress and metabolic reprogramming during liver cancer progression, providing potential therapeutic implications for liver cancer.
Authors
Yongkang Wu, Yankun Zhang, Xiaojia Shi, Mengting Wu, Min Sun, Ying Feng, Wenmeng Ma, Xiule Jiang, Dingqi Fei, Mingjian Zhao, Zhuanchang Wu, Chunyang Li, Xiaohong Liang, Lifen Gao, Chunhong Ma, Xuetian Yue
Abstract
BACKGROUND. Axonal degeneration is believed to be an early hallmark of Alzheimer’s disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using diffusion MRI-derived Axonal Density Index (dMRI-ADI). METHODS. Longitudinal dMRI, CSF and PET data from the ADNI were analyzed, including 117 cognitively normal (CN) and 88 impaired (CI) subjects, consisting of 74 mild cognitive impairment (MCI) and 14 AD individuals. Linear mixed-effects models examined group differences as well as associations between baseline and longitudinal changes in ADI, CSF or PET biomarkers and clinical outcomes. Results derived from larger CSF (n=527) and PET (tau-PET: n=870; amyloid-PET: n=1581) data were also presented. RESULTS. Compared to CN, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (p<10–⁶). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: p=0.03; CDR-SB: p<10–⁴), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: p=0.001; CDR-SB: p<10–¹²). Compared to CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; an association observed only with amyloid-PET, but not CSF biomarkers. CONCLUSION. Axonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring. TRIAL REGISTRATION. ClinicalTrials.gov NCT00106899. FUNDING. This work was supported by the National Institute on Aging IRP.
Authors
Zhaoyuan Gong, John P. Laporte, Alexander Y. Guo, Murat Bilgel, Jonghyun Bae, Noam Y. Fox, Angelique de Rouen, Nathan Zhang, Aaliya Taranath, Rafael de Cabo, Josephine M. Egan, Luigi Ferrucci, Mustapha Bouhrara
Abstract
Epstein-Barr virus (EBV) is of growing interest for its potential role in neurodegenerative diseases such as multiple sclerosis (MS) and its possible utility as a therapeutic target in herpesvirus-associated chronic diseases. The effects of brincidofovir (BCV) on EBV reactivation were evaluated in vitro using EBV-infected spontaneous lymphoblastoid cell lines (SLCLs) and peripheral blood mononuclear cells (PBMCs) derived from MS patients and healthy controls. In addition, a B lymphoblastoid cell line and PBMCs from common marmosets (Callithrix jacchus) naturally infected with an EBV-related gammaherpesvirus (Callitrichine herpesvirus 3, CalHV-3) were used to measure BCV efficacy in a nonhuman primate model. BCV significantly inhibited gammaherpesvirus reactivation, with decreased lytic and latent viral transcript expression. These results suggest that BCV may be a useful antiviral for inhibiting EBV activity in MS patients. Additionally, this work further validates the utility of CalHV-3 in marmosets as a translational model for the investigation of successful EBV-targeting therapeutics.
Authors
Abaigeal Donaldson, Madeleine R. Druker, Maria Chiara Monaco, Emily H. Stack, Paige Zimmerman, Amanda Lee, Izabela Bialuk, William Frazier, Irene Cortese, Heather Narver, Masatoshi Hazama, Fuminori Yoshida, Xiaofan Li, Laurie T. Krug, Stacey L. Piotrowski, Steven Jacobson
Abstract
Acute myeloid leukemia (AML) is an aggressive cancer with very poor outcomes. To identify additional drivers of leukemogenesis, we analyzed sequencing data from 1,727 unique individual AML patients, which revealed mutations in ubiquitin ligase family genes in 11.2% of adult AML samples with mutual exclusivity. The SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase complex gene, FBXO11, was the most significantly downregulated gene of the SCF complex in AML. We found that FBXO11 interacts with and catalyzes K63-linked ubiquitination of LONP1 in the cytosol, to promote LONP1 entry into mitochondria. We show that depletion of FBXO11 or LONP1 reduces mitochondrial respiration through impaired LONP1 chaperone activity to assemble electron transport chain Complex IV. Reduced mitochondrial respiration secondary to FBXO11 or LONP1 depletion imparted myeloid-biased stem cell properties in primary CD34+ hematopoietic stem and progenitor cells (HSPC) in vitro. In a human xenograft model, depletion of FBXO11 cooperated with AML1-ETO and mutant KRASG12D to generate serially transplantable AML. Our findings suggest that reduced FBXO11 cooperates to initiate AML by priming HSPC for myeloid-biased self-renewal through attenuation of LONP1-mediated regulation of mitochondrial respiration.
Authors
Hayle Kincross, Ya-Chi Angela Mo, Xuan Wang, Linda Chang, Gerben Duns, Franziska Mey, Jihong Jiang, Zurui Zhu, Naomi Isak, Harwood Kwan, Tammy T.Y. Lau, T. Roderick Docking, Pranav Garg, Jessica Tran, Shane Colborne, Se-Wing Grace Cheng, Shujun Huang, Nadia Gharaee, Elijah Willie, Jeremy D.K. Parker, Joshua Bridgers, Davis Wood, Ramon I. Klein Geltink, Gregg B. Morin, Aly Karsan
Abstract
Authors
Antonio Carlos Tallon-Cobos, Konstantinos Vazaios, Piotr Waranecki, Marliek van Hoesel, Annelisa M. Cornel, Benjamin Schwalm, Norman Mack, Ella de Boed, Jasper van der Lugt, Stefan Nierkens, Marcel Kool, Eelco W. Hoving, Dennis S. Metselaar, Esther Hulleman
Abstract
Authors
Alexander M. Loiben, Wei-Ming Chien, Ashley McKinstry, Dania Ahmed, Matthew C. Childers, Michael Regnier, Charles E. Murry, Kai-Chun Yang
Abstract
BACKGROUND. Cardiac allograft vasculopathy (CAV) is consistently accompanied by immune infiltrates surrounding affected coronary arteries, including antibody-producing plasma cells (PC). The antigenic drivers of these intragraft PC responses remain poorly defined. METHODS. We characterized graft-infiltrating PC by single-cell RNA sequencing and immunoglobulin gene profiling. Using immunoglobulin sequences we generated 37 recombinant monoclonal antibodies (mAb) from dominant intragraft PC clones and 24 control mAb from peripheral blood PC. Antigen reactivity was screened against chemical adducts, including bilirubin, a heme-degradation by-product. Histologic and tissue analyses assessed bilirubin deposition as well as expression of heme-catabolic enzymes, and the presence of Fe2+ in heart explants with CAV. RESULTS. A majority of graft-derived mAb (21/37; ~57%) but none of the mAb derived from blood PC reacted to bilirubin. Bilirubin deposition was detected within lymphocytic aggregates in CAV grafts. In coronary arteries with CAV lesions, bilirubin accumulated in the cytoplasm and nuclei of smooth muscle cells in the tunica media, a pattern not observed in healthy heart tissue. Lastly, we detected the expression of heme-oxygenase-1 and biliverdin reductases in graft-infiltrating macrophages along with the presence of Fe2+ ion in the media of arteries with hyperplasia. CONCLUSION. These findings suggest that local heme catabolism and resultant bilirubin accumulation create a prominent target for intragraft antibody responses in CAV. Bilirubin-specific antibodies and heme-catabolic pathways may contribute to CAV pathogenesis and represent potential mechanistic and therapeutic avenues for further investigation. FUNDING. National Institute of Health.
Authors
Sarah B. See, Talita Aguiar, Max Dietzel, Mattea Ausmeier, Hang T.T. Nguyen, Shunya Mashiko, Laura Donadeu, Hector Cordero, Poulomi Roy, Lorea Roson, Charles C. Marboe, Matthias J. Szabolcs, Maryjane Farr, Jose González-Costello, Aleix Olivella, Yoshifumi Naka, Koji Takeda, Rodica Vasilescu, Kevin J. Clerkin, Gilles Benichou, Joren C. Madsen, R. Glenn King, Oriol Bestard, Evan P. Kransdorf, Emmanuel Zorn
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ISSN: 0021-9738 (print), 1558-8238 (online)