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| Open AccessDysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury
Necroptosis, a form of cell death, occurs in acute renal injury. Here, the authors show that ferroptosis—a form of cell death dependent on iron - also occurs during acute kidney injury, and show that an inhibitor of ferroptosis can improve survival in a mouse model of acute kidney damage.
- Wulf Tonnus
- , Claudia Meyer
- & Andreas Linkermann
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Article
| Open AccessInsulin protects acinar cells during pancreatitis by preserving glycolytic ATP supply to calcium pumps
Acute pancreatitis is a serious inflammatory disease, which is more severe in diabetic mice. Here the authors use mice lacking pancreatic acinar cell insulin receptors to show that this may be because insulin preserves glycolytic energy supply in acinar cell during pancreatitis, which prevents cytotoxic calcium overload and cell death.
- Jason I. E. Bruce
- , Rosa Sánchez-Alvarez
- & John A. Williams
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Article
| Open AccessMyofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin
Myofibroblasts drive fibrosis in systemic sclerosis (SSc), but the cellular progenitors are unknown. Utilizing single cell RNA-sequencing, the authors show that SSc dermal myofibroblasts arise in a two-step process from SFRP2/DPP4-expressing progenitors and implicate upstream transcription factors.
- Tracy Tabib
- , Mengqi Huang
- & Robert Lafyatis
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Article
| Open AccessTargeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
Different types of mesenchymal progenitors participate in ectopic bone formation. Here, the authors show Col2+ lineage cells adopt a lymphatic endothelium cell fate, which regulates local inflammatory microenvironment after trauma, thus influencing heterotopic ossification (HO) development via a FGFR3-BMPR1a pathway.
- Dali Zhang
- , Junlan Huang
- & Yangli Xie
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Article
| Open AccessSARS-CoV-2 antibody dynamics and transmission from community-wide serological testing in the Italian municipality of Vo’
Vo’, Italy, is a unique setting for studying SARS-CoV-2 antibody dynamics because mass testing was conducted there early in the pandemic. Here, the authors perform two follow-up serological surveys and estimate seroprevalence, the extent of within-household transmission, and the impact of contact tracing.
- Ilaria Dorigatti
- , Enrico Lavezzo
- & Andrea Crisanti
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Perspective
| Open AccessConsensus statement on the role of health systems in advancing the long-term well-being of people living with HIV
- Jeffrey V. Lazarus
- , Kelly Safreed-Harmon
- & Laura Waters
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Article
| Open AccessA small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion
Premature termination codons can cause early translation termination and lead to disease. Here the authors perform a screen to identify compounds with readthrough activity and show that these reduce eRF1 levels to suppress premature termination associated with cystic fibrosis.
- Jyoti Sharma
- , Ming Du
- & David M. Bedwell
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Article
| Open AccessDiscovery and prioritization of variants and genes for kidney function in >1.2 million individuals
Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.
- Kira J. Stanzick
- , Yong Li
- & Thomas W. Winkler
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Article
| Open AccessBiochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting
KRAS is commonly mutated at codon 12 in several cancer types, offering a unique opportunity for the development of neoantigen-targeted immunotherapy. Here the authors present a pipeline for the prediction, identification and validation of HLA class-I restricted mutant KRAS G12 peptides, leading to the generation of mutant KRAS-specific T cell receptors for adoptive T cell immunotherapy.
- Adham S. Bear
- , Tatiana Blanchard
- & Beatriz M. Carreno
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Article
| Open AccessAssociations between dimensions of behaviour, personality traits, and mental-health during the COVID-19 pandemic in the United Kingdom
The COVID-19 pandemic has affected people’s health and well-being. Here, the authors characterize self-reported impact of the pandemic (positive and negative) at a large scale in the United Kingdom, and show variance among individual circumstances.
- Adam Hampshire
- , Peter J. Hellyer
- & Samuel R. Chamberlain
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Article
| Open AccessSelf-rechargeable cardiac pacemaker system with triboelectric nanogenerators
Self-powered implantable devices have the potential to extend device operation, though current energy harvesters are both insufficient and inconvenient. Here the authors report on a commercial coin battery-sized high-performance inertia-driven triboelectric nanogenerator based on body motion and gravity that can be used to charge a lithium-ion battery and integrated into a cardiac pacemaker.
- Hanjun Ryu
- , Hyun-moon Park
- & Sang-Woo Kim
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Article
| Open AccessFrancisella tularensis induces Th1 like MAIT cells conferring protection against systemic and local infection
Mucosal-Associated Invariant T (MAIT) cells are associated with established functions during bacterial infection. Here the authors show inoculation with Francisella tularensis results in induction of MAIT cells associated with prototypic Th1 immunity and confer protection to systemic and local infection.
- Zhe Zhao
- , Huimeng Wang
- & Zhenjun Chen
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Article
| Open AccessLarge parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects
A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.
- Xing Jian
- & Gary Felsenfeld
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Article
| Open AccessChronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity
Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.
- Linh T. Bui
- , Nichelle I. Winters
- & Laure Emmanuelle Zaragosi
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Article
| Open AccessAdvancing diagnostic performance and clinical usability of neural networks via adversarial training and dual batch normalization
Unmasking the decision making process of machine learning models is essential for implementing diagnostic support systems in clinical practice. Here, the authors demonstrate that adversarially trained models can significantly enhance the usability of pathology detection as compared to their standard counterparts.
- Tianyu Han
- , Sven Nebelung
- & Daniel Truhn
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Article
| Open AccessSMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade
SMARCA4 is commonly inactivated in lung and ovarian cancers. Here the authors show that SMARCA4-deficient tumours have significantly reduced levels of the histone demethylases KDM6s and a strong dependency on these demethylases for tumour growth, so that they are vulnerable to KDM6s inhibition.
- Octavio A. Romero
- , Andrea Vilarrubi
- & Montse Sanchez-Cespedes
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Article
| Open AccessLineage-specific protection and immune imprinting shape the age distributions of influenza B cases
The earliest infections with influenza A shape the immune responses to future infections, but it is not known if this phenomenon applies to influenza B. Here, the authors use influenza B case data from New Zealand and find evidence for both lineage-specific and imprinting protection.
- Marcos C. Vieira
- , Celeste M. Donato
- & Sarah Cobey
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Article
| Open AccessPhosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome
Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.
- Alberto Lleó
- , Henrik Zetterberg
- & Juan Fortea
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Article
| Open AccessSensing leg movement enhances wearable monitoring of energy expenditure
Current methods to estimate energy expenditure are either infeasible for everyday use or associated with significant errors. Here the authors present a Wearable System using inertial measurement units worn on the shank and thigh that estimates metabolic energy expenditure in real-time during common steady-state and time-varying activities.
- Patrick Slade
- , Mykel J. Kochenderfer
- & Steven H. Collins
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Article
| Open AccessIn utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease
Lysosomal storage diseases like mucopolysaccharidosis type I (MPS I) cause pathology before birth and result in early morbidity and mortality. Here, the authors show that in utero base editing mediates multi-organ phenotypic and survival benefits in a mouse model recapitulating a common human MPSI mutation.
- Sourav K. Bose
- , Brandon M. White
- & William H. Peranteau
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Article
| Open AccessA novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke
Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.
- Toshiko Yamazawa
- , Takuya Kobayashi
- & Takashi Murayama
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Article
| Open AccessGene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons
Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare neurodevelopmental disorder. Here the authors describe a clinical trial of MR-guided delivery of AAV2-AADC for the treatment of AADC.
- Toni S. Pearson
- , Nalin Gupta
- & Krystof S. Bankiewicz
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Article
| Open AccessArtificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease
Traditional drug discovery process use differential, Bayesian and other network based approaches. We developed a Boolean approach for building disease maps and prioritizing pre-clinical models to discover a first-in-class therapy to restore and protect the leaky gut barrier in inflammatory bowel disease.
- Debashis Sahoo
- , Lee Swanson
- & Pradipta Ghosh
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Article
| Open AccessSingle-molecule, full-length transcript isoform sequencing reveals disease-associated RNA isoforms in cardiomyocytes
Alternative splicing generates RNA isoforms that contribute to phenotypic diversity. Here the authors perform single-molecule full-length RNA sequencing to identify disease-associated variant transcript isoforms.
- Chenchen Zhu
- , Jingyan Wu
- & Lars M. Steinmetz
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Article
| Open AccessStructural basis of LAIR1 targeting by polymorphic Plasmodium RIFINs
RIFINs are Plasmodium surface antigens that suppress the immune response by binding inhibitory receptors such as LAIR1. Here, Xu et al. characterize the interaction between RIFIN-variable 2 domain and a LAIR1 domain and identify LAIR1-binding RIFINs in several Plasmodium species.
- Kai Xu
- , Yiran Wang
- & Peter D. Kwong
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Article
| Open AccessA generative network model of neurodevelopmental diversity in structural brain organization
The formation of large-scale brain networks represents crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. Here, the authors use generative network modelling to provide a computational framework for understanding neurodevelopmental diversity.
- Danyal Akarca
- , Petra E. Vértes
- & Duncan E. Astle
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Article
| Open AccessA clinical deep learning framework for continually learning from cardiac signals across diseases, time, modalities, and institutions
Deep learning algorithms trained on data streamed temporally from different clinical sites and from a multitude of physiological sensors are generally affected by a degradation in performance. To mitigate this, the authors propose a continual learning strategy that employs a replay buffer.
- Dani Kiyasseh
- , Tingting Zhu
- & David Clifton
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Article
| Open AccessProkineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury
Prokineticin-2 (Prok2) is a secreted protein involved in many physiological processes. Here, the authors show that Prok2 prevents neuronal cell ferroptosis after traumatic brain injury and its administration before cortical injury reduces neuronal degeneration, and motor and cognitive impairments.
- Zhongyuan Bao
- , Yinlong Liu
- & Jing Ji
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Article
| Open AccessWhole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape
The genomic characterisation of nasopharyngeal carcinoma (NPC) remains crucial. Here, the authors perform whole-genome sequencing for 70 NPCs with EBV gene expression, report the somatic alterations and EBV-mediated effects converging on NF-κB activation and immune escape and identify targetable homozygous MTAP deletions.
- Jeff P. Bruce
- , Ka-Fai To
- & Kwok-Wai Lo
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Matters Arising
| Open AccessInconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets
- Xu Xiao
- , Canqiang Xu
- & Rongshan Yu
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Matters Arising
| Open AccessReply to: “Inconsistent prediction capability of ImmuneCells.Sig across different RNA-seq datasets”
- Donghai Xiong
- , Yian Wang
- & Ming You
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Article
| Open AccessThe epidemiology of Plasmodium vivax among adults in the Democratic Republic of the Congo
Plasmodium vivax generally accounts for a low proportion of malaria cases in Africa, but population-level data on the distribution of infections is limited. Here, the authors use data from the Democratic Republic of the Congo and show that the prevalence is low (~3%) and diffusely spread.
- Nicholas F. Brazeau
- , Cedar L. Mitchell
- & Jonathan J. Juliano
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Article
| Open AccessCross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women
GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.
- Babatunde Adedokun
- , Zhaohui Du
- & Dezheng Huo
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Article
| Open AccessGIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health
Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.
- Yajie Zhao
- , Stasa Stankovic
- & John R. B. Perry
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Article
| Open AccessNUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects.
- Rina Nishii
- , Takanori Mizuno
- & Jun J. Yang
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Article
| Open AccessA genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex
Klebsiella pneumoniae is a pathogen of increasing public health concern and antimicrobial resistance is becoming more prevalent. Here, the authors describe a K. pneumoniae genotyping tool, Kleborate, that can be used to identify lineages and detect antimicrobial resistance and virulence loci.
- Margaret M. C. Lam
- , Ryan R. Wick
- & Kathryn E. Holt
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Article
| Open AccessThe molecular basis for SARS-CoV-2 binding to dog ACE2
Many domestic animals, among them dogs, have been infected with SARS-CoV-2 during the COVID-19 pandemic. Here, the authors present the crystal structure of the SARS-CoV-2 spike protein receptor binding domain (RBD) bound to its receptor, dog angiotensin-converting enzyme 2 (dACE2), and show that the RBD N501Y mutation increases the infectivity and host range of SARS-CoV-2, which highlights the need to monitor emerging SARS-CoV-2 mutations in domestic animals.
- Zengyuan Zhang
- , Yanfang Zhang
- & Yeping Sun
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Article
| Open AccessLack of consideration of sex and gender in COVID-19 clinical studies
Sex and gender have been associated with differences in SARS-CoV-2 incidence and clinical outcomes and therefore warrant consideration in study designs. Here, the authors assess registered and published clinical COVID-19 studies and find that sex-disaggregated analyses are infrequently presented or planned.
- Emer Brady
- , Mathias Wullum Nielsen
- & Sabine Oertelt-Prigione
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Article
| Open AccessOncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.
- Quentin Van Thillo
- , Jolien De Bie
- & Charles E. de Bock
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Article
| Open AccessLactate sensing mechanisms in arterial chemoreceptor cells
Lactate levels in blood change during hypoxia or exercise, however whether this variable is sensed to evoke adaptive responses is unknown. Here the authors show that oxygen-sensing carotid body cells stimulated by hypoxia are also activated by lactate to potentiate a compensatory ventilatory response.
- Hortensia Torres-Torrelo
- , Patricia Ortega-Sáenz
- & José López-Barneo
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Article
| Open AccessJoint disease-specificity at the regulatory base-pair level
While many genetic loci have been found to be associated with disease, not many have had their causal variants and mechanisms investigated. Here, the authors experimentally dissect two loci near GDF5 which are associated with two different joint disorders and which map to independent regulatory elements.
- Pushpanathan Muthuirulan
- , Dewei Zhao
- & Terence D. Capellini
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Article
| Open AccessInflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients
Pre-engraftment syndrome is a major consideration during clinical application of unrelated cord blood transfusion and monocytes represent a critical cell type in immune-pathogenesis. Here the authors further establish the role of monocytes and GM-CSF in pre-engraftment syndrome and show clinical administration of tocilizumab limits pathology in pre-engraftment syndrome pathology in patients.
- Linlin Jin
- , Zimin Sun
- & Haiming Wei
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Article
| Open AccessBoth microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis
Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.
- Yoshiaki Ito
- , Tokio Matsuzaki
- & Hiroshi Asahara
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Article
| Open AccessEZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer
Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity.
- Marita Zoma
- , Laura Curti
- & Giuseppina M. Carbone
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Article
| Open AccessThe role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations
Chromosomal translocations involving the AF10 gene, especially with CALM, are associated with aggressive leukemias. Here the authors show that the PZP domain of AF10, a histone reader, is always excluded/impaired in AF10 fusions, whereas incorporation of this domain downregulates Hoxa genes and blocks leukemogenesis.
- Brianna J. Klein
- , Anagha Deshpande
- & Tatiana G. Kutateladze
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Article
| Open AccessMonocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity
The host immune response plays a critical role in the immunopathology of SARS-CoV2. Here the authors combine a systems biology approach to implicate monocytes as key drivers of cytokine storm and disturbed neutrophil activation in COVID-19 disease severity.
- L. Vanderbeke
- , P. Van Mol
- & J. Wauters
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Article
| Open AccessAgonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma
Agonistic CD40 antibodies (αCD40) have broad immunostimulatory properties, however their efficacy in glioma remains unclear. Here the authors show that αCD40 promotes the formation of tertiary lymphoid structures but does not improve survival and impairs the response to immune checkpoint blockade in murine glioma models.
- Luuk van Hooren
- , Alessandra Vaccaro
- & Anna Dimberg
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Article
| Open AccessThe T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival
Precision medicine needs prognostic markers to select the patients that will benefit more from targeted therapy. Authors show here that high level of baseline T cell receptor diversity is an indicator of favourable prognosis in multiple cancer types, and monoclonal expansion of T-cells correlates with good response to immune checkpoint blockade therapy in metastatic melanoma patients.
- Sara Valpione
- , Piyushkumar A. Mundra
- & Richard Marais
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Article
| Open AccessThe RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response
Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.
- Bo Liu
- , Jiancheng Huang
- & Cliff Y. Yang