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Publications in Clinical Medicine by NOMIS researchers

Reprogramming neuroblastoma by diet-enhanced polyamine depletion

NOMIS Researcher(s)

Published in

September 24, 2025

Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells1,2. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis3,4. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity5. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.

Research field(s)
Biochemistry & Molecular Biology, Developmental Biology, Genetics & Heredity, Pediatrics

DOI
10.1038/s41586-025-09564-0

Culture-independent meta-pangenomics enabled by long-read metagenomics reveals associations with pediatric undernutrition

NOMIS Researcher(s)

Published in

September 9, 2025

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44–64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species predictive of linear growth. Pangenome analyses revealed microbial genetic associations with linear growth, while genome instability correlated with declining length-for-age Z score (LAZ). This resource demonstrates the power of comparing cMAGs with health trajectories and establishes a new standard for microbiome association studies.

Research field(s)
Bioinformatics, Microbiology, Pediatrics

DOI
10.1016/j.cell.2025.08.020

SARS-CoV-2 nucleocapsid protein directly prevents cGAS–DNA recognition through competitive binding

NOMIS Researcher(s)

Published in

June 23, 2025
A hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the delayed interferon response. Interferons are typically produced upon host recognition of pathogen- or damage-associated molecular patterns, such as nucleic acids. While the mechanisms by which SARS-CoV-2 evades host recognition of its RNA are well studied, how it evades immune responses to cytosolic DNA—leaked from mitochondria or nuclei during infection—remains poorly understood. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein directly suppresses DNA sensing by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). Although primarily known for packaging the viral RNA genome, we uncover that the SARS-CoV-2 nucleocapsid protein also binds DNA with high affinity and competitively blocks cGAS activation. Using cell-free biochemical and biophysical approaches, including single-molecule optical tweezers, we show that the nucleocapsid protein binds to DNA at nanomolar concentrations and cocondenses with DNA at micromolar concentrations, thereby impeding stable cGAS-DNA interactions required for signal propagation. Hyperphosphorylation of the nucleocapsid protein diminishes its competitive binding capacity. Our findings reveal an unexpected role of the SARS-CoV-2 nucleocapsid protein in directly suppressing the cGAS-STING pathway, strongly suggesting that this contributes to the delayed interferon response during infection. This study raises the possibility that nucleocapsid proteins of other RNA viruses may also exhibit moonlighting functions by antagonizing host nucleic acid–sensing pathways.

Research field(s)
Biological Physics, Biochemistry & Molecular Biology, Virology, Immunology

DOI
10.1073/pnas.2426204122

Comprehensive interrogation of synthetic lethality in the DNA damage response

NOMIS Researcher(s)

Published in

April 9, 2025

The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability1,2. Unravelling the complementary interplay between these pathways remains a challenge3,4. Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.

Partnership(s)
,

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Genetics & Heredity, Oncology & Carcinogenesis

DOI
10.1038/s41586-025-08815-4

Adrenaline for the early resuscitation of children with sepsis – a randomized controlled pilot study (ANDES CHILD): study protocol and analysis plan

NOMIS Researcher(s)

Published in

March 12, 2025

Purpose

Sepsis is a leading cause of pediatric morbidity and mortality worldwide. Current guidelines recommend fluid bolus administration of 40–60 mL/kg as part of initial resuscitation, despite limited evidence and concerns about potential harm from high fluid volumes. The ANDES-CHILD pilot study hypothesizes that early initiation of inotropes is feasible and reduces fluid use compared to standard resuscitation.

Methods

Multicenter open label randomized controlled pilot trial conducted in three Pediatric Emergency Departments in Latin America. Children aged 28 days to 18 years with presumed septic shock will be randomized in a 1:1 ratio to receive either early adrenaline infusion after 20 mL/kg fluid bolus versus standard resuscitation with 40–60 mL/kg fluid bolus prior to initiating inotropes. The primary outcome is feasibility, with survival free of organ support censored at 28 days as the exploratory primary clinical outcome. The study will enroll 40 patients, representing approximately 10% of a full trial, with follow-up at 28 days. Baseline characteristics, adverse events and protocol violations will be summarized descriptively. Outcomes will be analyzed using difference estimates with 95% confidence intervals. An intention-to-treat approach will be used for statistical analysis.

Discussion

This pragmatic pilot study will generate essential data to evaluate the feasibility and guide the design of a full trial aimed to assessing the benefits of early inotrope use in pediatric septic shock. The study was registered on ClinicalTrials.gov prior to the start of recruitment (NCT06478797). Recruitment started on July 18, 2024.

Research field(s)
Pediatrics

DOI
10.1007/s44253-025-00066-5

Fluoxetine promotes IL-10–dependent metabolic defenses to protect from sepsis-induced lethality

NOMIS Researcher(s)

Published in

February 14, 2025

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19; however, the mechanisms underlying this protection are largely unknown. Here, we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin and instead increases levels of circulating interleukin-10 (IL-10). IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia, preventing cardiac effects including impairment of glucose oxidation, ectopic lipid accumulation, ventricular stretch and possibly cardiac failure. Our work reveals a beneficial “off-target” effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

Partnership(s)
,

Research field(s)
Biochemistry & Molecular Biology, Immunology, Pharmacology & Pharmacy, Microbiology

DOI
10.1126/sciadv.adu4034

Bile acid synthesis impedes tumor-specific T cell responses during liver cancer

NOMIS Researcher(s)

Published in

January 9, 2025

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

Partnership(s)

Research field(s)
Biomedical Research, Biochemistry & Molecular Biology, Microbiology, Immunology, Oncology & Carcinogenesis

DOI
10.1126/science.adl4100

Astrocytes in aging

NOMIS Researcher(s)

Published in

January 8, 2025

The mammalian nervous system is impacted by aging. Aging alters brain architecture, is associated with molecular damage, and can manifest with cognitive and motor deficits that diminish the quality of life. Astrocytes are glial cells of the CNS that regulate the development, function, and repair of neural circuits during development and adulthood; however, their functions in aging are less understood. Astrocytes change their transcriptome during aging, with astrocytes in areas such as the cerebellum, the hypothalamus, and white matter-rich regions being the most affected. While numerous studies describe astrocyte transcriptional changes in aging, many questions still remain. For example, how is astrocyte function altered by transcriptional changes that occur during aging? What are the mechanisms promoting astrocyte aged states? How do aged astrocytes impact brain function? This review discusses features of aged astrocytes and their potential triggers and proposes ways in which they may impact brain function and health span.

Partnership(s)
,

Research field(s)
Immunology, Neurology & Neurosurgery

DOI
10.1016/j.neuron.2024.12.010

Building global collaborative research networks in paediatric critical care: a roadmap

NOMIS Researcher(s)

Published in

December 20, 2024

Paediatric critical care units are designed for children at a vulnerable stage of development, yet the evidence base for practice and policy in paediatric critical care remains scarce. In this Health Policy, we present a roadmap providing strategic guidance for international paediatric critical care trials. We convened a multidisciplinary group of 32 paediatric critical care experts from six continents representing paediatric critical care research networks and groups. The group identified key challenges to paediatric critical care research, including lower patient numbers than for adult critical care, heterogeneity related to cognitive development, comorbidities and illness or injury, consent challenges, disproportionately little research funding for paediatric critical care, and poor infrastructure in resource-limited settings. A seven-point roadmap was proposed: (1) formation of an international paediatric critical care research network; (2) development of a web-based toolkit library to support paediatric critical care trials; (3) establishment of a global paediatric critical care trial repository, including systematic prioritisation of topics and populations for interventional trials; (4) development of a harmonised trial minimum set of trial data elements and data dictionary; (5) building of infrastructure and capability to support platform trials; (6) funder advocacy; and (7) development of a collaborative implementation programme. Implementation of this roadmap will contribute to the successful design and conduct of trials that match the needs of globally diverse paediatric populations.

Research field(s)
Emergency & Critical Care Medicine, Pediatrics

DOI
10.1016/S2352-4642(24)00303-1

Alzheimer’s disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain

NOMIS Researcher(s)

Published in

December 19, 2024

INTRODUCTION: While there may be microbial contributions to Alzheimer’s disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+)microglia subtype associated with increased immunoglobulinG4(IgG4) in the transverse colon (TC).

METHODS: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association.

RESULTS: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death.

DISCUSSION: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+)microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+)microglia.

Research field(s)
Genetics & Heredity, Neurology & Neurosurgery, Biology

DOI
10.1002/alz.14401

Spatial transcriptomic clocks reveal cell proximity effects in brain ageing

NOMIS Researcher(s)

Published in

December 18, 2024

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions—exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell–cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Immunology, Neurology & Neurosurgery

DOI
10.1038/s41586-024-08334-8

Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19

NOMIS Researcher(s)

Published in

December 11, 2024

SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.

Research field(s)
Molecular Biology, Virology, Immunology

DOI
10.1016/j.chom.2024.11.007

Digital solutions in paediatric sepsis: current state, challenges, and opportunities to improve care around the world

NOMIS Researcher(s)

Published in

September 1, 2024
The digitisation of health care is offering the promise of transforming the management of paediatric sepsis, which is a major source of morbidity and mortality in children worldwide. Digital technology is already making an impact in paediatric sepsis, but is almost exclusively benefiting patients in high-resource health-care settings. However, digital tools can be highly scalable and cost-effective, and—with the right planning—have the potential to reduce global health disparities. Novel digital solutions, from wearable devices and mobile apps, to electronic health record-embedded decision support tools, have an unprecedented opportunity to transform paediatric sepsis research and care. In this Series paper, we describe the current state of digital solutions in paediatric sepsis around the world, the advances in digital technology that are enabling the development of novel applications, and the potential effect of advances in artificial intelligence in paediatric sepsis research and clinical care.

Research field(s)
Pediatrics

DOI
10.1016/S2589-7500(24)00141-9

Quality improvement programmes in paediatric sepsis from a global perspective

NOMIS Researcher(s)

Published in

September 1, 2024

Sepsis is a major contributor to poor child health outcomes around the world. The high morbidity, mortality, and societal cost associated with paediatric sepsis render it a global health priority, as summarised in Paper 1 of this Series. Sepsis is characterised by a dysregulated host response to infection that manifests as organ failure, and children are uniquely susceptible to sepsis, as discussed in Paper 2. The focus of this third Series paper is quality improvement in paediatric sepsis. The 2017 WHO resolution on sepsis outlined key aims to reduce the burden of sepsis. As of 2024, only a small number of countries have implemented systematic, paediatric-focused quality improvement programmes to raise sepsis awareness, enhance recognition of sepsis, promote timely treatment, and provide long-term support for paediatric sepsis survivors. We examine programme successes and systematic barriers to quality improvement targeting paediatric sepsis. We highlight the need for programme design to consider the entire patient journey, starting with prevention, caregiver awareness, recognition at home, education of the health-care workforce, development of health-care systems, and establishment of long-term family and survivor support extending beyond the intensive care unit. Building on lessons learnt from existing quality improvement programmes, we outline implementation strategies and measures to enable benchmarking. Ultimately, quality improvement on a global scale can only be accelerated through a global learning platform focusing on paediatric sepsis.

This is the third in a Series of four papers on paediatric sepsis (Paper 4 appears in The Lancet Digital Health). All papers in the Series are available at thelancet.com/series/paediatric-sepsis

Research field(s)
Pediatrics

DOI
10.1016/S2352-4642(24)00142-1

Susceptibility to childhood sepsis, contemporary management, and future directions

NOMIS Researcher(s)

Published in

September 1, 2024

Sepsis disproportionally affects children across all health-care settings and is one of the leading causes of morbidity and mortality in neonatal and paediatric age groups. As shown in the first paper in this Series, the age-specific incidence of sepsis is highest during the first years of life, before approaching adult incidence rates during adolescence. In the second paper in this Series, we focus on the unique susceptibility of paediatric patients to sepsis and how the underlying dysregulated host response relates to developmental aspects of children’s immune system, genetic, perinatal, and environmental factors, and comorbidities and socioeconomic determinants of health, which often differ between children and adults. State-of-the-art clinical management of paediatric sepsis is organised around three treatment pillars—diagnosis, early resuscitation, and titration of advanced care—and we examine available treatment guidelines and the limitations of their supporting evidence. Serious evidence gaps remain in key areas of paediatric sepsis care, especially surrounding recognition, common interventions, and survivor support, and to this end we offer a research roadmap for the next decade that could accelerate targeted diagnostics and personalised use of immunomodulation. However, improving outcomes for children with sepsis relies fundamentally on systematic quality improvement in both recognition and treatment, which is the theme of the third paper in this Series. Digital health, as shown in the fourth and final paper of this Series, holds promising potential in breaking down the barriers that hinder progress in paediatric sepsis care and, ultimately, global child health.

This is the second in a Series of four papers on paediatric sepsis (Paper 4 appears in The Lancet Digital Health). All papers in the Series are available at thelancet.com/series/paediatric-sepsis

Research field(s)
Pediatrics

DOI
10.1016/S2352-4642(24)00141-X

The burden and contemporary epidemiology of sepsis in children

NOMIS Researcher(s)

Published in

September 1, 2024

Sepsis is a dysregulated host response to infection that leads to life-threatening organ dysfunction. Half of the 50 million people affected by sepsis globally every year are neonates and children younger than 19 years. This burden on the paediatric population translates into a disproportionate impact on global child health in terms of years of life lost, morbidity, and lost opportunities for children to reach their developmental potential. This Series on paediatric sepsis presents the current state of diagnosis and treatment of sepsis in children, and maps the challenges in alleviating the burden on children, their families, and society. Drawing on diverse experience and multidisciplinary expertise, we offer a roadmap to improving outcomes for children with sepsis. This first paper of the Series is a narrative review of the burden of paediatric sepsis from low-income to high-income settings. Advances towards improved operationalisation of paediatric sepsis across all age groups have facilitated more standardised assessment of the Global Burden of Disease estimates of the impact of sepsis on child health, and these estimates are expected to gain further precision with the roll out of the new Phoenix criteria for sepsis. Sepsis remains one of the leading causes of childhood morbidity and mortality, with immense direct and indirect societal costs. Although substantial regional differences persist in relation to incidence, microbiological epidemiology, and outcomes, these cannot be explained by differences in income level alone. Recent insights into post-discharge sequelae after paediatric sepsis, ranging from late mortality and persistent neurodevelopmental impairment to reduced health-related quality of life, show how common post-sepsis syndrome is in children. Targeting sepsis as a key contributor to poor health outcomes in children is therefore an essential component of efforts to meet the Sustainable Development Goals.

This is the first in a Series of four papers on paediatric sepsis (Paper 4 appears in The Lancet Digital Health). All papers in the Series are available at thelancet.com/series/paediatric-sepsis

Research field(s)
Pediatrics

DOI
10.1016/S2352-4642(24)00140-8

APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease

NOMIS Researcher(s)

Published in

June 19, 2024

Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer’s disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer’s disease caused by the PSEN1E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3Ch). Heterozygosity for the APOE3Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1E280A variant is prevalent.

Research field(s)
Health Sciences, Genetics & Heredity, Clinical Medicine

DOI
10.1056/NEJMoa2308583

Targeting nuclear receptor corepressors for reversible male contraception

NOMIS Researcher(s)

Published in

February 20, 2024

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)–dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

Research field(s)
Clinical Medicine

DOI
10.1073/pnas.2320129121

EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth

NOMIS Researcher(s)

Published in

January 25, 2024
The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation, which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF–PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy-resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF–PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
Significance:

Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell–based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.

Research field(s)
Oncology & Carcinogenesis

DOI
10.1158/2159-8290.CD-23-0434

International Consensus Criteria for Pediatric Sepsis and Septic Shock

NOMIS Researcher(s)

Published in

January 21, 2024

Importance  Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children.

Objective  To update and evaluate criteria for sepsis and septic shock in children.

Evidence Review  The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria.

Findings  Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4—respiratory, cardiovascular, coagulation, and/or neurological—organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively.

Conclusions and Relevance  The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Research field(s)
Emergency & Critical Care Medicine, Pediatrics

DOI
10.1001/jama.2024.0179

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock

NOMIS Researcher(s)

Published in

January 21, 2024

Importance  The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach.

Objective  To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings.

Design, Setting, and Participants  Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set.

Exposure  Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock.

Main Outcomes and Measures  The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity.

Results  Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings.

Conclusions and Relevance  The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

Research field(s)
Emergency & Critical Care Medicine, Pediatrics

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