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Publications in Health Sciences by NOMIS researchers

The Economics of Child Mental Health: Introducing the Causes and Consequences of Child Mental Health Special Issue

NOMIS Researcher(s)

Published in

April 1, 2024

This special issue of the Journal of Human Resources showcases an emerging literature on the economics of child mental health. Until recently, the severe stigma associated with mental health issues meant that few people felt comfortable talking about them or realized how very prevalent they are (Bharadwaj, Pai, and Suziedelyte 2017). Arguably, this changed with the COVID-19 pandemic, which precipitated widespread discussions of a child and youth mental health crisis (United States Public Health Service, Office of the Surgeon General 2021).

Research field(s)
Economics, Psychology & Cognitive Sciences

DOI
10.3368/jhr.2023SI-intro-child-mental-health

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis

NOMIS Researcher(s)

Published in

March 14, 2024

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC – a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

Research field(s)
Developmental Biology, Genetics & Heredity, Evolutionary Biology

DOI
10.7554/eLife.82564

Uncovering the potential of evaluative conditioning in shaping attitudes toward sustainable product packaging

NOMIS Researcher(s)

Published in

March 14, 2024

Introduction: The necessity to promote pro-environmental behavior change in individuals and society is increasingly evident. This study aimed to investigate the effect of evaluative conditioning on consumers’ perception of product packaging.

Methods: We first produced two stimulus sets: one including images of supermarket products with different packaging and the other containing affective images of healthy nature (positive) and climate change impact (negative). These images were then paired in an evaluative conditioning experiment where respondents were informed about the impact of product packaging.

Results: We found an effect of conditioning depending on the initial sustainability perception that participants had toward product packaging. Pairing products for which participants were uncertain about their sustainability with negative or positive affective images had a significant effect on the sustainable associations of the consumers in a negative or positive direction, respectively. However, the impact of conditioning on products that clearly had (un)sustainable packaging was not that strong.

Discussion: These results provide new tools and evidence to further investigate the power of evaluative conditioning in pro-environmental attitude and behavior change.

Research field(s)
Psychology & Cognitive Sciences

DOI
10.3389/fpsyg.2024.1284422

Massively parallel disruption of enhancers active in human neural stem cells

NOMIS Researcher(s)

Published in

February 27, 2024

Changes in gene regulation have been linked to the expansion of the human cerebral cortex and to neurodevelopmental disorders, potentially by altering neural progenitor proliferation. However, the effects of genetic variation within regulatory elements on neural progenitors remain obscure. We use sgRNA-Cas9 screens in human neural stem cells (hNSCs) to disrupt 10,674 genes and 26,385 conserved regions in 2,227 enhancers active in the developing human cortex and determine effects on proliferation. Genes with proliferation phenotypes are associated with neurodevelopmental disorders and show biased expression in specific fetal human brain neural progenitor populations. Although enhancer disruptions overall have weaker effects than gene disruptions, we identify enhancer disruptions that severely alter hNSC self-renewal. Disruptions in human accelerated regions, implicated in human brain evolution, also alter proliferation. Integrating proliferation phenotypes with chromatin interactions reveals regulatory relationships between enhancers and their target genes contributing to neurogenesis and potentially to human cortical evolution.

Research field(s)
Developmental Biology, Genetics & Heredity

DOI
10.1016/j.celrep.2024.113693

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

Addressing climate change with behavioral science: A global intervention tournament in 63 countries

NOMIS Researcher(s)

Published in

February 7, 2024

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions’ effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior—several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people’s initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors.

Research field(s)
Psychology & Cognitive Sciences, Public Health

DOI
10.1126/sciadv.adj5778

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

DNA-guided transcription factor cooperativity shapes face and limb mesenchyme

NOMIS Researcher(s)

Published in

January 22, 2024

Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest that it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how “Coordinator,” a long DNA motif composed of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines the regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, whereas HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in the shared regulation of genes involved in cell-type and positional identities and ultimately shapes facial morphology and evolution.

Research field(s)
Genetics & Heredity

DOI
10.1016/j.cell.2023.12.032

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

Inhibiting stromal Class I HDACs curbs pancreatic cancer progression

NOMIS Researcher(s)

Published in

December 6, 2023

Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.

Research field(s)
Oncology & Carcinogenesis

DOI
10.1038/s41467-023-42178-6

Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation

NOMIS Researcher(s)

Published in

November 23, 2023

The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Research field(s)
Health Sciences

DOI
10.1038/s41593-023-01496-0

Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity

NOMIS Researcher(s)

Published in

November 6, 2023

Chromatin conformation reorganization is emerging as an important layer of regulation for gene expression and lineage specification. Yet, how lineage-specific transcription factors contribute to the establishment of cell type-specific 3D chromatin architecture in the immune cells remains unclear, especially for the late stages of T cell subset differentiation and maturation. Regulatory T cells (Treg) are mainly generated in the thymus as a subpopulation of T cells specializing in suppressing excessive immune responses. Here, by comprehensively mapping 3D chromatin organization during Treg cell differentiation, we show that Treg-specific chromatin structures were progressively established during its lineage specification, and highly associated with Treg signature gene expression. Additionally, the binding sites of Foxp3, a Treg lineage specifying transcription factor, were highly enriched at Treg-specific chromatin loop anchors. Further comparison of the chromatin interactions between wide-type Tregs versus Treg cells from Foxp3 knock-in/knockout or newly-generated Foxp3 domain-swap mutant mouse revealed that Foxp3 was essential for the establishment of Treg-specific 3D chromatin architecture, although it was not dependent on the formation of the Foxp3 domain-swapped dimer. These results highlighted an underappreciated role of Foxp3 in modulating Treg-specific 3D chromatin structure formation.

Research field(s)
Genetics & Heredity, Immunology, Oncology & Carcinogenesis

DOI
10.1038/s41467-023-42647-y

From the Viscera to First Impressions: Phase-Dependent Cardio-Visual Signals Bias the Perceived Trustworthiness of Faces

NOMIS Researcher(s)

Published in

November 2, 2023

When we see new people, we rapidly form first impressions. Whereas past research has focused on the role of morphological or emotional cues, we asked whether transient visceral states bias the impressions we form. Across three studies (N = 94 university students), we investigated how fluctuations of bodily states, driven by the interoceptive impact of cardiac signals, influence the perceived trustworthiness of faces. Participants less often chose faces presented in synchrony with their own cardiac systole as more trustworthy than faces presented out of synchrony. Participants also explicitly judged faces presented in synchrony with their cardiac systole as less trustworthy. Finally, the presentation of faces in synchrony with participants’ cardiac diastole did not modulate participants’ perceptions of the faces’ trustworthiness, suggesting that the systolic phase is necessary for such interoceptive effects. These findings highlight the role of phasic interoceptive information in the processing of social information and provide a mechanistic account of the role of visceroception for social perception. © The Author(s) 2022.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Experimental Psychology

DOI
10.1177/09567976221131519

Fronto-striatal alterations correlate with apathy severity in behavioral variant frontotemporal dementia

NOMIS Researcher(s)

Published in

October 19, 2023

Structural and functional changes in cortical and subcortical regions have been reported in behavioral variant frontotemporal dementia (bvFTD), however, a multimodal approach may provide deeper insights into the neural correlates of neuropsychiatric symptoms. In this multicenter study, we measured cortical thickness (CTh) and subcortical volumes to identify structural abnormalities in 37 bvFTD patients, and 37 age- and sex-matched healthy controls. For seed regions with significant structural changes, whole-brain functional connectivity (FC) was examined in a sub-cohort of N = 22 bvFTD and N = 22 matched control subjects to detect complementary alterations in brain network organization. To explore the functional significance of the observed structural and functional deviations, correlations with clinical and neuropsychological outcomes were tested where available. Significantly decreased CTh was observed in the bvFTD group in caudal middle frontal gyrus, left pars opercularis, bilateral superior frontal and bilateral middle temporal gyrus along with subcortical volume reductions in bilateral basal ganglia, thalamus, hippocampus, and amygdala. Resting-state functional magnetic resonance imaging showed decreased FC in bvFTD between: dorsal striatum and left caudal middle frontal gyrus; putamen and fronto-parietal regions; pallidum and cerebellum. Conversely, bvFTD showed increased FC between: left middle temporal gyrus and paracingulate gyrus; caudate nucleus and insula; amygdala and parahippocampal gyrus. Additionally, cortical thickness in caudal, lateral and superior frontal regions as well as caudate nucleus volume correlated negatively with apathy severity scores of the Neuropsychiatry Inventory Questionnaire. In conclusion, multimodal structural and functional imaging indicates that fronto-striatal regions have a considerable influence on the severity of apathy in bvFTD. © 2023, The Author(s).

Research field(s)
Health Sciences

DOI
10.1007/s11682-023-00812-3

Bradyphrenia and Tachyphrenia in Idiopathic Parkinsonism Appear, in Part, Iatrogenic: An Observational Study with Systematic Review Background

NOMIS Researcher(s)

Published in

October 12, 2023

We question whether bradyphrenia, slowing of cognitive processing not explained by depression or a global cognitive assessment, is a nosological entity in idiopathic parkinsonism (IP). The time taken to break contact of an index finger with a touch-sensitive plate was measured, with and without a warning in the alerting signal as to which side the imperative would indicate, in 77 people diagnosed with IP and in 124 people without an IP diagnosis. The ability to utilise a warning, measured by the difference between loge-transformed reaction times (unwarned minus warned), was termed ‘cognitive efficiency’. It was approximately normally distributed. A questionnaire on self- and partner perception of proband’s bradyphrenia was applied. A multivariable model showed that those prescribed levodopa were less cognitively efficient (mean −5.2 (CI −9.5, −1.0)% per 300 mg/day, p = 0.02), but those prescribed the anti-muscarinic trihexyphenidyl were more efficient (14.7 (0.2, 31.3)% per 4 mg/day, p < 0.05) and those prescribed monoamine oxidase-B inhibitor (MAOBI) tended to be more efficient (8.3 (0.0, 17.4)%, p = 0.07). The variance in efficiency was greater within IP (F-test, p = 0.01 adjusted for any demographic covariates: coefficient of variation, with and without IP, 0.68 and 0.46, respectively), but not so after adjustment for anti-parkinsonian medication (p = 0.13: coefficient of variation 0.62). The within-participant follow-up time, a median of 4.8 (interquartile range 3.1, 5.5) years (101 participants), did not influence efficiency, irrespective of IP status. Perception of bradyphrenia did not usefully predict efficiency. We conclude that both bradyphrenia and ‘tachyphrenia’ in IP appear to have iatrogenic components, of clinically important size, related to the dose of antiparkinsonian medication. Levodopa is the most commonly prescribed first-line medication: co-prescribing a MAOBI may circumvent its associated bradyphrenia. The previously reported greater efficiency associated with (low-dose) anti-muscarinic was confirmed. © 2023 by the authors.

Research field(s)
Health Sciences

DOI
10.3390/jcm12206499

CD8+ T cells in the cancer-immunity cycle

NOMIS Researcher(s)

Published in

October 10, 2023

CD8+ T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8+ T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8+ T cell subtypes and states. We discuss factors that influence CD8+ T cell differentiation and function in cancer through a framework that incorporates the classic three-signal model and a fourth signal—metabolism—and also consider the impact of the tumor microenvironment from a T cell perspective. We argue for the notion of immunotherapies as “pro-drugs” that act to augment or modulate T cells, which ultimately serve as the drug in vivo, and for the importance of overall immune health in cancer treatment and prevention. The progress in understanding T cell function in cancer has and will continue to improve harnessing of the immune system across broader tumor types to benefit more patients. © 2023 Elsevier Inc.

Research field(s)
Health Sciences

DOI
10.1016/j.immuni.2023.09.005

The interplay of nuclear pores and lipids

NOMIS Researcher(s)

Published in

October 5, 2023

Nuclear pore complexes (NPCs) mediate the bidirectional transport of cargo across the nuclear envelope (NE). NPCs are also membrane remodeling machines with a capacity to curve and fuse the membranes of the NE. However, little is known about the interplay of NPCs and lipids at a mechanistic level. A full understanding of NPC structure and function needs to encompass how the NPC shapes membranes and is itself shaped by lipids. Here we attempt to connect recent findings in NPC research with the broader field of membrane biochemistry to illustrate how an interplay between NPCs and lipids may facilitate the conformational plasticity of NPCs and the generation of a unique pore membrane topology. We highlight the need to better understand the NPC’s lipid environment and outline experimental avenues towards that goal. © 2023 The Authors

Research field(s)
Health Sciences

DOI
10.1016/j.ceb.2023.102251

Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes—an international multicentre retrospective study

NOMIS Researcher(s)

Published in

October 5, 2023

Background: Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. Methods: We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n = 383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n = 1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24 h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. Findings: LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p < 0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04–3.34) in the European cohort and 1.6 (1.2–2.2) in the U.S. cohort. Interpretation: We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Funding: Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. © 2023 The Authors

Research field(s)
Health Sciences

DOI
10.1016/j.eclinm.2023.102252

Psychological Status of the Participants in Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease Colombia

NOMIS Researcher(s)

Published in

September 26, 2023

The SARS-CoV2 global pandemic impacted participants in the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. Objective: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. Methods: Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. Results: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. Conclusions: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19. © 2023 – IOS Press. All rights reserved.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.3233/JAD-220941

Fueling next-generation genome editing with DNA repair

NOMIS Researcher(s)

Published in

September 22, 2023

Genome editing technologies generate targeted DNA lesions and rely on cellular DNA repair pathways for resolution. Understanding the DNA repair mechanisms responsible for resolving the specific damage caused by gene editing tools can significantly advance their optimization and facilitate their broader application in research and therapeutic contexts. Here we explore the cellular processes involved in repairing base and prime editor-generated DNA lesions and strategies to leverage and manipulate DNA repair pathways for desired genomic changes. © 2023 The Author(s)

Research field(s)
Health Sciences

DOI
10.1016/j.cobme.2023.100506

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