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Katelynn E Weber,1 Andrea FR Fischl,2 Pamela J Murray,3 Baqiyyah N Conway1 1Department of Epidemiology, West Virginia University, Morgantown, WV, USA; 2University of Pittsburgh School of Nursing, Pittsburgh, PA, USA; 3Department of Pediatrics, West Virginia University, Morgantown, WV, USA Background: The purpose of this study was to characterize cardiovascular risk factors in a rural pediatric population by body mass index (BMI) category and the presence of the metabolic syndrome.Methods: Data on 13,018 children and adolescents (aged younger than 20 years) from West Virginia and Ohio in 2005–2006 were obtained from the C8 Health Project to determine the prevalence of overweight/obesity and the metabolic syndrome, which was then compared with National Health and Nutrition Examination Survey 2005–2006 data. Cardiovascular risk factors were assessed by age-standardized and sex-standardized BMI category (95th percentiles) and the presence of metabolic syndrome, defined as the presence of three or more of the following criteria: BMI >97th percentile, triglycerides >110 mg/dL, high-density lipoprotein cholesterol 110 mg/dL.Results: The population was 51% male and 95% white. The prevalence of overweight/obesity was 38% and metabolic syndrome was 4.6% in the C8 population, compared with a prevalence of 30% and 3.4%, respectively, within the National Health and Nutrition Examination Survey population. In our Appalachian population, a significant adverse trend across BMI categories was observed for lipids, insulin, inflammatory markers, white blood cell count, and C-reactive protein. Significant differences in these risk factors were seen among those with metabolic syndrome compared with those without metabolic syndrome.Conclusion: The increased prevalence of overweight/obesity and the metabolic syndrome along with the increase in cardiovascular risk factors in Appalachian children and adolescents, suggests a cohort that may develop earlier onset and possibly increased severity of cardiovascular disease and other complications associated with metabolic syndrome and obesity. Keywords: body mass index, cardiovascular, metabolic syndrome, risk factors, pediatric population, Appalachian

Objective: To discuss international aspects as they relate to the convergence of disciplines in health informatics.Method: A group of international experts was invited at a symposium to present and discuss their perspectives on this topic. These have been collated in a single manuscript.Results and Conclusions: Significant challenges, as well as opportunities, appear when cumulating the intrinsic multidisciplinary nature of health informatics interventions with the diversity of contexts at the global level, in particular when considered in the perspective of a confluence, i.e., the mixing of different waters and their merging into a new, stronger entity. Health informatics experts reflect on key issues such as collaborative software development and distributed knowledge sourcing, social media and mobile technologies, the evolutions of the discipline from an historical perspective, as well as examples of challenges for implementing ubiquitous healthcare or for supporting disaster situations when infrastructures get disrupted. [ABSTRACT FROM AUTHOR]

Background: Education has long been, and continues to be, one of the major thematic areas of the activities of IMIA, the International Medical Informatics Association.Objective: To report on IMIA's past activities and to discuss possible future perspectives on IMIA's role on biomedical and health informatics education.Methods: Summarizing past activities by searching in reports and publications. Making suggestions for wider discussion on possible future activities.Results: Since its inception, IMIA has been active in the field of education, mainly through its working group on education. Among other activities, nine working conferences have been held, many of which have resulted in publications as outcomes, which have helped to exchange knowledge on the development of high-quality health and biomedical informatics education. Recommendations on education in health and medical informatics were endorsed by IMIA in 1999, and a revised version is currently in preparation.Conclusions: IMIA should continue to stimulate the exchange of knowledge on a range of aspects of health and biomedical informatics education in the countries and regions of the world, with IMIA's academic institutional members playing an increasing role. Establishing procedures for the international accreditation of high-level programs in health and biomedical informatics through IMIA is one of several areas that need to be discussed as IMIA plans and develops its future activities. [ABSTRACT FROM AUTHOR]

Complete rupture of the origin of the hamstrings is an uncommon injury. Primary surgical repair is the treatment of choice, but in some not possible. We present a case of an avid cyclist who had significant disability from a 6-year-old injury. He underwent reconstruction with Achilles allograft and suture anchors. With the knee flexed to 90 degrees and after extensive mobilization, the retracted musculotendinous unit would not reach the ischial tuberosity. Two suture anchors were placed in the ischial tuberosity after soft tissue debridement. One limb of suture from each anchor was placed in the end of an Achilles allograft with a locking suture, with the other end used to pull the end of the graft to the ischial tuberosity. An additional suture was placed in running fashion down each side of the graft. Distally, the graft was fanned out and attached to the retracted hamstrings with interrupted sutures with the knee at 40 degrees and maximal proximal pull on the hamstrings. The patient outcome was excellent. He resumed high level cycling by 6 months after surgery with no symptoms. Isokinetic testing demonstrated a hamstring deficit of 25% at 60 degrees/s, and 20% at 180 degrees/s at 8 months. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging has become an important diagnostic adjunct in the evaluation of shoulder conditions, and the technology continues to evolve. Direct magnetic resonance arthrography can improve detection of labral and rotator cuff pathology, especially partial thickness tears of the rotator cuff. Special positioning, such as abducted-externally rotated views, improves visualization of the rotator cuff and posterior superior labrum in throwing athletes. Diagnosis-specific sequencing such as fat suppression, spin-echo and proton-density techniques, and higher power magnets (3.0 T) allow for an unprecedented level of soft tissue detail. Clinical expertize is required to differentiate between normal anatomic variants, incidental findings, and true pathology. Although magnetic resonance imaging findings may be diagnostic in some cases, clinical correlation with history and physical examination findings is critical. [ABSTRACT FROM AUTHOR]

Substance use and related problems were assessed in a sample of primary care patients (n = 450) ages 13-21 who screened positive for depression at a clinic visit. Patients were classified as having no substance use (n = 248), non-problematic use (substance use without reported school, work, social, or family problems, n = 90), or use that reportedly caused problems in at least one area (n = 112). In logistic regression models, older age, externalizing symptoms, and not being African American were significantly associated with non-problematic use; older age, male gender, externalizing symptoms, Caucasian/White ethnicity/race, and more friends were associated with problematic use. Odds ratios were similar for patients reporting non-problematic and problematic use, suggesting that, in the presence of depression, any substance use merits evaluation and monitoring to determine treatment needs and to prevent escalation of dysfunction. [ABSTRACT FROM AUTHOR]

OBJECTIVE: It is well documented that injection drug users (IDUs) have a high prevalence of antibodies to hepatitis C virus (HCV). Sexual transmission of HCV can occur, but studies have shown that men who have sex with men (MSM) without a history of injection drug use are not at increased risk for infection. Still, some health-care providers believe that all MSM should be routinely tested for HCV infection. To better understand the potential role of MSM in risk for HCV infection, we compared the prevalence of antibody to HCV (anti-HCV) in non-IDU MSM with that among other non-IDU men at sexually transmitted disease (STD) clinics and human immunodeficiency virus (HIV) counseling and testing sites in three cities. METHODS: During 1999-2003, public health STD clinics or HIV testing programs in Seattle, San Diego, and New York City offered counseling and testing for anti-HCV for varying periods to all clients. Sera were tested using enzyme immunoassays, and final results reported using either the signal-to-cutoff ratio or recombinant immunoblot assay results. Age, sex, and risk information were collected. Prevalence ratios and 95% confidence intervals were calculated. RESULTS: Anti-HCV prevalence among IDUs (men and women) was between 47% and 57% at each site, with an overall prevalence of 51% (451/887). Of 1,699 non-IDU MSM, 26 (1.5%) tested anti-HCV positive, compared with 126 (3.6%) of 3,455 other non-IDU men (prevalence ratio 0.42, 95% confidence interval 0.28, 0.64). CONCLUSION: The low prevalence of anti-HCV among non-IDU MSM in urban public health clinics does not support routine HCV testing of all MSM. [ABSTRACT FROM AUTHOR]

PURPOSE: We sought to determine the practices of physicians who prescribe for adolescents extended cycles of combined hormonal contraception, in which hormones are taken for longer than 21 days and menstruation is delayed. METHODS: Five hundred physicians from the membership rosters of the Society for Adolescent Medicine and the North American Society for Pediatric and Adolescent Gynecology were asked to complete an online 39-question survey. RESULTS: The 222 respondents (44% of those contacted) were mostly pediatricians (55%) and gynecologists (34%). Ninety percent reported having ever prescribed extended cycles of hormonal contraception to adolescents, and 33% said extended cycles make up more than 10% of their total combined hormonal contraceptive prescriptions. Respondents most commonly prescribed extended cycles to accommodate patients' requests to induce amenorrhea for specific events (82%) or for fewer menses per year (72%), and to treat menorrhagia (68%), dysmenorrhea (65%), and endometriosis (62%). The most commonly prescribed extended regimen was 84 continuous hormone days followed by 7 hormone-free days (46%), most often with an oral contraceptive containing 30 mug of ethinyl estradiol. Gynecologists were more likely than other physicians to prescribe extended cycles frequently, to prescribe hormone-free intervals shorter than 7 days, and to prescribe continuous regimens that eliminate the hormone-free interval completely. CONCLUSIONS: Physicians prescribe extended cycles of combined hormonal contraceptives to adolescents to accommodate patient requests and to treat common gynecologic conditions. Currently, a variety of extended cycling regimens are prescribed, suggesting that further study is needed to determine the optimal regimen for this subset of patients and their individual needs. [ABSTRACT FROM AUTHOR]

A longitudinal randomized design was used to evaluate the impact of a theoretically based, stand-alone interactive video intervention on 300 urban adolescent girls' (a) knowledge about sexually transmitted diseases (STDs), (b) self-reported sexual risk behavior, and (c) STD acquisition. It was compared to two controls, representing high-quality informational interventions. One used the same content in book form; the other used commercially available brochures. Following randomization, the interventions were administered at baseline, with booster sessions at 1, 3, and 6 months. Self-reports revealed that those assigned to the interactive video were significantly more likely to be abstinent in the first 3 months following initial exposure to the intervention, and experienced fewer condom failures in the following 3 months, compared to controls. Six months after enrollment, participants in the video condition were significantly less likely to report having been diagnosed with an STD. A non-significant trend in data from a clinical PCR assay of Chlamydia trachomatis was consistent with that finding. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to assess identification of epithelial abnormalities of both in vivo examination as compared with colposcopically obtained images and interobserver assessment of the same images of the lower genital tract in healthy women.Materials and Methods: Ninety women between the ages of 14 and 21 years were recruited for a phase II trial of a vaginal Lactobacillus crispatus capsule. All women underwent a baseline and 1-week colposcopic examination. Multiple genital tract areas were evaluated for abnormalities and photographed. The original examiner and two experienced colposcopists reevaluated all images masked to previous interpretations. Agreement was evaluated using kappa statistics.Results: The representative kappa statistics for direct observation vs photographic interpretation for the vulva, vagina, and cervix are: 37%, -2%, and -4%, respectively. The kappa statistics comparing the three observers ranged from 1% to 39%. CONCLUSIONS.: There is poor agreement between in vivo exams and photographic interpretation, and interobserver assessments of lower genital tract photographs. [ABSTRACT FROM AUTHOR]

Twenty-five patients, admitted through a Coronary Care Unit with their first myocardial infarction (MI), were interviewed close to discharge home about (a) their perceptions regarding the causes of their MI and (b) their knowledge of coronary heart disease (CHD) risk factors. Psychosocial factors (overwork, stress, worry) were the most frequently cited causes of MI, with smoking and being overweight or overeating the most frequently cited physical causes. Knowledge of CHD risk factors concentrated on smoking, being overweight and dietary factors, although psychosocial factors were relatively frequently cited. High levels of satisfaction with staff-patient communication were expressed, but knowledge of advice given was generally vague or imprecise and concentrated on dietary modification. Smoking was well-recognized by smokers as a risk factor but less commonly related to their own MI. The main recommendation is for coronary rehabilitation information programmes to be more individualized to the patients' specific needs, based on a Personal Risk Factor and Health Beliefs Assessment for all patients. [ABSTRACT FROM AUTHOR]

PURPOSE: This article describes adolescents' attitudes and practices toward body piercing and their awareness of associated health risks. METHODS: An anonymous, 32-item, random, convenience-sample survey was administered to 225 participants, ages 12-21 years, at an urban, hospital-based, adolescent clinic. RESULTS: The mean participant age was 16.5 +/- 2.1 years; 78% were female; and 58% were African-American and 30% were Caucasian. Forty-eight percent had a body piercing. About half of participants (range, 45%-62%) endorsed each site as accepted by the public, except for nipple and genital sites, which fewer than 10% endorsed as accepted. African-Americans were more likely to have pierced noses, and to find that site acceptable, whereas Caucasians were more likely to have pierced navels and nipples, and to find those sites acceptable (odds ratio [OR] range, 3.05-19.37). Youth tended to see their own pierced site as more acceptable and less risky than others did (OR range, 8.99-23.61; effect sizes [r] range, .15-.60). The most common health problems from body piercing reported by participants from their personal experience were infection (10%), allergic reaction (1%), and bruising (1%). The most common health problems from body piercing reported by participants based on others' experiences were infection (74%), bleeding (30%), allergic reaction (26%), bruising (19%), and keloids (19%). Those who were pierced in a body-piercing shop reported more infections (18.4%) than those pierced in other places (1.9%) (OR, 11.49; 95% confidence interval [CI], 1.39-90.91). Youth who had pierced themselves perceived less risk from piercing from a nonprofessional (50%) compared with those pierced by a professional (77%) (p = .003). CONCLUSIONS: Youth from this hospital-based urban adolescent clinic considered body piercings to be generally accepted by the public. Pierced youth in our survey often participated in body piercing practices that they perceived as minimally risky and that they defined as normative. Based on these findings, clinicians should discuss body piercing in the context of providing routine anticipatory guidance to adolescents and should educate adolescents about safer piercing strategies to help minimize associated health risks. [ABSTRACT FROM AUTHOR]

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue 1-3 . Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN 4-6 . Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics 7,8 . We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy., (© 2024. The Author(s).)

Purpose: Family caregivers (CGs) of individuals with cancer are increasingly relied upon to provide long-term, sometimes intense care, although their integration into clinical cancer care remains minimal. The Caregiver Advocacy, Research, and Education (CARE) Center is a novel nurse-led academic-clinical partnership to support family CGs of individuals with gynecologic cancer. This study aims to describe the implementation of the Center protocols and report metrics of CG needs and Center support., Materials and Methods: The Center's goals are to identify, assess, and provide tailored support to CGs. Initially, Center protocols included assessment of CGs' self-identified distress (distress thermometer, 0 = no distress to 10 = extreme distress) and needs (yes or no). Tailored support on the basis of CG distress was provided by in-person and remote staff who provided complementary, concurrent support based on CG need: evidence-based self-management guides, self-management support, referral to specialty services. Center documentation was analyzed to describe Center reach and CG distress., Results: From November 2019 to June 2023, CGs (N = 1,250) were identified through referrals, new patient outreach, and inpatient visits. Seven hundred and six CGs (56.5%) were assessed through a needs-based assessment, and 515 (41.2%) CGs received tailored support. CGs were mostly men (53.0%) and the mean distress was 4.4/10 (standard deviation, 3.1). CG distress was moderately associated with CG needs including maintaining emotional (ρ = 0.40; P < .001) and physical (ρ = 0.31; P < .001) health and managing patient symptoms (ρ = 0.33; P < .001)., Conclusion: Center protocols facilitate identification of high-need CGs within a cancer clinic. Future research will longitudinally evaluate the impact of Center protocols on CG and patient outcomes, incorporating updated assessment tools.

Spiders have important ecological roles as generalist predators, are a significant source of food for many other species, and are bioindicators of environmental health. However, spiders are poorly studied. Given their importance, a comparison of spider survey methods used to determine differences in spider diversity and abundance is required to understand their limitations and biases. A new survey method to attract spiders, based on vibration from an idling diesel tractor, was tested and compared to the traditional methods of pitfall trapping and hand collection of spiders at night. Across the three survey methods, there were, in total, 2294 spiders in 34 families, 138 genera, and 226 species identified. Spider species diversity and richness were significantly greater for spiders collected at night than from the other two methods (spiders collected in pitfall traps and attracted to vibration). The collection of spiders using the night collection and vibration-based methods were very similar in terms of labor required and material costs. Of all spider species identified, 80% were captured during hand collection, 30% through pitfall trapping, and 30% from vibration-based collection. Most species of spiders caught in pitfall traps were species known to be primarily ground-dwelling, whereas both arboreal and ground-dwelling spiders were collected at night and as a result of being attracted and collected using the vibration-based method.

Targeted protein degradation (TPD) modulates protein function beyond inhibition of enzyme activity or protein-protein interactions. Most degraders function by proximity induction, and directly bridge an E3 ligase with the target to be degraded. However, many proteins might not be addressable via proximity-based degraders, and other challenges, such as resistance acquisition, exist. Here, we identified pseudo-natural products derived from (-)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs induce a unique conformational change and, thereby, boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2 KLHDC3 , which we identified to also mediate native IDO1 degradation. Therefore, iDegs supercharge the native proteolytic pathway of IDO1, rendering this mechanism of action distinct from traditional degrader approaches involving proteolysis-targeting chimeras (PROTACs) or molecular-glue degraders (MGDs). In contrast to clinically explored IDO1 inhibitors, iDegs reduce formation of kynurenine by both inhibition and induced degradation of the enzyme and should also modulate non-enzymatic functions of IDO1. This unique mechanism of action may open up new therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.

Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide 1,2 , in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes 3-7 . Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6 + CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6 + CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion., (© 2024. The Author(s).)

Genomes are self-organized and self-maintained as long, complex macromolecules of chromatin. The inherent heterogeneity, stochasticity, phase separation, and chromatin dynamics of genome operation make it challenging to study genomes using ensemble methods. Various single-molecule force-, fluorescent-, and sequencing-based techniques rooted in different disciplines have been developed to fill critical gaps in the capabilities of bulk measurements, each providing unique, otherwise inaccessible, insights into the structure and maintenance of the genome. Capable of capturing molecular-level details about the organization, conformational changes, and packaging of genetic material, as well as processive and stochastic movements of maintenance factors, a single-molecule toolbox provides an excellent opportunity for collaborative research to understand how genetic material functions in health and malfunctions in disease. In this review, we discuss novel insights brought to genomic sciences by single-molecule techniques and their potential to continue to revolutionize the field-one molecule at a time.

We explored the ecological and historical factors that led to formation of the unique guild of native and introduced mammalian herbivores between 5 and 1000 kg in northern Australia. Following the disappearance of large native herbivores about 46 kya, and until the arrival of Europeans and their livestock, the only herbivorous mammals were mid-sized endemic marsupial macropods, which continued to utilise the same vegetation as their much larger former neighbours. Only one species of contemporary native herbivore has an adult bodyweight approaching 100 kg, and for the past 150-200 years, the total biomass of introduced domestic and wild vertebrate herbivores has massively exceeded that of native herbivorous species. We conclude that the current guild of native and introduced mammalian herbivores differentially utilises the landscape ecologically. However, climate- and anthropogenically related changes due to fire, drought, flooding, predation and introduced weeds are likely to have significant impacts on the trajectory of their relative ecological roles and populations. Given their differing ecological and dietary characteristics, against this backdrop, it is unclear what the potential impact of the dispersal of deer species could have in northern Australia. We hence focus on whether sufficient knowledge exists against which the potential impacts of the range expansion of three deer species can be adequately assessed and have found a dearth of supporting evidence to inform appropriate sustainable management. We identify suitable research required to fill the identified knowledge gaps.

The yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs of metabolic enzyme substrates. The orthologous higher eukaryotic C-terminal to LisH (CTLH) E3 complex has been proposed to also recognize substrates through an alternative subunit, WDR26, which promotes the formation of supramolecular CTLH E3 assemblies. Here, we discover that human WDR26 binds the metabolic enzyme nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) and mediates its CTLH E3-dependent ubiquitylation independently of canonical GID/CTLH E3-family substrate receptors. The CTLH subunit YPEL5 inhibits NMNAT1 ubiquitylation and cellular turnover by WDR26-CTLH E3, thereby affecting NMNAT1-mediated metabolic activation and cytotoxicity of the prodrug tiazofurin. Cryoelectron microscopy (cryo-EM) structures of NMNAT1- and YPEL5-bound WDR26-CTLH E3 complexes reveal an internal basic degron motif of NMNAT1 essential for targeting by WDR26-CTLH E3 and degron mimicry by YPEL5's N terminus antagonizing substrate binding. Thus, our data provide a mechanistic understanding of how YPEL5-WDR26-CTLH E3 acts as a modulator of NMNAT1-dependent metabolism., Competing Interests: Declaration of interests B.A.S. is a member of the scientific advisory boards of Proxygen and BioTheryX and a co-inventor of intellectual property licensed to Cinsano. P.J.M. is a member of the scientific advisory boards of Palleon Pharmaceuticals and ImCheck Pharma. These relationships have no bearing on or relevance to this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)