Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome.

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of ∼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.

JAK inhibition decreases the autoimmune burden in Down syndrome.

Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmune disorders and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. Here, we report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS. We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. We then report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. Analysis of the first 10 participants to complete the 16-week study shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. ClinicalTrials.gov identifier: NCT04246372.

Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome.

Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.

Moving the needle: Quality improvement strategies to achieve guideline-concordant care of obstetric patients with severe hypertension.

OBJECTIVES: To improve timely treatment and follow-up of birthing individuals with severe hypertension. STUDY DESIGN: A quality improvement (QI) initiative was implemented at an academic tertiary care center in the United States of America for individuals with obstetric hypertensive emergencies. Statistical process control charts were utilized to track process measures and interventions tested through plan-do-study-act cycles. Measures were disaggregated by race and ethnicity to identify and improve disparities. MAIN OUTCOME MEASURES: Treatment of hypertensive events within 60 min, receipt of blood pressure (BP) device at discharge and completed postpartum follow-up BP check within 7 days of discharge. RESULTS: All process measures showed statistically significant improvements. The primary process measure, timely treatment of hypertensive emergencies, improved from 29 % to 76 %. Receipt of BP device improved from 37 % to 91 % and follow-up BP checks from 58 % to 81 %. No racial or ethnic disparities were noted at baseline or after interventions. Readmission rates within 6 weeks of delivery increased from 2.3 % to 6.1 % for the cohort with no severe morbidity or mortality events after discharge. Strategies associated with improvement included project launch with establishment of the "why," telehealth, simulation, a video display of quality metrics on the birthing unit, promoting BP cuff access, and automated orders. CONCLUSIONS: This comprehensive QI initiative provides novel improvement strategies for the management of individuals with severe hypertensive disorders of pregnancy for the timely treatment of severe BP, attainment of home BP devices, and follow-up after discharge. Quality improvement methodology is practical and essential for achieving guideline-concordant care.

Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM.

This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.

Classroom Innovation Using the NCJMM: Preparing Nursing Students for the Next Generation NCLEX.

BACKGROUND: There is a growing demand for classroom creativity to increase engagement and build clinical judgment skills for nursing students. This article describes the design and implementation of an interactive classroom activity to enhance the development of clinical judgment while simultaneously orienting students to the new NCLEX Next Generation testing model. METHOD: Faculty developed an interactive unfolding case study incorporating the six dimensions of the NCSBN Clinical Judgment Measurement Model. The case study question types were adapted to use an interactive learning platform for first-year nursing students. Students' perceptions of learning, engagement, and clinical judgment were surveyed. RESULTS: Student responses regarding the case study implementation indicated this method was effective in maintaining engagement and persistence, as well as promoting nursing decision making. CONCLUSION: The time used for building innovative classroom activities is well spent to meet the objective of enhancing clinical judgment in the next generation of nursing students. [J Nurs Educ. 2024;63(3):188-191.].

Modeling the health impact of increasing vaccine coverage and nonpharmaceutical interventions against coronavirus disease 2019 in Ghana.

Seroprevalence studies assessing community exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Ghana concluded that population-level immunity remained low as of February 2021. Thus, it is important to demonstrate how increasing vaccine coverage reduces the economic and public health impacts associated with SARS-CoV-2 transmission. To that end, this study used a Susceptible-Exposed-Presymptomatic-Symptomatic-Asymptomatic-Recovered-Dead-Vaccinated compartmental model to simulate coronavirus disease 2019 (COVID-19) transmission and the role of public health interventions in Ghana. The impact of increasing vaccination rates and decline in transmission rates due to nonpharmaceutical interventions (NPIs) on cumulative infections and deaths averted was explored under different scenarios. Latin hypercube sampling-partial rank correlation coefficient (LHS-PRCC) was used to investigate the uncertainty and sensitivity of the outcomes to the parameters. Simulation results suggest that increasing the vaccination rate to achieve 50% coverage was associated with almost 60,000 deaths and 25 million infections averted. In comparison, a 50% decrease in the transmission coefficient was associated with the prevention of about 150,000 deaths and 50 million infections. The LHS-PRCC results indicated that in the context of vaccination rate, cumulative infections and deaths averted were most sensitive to vaccination rate, waning immunity rates from vaccination, and waning immunity from natural infection. This study's findings illustrate the impact of increasing vaccination coverage and/or reducing the transmission rate by NPI adherence in the prevention of COVID-19 infections and deaths in Ghana.

Integrating wellness into curricula using the ten dimensions of wellness as a framework.

Burnout is a public health crisis that persists at the expense of clinician well-being, the healthcare workforce, and the quality of care provided. Clinician well-being is a professional imperative, yet nursing students still report higher levels of burnout than non-nursing students. Cultivating an academic learning environment that supports the development of resiliency, well-being, and improved student mental health requires a coordinated and sustained effort from nurse educators and academic leaders. This article aims to inspire nurse educators to take the first or next steps toward integrating wellness into nursing curricula. The ten dimensions of wellness provide a framework for wellness programming. Practical strategies aligned with each dimension are offered. As an exemplar, the Banding Together for Wellness program is summarized, including innovative incentives for student participation. Over the past five years, 426 (approximately 54 %) undergraduate nursing students voluntarily completed the program. While best practices may vary by institution, the strategies and resources offered herein can support nurse educators in the classroom, lab, and clinical setting as we all work to foster personal and professional well-being in nursing students. Nurse educators can be instrumental in cultivating the knowledge, skills, and attitudes required for life-long self-care, well-being, and nursing practice.

Academic-Practice Partnership to Strengthen Nursing Care of Older Adults.

A long-standing academic-practice partnership was leveraged to facilitate student learning opportunities pertaining to care provision for older adults living with multiple chronic conditions and complex medical problems. Students from a gerontological nursing course in an accelerated baccalaureate nursing program were partnered with gerontology-educated population health nurses in primary care settings. Students observed how population health nurses integrated the Institute for Healthcare Improvement Age-Friendly 4Ms framework into clinical practice as they performed behavioral, psychosocial, and biometric health risks assessments for older adults during their Medicare annual wellness visit. The population health nurses served as role models for professional delivery of age-friendly care including preventative health and wellness care. Student confidence and perception of their understanding of age-friendly and gerontological nursing care improved. Post clinical experience debrief sessions and clinical reflection assignments demonstrated students' admiration of the expansive role and person-centered approach that population health nurses undertake to ensure comprehensive assessment and wellness promotion. Students appreciated the fluidity of population health nurses' conversation regarding the things that matter most to older adults with complex medical conditions.

Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.

Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline.

In both vertebrates and invertebrates, commissural neurons prevent premature responsiveness to the midline repellant Slit by downregulating surface levels of its receptor Roundabout1 (Robo1). In Drosophila, Commissureless (Comm) plays a critical role in this process; however, there is conflicting data on the underlying molecular mechanism. Here, we demonstrate that the conserved PY motifs in the cytoplasmic domain of Comm are required allow the ubiquitination and lysosomal degradation of Robo1. Disruption of these motifs prevents Comm from localizing to Lamp1 positive late endosomes and to promote axon growth across the midline in vivo. In addition, we conclusively demonstrate a role for Nedd4 in midline crossing. Genetic analysis shows that nedd4 mutations result in midline crossing defects in the Drosophila embryonic nerve cord, which can be rescued by introduction of exogenous Nedd4. Biochemical evidence shows that Nedd4 incorporates into a three-member complex with Comm and Robo in a PY motif-dependent manner. Finally, we present genetic evidence that Nedd4 acts with Comm in the embryonic nerve cord to downregulate Robo1 levels. Taken together, these findings demonstrate that Comm promotes midline crossing in the nerve cord by facilitating Robo ubiquitination by Nedd4, ultimately leading to its degradation.

External validation of GO-FAR 2 calculator for outcomes after in-hospital cardiac arrest with comparison to GO-FAR and trial of expanded applications.

Aim: Externally validate the GO-FAR 2 tool for predicting survival with good neurologic function after in-hospital cardiac arrest with comparison to the original GO-FAR tool. Additionally, we collected qualitative descriptors and performed exploratory analyses with various levels of neurologic function and discharge destination. Methods: Retrospective chart review of all patients who underwent in-hospital resuscitation after cardiac arrest during the calendar years 2016-2019 in our institution (n = 397). GO-FAR and GO-FAR 2 scores were calculated based on information available in the medical record at the time of hospital admission. Cerebral performance category (CPC) scores at the time of admission and discharge were assessed by chart review. Results: The GO-FAR 2 score accurately predicted outcomes in our study population with a c-statistic of 0.625. The original GO-FAR score also had accurate calibration with a stronger c-statistic of 0.726. The GO-FAR score had decreased predictive value for lesser levels of neurologic function (c-statistic 0.56 for alive at discharge) and discharge destination (0.69). Descriptors of functional status by CPC score were collected. Conclusion: Our findings support the validity of the GO-FAR and GO-FAR 2 tools as published, but the c-statistics suggest modest predictive discrimination. We include functional descriptors of CPC outcomes to aid clinicians in using these tools. We propose that information about expected outcomes could be valuable in shared decision-making conversations.

Effects of Educational Interventions in Facilitating Mammography Screening Among Asian American Women: A Meta-Analysis.

PROBLEM IDENTIFICATION: This meta-analysis evaluated the effects of various types of educational interventions on increasing breast cancer screening uptake among Asian American women. LITERATURE SEARCH: Web of Science, MEDLINE®, PubMed®, and Cochrane Library were searched for randomized controlled trials published from 2010 to 2020 of interventions developed to promote mammography uptake among Asian American women. DATA EVALUATION: A random-effects model was used to estimate pooled effect sizes using relative risk measures. A funnel plot was used to assess publication bias. SYNTHESIS: Seven studies were included in this review. Educational interventions identified were primarily culturally sensitive approaches combined with access-enhancing, individually tailored, or group-based approaches. The interventions were effective at increasing the receipt of mammography. IMPLICATIONS FOR NURSING: This review provides insight into the importance of combining other approaches with educational interventions to increase their effectiveness for Asian American women. Future interventions can incorporate various approaches to enhance the ability of Asian American women to overcome barriers to breast cancer screening.

Down syndrome is associated with altered frequency and functioning of tracheal multiciliated cells, and response to influenza virus infection.

Individuals with Down syndrome (DS) clinically manifest severe respiratory illnesses; however, there is a paucity of data on how DS influences homeostatic physiology of lung airway, and its reactive responses to pulmonary pathogens. We generated well-differentiated ciliated airway epithelia using tracheas from wild-type and Dp(16)1/Yey mice in vitro, and discovered that Dp(16)1/Yey epithelia have significantly lower abundance of ciliated cells, an altered ciliary beating profile, and reduced mucociliary transport. Interestingly, both sets of differentiated epithelia released similar quantities of viral particles after infection with influenza A virus (IAV). However, RNA-sequencing and proteomic analyses revealed an immune hyperreactive phenotype particularly for monocyte-recruiting chemokines in Dp(16)1/Yey epithelia. Importantly, when we challenged mice in vivo with IAV, we observed immune hyper-responsiveness in Dp(16)1/Yey mice, evidenced by higher quantities of lung airway infiltrated monocytes, and elevated levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid. Our findings illuminate mechanisms underlying DS-mediated pathophysiological changes in airway epithelium.

Enhancing early parenting in the community: Preliminary results from a learning collaborative approach to scale up Attachment and Biobehavioral Catch-up.

Attachment and Biobehavioral Catch-up (ABC) is a promising home-visiting intervention promoting sensitive caregiving and secure parent-child attachment in families with young children. The goal of this study was to examine a learning collaborative approach to disseminating ABC in a community setting. Training outcomes (e.g., trainee completion, satisfaction, effectiveness of training methods) and intervention outcomes (e.g., parent behavior, parent beliefs, child socioemotional development) were examined. Eighteen practitioners participated in the ABC learning collaborative; 13 completed training. Quantitative and qualitative measures indicated that trainees were satisfied with their experience and valued the unique collaboration opportunities offered by the learning collaborative. In addition, trainees served 67 families in the community, 37 of whom completed all sessions of ABC. The study was conducted in the United States. Racial demographics of the children in the sample included: 56.7% White, 22.4% Black/African-American, 17.9% Bi- or Multi-racial, and 3.0% unknown. Regarding ethnicity, 80.6% were Non-Hispanic/Latino, 10.4% were Hispanic/Latino, and 9.0% were unknown. Caregivers who completed ABC showed more sensitive parenting behavior and reported positive changes in their perceived self-efficacy and their beliefs around infant crying. Children who received ABC showed increased socioemotional functioning. Results demonstrate successful dissemination of ABC in the community using a learning collaborative approach.

El Alcance de Afectividad y Bio-comportamiento (ABC) es una prometedora intervención de visita a casa que promueve el cuidado sensible y una relación progenitor-niño segura en familias con niños pequeños. El propósito de este estudio fue examinar un acercamiento de aprendizaje colaborativo para diseminar el ABC en un escenario comunitario. Se examinaron los resultados de entrenamiento (v.g. que el entrenado completó el proceso, satisfacción, efectividad de los métodos de entrenamiento) y los resultados de intervención (v.g. comportamiento del progenitor, creencias del progenitor, desarrollo socioemocional del niño). Dieciocho profesionales en la práctica participaron en el proceso de aprendizaje colaborativo; 13 completaron el entrenamiento, Las medidas cuantitativas y cualitativas indicaron que quienes se entrenaban estaban satisfechos con su experiencia y valoraron las oportunidades de colaboración que el proceso de aprendizaje colaborativo ofrecía de manera única. Adicionalmente, quienes se entrenaban les sirvieron a 67 familias en la comunidad, 37 de las cuales completaron todas las sesiones del ABC. El estudio se llevó a cabo en los Estados Unidos. Los perfiles demográficos raciales de los niños incluyen: 56.7% de raza blanca, 22.4% de raza negra o Afroamericanos, 17.9% birraciales o multirraciales, con un 3.0% cuya raza se desconoce. En cuanto a la etnicidad, 80.6% no eran hispanos o latinos, 10.4% eran hispanos o latinos, con un 9.0% cuya etnicidad se desconoce. Los cuidadores que completaron el ABC mostraron una conducta de crianza más sensible y reportaron cambios positivos en cuanto a su percepción de auto efectividad y su creencia acerca del llanto del infante. Los niños que recibieron el ABC mostraron un aumento en su funcionamiento socioemocional. Los resultados demuestran una exitosa diseminación del ABC en la comunidad usando un acercamiento de aprendizaje colaborativo.

L'attachement et le rattrapage bio-comportemental (en anglais Attachment and Biobehavioral Catch-up, soit ABC) est une intervention prometteuse de visite à domicile promouvant des soins sensibles et un attachement parent-enfant sécure chez les familles avec de jeunes enfants. Le but de cette étude est d'examiner une approche collaborative d'apprentissage à la dissémination de l'ABC dans le contexte d'une communauté. Les résultats de la formation (par exemple le fait de terminer le stage, la satisfaction, l'efficacité des méthodes de formation) et les résultats de l'intervention (par exemple le comportement du parent, les croyances parentales, le développement socio-émotionnel de l'enfant) ont été examinés. Dix-huit praticiens ont participé à la collaboration d'apprentissage ABC; 13 ont terminé la formation. Les mesures quantitatives and qualitatives ont indiqué que les stagiaires étaient satisfaits de leur expérience et avaient apprécié la chance d'une collaboration unique offerte par la collaboration d'apprentissage. De plus les stagiaires ont aidé 67 familles dans la communauté, 37 d'entre elles ayant terminé toutes les séances de l'ABC. L'étude a été faite aux Etats-Unis d'Amérique. Les données démographiques raciales des enfants dans l'échantillon ont inclus: 56,7% blancs, 22,4% noirs américains, 17,9% métisses ou multi-ethniques, et 3,0% de race inconnue. Concernant l'ethnicité, 80,6% était Non-Hispaniques/Non-Latinos, 10,4% étaient Hispaniques/Latinos et 9,0% étaient d'une ethnicité inconnue. Les personnes prenant soin des enfants qui ont complété l'ABC ont fait preuve d'un comportement de parentage plus sensible et fait état de changements positifs dans leur auto-efficacité perçue et leurs croyances concernant les pleurs des bébés. Les enfants ayant reçu l'ABC ont démontré un fonctionnement socio-émotionnel plus élevé. Les résultats démontrent une dissémination réussie de l'ABC dans une communauté en utilisant une approche collaborative d'apprentissage.

Evaluation of a retinol containing topical treatment to improve signs of neck aging.

BACKGROUND: The neck region is an area that can be indicative of signs of skin aging. A novel topical product that combines multiple active ingredients including retinol, tripeptide and glaucine was formulated to specifically target neck aging correction and complement post-procedure as part of an integrated skincare regimen. OBJECTIVES: To evaluate the efficacy of a topical neck treatment through clinical subject evaluation, in addition to ultrasound and biopsy assessment. METHODS: Evaluation for the efficacy of this novel topical product on improving the aging signs of neck skin was performed in multiple clinical trials. The first trial focused on clinical efficacy and included clinical assessment, subject questionnaires, ultrasound imaging and digital photographs. The second trial focused on biomarker analysis through skin biopsy. RESULTS: Data from the clinical trials showed that aging signs on the neck were significantly improved after 12 or 16 weeks of product usage. Changes were readily observed by clinical evaluators and participants. They were documented with digital photos, ultrasound images, and biomarker expression in the skin which clearly display the improvements. CONCLUSIONS: This novel topical product is effective in treating the aging signs on the neck skin and has been shown to provide statistically significant improvement on a myriad of neck aging attributes including fine lines/wrinkles, crepiness, laxity, and texture.

Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition.

Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS.

Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model.

Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.

Proteasome Inhibition Sensitizes Liposarcoma to MDM2 Inhibition with Nutlin-3 by Activating the ATF4/CHOP Stress Response Pathway.

Liposarcoma is the most commonly occurring soft-tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacologic studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma. SIGNIFICANCE: Targeting the proteasome in combination with MDM2 inhibition activates the ATF4/CHOP stress response axis to induce apoptosis in liposarcoma, providing a potential therapeutic approach for the most common soft-tissue sarcoma.