Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.

Loss of anticancer NK cell function in AML patients is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML-blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML-blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cAMP signalling, confirmed by uniform production of the cAMP-inducing prostanoid PGE2 by all AML-blast isolates from patients.

The sarcoma ring trial: a case-based analysis of inter-center agreement across 21 German-speaking sarcoma centers.

Purpose: The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers.

miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthma.

Background: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma.

Methods: We performed miRNAome-metabolome-wide association studies ('miR-metabo-WAS') in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (N = 312 and N = 454).

The Feasibility of Personalized Endpoints in Assessing Treatment Outcomes in Rare Disease: A Pilot Study of Goal Attainment Scaling in SCN2A-Associated Developmental Epileptic Encephalopathy.

Objectives: For individuals living with rare neurodevelopmental disorders, especially those who are at the most severe end of the spectrum, standardized outcome measures may lack the sensitivity to capture small but meaningful changes. Personalized endpoints such as Goal Attainment Scaling (GAS) allow the assessment of treatment response across variable baseline states and disease manifestations and thus provide a highly sensitive measure of efficacy. The current study tested the feasibility of using GAS in rare SCN2A-associated developmental and epileptic encephalopathy (SCN2A-DEE).

Saliva Proteome, Metabolome and Microbiome Signatures for Detection of Alzheimer's Disease.

As the burden of Alzheimer's disease (AD) escalates with an ageing population, the demand for early and accessible diagnostic methods becomes increasingly urgent. Saliva, with its non-invasive and cost-effective nature, presents a promising alternative to cerebrospinal fluid and plasma for biomarker discovery. : In this study, we conducted a comprehensive multi-omics analysis of saliva samples ( = 20 mild cognitive impairment (MCI), = 20 Alzheimer's disease and age- and = 40 gender-matched cognitively normal individuals), from the South Australian Neurodegenerative Disease (SAND) cohort, integrating proteomics, metabolomics, and microbiome data with plasma measurements, including pTau181.

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies.

Background: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets.

Positive reinforcement-based magnet training permits social housing in catheterized squirrel monkeys.

Background: Non-human primates play a critical role in neuroscience research. Though they are social animals, laboratory study requirements can sometimes require single housing and thereby prevent social housing.

New Method: To eliminate single housing and promote well-being within our squirrel monkey colony, we used positive reinforcement training in combination with magnetic/mechanical clasps and custom jackets to permit pair housing of catheterized squirrel monkeys used in behavioral studies.

Novel approaches to measuring cognition in individuals with severe to profound functional impairment: A pilot study in SCN2A-related disorder.

Valid clinical outcome assessments with the ability to capture meaningful aspects of neurodevelopment for individuals with neurogenetic conditions associated with profound functional impairments are lacking, yet critical for clinical care and clinical trial readiness. The purpose of this pilot study was to examine and compare the initial psychometric properties of a series of commonly used standardized and norm-referenced measures of cognition and adaptive functioning as well as alternative measures of neurobehavioral functioning designed to capture responsivity (i.e.

Unraveling the role of local ablative therapies for patients with metastatic soft tissue sarcoma - A retrospective multicenter study of the Bavarian university hospitals.

Background: Local ablative therapies (LAT) are increasingly used in patients with metastatic soft tissue sarcoma (STS), yet evidence-based standards are lacking. This study aimed to assess the impact of LAT on survival of metastatic STS patients and to identify prognostic factors.

Methods: In this retrospective multicenter study, 246 STS patients with metastatic disease who underwent LAT on tumor board recommendation between 2017 and 2021 were analyzed.

Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation.

Osteopenia and osteoporosis are common long-term complications of the cytotoxic conditioning regimen for hematopoietic stem cell transplantation (HSCT). We examined mesenchymal stem and progenitor cells (MSPCs), which include skeletal progenitors, from mice undergoing HSCT. Such MSPCs showed reduced fibroblastic colony-forming units frequency, increased DNA damage, and enhanced occurrence of cellular senescence, whereas there was a reduced bone volume in animals that underwent HSCT.

Association of with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study ( = 6144 participants of European ancestry and = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group).

Quantifying the massive pleiotropy of microRNA: a human microRNA-disease causal association database generated with ChatGPT.

MicroRNAs (miRNAs) are recognized as key regulatory factors in numerous human diseases, with the same miRNA often involved in several diseases simultaneously or being identified as a biomarker for dozens of separate diseases. While of evident biological importance, miRNA pleiotropy remains poorly understood, and quantifying this could greatly aid in understanding the broader role miRNAs play in health and disease. To this end, we introduce miRAIDD (miRNA Artificial Intelligence Disease Database), a comprehensive database of human miRNA-disease causal associations constructed using large language models (LLM).

Polygenic hazard score models for the prediction of Alzheimer's free survival using the lasso for Cox's proportional hazards model.

The prediction of the susceptibility of an individual to a certain disease is an important and timely research area. An established technique is to estimate the risk of an individual with the help of an integrated risk model, that is, a polygenic risk score with added epidemiological covariates. However, integrated risk models do not capture any time dependence, and may provide a point estimate of the relative risk with respect to a reference population.

Patient-advocate-led global coalition adapting fit-for-purpose outcomes measures to assure meaningful inclusion of DEEs in clinical trials.

Existing clinical tools that measure non-seizure outcomes lack the range and granularity needed to capture skills in developmental and epileptic encephalopathy (DEE)-affected individuals who also fall in the severe to profound range of intellectual disability. This effectively excludes those with severe impairments from clinical trials, impeding the ability of sponsors to evaluate disease-modifying therapies (DMTs). The Inchstone Project, an international, patient advocate-led collaboration, brings together leading researchers, clinicians, pharmaceutical companies, and advocates to develop an adapted, validated assessment battery within 5 years.

Prediction of disease-free survival for precision medicine using cooperative learning on multi-omic data.

In precision medicine, both predicting the disease susceptibility of an individual and forecasting its disease-free survival are areas of key research. Besides the classical epidemiological predictor variables, data from multiple (omic) platforms are increasingly available. To integrate this wealth of information, we propose new methodology to combine both cooperative learning, a recent approach to leverage the predictive power of several datasets, and polygenic hazard score models.

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes.

Rationale: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear.

Objectives: Define high-risk COPD subtypes using both genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximizing differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets.

Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders.

Objective: We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders.

Methods: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process.

Global modified-Delphi consensus on comorbidities and prognosis of SCN8A-related epilepsy and/or neurodevelopmental disorders.

Objectives: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A-related disorders.

Methods: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis.

Examining the Effect of Genes on Depression as Mediated by Smoking and Modified by Sex.

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components).

The Asthma Risk Gene, , Promotes Mitochondrial DNA-induced Expression.

Released mitochondrial DNA (mtDNA) in cells activates cGAS-STING pathway, which induces expression of interferon-stimulated genes (ISGs) and thereby promotes inflammation, as frequently seen in asthmatic airways. However, whether the genetic determinant, Gasdermin B (GSDMB), the most replicated asthma risk gene, regulates this pathway remains unknown. We set out to determine whether and how GSDMB regulates mtDNA-activated cGAS-STING pathway and subsequent induction in human airway epithelial cells.