Targeting metastasis in paediatric bone sarcomas.

Paediatric bone sarcomas (e.g. Ewing sarcoma, osteosarcoma) comprise significant biological and clinical heterogeneity.

Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor-ligand interactions.

Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging.

Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer.

Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation. It also remains unclear how the intertumor variability of mutation rates compares to intratumor diversification and evolves along disease progression, whether mutation rates are functionally relevant in CIN cancers, and which mutational processes shape mutational accrual during CIN tumor onset and evolution.

Nephrotoxicity Surveillance for Childhood and Young Adult Survivors of Cancer: Recommendations From the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Purpose: Childhood, adolescent, and young adult (CAYA) survivors of cancer are at risk of nephrotoxicity. Surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could slow the progression to higher stages of kidney dysfunction.

Methods: The International Late Effects of Childhood Cancer Guideline Harmonization Group established a multidisciplinary panel of 34 experts from 11 countries.

Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12.

Nucleoporin 98 (NUP98) fusion oncoproteins are strong drivers of pediatric acute myeloid leukemia (AML) with poor prognosis. Here we show that NUP98 fusion-expressing AML harbors an epigenetic signature that is characterized by increased accessibility of hematopoietic stem cell genes and enrichment of activating histone marks. We employ an AML model for ligand-induced degradation of the NUP98::KDM5A fusion oncoprotein to identify epigenetic programs and transcriptional targets that are directly regulated by NUP98::KDM5A through CUT&Tag and nascent RNA-seq.

MONALISA: A Privacy-Preserving Infrastructure Supporting Liquid Biopsies to Monitor Relapsed Neuroblastoma.

The survival rate for high-risk neuroblastoma remains below 50%. Current monitoring methods are costly, invasive, and stressful for patients. MONALISA will evaluate liquid biopsies as a minimally invasive alternative, to enable frequent sampling and consequently early detection of genetic tumour markers.

Data- and knowledge-derived functional landscape of human solute carriers.

The human solute carrier (SLC) superfamily of ~460 membrane transporters remains the largest understudied protein family despite its therapeutic potential. To advance SLC research, we developed a comprehensive knowledgebase that integrates systematic multi-omics data sets with selected curated information from public sources. We annotated SLC substrates through literature curation, compiled SLC disease associations using data mining techniques, and determined the subcellular localization of SLCs by combining annotations from public databases with an immunofluorescence imaging approach.

Clec12a is required for the pathogenesis of NUP98::NSD1 AML.

NUP98::NSD1 is one of the most recurring nucleoporin 98 (NUP98) fusions in acute myeloid leukemia (AML). NUP98::NSD1 positive AML is often associated with adverse outcomes and poor response to conventional treatments. However, limited studies have been done to identify new potential targets to develop better treatment approaches.

Dissecting the immune landscape in pediatric high-grade glioma reveals cell state changes under therapeutic pressure.

Pediatric high-grade gliomas (pHGGs) are among the most lethal childhood tumors. While therapeutic approaches were largely adapted from adult treatment regime, significant biological differences between pediatric and adult gliomas exist, which influence the immune microenvironment and may contribute to the limited response to current pHGG treatment strategies. We provide a comprehensive transcriptomic analysis of the pHGG immune landscape using single-cell RNA sequencing and spatial transcriptomics.

The role of microheterogeneity in cell fate decisions in neural progenitors and neural crest.

Neuroprogenitors must integrate a multitude of signals, including gradients of morphogens, transcriptional programs, and temporal cues to generate an astonishing diversity of cell types inhabiting the nervous system. How do these different layers of information come together to influence cell fate in progenitor cells in a coordinated way? Here we provide a nuanced perspective on cell fate selection in the nervous system and neural crest lineage, suggesting that it is not a straightforward, deterministic process governed by rigid on-off switches. Instead, the process involves probabilistic transitions influenced by small variations - termed "microheterogeneity" - within a progenitor cell population.

DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes.

The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization.

High-Content Imaging-Based Screening for Anticancer Compounds in Zebrafish Xenografts.

Larval zebrafish xenografts are a vertebrate model system suited for screening small compounds towards their anticancer effects. The small size and transparency of zebrafish larvae allow for phenotypic screening in 96-well format. Due to the achievable throughput in a living vertebrate organism, zebrafish xenografts promise to bridge the gap between in vitro screening and testing compounds in mouse xenografts.

Clinical and Immunological Prognostic Factors With Novel Variants in a Large Cohort of Diacylglycerol Acyltransferase 1 Deficiency.

Background: Biallelic variants in diacylglycerol acyltransferase 1 (DGAT1) genegene have been implicated congenital diarrhea and protein-losing enteropathy. Insights into the immunopathologic features of this ultrarare disorder remain scarce, with only one cohort published to date.

Objective: To delineate the clinical presentations, laboratory and immunologic profiles, and therapeutic responses associated with DGAT1 deficiency and identify prognostic indicators that affect survival rates.

Effective targeting of PDGFRA-altered high-grade glioma with avapritinib.

PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans.

YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1-mediated reprogramming of bone mesenchymal stem cells.

Ewing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatment. Insulin-like growth factor (IGF)-1 is an autocrine growth factor for EwS, but only 10% of patients respond to IGF-1 receptor (IGF-1R) blockade. Although EwS is presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a mouse model does not result in tumor formation but in skeletal malformations and perinatal death.

Flow-cytometric MRD detection in pediatric T-ALL: a multicenter AIEOP-BFM consensus-based guided standardized approach.

Objectives: Risk-based stratification approaches using measurable residual disease (MRD) successfully help to identify T-acute lymphoblastic leukemia (T-ALL) patients at risk of relapse, whose treatment outcomes are very poor. Because of T-ALL heterogeneity and rarity, a reliable and standardized approach for flow cytometry (FC)-based MRD measurement and analysis is often missing.

Methods: Within the international AIEOP-BFM-ALL-FLOW study group we made a consensus on markers and a standard operating procedure for common 8- and 12-color T-ALL MRD panels.

Risk stratification in neuroblastoma patients through machine learning in the multicenter PRIMAGE cohort.

Introduction: Neuroblastoma, the most prevalent solid cancer in children, presents significant biological and clinical heterogeneity. This inherent heterogeneity underscores the need for more precise prognostic markers at the time of diagnosis to enhance patient stratification, allowing for more personalized treatment strategies. In response, this investigation developed a machine learning model using clinical, molecular, and magnetic resonance (MR) radiomics features at diagnosis to predict patient's overall survival (OS) and improve their risk stratification.

Management of children and adolescents with chronic myeloid leukemia in chronic phase: International pediatric chronic myeloid leukemia expert panel recommendations.

The treatment strategy for children and adolescents with chronic myeloid leukemia in the chronic phase (CML-CP) has evolved from allogeneic hematopoietic stem cell transplantation (HSCT) to tyrosine kinase inhibitors (TKIs). With the advent of next-generation TKIs and new targeted therapies in the CML field, an international pediatric CML expert panel provides recommendations based on the medical literature (including previous pediatric guidelines), national standards, and treatment principles used in adults with CML-CP. Recommendations include diagnosis of the disease and details on managing the initial steps of care of children and adolescents with newly diagnosed CML-CP, including complications such as leukostasis.

Ask, do not tell: consulting a patient advisory board to understand unmet needs of patients with GVHD in Europe.

Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation (HCT) that has a low chance of complete remission and a substantial effect on morbidity and mortality. To better understand how to improve the field of GVHD research, management, and care, the cGVHD Eurograft Initiative organised a European community advisory board of patient advocates, with the assistance of the Lymphoma Coalition, to identify unmet needs. We present the results of this project in this Viewpoint, which identify unmet GVHD needs from the patient advocates' perspectives and provide five key actionable themes to improve GVHD management and care.

Evaluation of Patients with Combined Immunodeficiency: A Single Center Experience.

Background: Severe combined immunodeficiency (SCID) is the most severe form of inborn errors of immunity (IEIs) and typically leads to death within the first year of life. Combined immunodeficiencies (CID) are immune disorders that are less severe than SCID and are characterized by qualitative or quantitative defects in T and B cells.

Objective: To explore the clinical, laboratory, and genetic diagnostic approaches for patients diagnosed with SCID and CID.

The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation.

Regulatory T (T) cells are a critical immune component guarding against excessive inflammation. T cell dysfunction can lead to chronic inflammatory diseases with current therapies aimed at inhibiting effector T cells rather than rescuing T cell function. We utilized single-cell RNAsequencing data from patients with chronic inflammation to identify SAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a driver of skin-resident T cell dysfunction.

Precise photopharmacological eradication of metastatic tumor cells.

Owing to their high efficacy, antimitotic chemotherapeutics are the mainstay for most cancer treatments. However, these drugs do not discriminate between tumor and healthy cells, thus show dose-limiting toxicity and severe adverse effects. To improve treatments, rendering chemotherapeutics tumor-cell specific is highly desirable.

Ex vivo T-lymphopoiesis assays assisting corrective treatment choice for genetically undefined T-lymphocytopenia.

Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. Ex vivo T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients.

Extracellular vesicles in uveal melanoma - Biological roles and diagnostic value.

Uveal melanoma (UM), which originates from the uveal tract of the eye, is the most common and aggressive intraocular cancer in adults. The detection of genetic markers is crucial for an accurate diagnosis, but this requires tumor biopsies that can be challenging to obtain. Extracellular vesicles (EVs) have emerged as potential biomarkers for UM due to their presence in biological fluids and their ability to carry disease-related biomolecules such as proteins and nucleic acids.