Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation.

Actin cytoskeleton remodelling drives the migration of immune cells and their engagement in dynamic cell-cell contacts. The importance of actin cytoskeleton dynamics in immune cell function is highlighted by the discovery of inborn errors of immunity (IEIs) that are caused by defects in individual actin-regulatory proteins, resulting in immune-related actinopathies. In addition to susceptibility to infection, these often present with a vast array of autoimmune and autoinflammatory manifestations.

Teleangiectatic Osteosarcoma Treated by Surgery and Chemotherapy: A Report of 223 Affected Patients From the Cooperative Osteosarcoma Study Group (COSS).

Purpose: Teleangiectatic osteosarcoma is a histologic subtype of osteosarcoma that can mimic aneurysmal bone cysts and has so far been incompletely characterized.

Patients And Methods: We used the database of the Cooperative Osteosarcoma Study Group COSS (patient-registration 1980-2019) to better understand this rare histologic variant.

Results: 223 eligible patients were identified, 164 having reference pathology (median age 15.

Results in pediatric T-ALL patients treated in trial AIEOP-BFM ALL 2009: Prognostic factors in the context of modern risk-adapted therapy.

To improve the outcome of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients, the AIEOP-BFM ALL 2009 trial modified T-ALL stratification and treatment based on AIEOP-BFM ALL 2000 and other pediatric ALL groups' results. This report aims to describe the outcome of T-ALL patients in trial AIEOP-BFM ALL 2009 and evaluate prognostic features defined within the end of induction (EOI) therapy, for future protocols stratification and interventions. From 06/2010 to 02/2017, 872 T-ALL patients, aged 1-17, were enrolled.

Harmonized Immune Recovery Monitoring after HCT: Evidence & Practical Guidance from the Westhafen Intercontinental Group.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative option for patients with high-risk malignancies and non-malignant disorders. Long-term survival depends on robust immune reconstitution (IR), which governs overall immune homeostasis and risks of infection, graft-versus-host disease, and relapse. However, despite its centrality to post-transplant outcomes, IR is not consistently monitored across transplant centers, limiting ability to generate meaningful, comparable, and translatable data.

A stem cell differentiation model reveals two alternative fates in CBFA2T3::GLIS2-driven acute megakaryoblastic leukemia initiation.

The CBFA2T3::GLIS2 (CG) fusion protein causes aggressive pediatric acute megakaryoblastic leukemia (AMKL). Although dysregulated molecular pathways in AMKL have been identified, their role in early pre-leukemic transformation remains poorly understood. We developed a disease model utilizing genetically modified human induced pluripotent stem cells (hiPSC) physiologically and conditionally expressing CG.

International neuroblastoma risk group consortium: a model of a networking for rare cancers.

It is critical to share knowledge and harmonize approaches to optimize progress in rare cancers. The International Neuroblastoma Risk Group (INRG) Task Force was formed by the four major neuroblastoma cooperative groups in 2004 to achieve this goal. Strategies developed for neuroblastoma are an exemplar for other rare malignancies.

Image-based drug screening combined with molecular profiling identifies signatures and drivers of therapy resistance in pediatric AML.

Despite recent advances in the understanding of the genomic landscape of pediatric acute myeloid leukemia (pedAML), targeted treatments are only available for selected genomic alterations, and the functional link between genotype and outcome remains partially elusive. Functional precision medicine approaches to investigate treatment resistance and patient risk have not been applied systematically for pedAML. Here, we describe an advanced functional screening platform combining high-content imaging and deep learning-based phenotyping.

Anemia and malnutrition in geriatric hospitalized patients: a cross-sectional retrospective study.

Background: Nutritional factors contributing to anemia in older adults are in need of clarification. We investigated associations between nutritional biomarkers and the incidence of anemia.

Methods: A cross-sectional study was conducted in two centers.

Impact of minimal residual disease on the outcome of hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia within the FORUM Trial.

In the randomized cohort of the international phase-III FORUM trial, which showed the superiority of total-body irradiation (TBI) over chemotherapy-based conditioning prior to hematopoietic stem cell transplantation (HSCT) for pediatric acute lymphoblastic leukemia (ALL), type of conditioning and remission phase, but not pre-HSCT minimal residual disease (MRD), were associated with outcome. We report the impact of MRD within the extended FORUM cohort. Patients (n=1014), 4-21 years old, transplanted from a matched donor who had ≥1 MRD measurement prior to and/or 100 days and/or 1 year after HSCT were eligible.

Prognostic Value of Molecular Genetic Measurable Residual Disease (MRD) Monitoring in Pediatric Acute Myeloid Leukemia Expressing KMT2A::MLLT10.

Objectives: Pediatric AML with KMT2A::MLLT10 accounts for 10%-15% of KMT2A-rearranged AML and is associated with poor prognosis. Lately, the assessment of measurable residual disease (MRD) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) has become an important tool for disease management; however, in the pediatric setting, it lacks standardized protocols. Therefore, we investigated the prognostic relevance of MRD monitoring by RT-qPCR during high-dose polychemotherapy in pediatric patients with AML expressing KMT2A::MLLT10.

Integrated time-series analysis and high-content CRISPR screening delineate the dynamics of macrophage immune regulation.

Macrophages are innate immune cells involved in host defense. Dissecting the regulatory landscape that enables their swift and specific response to pathogens, we performed time-series analysis of gene expression and chromatin accessibility in murine macrophages exposed to various immune stimuli, and we functionally evaluated gene knockouts at scale using a combined CROP-seq and CITE-seq assay. We identified new roles of transcription regulators such as Spi1/PU.

Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma - a multi-center study.

Background: Bone marrow dissemination of tumor cells, common in various cancers, including neuroblastoma, is associated with poor outcome, necessitating sensitive detection methods for bone marrow minimal residual disease (MRD) and offer detection of biomarkers for therapy stratification. Current standard-of-care diagnostics, involving cytomorphological and histological assessment of bone marrow aspirates and trephine biopsies, lack sensitivity, leading to undetected MRD in many patients, and do not allow molecular biomarker assessment.

Methods: This study evaluates advanced multi-modal high-sensitivity MRD detection techniques in 509 bone marrow specimens from 108 high-risk neuroblastoma patients across two centers.

Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency.

GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children.

The NUDIX hydrolase NUDT5 influences purine nucleotide metabolism and thiopurine pharmacology.

Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (TPMT) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (NUDT15).

Small Particles, Big Problems: Polystyrene nanoparticles induce DNA damage, oxidative stress, migration, and mitogenic pathways predominantly in non-malignant lung cells.

Polystyrene micro- and nanoplastics (PS-MNPs) are emerging environmental pollutants with potential implications for human health. This study investigated the cytotoxic effects of PS particles by using two different sizes of PS-MNPs (0.25 µm and 1 µm) on non-small cell lung cancer (A549, H460), small cell lung cancer (DMS53, H372), and normal lung epithelial (BEAS-2B) cells as well as on human-derived lung organoids.

zHORSE as an optogenetic zebrafish strain for precise spatiotemporal control over gene expression during development.

Proper vertebrate development is dependent on tightly regulated expression of genes at the correct time and place. To identify normal but also dysregulated development leading to disease, in vivo interrogation methods with high spatiotemporal resolution are required. Recently, optogenetic tools to manipulate gene expression with spatiotemporal control have emerged, but their in vivo applications remain challenging.

Multimodal Investigation of Angiogenesis and Its Prevention by Small Compounds in a Zebrafish Cancer Model.

Aberrant angiogenesis is a hallmark of many pathologies. In cancer, tumor growth and metastasis strongly depend on angiogenesis triggered by neoplastic cells. Antiangiogenic therapies are approved to treat different kinds of cancer.

No evidence of leukaemia (NEL) as a response criteria in paediatric AML: a multicentre analysis.

Background: In AML, the assessment of response is one of the most important prognostic markers and is crucial for assessing clinical trials. Remission criteria for AML defined by Cheson et al. has remained virtually unchanged over the last two decades.

Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm.

Unlabelled: Cancer drug resistance is multifactorial, driven by heritable (epi)genetic changes but also by phenotypic plasticity. In this study, we dissected the drivers of resistance by perturbing organoids derived from patients with colorectal cancer longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single-cell multiomics analysis, evolutionary modeling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences.

Extramedullary plasmacytoma in children is a genetically distinct localized neoplasia curable by surgical resection.

Extramedullary plasmacytomas (EMPs) are exceedingly rare in children and adolescents. We describe clinical, pathological, and molecular features of 13 patients with EMP in this age group (8 males and 5 females; age 3-18 years). EMPs presented as localized disease involving the Waldeyer's ring (n = 9), larynx (n = 2), ocular adnexa (n = 1), or epipharynx and conjunctiva simultaneously (n = 1).

Probing condensate microenvironments with a micropeptide killswitch.

Biomolecular condensates are thought to create subcellular microenvironments that have different physicochemical properties compared with their surrounding nucleoplasm or cytoplasm. However, probing the microenvironments of condensates and their relationship to biological function is a major challenge because tools to selectively manipulate specific condensates in living cells are limited. Here, we develop a non-natural micropeptide (that is, the killswitch) and a nanobody-based recruitment system as a universal approach to probe endogenous condensates, and demonstrate direct links between condensate microenvironments and function in cells.

HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection.

CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner.

Colorectal Carcinoma in Childhood and Adolescence: Microsatellite Instability Correlates With a Favorable Prognosis.

Background: Colorectal cancer (CRC) accounts for 10% of cancer cases worldwide; however, pediatric CRC is extremely rare, with an annual incidence of one to two cases per million. Microsatellite instability (MSI) has been shown to play a relevant prognostic role in adult CRC. Corresponding data for pediatric CRC are lacking.