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The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

These patients were further stratified by ctDNA levels and GS, and those unfavorable GS or ctDNA concentration >4 log hGE/ml presented worse PFS and OS than without risk factors a 3-year PFS of 34.6% and 90.9%, respectively (Figure 1B). Circulating tumour DNA concentration and genetic classification improve risk stratification in newly diagnosed patients with Diffuse Large B-Cell Lymphoma B Introduction: b Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease with poor outcomes for the 40% of patients who relapse or are refractory to upfront therapy, and current prognostic tools are unable to identify many of those patients. [Extracted from the article]

Zirconium titanate is a well known compound in the field of electroceramics, although it has also been used in catalyst and sensors applications. The crystallographic thermal expansion anisotropy of this compound makes it a potential candidate as constituent of structural components. In general, to assure the structural integrity and microstructural homogeneity of a ceramic piece, relatively low cooling rates from the fabrication temperature are required. This requirement is essential for zirconium titanate because thermal expansion as well as phase distribution is affected by small variations in the composition and cooling rate. This work reviews the available data on the phase equilibrium relationships in the systems ZrO2-TiO2 and ZrO2-TiO2-Y2O3. The main discrepancies as well as the possible origins of them are discussed. Additionally, the crystallographic thermal expansion data in the current literature are reviewed.El titanato de circonio es un compuesto muy usado en aplicaciones electrocerámicas, aunque también se han descrito aplicaciones en el campo de la catálisis y de los sensores. Dada la anisotropía en la expansión térmica cristalográfica de este compuesto, podría ser planteado como constituyente de componentes estructurales. En general, para asegurar la integridad estructural y la homogeneidad microestructural de una pieza cerámica, es preciso utilizar velocidades de enfriamiento desde la temperatura de fabricación relativamente bajas. Este requerimiento tiene una importancia fundamental en el titanato de circonio, ya que pequeñas variaciones en la composición y en la velocidad de enfriamiento, producen variaciones significativas tanto en la distribución de fases como en la expansión térmica. En este trabajo se revisan los trabajos existentes sobre la estabilidad del titanato de circonio dentro de los sistemas ZrO2-TiO2 y ZrO2-TiO2-Y2O3. Se describen las principales discrepancias acerca de las fases compatibles existentes en la bibliografía actual y se discute el posible origen de estas discrepancias. Asimismo, se revisan los datos existentes sobre la expansión térmica cristalográfica de este compuesto.

Steroids are a mainstay in the treatment of acute lymphoblastic leukaemia (ALL) in children and adolescents; however, their use can cause clinically significant steroid-related neuropsychiatric symptoms (SRNS). As current knowledge on SRNS during ALL treatment is limited, we mapped the phenotypes, occurrence and treatment strategies using a database created by the international Ponte di Legno Neurotoxicity Working Group including data on toxicity in the central nervous system (CNS) in patients treated with frontline ALL protocols between 2000 and 2017. Ninety-four of 1813 patients in the CNS toxicity database (5.2%) experienced clinically significant SRNS with two peaks: one during induction and one during intensification phase. Dexamethasone was implicated in 86% of SRNS episodes. The most common symptoms were psychosis (52%), agitation (44%) and aggression (31%). Pharmacological treatment, mainly antipsychotics and benzodiazepines, was given to 87% of patients while 38% were hospitalised due to their symptoms. Recurrence of symptoms was reported in 29% of patients and two previously healthy patients required ongoing pharmacological treatment at the last follow up. Awareness of SRNS during ALL treatment and recommendation on treatment strategies merit further studies and consensus., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Collective intelligence underpins the success of groups, organizations, markets and societies. Through distributed cognition and coordination, collectives can achieve outcomes that exceed the capabilities of individuals-even experts-resulting in improved accuracy and novel capabilities. Often, collective intelligence is supported by information technology, such as online prediction markets that elicit the 'wisdom of crowds', online forums that structure collective deliberation or digital platforms that crowdsource knowledge from the public. Large language models, however, are transforming how information is aggregated, accessed and transmitted online. Here we focus on the unique opportunities and challenges this transformation poses for collective intelligence. We bring together interdisciplinary perspectives from industry and academia to identify potential benefits, risks, policy-relevant considerations and open research questions, culminating in a call for a closer examination of how large language models affect humans' ability to collectively tackle complex problems., (© 2024. Springer Nature Limited.)

Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising six genetic subtypes and seven B-cell controls from two independent cohorts we demonstrated that circRNAs properly stratified B-ALL subtypes. By differential expression analysis of each subtype vs. controls, 156 overexpressed and 134 underexpressed circRNAs were identified consistently in at least one subtype, most of them with subtype-specific expression. TCF3::PBX1 subtype was the one with the highest number of unique and overexpressed circRNAs, and the circRNA signature could effectively discriminate new patients with TCF3::PBX1 subtype from others. Our results indicated that NUDT21 , an RNA-binding protein (RBP) involved in circRNA biogenesis, may contribute to this circRNA enrichment in TCF3::PBX1 ALL. Further functional characterization using the CRISPR-Cas13d system demonstrated that circBARD1 , overexpressed in TCF3::PBX1 patients and regulated by NUDT21 , might be involved in leukemogenesis through the activation of p38 via hsa-miR-153-5p . Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL.

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Although recent multi-omic studies have led to advances in MB classification, there is still room for improvement with regard to treatment response and survival. Therefore, identification of new and less invasive biomarkers is needed to refine the diagnostic process and to develop more personalized treatment strategies. In this context, non-coding RNAs (ncRNAs) could be useful biomarkers for MB. In this article, we reviewed the role of two types of ncRNAs, long non-coding (lncRNAs) and circular RNAs (circRNAs), as biomarkers for the diagnosis, subgroup classification, and prognosis of MB. We also reviewed potential candidates with specific functions and mechanisms of action in the disease. We performed a search in PubMed and Scopus using the terms ("long non coding RNAs" OR "lncRNAs") and ("circular RNAs" OR "circRNAs") AND "medulloblastoma" to identify biomarker discovery or functional studies evaluating the effects of these ncRNAs in MB. A total of 26 articles met the inclusion criteria. Among the lncRNAs, the tumorigenic effects of the upregulated lnc-IRX3-80 and lnc-LRRC47-78 were the most studied in MB. Among the circRNAs, the upregulation of circSKA3 and its functional impact in MB cell lines were the most consistent results, so this circRNA could be considered a potential biomarker in MB. Additional validation is required for many deregulated lncRNAs and circRNAs; therefore, further studies are warranted.

Despite being considered a single disease, Diffuse Large B Cell Lymphoma (DLBCL) presents with variable backgrounds, which results in heterogeneous outcomes among patients, with 40% of them still having primary refractory disease or relapse. Thus, novel biomarkers are needed. In addition, multiple factors regarding its pathogenesis remain unclear. In this context, recent investigations point to the relevance of microRNAs (miRNAs) in cancer. However, regarding DLBCL, there is inconsistency in the data reported. Therefore, in this work, the main goals were to determine a miRNA set with utility as biomarkers for DLBCL diagnosis, classification, prognosis and treatment response, as well as to decipher the mechanism of action of deregulated miRNAs in the origin of the disease. We analyzed miRNA expression in a cohort of 78 DLBCL patients and 17 controls using small RNA sequencing and performed a miRNA-mRNA interaction network analysis. This way, we were able to define new miRNA expression signatures for diagnosis, classification, treatment response and prognosis, and we identified plausible mechanisms of action by which deregulated miRNAs could be involved in DLBCL pathogenesis. In summary, our study remarks that miRNAs could play an important role in DLBCL., (© 2023. The Author(s).)

Many of the most common diseases are influenced by a combination of multiple factors, which include environmental effectors, as well as genetic and epigenetic variations [...].

Background: White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood., Methods: We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations., Results: We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (ρ BCP-ALL  = -.17, ρ T-ALL  = -.19; p < 3 × 10 -4 ). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ = .43, p << 2 × 10 -6 ). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation., Conclusion: These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Childhood acute lymphoblastic leukemia (ALL), the most common pediatric cancer, is a heterogeneous disease comprised of multiple molecular subtypes with distinct somatic genetic alterations, which results in different outcomes for the patients. Accurate patient risk stratification through genetic markers could increase survival rates, but the identification of reliable biomarkers is needed, as 20‑30% of B‑ALL patients cannot be classified in the clinic with routine techniques and some patients classified as low‑risk and good‑responders to treatment will eventually relapse. Long non‑coding RNAs (lncRNAs) can represent novel candidates with diagnostic, classification, prognosis, and treatment response potential. However, regarding childhood ALL, there is inconsistency in the data reported due to the lack of a consensus nomenclature for lncRNA naming and the methodology and designing applied for their study. Therefore, the aim of the article is to clarify the potential of lncRNAs as biomarkers in childhood ALL through a systematic review. From a revision of 23 manuscripts, it was found that AWPPH overexpression could represent a novel marker for ALL diagnosis, including both B and T immunophenotypes, and 18 lncRNAs were specifically associated with B‑cell ALL (B‑ALL) patients. We identified subtype‑specific signatures for ETV6‑RUNX1 , hyperdiploidy and KMT2A subtypes. These signatures hold promise as novel diagnostic markers and could refine the classification of patients.

Background: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of incidence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contemporary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking., Method and Patients: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Information on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis., Results: Newly diagnosed patients with ALL (n = 5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence interval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively., Conclusion: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leiah J Brigitha: none. Marta Fiocco: none. Rob Pieters received research support and consultancy fees from Jazz Pharmaceuticals and Servier. Birgitte K Albertsen is sponsor of the investigator-initiated trial NOR-GRASPALL2016 supported by Erytech and was speaker and/or Advisory Board Honoraria from Erytech (2021) and Servier (2021). Gabriele Escherich: none. Elixabet Lopez-Lopez: none. Veerle Mondelaers acknowledges support from the Cancer Plan Action 29 from the Belgian Federal Public Service of Health, the Flemisch League Against Cancer and vzw. Kinderkankerfonds. Ajay Vora acknowledges Bloodwise funding for UKALL 2011. Lynda Vrooman: none. Kjeld Schmiegelow was speaker and/or Advisory Board Honoraria from Jazz Pharmaceuticals (2020, 2021) and Servier (2020), and received a speaker fee from Amgen (2020) and Medscape (2020, 2021), and Educational grant from Servier (2020, 2021). All the services relate to the use of asparaginase and/or treatment of acute lymphoblastic leukemia. Inge M van der Sluis received research support and consultancy fees from Jazz Pharmaceuticals and Servier., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin lymphoma (NHL), is a highly heterogeneous and aggressive disease. Regardless of this heterogeneity, all patients receive the same first-line therapy, which fails in 30-40 % of patients, who are either refractory or relapse after remission. With the aim of stratifying patients to improve treatment outcome, different clinical and genetic biomarkers have been studied. The present systematic review aimed to identify somatic mutations that could serve as prognosis biomarkers or as therapeutic target mutations in DLBCL. Regarding their role as prognostic markers, mutations in CD58 and TP53 seem the most promising predictors of poor outcome although the combination of different alterations and other prognostic factors could be a more powerful strategy. On the other hand, different approaches regarding targeted therapy have been proposed. Therefore, mutational analysis could help guide treatment choice in DLBCL yet further studies and clinical trials are needed., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1 .

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma and usually presents as an indolent disease. However, some patients present poor outcomes, and FL can transform into more aggressive lymphomas, such as Diffuse Large B cell lymphoma (DLBCL). MicroRNAs (miRNA) are small RNA molecules that participate in posttranscriptional regulation of gene expression, that are emerging biomarkers in cancer. In this systematic review, we included studies evaluating miRNA expression in tumor tissue as diagnosis, transformation or prognosis biomarkers in FL. We identified several miRNAs, which could be diagnostic biomarkers in FL: miR-155-5p and miR-9-3p as miRNAs of potential utility for diagnosis of FL, and miR-150 and miR-17-92 cluster for differential diagnosis between FL and DLBCL. Prognosis and transformation prediction have not been studied in enough depth to draw solid conclusions. Further research is needed to exploit the potential of this field., (Copyright © 2021 Elsevier B.V. All rights reserved.)