DNTT-mediated DNA Damage Response Drives Inotuzumab Ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia.

Inotuzumab Ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide inter-patient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered the loss of DNTT as a primary driver of InO resistance.

Repeated social stress increases posterior medial amygdala neuronal activity in stress-susceptible adult male rats.

The medial amygdala (MeA) is activated by social stimuli and manipulations of the MeA disrupt a wide range of social behaviors. Social stress can shift social behaviors and may accomplish this partly via effects on the MeA. However, very little is known about the effects of social stress on the electrophysiological activity of MeA neurons.

The Proteomics of T-Cell and Early T-Cell Precursor (ETP) Acute Lymphocytic Leukemia: Prognostic Patterns in Adult and Pediatric-ETP ALL.

Background: The 5-year overall survival (OS) rates of T-cell lymphocytic leukemia (T-ALL) are better for children (>90%) compared to adults (~57%). The early T-cell precursor (ETP) T-ALL subtype is prognostically unfavorable in adults, but less significant in pediatric T-ALL, and the diagnosis and prognosis of "near"-ETP is controversial. We compared protein and RNA expression patterns in pediatric and adult T-ALL to identify prognostic subgroups, and to further characterize ETP and near-ETP T-ALL in both age groups.

DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts.

Exploring the molecular correlates of metabolic health measures may identify their shared and unique biological processes and pathways. Molecular proxies of these traits may also provide a more objective approach to their measurement. Here, DNA methylation (DNAm) data were used in epigenome-wide association studies (EWASs) and for training epigenetic scores (EpiScores) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio, and blood-based measures of glucose, high-density lipoprotein cholesterol, and total cholesterol in >17,000 volunteers from the Generation Scotland (GS) cohort.

Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.

Background: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.

Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.

Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific.

Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia.

Genomic alterations of are common and associated with adverse clinical features in B-ALL. The relationship between the type of alteration, disease subtype and outcome are incompletely understood. Leukemia subtype and genomic alterations were determined using transcriptome and genomic sequencing and SNP microarray in 688 pediatric patients with B-ALL in St.

A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia.

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases.

The relationships between sleep and adiposity amongst multi-ethnic Asian populations: a cross-sectional analysis of the Health for Life in Singapore (HELIOS) study.

Background: Short sleep duration and poor sleep quality have been associated with obesity. Asian populations report shorter sleep duration compared to other groups. We therefore aimed to explore the relationships between sleep duration, sleep quality, dozing, daytime napping, snoring, insomnia and adiposity in a multi-ethnic Asian population, and investigate the potential contribution of disturbed sleep to the risk of obesity amongst Asian populations.

Understanding Atopic Dermatitis in Asian and European Population Cohorts Using Complementary Omics Techniques.

Atopic dermatitis is highly heterogeneous with respect to pathogenesis, clinical manifestations, and treatment response. There is evidence that ancestry and skin type each contribute to this heterogeneity, indicating the need to improve understanding of disease mechanisms in diverse populations. Methods to integrate multiomics studies have been well-described, but this review focuses on the importance and the strategies needed to integrate data across different ancestral groups, focusing, because of data availability, on Asian and European populations.

Recombinant Erwinia asparaginase (JZP458) in ALL/LBL: complete follow-up of the Children's Oncology Group AALL1931 study.

Children's Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli-derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient's treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.

Lateralization of activation within the superior temporal gyrus during speech perception in sleeping infants is associated with subsequent language skills in kindergarten: A passive listening task-fMRI study.

Brain asymmetries are hypothesized to reduce functional duplication and thus have evolutionary advantages. The goal of this study was to examine whether early brain lateralization contributes to skill development within the speech-language domain. To achieve this goal, 25 infants (2-13 months old) underwent behavioral language examination and fMRI during sleep while listening to forward and backward speech, and then were assessed on various language skills at 55-69 months old.

Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study.

Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children's Oncology Group frontline ALL trials (1996-2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.

Translating psychosocial safety climate (PSC) into real-world practice: two PSC intervention case studies.

Objectives: Translating research into practice is often a goal for evidence-based organizational researchers to help improve workplace conditions and worker well-being. Improving worker well-being can be achieved by using empirical evidence to inform organizational interventions. However, despite the well-established intervention literature, practitioners appear not to appreciate fully how research findings can inform real-world practice.

Adiposity and metabolic health in Asian populations: an epidemiological study using dual-energy x-ray absorptiometry in Singapore.

Background: Type 2 diabetes, cardiovascular disease, and related cardiometabolic disturbances are increasing rapidly in the Asia-Pacific region. We investigated the contribution of excess adiposity, a key determinant of type 2 diabetes and cardiovascular risk, to unfavourable cardiometabolic profiles among Asian ethnic subgroups.

Methods: The Health for Life in Singapore (HELIOS) Study is a population-based cohort comprising multiethnic Asian men and women living in Singapore, aged 30-84 years.

A multi-centre randomised controlled trial comparing megestrol acetate to levonorgestrel-intrauterine system in fertility sparing treatment of atypical endometrial hyperplasia.

Purpose: The objective of the trial was to compare the regression rate of atypical endometrial hyperplasia (AEH) in patients treated with megestrol acetate (MA) vs. levonorgestrel-intrauterine device (LNG-IUS). We also aimed to assess the fertility and pregnancy outcomes in these patients.

The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes.

Coupling of droplet-on-demand microfluidcs with ESI/MS to study single-cell catalysis.

Droplet microfluidics provides an efficient method for analysing reactions within the range of nanoliters to picoliters. However, the sensitive, label-free and versatile detection with ESI/MS poses some difficulties. One challenge is the difficult association of droplets with the MS signal in high-throughput droplet analysis.

Effect of simultaneous multislice imaging, slice properties, and repetition time on the measured magnetic resonance biexponential intravoxel incoherent motion in the liver.

Objectives: This study aims to investigate the previously reported dependency of intravoxel incoherent motion (IVIM) parameters on simultaneous multislice (SMS) acquisition and repetition time (TR). This includes the influence of slice thickness, slice gaps, and slice order on measured IVIM parameters.

Materials And Methods: Diffusion-weighted imaging (DWI) of the liver was performed on 10 healthy volunteers (aged 20-30 years) at 3T with a slice thickness of 5 mm, a slice gap of 5 mm, and a linear slice order.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs.