A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing.

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program.

Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States.

Introduction: Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective.

Methods: A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL.

IRE1 signaling increases PERK expression during chronic ER stress.

The Unfolded Protein Response (UPR) is an essential cellular process activated by the accumulation of unfolded proteins within the Endoplasmic Reticulum (ER), a condition referred to as ER stress. Three ER anchored receptors, IRE1, PERK and ATF6 act as ER stress sensors monitoring the health of the ER. Upon detection of ER stress, IRE1, PERK and ATF6 initiate downstream signaling pathways collectively referred to as the UPR.

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome.

Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease-relevant pathologies.

There are hundreds of risk genes associated with autism spectrum disorder (ASD), but signaling networks at the protein level remain unexplored. We use neuron-specific proximity-labeling proteomics (BioID2) to identify protein-protein interaction (PPI) networks for 41 ASD risk genes. Neuron-specific PPI networks, including synaptic transmission proteins, are disrupted by de novo missense variants.

TCF/LEF regulation of the topologically associated domain ADI promotes mESCs to exit the pluripotent ground state.

Mouse embryonic stem cells (mESCs) can be maintained in vitro in defined N2B27 medium supplemented with two chemical inhibitors for GSK3 and MEK (2i) and the cytokine leukemia inhibitory factor (LIF), which act synergistically to promote self-renewal and pluripotency. Here, we find that genetic deletion of the four genes encoding the TCF/LEF transcription factors confers mESCs with the ability to self-renew in N2B27 medium alone. TCF/LEF quadruple knockout (qKO) mESCs display dysregulation of several genes, including Aire, Dnmt3l, and IcosL, located adjacent to each other within a topologically associated domain (TAD).

Arhgef2 regulates mitotic spindle orientation in hematopoietic stem cells and is essential for productive hematopoiesis.

How hematopoietic stem cells (HSCs) coordinate their divisional axis and whether this orientation is important for stem cell-driven hematopoiesis is poorly understood. Single-cell RNA sequencing data from patients with Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome, show that ARHGEF2, a RhoA-specific guanine nucleotide exchange factor and determinant of mitotic spindle orientation, is specifically downregulated in SDS hematopoietic stem and progenitor cells (HSPCs). We demonstrate that transplanted Arhgef2-/- fetal liver and bone marrow cells yield impaired hematopoietic recovery and a production deficit from long-term HSCs, phenotypes that are not the result of differences in numbers of transplanted HSCs, their cell cycle status, level of apoptosis, progenitor output, or homing ability.

Economic burden of asthma in Singapore.

Background And Objective: Up-to-date economic burden of asthma in Singapore is currently unknown.

Methods: We quantify the per capita and total annual costs of asthma for adults and children by level of symptom control (uncontrolled, partly controlled, and well controlled) via a cross-sectional online survey administered to a national web panel. Participants were asked about healthcare utilisation, days missed from work, and reduced productivity due to their symptoms.

End-of-life cost trajectories and the trade-off between treatment costs and life-extension: Findings from the Cost and Medical Care of Patients with Advanced Serious Illness (COMPASS) cohort study.

Background: Few studies have assessed how patient preferences influence end-of-life costs.

Aim: To estimate mean monthly healthcare costs in 2019 Singapore Dollars (SGD) at five time points within the last year of life and identify how patients' preferences for the trade-off between treatment cost containment and life-extension and other factors affect these costs.

Design: Mean monthly costs were quantified in the last 1, 3, 6, 9, and 12-months before death.

Multimerin 1 supports platelet function in vivo and binds to specific GPAGPOGPX motifs in fibrillar collagens that enhance platelet adhesion.

Background: Multimerin 1 (human: MMRN1, mouse: Mmrn1) is a homopolymeric, adhesive, platelet and endothelial protein that binds to von Willebrand factor and enhances platelet adhesion to fibrillar collagen ex vivo.

Objectives: To examine the impact of Mmrn1 deficiency on platelet adhesive function, and the molecular motifs in fibrillar collagen that bind MMRN1 to enhance platelet adhesion.

Methods: Mmrn1-deficient mice were generated and assessed for altered platelet adhesive function.

The association of self-blame with treatment preferences in a multi-country cohort of advanced cancer patients from the APPROACH study.

Objective: To understand the prevalence of behavioral and characterological self-blame and their associations with stated preferences for life-extension and the use of pain-relief medication in a multi-country cohort of advanced cancer patients.

Methods: The prevalence of self-blame and reasons participants attributed to their diagnosis was assessed in a sample of 968 advanced cancer patients enrolled in one of five sites from four Asian countries of the multi-country cross-sectional survey titled APRROACH. Ordered probit and Firth logistic regressions were used to determine associations between each type of self-blame and two treatment-related outcomes: participants' stated preference for life-extension and the use of pain-relief medication in the last 24 h.

A randomized controlled trial testing the effects of a positive front-of-pack label with or without a physical activity equivalent label on food purchases.

Background: Positive front-of-pack (FOP) labels, including Singapore's Healthier Choice Symbol (HCS), target a subset of healthier products whose consumption is to be encouraged. However, this may inadvertently lead to excess caloric intake, which could be addressed by including an additional label identifying calories per serving. We test this hypothesis by adding a Physical Activity Equivalent (PAE) label, an indicator of calorie content, to all products available in an on-line grocery store.

Wnt activation as a therapeutic strategy in medulloblastoma.

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB.

β-Catenin safeguards the ground state of mousepluripotency by strengthening the robustness of the transcriptional apparatus.

Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL.

Clinical and cost-effectiveness of a diabetes education and behavioural weight management programme versus a diabetes education programme in adults with a recent diagnosis of type 2 diabetes: study protocol for the Glucose Lowering through Weight management (GLoW) randomised controlled trial.

Introduction: People with type 2 diabetes (T2D) can improve glycaemic control or even achieve remission through weight loss and reduce their use of medication and risk of cardiovascular disease. The Glucose Lowering through Weight management (GLoW) trial will evaluate whether a tailored diabetes education and behavioural weight management programme (DEW) is more effective and cost-effective than a diabetes education (DE) programme in helping people with overweight or obesity and a recent diagnosis of T2D to lower their blood glucose, lose weight and improve other markers of cardiovascular risk.

Methods And Analysis: This study is a pragmatic, randomised, single-blind, parallel group, two-arm, superiority trial.

Randomized trial evaluating the effectiveness of within versus across-category front-of-package lower-calorie labelling on food demand.

Background: Several front-of-pack (FOP) labels identify healthier options by comparing foods within product categories. Alternative approaches label healthier options by comparing across categories. Which approach is superior remains unknown.

The effect of implicit and explicit taxes on the purchasing of 'high-in-calorie' products: A randomized controlled trial.

Public health taxes on less healthy food and beverage products have been shown to be effective in various settings. However, it is unclear if observed reductions in the quantity of taxed products purchased is a result of price increases due to the tax or the accompanying messaging and if the effects are influenced by the level of support for such taxes within the population. 941 adults residing in Singapore were randomized and asked to shop in one of four versions of a fully functional on-line experimental grocery store: 1) no tax control; 2) implicit tax showing only post-tax prices (i.

Strategies to improve survival outcomes of out-of-hospital cardiac arrest (OHCA) given a fixed budget: A simulation study.

Background: Our study aimed to identify a strategy that maximizes survival upon hospital discharge or 30-days post out-of-hospital cardiac arrest (OHCA) in Singapore for fixed investments of S$1, S$5, or S$10 million. Four strategies were compared: (1) no additional investment; (2) reducing response time via leasing of more ambulances; (3) increasing number of people trained in cardiopulmonary resuscitation (CPR); and (4) automated external defibrillators (AED).

Methods: We estimated the effect of ambulance response time, bystander CPR and AED on survival based on Singapore's 2010-2015 OHCA registry data.

Impacts of genomics on the health and social costs of intellectual disability.

Background: This study provides an integrated assessment of the economic and social impacts of genomic sequencing for the detection of monogenic disorders resulting in intellectual disability (ID).

Methods: Multiple knowledge bases were cross-referenced and analysed to compile a reference list of monogenic disorders associated with ID. Multiple literature searches were used to quantify the health and social costs for the care of people with ID.

Cost-effectiveness of Intravitreal Ranibizumab With Verteporfin Photodynamic Therapy Compared With Ranibizumab Monotherapy for Patients With Polypoidal Choroidal Vasculopathy.

Importance: The EVEREST II trial showed that for patients with polypoidal choroidal vasculopathy (PCV), intravitreal ranibizumab in combination with verteporfin photodynamic therapy improves visual acuity relative to ranibizumab monotherapy. However, whether combination therapy is incrementally cost-effective relative to monotherapy during a lifetime is unclear.

Objective: To assess the incremental cost-effectiveness of combination therapy compared with ranibizumab monotherapy in patients with PCV.

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

Objectives: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients.