Epigenetic reprogramming in pediatric gliomas: from molecular mechanisms to therapeutic implications.

Brain tumors in children and adults differ greatly in patient outcomes and responses to radiotherapy and chemotherapy. Moreover, the prevalence of recurrent mutations in histones and chromatin regulatory proteins in pediatric and young adult gliomas suggests that the chromatin landscape is rewired to support oncogenic programs. These early somatic mutations dysregulate widespread genomic loci by altering the distribution of histone post-translational modifications (PTMs) and, in consequence, causing changes in chromatin accessibility and in the histone code, leading to gene transcriptional changes.

Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis.

Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young and malnourished children from low- and middle-income countries, with no vaccine or effective treatment. Here we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor, designed to be active at the infection site in the gastrointestinal tract and undergo rapid metabolism in the liver. By using mutational analysis and crystal structure, we show that EDI048 binds to highly conserved amino acid residues in the ATP-binding site.

Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining.

Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double-strand-break (DSB) repair, directly re-ligates broken DNA ends. Damaged DSB ends that cannot be immediately re-ligated are modified by NHEJ processing enzymes, including error-prone polymerases and nucleases, to enable ligation. However, DSB ends that are initially compatible for re-ligation are typically joined without end processing.

Fluid dynamics alters liquid-liquid phase separation in confined aqueous two-phase systems.

Liquid-liquid phase separation is key to understanding aqueous two-phase systems (ATPS) arising throughout cell biology, medical science, and the pharmaceutical industry. Controlling the detailed morphology of phase-separating compound droplets leads to new technologies for efficient single-cell analysis, targeted drug delivery, and effective cell scaffolds for wound healing. We present a computational model of liquid-liquid phase separation relevant to recent laboratory experiments with gelatin-polyethylene glycol mixtures.

Reflective supervision and reflective practice in infant mental health: A scoping review of a diverse body of literature.

Reflective practice is a core component of Infant Mental Health (IMH) training and work in the form of reflective supervision/consultation (RS/C). RS/C supports and facilitates relationship-based practice, and is considered to help prevent burnout and promote work satisfaction. In response to an identified gap in empirical research on RS/C, this scoping review aimed to give an overview of the broad range of study designs and outcomes by systematically charting empirical studies on RS/C in IMH-based work with children and families.

Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance.

Purpose: Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR).

Experimental Design: We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1-specific inhibitor, AGI-5198.

Modeling electrokinetic flows with the discrete ion stochastic continuum overdamped solvent algorithm.

In this article we develop an algorithm for the efficient simulation of electrolytes in the presence of physical boundaries. In previous work the discrete ion stochastic continuum overdamped solvent (DISCOS) algorithm was derived for triply periodic domains, and was validated through ion-ion pair correlation functions and Debye-Hückel-Onsager theory for conductivity, including the Wien effect for strong electric fields. In extending this approach to include an accurate treatment of physical boundaries we must address several important issues.

Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression.

Smoking Cessation by Phone Counselling in a Lung Cancer Screening Program: A Retrospective Comparative Cohort Study.

Introduction: Smoking cessation integration within lung cancer screening programs is challenging. Currently, phone counselling is available across Canada for individuals referred by healthcare workers and by self-referral. We compared quit rates after phone counselling interventions between participants who self-refer, those referred by healthcare workers, and those referred by a lung cancer screening program.

"I didn't know you could do that": A Pilot Assessment of EHR Optimization Training.

Background: Informatics tools within electronic health records (EHRs)-for example, data rosters and clinical reminders-can help disseminate care guidelines into clinical practice. Such tools' adoption varies widely, however, possibly because many primary care providers receive minimal training in even basic EHR functions.

Objectives: This mixed-methods evaluation of a pilot training program sought to identify factors to consider when providing EHR use optimization training in community health centers (CHCs) as a step toward supporting CHC providers' adoption of EHR tools.

Kinetic and structural mechanism for DNA unwinding by a non-hexameric helicase.

UvrD, a model for non-hexameric Superfamily 1 helicases, utilizes ATP hydrolysis to translocate stepwise along single-stranded DNA and unwind the duplex. Previous estimates of its step size have been indirect, and a consensus on its stepping mechanism is lacking. To dissect the mechanism underlying DNA unwinding, we use optical tweezers to measure directly the stepping behavior of UvrD as it processes a DNA hairpin and show that UvrD exhibits a variable step size averaging ~3 base pairs.

G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy.

Mutant isocitrate-dehydrogenase 1 () synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the TME are mainly nonsuppressive neutrophils and preneutrophils.

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies.

High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors.

Current Approaches for Glioma Gene Therapy and Virotherapy.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies.

XLF acts as a flexible connector during non-homologous end joining.

Non-homologous end joining (NHEJ) is the predominant pathway that repairs DNA double-strand breaks in vertebrates. During NHEJ DNA ends are held together by a multi-protein synaptic complex until they are ligated. Here, we use egg extract to investigate the role of the intrinsically disordered C-terminal tail of the XRCC4-like factor (XLF), a critical factor in end synapsis.

Expression of UDP Glucuronosyltransferases and is associated with methylation status in prostate cancer cells.

Studies have suggested that abrogated expression of detoxification enzymes, UGT2B15 and UGT2B17, are associated with prostate tumour risk and progression. We investigated the role of EGF on the expression of these enzymes since it interacts with signalling pathways to also affect prostate tumour progression and is additionally associated with decreased DNA methylation. The expression of , methyltransferases, and was assessed in prostate cancer cells (LNCaP) treated with EGF, an EGFR inhibitor PD16893, and the methyltransferase inhibitor, 5-azacytidine, respectively.