Medical Record Level-Evaluation of Impact of Demographic and Socioeconomic Factors on Pediatric Neuro-Oncology Outcomes at Children's Hospital Colorado.

Purpose: A medical record-level cohort study to investigate demographic and socioeconomic factors influencing treatment, timing of care, and survival outcomes in pediatric patients diagnosed with central nervous system (CNS) tumors.

Methods: Using electronic health records of patients at Children's Hospital Colorado from 1986-2020, we identified 898 patients treated for CNS tumors. The primary outcomes of interest were 5-year survival, timing of diagnosis, and treatment.

Interplay between and mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in , defining molecular alterations in -mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and mutation on innate immunity.

Identifying patterns of neurocognitive dysfunction through direct comparison of children with leukemia, central nervous system tumors, and sickle cell disease.

Purpose: To quantify and compare the magnitude and type of neurocognitive dysfunction in at-risk children with central nervous system (CNS) tumors, acute lymphoblastic leukemia (ALL), and sickle cell disease (SCD) using a common instrument and metric to directly compare these groups with each other.

Methods: Fifty-three participants between the ages of 7 and 12 years (n = 27 ALL, n = 11 CNS tumor, n = 15 SCD) were enrolled and assessed using the NIH Toolbox Cognition Battery (NIHTCB). Participants with ALL or CNS tumor were 0-18 months posttherapy, while participants with SCD possessed the SS or Sβ genotype, took hydroxyurea, and had no known history of stroke.

Therapy Selection for Hodgkin Lymphoma in Sickle Cell Disease: balancing risks and benefits.

Advances in treatment have reduced mortality from Hodgkin lymphoma; therefore, greater attention should be focused on minimizing the late effects. A variety of risk-adapted treatment regimens exist that prioritize disease presentation but not patient-specific comorbidities. Herein, we describe a patient with sickle cell disease diagnosed with Hodgkin lymphoma and the considerations made in treatment planning to minimize therapy-related acute toxicity and late effects that overlap with the patient's preexisting sickle cell disease complications.

Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes.

Mechanisms and Insights for the Development of Heart Failure Associated with Cancer Therapy.

Cardiotoxicity is a well-recognized late effect among childhood cancer survivors. With various pediatric cancers becoming increasingly curable, it is imperative to understand the disease burdens that survivors may face in the future. In order to prevent or mitigate cardiovascular complications, we must first understand the mechanistic underpinnings.

Encephalitis in Previously Healthy Children.

Encephalitis is defined as altered mental status for more than 24 hours accompanied by 2 or more findings concerning for inflammation of the brain parenchyma: fever, seizures or other focal neurologic disorders, cerebrospinal fluid pleocytosis, and abnormal neuroimaging and electroencephalographic findings. Herpes simplex virus causes the most severe form of virus-induced encephalitis; the early administration of acyclovir can improve the prognosis of this disease. The rising interest in autoimmune causes of encephalitis, most notably anti--methyl-d-aspartate receptor, should prompt the clinician to consider immunomodulatory treatments, which may improve outcomes.

Predictors of cognitive function in pediatric brain tumor patients: Pre-surgery through 24-month follow-up.

The aim of this study was to examine the feasibility of cognitive assessment from pre-surgery through 2-year follow-up in a sample of pediatric brain tumor (BT) patients. We sought to investigate cognitive function over the course of diagnosis and treatment, and as a function of presenting problems, tumor location, treatment type, and tumor severity. Using a prospective, longitudinal design, standardized IQ measures were administered to pediatric BT patients (ages 6-16) prior to surgery ( = 25), 6 months post-diagnosis ( = 24), and 24 months post-diagnosis ( = 23).

Parent reports of children's working memory, coping, and emotional/behavioral adjustment in pediatric brain tumor patients: A pilot study.

Neurocognitive problems in childhood survivors of brain tumors are well documented. Further, research has shown that problems in cognitive functioning may be associated with impairment in the use of complex strategies needed to cope with stress, including secondary control coping strategies (e.g.

Presurgical assessment of cognitive function in pediatric brain tumor patients: feasibility and initial findings.

Background: Establishing a presurgical baseline of neurocognitive functioning for pediatric brain tumor patients is a high priority to identify level of functioning prior to medical interventions. However, few studies have obtained adequate samples of presurgery assessments.

Methods: This study examines the feasibility of completing tests to assess pre-surgical neurocognitive functioning in 59 identified pediatric brain tumor patients.

Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor.

Circulating low-density lipoprotein cholesterol (LDLc) is regulated by membrane-bound LDL receptor (LDLr). Upon LDLc and LDLr interaction the complex is internalized by the cell, leading to LDLc degradation and LDLr recycling back to the cell surface. The proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates this cycling.

Model-Averaged [Formula: see text] Regularization using Markov Chain Monte Carlo Model Composition.

Bayesian Model Averaging (BMA) is an effective technique for addressing model uncertainty in variable selection problems. However, current BMA approaches have computational difficulty dealing with data in which there are many more measurements (variables) than samples. This paper presents a method for combining [Formula: see text] regularization and Markov chain Monte Carlo model composition techniques for BMA.

Discovery and structure-activity relationships of small molecules that block the human immunoglobulin G-human neonatal Fc receptor (hIgG-hFcRn) protein-protein interaction.

The neonatal Fc receptor, FcRn, prolongs the half-life of IgG in the serum and represents a potential therapeutic target for the treatment of autoimmune disease. Small molecules that block the protein-protein interactions of human IgG-human FcRn may lower pathogenic autoantibodies and provide effective treatment. A novel class of quinoxalines has been discovered as antagonists of the IgG:FcRn protein-protein interaction through optimization of a hit derived from a virtual ligand-based screen.

Neurocognitive late effects of pediatric brain tumors of the posterior fossa: a quantitative review.

Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors; however, a quantitative analysis of the magnitude of these deficits in survivors of brain tumors of the posterior fossa has not been conducted. Despite tumor locations in the posterior regions of the brain, individual studies have documented deficits in a variety of domains, reflective of impairment in other brain regions. The current study provides a comprehensive meta-analysis of literature on neurocognitive late effects found in survivors of posterior fossa tumors.

Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs.

Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs.

Synthesis and structure-activity relationships of dimeric peptide antagonists of the human immunoglobulin G-human neonatal Fc receptor (IgG-FcRn) interaction.

The neonatal Fc receptor, FcRn, regulates the half-life of IgG in vivo and may be a target in the treatment of autoimmune disease. Monomeric peptide antagonists of the human IgG-human FcRn interaction were dimerized using three different synthetic methodologies: thiol/alkyl halide coupling of unprotected peptides, reductive alkylation of unprotected peptides, and on-resin amide bond formation with protected peptides. It was found that dimerization of monomeric peptides increased the in vitro activity of the peptide monomers more than 200-fold.

Structure-activity relationships of a peptide inhibitor of the human FcRn:human IgG interaction.

A family of five peptides was previously discovered by phage display techniques that binds to the human neonatal Fc receptor (FcRn) and inhibits the human IgG:human FcRn protein-protein interaction [Proc. Nat. Acad.

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn.

The neonatal Fc receptor FcRn provides IgG molecules with their characteristically long half-lives in vivo by protecting them from intracellular catabolism and then returning them to the extracellular space. Other investigators have demonstrated that mice lacking FcRn are protected from induction of various autoimmune diseases, presumably because of the accelerated catabolism of pathogenic IgGs in the animals. Therefore, targeting FcRn with a specific inhibitor may represent a unique approach for the treatment of autoimmune disease or other diseases where the reduction of pathogenic IgG will have a therapeutic benefit.

Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death.

Polyphosphate (polyP) consists of tens to hundreds of phosphates, linked by ATP-like high-energy bonds. Although polyP is present in mammalian mitochondria, its physiological roles there are obscure. Here, we examine the involvement of polyP in mitochondrial energy metabolism and ion transport.

Polyphosphate kinase 1 is a pathogenesis determinant in Campylobacter jejuni.

Campylobacter jejuni is the leading cause of bacterial gastroenteritis in the developed world. Despite its prevalence, relatively little is known about C. jejuni's precise pathogenesis mechanisms, particularly in comparison to other well-studied enteric organisms such as Escherichia coli and Salmonella spp.

A polyphosphate kinase 1 (ppk1) mutant of Pseudomonas aeruginosa exhibits multiple ultrastructural and functional defects.

Pseudomonas aeruginosa, of medical, environmental, and industrial importance, depends on inorganic polyphosphate (poly P) for a wide range of functions, especially survival. Mutants of PAO1 lacking poly P kinase 1, PPK1, the enzyme responsible for most poly P synthesis in Escherichia coli and other bacteria, are defective in motility, quorum sensing, biofilm formation, and virulence. We describe here multiple defects in the ppk1 mutant PAOM5, including a striking compaction of the nucleoid, distortion of the cell envelope, lack of planktonic motility and exopolymer production, and susceptibility to the beta-lactam antibiotic carbenicillin as well as desiccation.

Model-based region-of-interest selection in dynamic breast MRI.

Magnetic resonance imaging (MRI) is emerging as a powerful tool for the diagnosis of breast abnormalities. Dynamic analysis of the temporal pattern of contrast uptake has been applied in differential diagnosis of benign and malignant lesions to improve specificity. Selecting a region of interest (ROI) is an almost universal step in the process of examining the contrast uptake characteristics of a breast lesion.

Diverse phenotypes resulting from polyphosphate kinase gene (ppk1) inactivation in different strains of Helicobacter pylori.

Connections among biochemical pathways should help buffer organisms against environmental stress and affect the pace and trajectory of genome evolution. To explore these ideas, we studied consequences of inactivating the gene for polyphosphate kinase 1 (ppk1) in strains of Helicobacter pylori, a genetically diverse gastric pathogen. The PPK1 enzyme catalyzes synthesis of inorganic polyphosphate (poly P), a reservoir of high-energy phosphate bonds with multiple roles.