Radiosensitizing the Vasculature of Primary Brainstem Gliomas Fails to Improve Tumor Response to Radiation Therapy.

Purpose: Diffuse intrinsic pontine gliomas (DIPGs) arise in the pons and are the leading cause of death from brain tumors in children. DIPGs are routinely treated with radiation therapy, which temporarily improves neurological symptoms but generally fails to achieve local control. Because numerous clinical trials have not improved survival from DIPG over standard radiation therapy alone, there is a pressing need to evaluate new therapeutic strategies for this devastating disease.

Prenatal overexpression of platelet-derived growth factor receptor A results in central nervous system hypomyelination.

Background: Platelet-derived growth factor (PDGF) signaling, through the ligand PDGF-A and its receptor PDGFRA, is important for the growth and maintenance of oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS). PDGFRA signaling is downregulated prior to OPC differentiation into mature myelinating oligodendrocytes. By contrast, PDGFRA is often genetically amplified or mutated in many types of gliomas, including diffuse midline glioma (DMG) where OPCs are considered the most likely cell-of-origin.

Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models.

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity.

The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction.

Background: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND.

Biomarkers Associated with Physical Resilience After Hip Fracture.

Background: Clinically similar older adults demonstrate variable responses to health stressors, heterogeneity attributable to differences in physical resilience. However, molecular mechanisms underlying physical resilience are unknown. We previously derived a measure of physical resilience after hip fracture-the expected recovery differential (ERD)-that captures the difference between actual recovery and predicted recovery.

Resiliency Groups Following Hip Fracture in Older Adults.

Objectives: Defining common patterns of recovery after an acute health stressor (resiliency groups) has both clinical and research implications. We sought to identify groups of patients with similar recovery patterns across 10 outcomes following hip fracture (stressor) and to determine the most important predictors of resiliency group membership.

Design: Secondary analysis of three prospective cohort studies.

Two Approaches to Classifying and Quantifying Physical Resilience in Longitudinal Data.

Background: Approaches for quantifying physical resilience in older adults have not been described.

Methods: We apply two conceptual approaches to defining physical resilience to existing longitudinal data sets in which outcomes are measured after an acute physical stressor. A "recovery phenotype" approach uses statistical methods to describe how quickly and completely a patient recovers.

Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis.

PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked PICALM Single Nucleotide Polymorphisms (SNPs) to Alzheimer's disease.

A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.

Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss.

Genetically engineered mouse models of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting more than 1% of the population over age 60. The most common feature of PD is a resting tremor, though there are many systemic neurological effects, such as incontinence and sleep disorders. PD is histopathologically identified by the presence of Lewy bodies (LB), proteinaceous inclusions constituted primarily by α-synuclein.