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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. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. Gas Chromatography-Mass Spectrometry (GC-MS) studies indicated that loss of PICALM increases cellular cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters increased net scavenging of cholesterol. Flow cytometry analyses confirmed that internalization of the LDL receptor is enhanced in PICALM-deficient cells as a result of higher levels of LDLR expression. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease.

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. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs., Introduction Diffuse intrinsic pontine glioma (DIPG), also referred to as highgrade brainstem glioma, is an incurable cancer that originates in the pons and occurs primarily in children. Focal radiation therapy [...]

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. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity.Objective: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity.Methods: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications.Conclusion: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes. [ABSTRACT FROM AUTHOR]

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. Statistical methods using a recovery phenotype approach can consider multiple outcomes simultaneously in a composite score (eg, factor analysis and principal components analysis) or identify groups of patients with similar recovery trajectories across multiple outcomes (eg, latent class profile analysis). An "expected recovery differential" approach quantifies how patients' actual outcomes are compared to their predicted outcome based on a population-derived model and their individual clinical characteristics at the time of the stressor.Results: Application of the approaches identified different participants as being the most or least physically resilient. In the viral respiratory cohort (n = 186) weighted kappa for agreement across resilience quartiles was 0.37 (0.27-0.47). The expected recovery differential approach identified a group with more comorbidities and lower baseline function as highly resilient. In the hip fracture cohort (n = 541), comparison of the expected recovery differentials across 10 outcome measures within individuals provided preliminary support for the hypothesis that there is a latent resilience trait at the whole-person level.Conclusions: We posit that recovery phenotypes may be useful in clinical applications such as prediction models because they summarize the observed outcomes across multiple measures. Expected recovery differentials offer insight into mechanisms behind physical resilience not captured by age and other comorbidities. [ABSTRACT FROM AUTHOR]