Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency.

Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice.

A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups.

Background: Relapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach.

Methods And Materials: We analyzed 302 pediatric ependymoma cases.

Prevalence and Diversity of Avian Influenza Virus Hemagglutinin Sero-Subtypes in Poultry and Wild Birds in Bangladesh.

Highly pathogenic avian influenza H5 viruses have pandemic potential, cause significant economic losses and are of veterinary and public health concerns. This study aimed to investigate the distribution and diversity of hemagglutinin (HA) subtypes of avian influenza virus (AIV) in poultry and wild birds in Bangladesh. We conducted an avian influenza sero-surveillance in wild and domestic birds in wetlands of Chattogram and Sylhet in the winter seasons 2012-2014.

Implementing a pediatric oncology nursing multisite trial.

Purpose/background: The Parent Educational Discharge Support Strategies (PEDSS) nursing study includes 16 magnet pediatric oncology institutions across the United States and one in Saudi Arabia, evaluating a nurse-led parent educational discharge support strategy for families experiencing a child newly diagnosed with cancer.

Methods: During the first 3 months of the study, a research implementation survey was administered electronically to each site principal investigator to evaluate facilitators and barriers in the research process for this multisite nurse-led pediatric oncology study.

Results: Facilitators included nursing leadership support and commitment from the nursing staff.

Ocular Complications in School-Age Children and Adolescents after Allogeneic Bone Marrow Transplantation.

Purpose: To determine the ocular complications in school-age children and adolescents surviving at least 1 year following allogeneic bone marrow transplantation.

Design: Retrospective cohort study.

Methods: In this institutional study, 162 patients (7-18 years old) met our inclusion criteria with a mean age of 13.

Mechanisms of -Mediated Thiopurine Resistance in Acute Lymphoblastic Leukemia.

Relapse remains a formidable challenge for acute lymphoblastic leukemia (ALL). Recently, recurrent mutations in were identified as a common genomic lesion unique in relapsed ALL and were linked to acquired thiopurine resistance. However, molecular mechanisms by which regulates thiopurine cytotoxicity were incompletely understood.

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.

Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response.

Treatment patterns and disease outcomes for pediatric patients with refractory or recurrent Hodgkin lymphoma treated with curative-intent salvage radiotherapy.

Background And Purpose: The use of radiotherapy (RT) for pediatric patients with Hodgkin lymphoma (HL) experiencing disease progression or recurrence (15%) is controversial. We report treatment patterns and outcomes for pediatric patients with refractory/recurrent HL (rrHL) treated with curative-intent RT.

Materials And Methods: Forty-six patients with rrHL treated with salvage RT at our institution were identified.

Preserve Cultured Cell Cytonemes through a Modified Electron Microscopy Fixation.

Immunocytochemistry of cultured cells is a common and effective technique for determining compositions and localizations of proteins within cellular structures. However, traditional cultured cell fixation and staining protocols are not effective in preserving cultured cell cytonemes, long specialized filopodia that are dedicated to morphogen transport. As a result, limited mechanistic interrogation has been performed to assess their regulation.

A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia.

Consolidation therapies for children with intermediate- or high-risk acute myeloid leukemia (AML) are urgently needed to achieve higher cure rates while limiting therapy-related toxicities. We determined if adoptive transfer of natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA)-mismatched donors may prolong event-free survival in children with intermediate-risk AML who were in first complete remission after chemotherapy. Patients received cyclophosphamide (Day - 7), fludarabine (Days - 6 through - 2), and subcutaneous interleukin-2 (Days - 1, 1, 3, 5, 7, and 9).

Effects of Demographic Variables on Subjective Neurocognitive Complaints Using the Neurocognitive Questionnaire (NCQ) in an Aged Japanese Population.

Objectives: In an aged Japanese population, we investigated associations of demographic variables with subjective neurocognitive complaints using the Neurocognitive Questionnaire (NCQ).

Methods: Participants ( = 649) provided answers to the NCQ in both 2011 and 2013. Using fully-completed NCQs from 503 participants in 2011, we identified latent factors of subjective neurocognitive complaints using exploratory factor analysis; then examined associations of demographic variables with the identified factors for all 649 participants over the two years.

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403.

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response.

A quality improvement project to improve pediatric medical provider sleep and communication during night shifts.

Quality Problem Or Issue: Night-shift medical providers frequently experience limited sleep resulting in fatigue, often because of paging activity. Streamlined medical-specific communication interventions are known to improve sleep and communication among these providers.

Initial Assessment: We found that non-urgent paging communication occurred frequently during night-shifts, leading to provider sleep disturbances within our institution.

Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes.

In its landmark paper about Standards and Guidelines for the Interpretation of Sequence Variants, the American College of Medical Genetics and Genomics (ACMG), and Association for Molecular Pathology (AMP) did not address how to use tumor data when assessing the pathogenicity of germline variants. The Clinical Genome Resource (ClinGen) established a multidisciplinary working group, the Germline/Somatic Variant Subcommittee (GSVS) with this focus. The GSVS implemented a survey to determine current practices of integrating somatic data when classifying germline variants in cancer predisposition genes.

Ythdf2-mediated mA mRNA clearance modulates neural development in mice.

Background: N -methyladenosine (mA) modification in mRNAs was recently shown to be dynamically regulated, indicating a pivotal role in multiple developmental processes. Most recently, it was shown that the Mettl3-Mettl14 writer complex of this mark is required for the temporal control of cortical neurogenesis. The mA reader protein Ythdf2 promotes mRNA degradation by recognizing mA and recruiting the mRNA decay machinery.

Why Don't Cancer Survivors Quit Smoking? An Evaluation of Readiness for Smoking Cessation in Cancer Survivors.

Background: Cancer survivors have a high rate of participation in cigarette-smoking cessation programs but their smoking-abstinence rates remain low. In the current study, we evaluated the readiness to quit smoking in a cancer-survivor population.

Methods: Cross-sectional data survey conducted among 112 adult cancer survivors who smoked cigarettes in Tennessee.

Psychometric Properties of Korean Version of the Second Victim Experience and Support Tool (K-SVEST).

Objectives: "Second victims" are defined as healthcare professionals whose wellness is influenced by adverse clinical events. The Second Victim Experience and Support Tool (SVEST) was used to measure the second-victim experience and quality of support resources. Although the reliability and validity of the original SVEST have been validated, those for the Korean tool have not been validated.

Ocular complications in a young pediatric population following bone marrow transplantation.

Purpose: To investigate ocular complications associated with bone marrow transplant and associated continued maintenance therapy in a preschool population.

Methods: The medical records of patients <7 years of age were reviewed retrospectively. Patient charts were screened for cataract formation, dry eye, and other anterior and posterior segment disease.

Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer.

Androgen receptor (AR) mediates the growth of prostate cancer throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced prostate cancer requires the development of agents that can sustainably degrade variant isoforms for effective therapy.

Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor.

Direct interactions between pro- and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three anti-apoptotic BCL-2 proteins (MCL-1, BCL-2 and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Anti-apoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in SUFU (suppressor of fused), a tumour suppressor and antagonist of the GLI DNA-binding proteins.

The effect of motorcycle helmet fit on estimating head impact kinematics from residual liner crush.

Proper helmet fit is important for optimizing head protection during an impact, yet many motorcyclists wear helmets that do not properly fit their heads. The goals of this study are i) to quantify how a mismatch in headform size and motorcycle helmet size affects headform peak acceleration and head injury criteria (HIC), and ii) to determine if peak acceleration, HIC, and impact speed can be estimated from the foam liner's maximum residual crush depth or residual crush volume. Shorty-style helmets (4 sizes of a single model) were tested on instrumented headforms (4 sizes) during linear impacts between 2.

RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host.

Unlabelled: Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp).