Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.

Ceramides are lipids that play vital roles in complex lipid synthesis, membrane function, and cell signaling. Disrupted ceramide homeostasis is implicated in cell-death and several neurologic diseases. Ceramides are often analyzed in tissue, but this approach fails to resolve cell-type differences in ceramide homeostasis that are likely essential to understanding cell and non-cell autonomous contributions to neurodegeneration.

BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis.

Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton's tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS.

Extended survival of 9- and 10-gene-edited pig heart xenografts with ischemia minimization and CD154 costimulation blockade-based immunosuppression.

Background: Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory ''transgenes''. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique.

Methods: Eight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.

Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice.

Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid -glucosidase, which leads to muscle weakness, cardiac and respiratory failure, and early mortality. Alglucosidase alfa, a recombinant human acid -glucosidase, was the first approved treatment of Pompe disease, but its uptake into skeletal muscle via the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) is limited. Avalglucosidase alfa has received marketing authorization in several countries for infantile-onset and/or late-onset Pompe disease.

Transcriptomic characterization of clinical skeletal muscle biopsy from late-onset Pompe patients.

Pompe disease is a rare lysosomal storage disorder arising from recessive mutations in the acid α-glucosidase gene and resulting in the accumulation of glycogen, particularly in the cardiac and skeletal muscle. The current standard of care is administration of enzyme replacement therapy in the form of alglucosidase alfa or the recently approved avalglucosidase alfa. In order to better understand the underlying cellular processes that are disrupted in Pompe disease, we conducted gene expression analysis on skeletal muscle biopsies obtained from late-onset Pompe disease patients (LOPD) prior to treatment and following six months of enzyme replacement with avalglucosidase alfa.

"I Was Here First, Why Did They Go Before Me": Examining Patients'Perceptions of Priority in a Psychometric Study of Emergency Department Triage.

Introduction: Unrealistic patient expectations for wait times can lead to poor satisfaction. This study's dual purpose was: (1) to address disparities between patients' perceived priority level and the Emergency Severity Index (ESI) assigned by emergency room triage nurses; and (2) to evaluate validity and reliability of using the Patient Perception of Priority to be Seen Survey (PPPSS) to investigate patient expectations for emergency department urgency.

Methods: A two-group pretest-posttest quasi-experimental approach compared patient urgency opinions to nurse urgency ratings with and without a scripted educational intervention.

Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry.

Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced.

Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells.

Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the histone deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear.

The XylR variant (R121C and P363S) releases arabinose-induced catabolite repression on xylose fermentation and enhances coutilization of lignocellulosic sugar mixtures.

Microbial production of fuels and chemicals from lignocellulosic biomass provides a promising alternative to conventional petroleum-derived routes. However, the heterogeneous sugar composition of lignocellulose prevents efficient microbial sugar co-fermentation due to carbon catabolite repression, which negatively affects production metrics. We previously discovered that a mutant copy of the transcriptional regulator XylR (P363S and R121C; denoted as XylR*) in Escherichia coli has a higher DNA-binding affinity than wild-type XylR, leading to a stronger activation of the d-xylose catabolic genes and a release from glucose-induced repression on xylose fermentation.

An Interprofessional Approach to Amyotrophic Lateral Sclerosis Care.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that is characterized by the death of motor neurons in the spinal cord, brain stem, and motor cortex that are responsible for voluntary movement. For unknown reasons, military veterans are approximately twice as likely as the public to be given a diagnosis of ALS. Currently, there is no cure for ALS.

Prone positioning in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a condition with a high morbidity and mortality rate, and treatment is often long and costly. Prone positioning is a rarely used intervention for patients with this syndrome, although research suggests it may be effective. A literature search was undertaken to examine the effects of prone positioning on oxygenation, morbidity and mortality in patients with ARDS.

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration.

Linkage analysis, positional cloning, candidate gene mutation scanning and genome-wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered.

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function.

Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.

Translating an evidence-based protocol for nurse-to-nurse shift handoffs.

Purpose: Ineffective communication is the most frequently reported cause of sentinel events in U.S. hospitals.

Knockdown of human deubiquitinase PSMD14 induces cell cycle arrest and senescence.

The PSMD14 (POH1, also known as Rpn11/MPR1/S13/CepP1) protein within the 19S complex (19S cap; PA700) is responsible for substrate deubiquitination during proteasomal degradation. The role of PSMD14 in cell proliferation and senescence was explored using siRNA knockdown in carcinoma cell lines. Our results reveal that down-regulation of PSMD14 by siRNA transfection had a considerable impact on cell viability causing cell arrest in the G0-G1 phase, ultimately leading to senescence.

Translating best practices in assessing capillary refill.

Purpose: A research roundtable was held in an urban community hospital in the United States to determine the strength, usefulness, and feasibility of empirical and clinical evidence evaluated in a systematic review assessing capillary refill.

Approach: The roundtable was undertaken to provide an additional dimension for the development of a best-practice guideline. Current practices and policies in this acute care hospital were examined concerning the strength of the evidence.

Testing a collaborative research utilization model to translate best practices in pain management.

While millions of dollars are being spent developing the seeds of research to improve the care we give to patients, significant barriers to using empirical evidence by health care professionals and policymakers still exist. The gap between what we know from research and what we use in practice is at the heart of the translation research problem. How do we get empirical knowledge uptake and use by clinicians in the fields of practice? In addition, how do we measure if practice changes are occurring? This article describes a program of translation research in which the intervention, called the Collaborative Research Utilization model, was developed and tested in four clinical studies over 18 years.

Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.

Background: A major focus of prostate cancer research has been to identify genes that are deregulated during tumor progression, potentially providing diagnostic markers and therapeutic targets.

Methods: We have employed serial analysis of gene expression (SAGE) and microarray hybridization to identify alterations that occur during malignant transformation in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. Many of these alterations were validated by real-time PCR (rtPCR).

Translating best practices in nondrug postoperative pain management.

Background: The research-to-practice gap is at the heart of the problem in the underuse of nondrug complementary methods to manage postoperative pain.

Purpose: To show how the six steps of the Collaborative Research Utilization (CRU) model can be used to translate research into practice, using an example of nondrug pain management protocols.

Methods: The CRU model was used to translate empirically tested nondrug interventions for surgical pain management enhancement into cost-effective, easy-to-use, best-practice nursing interventions, using tailored patient teaching.

Protein tyrosine phosphatase PRL-3 in malignant cells and endothelial cells: expression and function.

Protein tyrosine phosphatase PRL-3 mRNA was found highly expressed in colon cancer endothelium and metastases. We sought to associate a function with PRL-3 expression in both endothelial cells and malignant cells using in vitro models. PRL-3 mRNA levels were determined in several normal human endothelial cells exposed or unexposed to the phorbol ester phorbol 12-myristate 13-acetate (PMA) and in 27 human tumor cell lines.

Vascular gene expression in nonneoplastic and malignant brain.

Malignant gliomas are uniformly lethal tumors whose morbidity is mediated in large part by the angiogenic response of the brain to the invading tumor. This profound angiogenic response leads to aggressive tumor invasion and destruction of surrounding brain tissue as well as blood-brain barrier breakdown and life-threatening cerebral edema. To investigate the molecular mechanisms governing the proliferation of abnormal microvasculature in malignant brain tumor patients, we have undertaken a cell-specific transcriptome analysis from surgically harvested nonneoplastic and tumor-associated endothelial cells.

Limited relevance of the CHEK2 gene in hereditary breast cancer.

To establish the importance of CHEK2 mutations for familial breast cancer incidence in the German population, we have screened all 14 of the coding exons in 516 families negative for mutations in both the BRCA1 and BRCA2 genes. We found 12 distinct variants in 30 unrelated patients (5.81%), including 5 that are novel and an additional 4 found for the first time in breast cancer.

Gene expression profiling in a renal cell carcinoma cell line: dissecting VHL and hypoxia-dependent pathways.

The von Hippel-Lindau tumor suppressor, pVHL, is a key player in one of the best characterized hypoxia signaling pathways, the VHL-hypoxia-inducible factor (VHL-HIF) pathway. To better understand the role of VHL in the hypoxia signaling pathways of tumor cells, we used serial analysis of gene expression (SAGE) to investigate hypoxia-regulated gene expression in renal carcinoma cells (786-0), with and without VHL. The gene expression profiles of the cancer cells were compared to SAGE profiles from normal renal proximal tubule cells grown under both normoxia and hypoxia.