Sustainability of a Clinical Decision Support Intervention for Outpatient Care for Emergency Department Patients With Acute Pulmonary Embolism.

Importance: Physicians commonly hospitalize patients presenting to the emergency department (ED) with acute pulmonary embolism (PE), despite eligibility for safe outpatient management. Risk stratification using electronic health record-embedded clinical decision support systems can aid physician site-of-care decision-making and increase safe outpatient management. The long-term sustainability of early improvements after the cessation of trial-based, champion-led promotion is uncertain.

Utility of Pooled Cryopreserved Human Enterocytes as an In vitro Model for Assessing Intestinal Clearance and Drug-Drug Interactions.

Background: A recent advancement in isolation and cryopreservation has resulted in commercially available primary human enterocytes that express various drug metabolizing enzymes (DMEs) and transporters. The main objective of this study was to further evaluate the utility of pooled cryopreserved enterocytes, specifically MetMax™ cryopreserved human enterocytes (In vitro ADMET Laboratories), as an in vitro model for assessing intestinal clearance in comparison to hepatocytes.

Methods: It was found that, for CYP3A4/5 substrates such as midazolam, amprenavir and loperamide, in vitro metabolic clearance is generally lower in enterocytes compared to that of hepatocytes, which is consistent with the relative abundance of the enzyme between the intestine and liver.

"Awake" clipping of cerebral aneurysms: report of initial series.

OBJECTIVE Risk of ischemia during aneurysm surgery is significantly related to temporary clipping time and final clipping that might incorporate a perforator. In this study, the authors attempted to assess the potential added benefit to patient outcomes of "awake" neurological testing when compared with standard neurophysiological testing performed under general anesthesia. The procedure is performed after the induction of conscious sedation, and for the neurological testing, the patient is fully awake.

Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers.

Human tumors show a high level of genetic heterogeneity, but the processes that influence the timing and route of metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencing of 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumor, supporting parallel rather than linear evolution as the predominant model of metastasis. Shared mutations between primary carcinomas and their matched metastases have the distinct A-to-T signature of the initiating carcinogen dimethylbenzanthracene, but non-shared mutations are primarily G-to-T, a signature associated with oxidative stress.

Dependence of brown adipose tissue function on CD36-mediated coenzyme Q uptake.

Brown adipose tissue (BAT) possesses the inherent ability to dissipate metabolic energy as heat through uncoupled mitochondrial respiration. An essential component of the mitochondrial electron transport chain is coenzyme Q (CoQ). While cells synthesize CoQ mostly endogenously, exogenous supplementation with CoQ has been successful as a therapy for patients with CoQ deficiency.

RTP801 is a novel retinoic acid-responsive gene associated with myeloid differentiation.

Objective: Retinoids are crucial in the regulation of fundamental cellular processes including terminal differentiation of both normal and malignant myeloid progenitors. The aim of this study was to identify and characterize retinoic acid (RA) target genes.

Methods And Results: RTP801 is a recently cloned stress response gene that acts as a negative regulator of the mTOR pathway.

Detection of aberrant gene expression in CD34+ hematopoietic stem cells from patients with agnogenic myeloid metaplasia using oligonucleotide microarrays.

Agnogenic myeloid metaplasia (AMM) is a clonal stem cell disorder that leads to ineffective hematopoiesis, bone marrow fibrosis, and extramedullary hematopoiesis. The molecular mechanisms underlying the development of this syndrome are currently unknown. Therefore, the aim of this study was to characterize aberrant gene expression in CD34+ hematopoietic stem cells from patients with AMM.

Protein partners of C/EBPepsilon.

CCAAT-enhancer binding protein-epsilon (C/EBPepsilon) is a nuclear transcription factor implicated in the regulation of terminal myeloid differentiation. Using a yeast two-hybrid screen, potential interaction partners of C/EBPepsilon involved in myeloid development were identified. C/EBPepsilon was found to associate with other C/EBP family members, including C/EBPepsilon and CHOP as well as other proteins that are known to contain a leucine-zipper protein interaction motif including CREB2, LDOC1, E6TP1, and AF-17.

Retinoic acid regulates C/EBP homologous protein expression (CHOP), which negatively regulates myeloid target genes.

Retinoic acid (RA) promotes granulocytic differentiation of normal hematopoietic cells and acute promyelocytic leukemia (APL) blasts by transcriptional modulation of myeloid regulatory genes. In this study, we have identified the C/EBP homologous protein (CHOP) as a novel retinoid-responsive gene using a polymerase chain reaction (PCR)-based cDNA subtraction method. All-trans retinoic acid (ATRA) induced a biphasic expression of CHOP mRNA in the NB4 and HL60 AML cell lines.

Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation.

The transcription factor C/EBPalpha plays a critical role in the process of granulocytic differentiation. Recently, mutations that abrogated transcriptional activation of C/EBPalpha were detected in acute myeloid leukemia patient samples. Moreover, the progression of chronic myelogenous leukemia (CML) to blast crisis in patients was correlated with down-modulation of C/EBPalpha.

Comparative analysis of genes regulated by PML/RAR alpha and PLZF/RAR alpha in response to retinoic acid using oligonucleotide arrays.

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations involving retinoic acid receptor alpha (RAR alpha) and its fusion partners including promyelocytic leukemia (PML) and promyelocytic leukemia zinc finger (PLZF). Using oligonucleotide arrays, we examined changes in global gene expression mediated by the ectopic expression of either PML/RAR alpha (retinoid-sensitive) or PLZF/RAR alpha (retinoid-resistant) in U937 cells. Of more than 5000 genes analyzed, 16 genes were commonly up-regulated, and 57 genes were down-regulated by both fusion proteins suggesting their role in the APL phenotype.

Macrophage functional maturation and cytokine production are impaired in C/EBP epsilon-deficient mice.

Members of the CCAAT/enhancer-binding protein (C/EBP) family are involved in the regulation of cellular differentiation and function of many tissues. Unlike the other members of the family, C/EBP epsilon expression is restricted to granulocytes, macrophages, and lymphocytes. C/EBP epsilon is highly conserved between human and rodents and is essential for terminal granulopoiesis in both species.