A feasibility study of the Canadian Occupational Performance Measure (COPM) in the burn cohort in an acute tertiary facility.

BACKGROUND: Retrospective auditing identified the need to implement a client centered tool to measure occupational performance and re engagement in activities after burn injury. The Canadian Occupational Performance Measure (COPM) was chosen as it has a broad focus on occupational performance across the lifespan. However, given the time constraints that acute care clinicians work within in a tertiary teaching hospital, a feasibility study was warranted to identify the time to complete the COPM and any potential barriers which may arise in order to evaluate the appropriateness of using this tool. METHODS: This project was a prospective cohort study. All patients presenting to the ward and the Specialist Burns Outpatient Clinic were consecutively enrolled in this study. Information was collected regarding administration of the COPM including administration time, number of interruptions and reasons for non-completion of the outcome measure e.g. wound dressing procedures, surgery, scheduling conflicts. A survey method was used to explore the perceptions of Occupational Therapy clinicians regarding use of the COPM in clinical practice. RESULTS: Over the course of the study period 70 COPM's were administered. The average time for administration across both settings was 9 min. Individually the average time taken for administration of the COPM with inpatients was 11.21 min, in the outpatient setting 7.85 min. The Survey Monkey questionnaire was emailed to 58 occupational therapy clinicians working at the facility associated with the study. The response rate was 41.4% (24). DISCUSSION: Patient reported outcome measures are central to patient centred care which is a core element of health care provision. Results from this study found that the COPM took approximately 9 min to administer, which is suitable within the time constraints of an acute tertiary environment and would be feasible in our setting. Fifty one percent of the participants identified return to work as the activity of daily living most impacted by their burn injury. As burn injuries impact all domains of daily life the use of patient reported outcome measures to direct goal orientated care is imperative. CONCLUSION: This study found that the time to administer the COPM is feasible within the acute tertiary setting. Perceived barriers identified can be overcome with increased knowledge of client centred practice and the importance of goal directed care. The use of patient reported outcome measures in clinical practice empowers consumers to identify what goals they would like to achieve.

Targeting metabolic activity in high-risk neuroblastoma through Monocarboxylate Transporter 1 (MCT1) inhibition.

Amplification of the MYCN oncogene occurs in ~25% of primary neuroblastomas and is the single most powerful biological marker of poor prognosis in this disease. MYCN transcriptionally regulates a range of biological processes important for cancer, including cell metabolism. The MYCN-regulated metabolic gene SLC16A1, encoding the lactate transporter monocarboxylate transporter 1 (MCT1), is a potential therapeutic target. Treatment of neuroblastoma cells with the MCT1 inhibitor SR13800 increased intracellular lactate levels, disrupted the nicotinamide adenine dinucleotide (NADH/NAD+) ratio, and decreased intracellular glutathione levels. Metabolite tracing with 13C-glucose and 13C-glutamine following MCT1 inhibitor treatment revealed increased quantities of tricarboxylic acid (TCA) cycle intermediates and increased oxygen consumption rate. MCT1 inhibition was highly synergistic with vincristine and LDHA inhibition under cell culture conditions, but this combination was ineffective against neuroblastoma xenografts. Posttreatment xenograft tumors had increased synthesis of the MCT1 homolog MCT4/SLC16A, a known resistance factor to MCT1 inhibition. We found that MCT4 was negatively regulated by MYCN in luciferase reporter assays and its synthesis in neuroblastoma cells was increased under hypoxic conditions and following hypoxia-inducible factor (HIF1) induction, suggesting that MCT4 may contribute to resistance to MCT1 inhibitor treatment in hypoxic neuroblastoma tumors. Co-treatment of neuroblastoma cells with inhibitors of MCT1 and LDHA, the enzyme responsible for lactate production, resulted in a large increase in intracellular pyruvate and was highly synergistic in decreasing neuroblastoma cell viability. These results highlight the potential of targeting MCT1 in neuroblastoma in conjunction with strategies that involve disruption of pyruvate homeostasis and indicate possible resistance mechanisms.

In vitro regulation of neural differentiation and axon growth by growth factors and bioactive nanofibers.

Human embryonic stem cell (ESC)-derived neural cells are a potential cell source for neural tissue regeneration. Understanding the biochemical and biophysical regulation of neural differentiation and axon growth will help us develop cell therapies and bioactive scaffolds. We demonstrated that basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) had different effects on human ESC differentiation into neural cells. EGF was more effective in inducing expression of neuron and glial markers and cell extensions. In addition to biochemical cues, poly(l-lactic acid) scaffolds with aligned nanofibers increased axon growth from ESC-derived neural cells, demonstrating the significant effects of biophysical guidance at nanoscale. To combine the biochemical and biophysical cues, bFGF and EGF were either adsorbed or bound to heparin on nanofibrous scaffolds. EGF, but not bFGF, was effectively adsorbed onto nanofibers. However, adsorbed EGF and bFGF did not effectively enhance axon growth. In contrast, immobilization of bFGF or EGF onto nanofibers using heparin as the adapter molecule significantly promoted axon growth. This study elucidated the effect of bFGF and EGF in neural differentiation and axon growth, and demonstrated a method to immobilize active bFGF and EGF onto aligned nanofibers to promote neural tissue regeneration.

Transforming growth factor-beta and notch signaling mediate stem cell differentiation into smooth muscle cells.

The differentiation of stem cells into smooth muscle cells (SMCs) plays an important role in vascular development and remodeling. In addition, stem cells represent a potential source of SMCs for regenerative medicine applications such as constructing vascular grafts. Previous studies have suggested that various biochemical factors, including transforming growth factor-beta (TGF-beta) and the Notch pathway, may play important roles in vascular differentiation. However, the interactions of these two signaling pathways in the differentiation of bone marrow mesenchymal stem cells (MSCs) have not been clearly defined. In this study, we profiled the gene expression in MSCs in response to TGF-beta, and showed that TGF-beta induced Notch ligand Jagged 1 (JAG1) and SMC markers, including smooth muscle alpha-actin (ACTA2), calponin 1 (CNN1), and myocardin (MYOCD), which were dependent on the activation of SMAD3 and Rho kinase. In addition, knocking down JAG1 expression partially blocked ACTA2 and CNN1 expression and completely blocked MYOCD expression, suggesting that JAG1 plays an important role in TGF-beta-induced expression of SMC markers. On the other hand, the activation of Notch signaling induced the expression of SMC markers in MSCs and human embryonic stem cells (hESCs). Notch activation in hESCs also resulted in an increase of neural markers and a decrease of endothelial markers. These results suggest that Notch signaling mediates TGF-beta regulation of MSC differentiation and that Notch signaling induces the differentiation of MSCs and hESCs into SMCs, which represents a novel mechanism involved in stem cell differentiation.

Localized decrease of beta-catenin contributes to the differentiation of human embryonic stem cells.

Human embryonic stem cells (hESC) are pluripotent, and can be directed to differentiate into different cell types for therapeutic applications. To expand hESCs, it is desirable to maintain hESC growth without differentiation. As hESC colonies grow, differentiated cells are often found at the periphery of the colonies, but the underlying mechanism is not well understood. Here, we utilized micropatterning techniques to pattern circular islands or strips of matrix proteins, and examined the spatial pattern of hESC renewal and differentiation. We found that micropatterned matrix restricted hESC differentiation at colony periphery but allowed hESC growth into multiple layers in the central region, which decreased hESC proliferation and induced hESC differentiation. In undifferentiated hESCs, beta-catenin primarily localized at cell-cell junctions but not in the nucleus. The amount of beta-catenin in differentiating hESCs at the periphery of colonies or in multiple layers decreased significantly at cell-cell junctions. Consistently, knocking down beta-catenin decreased Oct-4 expression in hESCs. These results indicate that localized decrease of beta-catenin contributes to the spatial pattern of differentiation in hESC colonies.