MicroRNA biomarkers for acute traumatic spinal cord injury

Spinal cord injury is a devastating condition with variability in injury mechanisms and neurologic recovery. Spinal cord impairment is measured and classified by a widely accepted standard neurologic examination, however this examination is extremely challenging to conduct due to the fact that patients are often sedated, unconscious, or have multiple injuries. The lack of objective diagnostic or prognostic tools is a barrier for clinical trials. Biological markers (biomarkers) are promising as they represent an unbiased approach to classify injury severity and predict neurologic outcome. MicroRNAs are attractive biomarker candidates in neurological disorders due to their stability in biological fluids, conservation between humans and model mammals, and tissue specificity. These features of microRNAs motivated my research to identify the changes in expression of microRNAs following different injury severities in human patients with spinal cord injury, as well as in a large animal model of spinal cord injury using pigs. In Chapter 1, I provide background on the diagnosis and prognosis of spinal cord injury and discuss the current status of biomarkers for spinal cord injury. In Chapter 2, I provide the historical context for the use of animal models for studying spinal cord injury and review the current status of such animal models and injury paradigms in spinal cord injury research. In Chapter 3, I used a porcine model of thoracic spinal cord injury to study the effects of injury severity on microRNA expression. I identified a set of microRNAs that are diagnostic for injury severity and prognostic for behavioural and histological outcome. In Chapter 4, I identified changes in microRNA expression following acute spinal cord injury in a cohort of 44 human patients. I identified a set of microRNAs that are diagnostic for baseline injury severity and prognostic for neurologic outcome. These data describe the alterations in the microRNA profiles following acute spinal cord injury and identify a common set of microRNAs that can be used as diagnostic and prognostic tools. Furthermore, the data obtained and analyzed in pigs and humans with spinal cord injury provides a reference data set for future work as well as for correlative pig-human investigations.Medicine, Faculty ofGraduat

Metastatic Pattern of Truncal and Extremity Leiomyosarcoma: Retrospective Analysis of Predictors, Outcomes, and Detection

Leiomyosarcomas (LMS) are a heterogenous group of malignant mesenchymal neoplasms with smooth muscle origin and are classified as either non-uterine (NULMS) or uterine (ULMS). Metastatic pattern, prognostic factors, and ideal staging/surveillance studies for truncal and extremity LMS have not been defined. A retrospective analysis of patients diagnosed with histopathology-confirmed truncal or extremity LMS between 2009 and 2019 was conducted. Data collected included demographics, tumor characteristics, staging, surveillance, and survival endpoints. The primary site was defined as: (1) extremity, (2) flank/Pelvis, or (3) chest wall/Spine. We identified 73 patients, 23.3% of which had metastatic LMS at primary diagnosis, while 68.5% developed metastatic disease at any point. The mean metastatic-free survival from primary diagnosis of localized LMS was 3.0 ± 2.8 years. Analysis of prognostic factors revealed that greater age (≥50 years) at initial diagnosis (OR = 3.74, p = 0.0003), higher tumor differentiation scores (OR = 12.09, p = 0.002), and higher tumor necrosis scores (OR = 3.65, p = 0.026) were significantly associated with metastases. Older patients (≥50 years, OR = 4.76, p = 0.017), patients with larger tumors (≥5 cm or ≥10 cm, OR = 2.12, p = 0.02, OR = 1.92, p = 0.029, respectively), higher differentiation scores (OR = 15.92, p = 0.013), and higher necrosis scores (OR = 4.68, p = 0.044) show worse survival outcomes. Analysis of imaging modality during initial staging and during surveillance showed greater tumor detection frequency when PET imaging was employed, compared to CT imaging (p < 0.0001). In conclusion, truncal and peripheral extremity LMS is an aggressive tumor with high metastatic potential and mortality. While there is a significant risk of metastases to lungs, extra-pulmonary tumors are relatively frequent, and broad surveillance may be warranted

Characterization of the gut microbiome in a porcine model of thoracic spinal cord injury

Background The gut microbiome is a diverse network of bacteria which inhabit our digestive tract and is crucial for efficient cellular metabolism, nutrient absorption, and immune system development. Spinal cord injury (SCI) disrupts autonomic function below the level of injury and can alter the composition of the gut microbiome. Studies in rodent models have shown that SCI-induced bacterial imbalances in the gut can exacerbate the spinal cord damage and impair recovery. In this study we, for the first time, characterized the composition of the gut microbiome in a Yucatan minipig SCI model. We compared the relative abundance of the most dominant bacterial phyla in control samples to those collected from animals who underwent a contusion-compression SCI at the 2nd or 10th Thoracic level. Results We identify specific bacterial fluctuations that are unique to SCI animals, which were not found in uninjured animals given the same dietary regimen or antibiotic administration. Further, we identified a specific time-frame, “SCI-acute stage”, during which many of these bacterial fluctuations occur before returning to “baseline” levels. Conclusion This work presents a dynamic view of the microbiome changes that accompany SCI, establishes a resource for future studies and to understand the changes that occur to gut microbiota after spinal cord injury and may point to a potential therapeutic target for future treatment.Medicine, Faculty ofOther UBCOrthopaedic Surgery, Department ofReviewedFacultyResearcherOthe

Adapting inpatient addiction medicine consult services during the COVID‑19 pandemic

Medicine, Faculty ofNon UBCOrthopaedic Surgery, Department ofReviewedFacultyResearcherOthe

Cardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury

Clinical neuroprotective strategies for acute spinal cord injury (SCI) have largely overlooked the heart. Here the authors show cardiac contractility is immediately impaired in a porcine model of T2 SCI, and cardio-centric treatment with dobutamine optimizes cord oxygenation and mitigates haemorrhage

The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury.

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) within a polyethylene glycol (PEG) formulation, called AC105 (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO4), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO4 did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4 treatment. Finally, AC105 did not result in higher Mg2+ levels in CSF than with the use of standard MgSO4. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI