Differential Gene Expression following DHX36/G4R1 Knockout Is Associated with G-Quadruplex Content and Cancer.

G-quadruplexes (G4s) are secondary DNA and RNA structures stabilized by positive cations in a central channel formed by stacked tetrads of Hoogsteen base-paired guanines. G4s form from G-rich sequences across the genome, whose biased distribution in regulatory regions points towards a gene-regulatory role. G4s can themselves be regulated by helicases, such as DHX36 (aliases: G4R1 and RHAU), which possess the necessary activity to resolve these stable structures. G4s have been shown to both positively and negatively regulate gene expression when stabilized by ligands, or through the loss of helicase activity. Using DHX36 knockout Jurkat cell lines, we identified widespread, although often subtle, effects on gene expression that are associated with the presence or number of observed G-quadruplexes in promoters or gene regions. Genes that significantly change their expression, particularly those that show a significant increase in RNA abundance under DHX36 knockout, are associated with a range of cellular functions and processes, including numerous transcription factors and oncogenes, and are linked to several cancers. Our work highlights the direct and indirect role of DHX36 in the transcriptome of T-lymphocyte leukemia cells and the potential for DHX36 dysregulation in cancer.

Current understanding of the chronic stress response to burn injury from human studies.

There is a marked inflammatory and hypermetabolic response following a burn injury. The interlinked responses are more pronounced than for other forms of trauma and can persist for ≥3 years post-injury in burned patients. After a burn, patients have an increased risk of diseases of ageing including cancer, diabetes and cardiovascular disease, highlighting the need for effective long-term strategies to ameliorate the stress response post-burn. Current therapeutic strategies for post-burn recovery include removal of damaged tissue with surgical excision and wound repair, nutritional supplementation and rehabilitative exercise. These strategies aim to minimize the hypermetabolic and inflammatory responses, as well as reducing the loss of lean body mass. This review briefly summarises the inflammatory and hypermetabolic responses and provides an update on the current therapeutic strategies for burned patients. The review examines the persistent nutritional challenge of ensuring sufficient energy intake of each macronutrient to fuel the hypermetabolic and counteract the catabolic response of burn injury, whilst reducing periods of hyperglycaemia and hypertriglyceridemia. Patients require individualized treatment options tailored to unique systemic responses following a burn, facilitated by a precision medicine approach to improve clinical and physiological outcomes in burned patients. Thus, this review discusses the utility of metabolic flexibility assessment to aid clinical decision making and prescription relating to nutritional supplementation and rehabilitative exercise in the burned patient.

Does exercise influence burn-induced inflammation: A cross-over randomised controlled feasibility trial.

BACKGROUND: Burn injuries trigger a greater and more persistent inflammatory response than other trauma cases. Exercise has been shown to positively influence inflammation in healthy and diseased populations, however little is known about the latent effect of exercise on chronic inflammation in burn injured patients. The aims of the pilot study were to assess the feasibility of implementing a long duration exercise training program, in burn injured individuals including learnings associated with conducting a clinical trial in COVID-19 pandemic. METHODS: Fifteen participants with a burn injury between 5-20% total body surface area acquired greater than a year ago were randomised in a within-subject designed study, into one of two conditions, exercise-control or control-exercise. The exercise condition consisted of six weeks of resistance and cardiovascular exercises, completed remotely or supervised in a hospital gym. A comprehensive outcome measurement was completed at the initial, mid and end point of each exercise and control condition. To determine the success of implementation, the feasibility indicator for the data completeness across the comprehensive outcome battery was set at 80%. RESULTS: Half (49%) of eligible participants in the timeframe, were recruited and commenced the study. Six participants withdrew prior to completion and a total of 15 participants completed the study. Eight participants were randomised to the exercise-control and seven to the control exercise group. Five participants trained remotely and seven did supervised training. Three participants completed a mix of both supervised and remote training initiated due to COVID restrictions. Outcome measures were completed on 97% of protocolised occasions and 100% of participants completed the exercise training. CONCLUSIONS: Conducting a long duration exercise training study on burn injured individuals is feasible using the described methods. The knowledge gained helps improve the methodology in larger-scale projects. Insights into the impact of COVID-19 on this clinical trial and success enhancing adaptations for the researcher, research practice and the participant, are presented.

A prospective pilot study of the energy balance profiles in acute non-severe burn patients.

BACKGROUND: Major burn patients have been shown to exhibit a hyper-metabolic state of activity which can persist for up to two years after burn. The relationship between total body surface area (TBSA) and resting metabolic rate (RMR) has been investigated in larger burns (≥20% TBSA), however not in non-severe burns (≤15% TBSA). The primary aim of this observational study was to examine the association between the acute effects of burns <15% TBSA with RMR in patients using indirect calorimetry, as well as any potential covariates. The secondary aim was to determine 24-h energy balance. METHODS: The study included data from 39 participants (82% male), all admitted to the State Adult Burn Unit at Fiona Stanley Hospital. Each patient was recruited upon admission and RMR data was collected on day four (± one day) after burn. RESULTS: The pooled data bivariate correlation showed a significant relationship between RMR and TBSA (r=0.435, p=0.009). A stronger relationship was also found between RMR and TBSA in males (r=0.634, p=0.001). Patients recorded a caloric deficit of 116kcal/day. CONCLUSION: This study demonstrated that a moderately strong linear association exists between RMR and TBSA in males for burns of ≤15% TBSA. The energy balance data indicated that supplementation of calorific intake for non-severe burns suggests careful consideration.