Plasma interleukin responses as predictors of outcome stratification in patients after major trauma: a prospective observational two centre study.

Background and objectives: There is a need to develop objective risk stratification tools to define efficient care pathways for trauma patients. Biomarker-based point of care testing may strengthen existing clinical tools currently available for this purpose. The dysregulation of pro- and anti-inflammatory cytokines in the pathogenesis of organ failure is well recognised. This study was carried out to evaluate whether blood concentrations of IL-6, IL-10, and IL-6:IL-10 ratios in the early stages of the illness are significantly different in patients with worsening organ function. Materials and methods: In this prospective observational cohort study, plasma concentrations of IL-6 and IL-10 on days 1, 3 and 5 were measured in 91 major trauma patients using a multiplexed cytometric bead array approach. A composite measure of adverse outcome - defined as SOFA ≥ 2 or mortality at 7 days, was the primary outcome. IL-6 and IL-10 concentrations in early samples (days 1, 3 & 5) in patients who developed SOFA ≥ 2 on day 7 were compared against those who did not. Similar composite outcome groups at day 5 and in groups with worsening or improving SOFA scores (ΔSOFA) at days 7 and 5 were undertaken as secondary analyses. Results: Stratification on day 7, 44 (48%) patients showed adverse outcomes. These adverse outcomes associated with significantly greater IL-6 concentrations on days 1 and 5 (Day 1: 47.65 [23.24-78.68] Vs 73.69 [39.93 - 118.07] pg/mL, P = 0.040 and Day 5: 12.85 [5.80-19.51] Vs 28.90 [8.78-74.08] pg/mL; P = 0.0019). Similarly, IL-10 levels were significantly greater in the adverse outcome group on days 3 and 5 (Day 3: 2.54 [1.76-3.19] Vs 3.16 [2.68-4.21] pg/mL; P = 0.044 and Day 5: 2.03 [1.65-2.55] Vs 2.90 [2.00-5.06] pg/mL; P <0.001). IL-6 and IL-10 concentrations were also significantly elevated in the adverse outcome groups at day 3 and day 5 when stratified on day 5 outcomes. Both IL-6 and IL-6:IL-10 were found to be significantly elevated on days 1 and 3 when stratified based on ΔSOFA at day 5. This significance was lost when stratified on day 7 scores. Conclusions: Early IL-6 and IL-10 concentrations are significantly greater in patients who develop worsening organ functions downstream. These differences may provide an alternate biomarker-based approach to strengthen risk stratification in trauma patients.

Boswellia carterii oleoresin extracts induce caspase-mediated apoptosis and G1 cell cycle arrest in human leukaemia subtypes.

Background: Leukemias are a common cancer in adults and children. While existing treatments are effective, they are associated with severe side-effects compounded by the emergence of drug resistance. This necessitates the need to develop new drugs and phytopharmaceuticals offer a largely untapped source. Oleoresins produced by plants in the genus Boswellia have been used for centuries in traditional medicine and recent work suggests they may exhibit anti-cancer activity. However, the underlying mechanisms remain unclear and most existing research focusses on Boswellia serrata; just one of many species in the Boswellia genus. To address these limitations, we elucidated the anti-cancer potential and associated mechanisms of action of Boswellia carterii. Methods: A methanolic solvent extraction method was optimised. The effect of methanolic extracts of B. carterii on leukaemia (K562, MOLT-4 and CCRF-CEM) and normal (PBMC) cell line viability was assessed using MTT assay and flow cytometry. Cell morphology, apoptosis (Annexin-V/propidium iodide), mitochondrial membrane potential (Rhodamine-123) and the cell cycle (propidium iodide) were evaluated using flow cytometry. Regulatory protein expression was quantified using Western Blot. Results: Methanolic extracts of B. carterii oleoresin reduced the viability of K562, MOLT-4 and CCRF-CEM cell lines with selectivity indexes of between 1.75 and 2.68. Extracts increased the proportion of cells in late apoptosis by 285.4% ± 51.6%. Mitochondrial membrane potential was decreased by 41% ± 2% and the expression of cleaved caspase-3, -7, and -9 was increased by 5.7, 3.3, and 1.5-fold respectively. Extracts increased the proportion of cells in subG1 and G1 phase by 867.8% ± 122.9% and 14.0 ± 5.5 and decreased those in S phase and G2/M by 63.4% ± 2.0% and 57.6% ± 5.3%. Expression of CDK2, CDK6, cyclin D1, and cyclin D3 were decreased by 2.8, 4.9, 3.9, and 2.5-fold. Conclusion: We are the first to report that methanolic extracts of B. carterii are selectively cytotoxic against three leukemia cell lines. Cytotoxic mechanisms likely include activation of the intrinsic apoptotic pathway and cell cycle arrest through downregulation of CDK2, CDK6, cyclin D1, and cyclin D3. Our findings suggest that B. carterii may be an important source of novel chemotherapeutic drugs and justifies further investigation.