Combining regenerative medicine strategies to provide durable reconstructive options: auricular cartilage tissue engineering

Recent advances in regenerative medicine place us in a unique position to improve the quality of engineered tissue. We use auricular cartilage as an exemplar to illustrate how the use of tissue-specific adult stem cells, assembly through additive manufacturing and improved understanding of postnatal tissue maturation will allow us to more accurately replicate native tissue anisotropy. This review highlights the limitations of autologous auricular reconstruction, including donor site morbidity, technical considerations and long-term complications. Current tissue-engineered auricular constructs implanted into immune-competent animal models have been observed to undergo inflammation, fibrosis, foreign body reaction, calcification and degradation. Combining biomimetic regenerative medicine strategies will allow us to improve tissue-engineered auricular cartilage with respect to biochemical composition and functionality, as well as microstructural organization and overall shape. Creating functional and durable tissue has the potential to shift the paradigm in reconstructive surgery by obviating the need for donor sites

Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer.

BACKGROUND: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer. METHODS: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures. RESULTS: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression. CONCLUSIONS: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming. TRIAL REGISTRATION: Not applicable (non-interventional study). CRUK Internal Database Number 14232

Absolute stability of time-varying delay Lurie indirect control systems with unbounded coefficients

This paper investigates the absolute stability problem of time-varying delay Lurie indirect control systems with variable coefficients. A positive-definite Lyapunov-Krasovskii functional is constructed. Some novel sufficient conditions for absolute stability of Lurie systems with single nonlinearity are obtained by estimating the negative upper bound on its total time derivative. Furthermore, the results are generalised to multiple nonlinearities. The derived criteria are especially suitable for time-varying delay Lurie indirect control systems with unbounded coefficients. The effectiveness of the proposed results is illustrated using simulation examples

Effectiveness of recombinant human granulocyte macrophage colony-stimulating factor for treating deep second-degree burns: a systematic review and meta-analysis

IntroductionIt is uncertain whether treatment by recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) can promote healing of deep second-degree burns. This meta-analysis aimed to systematically review and assess randomised controlled trials (RCTs) that investigated the efficacy and safety of rhGM-CSF for treating deep second-degree burns.MethodsThis meta-analysis conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. The PubMed, Cochrane Library, Medline and Embase databases and relevant references were systematically searched for RCTs (published up to November 2019). Main outcome measures included the wound healing rate, wound healing time and average optical densities of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). We performed a meta-analysis using fixed or random effects models.ResultsSeven RCTs comprising 982 patients with 1184 burns (652 patients received rhGM-CSF vs 532 controls) were included. Compared with standard wound care alone, the use of rhGM-CSF significantly reduced wound healing time by 4.77 days (weighted mean difference=−4.77; 95% CI −6.45 to −3.09; p&lt;0.001) and significantly increased the wound healing rate on days 7, 10, 14 and 20 by 6.46%, 19.78%, 17.07% and 11.38%, respectively. There was no significant difference between the groups in the wound healing rate on day 28 and average optical densities of VEGF and FGF. No systematic adverse event occurred. Redder, more swollen and painful wounds were reported after using rhGM-CSF compared with the control.ConclusionsrhGM-CSF could be effective and safe for treating deep second-degree burns.</jats:sec

Reducing olanzapine-induced weight gain side-effect by using betahistine: a study in the rat model

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug’s antagonistic affinity to histamine H1 receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H1 receptor agonist and H3 receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H3 receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H1 receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects

Redox responses of Arabidopsis thaliana

The green peach aphid (Myzus persicae) is a phloem-feeding insect that causes economic damage on a wide array of crops. Using a luminol-based assay, a superoxide-responsive reporter gene (Zat12::luciferase), and a probe specific to hydrogen peroxide (HyPer), we demonstrated that this aphid induces accumulation of reactive oxygen species (ROS) in Arabidopsis thaliana. Similar to the apoplastic oxidative burst induced by pathogens, this response to aphids was rapid and transient, with two peaks occurring within 1 and 4 hr after infestation. Aphid infestation also induced an oxidative response in the cytosol and peroxisomes, as measured using a redox-sensitive variant of green fluorescent protein (roGFP2). This intracellular response began within minutes of infestation but persisted 20 hr or more after inoculation, and the response of the peroxisomes appeared stronger than the response in the cytosol. Our results suggest that the oxidative response to aphids involves both apoplastic and intracellular sources of ROS, including ROS generation in the peroxisomes, and these different sources of ROS may potentially differ in their impacts on host suitability for aphids