Обзор практики создания научно-технических парков

Материалы VII Междунар. межвуз. науч.-техн. конф. студентов, магистрантов и аспирантов,Гомель, 3–4 мая 2007 г

Rapid Production of Human VEGF-A following Intradermal Injection of Modified VEGF-A mRNA Demonstrated by Cutaneous Microdialysis in the Rabbit and Pig In Vivo

Chemically modified mRNA is a novel, highly efficient, biocompatible modality for therapeutic protein expression that may overcome the challenges and safety concerns with current gene therapy strategies. We explored the efficiency of intradermally injected modified VEGF-A165 mRNA (VEGF-A mRNA) formulated in a biocompatible citrate/saline buffer to locally produce human VEGF-A165 protein. Rabbits (n=4) and minipigs (n=3) were implanted with subcutaneous microdialysis probes close to the injection sites and interstitial-fluid samples and skin biopsies were analysed for production of VEGF-A protein over time for up to 8 hours. Three to 4 hours after the intradermal injection of VEGF-A mRNA, detectable levels of human VEGF-A protein were seen in the microdialysis eluates in both species. In the pig, the VEGF-A concentrations increased dose-dependently reaching a maximum 6 hours after dosing (62.7±28.4, 357.6±240.6, and 746.3±210.2 pg/mL following injection of 24, 120, and 600 μg VEGF-A mRNA, respectively). Likewise, in tissue biopsies harvested at study end (8 hours after VEGF-A mRNA injection), the content of VEGF-A protein increased dose-dependently. In contrast, VEGF-A protein was not detected in eluates originating from sites injected with citrate/saline vehicle. It is concluded that intradermal injection of VEGF-A mRNA is associated with a rapid and local production of VEGF-A protein. Considering the pro-angiogenic effect of VEGF-A, VEGF-A mRNA may hold promise for regenerative treatment of patients with diabetic wounds and ischemic cardiovascular disease

Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans

AIMS: We aimed at examining the acetylcholine-dependent inward-rectifier current (IKAch) as a target for the management of atrial fibrillation (AF). METHODS AND RESULTS: The investigative agents AZD2927 and A7071 concentration-dependently blocked IKACh in vitro with minimal off-target activity. In anaesthetized dogs (n = 17) subjected to 8 weeks of rapid atrial pacing (RAP), the left atrial effective refractory period (LAERP) was maximally increased by 50 ± 7.4 and 50 ± 4.8 ms following infusion of AZD2927 and A7071. Ventricular refractoriness and the QT interval were unaltered. During sustained AF, both drugs significantly reduced AF frequency and effectively restored sinus rhythm. AZD2927 successfully restored sinus rhythm at 10/10 conversion attempts and A7071 at 14/14 attempts, whereas saline converted 4/17 episodes only (P&lt;0.001 vs. AZD2927 and A7071). In atrial flutter patients (n = 18) undergoing an invasive investigation, AZD2927 did not change LAERP, the paced QT interval, or ventricular refractoriness when compared with placebo. To address the discrepancy on LAERP by IKACh blockade in man and dog and the hypothesis that atrial electrical remodelling is a prerequisite for IKACh blockade being efficient, six dogs were studied after 8 weeks of RAP followed by sinus rhythm for 4 weeks to reverse electrical remodelling. In these dogs, both AZD2927 and A7071 were as effective in increasing LAERP as in the dogs studied immediately after the 8-week RAP period. CONCLUSION: Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.This work was supported by AstraZeneca R&amp;D, CVMD Innovative Medicine, Molndal, Sweden.</p

Functional Role of Glycosaminoglycans in Decellularized Lung Extracellular Matrix

Despite progress in use of decellularized lung scaffolds in ex vivo lung bioengineering schemes, including use of gels and other materials derived from the scaffolds, the detailed composition and functional role of extracellular matrix (ECM) proteoglycans (PGs) and their glycosaminoglycan (GAG) chains remaining in decellularized lungs, is poorly understood. Using a commonly utilized detergent-based decellularization approach in human autopsy lungs resulted in disproportionate losses of GAGs with depletion of chondroitin sulfate/dermatan sulfate (CS/DS) > heparan sulfate (HS) > hyaluronic acid (HA). Specific changes in disaccharide composition of remaining GAGs were observed with disproportionate loss of NS and NS2S for HS groups and of 4S for CS/DS groups. No significant influence of smoking history, sex, time to autopsy, or age was observed in native vs. decellularized lungs. Notably, surface plasmon resonance demonstrated that GAGs remaining in decellularized lungs were unable to bind key matrix-associated growth factors FGF2, HGF, and TGFβ1. Growth of lung epithelial, pulmonary vascular, and stromal cells cultured on the surface of or embedded within gels derived from decellularized human lungs was differentially and combinatorially enhanced by replenishing specific GAGs and FGF2, HGF, and TGFβ1. In summary, lung decellularization results in loss and/or dysfunction of specific GAGs or side chains significantly affecting matrix-associated growth factor binding and lung cell metabolism. GAG and matrix-associated growth factor replenishment thus needs to be incorporated into schemes for investigations utilizing gels and other materials produced from decellularized human lungs

Unraveling the Metabolic Derangements Occurring in Non-infarcted Areas of Pig Hearts With Chronic Heart Failure

Objective: After myocardial infarction (MI), the non-infarcted left ventricle (LV) ensures appropriate contractile function of the heart. Metabolic disturbance in this region greatly exacerbates post-MI heart failure (HF) pathology. This study aimed to provide a comprehensive understanding of the metabolic derangements occurring in the non-infarcted LV that could trigger cardiovascular deterioration. Methods and Results: We used a pig model that progressed into chronic HF over 3 months following MI induction. Integrated gene and metabolite signatures revealed region-specific perturbations in amino acid- and lipid metabolism, insulin signaling and, oxidative stress response. Remote LV, in particular, showed impaired glutamine and arginine metabolism, altered synthesis of lipids, glucose metabolism disorder, and increased insulin resistance. LPIN1, PPP1R3C, PTPN1, CREM, and NR0B2 were identified as the main effectors in metabolism dysregulation in the remote zone and were found differentially expressed also in the myocardium of patients with ischemic and/or dilated cardiomyopathy. In addition, a simultaneous significant decrease in arginine levels and altered PRCP, PTPN1, and ARF6 expression suggest alterations in vascular function in remote area. Conclusions: This study unravels an array of dysregulated genes and metabolites putatively involved in maladaptive metabolic and vascular remodeling in the non-infarcted myocardium and may contribute to the development of more precise therapies to mitigate progression of chronic HF post-MI.CC BY 4.0Correspondence:Cláudia [email protected] Synnergren [email protected]: This work was supported by AstraZeneca and the University of Skövde, Sweden under grants from the Knowledge Foundation [2014/301, 2016/294, and 2016/330]. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.</p

Identification of myocardial injury using perioperative troponin surveillance in major noncardiac surgery and net benefit over the Revised Cardiac Risk Index

Background: Patients with perioperative myocardial injury are at risk of death and major adverse cardiovascular and cerebrovascular events (MACCE). The primary aim of this study was to determine optimal thresholds of preoperative and perioperative changes in high-sensitivity cardiac troponin T (hs-cTnT) to predict MACCE and mortality. Methods: Prospective, observational, cohort study in patients &amp;gt;= 50 yr of age undergoing elective major noncardiac surgery at seven hospitals in Sweden. The exposures were hs-cTnT measured before and days 0-3 after surgery. Two previously published thresholds for myocardial injury and two thresholds identified using receiver operating characteristic analyses were evaluated using multivariable logistic regression models and externally validated. The weighted comparison net benefit method was applied to determine the additional value of hs-cTnT thresholds when compared with the Revised Cardiac Risk Index (RCRI). The primary outcome was a composite of 30-day all-cause mortality and MACCE. Results: We included 1291 patients between April 2017 and December 2020. The primary outcome occurred in 124 patients (9.6%). Perioperative increase in hs-cTnT &amp;gt;= 14 ng L-1 above preoperative values provided statistically optimal model performance and was associated with the highest risk for the primary outcome (adjusted odds ratio 2.9, 95% confidence interval 1.8-4.7). Validation in an independent, external cohort confirmed these findings. A net benefit over RCRI was demonstrated across a range of clinical thresholds. Conclusions: Perioperative increases in hsTnT &amp;gt;= 14 ng L-1 above baseline values identifies acute perioperative myocardial injury and provides a net prognostic benefit when added to RCRI for the identification of patients at high risk of death and MACCE.Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-02833]; South Eastern Sweden Research Council [746981, 712291]; Linkoping University-Region Ostergotland ALF [687681, 792291]; Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission [320030-179362]; Swiss Heart Foundation; University Hospital of Basel; Roche Diagnostics; University of Basel; AstraZenecaAstraZeneca</p

Biocompatible, Purified VEGF-A mRNA Improves Cardiac Function after Intracardiac Injection 1 Week Post-myocardial Infarction in Swine

mRNA can direct dose-dependent protein expression in cardiac muscle without genome integration, but to date has not been shown to improve cardiac function in a safe, clinically applicable way. Herein, we report that a purified and optimized mRNA in a biocompatible citrate-saline formulation is tissue specific, long acting, and does not stimulate an immune response. In small- and large-animal, permanent occlusion myocardial infarction models, VEGF-A 165 mRNA improves systolic ventricular function and limits myocardial damage. Following a single administration a week post-infarction in mini pigs, left ventricular ejection fraction, inotropy, and ventricular compliance improved, border zone arteriolar and capillary density increased, and myocardial fibrosis decreased at 2 months post-treatment. Purified VEGF-A mRNA establishes the feasibility of improving cardiac function in the sub-acute therapeutic window and may represent a new class of therapies for ischemic injury. Keywords: modRNA, mRNA, mRNA, VEGF, heart failur