2021 MiECTiS focused update on the 2016 position paper for the use of minimal invasive extracorporeal circulation in cardiac surgery.

The landmark 2016 Minimal Invasive Extracorporeal Technologies International Society (MiECTiS) position paper promoted the creation of a common language between cardiac surgeons, anesthesiologists and perfusionists which led to the development of a stable framework that paved the way for the advancement of minimal invasive perfusion and related technologies. The current expert consensus document offers an update in areas for which new evidence has emerged. In the light of published literature, modular minimal invasive extracorporeal circulation (MiECC) has been established as a safe and effective perfusion technique that increases biocompatibility and ultimately ensures perfusion safety in all adult cardiac surgical procedures, including re-operations, aortic arch and emergency surgery. Moreover, it was recognized that incorporation of MiECC strategies advances minimal invasive cardiac surgery (MICS) by combining reduced surgical trauma with minimal physiologic derangements. Minimal Invasive Extracorporeal Technologies International Society considers MiECC as a physiologically-based multidisciplinary strategy for performing cardiac surgery that is associated with significant evidence-based clinical benefit that has accrued over the years. Widespread adoption of this technology is thus strongly advocated to obtain additional healthcare benefit while advancing patient care.

Probing Adsorption of Dipeptides on Anatase in H2 O and D2 O: Thermodynamics and Molecular Geometry.

Considering the vast importance of peptide and protein interactions with inorganic surfaces, probing hydrogen bonding during their adsorption on metal oxide surfaces is a relevant task that could shed light on the essential features of their interplay. This work is devoted to studying the dipeptides' adsorption on anatase nanoparticles (ANs) in light and heavy water to reveal differences arising upon the change of the major hydrogen bonding carrier. Thermodynamic study of six native dipeptides' adsorption on ANs in both media shows a strong influence of the solvent on the Gibbs free energy and the effect of side-chain mobile protons on the entropy of the process. The adsorption is endothermic irrespective of the medium and is entropy-driven. Computer simulations of peptide adsorption in both media shows similarity in binding via an amino group and demonstrates structural features of protonated and deuterated peptides in obtained complexes. Calculated peptide- anatase nanoparticle (AN) descriptors indicate surface oxygens as points of peptide-nanoparticle contacts.

Benzothiadiazole vs. iso-Benzothiadiazole: Synthesis, Electrochemical and Optical Properties of D-A-D Conjugated Molecules Based on Them.

This paper presents an improved synthesis of 4,7-dibromobenzo[d][1,2,3]thiadiazole from commercially available reagents. According to quantum-mechanical calculations, benzo[d][1,2,3]thiadiazole (isoBTD) has higher values of ELUMO and energy band gap (Eg), which indicates high electron conductivity, occurring due to the high stability of the molecule in the excited state. We studied the cross-coupling reactions of this dibromide and found that the highest yields of π-spacer-acceptor-π-spacer type compounds were obtained by means of the Stille reaction. Therefore, 6 new structures of this type have been synthesized. A detailed study of the optical and electrochemical properties of the obtained π-spacer-acceptor-π-spacer type compounds in comparison with isomeric structures based on benzo[c][1,2,5]thiadiazole (BTD) showed a red shift of absorption maxima with lower absorptive and luminescent capacity. However, the addition of the 2,2'-bithiophene fragment as a π-spacer resulted in an unexpected increase of the extinction coefficient in the UV/vis spectra along with a blue shift of both absorption maxima for the isoBTD-based compound as compared to the BTD-based compound. Thus, a thorough selection of components in the designing of appropriate compounds with benzo[d][1,2,3]thiadiazole as an internal acceptor can lead to promising photovoltaic materials.

Synthesis of 2-((2-(Benzo[d]oxazol-2-yl)-2H-imidazol-4-yl)amino)-phenols from 2-((5H-1,2,3-Dithiazol-5-ylidene)amino)phenols through Unprecedented Formation of Imidazole Ring from Two Methanimino Groups.

A new synthetic pathway to four substituted imidazoles from readily available 2-((4-aryl(thienyl)-5H-1,2,3-dithiazol-5-ylidene)amino)phenols has been developed. Benzo[d]oxazol-2-yl(aryl(thienyl))methanimines were proved as key intermediates in their synthesis. The formation of an imidazole ring from two methanimine derivatives likely includes the opening of one benzoxazole ring followed by ring closure by intermolecular nucleophilic attack of the N-methanimine atom to a carbon atom of another methanimine.

Randomized Clinical Trial of Surgical vs. Percutaneous vs. Hybrid Revascularization in Multivessel Coronary Artery Disease: Residual Myocardial Ischemia and Clinical Outcomes at One Year-Hybrid coronary REvascularization Versus Stenting or Surgery (HREVS).

AIM: Optimal revascularization strategy in multivessel (MV) coronary artery disease (CAD) eligible for percutaneous management (PCI) and surgery remains unresolved. We evaluated, in a randomized clinical trial, residual myocardial ischemia (RI) and clinical outcomes of MV-CAD revascularization using coronary artery bypass grafting (CABG), hybrid coronary revascularization (HCR), or MV-PCI. METHODS: Consecutive MV-CAD patients (n = 155) were randomized (1 : 1 : 1) to conventional CABG (LIMA-LAD plus venous grafts) or HCR (MIDCAB LIMA-LAD followed by PCI for remaining vessels) or MV-PCI (everolimus-eluting CoCr stents) under Heart Team agreement on equal technical and clinical feasibility of each strategy. SPECT at 12 months (primary endpoint of RI that the trial was powered for; a measure of revascularization midterm efficacy and an independent predictor of long-term prognosis) preceded routine angiographic control. RESULTS: Data are given, respectively, for the CABG, HCR, and MV-PCI arms. Incomplete revascularization rate was 8.0% vs. 7.7% vs. 5.7% (p=0.71). Hospital stay was 13.8 vs. 13.5 vs. 4.5 days (p < 0.001), and sick-leave duration was 23 vs. 16 vs. 8 weeks (p < 0.001). At 12 months, RI was 5 (2, 9)% vs. 5 (3, 7)% vs. 6 (3, 10)% (median; Q1, Q3) with noninferiority p values of 0.0006 (HCR vs. CABG) and 0.016 (MV-PCI vs. CABG). Rates of angiographic graft stenosis/occlusion or in-segment restenosis were 20.4% vs. 8.2% vs. 5.9% (p=0.05). Clinical target vessel/graft failure occurred in 12.0% vs. 11.5% vs. 11.3% (p=0.62). Major adverse cardiac and cerebral event (MACCE) rate was similar (12% vs. 13.4% vs. 13.2%; p=0.83). CONCLUSION: In this first randomized controlled study comparing CABG, HCR, and MV-PCI, residual myocardial ischemia and MACCE were similar at 12 months. There was no midterm indication of any added value of HCR. Hospital stay and sick-leave duration were shortest with MV-PCI. While longer-term follow-up is warranted, these findings may impact patient and physician choices and healthcare resources utilization. This trial is registered with NCT01699048.

[1,2,5]Thiadiazolo[3,4-d]Pyridazine as an Internal Acceptor in the D-A-π-A Organic Sensitizers for Dye-Sensitized Solar Cells.

Four new D-A-π-A metal-free organic sensitizers for dye-sensitized solar cells (DSSCs), with [1,2,5]thiadiazolo[3 ,4-d]pyridazine as internal acceptor, thiophene unit as π-spacer and cyanoacrylate as anchoring electron acceptor, have been synthesized. The donor moiety was introduced into [1,2,5]thiadiazolo[3,4-d]pyridazine by nucleophilic aromatic substitution and Suzuki cross-coupling reactions, allowing design of D-A-π-A sensitizers with the donor attached to the internal heterocyclic acceptor not only by the carbon atom, as it is in a majority of DSSCs, but by the nitrogen atom also. Although low values of power conversion efficiency (PCE) were found, a few important consequences were identified: (i) poor PCE data can be attributed to high electron deficiency of the internal [1,2,5]thiadiazolo[3,4-d]pyridazine acceptor due to lower light harvesting by the dye; (ii) the manner in which the donor was attached to the internal acceptor (by carbon or nitrogen) did not play an essential role in the photovoltaic properties of the dyes; (iii) dyes based on the novel donor 2,3,4,4a,9,9a-hexahydro-1H-1,4-methanocarbazolyl and 9-(p-tolyl)-2,3,4,4a,9,9a-hexahydro-1H- carbazole moieties showed similar photovoltaic properties to dyes based on the well-known 4-(p-tolyl)-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indolyl building block, which opens the door for further optimization potential of new dye families.

Safe Synthesis of 4,7-Dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine and Its SNAr Reactions.

A safe and efficient synthesis of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine from the commercial diaminomaleonitrile is reported. Conditions for selective aromatic nucleophilic substitution of one or two bromine atoms by oxygen and nitrogen nucleophiles are found, whereas thiols formed the bis-derivatives only. Buchwald-Hartwig or Ullmann techniques are successful for incorporation of a weak nitrogen base, such as carbazole, into the [1,2,5]thiadiazolo[3,4-d]pyridazine core. The formation of rather stable S…η²-(N=N) bound chains in 4,7-bis(alkylthio)-[1,2,5]thiadiazolo[3,4-d]pyridines makes these compounds promising for the design of liquid crystals.

Molecular Imaging of Sirtuin1 Expression-Activity in Rat Brain Using Positron-Emission Tomography-Magnetic-Resonance Imaging with [18F]-2-Fluorobenzoylaminohexanoicanilide.

Sirtuin 1 (SIRT1) is a class III histone deacetylase that plays significant roles in the regulation of lifespan, metabolism, memory, and circadian rhythms and in the mechanisms of many diseases. However, methods of monitoring the pharmacodynamics of SIRT1-targeted drugs are limited to blood sampling because of the invasive nature of biopsies. For the noninvasive monitoring of the spatial and temporal dynamics of SIRT1 expression-activity in vivo by PET-CT-MRI, we developed a novel substrate-type radiotracer, [18F]-2-fluorobenzoylaminohexanoicanilide (2-[18F]BzAHA). PET-CT-MRI studies in rats demonstrated increased accumulation of 2-[18F]BzAHA-derived radioactivity in the hypothalamus, hippocampus, nucleus accumbens, and locus coeruleus, consistent with autoradiographic and immunofluorescent (IMF) analyses of brain-tissue sections. Pretreatment with the SIRT1 specific inhibitor, EX-527 (5 mg/kg, ip), resulted in about a 20% reduction of 2-[18F]BzAHA-derived-radioactivity accumulation in these structures. In vivo imaging of SIRT1 expression-activity should facilitate studies that improve the understanding of SIRT1-mediated regulation in the brain and aid in the development and clinical translation of SIRT1-targeted therapies.

The Conversion of 5,5'-Bi(1,2,3-dithiazolylidenes) into Isothiazolo[5,4-d]isothiazoles.

Thermolysis of 4,4'-dichloro-, 4,4'-diaryl-, and 4,4'-di(thien-2-yl)-5,5'-bi(1,2,3-dithiazol-ylidenes) affords the respective 3,6-dichloro-, 3,6-diaryl- and 3,6-di(thien-2-yl)isothiazolo[5,4-d]-isothiazoles in low to high yields. The transformation of the 4,4'-diaryl- and 4,4'-di(thien-2-yl)-5,5'-bi(1,2,3-dithiazolylidenes) occurs at lower temperatures in the presence of the thiophiles triphenylphosphine or tetraethylammonium iodide. Optimized reaction conditions and a mechanistic rationale for the thiophile-mediated ring transformation are presented.

A Novel Substrate Radiotracer for Molecular Imaging of SIRT2 Expression and Activity with Positron Emission Tomography.

PURPOSE: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues. PROCEDURES: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (Kcat/Km 716.5 ± 72.8, 615.4 ± 50.5, 269.5 ± 52.1/s mol, respectively). Radiosynthesis of 12- [18F]fluorododecanoic aminohexanoicanilide (12-[18F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor. RESULTS: A significantly higher accumulation of 12-[18F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[18F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid defluorination of this radiotracer upon intravenous administration, as evidenced by significant accumulation of F-18 radioactivity in the skull and other bones, which confounded the interpretation of images of radiotracer accumulation within the tumor and other regions of the brain. CONCLUSIONS: The next generation of SIRT2-specific radiotracers resistant to systemic defluorination should be developed using alternative sites of radiofluorination on the aliphatic chain of DDAHA. A SIRT2-selective radiotracer may provide information about SIRT2 expression and activity in tumors and normal organs and tissues, which may help to better understand the roles of SIRT2 in different diseases.

The Case of Successful Surgical Treatment of a Patient With Thoracic Endograft Infection in 5 Years After Thoracic Endovascular Aortic Repair.

We present here a case of successful staged treatment of a patient with para-aortic abscess that arose 5 years after thoracic endovascular aortic repair because of thoracic aortic aneurysm. After stabilization of the patient's condition by intensive antibiotic therapy we performed left-subclavian extra-thoracic debranching as the first stage of the surgical treatment. In 2 weeks via median sternotomy and on-pump we removed the infected endograft and performed extraanatomical ascending-to-descending aortic bypass with good postoperative result.

Investigating carbohydrate based ligands for galectin-3 with docking and molecular dynamics studies.

Galectin-3 (Gal-3) is a carbohydrate binding protein that is overexpressed in several types of cancers, including pancreatic cancer, which makes it a good target for both imaging and therapeutic drug design. A ligand library specialized for 18F positron emission tomography (PET) has been investigated with molecular dynamics (MD) and free energy methods to determine the relative binding energies of various potential ligands. Our results suggest that traditional docking methods can give good results when complemented by molecular dynamics and free energy methods for these types of ligands. Available experimental binding affinities for a small number of the tested compounds show very good agreement with the calculated energies and provide the rational approach for design of Gal-3 ligands with even higher affinity.

Outcome of extracorporeal membrane oxygenation support for complex high-risk elective percutaneous coronary interventions: A single-center experience.

OBJECTIVE: We report our initial experience with extracorporeal membrane oxygenation (ECMO) use in elective high-risk complex percutaneous coronary intervention (PCI). BACKGROUND: ECMO has been employed as hemodynamic support in patients with cardiac arrest and hemodynamic shock. METHODS: We performed a single-center prospectical study, enrolling all patients at very high-risk for coronary artery bypass grafting (CABG). Major adverse cardiac and cerebrovascular events (MACCE) were defined as a composite of death, acute myocardial infarction (MI), stroke and further need for revascularization. RESULTS: Twelve patients underwent elective high-risk PCI with ECMO support (mean age = 63.5 ± 8.7 years). The mean SYNTAX score was 30.1 ± 10.1. All PCI procedures were successful and no in-hospital MACCE was observed. At 6-months, neither death nor MI was noticed. Two patients (17%) required further revascularization, and one patient required chronic hemodialysis. CONCLUSIONS: Elective high-risk PCI supported by ECMO is a viable alternative for patients who are at very high risk for CABG.

A comparison of genome-wide DNA methylation patterns between different vascular tissues from patients with coronary heart disease.

Epigenetic mechanisms of gene regulation in context of cardiovascular diseases are of considerable interest. So far, our current knowledge of the DNA methylation profiles for atherosclerosis affected and healthy human vascular tissues is still limited. Using the Illumina Infinium Human Methylation27 BeadChip, we performed a genome-wide analysis of DNA methylation in right coronary artery in the area of advanced atherosclerotic plaques, atherosclerotic-resistant internal mammary arteries, and great saphenous veins obtained from same patients with coronary heart disease. The resulting DNA methylation patterns were markedly different between all the vascular tissues. The genes hypomethylated in athero-prone arteries to compare with atherosclerotic-resistant arteries were predominately involved in regulation of inflammation and immune processes, as well as development. The great saphenous veins exhibited an increase of the DNA methylation age in comparison to the internal mammary arteries. Gene ontology analysis for genes harboring hypermethylated CpG-sites in veins revealed the enrichment for biological processes associated with the development. Four CpG-sites located within the MIR10B gene sequence and about 1 kb upstream of the HOXD4 gene were also confirmed as hypomethylated in the independent dataset of the right coronary arteries in the area of advanced atherosclerotic plaques in comparison with the other vascular tissues. The DNA methylation differences observed in vascular tissues of patients with coronary heart disease can provide new insights into the mechanisms underlying the development of pathology and explanation for the difference in graft patency after coronary artery bypass grafting surgery.

Long-range chemical ligation from N→N acyl migrations in tryptophan peptides via cyclic transition states of 10- to 18-members.

Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N-C bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.

Ligations from tyrosine isopeptides via 12- to 19-membered cyclic transition states.

Efficient syntheses of O-acyl Tyr-peptides allow chemical long-range ligation (O-acyl to N-acyl transfer) via each of 12- to 19-membered cyclic transition states. The results represent the first examples of successful isopeptide ligations starting from O-acyl Tyr-peptides.

Ligations of N-acyl tryptophan units to give native peptides via 7-, 10-, 11- and 12-membered cyclic transition states.

N-Acyl tryptophan isopeptides undergo acyl transfer in chemical ligations via 7-, 10-, 11- and 12-membered cyclic transition states to yield natural peptides, representing the first examples of successful isopeptide ligations from N-acyl tryptophan units.