OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine

Background and Purpose Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia-induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia-activated prodrug of lidocaine. Experimental Approach The rat Langendorff-perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results In isolated hearts, OCT2013 and lidocaine prevented ischaemia-induced VF equi-effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi-effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg⁻¹ i.v., whereas lidocaine reduced it even at 1 mg·kg⁻¹. In adult rat ventricular myocytes, OCT2013 had no effect on Ca²⁺ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate-dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi-effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013-perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications OCT2013 is inactive but is bio-reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia-activated and ischaemia-selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity

Cloning of cDNA and chromosomal location of genes encoding the three types of subunits of the wheat tetrameric inhibitor of insect a-amylase

We have characterized three cDNA clones corresponding to proteins CM1, CM3 and CM16, which represent the three types of subunits of the wheat tetrameric inhibitor of insect -amylases. The deduced amino acid sequences of the mature polypeptides are homologous to those of the dimeric and monomeric -amylase inhibitors and of the trypsin inhibitors. The mature polypeptides are preceded by typical signal peptides. Southern blot analysis of appropriate aneuploids, using the cloned cDNAs as probes, has revealed the location of genes for subunits of the CM3 and of the CM16 type within a few kb of each other in chromosomes 4A, 4B and 4D, and those for the CM1 type of subunit in chromosomes 7A, 7B and 7D. Known subunits of the tetrameric inhibitor corresponding to genes from the B and D genomes have been previously characterized. No proteins of this class have been found to be encoded by the A genome in hexaploid wheat (genomes AA, BB, DD) or in diploid wheats (AA) and no anti -amylase activity has been detected in the latter, so that the A-genome genes must be either silent (pseudogenes) or expressed at a much lower level

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies

Summary of the proceedings of the International Forum 2021: "A more visible radiologist can never be replaced by AI"

The ESR International Forum at the ECR 2021 discussed effects of artificial intelligence on the future of radiology and the need for increased visibility of radiologists. The participating societies were invited to submit written reports detailing the current situation in their country or region. The European Society of Radiology (ESR) established the ESR International Forum in order to discuss hot topics in the profession of radiology with non-European radiological partner societies. At the ESR International Forum 2021, different strategies, initiatives and ideas were presented with regard to radiology community’s response to the changes caused by the emerging AI technology

Internet of Things for Environmental Sustainability and Climate Change

Our world is vulnerable to climate change risks such as glacier retreat, rising temperatures, more variable and intense weather events (e.g., floods, droughts, and frosts), deteriorating mountain ecosystems, soil degradation, and increasing water scarcity. However, there are big gaps in our understanding of changes in regional climate and how these changes will impact human and natural systems, making it difficult to anticipate, plan, and adapt to the coming changes. The IoT paradigm in this area can enhance our understanding of regional climate by using technology solutions, while providing the dynamic climate elements based on integrated environmental sensing and communications that is necessary to support climate change impacts assessments in each of the related areas (e.g., environmental quality and monitoring, sustainable energy, agricultural systems, cultural preservation, and sustainable mining). In the IoT in Environmental Sustainability and Climate Change chapter, a framework for informed creation, interpretation and use of climate change projections and for continued innovations in climate and environmental science driven by key societal and economic stakeholders is presented. In addition, the IoT cyberinfrastructure to support the development of continued innovations in climate and environmental science is discussed

Robotic neurorehabilitation: a computational motor learning perspective

Conventional neurorehabilitation appears to have little impact on impairment over and above that of spontaneous biological recovery. Robotic neurorehabilitation has the potential for a greater impact on impairment due to easy deployment, its applicability across of a wide range of motor impairment, its high measurement reliability, and the capacity to deliver high dosage and high intensity training protocols

The desmosome and pemphigus

Desmosomes are patch-like intercellular adhering junctions (“maculae adherentes”), which, in concert with the related adherens junctions, provide the mechanical strength to intercellular adhesion. Therefore, it is not surprising that desmosomes are abundant in tissues subjected to significant mechanical stress such as stratified epithelia and myocardium. Desmosomal adhesion is based on the Ca2+-dependent, homo- and heterophilic transinteraction of cadherin-type adhesion molecules. Desmosomal cadherins are anchored to the intermediate filament cytoskeleton by adaptor proteins of the armadillo and plakin families. Desmosomes are dynamic structures subjected to regulation and are therefore targets of signalling pathways, which control their molecular composition and adhesive properties. Moreover, evidence is emerging that desmosomal components themselves take part in outside-in signalling under physiologic and pathologic conditions. Disturbed desmosomal adhesion contributes to the pathogenesis of a number of diseases such as pemphigus, which is caused by autoantibodies against desmosomal cadherins. Beside pemphigus, desmosome-associated diseases are caused by other mechanisms such as genetic defects or bacterial toxins. Because most of these diseases affect the skin, desmosomes are interesting not only for cell biologists who are inspired by their complex structure and molecular composition, but also for clinical physicians who are confronted with patients suffering from severe blistering skin diseases such as pemphigus. To develop disease-specific therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required