Hyperthermia, thermotolerance and topoisomerase II inhibitors.

The cytoxicity of both intercalating (m-AMSA) and non-intercalating (VP16, VM26) topoisomerase II-targeting drugs is thought to occur via trapping DNA topoisomerase II on DNA in the form of cleavable complexes. First, analysis of cleavable complexes (detected as DNA double-strand breaks) by pulsed-field gel electrophoresis confirmed the correlation between cleavable complex formation and cytotoxicity of three topoisomerase-targeting drugs in HeLa S3 cells (the order of effects being VM26 > m-AMSA > VP16). In contrast to many antineoplastic agents, hyperthermic treatments were found to protect cells against the toxicity of all three topoisomerase II drugs. Hyperthermia treatment does not alter drug accumulation but reduces the ability of the drug-topoisomerase II complex to form the cleavable complexes. Nuclear protein aggregation induced by heat at the sites of topoisomerase II-DNA interaction may explain such an effect. In thermotolerant cells, the toxic effects of VP16 but not m-AMSA were reduced. For both drugs, however, the status of thermotolerance did not affect cleavable complex formation by the drugs. Thus, protection against VP-16 toxicity seems not to be associated with heat-induced activation of the P-gp 170 pump or altered topoisomerase II-DNA interactions. Rather, a protective (heat shock protein mediated?) mechanism against non-intercalating topoisomerase II drugs seems to occur at a stage after DNA-drug interaction. Finally, heat treatment before topoisomerase II drug treatment reduced toxicity and cleavable complex formation in thermotolerant cells to about the same extent as in non-tolerant cells, consistent with the presumption of nuclear protein aggregation being responsible for this effect

The coupling of a hearing aid loudspeaker membrane to visco-thermal air layers

Hearing aids and their components are becoming smaller. This presents new problems for the acoustical components, such as the loudspeaker. A circular membrane of a hearing aid loudspeaker is modeled in this paper. Neglecting air influences, the membrane and its suspension behave as a mass spring system. However, under operating conditions, thin layers of air on both sides of the membrane influence its behavior. Air can enter and leave these layers at certain locations on the circular edge of the layer. Since these air layers are thin, visco-thermal effects may have to be taken into account. Therefore, the air layers are not modeled by the wave equation, but by the low reduced frequency model that takes these visco-thermal effects into account. The equations of this model are solved in a polar coordinate system, using a wave-based method. The other acoustical parts of the hearing aid loudspeaker, and the membrane itself are modeled by simple lumped models. The emphasis in this paper is on the coupling of the viscothermal air layer model to the mechanical model of the membrane. Coupling of the air layer to other acoustical parts by using an impedance as boundary condition for the layer model, is also described. The resulting model is verified by experiments. The model and the measurements match reasonably well, considering the level of approximation with lumped parts

Thermotolerance in mammalian cells. Protein denaturation and aggregation, and stress proteins

Cells that have been pre-exposed to thermal stress can acquire a transient resistance against the killing effect of a subsequent thermal stress. The cause for this phenomenon, called thermotolerance, seems to be an enhanced resistance of proteins against thermal denaturation and aggregation. This resistance can be expressed as an attenuation of damage formation (less initial damage) or as a better repair of the protein damage (facilitated recovery). Heat Shock (or better, Stress) Proteins (HSPs) may play a role in and even be required for thermal resistance. However, rather than stress-induced enhanced synthesis and elevated total levels of HSPs per se, the concentration of, both constitutive and inducible, HSPs at and/or (re)distributed to specific subcellular sites may be the most important factor for the acquisition of thermotolerance. Specific HSPs may be involved either in damage protection or in damage repair

DNAJs:more than substrate delivery to HSPA

Proteins are essential components of cellular life, as building blocks, but also to guide and execute all cellular processes. Proteins require a three-dimensional folding, which is constantly being challenged by their environment. Challenges including elevated temperatures or redox changes can alter this fold and result in misfolding of proteins or even aggregation. Cells are equipped with several pathways that can deal with protein stress. Together, these pathways are referred to as the protein quality control network. The network comprises degradation and (re)folding pathways that are intertwined due to the sharing of components and by the overlap in affinity for substrates. Here, we will give examples of this sharing and intertwinement of protein degradation and protein folding and discuss how the fate of a substrate is determined. We will focus on the ubiquitylation of substrates and the role of Hsp70 co-chaperones of the DNAJ class in this process

Considering sustainability in project management decision making; an investigation using Q-methodology

Abstract: Sustainability is one of the most important challenges of our time. Projects play a pivotal role in the realization of more sustainable business practices and the concept of sustainability has also been linked to project management. However, how managers of projects consider sustainability in their operational daily work is still to be explored. This paper uses Q-methodology to investigate the consideration of sustainability aspects in the decision making processes of project managers. The research question was How are dimensions of sustainability considered in the decision-making processes of project managers in relation to the triple constraint of time, cost and quality? Based on the Q-sort of selected respondents, the study found that the consideration of sustainability principles is underrepresented, compared to the triple constraint criteria. However, the analysis of the individual Q-sorts revealed four distinct perspectives that differ significantly in their consideration of sustainability principles and triple constraint criteria

Cisplatin sensitivity and thermochemosensitisation in thermotolerant cDDP-sensitive and -resistant cell lines.

Development of thermotolerance is an important phenomenon that must be considered when thermochemotherapy with multiple heat treatments is used clinically. To study the effect of thermotolerance on cellular cisplatin (cDDP) sensitivity at 37 degrees C and 43 degrees C in cell lines with different cDDP sensitivities, two Ehrlich ascites tumour cell lines (one with high cDDP sensitivity and one with in vitro acquired cDDP resistance) were used. The results indicate that in both cell lines the state of thermotolerance per se did not affect the cDDP sensitivity at 37 degrees C. Thus, general elevations in 'all' heat shock protein levels as found in thermotolerant cells apparently do not influence cDDP sensitivity to a considerable extent. The sensitising effect of a (second) heat treatment given simultaneously with a cDDP treatment was less in thermotolerant cells. Thermal enhancement ratios (TERs) at the 10% survival level for heat doses of 43 degrees C for 30 min or 43 degrees C for 60 min were reduced by a factor of 1.6 and 2.1 in cDDP-resistant and -sensitive thermotolerant cells respectively, as compared with control cells. Thus, protection against heat damage in thermotolerant cells seems to be paralleled by diminished thermal chemosensitisation. Although the effect of thermotolerance on the cDDP-sensitising effect was less pronounced in the resistant cells, a modifying effect on the resistance factor was not achieved

Protein quality control:from mechanism to disease EMBO Workshop, Costa de la Calma (Mallorca), Spain, April 28-May 03, 2019

The cellular protein quality control machinery with its central constituents of chaperones and proteases is vital to maintain protein homeostasis under physiological conditions and to protect against acute stress conditions. Imbalances in protein homeostasis also are keys to a plethora of genetic and acquired, often age-related, diseases as well as aging in general. At the EMBO Workshop, speakers covered all major aspects of cellular protein quality control, from basic mechanisms at the molecular, cellular, and organismal level to medical translation. In this report, the highlights of the meeting will be summarized