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Death due to cancer is mostly associated with therapy ineffectiveness, i.e. tumor cells no longer responding to treatment. The underlying dynamics that facilitate this mutational escape from selective pressure are well studied in several other fields and several interesting approaches exist to combat this phenomenon, for example in the context of antibiotic-resistance in bacteria.Ninety percent of all cancer-related deaths are associated with treatment failure. Here, we discuss the common treatment modalities and prior attempts to overcome acquired resistance to therapy. The underlying molecular mechanisms are discussed and the implications of emerging resistance in other systems, such as bacteria, are discussed in the context of cancer.Reevaluating emerging therapy resistance in tumors as an evolutionary mechanism to survive in a rapidly and drastically altering fitness landscape leads to novel treatment strategies and distinct requirements for new drugs. Here, we propose a scheme of considerations that need to be applied prior to the discovery of novel therapeutic drugs.

Background:To evoke a therapeutically effective seizure, electrical stimulation in electroconvulsive therapy (ECT) has to overcome the combined resistivity of scalp, skull and other tissues. Static impedances are measured prior to stimulation using high-frequency electrical alternating pulses, dynamic impedances during passage of the stimulation current. Static impedance can partially be influenced by skin preparation techniques. Earlier studies showed a correlation between dynamic and static impedance in bitemporal and right unilateral ECT.Objective:This study aims at assessing the correlation of dynamic and static impedance with patient characteristics and seizure quality criteria in bifrontal ECTMethods:We performed a cross-sectional single-centre retrospective analysis of ECT treatments at the Psychiatric University Hospital Zurich between May 2012 and March 2020 and used linear mixed-effects regression models in 78 patients with a total of 1757 ECT sessions.Results:Dynamic and static impedance were strongly correlated. Dynamic impedance was significantly correlated with age and higher in women. Energy set and factors positively (caffeine) and negatively (propofol) affecting seizure at the neuronal level were not associated with dynamic impedance. For secondary outcomes, dynamic impedance was significantly related to Maximum Sustained Power and Average Seizure Energy Index. Other seizure quality criteria showed no significant correlation with dynamic impedance.Conclusion:Aiming for low static impedance might reduce dynamic impedance, which is correlated with positive seizure quality parameters. Therefore, good skin preparation to achieve low static impedance is recommended.

This paper presents model simulations of stratospheric aerosols with a focus on explosive volcanic eruptions. Using various (occultation and limb-based) satellite instruments, providing vertical profiles of sulfur dioxide (SO$_2$) and aerosol extinction, we characterized the chemical and radiative influence of volcanic aerosols for the period between 1990 and 2019. We established an improved and extended volcanic SO$_2$ emission inventory that includes more than 500 explosive volcanic eruptions reaching the upper troposphere and the stratosphere. Each perturbation identified was derived from the satellite data and incorporated as a three-dimensional SO$_2$ plume into a chemistry-climate model without the need for additional assumptions about altitude distribution and eruption duration as needed for a “point source” approach. The simultaneous measurements of SO$_2$ and aerosol extinction by up to four satellite instruments enabled a reliable conversion of extinction measurements into injected SO$_2$. In the chemistry-climate model, the SO$_2$ from each individual plume was converted into aerosol particles and their optical properties were determined. Furthermore, the aerosol optical depth (AOD) and the instantaneous radiative forcing on climate were calculated online. Combined with model improvements, the results of the simulations are consistent with the observations of the various satellites. Slight deviations between the observations and model simulations were found for the large volcanic eruption of Pinatubo in 1991 and cases where simultaneous satellite observations were not unique or too sparse. Weak- and medium-strength volcanic eruptions captured in satellite data and the Smithsonian database typically inject about 10 to 50 kt SO$_2$ directly into the upper troposphere/lower stratosphere (UTLS) region or the sulfur species are transported via convection and advection. Our results confirm that these relatively minor eruptions, which occur quite frequently, can nevertheless contribute to the stratospheric aerosol layer and are relevant for the Earth's radiation budget. These minor eruptions cause a total global instantaneous radiative forcing of the order of −0.1 W m$^{−2}$ at the top of the atmosphere (TOA) compared to a background stratospheric aerosol forcing of about −0.04 W m$^{−2}$. Medium-strength eruptions injecting about 400 kt SO$_2$ into the stratosphere or accumulation of consecutive smaller eruptions can lead to a total instantaneous forcing of about −0.3 W m$^{−2}$. We show that it is critical to include the contribution of the extratropical lowermost stratospheric aerosol in the forcing calculations.