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Abstract Background BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. Methods Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. Results DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. Conclusions The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. Trial registration: NCT02674152 and NCT02689505.

Abstract The disodium salt of 9,10‐anthraquinone‐2,7‐disulphonic acid (2,7‐AQDS) is an interesting platform for developing anthraquinone derivative negolytes for aqueous organic flow batteries. Recently, ammonium sulphate supporting electrolytes have been considered for improved stability and solubility. This work advances the 2,7‐AQDS/ferrocyanide flow battery with an ammonium sulphate supporting electrolyte (pH 5) by studying the suitability of six commercially available cation exchange membranes: E‐620, NR‐212, FS‐930, F‐1075‐PK, F‐1850 and N‐115. Cell cycling under galvanostatic regime plus potential hold was performed to determine coulombic efficiency, energy efficiency and accessible capacity for each membrane as well as capacity fade rate for three selected membranes under extended operation. Cell cycling under galvanostatic control only was carried out to observe transient membrane behavior alongside accessible capacity and apparent capacity fade rate. It was found that the capacity set by the limiting negolyte is consistent with 1.5 electrons per 2,7‐AQDS molecule and that energy efficiency shows a simple direct relationship to membrane thickness, with one exception. Meanwhile, four membranes displayed similar apparent capacity fade rates at this laboratory scale irrespective of their thickness, with capacity loss explained in terms of crossover. The best overall performance was attained by the thinnest membranes, E‐620 and NR‐212.

The use of gas diffusion electrodes (GDEs) in microbial fuel cells (MFCs) can improve their cell performance, but tends to cause fouling. In order to allow long-term stable operation, the search for antifouling methods is necessary. Therefore, an antibacterial coating with ammonium compounds is investigated. Within the first 30 days of operation, the maximum measured power density of a GDE with antibacterial ionomer was 606 mW m−2. The GDE without an antifouling treatment could only reach a maximum of 284 mW m−2. Furthermore, there was an optimum in the loading amount with ionomer below 2.6 mg cm−2. Further investigations showed that additional aeration of the GDEs by a fan had a negative effect on their performance. Despite the higher performance, the antibacterial coating could not prevent biofilm growth at the surface of the GDE. The thickness of the biofilm was only reduced by 14–16%. However, the weight of the biofilm on the treated GDEs was 62–80% less than on a GDE without an antifouling treatment. Consequently, the coating cannot completely prevent fouling, but possibly leads to a lower density of the biofilm or prevents clogging of the pores inside the electrodes and improves their long-term stability.

Using electrolysis systems to degrade organics in wastewater encourages this technique to remove micropollutants (MPs) in different types of water. In this work, a cell consisting of an anode as a boron-doped diamond (BDD) electrode combined with a gas diffusion (GDE) cathode without a separator showed that MPs degradation can be effectively achieved. Investigating different operating parameters, it was stated that applying a low current density (2 mA/cm2) and setting the Reynolds number of the electrolyte flow through the cell at the laminar range raised the treatment time by 3-fold at the same energy demand. This arrangement increased the MPs removal. Some substances like diclofenac were removed up to 84% at a longer treatment time of 180 min coupled with an increase in energy demand. The results at the mentioned parameters indicated an adequate generation rate of radicals needed to remove MPs and the oxidation reactions were promoted. The results show high potential to the investigated electrolysis system in removing MPs in wastewater under considering the need for further reduction of the energy demand. HIGHLIGHTS Investigaton of innovative electrolysis system to remove water micropollutants.; Explanation and controlling the system reactions towards the highest yield.; Confirmation of removal possibility at different operating parameters.; Studying how the operating parameters affect the treatment process effectivity.; Determination of the best system settings to get the best removal efficiency.;

Microbial fuel cells are a promising technology for future wastewater treatment, as it allows cleaning and power generation simultaneously. The bottleneck of microbial fuel cells is often its cathodes because they determine the power output. Gas diffusion electrodes might overcome this bottleneck due to their low production costs and high oxygen reduction rates. However, biofilm formation on the gas diffusion electrodes reduces their performance over time. In this work, a new reactor design of the microbial fuel cell using rotating gas diffusion electrodes is presented. The biofilm growth on the electrode during operation was observed and its effect on the performance of the microbial fuel cell was examined. In addition, different antifouling strategies were investigated over a period of 80 days. It was found that already after 7 days of operation a complete biofilm had grown on an untreated gas diffusion electrode. However, this does not seem to affect the performance of the cells in the beginning. Differences in the performance of the reactors with and without an antifouling strategy only become apparent from day 15 onwards. The use of UV radiation and antibacterial membranes leads to the best results with maximum power densities of approx. 200 mW m−2 while the untreated microbial fuel cell only achieves a maximum power density of approx. 20 mW m−2.

New electrochemical advanced oxidation processes (EAOPs) are becoming increasingly attractive for use in wastewater treatment. A reactor with a boron-doped diamond anode and a gas diffusion cathode seems to be a promising approach for water purification, because of the in situ generation of highly reactive species such as anodic •OH radicals and cathodic H2O2.To evaluate the application potential of this EAOP concept, the treatment efficiency and energy efficiency were compared with those of well-established AOPs such as ozonation and peroxone processes (O3 + H2O2). In this study, the innovative electrochemical batch treatment of artificial toilet wastewater showed a COD degradation efficiency of 38.1%, which is higher than that obtained using ozonation (17.0%) or the peroxone process (25.7%). Additionally, the specific energy demand is lower for EAOP (93.6 kWh/kg mCOD) than for ozonation (125.4 kWh/kg mCOD) or the peroxone process (134.5 kWh/kg mCOD). Keywords: Electrochemical wastewater treatment, Boron-doped diamond electrode, Gas diffusion electrode

A core component of energy storage systems like vanadium redox flow batteries (VRFB) is the polymer electrolyte membrane (PEM). In this work, the frequently used perfluorosulfonic-acid (PFSA) membrane Nafion™ 117 and a novel poly (vinylidene difluoride) (PVDF)-based membrane are investigated. A well-known problem in VRFBs is the vanadium permeation through the membrane. The consequence of this so-called vanadium crossover is a severe loss of capacity. For a better understanding of vanadium transport in membranes, the uptake of vanadium ions from electrolytes containing Vdimer(IV–V) and for comparison also V(II), V(III), V(IV), and V(V) by both membranes was studied. UV/VIS spectroscopy, X-ray absorption near edge structure spectroscopy (XANES), total reflection X-ray fluorescence spectroscopy (TXRF), inductively coupled plasma optical emission spectrometry (ICP-OES), and micro X-ray fluorescence spectroscopy (microXRF) were used to determine the vanadium concentrations and the species inside the membrane. The results strongly support that Vdimer(IV–V), a dimer formed from V(IV) and V(V), enters the nanoscopic water-body of Nafion™ 117 as such. This is interesting, because as of now, only the individual ions V(IV) and V(V) were considered to be transported through the membrane. Additionally, it was found that the Vdimer(IV–V) dimer partly dissociates to the individual ions in the novel PVDF-based membrane. The Vdimer(IV–V) dimer concentration in Nafion™ was determined and compared to those of the other species. After three days of equilibration time, the concentration of the dimer is the lowest compared to the monomeric vanadium species. The concentration of vanadium in terms of the relative uptake λ = n(V)/n(SO3) are as follows: V(II) [λ = 0.155] > V(III) [λ = 0.137] > V(IV) [λ = 0.124] > V(V) [λ = 0.053] > Vdimer(IV–V) [λ = 0.039]. The results show that the Vdimer(IV–V) dimer needs to be considered in addition to the other monomeric species to properly describe the transport of vanadium through Nafion™ in VRFBs.

Redox flow batteries such as the all-vanadium redox flow battery (VRFB) are a technical solution for storing fluctuating renewable energies on a large scale. The optimization of cells regarding performance, cycle stability as well as cost reduction are the main areas of research which aim to enable more environmentally friendly energy conversion, especially for stationary applications. As a critical component of the electrochemical cell, the membrane influences battery performance, cycle stability, initial investment and maintenance costs. This review provides an overview about flow-battery targeted membranes in the past years (1995–2020). More than 200 membrane samples are sorted into fluoro-carbons, hydro-carbons or N-heterocycles according to the basic polymer used. Furthermore, the common description in membrane technology regarding the membrane structure is applied, whereby the samples are categorized as dense homogeneous, dense heterogeneous, symmetrical or asymmetrically porous. Moreover, these properties as well as the efficiencies achieved from VRFB cycling tests are discussed, e.g., membrane samples of fluoro-carbons, hydro-carbons and N-heterocycles as a function of current density. Membrane properties taken into consideration include membrane thickness, ion-exchange capacity, water uptake and vanadium-ion diffusion. The data on cycle stability and costs of commercial membranes, as well as membrane developments, are compared. Overall, this investigation shows that dense anion-exchange membranes (AEM) and N-heterocycle-based membranes, especially poly(benzimidazole) (PBI) membranes, are suitable for VRFB requiring low self-discharge. Symmetric and asymmetric porous membranes, as well as cation-exchange membranes (CEM) enable VRFB operation at high current densities. Amphoteric ion-exchange membranes (AIEM) and dense heterogeneous CEM are the choice for operation mode with the highest energy efficiency.

Polymer electrolyte membranes have found broad application in a number of processes, being fuel cells, due to energy concerns, the main focus of the scientific community worldwide. Relatively little attention has been paid to the use of these materials in electrochemical production and separation processes. In this review, we put emphasis upon the application of Nafion membranes in electrochemical membrane reactors for chlorine recycling. The performance of such electrochemical reactors can be influenced by a number of factors including the properties of the membrane, which play an important role in reactor optimization. This review discusses the role of Nafion as a membrane, as well as its importance in the catalyst layer for the formation of the so-called three-phase boundary. The influence of an equilibrated medium on the Nafion proton conductivity and Cl− crossover, as well as the influence of the catalyst ink dispersion medium on the Nafion/catalyst self-assembly and its importance for the formation of an ionic conducting network in the catalyst layer are summarized.

In this contribution we present for the first time a continuous process for the production of highly active Pt catalysts supported by carbon nanotubes by use of an electrically heated tubular reactor. The synthesized catalysts show a high degree of dispersion and narrow distributions of cluster sizes. In comparison to catalysts synthesized by the conventional oil-bath method a significantly higher electrocatalytic activity was reached, which can be attributed to the higher metal loading and smaller and more uniformly distributed Pt particles on the carbon support. Our approach introduces a simple, time-saving and cost-efficient method for fuel cell catalyst preparation in a flow reactor which could be used at a large scale.

Polymer electrolyte membranes (PEM) prepared by radiation-induced graft copolymerization are investigated. For this purpose, commercial poly(ethylene-alt-tetrafluoroethylene) (ETFE) films were activated by electron beam treatment and subsequently grafted with the monomers glycidyl methacrylate (GMA), hydroxyethyl methacrylate (HEMA) and N,N′-methylenebis(acrylamide) (MBAA) as crosslinker. The target is to achieve a high degree of grafting (DG) and high proton conductivity. To evaluate the electrochemical performance, the PEMs were tested in a fuel cell and in a vanadium redox-flow battery (VRFB). High power densities of 134 mW∙cm−2 and 474 mW∙cm−2 were observed, respectively.

Background. We conducted a pilot study to investigate the value of an Iso-C3D imaging system in determining the extent of decompression of lumbar spinal stenosis during surgery. We now address the question whether this imaging has become a routine tool. Material and Methods. Ten patients who underwent unilateral decompression for lumbar spinal stenosis were intraoperatively examined using the Iso-C3D imaging system. Four years after this study, we investigated whether this intraoperative imaging modality is still being used. Results. Evaluable images were intraoperatively obtained for all patients. In two cases, the surgical procedure was changed on the basis of the images. Myelography did not provide any additional information. In the four years following the study, this intraoperative imaging technique has not been used again. Conclusion. Intraoperative imaging using the Iso-C3D system provides additional safety. It, however, has not become established as a routine procedure.

Until recently traditional heating in organic chemistry has been done with oil heating baths or using electric heat exchangers. With the advent of microwave equipment, heating by microwaves was rapidly introduced as standard method in organic chemistry laboratories, mainly because of the convenient possibility to operate at high temperature accompanied by accelerated reaction rates. In the present contribution we discuss the method of heating small, continuously operated reactors by passing electric current directly through the reactor wall as an enabling technology in organic chemistry. The benefit of this method is that the heat is generated directly inside the reactor wall. By this means high heating rates comparable to microwave ovens can be reached but at much lower cost for the equipment. A tool for the comparison of microwave heating and traditional heating is provided. As an example kinetic data for the acid catalyzed hydrolysis of methyl formate were measured using this heating concept. The reaction is not only a suitable model but also one of industrial importance since this is the main production process for formic acid.

Introduction Despite continued efforts, long-term outcomes of kidney transplantation remain unsatisfactory. Kidney graft rejections are independent risk factors for graft failure. At the participating centres of the TRAnsplant BIOpsies study group, a common therapeutic standard has previously been defined for the treatment of graft rejections. The outcomes of this strategy will be assessed in a prospective, observational cohort study.Methods and analysis A total of 800 kidney transplantation patients will be enrolled who undergo a graft biopsy because of deteriorating kidney function. Patients will be stratified according to the Banff classification, and the influence of the treatment strategy on end points will be assessed using regression analysis. Primary end points will be all-cause mortality and graft survival. Secondary end points will be worsening of kidney function (≥30% decline of estimated Glomerular Filtration Rate [eGFR] or new-onset large proteinuria), recurrence of graft rejection and treatment response. Baseline data and detailed histopathology data will be entered into an electronic database on enrolment. During a first follow-up period (within 14 days) and subsequent yearly follow-ups (for 5 years), treatment strategies and clinical course will be recorded. Recruitment at the four participating centres started in September 2016. As of August 2020, 495 patients have been included.Ethics and dissemination Ethical approval for the study has been obtained from the ethics committee of Kiel (AZ B 278/16) and was confirmed by the committees of Munich, Mainz and Stuttgart. The results will be reported in a peer-reviewed journal, according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria.Trial registration number ISRCTN78772632; Pre-results.

Ten years after its initial description, ferroptosis has emerged as the most intensely studied entity among the non-apoptotic forms of regulated cell death. The molecular features of ferroptotic cell death and its functional role have been characterized in vitro and in an ever-growing number of animal studies, demonstrating that it exerts either highly detrimental or, depending on the context, occasionally beneficial effects on the organism. Consequently, two contrary therapeutic approaches are being explored to exploit our detailed understanding of this cell death pathway: the inhibition of ferroptosis to limit organ damage in disorders such as drug-induced toxicity or ischemia-reperfusion injury, and the induction of ferroptosis in cancer cells to ameliorate anti-tumor strategies. However, the path from basic science to clinical utility is rocky. Emphasizing ferroptosis inhibition, we review the success and failures thus far in the translational process from basic research in the laboratory to the treatment of patients.

Necroptosis and pyroptosis are two forms of regulated cell death. They are executed by the proteins mixed-lineage kinase domain-like (MLKL) and gasdermin D (GSDMD), respectively. Once activated by numerous pathways, these proteins form membrane pores that allow the influx and efflux of various ions, proteins, and water, ultimately resulting in the death of the cell. These modalities of cell death are considered highly inflammatory because of the release of inflammatory cytokines and damage-associated molecular patterns, and are thereby not only deleterious for the dying cell itself, but also its environment or the entire organism. The relevance for these processes has been observed in various physiological and pathophysiological conditions, ranging from viral and bacterial infections over autoimmune and chronic inflammatory diseases to ischemic organ damage. In recent years, initial in vitro experiments have shed light on a range of connections between necroptosis and pyroptosis. Initial in vivo studies also indicate that, in many disease models, these two forms of cell death cannot be considered individually, as they demonstrate a complex interaction. In this article, we provide an overview of the currently known structure, pathways of activation, and functions of MLKL and GSDMD. With emerging evidence for an interconnection between necroptosis and pyroptosis in not only in vitro, but also in vivo models of disease, we highlight in particular the clinical relevance of the crosslinks between these two forms of inflammatory cell death and their implications for novel therapeutic strategies in a variety of diseases.

BackgroundSince 2010, the number of organ donations in Germany has decreased by one third, mostly due to undetected organ donors. It is unclear, how the undetected potential donor pool is distributed among the different German hospital categories (A = university hospital, B = hospitals with neurosurgery, C = hospitals without neurosurgery) and region types.MethodsWe performed a nationwide secondary data analysis of all German inpatient cases of the year 2016 (n = 20,063,689). All fatalities were regarded as potential organ donors, in which primary or secondary brain damage was encoded and organ donation was not excluded by a contraindication or a lack of ventilation therapy.ResultsIn 2016, 28,087 potential organ donors were identified. Thereof 21% were found in category A, 28% in category B and 42% in category C hospitals. The contact rate (= organ donation related contacts/ potential organ donors) and realization rate (= realized organ donations/ potential organ donors) of category A, B and C hospitals was 10.6% and 4.6%, 10.9% and 4.8% and 6.0% and 1.7%, respectively. 58.2% of the donor potential of category C hospitals was found in the largest quartile of category C hospitals. 51% (n = 14,436) of the potential organ donors were treated in hospitals in agglomeration areas, 28% (n = 7,909) in urban areas and 21% (n = 5,742) in rural areas. The contact- and realization rate did not significantly differ between these areas.ConclusionsThe largest proportion of potential organ donors and the lowest realization rate are found in category C hospitals. Reporting and donation practice do not differ between urban and rural regions.

Necroptosis is a form of regulated necrosis that results in cell death and content release after plasma membrane permeabilization. However, little is known about the molecular events responsible for the disruption of the plasma membrane. Here, we find that early increase in cytosolic calcium in TNF-induced necroptosis is mediated by treatment with a Smac mimetic via the TNF/RIP1/TAK1 survival pathway. This does not require the activation of the necrosome and is dispensable for necroptosis. Necroptosis induced by the activation of TLR3/4 pathways does not trigger early calcium flux. We also demonstrate that necroptotic plasma membrane rupture is mediated by osmotic forces and membrane pores around 4 nm in diameter. This late permeabilization step represents a hallmark in necroptosis execution that is cell and treatment independent and requires the RIP1/RIP3/MLKL core. In support of this, treatment with osmoprotectants reduces cell damage in an in vivo necroptosis model of ischemia-reperfusion injury.

Necroptosis, initially identified as a backup cell death program when apoptosis is hindered, is a prominent feature in the etiology and progression of many human diseases, such as ischemic injury and sepsis. Receptor-interacting protein kinase 3 (RIPK3) is the cardinal regulator of this cell death modality, recruiting and phosphorylating the executioner mixed lineage kinase domain-like protein (MLKL) to signal necroptosis, which is terminated by a cellular plasma membrane rupture and the leakage of intracellular contents from dying cells. Experimental data to date indicate that RIPK3 and MLKL is the core machinery essential for all necroptotic cell death responses. By using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9) technology, we showed that Ripk3 and Mlkl knockout and Ripk3/Mlkl double-knockout in necroptosis-sensitive cell lines extensively block susceptibility to necroptosis, in each case to an indistinguishable degree. In vivo studies using Ripk3- or Mlkl-deficient mice validated kidney ischemia reperfusion injury and high-dose tumor necrosis factor (TNF) availability, as druggable targets in necroptotic-mediated pathologies. Here, we demonstrated that Ripk3 or Mlkl-deficient mice are protected to a similar extent from kidney ischemia reperfusion injury and TNF-induced toxicity. Remarkably, in contrast to each single knockout, Ripk3/Mlkl double-deficient mice did not have appreciable protection from either of the above necroptotic-mediated pathologies. Paradoxically, the double-knockout mice resembled, in each case, the vulnerable wild-type mice, revealing novel complexities in the mechanisms of inflammation-driven diseases, due to aberrant cell death.

Abstract This work describes a novel methodology for measuring the potential distribution within the porous copper foam electrode of a zinc‐air/silver hybrid (ZASH) flow battery by using local potential probes. The suitability of dynamic hydrogen electrodes (DHEs) and a quasi‐reference electrode as probes is evaluated, with the latter chosen in view of stability. Liquid and solid‐phase potentials are recorded at varying applied current densities over multiple charge‐discharge cycles. Various zinc structures are found within specific overpotential ranges, with moss‐like structures appearing between 7.8 mV and 13.2 mV and the desired boulder structures in the range of 22 mV to 100 mV. Regardless of the current density, the highest liquid‐phase potentials are always measured in the outermost region of the porous foam near to the separator. In practice, this means that increasing the thickness of the copper foam over about 5 mm does not provide significant performance benefits. Conversely, solid‐phase potentials across the copper foam remain nearly uniform, resulting in negligible effects on local overpotential. The presented technique provides unique insights into the behavior of porous electrodes in electrochemical energy conversion technologies, facilitating the determination of the optimal properties for maximum efficiency, such as electrode thickness.