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The introduction of novel targeted therapies during the last 2 decades has led to a significant improvement in patients' clinical outcomes with renal cell carcinoma. However, this improvement came at the price of a whole new spectrum of adverse events, including renal toxicity. Systemic treatment of patients with kidney neoplasms who often present with impairment of kidney function, even prior to treatment, poses an increasing diagnostic and therapeutic challenge for clinicians. Common lifestyle-related comorbidities, i.e., hypertension and diabetes, may contribute to further impairment of kidney function. The lack of official guidelines and the exclusion of patients with reduced kidney function from the clinical trials of recently approved drugs complicate the issue even further. Early detection and correct management of renal toxic effects are crucial to preserve kidney function and ensure the optimal administration of life-prolonging therapies. This review presents detailed information on the renal toxicities of three groups of drugs commonly used in renal cell carcinoma treatment: tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and immune checkpoint inhibitors. We outline the incidence and underlying mechanisms of renal adverse effects with a focus on patients on renal replacement therapy, as well as present suggestions for their management.

While supramolecular chemistry is a firmly established research field in laboratory conditions, the experimental study of non-covalent interactions, such as hydrogen bonding and piinteractions, between different molecules in chemically rich, non-crystalline matter remains highly challenging. We demonstrate that soft ion bombardment can trigger the joint desorption of weakly interacting adjacent molecules, and that this in turn allows molecular interaction probabilities, surroundings, and arrangement in organic matter to be probed. Assemblies of organic molecules linked by hydrogen bonds or dipole- interactions are extracted here with preservation of chemistry and structure as single-charged supramolecular secondary ions. Among the examples shown is the desorption of stable 12-molecular clusters of the amino acid L-proline, which suggest an icosahedral on-surface self-assembly, and the desorption of supramolecular linear oligomers of 2,5-piperazinedione. The second half of the study lays down the statistical framework for the reconstruction of a molecular interactome based on the relative abundances of supramolecular dimers of different compositions within a mass spectrum acquired on organic matter containing more than one type of molecule.

Drug testing in hair is a controversial subject of discussion. Claims that decontamination protocols could generate false-positive samples, by washing contamination in hair, have unsettled many toxicologists. At least for zolpidem (known for showing only minor contamination), it could be shown that differentiation of the drug incorporated via the bloodstream from contamination was possible. The current work addresses cocaine and methadone, known for their high concentrations and contamination issues. Longitudinally and cross-sectioned samples of drug-soaked hair, consumer hair and cocaine powder contaminated hair were investigated using time of flight-secondary ion mass spectrometry (ToF-SIMS) and matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). In addition, the resulting wash solutions were investigated using LC-MS/MS. Differentiation of contamination from incorporation was possible for soaked and consumer hair samples. Therefore, contamination could be localized in the superficial compartments of hair and could be removed using strong wash protocols. In the case of powder contaminated hair samples, a small amount of cocaine remained in the inner structures even after the application of the strongest wash protocols. However, taking into consideration the differences in their behavior during decontamination steps compared to both soaked and authentic hair samples, the validity of this contamination protocol (rubbing cocaine powder into hair) must be questioned. Furthermore, when using cut-off values and metabolite ratios (from routine hair analysis), the differentiation of incorporation from contamination was possible also for all our experimental samples in this study. Inclusion of metabolites and application of cut-off values are therefore a must in routine hair analysis.

Entangled polymers are deformed by a strong shear flow. The shape of the polymer, called the form factor, is measured by small angle neutron scattering. However, the real-space molecular structure is not directly available from the reciprocal-space data, due to the phase problem. Instead, the data has to be fitted with a theoretical model of the molecule. We approximate the unknown structure using piecewise straight segments, from which we derive an analytical form factor. We fit it to our data on a semi-dilute entangled polystyrene solution under in situ shear flow. The character of the deformation is shown to lie between that of a single ideal chain (viscous) and a cross-linked network (elastic rubber). Furthermore, we use the fitted structure to estimate the mechanical stress, and find a fairly good agreement with rheology literature.

The dehydrogenation of bisheptahelicene leads to specific products and induces desorption of the side-product bromine as hydrogen bromide., The on-surface synthesis of bisheptahelicene by Ullmann coupling of 9-bromoheptahelicene on Au(111) and its temperature-induced dehydrogenation is studied using temperature-programmed reaction spectroscopy and time-of-flight secondary ion mass spectrometry. Specific dehydrogenation products of bisheptahelicene after loss of 6, 8 and 10 hydrogen atoms are identified, corresponding to molecules having undergone Diels–Alder transformations and intramolecular C–C coupling reactions. By combining with atomic hydrogen produced by dehydrogenation, the Ullmann coupling side-product bromine desorbs as HBr. H2 desorption emerges only after all Br has desorbed. Such characteristic behavior is explained by a kinetic model which explicitly considers the coverage of transient atomic H on the surface. Heating experiments performed with saturated layers of different Br-containing molecules reveal that the onset of HBr desorption depends strictly on the dehydrogenation step and therefore on the structure of the molecules.

Over the last years, the operational stability of perovskite solar cells has been significantly improved by compositional engineering, interface modification, and improved encapsulation techniques. However, irreversible degradation is still ubiquitously observed during the first 1000 hours of operation, particularly at elevated temperatures. In this work, we elucidate a major mechanism controlling this degradation. For that, formamidinium lead iodide-based perovskite solar cells were stressed under continuous 1 sun illumination at 80 °C in N2, before extensive characterization of their microstructure and composition. The cell active area and hence the photocurrent are found to decrease with time due to the growth of porous PbI2-rich regions. This degradation was observed to originate from a few seed points in the perovskite bulk rather than from the interfaces with the charge-selective layers or from the cell edges. I2 vapor, first released at these defective points and then further released from the decomposition of the perovskite exposed to this vapor, controls the degradation process. Furthermore, this autocatalytic degradation process is shown to locally rupture the top electrode due to vapor pressure build-up. In addition to highlighting the detrimental influence of residual PbI2, we show that such a degradation pathway can be alleviated by reducing the methylammonium and/or iodine content, providing a path to more stable perovskite solar cells.

In the paper, the construction of unconditional bootstrap prediction intervals and regions for some class of second order stationary multivariate linear time series models is considered. Our approach uses the sieve bootstrap procedure introduced by Kreiss 1992 and Bühlmann 1997. Basic theoretical results concerning consistency of the bootstrap replications and the bootstrap prediction regions are proved. We present a simulation study comparing the proposed bootstrap methods with the Box–Jenkins approach.

In light‐emitting electrochemical cells (LECs), the position of the emission zone (EZ) is not predefined via a multilayer architecture design, but governed by a complex motion of electrical and ionic charges. As a result of the evolution of doped charge transport layers that enclose a dynamic intrinsic region until steady state is reached, the EZ is often dynamic during turn‐on. For thick sandwich polymer LECs, a continuous change of the emission color provides a direct visual indication of a moving EZ. Results from an optical and electrical analysis indicate that the intrinsic zone is narrow at early times, but starts to widen during operation, notably well before the electrical device optimum is reached. Results from numerical simulations demonstrate that the only precondition for this event to occur is that the mobilities of anions (µa) and cations (µc) are not equal, and the direction of the EZ shift dictates µc > µa. Quantitative ion profiles reveal that the displacement of ions stops when the intrinsic zone stabilizes, confirming the relation between ion movement and EZ shift. Finally, simulations indicate that the experimental current peak for constant‐voltage operation is intrinsic and the subsequent decay does not result from degradation, as commonly stated.

Solar cells based on metal halide perovskites are one of the most promising photovoltaic technologies(1-4). Over the past few years, the long-term operational stability of such devices has been greatly improved by tuning the composition of the perovskites(5-9), optimizing the interfaces within the device structures(10-13), and using new encapsulation techniques(14,15). However, further improvements are required in order to deliver a longer-lasting technology. Ion migration in the perovskite active layer-especially under illumination and heat-is arguably the most difficult aspect to mitigate(16-18). Here we incorporate ionic liquids into the perovskite film and thence into positive-intrinsic-negative photovoltaic devices, increasing the device efficiency and markedly improving the long-term device stability. Specifically, we observe a degradation in performance of only around five per cent for the most stable encapsulated device under continuous simulated full-spectrum sunlight for more than 1,800 hours at 70 to 75 degrees Celsius, and estimate that the time required for the device to drop to eighty per cent of its peak performance is about 5,200 hours. Our demonstration of long-term operational, stable solar cells under intense conditions is a key step towards a reliable perovskite photovoltaic technology. Funding Agencies|UK Engineering and Physical Sciences Research Council (EPSRC) [EP/M015254/2, EP/M024881/1]; European Research Council (ERC) [717026]; Swedish Research Council Vetenskapsradet [330-2014-6433]; European Commission Marie Sklodowska-Curie action [INCA 600398]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University [SFO-Mat-LiU 2009-00971]; European Union [763977]; China Scholarship Council (CSC); Bavarian State Ministry of Science, Research, and the Arts; German Research Foundation (DFG); Swiss National Science Foundation [cr23i2-162828]

Reflectivity measurements offer unique opportunities for the study of surfaces and interfaces, and specular reflectometry has become a standard tool in materials science to resolve structures normal to the surface of a thin film. Off-specular scattering, which probes lateral structures, is more difficult to analyse, because the Fourier space being probed is highly anisotropic and the scattering pattern is truncated by the interface. As a result, scattering patterns collected with (especially time-of-flight) neutron reflectometers are difficult to transform into reciprocal space for comparison with model calculations. A program package is presented for a generic two-dimensional transformation of reflectometry data into q space and back. The data are represented on an orthogonal grid, allowing cuts along directions relevant for theoretical modelling. This treatment includes background subtraction as well as a full characterization of the resolution function. The method is optimized for computational performance using repeatable operations and standardized instrument settings.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric population. In 35% of cases, RMS develops in the head and neck (H&N) region, and only combined therapy is recognized as a curative treatment. However, recent advances in skull base and reconstructive surgery, along with microsurgery and endoscopic surgery, have strengthened the role of surgery as an important part of RMS treatment. In the present study, 36 pediatric RMS cases (24 males and 12 females) were analyzed after surgical treatment. The average age at diagnosis was 7 years. In total, 67% of tumors were localized in the parameningeal region. Alveolar RMS was the most common histopathological type. A total of 16 patients were treated due to disease recurrence or a previous non-radical surgical procedure, while 19 cases had inductive chemotherapy and/or radiotherapy preceding surgical treatment due to locally advanced disease. In 1 case, only diagnostic biopsy was performed. It is recommended that the management of H&N RMS is interdisciplinary from the beginning. Extensive surgical dissection in the H&N region for RMS may result in severe cosmetic defects and functional impairment; thus, these risks should be considered during treatment planning, and the surgical approach should be based on the individual characteristics of each patient.

We present in-situ neutron spin echo measurements on an entangled polydimethylsiloxane melt under shear and demonstrate the ability to monitor nano-scale dynamics in flowing liquids. We report no changes in the topological interactions of the chains for shear rates approaching the inverse longest relaxation time. Further experiments following along this line will allow to systematically test the predictions of theories, like e.g. convective constraint release.

The redistribution of ions in light-emitting electrochemical cells (LECs) plays a key role in their functionality. The direct quantitative mapping of ion density distributions in operating realistic sandwich-type devices, however, has not been experimentally achieved. Here we operate high-performing [Super Yellow/trimethylolpropane ethoxylate/lithium trifluoromethanesulfonate (Li+CF3SO3–)] LEC devices inside a time-of-flight secondary ion mass spectrometer and cool the devices after different operation times to liquid nitrogen temperatures before depth profiling is performed. The results reveal the dependence of the elemental and molecular distributions across the device layer on operation conditions. We find that the ion displacements lead to a substantial shift of the local chemical equilibria governing the free ion concentration.

Significance Cell instructive biomaterial cues are a major topic of interest in both basic and applied research. In this work, we clarify how surface energy of soft biomaterials can dramatically affect mesenchymal stem cell receptor recruitment and downstream signaling related to cell fate. We elucidate how surface protein self-assembly and the resulting surface topology can act to steer mechanotransduction and related biological response of attached cells. These findings fill a critical gap in our basic understanding of cell–biomaterial interaction and highlight soft biomaterial surface energy as a dominant design factor that should not be neglected., Although mechanisms of cell–material interaction and cellular mechanotransduction are increasingly understood, the mechanical insensitivity of mesenchymal cells to certain soft amorphous biomaterial substrates has remained largely unexplained. We reveal that surface energy-driven supramolecular ligand assembly can regulate mesenchymal stem cell (MSC) sensing of substrate mechanical compliance and subsequent cell fate. Human MSCs were cultured on collagen-coated hydrophobic polydimethylsiloxane (PDMS) and hydrophilic polyethylene-oxide-PDMS (PEO-PDMS) of a range of stiffnesses. Although cell contractility was similarly diminished on soft substrates of both types, cell spreading and osteogenic differentiation occurred only on soft PDMS and not hydrophilic PEO-PDMS (elastic modulus

In order to facilitate long-term treatment decisions, we aimed to define biomarkers defining the probability of receiving second-line (SL) targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC) based on their characteristics present at first-line TT initiation. We analysed 152 consecutive mRCC patients treated and used multivariable binominal logistic regression to identify factors contributing to the probability of receiving SL TT. Final model was assessed with bias-corrected indices (Nagelkerke’s R2 and area under receiver operating characteristic curve [AUC]) and two bootstrap procedures were used for internal validation. Factors associated with the probability of SL TT eligibility were the presence of brain metastases (odds ratio [OR] 0.084, 95% confidence interval [CI] 0.010–0.707), number of metastatic sites (OR 0.740, 95% CI 0.575–0.953 per each site), platelet count (OR 0.971, 95% CI 0.947–0.997, per 104/ml), lactate dehydrogenase level (OR 0.952, 95% CI 0.910–0.997 per 10 units/l), and albumin concentration (OR 1.924, 95% CI 1.057–3.503 per 1 g/dl). We developed on-line calculator that enables practicing clinicians to estimate SL treatment probability ( http://www.r-calc.com ).

Carbohydrate metabolism disorders increase the risk of carcinogenesis. Diabetes mellitus alters numerous physiological processes that may encourage cancer growth. However, treating impaired glucose homeostasis may actually promote neoplasia; maintaining proper glucose plasma concentrations reduces metabolic stresses, however, certain medications may themselves result in oncogenic effects. A number of previous studies have demonstrated that metformin reduces the cancer risk. However, the use of sulfonylurea derivatives correlates with an increased risk of developing a malignancy. Another form of treatment, insulin therapy, involves using various forms of insulin that differ in pharmacodynamics, pharmacokinetics and efficacy. Previous studies have indicated that certain insulin variants also affect the cancer risk. The results from analyses that address the safety of long-lasting insulin types raise the most concern regarding the increased risk of malignancy. Rapid development of novel diabetic medications and their widespread use carries the risk of potentially increased rates of cancer, unnoticeable in limited, randomized, controlled trials. In the present review, the results of clinical and epidemiological studies are evaluated to assess the safety of anti-hyperglycemic medications and their effect on cancer risk and outcomes.

The number of time-of-flight secondary ion mass spectrometry studies on biological tissues and cells has significantly increased since the development of primary ion sources that allow not only elemental but also molecular analysis. Substantial fragmentation during ionic bombardment results in a large number of peaks, rendering data analysis complex. Complete and trustable sets of reference spectra for the main biological building blocks, i.e., amino acids, monosaccharides, fatty acids, and nucleotides, are required. This work aims to provide an accurate and extensive library of reference spectra for monosaccharides, measured with the Bi3+ primary ion. Here (Paper I), the negative polarity spectra and lists of associated characteristic fragments are presented.The number of time-of-flight secondary ion mass spectrometry studies on biological tissues and cells has significantly increased since the development of primary ion sources that allow not only elemental but also molecular analysis. Substantial fragmentation during ionic bombardment results in a large number of peaks, rendering data analysis complex. Complete and trustable sets of reference spectra for the main biological building blocks, i.e., amino acids, monosaccharides, fatty acids, and nucleotides, are required. This work aims to provide an accurate and extensive library of reference spectra for monosaccharides, measured with the Bi3+ primary ion. Here (Paper I), the negative polarity spectra and lists of associated characteristic fragments are presented.

Effects of ion concentration and active layer thickness play a critical role on the performance of light-emitting electrochemical cells. Expanding on a pioneering materials system comprising the super yellow (SY) polymer and the electrolyte trimethylolpropane ethoxylate (TMPE)/Li+CF3SO3-, it is reported that a slightly lowered salt concentration and layer thickness result in a substantial efficiency increase, and that this increase is confined to a narrow concentration and thickness range. For a film thickness of 70 nm, a blend ratio SY:TMPE:Li+CF3SO3- = 1:0.075:0.0225, and a current of 7.7 mA cm(-2) the current efficacy is 11.6 cd A(-1), on a par with SY light-emitting diodes. The optimized salt content can be explained by increased exciton quenching at higher concentrations and hindered carrier injection and conduction at lower concentrations, while the optical dependence on the layer thickness is due to weak microcavity effects. A comprehensive optical modeling study is presented, which includes the doping-induced changes of the refractive indices and self-absorption losses due the emission-absorption overlap of intrinsic and doped SY. The analysis indicates either a thickness-independent emitter position (EP) close to the anode or a thickness-dependent EP, shifted to the cathode for increased thicknesses.

The number of time-of-flight secondary ion mass spectrometry studies on biological tissues and cells strongly increased since the development of primary ion sources that allow not only elemental but also molecular analysis. Still, substantial fragmentation during ionic bombardment results in a large amount of peaks, rendering data analysis complex. Complete and trustable sets of reference spectra for the main biological building blocks such as proteins, sugars, and lipids are required. Here, the authors provide a database of reference spectra for the 21 proteinogenic amino acids + glycine for bismuth instruments. Paper 1 of this two-part article series contains the negative polarity spectra and Paper II the positive polarity spectra. These reference spectra were obtained with the primary ion Bi3+, and spectra for the primary ions Bi1+ and Bi3++ are contained in the supplementary material as ASCII files.The number of time-of-flight secondary ion mass spectrometry studies on biological tissues and cells strongly increased since the development of primary ion sources that allow not only elemental but also molecular analysis. Still, substantial fragmentation during ionic bombardment results in a large amount of peaks, rendering data analysis complex. Complete and trustable sets of reference spectra for the main biological building blocks such as proteins, sugars, and lipids are required. Here, the authors provide a database of reference spectra for the 21 proteinogenic amino acids + glycine for bismuth instruments. Paper 1 of this two-part article series contains the negative polarity spectra and Paper II the positive polarity spectra. These reference spectra were obtained with the primary ion Bi3+, and spectra for the primary ions Bi1+ and Bi3++ are contained in the supplementary material as ASCI...

Neutron Spin Echo spectroscopy provides unique insight into molecular and submolecular dynamics as well as intra- and inter-molecular interactions in soft matter. These dynamics may change drastically under shear flow. In particular in polymer physics a stress plateau is observed, which might be explained by an entanglement-disentanglement transition. However, such a transition is difficult to identify directly by experiments. Neutron Spin Echo has been proven to provide information about entanglement length and degree by probing the local dynamics of the polymer chains. Combining shear experiments and neutron spin echo is challenging since, first the beam polarisation has to be preserved during scattering and second, Doppler scattered neutrons may cause inelastic scattering. In this paper we present a new shear device adapted for these needs. We demonstrate that a high beam polarisation can be preserved and present first data on an entangled polymer solution under shear. To complement the experiments on the dynamics we present novel SANS data revealing shear- induced conformational changes in highly entangled polymers.

Aims: Sine efficiency of tyrosine kinase inhibitor (TKI) therapy in dialyzed patients is still unclear we aim to analyze the outcome of treatment in such cohort. Patients & methods: We analyzed treatment outcomes of patients with clear cell renal cell carcinoma (ccRCC) with special focus on those who were also treated with hemodialysis and described treatment safety and progression-free survival of eight patients treated with TKIs and hemodialysis. Discussion & conclusion: Our report supports statement that TKI treatment of dialyzed patients is safe and effective. ccRCC increases risk of developing renal insufficiency as well as end-stage renal disease that require dialysis. Introduction of multitargeted receptor kinase inhibitors (TKIs), including sunitinib, sorafenib and pazopanib significantly expanded life time expectancy of metastatic renal clear cell carcinoma. The advance also applies to patients with ccRCC and end-stage renal disease who undergo dialyses.

Organic materials, such as conjugated polymers, are attractive building blocks for bioelectronic interfaces. In particular, organic semiconductors show excellent performance in light-mediated excitation and silencing of neuronal cells and tissues. However, the main challenges of these organic photovoltaic interfaces compared to inorganic prostheses are the limited adhesion of conjugated polymers in aqueous environments and the exploitation of materials responsive in the visible spectrum. Here, we show a photovoltaic organic interface optimized for neuronal stimulation in the near-infrared spectrum. We adjusted the organic materials by chemical modification in order to improve the adhesion in an aqueous environment and to modulate the photoelectrical stimulation efficiency. As proof-of-principle, we tested this interface on explanted degenerated mice retinas, thus providing results on the efficiency and reliability of the device as an implant for neural stimulation. Organic materials are attractive for photovoltaic interfaces in bioelectronics, but are limited by adhesion in aqueous environments and responsiveness in the visible spectrum. Here, an organic interface is reported for neuronal stimulation in the near-infrared and tested on explanted mice retinas.