97 research outputs found
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Impedimetric Analysis of Trabecular Bone Based on Cole and Linear Discriminant Analysis
A spatially unambiguous characterization of electrical properties of osseous tissues is important for the therapy of osteopathy via electrical stimulation. Accordingly, the study aimed to characterize the highly inhomogeneous composition and structures of different anatomical regions of trabecular bone based on their electrical properties. The electrical properties of 64 porcine trabecular bone samples were analyzed in a parallel plate electrode configuration and compared with published results. Therefore, a novel method, combining traditional Cole model with a linear discriminant analysis (LDA), was developed to discriminate the different regions, i.e., femur head, greater trochanter, and femur neck. Possible mechanisms behind the distinction for different regions could be interpreted from both methods. Respective adjacent regions with similar structure and composition could be distinguished from statistically significant differences of Cole parameters, i.e., α (p < 0.01) and R∞ (p < 0.05). The latter was correlated especially with water content, indicating an association of individual differences in microstructures in particular with conductivity. Conversely, different regions were unambiguously discriminated with LDA based on permittivity or conductivity. Contributions to the discrimination were explicitly reflected by the coefficients of the derived LDA features. A clear distinction was obtained especially for a frequency response at 950 kHz. Moreover, predictions for the classification of unspecified samples assigned them correctly to their origin with a success of 92.9%. The combination of both methods offers the possibility for a spatially resolved and eventually patient specific discrimination and evaluation of bone tissues and their response to therapies, notably electrical stimulation
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Discrimination of different cell monolayers before and after exposure to nanosecond pulsed electric fields based on Cole-Cole and multivariate analysis
Normal and cancer cells, which were grown in monolayers, were investigated and discriminated by electrical bioimpedance spectroscopy (EBIS) before and after exposures to nanosecond pulsed electric fields (nsPEFs). Bioimpedance data were analysed with a Cole-Cole model and the principal component analysis (PCA). Normal and cancer cells could be clearly distinguished from each other either from Cole parameters (R 0, a, t) or from two dominant principal components. The trend of changes for Cole parameters indicated distinctively different post-nsPEF-effects between normal and cancer cells. PCA was also able to distinguish characteristic impedance spectra 30 min after exposures. The first principal component suggested that post-nsPEF-effects for normal cells were revealed especially at lower frequencies. The results indicated further that the extracellular resistance, which is dominated by cell-cell connections, might be an important factor with respect to selective nsPEF-effects on cancer cells that are organized in a monolayer or a tissue, respectively. Accordingly, the results support the application of EBIS as an early, non-invasive, label-free, and time-saving approach for the classification of cells to provide in particular predictive information on the success of cancer treatments with nsPEFs. © 2019 IOP Publishing Ltd
Combined In Vitro Toxicity and Immunogenicity of Cold Plasma and Pulsed Electric Fields
In modern oncology, therapies are based on combining monotherapies to overcome treatment resistance and increase therapy precision. The application of microsecond-pulsed electric fields (PEF) is approved to enhance local chemotherapeutic drug uptake within combination electrochemotherapy regimens. Reactive oxygen species (ROS) have been implicated in anticancer effects, and cold physical plasma produces vast amounts of ROS, which have recently been shown to benefit head and neck cancer patients. PEF and cold plasma technology have been linked to immunogenic cell death (ICD) induction, a regulated cell death accompanied by sterile inflammation that promotes antitumor immunity. To this end, we investigated the combined effect of both treatments regarding their intracellular ROS accumulation, toxicity, ICD-related marker expression, and optimal exposure sequence in a leukemia model cell line. The combination treatment substantially increased ROS and intracellular glutathione levels, leading to additive cytotoxic effects accompanied by a significantly increased expression of ICD markers, such as the eat-me signal calreticulin (CRT). Preconditioned treatment with cold plasma followed by PEF exposure was the most potent treatment sequence. The results indicate additive effects of cold plasma and PEF, motivating further studies in skin and breast tumor models for the future improvement of ECT in such patients
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Hydrogen peroxide production of underwater nanosecond-pulsed streamer discharges with respect to pulse parameters and associated discharge characteristics
Abstract Pulsed streamer discharges submerged in water have demonstrated potential in a number of applications. Especially the generation of discharges by short high-voltage pulses in the nanosecond range has been found to offer advantages with respect to efficacies and efficiencies. The exploited plasma chemistry generally relies on the initial production of short-lived species, e.g. hydroxyl radicals. Since the diagnostic of these transient species is not readily possible, a quantification of hydrogen peroxide provides an adequate assessment of underlying reactions. These conceivably depend on the characteristics of the high-voltage pulses, such as pulse duration, pulse amplitude, as well as pulse steepness. A novel electrochemical flow-injection system was used to relate these parameters to hydrogen peroxide concentrations. Accordingly, the accumulated hydrogen peroxide production for streamer discharges ignited in deionized water was investigated for pulse durations of 100 ns and 300 ns, pulse amplitudes between 54 kV and 64 kV, and pulse rise times from 16 ns to 31 ns. An independent control of the individual pulse parameters was enabled by providing the high-voltage pulses with a Blumlein line. Applied voltage, discharge current, optical light emission and time-integrated images were recorded for each individual discharge to determine dissipated energy, inception statistic, discharge expansion and the lifetime of a discharge. Pulse steepness did not affect the hydrogen peroxide production rate, but an increase in amplitude of 10 kV for 100 ns pulses nearly doubled the rate to (0.19 ± 0.01) mol l−1 s−1, which was overall the highest determined rate. The energy efficiency did not change with pulse amplitude, but was sensitive to pulse duration. Notably, production rate and efficiency doubled when the pulse duration decreased from 300 ns to 100 ns, resulting in the best peroxide production efficiency of (9.2 ± 0.9) g kWh−1. The detailed analysis revealed that the hydrogen peroxide production rate could be described by the energy dissipation in a representative single streamer. The production efficiency was affected by the corresponding discharge volume, which was comprised by the collective volume of all filaments. Hence, dissipating more energy in a filament resulted in an increased production rate, while increasing the relative volume of the discharge compared to its propagation time increased the energy efficiency
Comprehensive characterization of osseous tissues from impedance measurements by effective medium approximation
A unified mixing (UM) model was developed to derive microstructural information of trabecular bone, i.e., bone volume fraction (BV/TV), from electrical impedance spectroscopy. A distinct advantage of the UM-model over traditional methods, such as equivalent circuit models and multivariate analysis, is that the influence of both the environment (hydroxyapatite) and different inclusions (water, fat, and air) can be taken into account simultaneously. In addition, interactions between the different components such as interfacial polarization can be addressed by a dedicated fitting parameter v. Accordingly, values of BV/TV for different bone samples, e.g., including or not including water, were determined in the higher frequency range of 1-5 MHz. Results showed good agreement with experimental data obtained by micro-computer tomography. In particular, predictions for dielectric parameters that were derived for 3 and 4 MHz were found most promising for the assessment and distinction of osteopathic conditions and differences. This was shown by a clear differentiation of osseous tissues, e.g., the greater trochanter, femoral head, and femoral neck
Nanosecond Pulsed Electric Field Induced Cytoskeleton, Nuclear Membrane and Telomere Damage Adversely Impact Cell Survival
We investigated the effects of nanosecond pulsed electric fields (nsPEF) on three human cell lines and demonstrated cell shrinkage, breakdown of the cytoskeleton, nuclear membrane and chromosomal telomere damage. There was a differential response between cell types coinciding with cell survival. Jurkat cells showed cytoskeleton, nuclear membrane and telomere damage that severely impacted cell survival compared to two adherent cell lines. Interestingly, disruption of the actin cytoskeleton in adherent cells prior to nsPEF exposure significantly reduced cell survival. We conclude that nsPEF applications are able to induce damage to the cytoskeleton and nuclear membrane. Telomere sequences, regions that tether and stabilize DNA to the nuclear membrane, are severely compromised as measured by a pan-telomere probe. Internal pore formation following nsPEF applications has been described as a factor in induced cell death. Here we suggest that nsPEF induced physical changes to the cell in addition to pore formation need to be considered as an alternative method of cell death. We suggest nsPEF electrochemical induced depolymerization of actin filaments may account for cytoskeleton and nuclear membrane anomalies leading to sensitization
Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial
Background: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD. Methods/Design: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab-and/or alemtuzumab-refractory, CD20-positive low-or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial. Discussion: Promising data (e. g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse
Degradation of glyphosate in water by the application of surface corona discharges
Glyphosate (GLP) is one of the most widely applied herbicides, and is found ubiquitously in the environment. The removal of glyphosate from waste water and soil is challenging and can be achieved with chemical or biological methods, which, nevertheless, suffer from different disadvantages. The application of a physical plasma for the removal of GLP in water was examined by the application of surface corona discharges in a wire-to-cylinder setup filled with argon. The plasma was ignited at the liquid surface without any additives. By applying a photometric method, GLP was detected after derivatisation with fluorenyl methoxycarbonyl chloride, whereas phosphate was determined with ammonium molybdate. A GLP degradation rate of 90.8% could be achieved within a treatment time of 30 minutes with an estimated energy efficiency of 0.32 g/kWh
Uncertainty Quantification and Sensitivity Analysis for the Electrical Impedance Spectroscopy of Changes to Intercellular Junctions Induced by Cold Atmospheric Plasma
The influence of pertinent parameters of a Cole-Cole model in the impedimetric assessment of cell-monolayers was investigated with respect to the significance of their individual contribution. The analysis enables conclusions on characteristics, such as intercellular junctions. Especially cold atmospheric plasma (CAP) has been proven to influence intercellular junctions which may become a key factor in CAP-related biological effects. Therefore, the response of rat liver epithelial cells (WB-F344) and their malignant counterpart (WB-ras) was studied by electrical impedance spectroscopy (EIS). Cell monolayers before and after CAP treatment were analyzed. An uncertainty quantification (UQ) of Cole parameters revealed the frequency cut-off point between low and high frequency resistances. A sensitivity analysis (SA) showed that the Cole parameters, R0 and α were the most sensitive, while Rinf and τ were the least sensitive. The temporal development of major Cole parameters indicates that CAP induced reversible changes in intercellular junctions, but not significant changes in membrane permeability. Sustained changes of τ suggested that long-lived ROS, such as H2O2, might play an important role. The proposed analysis confirms that an inherent advantage of EIS is the real time observation for CAP-induced changes on intercellular junctions, with a label-free and in situ method manner
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