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The cortical silent period (CSP), assessed with transcranial magnetic stimulation (TMS), provides insights into motor cortex excitability. Alterations in the CSP have been observed in multiple sclerosis (MS), although a comparison of the sometimes contradictory results is difficult due to methodological differences. The aim of this study is to provide a more profound neurophysiological understanding of fatigue’s pathophysiology and its relationship to the CSP. Twenty-three patients with MS, along with a matched control group, underwent comprehensive CSP measurements at four intensities (125, 150, 175, and 200% resting motor threshold), while their fatigue levels were assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC) and its motor and cognitive subscore. MS patients exhibited a significantly increased CSP duration compared to controls (p = 0.02), but CSP duration was not associated with the total FSMC, or the motor or cognitive subscore. Our data suggest a systematic difference in MS patients compared to healthy controls in the CSP but no association with fatigue when measured with the FSMC. Based on these results, and considering the heterogeneous literature in the field, our study highlights the need for a more standardized approach to neurophysiological data collection and validation. This standardization is crucial for exploring the link between TMS and clinical impairments in diseases like MS.
Background
Telephone-Cardiopulmonary Resuscitation (T-CPR) significantly increases rate of bystander resuscitation and improves patient outcomes after out-of-hospital cardiac arrest (OHCA). Nevertheless, securing correct execution of instructions remains a difficulty. ERC Guidelines 2021 recommend standardised instructions with continuous evaluation. Yet, there are no explicit recommendations on a standardised wording of T-CPR in the German language. We investigated, whether a modified wording regarding check for breathing in a German T-CPR protocol improved performance of T-CPR.
Methods
A simulation study with 48 OHCA scenarios was conducted. In a non-randomised trial study lay rescuers were instructed using the real-life-CPR protocol of the regional dispatch centre and as the intervention a modified T-CPR protocol, including specific check for breathing (head tilt-chin lift instructions). Resuscitation parameters were assessed with a manikin and video recordings.
Results
Check for breathing was performed by 64.3% (n = 14) of the lay rescuers with original wording and by 92.6% (n = 27) in the group with modified wording (p = 0.035). In the original wording group the head tilt-chin manoeuvre was executed by 0.0% of the lay rescuers compared to 70.3% in the group with modified wording (p < 0.001). The average duration of check for breathing was 1 ± 1 s in the original wording group and 4 ± 2 s in the group with modified wording (p < 0.001). Other instructions (e.g. check for consciousness and removal of clothing) were well performed and did not differ significantly between groups. Quality of chest compression did not differ significantly between groups, with the exception of mean chest compression depth, which was slightly deeper in the modified wording group.
Conclusion
Correct check for breathing seems to be a problem for lay rescuers, which can be decreased by describing the assessment in more detail. Hence, T-CPR protocols should provide standardised explicit instructions on how to perform airway assessment. Each protocol should be evaluated for practicability.
Background: Methanogenic archaea represent a less investigated and likely underestimated part of the intestinal tract microbiome in swine.
Aims/Methods: This study aims to elucidate the archaeome structure and function in the porcine intestinal tract of healthy and H1N1 infected swine. We performed multi-omics analysis consisting of 16S rRNA gene profiling, metatranscriptomics and metaproteomics.
Results and discussion: We observed a significant increase from 0.48 to 4.50% of archaea in the intestinal tract microbiome along the ileum and colon, dominated by genera Methanobrevibacter and Methanosphaera. Furthermore, in feces of naïve and H1N1 infected swine, we observed significant but minor differences in the occurrence of archaeal phylotypes over the course of an infection experiment. Metatranscriptomic analysis of archaeal mRNAs revealed the major methanogenesis pathways of Methanobrevibacter and Methanosphaera to be hydrogenotrophic and methyl-reducing, respectively. Metaproteomics of archaeal peptides indicated some effects of the H1N1 infection on central metabolism of the gut archaea.
Conclusions/Take home message: Finally, this study provides the first multi-omics analysis and high-resolution insights into the structure and function of the porcine intestinal tract archaeome during a non-lethal Influenza A virus infection of the respiratory tract, demonstrating significant alterations in archaeal community composition and central metabolic functions.
Objective: Menopause is associated with multiple health risks. In several studies, a higher incidence or a higher risk for obstructive sleep apnea (OSA) in post-menopausal than pre-menopausal women is reported. This study was designed to verify such a connection between menopause and OSA in a population-based sample.
Methods: For a subsample (N = 1209) of the Study of Health in Pomerania (N = 4420), complete polysomnography data was available. Of these, 559 females completed a structured interview about their menstrual cycle. Splines and ordinal regression analysis were used to analyze the resulting data.
Results: In the ordinal regression analysis, a significant association between the apnea–hypopnea index (AHI) and menopause indicated that post-menopausal women had a substantially higher risk of OSA. In accordance with previous studies, risk indicators such as body mass index (BMI), age, and the influence of hysterectomies or total oophorectomies were included in the model.
Conclusions: Our results clearly confirmed the assumed connection between menopause and OSA. This is important because OSA is most often associated with male patients, and it warrants further research into the underlying mechanisms.
Manual sleep scoring for research purposes and for the diagnosis of sleep disorders is labor-intensive and often varies significantly between scorers, which has motivated many attempts to design automatic sleep stage classifiers. With the recent introduction of large, publicly available hand-scored polysomnographic data, and concomitant advances in machine learning methods to solve complex classification problems with supervised learning, the problem has received new attention, and a number of new classifiers that provide excellent accuracy. Most of these however have non-trivial barriers to use. We introduce the Greifswald Sleep Stage Classifier (GSSC), which is free, open source, and can be relatively easily installed and used on any moderately powered computer. In addition, the GSSC has been trained to perform well on a large variety of electrode set-ups, allowing high performance sleep staging with portable systems. The GSSC can also be readily integrated into brain-computer interfaces for real-time inference. These innovations were achieved while simultaneously reaching a level of accuracy equal to, or exceeding, recent state of the art classifiers and human experts, making the GSSC an excellent choice for researchers in need of reliable, automatic sleep staging.
Physiological and neural synchrony in emotional and neutral stimulus processing: A study protocol
(2023)
Background: As psychotherapy involves at least two individuals, it is essential to include the interaction perspective research. During interaction, synchrony, i.e., the occurrence of simultaneous responses, can be observed at the physiological, neural, and behavioral level. Physiological responses include heart rate and electrodermal activity; neural markers can be measured using electroencephalogram. Emotionally arousing stimuli are allocated more attentional resources (motivated attention), which is reflected in physiological activation and brain potentials. Here we present a protocol for a pilot study implementing a new research methodology, and replication of the motivated attention to emotion effect in in dyads. There is evidence that higher synchrony is associated with more positive (therapeutic) relationships. Thus, the secondary outcome will be the association between physiological and neural synchrony and subjective ratings.
Methods and design: Individuals (18−30 years) will participate in same-sex pairs in two experiments. In the first experiment (triadic interaction), both participants attentively watch unpleasant, neutral and pleasant pictures, and read/listen to standardized scripts (unpleasant, neutral, and pleasant, respectively) for the imagination task. In the second experiment, participants will read out three scripts (unpleasant, neutral, pleasant) to each other, followed by a joint imagination period. Stimuli will be presented in counterbalanced orders. After each picture and imagination, participants rate their subjective arousal and valence. In the beginning and in the end of the procedure, dyads rate their relationship, sympathy, and bonds (Working Alliance Inventory subscale). Heart rate, electrodermal activity and electroencephalogram will be continuously measured during both experiments using portable devices (EcgMove4 and EdaMove4, nine-channel B-Alert X-Series mobile-wireless EEG). Synchrony analyses will include the dual electroencephalography analysis pipeline, correlational analyses and Actor–Partner Interdependence Models.
Discussion: The present study protocol provides an experimental approach to investigate interpersonal synchrony during emotion processing, allowing for the establishment of research methods in a pilot study, which can later be translated into real-life psychotherapy research. In the future, fundamental understanding of such mechanisms in dyadic interactions is essential in order to promote therapeutic relationships, and thus, treatment effectiveness and efficiency.
Objective: To characterize a socially active humanoid robot’s therapeutic interaction as a therapeutic assistant when providing arm rehabilitation (i.e., arm basis training (ABT) for moderate-to-severe arm paresis or arm ability training (AAT) for mild arm paresis) to stroke survivors when using the digital therapeutic system Evidence-Based Robot-Assistant in Neurorehabilitation (E-BRAiN) and to compare it to human therapists’ interaction.
Methods: Participants and therapy: Seventeen stroke survivors receiving arm rehabilitation (i.e., ABT [n = 9] or AAT [n = 8]) using E-BRAiN over a course of nine sessions and twenty-one other stroke survivors receiving arm rehabilitation sessions (i.e., ABT [n = 6] or AAT [n = 15]) in a conventional 1:1 therapist–patient setting. Analysis of therapeutic interaction: Therapy sessions were videotaped, and all therapeutic interactions (information provision, feedback, and bond-related interaction) were documented offline both in terms of their frequency of occurrence and time used for the respective type of interaction using the instrument THER-I-ACT. Statistical analyses: The therapeutic interaction of the humanoid robot, supervising staff/therapists, and helpers on day 1 is reported as mean across subjects for each type of therapy (i.e., ABT and AAT) as descriptive statistics. Effects of time (day 1 vs. day 9) on the humanoid robot interaction were analyzed by repeated-measures analysis of variance (rmANOVA) together with the between-subject factor type of therapy (ABT vs. AAT). The between-subject effect of the agent (humanoid robot vs. human therapist; day 1) was analyzed together with the factor therapy (ABT vs. AAT) by ANOVA.
Main results and interpretation: The overall pattern of the therapeutic interaction by the humanoid robot was comprehensive and varied considerably with the type of therapy (as clinically indicated and intended), largely comparable to human therapists’ interaction, and adapted according to needs for interaction over time. Even substantially long robot-assisted therapy sessions seemed acceptable to stroke survivors and promoted engaged patients’ training behavior.
Conclusion: Humanoid robot interaction as implemented in the digital system E-BRAiN matches the human therapeutic interaction and its modification across therapies well and promotes engaged training behavior by patients. These characteristics support its clinical use as a therapeutic assistant and, hence, its application to support specific and intensive restorative training for stroke survivors.
Objective: The instrument THERapy-related InterACTion (THER-I-ACT) was developed to document therapeutic interactions comprehensively in the human therapist–patient setting. Here, we investigate whether the instrument can also reliably be used to characterise therapeutic interactions when a digital system with a humanoid robot as a therapeutic assistant is used.
Methods: Participants and therapy: Seventeen stroke survivors receiving arm rehabilitation (i.e., arm basis training (ABT) for moderate-to-severe arm paresis [n = 9] or arm ability training (AAT) for mild arm paresis [n = 8]) using the digital therapy system E-BRAiN over a course of nine sessions. Analysis of the therapeutic interaction: A total of 34 therapy sessions were videotaped. All therapeutic interactions provided by the humanoid robot during the first and the last (9th) session of daily training were documented both in terms of their frequency and time used for that type of interaction using THER-I-ACT. Any additional therapeutic interaction spontaneously given by the supervising staff or a human helper providing physical assistance (ABT only) was also documented. All ratings were performed by two trained independent raters.
Statistical analyses: Intraclass correlation coefficients (ICCs) were calculated for the frequency of occurrence and time used for each category of interaction observed.
Results: Therapeutic interactions could comprehensively be documented and were observed across the dimensions provision of information, feedback, and bond-related interactions. ICCs for therapeutic interaction category assessments from 34 therapy sessions by two independent raters were high (ICC ≥0.90) for almost all categories of the therapeutic interaction observed, both for the occurrence frequency and time used for categories of therapeutic interactions, and both for the therapeutic interaction performed by the robot and, even though much less frequently observed, additional spontaneous therapeutic interactions by the supervisory staff and a helper being present. The ICC was similarly high for an overall subjective rating of the concentration and engagement of patients (0.87).
Conclusion: Therapeutic interactions can comprehensively and reliably be documented by trained raters using the instrument THER-I-ACT not only in the traditional patient–therapist setting, as previously shown, but also in a digital therapy setting with a humanoid robot as the therapeutic agent and for more complex therapeutic settings with more than one therapeutic agent being present.
The reduction of individual carbon consumption could make an important contribution to the worldwide effort to limit global warming. Based on Bandura’s theory of moral disengagement, we hypothesized that the propensity to morally disengage concerning high-carbon behaviors (e.g., eating meat or traveling by plane) is one important factor that prevents individuals from reducing their carbon footprint. To measure the propensity to morally disengage in high-carbon-related behavior contexts, a questionnaire (MD-HCB) was developed and psychometrically validated in an online study with a German sample (N = 220). Confirmatory factor analyses revealed that the final nine-item scale had a one-dimensional structure, as intended. The internal consistency of the scale was excellent (Cronbach’s α = 0.94) and the scale interpretation had predictive validity for both past low-carbon consumption behavior and the intention to engage in such behavior in the future. Correlational analyses with relevant existing instruments confirmed the construct validity of the interpretations that can be drawn from the MD-HCB, as its resulting score is related to, yet separable from, the general tendency to morally disengage and is meaningfully connected to related constructs. A pre-study with a student sample (N = 89) not only helped to identify limitations in the study design but also showed a weak predictive ability of moral competence concerning high-carbon consumption behavior and intention to change. Based on our findings, future media campaigns designed to increase people’s intention to reduce high-carbon behavior could focus on the modification of common cognitive disengagement strategies.
In rural areas, healthcare providers, patients and relatives have to cover long distances. For specialised ambulatory palliative care (SAPV), a supply radius of max. 30 km is recommended. The aim of this study was to analyse whether there are regional disparities in the supply of SAPV and whether it is associated with the distance between the SAPV team’s site and the patient’s location. Therefore, anonymised data of the Association of Statutory Health Insurance Physicians of the Federal State of Mecklenburg-Western Pomerania (M-V) were retrospectively analysed for the period of 2014–2017. Identification as a palliative patient was based on palliative-specific items from the ambulatory reimbursement catalogue. In total, 6940 SAPV patients were identified; thereof, 48.9% female. The mean age was 73.3 years. For 28.3% of the identified SAPV patients (n = 1961), the SAPV teams had a travel distance of >30 km. With increasing distance, the average number of treatment days per patient increased. It was found that there are regional disparities in the provision of SAPV services in M-V and that local structures have an important impact on regional supply patterns. The distance between the SAPV team’s site and the patient’s location is not the only determining factor; other causes must be considered.
In micro-densitometry of wood it is standard procedure to extract resin and other soluble compounds before X-ray analysis to eliminate the influence of these extractives on wood-density. Dendrochemical studies using X-ray fluorescence analysis on the other hand are commonly conducted without previous extraction. However, it is well known that translocation processes of elements during heartwood formation in trees or (temporal) differences in sap content of wood samples can influence dendrochemical element profiles. This might bias environmental signals stored in time series of element concentrations in wood proxies. We hypothesize that metals tightly bound to cell walls show a more robust proxy potential for environmental conditions than easily translocated ones. To eliminate the noise of these soluble substances in wood elemental time series, their extraction prior to analysis might be necessary. In our study we tested the effect of different solvents (water, alcohol, and acetone) and different extraction times on elemental time series of three tree species with differing wood structure (Pinus sylvestris; Quercus robur and Populus tremula). Micro-XRF analysis was conducted on nine replicates per species using an ITRAX-Multiscanner. A set of elements commonly detected in wood (S, Cl, K, Ca, Ti, Mn, Fe, and Ni) was analysed at high resolution before and after several extraction runs. Besides lowering their levels, extraction did not significantly change the temporal trends for most elements. However, for some elements, e.g., Potassium, Chlorine or Manganese, especially the water extraction led to significant decreases in concentrations and altered temporal trends. Apparently the dipole effect of water produced the strongest extraction power of all three solvents. In addition we observed a dependency of extraction intensity from wood density which differed between wood types. Our results help in interpreting and evaluating element profiles and mark a step forward in establishing dendrochemistry as a robust proxy in dendro-environmental research.
Background
Lower cortisol concentrations in adulthood were repeatedly associated with more severe childhood maltreatment. Additionally, childhood maltreatment was reported to promote health risk behavior, such as smoking or alcohol consumption, and to increase the risk of mental and somatic diseases during adulthood, such as major depressive disorders or obesity. The present study investigated if health risk behavior and disease symptoms in adults mediate the associations between past childhood maltreatment and present basal serum cortisol concentrations.
Methods
Data from two independent adult cohorts of the general population-based Study of Health in Pomerania (SHIP-TREND-0: N = 3,517; SHIP-START-2: N = 1,640) was used. Childhood maltreatment was assessed via the Childhood Trauma Questionnaire (CTQ). Cortisol concentrations were measured in single-point serum samples. Health risk behavior and mental and physical symptoms were used as mediators. Mediation analyses were calculated separately for both cohorts; results were integrated via meta-analyses.
Results
In mediator-separated analyses, associations between childhood maltreatment and basal serum cortisol concentrations were partly mediated by depressive symptoms (BDI-II: βindirect effect = -.011, pFDR = .017, 21.0% mediated) and subjective somatic health complaints (somatic complaints: βindirect effect = -.010, pFDR = .005, 19.4% mediated). In the second step, both mediators were simultaneously integrated into one mediation model. The model replicated the mediation effects of the subjective somatic health complaints (whole model: βindirect effect = -.014, p = .001, 27.6% mediated; BDI-II: βindirect effect = -.006, p = .163, 11.4% mediated, somatic complaints: βindirect effect = -.020, p = .020, 15.5% mediated).
Conclusion
The results support the hypothesis that the long-lasting effects of childhood maltreatment on the stress response system are partly mediated through self-perceived disease symptoms. However, no mediation was found for health risk behavior or physically measured mediators. Mediation models with multiple simultaneous mediators pointed to a relevant overlap between the potential mediators. This overlap should be focused on in future studies.
Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave R²(pred) = 0.683, R²(pred) = 0.758, and R²(pred) = 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.
Background
Even with high standards of acute care and neurological early rehabilitation (NER) a substantial number of patients with neurological conditions still need mechanical ventilation and/or airway protection by tracheal cannulas when discharged and hence home-based specialised intensive care nursing (HSICN). It may be possible to improve the home care situation with structured specialized long-term neurorehabilitation support and following up patients with neurorehabilitation teams. Consequently, more people might recover over an extended period to a degree that they were no longer dependent on HSICN.
Methods
This healthcare project and clinical trial implements a new specialised neurorehabilitation outreach service for people being discharged from NER with the need for HSICN. The multicentre, open, parallel-group RCT compares the effects of one year post-discharge specialized outpatient follow-up to usual care in people receiving HSICN. Participants will randomly be assigned to receive the new form of healthcare (intervention) or the standard healthcare (control) on a 2:1 basis. Primary outcome is the rate of weaning from mechanical ventilation and/or decannulation (primary outcome) after one year, secondary outcomes include both clinical and economic measures. 173 participants are required to corroborate a difference of 30 vs. 10% weaning success rate statistically with 80% power at a 5% significance level allowing for 15% attrition.
Discussion
The OptiNIV-Study will implement a new specialised neurorehabilitation outreach service and will determine its weaning success rates, other clinical outcomes, and cost-effectiveness compared to usual care for people in need for mechanical ventilation and/or tracheal cannula and hence HSICN after discharge from NER.
Trial registration
The trial OptiNIV has been registered in the German Clinical Trials Register (DRKS) since 18.01.2022 with the ID DRKS00027326.
Background
Person-Centered-Care (PCC) requires knowledge about patient preferences. Among People-living-with-Dementia (PlwD) data on quantitative, choice-based preferences, which would allow to quantify, weigh and rank patient-relevant elements of dementia-care, and identify most/least preferred choices, are limited. The Analytic-Hierarchy-Process (AHP) may be one approach to elicit quantitative, choice-based preferences with PlwD, due to simple pairwise comparisons of individual criteria from a complex decision-problem, e.g. health care decisions. Furthermore, data on congruence of patient preferences with physicians’ judgements for PCC are missing. If patient preferences and physicians’ judgements differ, provision of PCC becomes unlikely. An understanding of patient preferences compared to physician’s judgements will support the implementation of truly PCC, i.e. state of the art dementia-care aligned with patient preferences.
Methods
This mixed-methods-study will be based on the results from a previous systematic review and conducted in three phases: (I) literature-based key intervention-categories of PCC will be investigated during qualitative interviews with Dementia-Care-Managers (DCMs) and PlwD to identify actually patient-relevant (sub) criteria of PCC; (II) based on findings from phase I, an AHP-survey will be designed and pre-tested for face- and content-validity, and consistency during face-to-face “thinking-aloud”-interviews with PlwD and two expert panels (DCMs and physicians); (III) the developed survey will elicit patient preferences and physicians’ judgements for PCC. To assess individual importance weights for (sub) criteria in both groups, the Principal-Eigenvector-Method will be applied. Weights will be aggregated per group by Aggregation-of-Individual-Priorities-mode. Descriptive and interferential statistical analyses will be conducted to assess congruence of importance-weights between groups. Subgroup-analyses shall investigate participant-heterogeneities, sensitivity of AHP-results shall be tested by inclusion/exclusion of inconsistent respondents.
Discussion
Little research is published on quantitative, choice-based preferences in dementia care. We expect that (1) PlwD have preferences and can express these, (2) that the AHP is a suitable technique to elicit quantitative, choice-based preferences among PlwD, and (3) to identify a divergence between patient preferences and physicians’ judgements for PCC. With the help of the AHP-technique, which supports systematic decision-making including multiple criteria, it may be possible to involve PlwD in future care decisions (patient participation) and ensure implementation of truly Person-Centered-Dementia-Care.
Trial registration
Approval of the study was granted by the Ethics Committee at the University Medicine Greifswald the 09Apr2021 (Reg.-Nr.: BB 018–21, BB 018-21a, BB 018-21b).
Background
Multimedia multi-device measurement platforms may make the assessment of prevention-related medical variables with a focus on cardiovascular outcomes more attractive and time-efficient. The aim of the studies was to evaluate the reliability (Study 1) and the measurement agreement with a cohort study (Study 2) of selected measures of such a device, the Preventiometer.
Methods
In Study 1 (N = 75), we conducted repeated measurements in two Preventiometers for four examinations (blood pressure measurement, pulse oximetry, body fat measurement, and spirometry) to analyze their agreement and derive (retest-)reliability estimates. In Study 2 (N = 150), we compared somatometry, blood pressure, pulse oximetry, body fat, and spirometry measurements in the Preventiometer with corresponding measurements used in the population-based Study of Health in Pomerania (SHIP) to evaluate measurement agreement.
Results
Intraclass correlations coefficients (ICCs) ranged from .84 to .99 for all examinations in Study 1. Whereas bias was not an issue for most examinations in Study 2, limits of agreement for most examinations were very large compared to results of similar method comparison studies.
Conclusion
We observed a high retest-reliability of the assessed clinical examinations in the Preventiometer. Some disagreements between Preventiometer and SHIP examinations can be attributed to procedural differences in the examinations. Methodological and technical improvements are recommended before using the Preventiometer in population-based research.
Primary and acquired therapy resistance is a major problem in patients with BRAF-mutant melanomas being treated with BRAF and MEK inhibitors (BRAFI, MEKi). Therefore, development of alternative therapy regimes is still required. In this regard, new drug combinations targeting different pathways to induce apoptosis could offer promising alternative approaches. Here, we investigated the combination of proteasome and Kv1.3 potassium channel inhibition on chemo-resistant, BRAF inhibitor-resistant as well as sensitive human melanoma cells. Our experiments demonstrated that all analyzed melanoma cell lines were sensitive to proteasome inhibitor treatment at concentrations that are not toxic to primary human fibroblasts. To further reduce proteasome inhibitor-associated side effects, and to foster apoptosis, potassium channels, which are other targets to induce pro-apoptotic effects in cancer cells, were blocked. In support, combined exposure of melanoma cells to proteasome and Kv1.3 channel inhibitor resulted in synergistic effects and significantly reduced cell viability. On the molecular level, enhanced apoptosis correlated with an increase of intracellular Kv1.3 channels and pro-apoptotic proteins such as Noxa and Bak and a reduction of anti-apoptotic proteins. Thus, use of combined therapeutic strategies triggering different apoptotic pathways may efficiently prevent the outgrowth of drug-resistant and -sensitive BRAF-mutant melanoma cells. In addition, this could be the basis for an alternative approach to treat other tumors expressing mutated BRAF such as non-small-cell lung cancer.
Organic anion transporters 1 and 3 (OAT1 and OAT3) play a crucial role in kidney function by regulating the secretion of multiple renally cleared small molecules and toxic metabolic by-products. Assessing the activity of these transporters is essential for drug development purposes as they can significantly impact drug disposition and safety. OAT1 and OAT3 are amongst the most abundant drug transporters expressed in human renal proximal tubules. However, their expression is lost when cells are isolated and cultured in vitro, which is a persistent issue across all human and animal renal proximal tubule cell models, including primary cells and cell lines. Although it is well known that the overall expression of drug transporters is affected in vitro, the underlying reasons for the loss of OAT1 and OAT3 are still not fully understood. Nonetheless, research into the regulatory mechanisms of these transporters has provided insights into the molecular pathways underlying their expression and activity. In this review, we explore the regulatory mechanisms that govern the expression and activity of OAT1 and OAT3 and investigate the physiological changes that proximal tubule cells undergo and that potentially result in the loss of these transporters. A better understanding of the regulation of these transporters could aid in the development of strategies, such as introducing microfluidic conditions or epigenetic modification inhibitors, to improve their expression and activity in vitro and to create more physiologically relevant models. Consequently, this will enable more accurate assessment for drug development and safety applications.
Acute pancreatitis (AP) is one of the most common inflammatory diseases of the gastrointestinal tract and a steady rising diagnosis for inpatient hospitalization. About one in four patients, who experience an episode of AP, will develop chronic pancreatitis (CP) over time. While the initiating causes of pancreatitis can be complex, they consistently elicit an immune response that significantly determines the severity and course of the disease. Overall, AP is associated with a significant mortality rate of 1-5%, which is caused by either an excessive pro-inflammation, or a strong compensatory inhibition of bacterial defense mechanisms which lead to a severe necrotizing form of pancreatitis. At the time-point of hospitalization the already initiated immune response is the only promising common therapeutic target to treat or prevent a severe disease course. However, the complexity of the immune response requires fine-balanced therapeutic intervention which in addition is limited by the fact that a significant proportion of patients is in danger of development or progress to recurrent and chronic disease. Based on the recent literature we survey the disease-relevant immune mechanisms and evaluate appropriate and promising therapeutic targets for the treatment of acute and chronic pancreatitis.
In musculoskeletal surgery, the treatment of large bone defects is challenging and can require the use of bone graft substitutes to restore mechanical stability and promote host-mediated regeneration. The use of bone allografts is well-established in many bone regenerative procedures, but is associated with low rates of ingrowth due to pre-therapeutic graft processing. Cold physical plasma (CPP), a partially ionized gas that simultaneously generates reactive oxygen (O2) and nitrogen (N2) species, is suggested to be advantageous in biomedical implant processing. CPP is a promising tool in allograft processing for improving surface characteristics of bone allografts towards enhanced cellularization and osteoconduction. However, a preclinical assessment regarding the feasibility of pre-therapeutic processing of allogeneic bone grafts with CPP has not yet been performed. Thus, this pilot study aimed to analyze the bone morphology of CPP processed allografts using synchrotron radiation-based microcomputed tomography (SR-µCT) and to analyze the effects of CPP processing on human bone cell viability and function. The analyzes, including co-registration of pre- and post-treatment SR-µCT scans, revealed that the main bone morphological properties (total volume, mineralized volume, surface area, and porosity) remained unaffected by CPP treatment if compared to allografts not treated with CPP. Varying effects on cellular metabolic activity and alkaline phosphatase activity were found in response to different gas mixtures and treatment durations employed for CPP application. It was found that 3 min CPP treatment using a He + 0.1% N2 gas mixture led to the most favourable outcome regarding a significant increase in bone cell viability and alkaline phosphatase activity. This study highlights the promising potential of pre-therapeuthic bone allograft processing by CPP prior to intraoperative application and emphasizes the need for gas source and treatment time optimization for specific applications.