KCa channel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by KCa expression levels.

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKCa and BKCa Ca2+-activated K+ channels. Therefore, we analyzed here the effect of IKCa- and BKCa-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K+ channel targeting. As a result, the IKCa- and BKCa-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IKCa- and BKCa-expressing pGSC cultures, respectively. In addition, BKCa- but not IKCa-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that KCa-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.

Efficacy of combined tumor irradiation and KCa3.1-targeting with TRAM-34 in a syngeneic glioma mouse model.

The intermediate-conductance calcium-activated potassium channel KCa3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and KCa3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged the survival of the animals, the combination significantly prolonged the survival of the mice. We found an irradiation-induced hyperinvasion of glioma cells into the brain, which was inhibited by concomitant TRAM-34 treatment. Interestingly, TRAM-34 did neither radiosensitize nor impair SMA-560's intrinsic migratory capacities in vitro. Exploratory findings hint at increased TGF-ß1 signaling after irradiation. On top, we found a marginal upregulation of MMP9 mRNA, which was inhibited by TRAM-34. Last, infiltration of CD3+, CD8+ or FoxP3+ T cells was not impacted by either irradiation or KCa3.1 targeting and we found no evidence of adverse events of the combined treatment. We conclude that concomitant irradiation and TRAM-34 treatment is efficacious in this preclinical glioma model.

Tetraploidization Increases the Motility and Invasiveness of Cancer Cells.

Polyploidy and metastasis are associated with a low probability of disease-free survival in cancer patients. Polyploid cells are known to facilitate tumorigenesis. However, few data associate polyploidization with metastasis. Here, by generating and using diploid (2n) and tetraploid (4n) clones from malignant fibrous histiocytoma (MFH) and colon carcinoma (RKO), we demonstrate the migration and invasion advantage of tetraploid cells in vitro using several assays, including the wound healing, the OrisTM two-dimensional cell migration, single-cell migration tracking by video microscopy, the Boyden chamber, and the xCELLigence RTCA real-time cell migration. Motility advantage was observed despite tetraploid cell proliferation weakness. We could also demonstrate preferential metastatic potential in vivo for the tetraploid clone using the tail vein injection in mice and tracking metastatic tumors in the lung. Using the Mitelman Database of Chromosome Aberrations in Cancer, we found an accumulation of polyploid karyotypes in metastatic tumors compared to primary ones. This work reveals the clinical relevance of the polyploid subpopulation and the strategic need to highlight polyploidy in preclinical studies as a therapeutic target for metastasis.

Potential of pre-operative MRI features in glioblastoma to predict for molecular stem cell subtype and patient overall survival.

AIM OF THE STUDY: A molecular signature based on 10 mRNA abundances that characterizes the mesenchymal-to-proneural phenotype of glioblastoma stem(like) cells (GSCs) enriched in primary culture has been previously established. As this phenotype has been proposed to be prognostic for disease outcome the present study aims to identify features of the preoperative MR imaging that may predict the GSC phenotype of individual tumors. MATERIAL/METHODS: Molecular mesenchymal-to-proneural mRNA signatures and intrinsic radioresistance (SF4, survival fraction at 4 Gy) of primary GSC-enriched cultures were associated with survival data and pre-operative MR imaging of the corresponding glioblastoma patients of a prospective cohort (n = 24). The analyzed imaging parameters comprised linear vectors derived from tumor volume, necrotic volume and edema as contoured manually. RESULTS: A necrosis/tumor vector ratio and to a weaker extent the product of this ratio and the edema vector were identified to correlate with the mesenchymal-to-proneural mRNA signature and the SF4 of the patient-derived GSC cultures. Importantly, both parameter combinations were predictive for overall survival of the whole patient cohort. Moreover, the combination of necrosis/tumor vector ratio and edema vector differed significantly between uni- and multifocally recurring tumors. CONCLUSION: Features of the preoperative MR images may reflect the molecular signature of the GSC population and might be used in the future as a prognostic factor and for treatment stratification especially in the MGMT promotor-unmethylated sub-cohort of glioblastoma patients.

Protein Levels of Anti-Apoptotic Mcl-1 and the Deubiquitinase USP9x Are Cooperatively Upregulated during Prostate Cancer Progression and Limit Response of Prostate Cancer Cells to Radiotherapy.

BACKGROUND: Radiotherapy constitutes an important therapeutic option for prostate cancer. However, prostate cancer cells often acquire resistance during cancer progression, limiting the cytotoxic effects of radiotherapy. Among factors regulating sensitivity to radiotherapy are members of the Bcl-2 protein family, known to regulate apoptosis at the mitochondrial level. Here, we analyzed the role of anti-apoptotic Mcl-1 and USP9x, a deubiquitinase stabilizing Mcl-1 protein levels, in prostate cancer progression and response to radiotherapy. METHODS: Changes in Mcl-1 and USP9x levels during prostate cancer progression were determined by immunohistochemistry. Neutralization of Mcl-1 and USP9x was achieved by siRNA-mediated knockdown. We analyzed Mcl-1 stability after translational inhibition by cycloheximide. Cell death was determined by flow cytometry using an exclusion assay of mitochondrial membrane potential-sensitive dye. Changes in the clonogenic potential were examined by colony formation assay. RESULTS: Protein levels of Mcl-1 and USP9x increased during prostate cancer progression, and high protein levels correlated with advanced prostate cancer stages. The stability of Mcl-1 reflected Mcl-1 protein levels in LNCaP and PC3 prostate cancer cells. Moreover, radiotherapy itself affected Mcl-1 protein turnover in prostate cancer cells. Particularly in LNCaP cells, the knockdown of USP9x expression reduced Mcl-1 protein levels and increased sensitivity to radiotherapy. CONCLUSION: Posttranslational regulation of protein stability was often responsible for high protein levels of Mcl-1. Moreover, we demonstrated that deubiquitinase USP9x as a factor regulating Mcl-1 levels in prostate cancer cells, thus limiting cytotoxic response to radiotherapy.

Ion channels as molecular targets of glioblastoma electrotherapy.

Therapies with weak, non-ionizing electromagnetic fields comprise FDA-approved treatments such as Tumor Treating Fields (TTFields) that are used for adjuvant therapy of glioblastoma. In vitro data and animal models suggest a variety of biological TTFields effects. In particular, effects ranging from direct tumoricidal, radio- or chemotherapy-sensitizing, metastatic spread-inhibiting, up to immunostimulation have been described. Diverse underlying molecular mechanisms, such as dielectrophoresis of cellular compounds during cytokinesis, disturbing the formation of the spindle apparatus during mitosis, and perforating the plasma membrane have been proposed. Little attention, however, has been paid to molecular structures that are predestinated to percept electromagnetic fields-the voltage sensors of voltage-gated ion channels. The present review article briefly summarizes the mode of action of voltage sensing by ion channels. Moreover, it introduces into the perception of ultra-weak electric fields by specific organs of fishes with voltage-gated ion channels as key functional units therein. Finally, this article provides an overview of the published data on modulation of ion channel function by diverse external electromagnetic field protocols. Combined, these data strongly point to a function of voltage-gated ion channels as transducers between electricity and biology and, hence, to voltage-gated ion channels as primary targets of electrotherapy.

Using a smartphone application maintains physical activity following pulmonary rehabilitation in patients with COPD: a randomised controlled trial.

BACKGROUND: Evidence suggests that patients with COPD struggle to maintain improved physical activity (PA) after completing pulmonary rehabilitation (PR). Smartphone applications (apps) providing a comprehensive training programme have conferred healthy benefits. This study was conducted to determine whether regular usage of an app maintains PA following PR. METHODS: Patients with stage II-IV COPD were enrolled in a 6-month trial following PR. After the screening period, participants were randomised into the Kaia COPD app group (intervention group (IG)) or the control group (CG). The primary outcome was PA (daily steps), measured using an activity tracker. Secondary outcomes included the COPD Assessment Test (CAT), the Chronic Respiratory Disease Questionnaire (CRQ) and the 1 min Sit-to-Stand Test (STST). RESULTS: Sixty participants completed the study. The median steps from baseline to 6 months were significantly different between the groups, in favour of the IG (-105.3, IQR -1970.1 to 2105.8, vs CG -1173.0, IQR -3813.1 to -93.8; p=0.007). CAT was significantly decreased in the IG (15.1±8.6 vs 19.7±6.4, p=0.02), whereas the CRQ subdomains for dyspnoea (4.5±1.7 vs 3.7±1.3, p=0.033) and fatigue (4.5±1.4 vs 3.5±1.3, p=0.028) improved significantly in the IG. The STST at 6 months was not significant. Sleep duration and sleep efficiency showed no significant differences between the two groups at any time. CONCLUSIONS: A comprehensive program by using the Kaia app following PR maintained PA and improved symptoms in patients with COPD at 6 months. The app might be an important accessory tool for enhanced COPD care. TRIAL REGISTRATION NUMBER: DRKS00017275.

Tumoricidal, Temozolomide- and Radiation-Sensitizing Effects of KCa3.1 K+ Channel Targeting In Vitro Are Dependent on Glioma Cell Line and Stem Cell Fraction.

Reportedly, the intermediate-conductance Ca2+-activated potassium channel KCa3.1 contributes to the invasion of glioma cells into healthy brain tissue and resistance to temozolomide and ionizing radiation. Therefore, KCa3.1 has been proposed as a potential target in glioma therapy. The aim of the present study was to assess the variability of the temozolomide- and radiation-sensitizing effects conferred by the KCa3.1 blocking agent TRAM-34 between five different glioma cell lines grown as differentiated bulk tumor cells or under glioma stem cell-enriching conditions. As a result, cultures grown under stem cell-enriching conditions exhibited indeed higher abundances of mRNAs encoding for stem cell markers compared to differentiated bulk tumor cultures. In addition, stem cell enrichment was paralleled by an increased resistance to ionizing radiation in three out of the five glioma cell lines tested. Finally, TRAM-34 led to inconsistent results regarding its tumoricidal but also temozolomide- and radiation-sensitizing effects, which were dependent on both cell line and culture condition. In conclusion, these findings underscore the importance of testing new drug interventions in multiple cell lines and different culture conditions to partially mimic the in vivo inter- and intra-tumor heterogeneity.

Comment on Chen et al. Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin. Biomolecules 2021, 11, 1373.

In the study of Chen et al. [...].

Patient-individual phenotypes of glioblastoma stem cells are conserved in culture and associate with radioresistance, brain infiltration and patient prognosis.

Identification of prognostic or predictive molecular markers in glioblastoma resection specimens may lead to strategies for therapy stratification and personalized treatment planning. Here, we analyzed in primary glioblastoma stem cell (pGSC) cultures the mRNA abundances of seven stem cell (MSI1, Notch1, nestin, Sox2, Oct4, FABP7 and ALDH1A3), and three radioresistance or invasion markers (CXCR4, IKCa and BKCa ). From these abundances, an mRNA signature was deduced which describes the mesenchymal-to-proneural expression profile of an individual GSC culture. To assess its functional significance, we associated the GSC mRNA signature with the clonogenic survival after irradiation with 4 Gy and the fibrin matrix invasion of the GSC cells. In addition, we compared the molecular pGSC mRNA signature with the tumor recurrence pattern and the overall survival of the glioblastoma patients from whom the pGSC cultures were derived. As a result, the molecular pGSC mRNA signature correlated positively with the pGSC radioresistance and matrix invasion capability in vitro. Moreover, patients with a mesenchymal (>median) mRNA signature in their pGSC cultures exhibited predominantly a multifocal tumor recurrence and a significantly (univariate log rank test) shorter overall survival than patients with proneural (≤median mRNA signature) pGSCs. The tumors of the latter recurred predominately unifocally. We conclude that our pGSC cultures induce/select those cell subpopulations of the heterogeneous brain tumor that determine disease progression and therapy outcome. In addition, we further postulate a clinically relevant prognostic/predictive value for the 10 mRNAs-based mesenchymal-to-proneural signature of the GSC subpopulations in glioblastoma.

Ion Transport and Radioresistance.

Neoplastic transformation is associated with alterations of the ion transports across plasma and intracellular membranes. These alterations are crucial elements of the phenotypical reprogramming of the transformed cells and may promote adaptation to hypoxia, malignant progression, tumor spreading and metastasis, as well as therapy resistance. The present review article focuses on ion transport processes in tumor cells that are induced by ionizing radiation and that contribute to radioresistance and therapy failure. In particular, this article introduces radiogenic ion transports across plasma and mitochondrial membranes and discusses their functional significance for cell cycle control, DNA repair, accelerated repopulation, cell migration and metastasis, metabolic reprogramming, adaptation to hypoxia, and radiogenic formation of reactive oxygen species.

Subunits of BK channels promote breast cancer development and modulate responses to endocrine treatment in preclinical models.

BACKGROUND AND PURPOSE: Pore-forming α subunits of the voltage- and Ca2+ -activated K+ channel with large conductance (BKα) promote malignant phenotypes of breast tumour cells. Auxiliary subunits such as the leucine-rich repeat containing 26 (LRRC26) protein, also termed BKγ1, may be required to permit activation of BK currents at a depolarized resting membrane potential that frequently occur in non-excitable tumour cells. EXPERIMENTAL APPROACH: Anti-tumour effects of BKα loss were investigated in breast tumour-bearing MMTV-PyMT transgenic BKα knockout (KO) mice, primary MMTV-PyMT cell cultures, and in a syngeneic transplantation model of breast cancer derived from these cells. The therapeutic relevance of BK channels in the context of endocrine treatment was assessed in human breast cancer cell lines expressing either low (MCF-7) or high (MDA-MB-453) levels of BKα and BKγ1, as well as in BKα-negative MDA-MB-157. KEY RESULTS: BKα promoted breast cancer onset and overall survival in preclinical models. Conversely, lack of BKα and/or knockdown of BKγ1 attenuated proliferation of murine and human breast cancer cells in vitro. At low concentrations, tamoxifen and its major active metabolites stimulated proliferation of BKα/γ1-positive breast cancer cells, independent of the genomic signalling controlled by the oestrogen receptor. Finally, tamoxifen increased the relative survival time of BKα KO but not of wild-type tumour cell recipient mice. CONCLUSION AND IMPLICATIONS: Breast cancer initiation, progression, and tamoxifen sensitivity depend on functional BK channels thereby providing a rationale for the future exploration of the oncogenic actions of BK channels in clinical outcomes with anti-oestrogen therapy. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

Using Postmarket Surveillance to Assess Safety-Related Events in a Digital Rehabilitation App (Kaia App): Observational Study.

BACKGROUND: Low back pain (LBP) affects nearly 4 out of 5 individuals during their lifetime and is the leading cause of disability globally. Digital therapeutics are emerging as effective treatment options for individuals experiencing LBP. Despite the growth of evidence demonstrating the benefits of these therapeutics in reducing LBP and improving functional outcomes, little data has been systematically collected on their safety profiles. OBJECTIVE: This study aims to evaluate the safety profile of a multidisciplinary digital therapeutic for LBP, the Kaia App, by performing a comprehensive assessment of reported adverse events (AEs) by users as captured by a standardized process for postmarket surveillance. METHODS: All users of a multidisciplinary digital app that includes physiotherapy, mindfulness techniques, and education for LBP (Kaia App) from 2018 to 2019 were included. Relevant messages sent by users via the app were collected according to a standard operating procedure regulating postmarket surveillance of the device. These messages were then analyzed to determine if they described an adverse event (AE). Messages describing an AE were then categorized based on the type of AE, its seriousness, and its relatedness to the app, and they were described by numerical counts. User demographics, including age and gender, and data on app use were collected and evaluated to determine if they were risk factors for increased AE reporting. RESULTS: Of the 138,337 active users of the Kaia App, 125 (0.09%) reported at least one AE. Users reported 0.00014 AEs per active day on the app. The most common nonserious AE reported was increased pain. Other nonserious AEs reported included muscle issues, unpleasant sensations, headache, dizziness, and sleep disturbances. One serious AE, a surgery, was reported. Details of the event and its connection to the intervention were not obtainable, as the user did not provide more information when asked to do so; therefore, it was considered to be possibly related to the intervention. There was no relationship between gender and AE reporting (P>.99). Users aged 25 to 34 years had reduced odds (odds ratio [OR] 0.31, 95% CI 0.08-0.95; P=.03) of reporting AEs, while users aged 55 to 65 years (OR 2.53, 95% CI 1.36-4.84, P=.002) and ≥75 years (OR 4.36, 95% CI 1.07-13.26; P=.02) had increased odds. AEs were most frequently reported by users who had 0 to 99 active days on the app, and less frequently reported by users with more active days on the app. CONCLUSIONS: This study on the Kaia App provides the first comprehensive assessment of reported AEs associated with real-world use of digital therapeutics for lower back pain. The overall rate of reported AEs was very low, but significant reporting bias is likely to be present. The AEs reported were generally consistent with those described for in-person therapies for LBP.

Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study.

Mesenchymal glioblastoma stem cells (GSCs), a subpopulation in glioblastoma that are responsible for therapy resistance and tumor spreading in the brain, reportedly upregulate aldehyde dehydrogenase isoform-1A3 (ALDH1A3) which can be inhibited by disulfiram (DSF), an FDA-approved drug formerly prescribed in alcohol use disorder. Reportedly, DSF in combination with Cu2+ ions exerts multiple tumoricidal, chemo- and radio-therapy-sensitizing effects in several tumor entities. The present study aimed to quantify these DSF effects in glioblastoma stem cells in vitro, regarding dependence on ALDH1A3 expression. To this end, two patient-derived GSC cultures with differing ALDH1A3 expression were pretreated (in the presence of CuSO4, 100 nM) with DSF (0 or 100 nM) and the DNA-alkylating agent temozolomide (0 or 30 µM) and then cells were irradiated with a single dose of 0-8 Gy. As read-outs, cell cycle distribution and clonogenic survival were determined by flow cytometry and limited dilution assay, respectively. As a result, DSF modulated cell cycle distribution in both GSC cultures and dramatically decreased clonogenic survival independently of ALDH1A3 expression. This effect was additive to the impairment of clonogenic survival by radiation, but not associated with radiosensitization. Of note, cotreatment with temozolomide blunted the DSF inhibition of clonogenic survival. In conclusion, DSF targets GSCs independent of ALDH1A3 expression, suggesting a therapeutic efficacy also in glioblastomas with low mesenchymal GSC populations. As temozolomide somehow antagonized the DSF effects, strategies for future combination of DSF with the adjuvant standard therapy (fractionated radiotherapy and concomitant temozolomide chemotherapy followed by temozolomide maintenance therapy) are not supported by the present study.

App-Based Feedback for Rehabilitation Exercise Correction in Patients With Knee or Hip Osteoarthritis: Prospective Cohort Study.

BACKGROUND: The use of digital therapeutic solutions for rehabilitation of conditions such as osteoarthritis provides scalable access to rehabilitation. Few validated technological solutions exist to ensure supervision of users while they exercise at home. Motion Coach (Kaia Health GmbH) provides audiovisual feedback on exercise execution in real time on conventional smartphones. OBJECTIVE: We hypothesized that the interrater agreement between physiotherapists and Motion Coach would be noninferior to physiotherapists' interrater agreement for exercise evaluations in a cohort with osteoarthritis. METHODS: Patients diagnosed with osteoarthritis of the knee or hip were recruited at a university hospital to perform a set of 6 exercises. Agreement between Motion Coach and 2 physiotherapists' corrections for segments of the exercises were compared using Cohen κ and percent agreement. RESULTS: Participants (n=24) were enrolled and evaluated. There were no significant differences between interrater agreements (Motion Coach app vs physiotherapists: percent agreement 0.828; physiotherapist 1 vs physiotherapist 2: percent agreement 0.833; P<.001). Age (70 years or under, older than 70 years), gender (male, female), or BMI (30 kg/m2 or under, greater than 30 kg/m2) subgroup analysis revealed no detectable difference in interrater agreement. There was no detectable difference in levels of interrater agreement between Motion Coach vs physiotherapists and between physiotherapists in any of the 6 exercises. CONCLUSIONS: The results demonstrated that Motion Coach is noninferior to physiotherapist evaluations. Interrater agreement did not differ between 2 physiotherapists or between physiotherapists and the Motion Coach app. This finding was valid for all investigated exercises and subgroups. These results confirm the ability of Motion Coach to detect user form during exercise and provide valid feedback to users with musculoskeletal disorders.

ANXA7 Regulates Platelet Lipid Metabolism and Ca2+ Release in Arterial Thrombosis.

[Figure: see text].

Potassium Channels in Cancer.

Neoplastic transformation is reportedly associated with alterations of the potassium transport across plasma and intracellular membranes. These alterations have been identified as crucial elements of the tumourigenic reprogramming of cells. Potassium channels may contribute to cancer initiation, malignant progression and therapy resistance of tumour cells. The book chapter focusses on (oncogenic) potassium channels frequently upregulated in different tumour entities, upstream and downstream signalling of these channels, their contribution to the maintenance of cancer stemness and the formation of an immunosuppressive tumour microenvironment. In addition, their role in adaptation to tumour hypoxia, metabolic reprogramming, as well as tumour spreading and metastasis is discussed. Finally, we discuss how (oncogenic) potassium channels may confer treatment resistance of tumours against radiation and chemotherapy and thus might be harnessed for new therapy strategies, for instance, by repurposing approved drugs known to target potassium channels.

γH2AX foci assay in glioblastoma: Surgical specimen versus corresponding stem cell culture.

AIM: To assess radiation response using γH2AX assay in surgical specimens from glioblastoma (GB) patients and their corresponding primary gliosphere culture. To test the hypothesis that gliospheres (stem cell enriched) are more resistant than specimens (bulky cell dominated) but that the interpatient heterogeneity is similar. MATERIAL AND METHODS: Ten pairs of specimens and corresponding gliospheres derived from patients with IDH-wildtype GB were studied. Specimens and gliospheres were irradiated with graded doses and after 24 h the number of residual γH2AX foci was counted. RESULTS: Gliospheres showed a higher Nestin expression than specimens and exhibited two different phenotypes: free floating (n = 7) and attached (n = 3). Slope analysis revealed an interpatient heterogeneity with values between 0.15 and 1.30 residual γH2AX foci/Gy. Free-floating spheres were more resistant than their parental specimens (median slope 0.13 foci/Gy versus 0.53) as well as than the attached spheres (2.14). The slopes of free floating spheres did not correlate with their corresponding specimens while a trend for a positive correlation was found for the attached spheres and the respective specimens. Association with MGMT did not reach statistical significance. CONCLUSION: Consistent with the clinical phenotype and our previous experiments, GB specimens show low radiation sensitivity. Stem-cell enriched free-floating gliospheres were more resistant than specimens supporting the concept of radioresistance in stem cell-like cells. The lack of correlation between specimens and their respective gliosphere cultures needs validation and may have a profound impact on future translational studies using γH2AX as a potential biomarker for personalized radiation therapy.

[Meta-Review on findings about teaching and learning in distance education during the Corona pandemic-evidence from Germany, Austria and Switzerland]. / Was wissen wir über schulische Lehr-Lern-Prozesse im Distanzunterricht während der Corona-Pandemie? ­ Evidenz aus Deutschland, Österreich und der Schweiz.

The review provides a systematic overview of the state of quantitative research on teaching and learning characteristics during school closures due to corona. The review comprises 97 online surveys conducted between 24th of March 2020 and 11th of November 2020 and covering 255,955 cases (students, parents, teachers, school leaders etc.). The analysis and synthesis of the findings was carried out along two models, the phase model of the research process and the "integrative model on distance education". The review makes clear that central aspects of teaching and learning during corona-based school closures in Spring 2020, such as distance learning characteristics (e.g. quality dimensions), student characteristics (e.g. self-sufficiency) and characteristics of home resources for learning (e.g. parental support) have already been the object of many surveys. The school situation during the corona pandemic is therefore no longer an unexplored phenomenon. Rather, the scientific ethos of researchers in this field demands that the current state of research needs to be considered in their work. The review presented here is intended to facilitate this task by not only listing the existing surveys, but also synthesizing their central findings. In addition, the review provides a relevant information basis for decisions and action in politics, administration and school practice. At the same time, the review warns against an unreflected adoption of the findings by critically discussing the scientific quality of the surveys.

Attitudes and Expectations of Health Care Professionals Toward App-Based Therapy in Patients with Osteoarthritis of the Hip or Knee: Questionnaire Study.

BACKGROUND: The use of mobile health (mHealth) apps is becoming increasingly widespread. However, little is known about the attitudes, expectations, and basic acceptance of health care professionals toward such treatment options. As physical activity and behavior modification are crucial in osteoarthritis management, app-based therapy could be particularly useful for the self-management of this condition. OBJECTIVE: The objective of the study was to determine the expectations and attitudes of medical professionals toward app-based therapy for osteoarthritis of the hip or knee. METHODS: Health care professionals attending a rehabilitation congress and employees of a university hospital were asked to fill out a questionnaire consisting of 16 items. A total of 240 questionnaires were distributed. RESULTS: A total of 127 participants completed the questionnaire. At 95.3% (121/127), the approval rate for app-based therapy for patients with osteoarthritis of the hip or knee was very high. Regarding possible concerns, aspects related to data protection and privacy were primarily mentioned (41/127, 32.3%). Regarding potential content, educational units, physiotherapeutic exercise modules, and practices based on motivation psychology were all met with broad approval. CONCLUSIONS: The study showed a high acceptance of app-based therapy for osteoarthritis, indicating a huge potential of this form of treatment to be applied, prescribed, and recommended by medical professionals. It was widely accepted that the content should reflect a multimodal therapy approach.