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Hyperactivity of the NOTCH pathway is associated with tumor growth and radiotherapy resistance in lung cancer, and NOTCH/γ‐secretase inhibitors (GSIs) are a potential therapeutic target. The therapeutic outcome, however, is often restricted by the dose‐limiting toxicity of combined treatments on the surrounding healthy tissue. The NOTCH signaling pathway is also crucial for homeostasis and repair of the normal airway epithelium. The effects of NOTCH/γ‐secretase inhibition on the irradiation of normal lung epithelium are unknown and may counteract antitumor activity. Here we, therefore, investigated whether normal tissue toxicity to radiation is altered upon NOTCH pathway inhibition. We established air‐liquid interface pseudostratified and polarized cultures from primary human bronchial epithelial cells and blocked NOTCH signaling alone or after irradiation with small‐molecule NOTCH inhibitor/GSI. We found that the reduction in proliferation and viability of bronchial stem cells (TP63+) in response to irradiation is rescued with concomitant NOTCH inhibition. This correlated with reduced activation of the DNA damage response and accelerated repair by 24 hours and 3 days postirradiation. The increase in basal cell proliferation and viability in GSI‐treated and irradiated cultures resulted in an improved epithelial barrier function. Comparable results were obtained after in vivo irradiation, where the combination of NOTCH inhibition and irradiation increased the percentage of stem cells and ciliated cells ex vivo. These encourage further use of normal patient tissue for toxicity screening of combination treatments and disclose novel interactions between NOTCH inhibition and radiotherapy and opportunities for tissue repair after radiotherapy.

The hypoxia-inducible transcription factors (HIF)-1/2α are the main oxygen sensors which regulate the adaptation to intratumoral hypoxia. The aim of this study was to assess the role of the HIF proteins in regulating the radiation response of a non-small cell lung cancer (NSCLC) in vitro model. To directly assess the unique and overlapping functions of HIF-1α and HIF-2α, we use CRISPR gene-editing to generate isogenic H1299 non-small cell lung carcinoma cells lacking HIF-1α, HIF-2α or both. We found that in HIF1 knockout cells, HIF-2α was strongly induced by hypoxia compared to wild type but the reverse was not seen in HIF2 knockout cells. Cells lacking HIF-1α were more radiation resistant than HIF2 knockout and wildtype cells upon hypoxia, which was associated with a reduced recruitment of γH2AX foci directly after irradiation and not due to differences in proliferation. Conversely, double-HIF1/2 knockout cells were most radiation sensitive and had increased γH2AX recruitment and cell cycle delay. Compensatory HIF-2α activity in HIF1 knockout cells is the main cause of this radioprotective effect. Under hypoxia, HIF1 knockout cells uniquely had a strong increase in lactate production and decrease in extracellular pH. Using genetically identical HIF-α isoform-deficient cells we identified a strong radiosensitizing of HIF1, but not of HIF2, which was associated with a reduced extracellular pH and reduced glycolysis.

Background This paper presents the design, development and first evaluation of an algorithm, named Intelligent Therapy Assistant (ITA), which automatically selects, configures and schedules rehabilitation tasks for patients with cognitive impairments after an episode of Acquired Brain Injury. The ITA is integrated in “Guttmann, Neuro Personal Trainer” (GNPT), a cognitive tele-rehabilitation platform that provides neuropsychological services. Methods The ITA selects those tasks that are more suitable for the specific needs of each patient, considering previous experiences, and improving the personalization of the treatment. The system applies data mining techniques to cluster the patients according their cognitive impairment profile. Then, the algorithm rates every rehabilitation task, based on its cognitive structure and the clinical impact of executions done by similar patients. Finally, it configures the most suitable degree of difficulty, depending on the impairment of the patient and his/her evolution during the treatment. Results The ITA has been evaluated during 18 months by 582 patients. In order to evaluate the effectiveness of the ITA, a comparison between the traditional manual planning procedure and the one presented in this paper has been done, taking into account: a) the selected tasks assigned to rehabilitation sessions; b) the difficulty level configured for the sessions; c) and the improvement of their cognitive capacities after completing treatment. Conclusions The obtained results reveal that the rehabilitation treatment proposed by the ITA is as effective as the one performed manually by therapists, arising as a new powerful support tool for therapists. The obtained results make us conclude that the proposal done by the ITA is very close to the one done by therapists, so it is suitable for real treatments.