The purpose of this investigation was to examine whether playing video games affected children's ability to perform certain cognitive functions. Thirty middle school students 10 to 14 years old who ...played video games in their leisure time participated in this controlled study. Restricted measures of math performance, memory, attention and planning, reading rate and comprehension, as well as beta and theta activity in the brain were collected as pre- and post-test measures. Participants were randomly assigned to either the experimental or control group. Participants in the experimental group played video games for one hour, while participants in the control group played card or board games for one hour. Multivariate analysis of variance (MANOVA) procedures were used to analyze pre- and post-test mean differences between groups for all variables. No significant differences were noted. When this sample of middle school aged children engaged in video game play with mildly rated (E for Everyone) recreational video games without blood, gore, and carnage for a limited time (60 minutes), brain wave activity and ability to perform certain academic tasks did not appear to be disrupted. Practical applications of the study are discussed.
Ionizing irradiation is a commonly accepted treatment modality for lung cancer patients. However, the clinical outcome is hampered by normal tissue toxicity and tumor hypoxia. Since tumors often have ...higher levels of active heat shock protein 90 (Hsp90) than normal tissues, targeting of Hsp90 might provide a promising strategy to sensitize tumors towards irradiation. Hsp90 client proteins include oncogenic signaling proteins, cell cycle activators, growth factor receptors and hypoxia inducible factor-1α (HIF-1α). Overexpression of HIF-1α is assumed to promote malignant transformation and tumor progression and thus might reduce the accessibility to radiotherapy.
Herein, we describe the effects of the novel Hsp90 inhibitor NVP-AUY922 and 17-allylamino-17-demethoxygeldanamycin (17-AAG), as a control, on HIF-1α levels and radiosensitivity of lung carcinoma cells under normoxic and hypoxic conditions. NVP-AUY922 exhibited a similar biological activity to that of 17-AAG, but at only 1/10 of the dose. As expected, both inhibitors reduced basal and hypoxia-induced HIF-1α levels in EPLC-272H lung carcinoma cells. However, despite a down-regulation of HIF-1α upon Hsp90 inhibition, sensitivity towards irradiation remained unaltered in EPLC-272H cells under normoxic and hypoxic conditions. In contrast, treatment of H1339 lung carcinoma cells with NVP-AUY922 and 17-AAG resulted in a significant up-regulation of their initially high HIF-1α levels and a concomitant increase in radiosensitivity.
In summary, our data show a HIF-1α-independent radiosensitization of normoxic and hypoxic H1339 lung cancer cells by Hsp90 inhibition.
Abstract
Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas ...and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.
Iodine becomes increasingly popular as alternative propellant for electric propulsion (EP) systems offering several advantages over established xenon. However, iodine is also a reactive and corrosive ...element. Thus, a careful material selection for the EP system itself, but also for components employed on the satellite is required in the light of typical space mission durations of several years. Here, we carefully define an approach for mimicking long-term interaction of material specimens with iodine in a space environment. The space conditions cover typical iodine atmospheres (10
− 1
to 10
− 4
Pa), which occur in the vicinity of a satellite employing an iodine-fed EP system, and exposure times, which correspond to 10 years of mission duration. The approach is used to expose a wide range of metal specimens commonly used on spacecraft to iodine. Chemical modifications of the surfaces of the treated samples are analyzed by x-ray photoelectron spectroscopy (XPS). The elemental metals Fe, Ti, Al, and Nb chemically react with iodine, whereas the elemental metals Ni, Cr, Ta, W, and Mo are basically inert. The stainless-steel and aluminum metal alloys show the same behavior as the corresponding dominant elemental specimens, i.e., Fe and Al, respectively. Somewhat surprisingly, Cr as constituent in stainless steel reacts with iodine, in contrast to elemental Cr. Nevertheless, our studies reveal that long-term exposure to low-pressure iodine atmospheres is not critical for the macroscopic structural integrity of all tested specimens even over space mission durations of several years. The reaction with iodine is macroscopically a surface effect, which mainly affects the optical appearance.
Abstract
Therapy (radiation) resistance can, inter alia, be caused by an increased lactate dehydrogenase (LDH) activity, elevated concentrations of the oncometabolite lactate and an overexpression of ...anti-apoptotic heat shock proteins (HSPs). In this study we aimed to break radioresistance by targeting the cancer metabolism. We could show, for the first time, that the lactate metabolism and heat shock response are co-regulated in two cancer cell systems (murine B16F10 melanoma cells, human LS174T colorectal adenocarcinoma cells). A CRISPR/Cas9 induced double knockout of LDHA/B (LDH−/−) as well as a pharmacological inhibition of LDH by Oxamate or GNE-140 reduces tumor growth, ROS production and synthesis of different HSPs, including Hsp90, Hsp70 and Hsp27. Moreover, the membrane Hsp70 density was significantly reduced on tumor cells after inhibition of the LDH activity as a consequence of a down-regulated lipid metabolism affecting the Hsp70-anchoring, tumor-specific glycosphingolipid Gb3. Our results demonstrate that influencing cancer metabolism increases radiation sensitivity by an impairment of the stress response. Since presently available LDH inhibitors have a low stability and high toxicity in vivo, we are currently investigating more potent LDH inhibitors with a beneficial safety profile. In summary, targeting the lactate metabolism provides a promising strategy to improve radiosensitivity by impairing the stress response.
Citation Format: Melissa Schwab, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Maxim Shevtsov, Masa Zdralevic, Jacques Pouyssegur, Kathrin Renner, Marina Kreutz, Peter Vaupel, Gabriele Multhoff. Down-regulation of cancer metabolism enhances radiosensitivity by impairing the heat shock response abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5426.
Compared to indirect methods, direct parametric image reconstruction (PIR) has the advantage of high quality and low statistical errors. However, it is not yet clear if this improvement in quality is ...beneficial for physiological quantification. This study aimed to evaluate direct PIR for the quantification of tumor hypoxia using the hypoxic fraction (HF) assessed from immunohistological data as a physiological reference. Sixteen mice with xenografted human squamous cell carcinomas were scanned with dynamic 18FFMISO PET. Afterward, tumors were sliced and stained with H&E and the hypoxia marker pimonidazole. The hypoxic signal was segmented using k-means clustering and HF was specified as the ratio of the hypoxic area over the viable tumor area. The parametric Patlak slope images were obtained by indirect voxel-wise modeling on reconstructed images using filtered back projection and ordered-subset expectation maximization (OSEM) and by direct PIR (e.g., parametric-OSEM, POSEM). The mean and maximum Patlak slopes of the tumor area were investigated and compared with HF. POSEM resulted in generally higher correlations between slope and HF among the investigated methods. A strategy for the delineation of the hypoxic tumor volume based on thresholding parametric images at half maximum of the slope is recommended based on the results of this study.
Abstract Background and purpose Evaluate changes in total hypoxia and hypoxia subtypes in vital tumor tissue of human head and neck squamous cell carcinomas (hHNSCC) upon fractionated irradiation. ...Materials and methods Xenograft tumors were generated from 5 hHNSCC cell lines (UT-SCC-15, FaDu, SAS, UT-SCC-5 and UT-SCC-14). Hypoxia subtypes were quantified in cryosections based on (immuno-)fluorescent marker distribution patterns of Hoechst 33342 (perfusion), pimonidazole (hypoxia) and CD31 (endothelium) in m icro c irculatory s upply u nits (MCSUs). Tumors were irradiated with 5 or 10 fractions of 2 Gy, 5×/week. Results Upon irradiation with 10 fractions, the overall fraction of hypoxic MCSUs decreased in UT-SCC-15, FaDu and SAS, remained the same in UT-SCC-5 and increased in UT-SCC-14. Decreases were observed in the proportion of chronically hypoxic MCSUs in UT-SCC-15, in the fraction of acutely hypoxic MCSUs in UT-SCC-15 and SAS, and in the percentage of hypoxemically hypoxic MCSUs in SAS tumors. After irradiation with 5 fractions, there were no significant changes in hypoxia subtypes. Changes in the overall fraction of hypoxic MCSUs were comparable to corresponding alterations in the proportions of acutely hypoxic MCSUs. There was no correlation between radiation resistance (TCD50 ) and any of the investigated hypoxic fractions upon fractionated irradiation. Conclusions This study shows that there are large alterations in the fractions of hypoxia subtypes upon irradiation that can differ from changes in the overall fraction of hypoxic MCSUs.
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