Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradia- tion (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell inva- sion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic

Bayesian Estimators for Robins-Ritov's Problem

Bayesian or likelihood-based approaches to data analysis became very popular in the field of Machine Learning. However, there exist theoretical results which question the general applicability of such approaches; among those a result by Robins and Ritov which introduce a specific example for which they prove that a likelihood-based estimator will fail (i.e. it does for certain cases not converge to a true parameter estimate, even given infinite data). In this paper we consider various approaches to formulate likelihood-based estimators in this example, basically by considering various extensions of the presumed generative model of the data. We can derive estimators which are very similar to the classical Horvitz-Thompson and which also account for a priori knowledge of an observation probability function

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Social Support and Psychological Distress in Cancer: Stress as a Mediator

Cancer affects nearly 15 million Americans, and is the second leading cause of death in the U.S. Persons with cancer, including those in recovery, are at increased risk for mental health difficulties; 15% - 25% experience clinically significant depressive symptoms and approximately 12% meet criteria for an anxiety disorder. Poor mental health may be due to heightened levels of stress related to the illness experience, such as uncertainty about the course of disease or adapting to functional impairments (e.g., cleaning, walking) and illness symptoms (e.g., pain). Lack of predictability regarding symptoms and physical limitations may lead to negative mood states, such as fear, worry, or sadness. However, not all persons living with or recovering from cancer, experience psychological distress, perhaps due to individual-level factors, such as social support. An available network of persons (e.g., friends, family) who can provide emotional (e.g., empathy), instrumental (e.g., health advice), or tangible (e.g., assistance with chores) support may lower levels of perceived stress and, in turn, may reduce the likelihood of experiencing psychological distress. Based on this, we examined the linkage between social support and symptoms of psychopathology, and the mediating role of perceived stress. At the bivariate level, we hypothesized that social support would be negatively related to stress and symptoms of depression and anxiety, and that stress would be positively related to both depressive and anxiety symptoms. At the multivariate level, we hypothesized that stress would mediate the relations between social support and symptoms of anxiety and depression, such that higher levels of social support would be associated with lower levels of perceived stress and, in turn, to fewer symptoms of depression and anxiety. Our sample of persons living with, or in remission from, cancer (N = 236) was primarily White (91.5%; n = 216) and female (64.4%; n = 152). Participants completed self-report measures including the Modified Social Support Survey, Perceived Stress Scale, and Multidimensional Health Profile – Psychosocial Functioning. Bivariate correlations and multivariate analyses, per Hayes (2013), were conducted covarying age, sex, and ethnicity. In bivariate correlations, all variables were significantly related to one another in the hypothesized directions (p \u3c .01). In serial mediation analyses, the total effect of social support on depressive symptoms was significant (t = -5.22, p \u3c .001), and the direct effect was nonsignificant when stress was added to the model (t = -1.72, p = .09), indicating mediation. In the second model, stress also mediated the relation between social support and anxiety symptoms; the total effect was significant (t = -4.56, p \u3c .001), and the direct effect was nonsignificant (t = -1.73, p = .09). Supporting hypotheses, our results suggest that to the extent one has available social support, illness-related stress may be lessened and, in turn, cancer-affected persons may experience fewer symptoms of depression and anxiety. Therapeutic interventions focused on enhancing one’s social support network (e.g., cancer support groups) or lowering perceived stress (e.g., Mindfulness Based Stress Reduction) may reduce experiences of psychological distress among persons living with, or in remission from, cancer

Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradia- tion (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell inva- sion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic

Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradia- tion (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell inva- sion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic