The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer

The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy

Autistic adults and adults with sub-clinical autistic traits differ from non-autistic adults in social-pragmatic inferencing and narrative discourse

Abstract Since prior research has mostly focused on children, less is known about how autistic adults and adults with sub-clinical autistic traits interpret pragmatically complex social situations and the kind of narrative discourse they produce. 32 autistic young adults, 18 young adults with sub-clinical autistic traits and 34 non-autistic young adults participated this study. They were shown videos of social interactions which required complex pragmatic processing and were asked to freely narrate what they thought was occurring in each video. Their narratives were coded for aspects of social-pragmatic and narrative discourse. The results indicate that the autistic and sub-clinical groups differed from the comparison group in what they inferred as relevant video content. The narratives of the autistic group also differed from the comparison group in meaning, focus and emphasis on details. In addition, the comparison group produced more holistic narratives whereas the autistic and sub-clinical groups produced more atomistic narratives. Correlational findings indicated that perceptual reasoning has stronger associations with pragmatic inferencing in the autistic and sub-clinical groups than in the comparison group. This study suggests that autistic adults and adults with sub-clinical autistic traits differ from non-autistic adults in what they perceive to be relevant in their social world

Association of accelerometer-measured physical activity and midlife income:a Northern Finland Birth Cohort 1966 Study

Abstract This study investigated the association between physical activity (PA) and midlife income. The population-based data comprised employed members of the Northern Finland Birth Cohort 1966 (N = 2797). Using binned scatterplots and polynomial regressions, we evaluated the association between accelerometer-measured moderate PA (MPA), vigorous PA (VPA), and moderate-to-vigorous PA (MVPA) at 46 years old and register-based income at 50 years old. The models were adjusted for sex, marital status, number of children, education, adolescent PA, occupational physical strenuousness, and time preference. We found MPA (p < 0.001), VPA (p < 0.05), and MVPA (p < 0.001) to associate curvilinearly with income. In subgroup analyses, a curvilinear association was found between MPA (p < 0.01) and MVPA (p < 0.01) among those with physically strenuous work, VPA among all females (p < 0.01) and females with physically light work (p < 0.01), and MPA and MVPA among all males and males with physically strenuous work (p < 0.05; p < 0.01; p < 0.05; p < 0.05, respectively) and income. The highest income benefits occurred at PA volumes higher than current PA guidelines. Linear associations between PA and income were found among females for MPA (p < 0.05) and MVPA (p < 0.05), among those with physically light work for MPA (p < 0.05), VPA (p < 0.05), and MVPA (p < 0.05), and among females with physically strenuous work for VPA (p < 0.05). We conclude that PA up to the current recommended level is associated with income, but MPA exceeding 505.4 min/week, VPA exceeding 216.4 min/week, and MVPA exceeding 555.0 min/week might have a negative association with income

Non-linguistic comprehension, social inference and empathizing skills in autistic young adults, young adults with autistic traits and control young adults:group differences and interrelatedness of skills

Abstract Background: Despite increasing knowledge of social communication skills of autistic peole, the interrelatedness of different skills such as non-linguistic comprehension, social inference and empathizing skills is not much known about. A better understanding of the complex interplay between different domains of social communication helps us to develop assessment protocols for individuals with social communication difficulties. Aims: To compare the performances of autistic young adults, young adults with autistic traits identified in childhood and control young adults in social communication tasks measuring non-linguistic comprehension, social inference and empathizing skills. In addition, to examine associations between the different social communication measures. Methods & Procedures: Autistic young adults (n = 34), young adults with autistic traits (n = 19) and control young adults (n = 36) completed the extra- and paralinguistic scales of the Assessment Battery for Communication (ABaCo), the Faux Pas Recognition Test, Social–Pragmatic Questions (SoPra) and the Empathy Quotient (EQ). Outcomes & Results: Group differences were found in the performance in the ABaCo, SoPra and EQ scores. Compared with the control young adults, autistic young adults scored lower. The performance of the young adults in the autistic traits group fell in between the other two groups. There were no group differences in the Faux Pas Recognition Test. The variability within the groups was large in all measurements. In the control group, there was a significant correlation between EQ and SoPra scores and between the Faux Pas and SoPra scores. In the autistic group, a significant correlation was found between Faux Pas and SoPra scores. Also, other patterns were observed but these were not statistically significant. Conclusions & Implications: The young adults with autistic traits fell in between the control and autistic young adults, highlighting the presence of the continuum in the terms of features of social communication. The results support other current research that suggests that theory of mind and other social communication skills may not be universally or widely impaired in all autistic individuals without cognitive deficits. Although all tasks examined social communication skills, only a small number of significant correlations were found between test scores. This highlights that clinical conclusions about a person’s social communication should be based on the outcomes of different types of methods measuring different aspects of social communication. It is clear that the interrelatedness of different social communication skills needs further research. What This Paper Adds What is already known on this subject: For successful communication, the ability to infer others’ emotions, intentions and mental states is crucial. Autistic people have difficulty with many aspects of social communication. However, the associations between different aspects of social communication need to be better understood. What this paper adds to existing knowledge: The unique contribution of this study is to compare the performance of autistic people not only with that of a control group but also with people with childhood autistic traits. This provides an understanding of the interrelatedness of different social communication skills in people with varying degrees of autistic traits. This study used four assessment methods focusing on three different social communication elements (non-linguistic comprehension, social inference and empathizing skills). These elements have complex relationships to one another, some being closely overlapping, some more distally related and some reflect more complex multifactorial elements. This study shows that although groups differ from each other in most of the assessments, the performance of different groups overlapped showing that many autistic young adults can perform well in non-linguistic and social inference tasks in structured assessment contexts. What are the potential or actual clinical implications of this work? Our findings suggest that in the assessment of social communication, self-reports and clinical assessments can be used effectively together. They can complement each other, pointing out the strengths and weaknesses of a person, leading to more personalized therapeutic interventions

Nrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma

Accumulating evidence suggests that constitutively active Nrf2 has a pivotal role in cancer as it induces pro-survival genes that promote cancer cell proliferation and chemoresistance. The mechanisms of Nrf2 dysregulation and functions in cancer have not been fully characterized. Here, we jointly analyzed the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Atlas (TCGA) multi-omics data in order to identify cancer types where Nrf2 activation is present. We found that Nrf2 is hyperactivated in a subset of glioblastoma (GBM) patients, whose tumors display a mesenchymal subtype, and uncover several different mechanisms contributing to increased Nrf2 activity. Importantly, we identified a positive feedback loop between SQSTM1/p62 and Nrf2 as a mechanism for activation of the Nrf2 pathway. We also show that autophagy and serine/threonine signaling regulates p62 mediated Keap1 degradation. Our results in glioma cell lines indicate that both Nrf2 and p62 promote proliferation, invasion and mesenchymal transition. Finally, Nrf2 activity was associated with decreased progression free survival in TCGA GBM patient samples, suggesting that treatments have limited efficacy if this transcription factor is overactivated. Overall, our findings place Nrf2 and p62 as the key components of the mesenchymal subtype network, with implications to tumorigenesis and treatment resistance. Thus, Nrf2 activation could be used as a surrogate prognostic marker in mesenchymal subtype GBMs. Furthermore, strategies aiming at either inhibiting Nrf2 or exploiting Nrf2 hyperactivity for targeted gene therapy may provide novel treatment options for this subset of GBM