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We previously reported that DIRAS-3 is frequently inactivated in oligodendrogliomas due to promoter hypermethylation and loss of the chromosomal arm 1p. DIRAS-3 inactivation was associated with better overall survival. Consequently, we now investigated regulation and function of its family members DIRAS-1 and DIRAS-2. We found that DIRAS-1 was strongly downregulated in 65% and DIRAS-2 in 100% of analyzed glioma samples compared to non-neoplastic brain tissue (NNB). Moreover, a significant down-regulation of DIRAS-1 and -2 was detected in glioma data obtained from the TCGA database. Mutational analyses did not reveal any inactivating mutations in the DIRAS-1 and -2 coding regions. Analysis of the DIRAS-1 and -2 promoter methylation status showed significantly higher methylation in IDH-mutant astrocytic and IDH-mutant and 1p/19q-codeleted oligodendroglial tumors compared to NNB. Treatment of U251MG and Hs683 glioblastoma cells lines with 5-azacytidine led to significant re-expression of DIRAS-1 and -2. For IDH-wild-type primary gliomas, however, we did not observe significantly elevated DIRAS-1 and -2 promoter methylation levels, but still detected strong downregulation of both DIRAS family members. Additional analyses revealed that DIRAS-1 and -2 expression was also regulated by histone modifications. We observed a shift towards promoter heterochromatinization for DIRAS-1 and less promoter euchromatinization for DIRAS-2 in IDH-wild-type glioblastomas compared to controls. Treatment of the two glioblastoma cell lines with a histone deacetylase inhibitor led to significant re-expression of DIRAS-1 and -2. Functionally, overexpression of DIRAS-1 and -2 in glioblastoma cells translated into significantly higher sensitivity to lomustine treatment. Analyses of DNA damage markers revealed that DIRAS-1 and -2 may play a role in p53-dependent response to alkylating chemotherapy.

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If being weighed impacts perceptions of eating behavior, it is important that the order of questionnaires and weighing be considered in research and practice. A quasi-experimental study was performed to examine whether being weighed immediately prior to completing a questionnaire affects responses to eating behavior questions. It was hypothesized that being weighed would serve as a priming stimulus and increase measures of dietary restraint, disinhibition, and hunger. Trained researchers collected a sample of volunteers (n = 355) in 8 locations in the United States on two Saturdays in the summer of 2011. Half of the participants were weighed immediately prior to completing the Three Factor Eating Questionnaire (TFEQ), with the remaining half weighed immediately after TFEQ completion. A priori hypotheses were not supported despite replicating known relationships between weight, dietary restraint and disinhibition. Results indicated that being weighed first produced a difference in differences on disinhibition scores between low restraint score (95% CI = 4.65–6.02) and high restraint score (95% CI = 6.11–7.57) compared to being weighed after questionnaire completion (p = 0.003). However, this relationship was not significant when modeling restraint as a continuous variable, questioning the use of dichotomization. Being weighed is unlikely to be a strong enough prime to significantly change scores on eating behavior questionnaires for everyone, but may allow differences in restraint status to become more evident. Researchers assessing dietary restraint should be wary of the possibility of producing different results when treating restraint as continuous or dichotomous, which could lead to different interpretations.

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