The use of unreliable measures constitutes a threat to our understanding of psychopathology, because advancement of science using both behavioral and biologically-oriented measures can only be certain if such measurements are reliable. Two pillars of NIMH’s portfolio – the Research Domain Criteria (RDoC) initiative for psychopathology and the target engagement initiative in clinical trials – cannot succeed without measures that possess the high reliability necessary for tests involving mediation and selection based on individual differences. We focus on the historical lack of reliability of attentional bias measures as an illustration of how reliability can pose a threat to our understanding. Our own data replicate previous findings of poor reliability for traditionally-used scores, which suggests a serious problem with the ability to test theories regarding attentional bias. This lack of reliability may also suggest problems with the assumption (in both theory and the formula for the scores) that attentional bias is consistent and stable across time. In contrast, measures accounting for attention as a dynamic process in time show good reliability in our data. The field is sorely in need of research reporting findings and reliability for attentional bias scores using multiple methods, including those focusing on dynamic processes over time. We urge researchers to test and report reliability of all measures, considering findings of low reliability not just as a nuisance but as an opportunity to modify and improve upon the underlying theory. Full assessment of reliability of measures will maximize the possibility that RDoC (and psychological science more generally) will succeed.

In this report, we investigated the role and regulation of forkhead box M1 (FOXM1) in breast cancer and epirubicin resistance. We generated epirubicin-resistant MCF-7 breast carcinoma (MCF-7-EPI R ) cells and found FOXM1 protein levels to be higher in MCF-7-EPI R than in MCF-7 cells and that FOXM1 expression is downregulated by epirubicin in MCF-7 but not in MCF-7-EPI R cells. We also established that there is a loss of p53 function in MCF-7-EPI R cells and that epirubicin represses FOXM1 expression at transcription and gene promoter levels through activation of p53 and repression of E2F activity in MCF-7 cells. Using p53 À/À mouse embryo fibroblasts, we showed that p53 is important for epirubicin sensitivity. Moreover, transient promoter transfection assays showed that epirubicin and its cellular effectors p53 and E2F1 modulate FOXM1 transcription through an E2F-binding site located within the proximal promoter region. Chromatin immunoprecipitation analysis also revealed that epirubicin treatment increases pRB (retinoblastoma protein) and decreases E2F1 recruitment to the FOXM1 promoter region containing the E2F site. We also found ataxiatelangiectasia mutated (ATM) protein and mRNA to be overexpressed in the resistant MCF-7-EPI R cells compared with MCF-7 cells and that epirubicin could activate ATM to promote E2F activity and FOXM1 expression. Furthermore, inhibition of ATM in U2OS cells with caffeine or depletion of ATM in MCF-7-EPI R with short interfering RNAs can resensitize these resistant cells to epirubicin, resulting in downregulation of E2F1 and FOXM1 expression and cell death. In summary, our data show that ATM and p53 coordinately regulate FOXM1 via E2F to modulate epirubicin response and resistance in breast cancer.

Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation of ASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell lines. This adaptive transcriptional upregulation is blocked by neoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylated ASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquine accelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in a subset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpG island retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two key genes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate that methylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to arginine deprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for which we have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/ brain barrier.

We identified public eating and drinking as bridge symptoms between EDs and SAD. Future research is needed to test if interventions focused on public eating and drinking might decrease symptoms of both EDs and SAD. Researchers can use this study (code provided) as an exemplar for how to use network analysis, as well as to use network analysis to conceptualize ED comorbidity and compare network structure and density across samples.

The forkhead box transcription factor FOXM1 is an essential effector of G2/M-phase transition, mitosis and the DNA damage response. As such, it is frequently deregulated during tumorigenesis. Here we report that FOXM1 is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites. We show that FOXM1 SUMOylation is enhanced in MCF-7 breast cancer cells in response to treatment with epirubicin and mitotic inhibitors. Mutation of five consensus conjugation motifs yielded a SUMOylation-deficient mutant FOXM1. Conversely, fusion of the E2 ligase Ubc9 to FOXM1 generated an auto-SUMOylating mutant (FOXM1-Ubc9). Analysis of wild-type FOXM1 and mutants revealed that SUMOylation inhibits FOXM1 activity, promotes translocation to the cytoplasm and enhances APC/Cdh1-mediated ubiquitination and degradation. Further, expression of the SUMOylation-deficient mutant enhanced cell proliferation compared with wild-type FOXM1, whereas the FOXM1-Ubc9 fusion protein resulted in persistent cyclin B1 expression and slowed the time from mitotic entry to exit. In summary, our findings suggest that SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response.