Validation of the WHO Disability Assessment Schedule (WHODAS 2.0) 12-item tool against the 36-item version for measuring functioning and disability associated with pregnancy and history of severe maternal morbidity.

OBJECTIVE: To validate the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) 12-item tool against the 36-item version for measuring functioning and disability associated with pregnancy and the occurrence of maternal morbidity. METHODS: This is a secondary analysis of the Brazilian retrospective cohort study on long-term repercussions of severe maternal morbidity (SMM) among women who delivered at a tertiary facility (COMMAG study). We compared WHODAS-12 and WHODAS-36 scores of women with and without SMM using measures of central tendency and variability, tests for instruments' agreement (Bland-Altman plot), confirmatory factor analysis (CFA), and Cronbach alpha coefficient for internal consistency. RESULTS: The COMMAG study enrolled 638 women up to 5 years postpartum. Although the median WHODAS-36 and -12 scores for all women were statistically different (13.04 and 11.76, respectively; P<0.001), there was a strong linear correlation between them. Furthermore, the mean difference and the differences in variance analyses demonstrated agreement of total scores between the two versions. CFA demonstrated how the WHODAS-12 questions are divided into six previously defined factors and Cronbach alpha showed good internal consistency. CONCLUSION: WHODAS-12 demonstrated agreement with WHODAS-36 for total score and was a good instrument for screening functioning and disability among postpartum women, with and without SMM

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

Non-cell autonomous tumor-growth driving supports sub-clonal heterogeneity

SUMMARY Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumors. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumor phenotypes and the competitive expansion of individual clones. We found that tumor growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumor by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumor collapse. We then developed a mathematical modeling framework to identify the rules underlying the generation of intratumor clonal heterogeneity. We found that non-cell autonomous driving, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits

Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer

Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells

Breaking ground in cross-cultural research on the fear of being laughed at (gelotophobia): A multi-national study involving 73 countries

The current study examines whether the fear of being laughed at (gelotophobia) can be assessed reliably and validly by means of a self-report instrument in different countries of the world. All items of the GELOPH (Ruch and Titze, GELOPH46, University of Düsseldorf, 1998; Ruch and Proyer, Swiss Journal of Psychology 67:19–27, 2008b) were translated to the local language of the collaborator (42 languages in total). In total, 22,610 participants in 93 samples from 73 countries completed the GELOPH. Across all samples the reliability of the 15-item questionnaire was high (mean alpha of .85) and in all samples the scales appeared to be unidimensional. The endorsement rates for the items ranged from 1.31% through 80.00% to a single item. Variations in the mean scores of the items were more strongly related to the culture in a country and not to the language in which the data were collected. This was also supported by a multidimensional scaling analysis with standardized mean scores of the items from the GELOPH15. This analysis identified two dimensions that further helped explaining the data (i.e., insecure vs. intense avoidant-restrictive and low vs. high suspicious tendencies towards the laughter of others). Furthermore, multiple samples derived from one country tended to be (with a few exceptions) highly similar. The study shows that gelotophobia can be assessed reliably by means of a self-report instrument in cross-cultural research. This study enables further studies of the fear of being laughed at with regard to differences in the prevalence and putative causes of gelotophobia in comparisons to different cultures