Since its first publication in 2003, the Gene Set Enrichment Analysis (GSEA) method, based on the Kolmogorov-Smirnov statistic, has been heavily used, modified, and also questioned. Recently a simplified approach, using a one-sample t-test score to assess enrichment and ignoring gene-gene correlations was proposed by Irizarry et al. 2009 as a serious contender. The argument criticizes GSEA’s nonparametric nature and its use of an empirical null distribution as unnecessary and hard to compute. We refute these claims by careful consideration of the assumptions of the simplified method and its results, including a comparison with GSEA’s on a large benchmark set of 50 datasets. Our results provide strong empirical evidence that gene-gene correlations cannot be ignored due to the significant variance inflation they produced on the enrichment scores and should be taken into account when estimating gene set enrichment significance. In addition, we discuss the challenges that the complex correlation structure and multi-modality of gene sets pose more generally for gene set enrichment methods.
Hepatocyte-enriched nuclear factor (HNF)6 and CUX2 are GH and STAT5-regulated homeobox transcription factors. CUX2 shows female-specific expression and contributes to liver sex differences by repressing many male-biased genes and inducing many female-biased genes, whereas HNF6 is expressed at similar levels in male and female liver. In cell-based transfection studies, CUX2 inhibited HNF6 transcriptional regulation of the sex-specific gene promoters CYP2C11 and CYP2C12, blocking HNF6 repression of CYP2C11 and HNF6 activation of CYP2C12. These inhibitory actions of CUX2 can be explained by competition for HNF6 DNA binding, as demonstrated by in vitro EMSA analysis and validated in vivo by global analysis of the HNF6 cistrome. Approximately 40 000 HNF6-binding sites were identified in mouse liver chromatin, including several thousand sites showing significant sex differences in HNF6 binding. These sex-biased HNF6-binding sites showed strong enrichment for correspondingly sex-biased DNase hypersensitive sites and for proximity to genes showing local sex-biased chromatin marks and a corresponding sex-biased expression. Further, approximately 90% of the genome-wide binding sites for CUX2 were also bound by HNF6. These HNF6/CUX2 common binding sites were enriched for genomic regions more accessible in male than in female mouse liver chromatin and showed strongest enrichment for male-biased genes, suggesting CUX2 displacement of HNF6 as a mechanism to explain the observed CUX2 repression of male-biased genes in female liver. HNF6 binding was sex independent at a majority of its binding sites, and HNF6 peaks were frequently associated with cobinding by multiple other liver transcription factors, consistent with HNF6 playing a global regulatory role in both male and female liver.
Girls had a significantly higher rate of DES than boys in all UTI and VUR subgroups in the current data. UTI significantly impacts the DES occurrence in patients with VUR. No statistically significant difference was detected in the DES rate between the unilateral and bilateral VUR groups, and the reflux group as a whole did not seem to have a higher rate of DES in boys or girls.
Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.
Previous characterizations of patients with new renal scars have relied on excretory urography for assessing renal architecture and ignored voiding patterns of the children affected. Using the DMSA scan we identified 31 children with reflux, urinary tract infection and dysfunctional voiding in whom new renal scars developed while they were under our care.
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