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The transcriptional coactivator complex Mediator facilitates transcription of nuclear hormone receptors and other transcription factors. We have previously isolated the Mediator complex from primary keratinocytes as the vitamin D receptor interacting protein complex. We identified a role for Mediator in keratinocyte proliferation and differentiation in cultured keratinocytes. Here, we investigated the in vivo role of Mediator by generating conditional null mice, where a critical subunit of the Mediator complex, MED1, is deleted from their keratinocytes. The MED1 ablation resulted in aberrant hair differentiation and cycling leading to hair loss. During the first hair follicle cycle, MED1 deletion resulted in a rapid regression of the hair follicles. Hair differentiation was reduced, and β-catenin/vitamin D receptor (VDR) regulated gene expression was dramatically decreased. In the subsequent adult hair cycle, MED1 ablation activated the initiation of hair follicle cycling. Shh signaling was increased, but terminal differentiation was not sufficient. Deletion of MED1 also caused hyper-proliferation of interfollicular epidermal keratinocytes, and increased the expression of epidermal differentiation markers. These results indicate that MED1 plays a critical role in regulating hair/epidermal proliferation and differentiation.

Objectives:The basis for over-representation of colorectal cancer (CRC) in African-American (AA) populations compared with Caucasians are multifactorial and complex. Understanding the mechanisms for this racial disparity is critical for delivery of better care. Several studies have investigated sporadic CRC for differences in somatic mutations between AAs and Caucasians, but owing to small study sizes and conflicting results to date, no definitive conclusions have been reached.Methods:Here, we present the first systematic literature review and meta-analysis investigating the mutational differences in sporadic CRC between AAs and Caucasians focused on frequent driver mutations (APC,TP53, KRAS,PI3CA, FBXW7,SMAD4, and BRAF). Publication inclusion criteria comprised sporadic CRC, human subjects, English language, information on ethnicity (AA, Caucasian, or both), total subject number >20, and information on mutation frequencies.Results:We identified 6,234 publications. Meta-analysis for APC, TP54, FBXW7, or SMAD4 was not possible owing to paucity of data. KRAS mutations were statistically less frequent in non-Hispanic Whites when compared with AAs (odds ratio, 0.640; 95% confidence interval (CI): 0.5342–0.7666; P=0.0001), while the mutational differences observed in BRAF and PI3CA did not reach statistical significance.Conclusions:Here, we report the mutational patterns for KRAS, BRAF, and PI3CA in sporadic CRC of AAs and Caucasians in a systematic meta-analysis of previously published data. We identified an increase in KRAS mutations in sporadic CRC in AAs, which may contribute to worse prognosis and increased mortality of CRC in AAs. Future studies investigating health-care disparities in CRC in AAs should control for KRAS mutational frequency.

Emphysematous pancreatitis (EP) is a subtype of acute necrotizing pancreatitis (ANP) characterized by the presence of gas in and around the pancreas. While investigators have studied prognostic factors in ANP, less is known about EP. We aimed to determine predictors of mortality and identify changes in management strategies for emphysematous pancreatitis. A PubMed search was performed to identify cases of EP. Data was gathered about patient demographics, clinical findings, laboratory results, radiological studies, procedures, outcomes and mortality. Collected data was analyzed using univariate and multivariate logistic regression analysis. Including a case from our institution, the study cohort included 64 subjects. The overall mortality rate was 32.8% (21/64). On univariate analysis, age (p=.019), hypotension (p=.007), gas outside of the pancreas on CT imaging (p=.003), initial surgical evacuation (p=.007) and the development of multi-organ failure (p=.008) were associated with mortality. On multivariate analysis, only the development of multi-organ failure was found to be an independent predictor of mortality (p=.039). The overall mortality rate of 32.8% for EP is similar to the mortality rates published for ANP. The development of multi-organ failure in EP is strongly associated with increased mortality. Percutaneous and endoscopic approaches have been replacing surgical interventions.