Etanercept combined with NB-UVB is more effective than etanercept monotherapy at 6 weeks as demonstrated at a clinical, histological and immunohistological level. However, as there is an increased risk for malignancy by treatment with TNF-α blockers alone or in combination with phototherapy, we recommend to restrict this highly effective combination to short periods of time, for instance to obtain a quicker response, and to avoid long-term treatment.

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BackgroundThe oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion.ResultsWe demonstrate that overactivation of Akt signaling in nonmalignant MCF10A cells and in primary cultures of normal human mammary epithelial tissue results in previously unreported inhibitory effects on EMT, cell motility and stem/progenitor cell expansion. Importantly, this effect is largely redundant and independent of Akt isoform types. However, using a series of isogenic cell lines derived from MCF-10A cells but exhibiting varying stages of progressive tumorigenesis, we observe that this inhibition of neoplastic behavior can be reversed in epithelial cells that have advanced to a highly malignant state. In contrast to the tumor suppressive properties of Akt, activated Akt signaling in MCF10A cells can rescue cell viability upon treatment with cytotoxic agents. This feature is regarded as tumor-promoting.ConclusionWe demonstrate that Akt signaling conveys novel dichotomy effects in which its oncogenic properties contributes mainly to sustaining cell viability, as opposed to the its tumor suppressing effects, which are mediated by repressing EMT, cell motility, and stem/progenitor cell expansion. While the former exerts a tumor-enhancing effect, the latter merely acts as a safeguard by restraining epithelial cells at the primary sites until metastatic spread can be moved forward, a process that is presumably dictated by the permissive tumor microenvironment or additional oncogenic insults.

Objective The study aimed to evaluate the validity of transcutaneous bilirubin (TcB) measurements at three sites in premature infants born at 230/7 to 346/7 weeks' gestational age (GA) compared with total serum bilirubin (TSB) measurements. Study Design A prospective study was conducted at Banner – University Medical Center Phoenix, where informed consent was obtained from the infant's parent or legally authorized representative. Cohort A was comprised of infants 230/7 to 286/7 weeks' GA and Cohort B contained subjects 290/7 to 346/7 weeks' GA. Baseline TSB measurements were collected at approximately 24 hours of life, as the standard of care and the TcB measurements were obtained from the sternum, interscapular, and buttock areas at approximately ± 30 minutes from collection of the TSB. Statistical analysis of measurements including sensitivity, specificity, positive, and negative predictive values, and the area under the receiver operator characteristic curve (AUROC) were performed. Results A total of 166 infants were included in the study population. Cohort A consisted of 41 subjects and Cohort B contained 125 subjects. The results showed that baseline TcB measurements from the interscapular area were the most sensitive and specific with TSB levels >5.0 mg/dL in Cohort A. Baseline TcB measurements from the sternum demonstrated greatest sensitivity and specificity when the TSB level was >8.0 mg/dL in Cohort B. In general, each of the three sites in both cohorts demonstrated excellent AUROCs and negative predictive values. Conclusion The use of a TcB meter in preterm infants can be a reliable noninvasive screening tool for hyperbilirubinemia, and it may be beneficial in decreasing painful stimuli and iatrogenic blood loss when used as an adjunct to TSB monitoring. Key Points

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The inability of early detection of pancreatic tumors is largely due to a lack of biomarkers and a poor understanding of molecular mechanisms conferring carcinogenic dissemination. Recent evidence has indicated that various neoplastic phenotypes are governed by epigenomic alterations (DNA methylation or histone modifications) which confer reversible effects without changing nucleotide sequences themselves. During the past years, we have compared DNA methylation profiles between the parental pancreatic cells FG and its isogenic variant L3.6pl that gained remarkable migratory and invasive properties in culture (33- and 20-fold increase) and in mice (Neoplasia; 1(1); page 50, 1999). DNA methylation profiling was conducted by a method known as MBD-isolated Genome Sequencing which captures methylated DNA via a methyl-CpG binding protein followed by genome-wide DNA sequencing using Illumina sequencer (GAII). Reads were then aligned to a reference human genome browser (HG18) whereby the abundance of read coverage was calculated and indicative of methylation levels occurring at given loci. These methylation profiles were used to generate a list of candidate genes that displayed higher levels of DNA methylation within the L3.6 compared to FG cell lines. We hypothesize that these hypermethylated loci may be correlated to the enhanced invasive properties associated with not only L3.6pl, but also other metastatic pancreatic carcinomas in general. Among these candidates, COL7A1 was of interest. It encodes for a basement membrane protein that is known to be a type VII collagen and is the main component of anchoring fibrils that are involved in cellular processes such as cell adhesion and motility. Silenced expression of COL7A1 by DNA methylation has been shown by two lines of evidence generated from our laboratory. (1) CpG islands situated within COL7A1 promoter displayed prominent promote activity. (2) The induction of methylation by an in vitro method impaired its transcriptional activity. To determine if other epigenetic alterations such as histone modifications led to a similar reduction of COL7A1 expression, a histone deacetylase inhibitor, Trichostatin A, was introduced. It was found that this agent was unable to restore similar expression levels of COL7A1 compared to treatment of de-methylation agent (5-azacytidine). These data suggest that DNA methylation is an important mechanism governing COL7A1 expression We further suggest that this aberration may serve as a general phenomenon, as COL7A1 was concordantly methylated in other metastatic pancreatic cell lines including ASPC-1, Capan-2, and Miacapa-2. Taken together, we hypothesize that promoter methylation leads to a reduced COL7A1 expression followed by an induction of metastasis in pancreatic adenocarcinoma. Thus, COL7A1 promoter could potentially serve as a diagnostic marker and a therapeutic target for impeding metastasis. Citation Format: Huey-Jen L. Lin, Zhengang Peng, Amanda Fisher, Jennifer C. Weber, Ying-Wei Li. Promoter DNA methylation is associated with metastatic properties of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 665. doi:10.1158/1538-7445.AM2013-665

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