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Barrett’s esophagus in gastrointestinal reflux patients constitutes a columnar epithelium with distal characteristics, prone to progress to esophageal adenocarcinoma. HOX genes are known mediators of position-dependent morphology. Here we show HOX collinearity in the adult gut while Barrett’s esophagus shows high HOXA13 expression in stem cells and their progeny. HOXA13 overexpression appears sufficient to explain both the phenotype (through downregulation of the epidermal differentiation complex) and the oncogenic potential of Barrett’s esophagus. Intriguingly, employing a mouse model that contains a reporter coupled to the HOXA13 promotor we identify single HOXA13-positive cells distally from the physiological esophagus, which is mirrored in human physiology, but increased in Barrett’s esophagus. Additionally, we observe that HOXA13 expression confers a competitive advantage to cells. We thus propose that Barrett’s esophagus and associated esophageal adenocarcinoma is the consequence of expansion of this gastro-esophageal HOXA13-expressing compartment following epithelial injury.

Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients and might play a role in the pathogenesis of inflammatory bowel disease (IBD). 6-Thioguanine (6-TG) has been widely used as an immunosuppressive drug for organ recipients and treatment of IBD in the clinic. This study aims to investigate the effects and mode-of-action of 6-TG on rotavirus replication. Human intestinal Caco2 cell line, 3D model of human primary intestinal organoids, laboratory rotavirus strain (SA11) and patient-derived rotavirus isolates were used. We have demonstrated that 6-TG significantly inhibits rotavirus replication in these intestinal epithelium models. Importantly, gene knockdown or knockout of Rac1, the cellular target of 6-TG, significantly inhibited rotavirus replication, indicating the supportive role of Rac1 for rotavirus infection. We have further demonstrated that 6-TG can effectively inhibit the active form of Rac1 (GTP-Rac1), which essentially mediates the anti-rotavirus effect of 6-TG. Consistently, ectopic over-expression of GTP-Rac1 facilitates but an inactive Rac1 (N17) or a specific Rac1 inhibitor (NSC23766) inhibits rotavirus replication. In conclusion, we have identified 6-TG as an effective inhibitor of rotavirus replication via the inhibition of Rac1 activation. Thus, for transplantation patients or IBD patients infected with rotavirus or at risk of rotavirus infection, the choice of 6-TG as a treatment appears rational.

Background and aim: Caspase-cleaved cytokeratin 18 (CK18-Asp396) is a potential clinically useful biomarker in liver disease as it is released from hepatocytes during apoptosis. In this study, we investigated serum CK18-Asp396 levels in chronic hepatitis B (CHB). Patients and methods: Overall, 163 patients with CHB were included. Serum CK18-Asp396 levels were determined by enzyme-linked immunosorbent assay (ELISA), and results were related to steatosis grade, histological activity index, inflammation score, and METAVIR fibrosis grade as well as to viral load, serum levels of liver enzymes, and albumin. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of serum CK18-Asp396 levels for assessing disease activity. Results: A higher level of serum CK 18 concentrations was found in patients with significant inflammation vs no significant inflammation (378.5 [interquartile range {IQR}: 173.2-629.6] vs 137.3 [87.5-197.7], P < 0.05; approximately threefold increase) and in patients with significant fibrosis vs no significant fibrosis (177.8 [IQR: 120.8-519.1] vs 142.7 [IQR: 88.8-214.4], P < 0.05; 1.25-fold increase). There was no differential CK 18 level by degree of steatosis. CK 18 was an independent predictor of significant inflammation with an 82% specificity and a 94% negative predictive value. We found the strongest correlation of CK 18 with alanine aminotransferase and aspartate aminotransferase (both r = 0.52; P < 0.001), but less with albumin (r = -0.24; P < 0.05) and viral load (log) (r = 0.19; P < 0.05). Conclusion: CHB appears to be accompanied by continuous high levels of hepatocyte apoptosis as judged from serum CK 18, suggesting that elimination of the infected compartment constitutes a defensive strategy against disease. Accordingly, CK 18 works as an independent predictor of significant inflammation with a high specificity.

Identification of pancreatic cysts with malignant potential is important to prevent pancreatic cancer development. Integrity of cell free DNA (cfDNA) has been described as tumor biomarker, but its potential for pancreatic cancer is unclear. While normal apoptotic cells release uniformly truncated DNA, malignant tissues release long fragments of cell free DNA (cfDNA). We measured 247 base pair (bp) and 115 bp DNA fragments of ALU repeats by qPCR in serum from healthy controls and pancreatic cancer patients, and in cyst fluid from pancreatic cyst patients. No differences in total cfDNA (ALU115) and cfDNA integrity (ALU247/115) were observed between sera from healthy controls (n=19) and pancreatic cancer patients (n=19). Although elevated as compared to serum, but no differences in cfDNA were found in cyst fluid from high risk (n=10) and low risk (n=20) cyst patients. We conclude that cfDNA integrity is not a useful marker to identify (pre)malignant pancreatic lesions.

Background & Aims Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. Methods We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. Results We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10-11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10-9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10-9). Conclusions We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Space flight strongly moderates human immunity but is in general well tolerated. Elucidation of the mechanisms by which zero gravity interacts with human immunity may provide clues for developing rational avenues to deal with exaggerated immune responses, e.g. as in autoimmune disease. Using two sounding rockets and one manned Soyuz launch, the influence of space flight on immunological signal transduction provoked by lipopolysaccharide (LPS) stimulation was investigated in freshly isolated peripheral blood monocytes and was compared to samples obtained from on-board centrifuge-loaded 1a'...g controls. The effect of microgravity on immunological signal transduction is highly specific, since LPS dependent Jun-N-terminal kinase activation is impaired in the 0a'...g condition, while the corresponding LPS dependent activation of p38 MAP kinase remains unaffected. Thus our results identify Jun-N-terminal kinase as a relevant target in immunity for microgravity and support using Jun-N-terminal kinase specific inhibitors for combating autoimmune disease.