The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells.

Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent substantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53. Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice. In addition, loss of Cul3 and p53 led to the formation of primary hepatocellular carcinomas. Importantly, loss of Cul3 expression was also detected in a large series of human liver cancers and correlated directly with tumor de-differentiation. The expression of Cul3 during hepatic differentiation therefore safeguards against the formation of progenitor cells that carry a great potential for transformation into tumor-initiating cells.

Improved serological diagnosis stresses the major role of Campylobacter jejuni in triggering Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a postinfectious autoimmune polyradiculoneuropathy. The most frequent antecedent pathogen is Campylobacter jejuni, followed by cytomegalovirus. However, more than 40% of GBS cases currently cannot be attributed to triggering events. This might be due to the shortcomings of the serological assays used for diagnosing infections, in particular for C. jejuni. In our study investigating 36 patients with acute GBS, standard serological methods identified the triggering viral or bacterial etiology in only 25% of cases. However, using a highly specific enzyme-linked immunosorbent assay based on two recombinant outer antigens encoded by C. jejuni genes Cj0017 (P39) and Cj0113 (P18), we found serological evidence of a preceding C. jejuni infection in 80.6% of the patients but in only 3.5% of the controls. We conclude that the role of C. jejuni in triggering GBS has been greatly underestimated.

Improved serodiagnosis of Campylobacter jejuni infections using recombinant antigens.

Campylobacter jejuni is a frequent cause of infectious diarrhoea and is increasingly recognized as a trigger for late-onset complications. The poor standardization of commonly used serological tests might explain the conflicting results regarding the frequency of antecedent C. jejuni infections in defined patient groups. In order to obtain reliable epidemiological data as to the role of C. jejuni in causing late-onset complications, a highly specific and sensitive diagnostic tool for the epidemiological investigation of C. jejuni-associated diseases was developed. It was shown that recombinant proteins encoded by the C. jejuni genes cj0017 (P39) and cj0113 (P18) are specifically recognized by antibodies in sera from patients with C. jejuni enteritis. An ELISA using recombinant P18 and P39 as antigens was 91.9% sensitive and 99.0% specific, with positive and negative predictive values of 97.1% and 97.0%, respectively, comparing favourably with the 27.0% sensitivity of a routinely used serological assay.