Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear β-catenin in cerebral metastasis of lung adenocarcinomas

An essential function of the transcription factors LEF1/TCF4 in cerebral metastases of lung adenocarcinomas has been described in mouse models, suggesting a WNT/β-catenin effect as potential mechanism. Their role in humans is still unclear, thus we analyzed LEF1, TCF4, β-catenin, and early stage prognostic markers in 25 adenocarcinoma brain metastases using immunohistochemistry (IHC). IHC revealed nuclear TCF4 in all adenocarcinoma samples, whereas only 36 % depicted nuclear LEF1 and nuclear β-catenin signals. Samples with nuclear LEF1 as well as high TCF4 (++++) expression were associated with a shorter survival (p = 0.01, HR = 6.68), while nuclear β-catenin had no significant impact on prognosis and did not significantly correlate with nuclear LEF1. High proliferation index Ki67 was associated with shorter survival in late-stage disease (p = 0.03, HR 3.27). Additionally, we generated a LEF1/TCF4 as well as an AXIN2 signature, the latter as representative of WNT/β-catenin activity, following a bioinformatics approach with a gene expression dataset of cerebral metastases in lung adenocarcinoma. To analyze the prognostic relevance in primary lung adenocarcinomas, we applied both signatures to a microarray dataset of 58 primary lung adenocarcinomas. Only the LEF1/TCF4 signature was able to separate clusters with impact on survival (p = 0.01, HR = 0.32). These clusters displayed diverging enrichment patterns of the cell cycle pathway. In conclusion, our data show that LEF1/TCF4, but not β-catenin, have prognostic relevance in primary and cerebrally metastasized human lung adenocarcinomas. In contrast to the previous in vivo findings, these results indicate that LEF1/TCF4 act independently of β-catenin in this setting

A New Highly Conserved Antibiotic Sensing/Resistance Pathway in Firmicutes Involves an ABC Transporter Interplaying with a Signal Transduction System

Signal transduction systems and ABC transporters often contribute jointly to adaptive bacterial responses to environmental changes. In Bacillus subtilis, three such pairs are involved in responses to antibiotics: BceRSAB, YvcPQRS and YxdJKLM. They are characterized by a histidine kinase belonging to the intramembrane sensing kinase family and by a translocator possessing an unusually large extracytoplasmic loop. It was established here using a phylogenomic approach that systems of this kind are specific but widespread in Firmicutes, where they originated. The present phylogenetic analyses brought to light a highly dynamic evolutionary history involving numerous horizontal gene transfers, duplications and lost events, leading to a great variety of Bce-like repertories in members of this bacterial phylum. Based on these phylogenetic analyses, it was proposed to subdivide the Bce-like modules into six well-defined subfamilies. Functional studies were performed on members of subfamily IV comprising BceRSAB from B. subtilis, the expression of which was found to require the signal transduction system as well as the ABC transporter itself. The present results suggest, for the members of this subfamily, the occurrence of interactions between one component of each partner, the kinase and the corresponding translocator. At functional and/or structural levels, bacitracin dependent expression of bceAB and bacitracin resistance processes require the presence of the BceB translocator loop. Some other members of subfamily IV were also found to participate in bacitracin resistance processes. Taken together our study suggests that this regulatory mechanism might constitute an important common antibiotic resistance mechanism in Firmicutes. [Supplemental material is available online at http://www.genome.org.

Manifestation von Lymphomen im HNO-Bereich

Einleitung: Lymphome machen nur eine geringe Anzahl aller malignen Neoplasien mit ca. 5% im Hals-, Nasen- und Ohrenbereich aus. Als extranodale Manifestation von Lymphomen steht der Kopf-Halsbereich an zweiter Stelle hinter dem Gastrointestinaltrakt. Am häufigsten tritt das Non-Hodgkin-Lymphom auf, Hodgkin-Lymphome kommen sehr selten vor.Methoden: Es wurden 3 Fälle von Non-Hodgkin-Lymphomen im Kopf-Halsbereich untersucht. Ein Lymphom des Sinus maxillaris et ethmoidalis, der Trachea und des Nasopharynx.Anamnese, Therapie, Histologie und Ergebnisse der interdisziplinären Tumorkonferenz wurden analysiert und erörtert.Ergebnisse: Anamnese und klinische Beschwerden der Patienten weisen zunächst nicht in allen Fällen auf eine maligne Neoplasie hin. Die histologische Differenzierung benötigt weiterführende immunhistochemische Untersuchungen mit Expressionsmarkern. Die Therapie ist abhängig vom Allgemeinzustand des Patienten. Als adjuvante Therapie wird in Abhängigkeit von B-oder T-Zell Lymphom eine Polychemotherapie und zusätzlich eine Radiatio angewendet.Schlussfolgerung: Obwohl Lymphome im Kopf-Hals-Bereich zu den seltenen Tumorentitäten gehören, sollten diese differentialdiagnostisch immer in Betracht gezogen werden. Die Therapie unterscheidet sich erheblich von anderen Tumoren im HNO Bereich, sie ist nicht primär chirurgisch. In den meisten Fällen ist eine primäre Chemotherapie indiziert, Radiotherapie, Antikörpertherapie, Radioimmuntherapie, Zytokine oder Stammzelltherapie kommen zum Einsatz.Die histopathologische Diagnose erfordert immunhistochemische Zusatzuntersuchungen.Der Erstautor gibt keinen Interessenkonflikt an