Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas.

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR.

Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis.

Background And Aims: Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis.

Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy.

Objective: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined.

Design: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras-driven pancreatic ductal adenocarcinoma.

MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation.

The circadian clock and the cell cycle are major cellular systems that organize global physiology in temporal fashion. It seems conceivable that the potentially conflicting programs are coordinated. We show here that overexpression of MYC in U2OS cells attenuates the clock and conversely promotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation.

Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer.

Background: Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real-time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer.

A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na(+)/H(+) exchanger (NHE1) associates with the EGFR in PDAC.

A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling.

Objective: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity.

Design: We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours.

Metabolism gene signatures and surgical site infections in abdominal surgery.

Introduction: Surgical site infections (SSI) represent a significant cause of morbidity in abdominal surgery. The objective of this study was to determine the gene expression signature in subcutaneous tissues in relation to SSI.

Methods: To determine differences in gene expression, microarray analysis were performed from bulk tissue mRNA of subcutaneous tissues prospectively collected in 92 patients during open abdominal surgery.

Complexity of molecular alterations impacts pancreatic cancer prognosis.

Individualized cancer treatment (e.g. targeted therapy) based on molecular alterations has emerged as an important strategy to improve the current standard-of-care chemotherapy.

An ensemble approach for inferring semi-quantitative regulatory dynamics for the differentiation of mouse embryonic stem cells using prior knowledge.

The process of differentiation of embryonic stem cells (ESCs) is currently becoming the focus of many systems biologists not only due to mechanistic interest but also since it is expected to play an increasingly important role in regenerative medicine, in particular with the advert to induced pluripotent stem cells. These ESCs give rise to the formation of the three germ layers and therefore to the formation of all tissues and organs. Here, we present a computational method for inferring regulatory interactions between the genes involved in ESC differentiation based on time resolved microarray profiles.