In the early 1980s, the oncogene field was in transition. The biological properties of more than 20 oncogenes had been described in animal tumor models and cell transformation assays. Attention was shifting to the question of how these genes actually function. In a few cases, it was obvious. The v-Sis protein (encoded by the transforming gene of simian sarcoma virus) was shown to be related to ...

Researchers in decision analysis and artificial intelligence (AI) have used Bayesian belief networks to build probabilistic expert systems. Using standard methods drawn from the theory of computational complexity, workers in the field have shown that the problem of probabilistic inference in belief networks is difficult and almost certainly intractable. We have developed a randomized approximat...

Models of spatially distributed populations and/or communities are still a matter of challenge for the students working in population biology, ecology, environmental sciences and mathematical modelling. An adequate model pattern to describe, model and predict the impact of spatial structure on a community dynamics, as well as the migration processes themselves, is a key problem here. Adequate m...

Adaptation in signaling systems, during which the output returns to a fixed baseline after a change in the input, often involves negative feedback loops and plays a crucial role in eukaryotic chemotaxis. We determined the dynamical response to a uniform change in chemoattractant concentration of a eukaryotic chemotaxis pathway immediately downstream from G protein-coupled receptors. The respons...

cAMP plays a major role in cystogenesis. Recent in vitro studies suggested that cAMP stimulates B-Raf/ERK activation and proliferation of cyst-derived cells in a Ca(2+) inhibitable, Ras-dependent manner. OPC-31260, a vasopressin V2 receptor (VPV2) antagonist, was shown to lower renal cAMP and inhibit renal disease development and progression in models orthologous to human cystic diseases. Here ...

K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation in murine models is sufficient to recapitulate the spectrum of lesions seen in human pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that Notch receptor signaling becomes reactivated in a subset of PDACs, leading to the hypothesis that Notch1 functions as an oncogene in this setting. To determine...

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately,...

Pancreatic ductal adenocarcinoma is believed to arise from precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). Mouse models have demonstrated that targeted expression of activated K-ras to mature acinar cells in the pancreas induces the spontaneous development of PanIN lesions; implying acinar-to-ductal metaplasia (ADM) is a key event in this process. Recent studies suggest N...

Ras-targeted therapy represents a 'holy grail' in oncology. Based on our model prediction, Spiclomazine freezing the intermediate conformation of activated Ras is central to cancer therapeutics. We show here that Spiclomazine leads to an effective suppression in Ras-mediated signaling through abrogating the KRas-GTP level in the KRas-driven pancreatic cancer. The Ras-mediated signaling inhibiti...

PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we s...