Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients

FGFR3, HRAS, KRAS, NRAS and PIK3CA Mutations in Bladder Cancer and Their Potential as Biomarkers for Surveillance and Therapy

Background: Fifty percent of patients with muscle-invasive bladder cancer (MI-BC) die from their disease and current chemotherapy treatment only marginally increases survival. Novel therapies targeting receptor tyrosine kinases or activated oncogenes may improve outcome. Hence, it is necessary to stratify patients based on mutations in relevant oncogenes. Patients with non-muscle-invasive bladder cancer (NMI-BC) have excellent survival, however two-thirds develop recurrences. Tumor specific mutations can be used to detect recurrences in urine assays, presenting a more patient-friendly diagnostic procedure than cystoscopy. Methodology/Principal Findings: To address these issues, we developed a mutation assay for the simultaneous detection of 19 possible mutations in the HRAS, KRAS, and NRAS genes. With this assay and mutation assays for the FGFR3 and PIK3CA oncogenes, we screened primary bladder tumors of 257 patients and 184 recurrences from 54 patients. Additionally, in primary tumors p53 expression was obtained by immunohistochemistry. Of primary tumors 64% were mutant for FGFR3, 11% for RAS, 24% for PIK3CA, and 26% for p53. FGFR3 mutations were mutually exclusive with RAS mutations (p = 0.001) and co-occurred with PIK3CA mutations (p = 0.016). P53 overexpression was mutually exclusive with PIK3CA and FGFR3 mutations (p≤0.029). Mutations in the RAS and PIK3CA genes were not predictors for recurrence-free, progression-free and disease-specific survival. In patients presenting with NMI-BC grade 3 and MI-BC, 33 and 36% of the primary tumors were mutant. In patients with low-grade NMI-BC, 88% of the primary tumors carried a mutation and 88% of the recurrences were mutant. Conclusions/Significance: The mutation assays present a companion diagnostic to define patients for targeted therapies. In addition, the assays are a potential biomarker to detect recurrences during surveillance. We showed that 88% of patients presenting with low-grade NMI-BC are eligible for such a follow-up. This may contribute to a reduction in the number of cystoscopical examinations

PI3Kinase signaling in glioblastoma

Glioblastoma (GBM) is the most common primary tumor of the CNS in the adult. It is characterized by exponential growth and diffuse invasiveness. Among many different genetic alterations in GBM, e.g., mutations of PTEN, EGFR, p16/p19 and p53 and their impact on aberrant signaling have been thoroughly characterized. A major barrier to develop a common therapeutic strategy is founded on the fact that each tumor has its individual genetic fingerprint. Nonetheless, the PI3K pathway may represent a common therapeutic target to most GBM due to its central position in the signaling cascade affecting proliferation, apoptosis and migration. The read-out of blocking PI3K alone or in combination with other cancer pathways should mainly focus, besides the cytostatic effect, on cell death induction since sublethal damage may induce selection of more malignant clones. Targeting more than one pathway instead of a single agent approach may be more promising to kill GBM cells

PeRsOnalised nutriTion for hEalthy livINg: The PROTEIN project

Personalised nutrition is a novel public health strategy aiming to promote positive diet and lifestyle changes. Tailored dietary and physical activity advice may be more appropriate than a generalised ‘one‐size‐fits‐all’ approach as it is more biologically relevant to the individual. Information and computing technology, smartphones and mobile applications have become an integral part of modern life and thereby present the opportunity for novel methods to encourage individuals to lead a healthier lifestyle. This article introduces the European Union‐funded PROTEIN project (PeRsOnalised nutriTion for hEalthy livINg) consortium and introduces the associated work packages. The primary objective of the PROTEIN project is to produce a novel adaptable mobile application suite based on sound nutrition and physical activity advice from experts in their field, accessible to all population groups, with differing health outcomes, whose behaviour can be tracked with a variety of sensors and health hazard perception. The mobile application ‘ecosystem’ that will be developed by the consortium includes a platform, mobile suite, cloud services, artificial intelligence advisor, game suite, modelling of expert’s knowledge, users’ behaviour data collection, data analysis and a dashboard for healthcare professionals. It is proposed that users will find the provision of personalised nutrition advice and real‐time data capture through a smartphone application useful, and importantly, will be encouraged by this to make positive health behaviour changes

NFU-Enabled FASTA: moving bioinformatics applications onto wide area networks

<p>Abstract</p> <p>Background</p> <p>Advances in Internet technologies have allowed life science researchers to reach beyond the lab-centric research paradigm to create distributed collaborations. Of the existing technologies that support distributed collaborations, there are currently none that simultaneously support data storage and computation as a shared network resource, enabling computational burden to be wholly removed from participating clients. Software using computation-enable logistical networking components of the Internet Backplane Protocol provides a suitable means to accomplish these tasks. Here, we demonstrate software that enables this approach by distributing both the FASTA algorithm and appropriate data sets within the framework of a wide area network.</p> <p>Results</p> <p>For large datasets, computation-enabled logistical networks provide a significant reduction in FASTA algorithm running time over local and non-distributed logistical networking frameworks. We also find that genome-scale sizes of the stored data are easily adaptable to logistical networks.</p> <p>Conclusion</p> <p>Network function unit-enabled Internet Backplane Protocol effectively distributes FASTA algorithm computation over large data sets stored within the scaleable network. In situations where computation is subject to parallel solution over very large data sets, this approach provides a means to allow distributed collaborators access to a shared storage resource capable of storing the large volumes of data equated with modern life science. In addition, it provides a computation framework that removes the burden of computation from the client and places it within the network.</p