“
“Background: Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood

disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological data is available, thus linking targeted therapies to patients most likely to buy IPI-145 respond to treatment.\n\nMethods: We applied a new unsupervised, iterative approach to stratify CRC tumor samples into subtypes based on genome-wide mRNA expression data. By applying this stratification to several CRC cell line panels and integrating pharmacological response data, we generated hypotheses regarding the targeted treatment of different subtypes.\n\nResults: In agreement with earlier studies, the two dominant CRC subtypes are highly correlated with a gene expression signature of epithelial-mesenchymal-transition (EMT). Notably, further dividing these two subtypes using iNMF (iterative Non-negative

Matrix Factorization) revealed five subtypes that exhibit activation of specific signaling pathways, and show significant differences in clinical and molecular characteristics. Importantly, we were able to validate the stratification on independent, published datasets comprising over 1600 samples. NU7441 Application of this stratification to four CRC cell line panels comprising 74 different cell lines, showed that the tumor subtypes are well

represented in available CRC cell line panels. Pharmacological response data for targeted inhibitors of SRC, WNT, GSK3b, aurora kinase, PI3 kinase, and mTOR, showed significant differences ARN-509 in sensitivity across cell lines assigned to different subtypes. Importantly, some of these differences in sensitivity were in concordance with high expression of the targets or activation of the corresponding pathways in primary tumor samples of the same subtype.\n\nConclusions: The stratification presented here is robust, captures important features of CRC, and offers valuable insight into functional differences between CRC subtypes. By matching the identified subtypes to cell line panels that have been pharmacologically characterized, it opens up new possibilities for the development and application of targeted therapies for defined CRC patient sub-populations.”
“A total of 25 patients with gliomatosis cerebri (19 males and 6 females; median age 51 years, range 10-73 years) were diagnosed and treated at the Sheba Medical Center between 1995 and 2009. Of these, 3 patients were 10 years old at the time of diagnosis. Seizures were the initial clinical presentation in 19 patients, focal signs in 16 patients, headaches in 7 patients, cognitive disorder in 4 patients and rapidly progressive hemiparesis in 1 patient.