Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease

Effective treatment options for advanced colorectal cancer (CRC) are limited, survival rates are poor and this disease continues to be a leading cause of cancer-related deaths worldwide. Despite being a highly heterogeneous disease, a large subset of individuals with sporadic CRC typically harbor relatively few established ‘driver’ lesions. Here, we describe a collection of genetically engineered mouse models (GEMMs) of sporadic CRC that combine lesions frequently altered in human patients, including well-characterized tumor suppressors and activators of MAPK signaling. Primary tumors from these models were profiled, and individual GEMM tumors segregated into groups based on their genotypes. Unique allelic and genotypic expression signatures were generated from these GEMMs and applied to clinically annotated human CRC patient samples. We provide evidence that a Kras signature derived from these GEMMs is capable of distinguishing human tumors harboring KRAS mutation, and tracks with poor prognosis in two independent human patient cohorts. Furthermore, the analysis of a panel of human CRC cell lines suggests that high expression of the GEMM Kras signature correlates with sensitivity to targeted pathway inhibitors. Together, these findings implicate GEMMs as powerful preclinical tools with the capacity to recapitulate relevant human disease biology, and support the use of genetic signatures generated in these models to facilitate future drug discovery and validation efforts

High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls

Background and Objectives Mucocutaneous bleeding (MCB) is the main expression of inherited disorders of primary hemostasis. However, the relative prevalence of these disorders, their clinical differential diagnosis, and the proportion of patients with MCB of unknown cause (BUC) after an initial comprehensive laboratory testing are unknown.Design and Methods We studied prospectively 280 consecutive patients with MCB and 299 matched controls, using strict inclusion and exclusion criteria. A single physician recorded the clinical data in a bleeding score and estimated the severity of bleeding in clinical categories. Laboratory criteria for the diagnosis of von Willebrand’s disease (VWD) and platelet function defects were established from reference values derived from controls.Results Fifty patients (17.9%) had VWD (type 1VWD=45, type 2=5). Platelet function defects and mild clotting factor deficiencies were found in 65 (23.2%) and 11 (3.9%) patients, respectively. Thirteen (11.5%) patients had combined defects. The remaining 167(59.6%) patients had BUC, with prolonged bleeding time in 18.6% as their only abnormality. All these disorders, including BUC, were clinically undistinguishable. Moreover, no relationship was found between the severity of bleeding and VWF/platelet function variables.Interpretation and Conclusions The diagnostic efficacy of a first laboratory testing in patients with hereditary MCB is 40.4%. Most patients have a disease(s) of high prevalence but unknown pathogenesis. Concurrent bleeding disorders in the same patient are frequent. Our results support the proposal that low plasma VWF levels, but also platelet function defects, should be considered risk factors rather than unequivocal causes of hemorrhages

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes