A favourable prognostic marker for EGFR mutant non-small cell lung cancer: immunohistochemical analysis of MUC5B

Objectives: To determine the use of the mucin proteins MUC5B and MUC5AC as prognosis markers for non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations. Setting: Patients who underwent surgical resection at Nagasaki University Hospital and related facilities in Japan between June 1996 and March 2013. Participant: 159 Japanese patients (male: n=103; female: n=56) with NSCLC, who underwent surgical resection (EGFR-mutant type: n=78, EGFR wild type: n=81). Results: Patients whose tumours expressed MUC5B had significantly longer overall survival and relapse-free survival compared to the MUC5B-negative patients with EGFR mutant NSCLC (p=0.0098 and p=0.0187, respectively). In patients with EGFR wild-type NSCLC, there was no association with MUC5B expression. MUC5AC expression was not different between EGFR mutant and wild-type NSCLC. Conclusions: Present findings indicate that MUC5B, but not MUC5AC, is a novel prognostic biomarker for patients with NSCLC carrying EGFR mutations but not for patients with NSCLC carrying wild-type EGFR

Use of Activity-Based Probes to Develop High Throughput Screening Assays That Can Be Performed in Complex Cell Extracts

Background: High throughput screening (HTS) is one of the primary tools used to identify novel enzyme inhibitors. However, its applicability is generally restricted to targets that can either be expressed recombinantly or purified in large quantities. Methodology and Principal Findings: Here, we described a method to use activity-based probes (ABPs) to identify substrates that are sufficiently selective to allow HTS in complex biological samples. Because ABPs label their target enzymes through the formation of a permanent covalent bond, we can correlate labeling of target enzymes in a complex mixture with inhibition of turnover of a substrate in that same mixture. Thus, substrate specificity can be determined and substrates with sufficiently high selectivity for HTS can be identified. In this study, we demonstrate this method by using an ABP for dipeptidyl aminopeptidases to identify (Pro-Arg)2-Rhodamine as a specific substrate for DPAP1 in Plasmodium falciparum lysates and Cathepsin C in rat liver extracts. We then used this substrate to develop highly sensitive HTS assays (Z’.0.8) that are suitable for use in screening large collections of small molecules (i.e.300,000) for inhibitors of these proteases. Finally, we demonstrate that it is possible to use broad-spectrum ABPs to identify target-specific substrates. Conclusions: We believe that this approach will have value for many enzymatic systems where access to large amounts o

A review of the predictability and prediction of ENSO

A hierarchy of El Niño-Southern Oscillation (ENSO) prediction schemes has been developed during the Tropical Ocean-Global Atmosphere (TOGA) program which includes statistical schemes and physical models. The statistical models are, in general, based on linear statistical techniques and can be classified into models which use atmospheric (sea level pressure or surface wind) or oceanic (sea surface temperature or a measure of upper ocean heat content) quantities or a combination of oceanic and atmospheric quantities as predictors. The physical models consist of coupled ocean-atmosphere models of varying degrees of complexity, ranging from simplified coupled models of the “shallow water” type to coupled general circulation models. All models, statistical and physical, perform considerably better than the persistence forecast in predicting typical indices of ENSO on lead times of 6 to 12 months. The TOGA program can be regarded as a success from this perspective. However, despite the demonstrated predictability, little is known about ENSO predictability limits and the predictability of phenomena outside the tropical Pacific. Furthermore, the predictability of anomalous features known to be associated with ENSO (e.g., Indian monsoon and Sahel rainfall, southern African drought, and off-equatorial sea surface temperature) needs to be addressed in more detail. As well, the relative importance of different physical mechanisms (in the ocean or atmosphere) has yet to be established. A seasonal dependence in predictability is seen in many models, but the processes responsible for it are not fully understood, and its meaning is still a matter of scientific discussion. Likewise, a marked decadal variation in skill is observed, and the reasons for this are still under investigation. Finally, the different prediction models yield similar skills, although they are initialized quite differently. The reasons for these differences are also unclear

A mechanistic design principle for protein tyrosine kinase sensors: Application to a validated cancer target

A new mechanistic principle for reporting the phosphorylation of tyrosine is described, which should prove applicable to even the most fastidious of protein tyrosine kinases, as demonstrated by the acquisition of a fluorescent sensor for the extraordinarily demanding anaplastic lymphoma kinase