TASK DEFINITION: In this task, you are given an abstract of article. Your task is to generate title for this article. Preferred titles are under thirty words.
PROBLEM: Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

SOLUTION: A quantitative analysis of kinase inhibitor selectivity

PROBLEM: Maintenance and accurate propagation of the genetic material are key features for physiological development and wellbeing. The replication licensing machinery is crucial for replication precision as it ensures that replication takes place once per cell cycle. Thus, the expression status of the components comprising the replication licensing apparatus is tightly regulated to avoid re-replication; a form of replication stress that leads to genomic instability, a hallmark of cancer. In the present review we discuss the mechanistic basis of replication licensing deregulation, which leads to systemic effects, exemplified by its role in carcinogenesis and a variety of genetic syndromes. In addition, new insights demonstrate that above a particular threshold, the replication licensing factor Cdc6 acts as global transcriptional regulator, outlining new lines of exploration. The role of the putative replication licensing factor ChlR1/DDX11, mutated in the Warsaw Breakage Syndrome, in cancer is also considered. Finally, future perspectives focused on the potential therapeutic advantage by targeting replication licensing factors, and particularly Cdc6, are discussed.

SOLUTION: Exploring and exploiting the systemic effects of deregulated replication licensing.

PROBLEM: Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid- (A) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of A42 compared to A40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of A isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS A42 to A40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble A42 relative to A40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of A42 into plaques, leading to reduced recovery of A42 in cerebrospinal fluid (CSF). Reversible exchange of A42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that A42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble A42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in A42 concentrations in the CSF.

SOLUTION:
Increased in vivo amyloid-42 production, exchange, and loss in presenilin mutation carriers.