Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients

Background Cancer driver genes are usually ranked by mutation frequency, which does not necessarily reflect their driver strength. We hypothesize that driver strength is higher for genes preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer. Methods We propose formulas for the Driver Strength Index (DSI) and the Normalized Driver Strength Index (NDSI), the latter independent of gene mutation frequency. We validate them using TCGA PanCanAtlas datasets, established driver prediction algorithms and custom computational pipelines integrating SNA, CNA and aneuploidy driver contributions at the patient-level resolution. Results DSI and especially NDSI provide substantially different gene rankings compared to the frequency approach. E.g., NDSI prioritized members of specific protein families, including G proteins GNAQ, GNA11 and GNAS, isocitrate dehydrogenases IDH1 and IDH2, and fibroblast growth factor receptors FGFR2 and FGFR3. KEGG analysis shows that top NDSI-ranked genes comprise EGFR/FGFR2/GNAQ/GNA11–NRAS/HRAS/KRAS–BRAF pathway, AKT1–MTOR pathway, and TCEB1–VHL–HIF1A pathway. Conclusion Our indices are able to select for driver gene attributes not selected by frequency sorting, potentially for driver strength. Genes and pathways prioritized are likely the strongest contributors to cancer initiation and progression and should become future therapeutic targets

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

ABSTRACT Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine

A citation-based, author- and age-normalized, logarithmic index for evaluation of individual researchers independently of publication counts [version 1; referees: 2 approved]

The use of citation metrics for evaluation of individual researchers has dramatically increased over the last decade. However, currently existing indices either are based on misleading premises or are cumbersome to implement. This leads to poor assessment of researchers and creates dangerous trends in science, such as overproduction of low quality articles. Here we propose an index (namely, the L-index) that does not depend on the number of publications, accounts for different co-author contributions and age of publications, and scales from 0.0 to 9.9. Moreover, it can be calculated with the help of freely available software

TCR-triggered extracellular superoxide production is not required for T-cell activation.

In the last decade, reactive oxygen species (ROS) production has been shown to occur upon T-cell receptor (TCR) stimulation and to affect TCR-mediated signalling. However, the exact reactive species that are produced, how ROS are generated and their requirement for T-cell activation, proliferation or cytokine production remain unclear, especially in the case of primary human T cells. Moreover, several groups have questioned that ROS are produced upon TCR stimulation