The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities.

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies.

Disease- and sex-specific differences in patients with heart valve disease: a proteome study.

Pressure overload in patients with aortic valve stenosis and volume overload in mitral valve regurgitation trigger specific forms of cardiac remodeling; however, little is known about similarities and differences in myocardial proteome regulation. We performed proteome profiling of 75 human left ventricular myocardial biopsies (aortic stenosis = 41, mitral regurgitation = 17, and controls = 17) using high-resolution tandem mass spectrometry next to clinical and hemodynamic parameter acquisition. In patients of both disease groups, proteins related to ECM and cytoskeleton were more abundant, whereas those related to energy metabolism and proteostasis were less abundant compared with controls.

Serum dihydrotestosterone levels are associated with adverse myocardial remodeling in patients with severe aortic valve stenosis before and after aortic valve replacement.

Animal studies show a pivotal role of dihydrotestosterone (DHT) in pressure overload-induced myocardial hypertrophy and dysfunction. The aim of our study was to evaluate the role of DHT levels and myocardial hypertrophy and myocardial protein expression in patients with severe aortic valve stenosis (AS). Forty-three patients [median age 68 (41-80) yr] with severe AS and indication for surgical aortic valve replacement (SAVR) were prospectively enrolled.

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death.

Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance.

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms.

Comprehensive micro-scaled proteome and phosphoproteome characterization of archived retrospective cancer repositories.

Formalin-fixed paraffin-embedded (FFPE) tissues are a valuable resource for retrospective clinical studies. Here, we evaluate the feasibility of (phospho-)proteomics on FFPE lung tissue regarding protein extraction, quantification, pre-analytics, and sample size. After comparing protein extraction protocols, we use the best-performing protocol for the acquisition of deep (phospho-)proteomes from lung squamous cell and adenocarcinoma with >8,000 quantified proteins and >14,000 phosphosites with a tandem mass tag (TMT) approach.

Drug repurposing for aging research using model organisms.

Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible.

Two forms of death in ageing Caenorhabditis elegans.

Ageing generates senescent pathologies, some of which cause death. Interventions that delay or prevent lethal pathologies will extend lifespan. Here we identify life-limiting pathologies in Caenorhabditis elegans with a necropsy analysis of worms that have died of old age.

SurvCurv database and online survival analysis platform update.

Unlabelled: Understanding the biology of ageing is an important and complex challenge. Survival experiments are one of the primary approaches for measuring changes in ageing. Here, we present a major update to SurvCurv, a database and online resource for survival data in animals.

Longevity GWAS Using the Drosophila Genetic Reference Panel.

We used 197 Drosophila melanogaster Genetic Reference Panel (DGRP) lines to perform a genome-wide association analysis for virgin female lifespan, using ~2M common single nucleotide polymorphisms (SNPs). We found considerable genetic variation in lifespan in the DGRP, with a broad-sense heritability of 0.413.

MDL-1, a growth- and tumor-suppressor, slows aging and prevents germline hyperplasia and hypertrophy in C. elegans.

In C. elegans, increased lifespan in daf-2 insulin/IGF-1 receptor mutants is accompanied by up-regulation of the MDL-1 Mad basic helix-loop-helix leucine zipper transcription factor. Here we describe the role of mdl-1 in C.

Unlocking the potential of survival data for model organisms through a new database and online analysis platform: SurvCurv.

Lifespan measurements, also called survival records, are a key phenotype in research on aging. If external hazards are excluded, aging alone determines the mortality in a population of model organisms. Understanding the biology of aging is highly desirable because of the benefits for the wide range of aging-related diseases.

Analysing variation in Drosophila aging across independent experimental studies: a meta-analysis of survival data.

Survival records of longevity experiments are a key component in research on aging. However, surprisingly there have been very few cross-study analyses, besides comparisons of median lifespans or similar summary information. Here, we use a large set of full survival data from various studies to address questions in aging, which are beyond the scope of individual studies.

Transcriptional feedback in the insulin signalling pathway modulates ageing in both Caenorhabditis elegans and Drosophila melanogaster.

Several components have been previously identified, that modulate longevity in several species, including the target of rapamycin (TOR) and the Insulin/IGF-1 (IIS) signalling pathways. In order to infer paths and transcriptional feedback loops that are likely to modulate ageing, we manually built a comprehensive and computationally efficient signalling network model of the IIS and TOR pathways in worms. The core insulin transduction is signalling from the sole insulin receptor daf-2 to ultimately inhibit the translocation of the transcription factor daf-16 into the nucleus.

Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway.

POPISK: T-cell reactivity prediction using support vector machines and string kernels.

Background: Accurate prediction of peptide immunogenicity and characterization of relation between peptide sequences and peptide immunogenicity will be greatly helpful for vaccine designs and understanding of the immune system. In contrast to the prediction of antigen processing and presentation pathway, the prediction of subsequent T-cell reactivity is a much harder topic. Previous studies of identifying T-cell receptor (TCR) recognition positions were based on small-scale analyses using only a few peptides and concluded different recognition positions such as positions 4, 6 and 8 of peptides with length 9.

Computational biology for ageing.

High-throughput genomic and proteomic technologies have generated a wealth of publicly available data on ageing. Easy access to these data, and their computational analysis, is of great importance in order to pinpoint the causes and effects of ageing. Here, we provide a description of the existing databases and computational tools on ageing that are available for researchers.