Stromal Signals Dominate Gene Expression Signature Scores That Aim to Describe Cancer Cell-intrinsic Stemness or Mesenchymality Characteristics.

Unlabelled: Epithelial-to-mesenchymal transition (EMT) in cancer cells confers migratory abilities, a crucial aspect in the metastasis of tumors that frequently leads to death. In multiple studies, authors proposed gene expression signatures for EMT, stemness, or mesenchymality of tumors based on bulk tumor expression profiling. However, recent studies suggested that noncancerous cells from the microenvironment or macroenvironment heavily influence such signature profiles.

Immune cell type signature discovery and random forest classification for analysis of single cell gene expression datasets.

Background: Robust immune cell gene expression signatures are central to the analysis of single cell studies. Nearly all known sets of immune cell signatures have been derived by making use of only single gene expression datasets. Utilizing the power of multiple integrated datasets could lead to high-quality immune cell signatures which could be used as superior inputs to machine learning-based cell type classification approaches.

Synthetic lethality prediction in DNA damage repair, chromatin remodeling and the cell cycle using multi-omics data from cell lines and patients.

Discovering synthetic lethal (SL) gene partners of cancer genes is an important step in developing cancer therapies. However, identification of SL interactions is challenging, due to a large number of possible gene pairs, inherent noise and confounding factors in the observed signal. To discover robust SL interactions, we devised SLIDE-VIP, a novel framework combining eight statistical tests, including a new patient data-based test iSurvLRT.

CONET: copy number event tree model of evolutionary tumor history for single-cell data.

Copy number alterations constitute important phenomena in tumor evolution. Whole genome single-cell sequencing gives insight into copy number profiles of individual cells, but is highly noisy. Here, we propose CONET, a probabilistic model for joint inference of the evolutionary tree on copy number events and copy number calling.

RosettaSX: Reliable gene expression signature scoring of cancer models and patients.

Gene expression signatures have proven their potential to characterize important cancer phenomena like oncogenic signaling pathway activities, cellular origins of tumors, or immune cell infiltration into tumor tissues. Large collections of expression signatures provide the basis for their application to data sets, but the applicability of each signature in a new experimental context must be reassessed. We apply a methodology that utilizes the previously developed concept of coherent expression of genes in signatures to identify translatable signatures before scoring their activity in single tumors.

Interpretable deep recommender system model for prediction of kinase inhibitor efficacy across cancer cell lines.

Computational models for drug sensitivity prediction have the potential to significantly improve personalized cancer medicine. Drug sensitivity assays, combined with profiling of cancer cell lines and drugs become increasingly available for training such models. Multiple methods were proposed for predicting drug sensitivity from cancer cell line features, some in a multi-task fashion.

Feature selection strategies for drug sensitivity prediction.

Drug sensitivity prediction constitutes one of the main challenges in personalized medicine. Critically, the sensitivity of cancer cells to treatment depends on an unknown subset of a large number of biological features. Here, we compare standard, data-driven feature selection approaches to feature selection driven by prior knowledge of drug targets, target pathways, and gene expression signatures.

Genetic Interactions and Tissue Specificity Modulate the Association of Mutations with Drug Response.

In oncology, biomarkers are widely used to predict subgroups of patients that respond to a given drug. Although clinical decisions often rely on single gene biomarkers, machine learning approaches tend to generate complex multi-gene biomarkers that are hard to interpret. Models predicting drug response based on multiple altered genes often assume that the effects of single alterations are independent.

Association of EGFR expression level and cetuximab activity in patient-derived xenograft models of human non-small cell lung cancer.

Purpose: To explore in a panel of patient-derived xenograft models of human non-small cell lung cancer (NSCLC) whether high EGFR expression, was associated with cetuximab activity.

Experimental Design: NSCLC patient-derived xenograft models (n=45) were implanted subcutaneously into panels of nude mice and randomization cohorts were treated with either cetuximab, cisplatin, cisplatin plus cetuximab, vehicle control, or else were left untreated. Responses according to treatment were assessed at week 3 by analyzing the relative change in tumor volume and an experimental analogue of the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.

An interferon response gene expression signature is activated in a subset of medulloblastomas.

Recent evidence suggests that cytomegalovirus infection contributes to the development of medulloblastomas. Differential activation of antiviral expression programs in medulloblastomas has not been investigated yet. In this study, we assess the relevance of an antiviral transcriptional response in medulloblastomas.

Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload.

We investigated sex differences and the role of estrogen receptor-beta (ERbeta) on myocardial hypertrophy in a mouse model of pressure overload. We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ERbeta knockout (ERbeta(-/-)) mice. All mice were characterized by echocardiography and hemodynamic measurements and were killed 9 wk after surgery.

An expression module of WIPF1-coexpressed genes identifies patients with favorable prognosis in three tumor types.

Wiskott-Aldrich syndrome (WAS) predisposes patients to leukemia and lymphoma. WAS is caused by mutations in the protein WASP which impair its interaction with the WIPF1 protein. Here, we aim to identify a module of WIPF1-coexpressed genes and to assess its use as a prognostic signature for colorectal cancer, glioma, and breast cancer patients.

Genome-wide expression patterns of invasion front, inner tumor mass and surrounding normal epithelium of colorectal tumors.

Colorectal tumors have characteristic genome-wide expression patterns that allow their distinction from normal colon epithelia and facilitate clinical prognosis. The expression heterogeneity within a primary colorectal tumor has not been studied on a genome scale yet. Here we investigated three compartments of colorectal tumors, the invasion front, the inner tumor mass, and surrounding normal epithelial tissue by microdissection and microarray-based expression profiling.

About the interrelation of evolutionary rate and protein age.

Evolutionary rate and gene age are interrelated when the age of a gene is assessed by the taxonomic distribution in the gene family. This is because homology detection by sequence comparison is depending on sequence similarity. We estimate family specific rates of protein evolution for orthologous families with representatives from man, fugu, fly, and worm.

The highly conserved LepA is a ribosomal elongation factor that back-translocates the ribosome.

The ribosomal elongation cycle describes a series of reactions prolonging the nascent polypeptide chain by one amino acid and driven by two universal elongation factors termed EF-Tu and EF-G in bacteria. Here we demonstrate that the extremely conserved LepA protein, present in all bacteria and mitochondria, is a third elongation factor required for accurate and efficient protein synthesis. LepA has the unique function of back-translocating posttranslocational ribosomes, and the results suggest that it recognizes ribosomes after a defective translocation reaction and induces a back-translocation, thus giving EF-G a second chance to translocate the tRNAs correctly.

An inventory of yeast proteins associated with nucleolar and ribosomal components.

Background: Although baker's yeast is a primary model organism for research on eukaryotic ribosome assembly and nucleoli, the list of its proteins that are functionally associated with nucleoli or ribosomes is still incomplete. We trained a naïve Bayesian classifier to predict novel proteins that are associated with yeast nucleoli or ribosomes based on parts lists of nucleoli in model organisms and large-scale protein interaction data sets. Phylogenetic profiling and gene expression analysis were carried out to shed light on evolutionary and regulatory aspects of nucleoli and ribosome assembly.

A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer.

Background: Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression.

Results: We investigated genome-wide gene expression in colorectal carcinoma (CRC) and normal epithelial tissues from 25 patients using oligonucleotide arrays.

Horizontal gene transfer in aminoacyl-tRNA synthetases including leucine-specific subtypes.

Aminoacyl-tRNA synthetases catalyze a fundamental reaction for the flow of genetic information from RNA to protein. Their presence in all organisms known today highlights their important role in the early evolution of life. We investigated the evolutionary history of aminoacyl-tRNA synthetases on the basis of sequence data from more than 200 Archaea, Bacteria, and Eukaryota.

Transcriptional census of 36 microdissected colorectal cancers yields a gene signature to distinguish UICC II and III.

UICC stage II and III colorectal cancers (CRC) differ fundamentally in prognosis and therapeutic concepts. To analyze differential gene expression between both stages and to establish a relationship between molecular background and clinical presentation, tumor material from 36 unselected consecutive patients presenting with sporadic CRC, 18 UICC stage II and 18 UICC stage III, were laser microdissected to separate epithelial tumor cells. Gene expression levels were measured using U133A Affymetrix gene arrays.

Nonribosomal peptide synthesis in Schizosaccharomyces pombe and the architectures of ferrichrome-type siderophore synthetases in fungi.

A nonribosomal peptide synthetase (NRPS) in Schizosaccharomyces pombe, which possesses an unusual structure incorporating three adenylation domains, six thiolation domains and six condensation domains, has been shown to produce the cyclohexapeptide siderophore ferrichrome. One of the adenylation domains is truncated and contains a distorted key motif. Substrate-binding specificities of the remaining two domains were assigned by molecular modelling to glycine and to N-acetyl-N-hydroxy-L-ornithine.

Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.

Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b (BMPR1B) and the BMP antagonist NOGGIN, respectively. We expressed the mutant proteins in limb bud micromass culture and treated ATDC5 and C2C12 cells with recombinant GDF5.

Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer.

Background: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines.

Methods: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells.

The human LAPTM4b transcript is upregulated in various types of solid tumours and seems to play a dual functional role during tumour progression.

LAPTM4b (lysosome associated protein transmembrane 4 beta) was recently identified as a gene overexpressed in human hepatocellular carcinoma and belongs to the mammalian LAPTM family. By analysing genome-wide expression profiles of microdissected solid tumour samples by the means of Affymetrix GenChip hybridisation, we found LAPTM4b to be upregulated in 88% (23/26) of lung and in 67% (18/27) of colon carcinoma patients. Northern blots revealed additionally an overexpression of LAPTM4b in the majority of carcinomas of the uterus (30/44), breast (27/53) and ovary (11/16).

The SYSTERS Protein Family Database in 2005.

The SYSTERS project aims to provide a meaningful partitioning of the whole protein sequence space by a fully automatic procedure. A refined two-step algorithm assigns each protein to a family and a superfamily. The sequence data underlying SYSTERS release 4 now comprise several protein sequence databases derived from completely sequenced genomes (ENSEMBL, TAIR, SGD and GeneDB), in addition to the comprehensive Swiss-Prot/TrEMBL databases.

Insights into the evolution of the nucleolus by an analysis of its protein domain repertoire.

Recently, the first investigation of nucleoli using mass spectrometry led to the identification of 271 proteins. This represents a rich resource for a comprehensive investigation of nucleolus evolution. We applied a protocol for the identification of known and novel conserved protein domains of the nucleolus, resulting in the identification of 115 known and 91 novel domain profiles.