Biochemical pathways represented by Gene Ontology-Causal Activity Models identify distinct phenotypes resulting from mutations in pathways.

Gene inactivation can affect the process(es) in which that gene acts and causally downstream ones, yielding diverse mutant phenotypes. Identifying the genetic pathways resulting in a given phenotype helps us understand how individual genes interact in a functional network. Computable representations of biological pathways include detailed process descriptions in the Reactome Knowledgebase and causal activity flows between molecular functions in Gene Ontology-Causal Activity Models (GO-CAMs).

Biochemical Pathways Represented by Gene Ontology Causal Activity Models Identify Distinct Phenotypes Resulting from Mutations in Pathways.

Gene inactivation can affect the process(es) in which that gene acts and causally downstream ones, yielding diverse mutant phenotypes. Identifying the genetic pathways resulting in a given phenotype helps us understand how individual genes interact in a functional network. Computable representations of biological pathways include detailed process descriptions in the Reactome Knowledgebase, and causal activity flows between molecular functions in Gene Ontology-Causal Activity Models (GO-CAMs).

The Gene Ontology knowledgebase in 2023.

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms.

Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non-small cell lung cancer.

Objective: Innate and acquired resistance is the principle factor limiting the efficacy of tyrosine kinase inhibitors in lung cancer. We have observed a dramatic upregulation of the cell surface co-receptor neuropilin-2b in lung cancers clinically treated with tyrosine kinase inhibitors correlating with acquired resistance. We hypothesize that neuropilin-2b plays a functional role in acquired tyrosine kinase inhibitor resistance.

Annotation of gene product function from high-throughput studies using the Gene Ontology.

High-throughput studies constitute an essential and valued source of information for researchers. However, high-throughput experimental workflows are often complex, with multiple data sets that may contain large numbers of false positives. The representation of high-throughput data in the Gene Ontology (GO) therefore presents a challenging annotation problem, when the overarching goal of GO curation is to provide the most precise view of a gene's role in biology.

Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources.

Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies.

Cabozantinib, a New Standard of Care for Patients With Advanced Renal Cell Carcinoma and Bone Metastases? Subgroup Analysis of the METEOR Trial.

Purpose Cabozantinib, an inhibitor of tyrosine kinases including MET, vascular endothelial growth factor receptors, and AXL, increased progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with advanced renal cell carcinoma (RCC) after previous vascular endothelial growth factor receptor-targeted therapy in the phase III METEOR trial. Because bone metastases are associated with increased morbidity in patients with RCC, bone-related outcomes were analyzed in METEOR. Patients and Methods Six hundred fifty-eight patients were randomly assigned 1:1 to receive 60 mg cabozantinib or 10 mg everolimus.

A Phase II Multi-Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma.

Lessons Learned: Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development.

Epigenetic Regulation of the Epithelial to Mesenchymal Transition in Lung Cancer.

Lung cancer is the leading cause of cancer deaths worldwide. It is an aggressive and devastating cancer because of metastasis triggered by enhanced migration and invasion, and resistance to cytotoxic chemotherapy. The epithelial to mesenchymal transition (EMT) is a fundamental developmental process that is reactivated in wound healing and a variety of diseases including cancer where it promotes migration/invasion and metastasis, resistance to treatment, and generation and maintenance of cancer stem cells.

Tutorial on Protein Ontology Resources.

The Protein Ontology (PRO) is the reference ontology for proteins in the Open Biomedical Ontologies (OBO) foundry and consists of three sub-ontologies representing protein classes of homologous genes, proteoforms (e.g., splice isoforms, sequence variants, and post-translationally modified forms), and protein complexes.

The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer.

Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non-small cell lung cancer (NSCLC) cell lines, transforming growth factor-β (TGFβ) signaling preferentially increased the abundance of NRP2b.

Erratum: Roche, J. et al. Global Decrease of Histone H3K27 Acetylation in ZEB1-Induced Epithelial to Mesenchymal Transition in Lung Cancer Cells. Cancers, 2013, 5, 334-356.

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Protein Ontology (PRO): enhancing and scaling up the representation of protein entities.

The Protein Ontology (PRO; http://purl.obolibrary.org/obo/pr) formally defines and describes taxon-specific and taxon-neutral protein-related entities in three major areas: proteins related by evolution; proteins produced from a given gene; and protein-containing complexes.

Urothelial carcinoma of donor origin in a kidney transplant patient.

Background: Malignancy after transplantation is an uncommon multifactorial occurrence. Immunosuppression to prevent graft rejection is described as a major risk factor in malignancy development in the post-transplant state. Donor-derived malignancy is a rare reported complication.

A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma.

Background: Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy.

ZEB1 Mediates Acquired Resistance to the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.

Epithelial-mesenchymal transition (EMT) is one mechanism of acquired resistance to inhibitors of the epidermal growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The precise mechanisms of EMT-related acquired resistance to EGFR-TKIs in NSCLC remain unclear. We generated erlotinib-resistant HCC4006 cells (HCC4006ER) by chronic exposure of EGFR-mutant HCC4006 cells to increasing concentrations of erlotinib.

Application of comparative biology in GO functional annotation: the mouse model.

The Gene Ontology (GO) is an important component of modern biological knowledge representation with great utility for computational analysis of genomic and genetic data. The Gene Ontology Consortium (GOC) consists of a large team of contributors including curation teams from most model organism database groups as well as curation teams focused on representation of data relevant to specific human diseases. Key to the generation of consistent and comprehensive annotations is the development and use of shared standards and measures of curation quality.

Nivolumab in renal cell carcinoma.

Introduction: Immune-based therapies (e.g., IL-2, IFN) have been used for some time in advanced clear cell renal cell carcinoma (RCC) with overall modest success.

A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma.

Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).

Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P.

Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations.

Background: Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or rather represent the differentiation stage of the leukemic cell.

Method: To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells. These various stages of myeloid differentiation represent matched counterparts of morphological subgroups of AML.

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial.

Purpose: Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC).

Patients And Methods: Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.

The emerging role of class-3 semaphorins and their neuropilin receptors in oncology.

The semaphorins, discovered over 20 years ago, are a large family of secreted or transmembrane and glycophosphatidylinositol -anchored proteins initially identified as axon guidance molecules crucial for the development of the nervous system. It has now been established that they also play important roles in organ development and function, especially involving the immune, respiratory, and cardiovascular systems, and in pathological disorders, including cancer. During tumor progression, semaphorins can have both pro- and anti-tumor functions, and this has created complexities in our understanding of these systems.

Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation.

It has emerged that palindrome-mediated genomic instability generates DNA-based rearrangements. The presence of palindromic AT-rich repeats (PATRRs) at the translocation breakpoints suggested a palindrome-mediated mechanism in the generation of several recurrent constitutional rearrangements: the t(11;22), t(17;22), and t(8;22). To date, all reported PATRR-mediated translocations include the PATRR on chromosome 22 (PATRR22) as a translocation partner.

DFLAT: functional annotation for human development.

Background: Recent increases in genomic studies of the developing human fetus and neonate have led to a need for widespread characterization of the functional roles of genes at different developmental stages. The Gene Ontology (GO), a valuable and widely-used resource for characterizing gene function, offers perhaps the most suitable functional annotation system for this purpose. However, due in part to the difficulty of studying molecular genetic effects in humans, even the current collection of comprehensive GO annotations for human genes and gene products often lacks adequate developmental context for scientists wishing to study gene function in the human fetus.