Cancer research
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Current models for correlating electronic medical records with -omics data largely ignore clinical text, which is an important source of phenotype information for patients with cancer. This data convergence has the potential to reveal new insights about cancer initiation, progression, metastasis, and response to treatment. ⋯ Here, we review the advances of NLP and information extraction methods relevant to oncology based on publications from PubMed as well as NLP and machine learning conference proceedings in the last 3 years. Given the interdisciplinary nature of the fields of oncology and information extraction, this analysis serves as a critical trail marker on the path to higher fidelity oncology phenotypes from real-world data.
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Although accumulation of myeloid-derived suppressor cells (MDSC) is a hallmark of cancer, the underlying mechanism of this accumulation within the tumor microenvironment remains incompletely understood. We report here that TNFα-RIP1-mediated necroptosis regulates accumulation of MDSCs. In tumor-bearing mice, pharmacologic inhibition of DNMT with the DNA methyltransferease inhibitor decitabine (DAC) decreased MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes. ⋯ Overall, our findings reveal that MDSCs establish a STAT3-DNMT epigenetic axis, regulated by autocrine IL6, to silence TNFα expression. This results in decreased TNFα-induced and RIP1-dependent necroptosis to sustain survival and accumulation. SIGNIFICANCE: These findings demonstrate that targeting IL6 expression or function represent potentially effective approaches to suppress MDSC survival and accumulation in the tumor microenvironment.
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Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer.
DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. ⋯ A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer. SIGNIFICANCE: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.
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FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with IC50 values of 1.4 to 3.7 nmol/L. ⋯ These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing. SIGNIFICANCE: Preclinical characterization of futibatinib, an irreversible FGFR1-4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4986/F1.large.jpg.
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The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. ⋯ In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies. Cancer Res; 76(16); 4627-36. ©2016 AACR.