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Natural products provide new opportunities for anticancer chemotherapeutics. We examined the associations of molecular features in the NCI‐60 cancer cell lines with response to 1302 plant, marine, and microbial compounds. Expression or mutations in multiple genes were associated with treatment responses, suggesting potential mechanisms of action of natural compounds. This information will assist in future design of new chemotherapy agents., Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well‐characterized NCI‐60 cancer cell line panel with in vitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein‐changing single nucleotide variants in 211 cancer‐related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI‐60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.

SUMMARY CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this “recalcitrant cancer.” We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities., In Brief Tlemsani et al. provide a unique resource, SCLC-CellMiner, integrating drug sensitivity and multi-omics data from 118 small cell lung cancer (SCLC) cell lines. They demonstrate that SCLCs have differential transcriptional networks driven by lineage-specific transcription factors (NEUROD1, ASCL1, POU2F3, and YAP1). Furthermore, YAP1-driven SCLCs have distinct drug sensitivity profiles., Graphical Abstract

Cellular glycosylation processes are vital to cell functioning. In malignant cells, they are profoundly altered. We used time-course gene expression data from the NCI-60 cancer cell lines treated with 11 antitumor agents to analyze expression changes of genes involved in glycosylation pathways, genes encoding glycosylation targets or regulators, and members of cancer pathways affected by glycosylation. We also identified glycosylation genes for which pretreatment expression levels or changes after treatment were correlated with drug sensitivity. Their products are involved in N-glycosylation and O-glycosylation, fucosylation, biosynthesis of poly- N-acetyllactosamine, removal of misfolded proteins, binding to hyaluronic acid and other glycans, and cell adhesion. Tumor cell sensitivity to multiple agents was correlated with transcriptional response of C1GALT1C1, FUCA1, SDC1, MUC1; members of the MGAT, GALNT, B4GALT, B3GNT, MAN, and EDEM families; and other genes. These genes may be considered as potential candidates for drug targeting in combination therapy to enhance treatment response.

DNA methylation patterns differ among children and adults and play an unambiguous role in several disease processes, particularly cancers. The origin of these differences is inadequately understood, and this is a question of specific relevance to childhood and adult cancer.DNA methylation levels at 26,485 autosomal CpGs were assayed in 201 newborns (107 African American and 94 Caucasian). Nonparametric analyses were performed to examine the relation between these methylation levels and maternal parity, maternal age, newborn gestational age, newborn gender, and newborn race. To identify the possible influences of confounding, stratification was performed by a second and third variable. For genes containing CpGs with significant differences in DNA methylation levels between races, analyses were performed to identify highly represented gene ontological terms and functional pathways.13.7% (3623) of the autosomal CpGs exhibited significantly different levels of DNA methylation between African Americans and Caucasians; 2% of autosomal CpGs had significantly different DNA methylation levels between male and female newborns. Cancer pathways, including four (pancreatic, prostate, bladder, and melanoma) with substantial differences in incidence between the races, were highly represented among the genes containing significant race-divergent CpGs.At birth, there are significantly different DNA methylation levels between African Americans and Caucasians at a subset of CpG dinucleotides. It is possible that some of the epigenetic precursors to cancer exist at birth and that these differences partially explain the different incidence rates of specific cancers between the races.

There is a substantial genetic component to birth weight variation. We tested eighteen single nucleotide polymorphisms (SNPs) in the IGF2, H19, and IGF2R genes for associations with birth weight variation in 342 mother-newborn pairs (birth weight 2.1 – 4.7 Kg at term) and 527 parent-newborn trios (birth weight 2.1 – 5.1 Kg) across three localities. SNPs in the IGF2R (rs8191754; maternal genotype), IGF2 (rs3741205; newborn genotype) and in the 5' region of the H19 (rs2067051, rs2251375, and rs4929984) genes were associated with birth weight. Detailed analyses to distinguish direct maternal, direct newborn, and parent of origin effects for the most strongly associated H19 SNP (rs4929984) determined that the association of maternal genotype with newborn birth weight was due to parent of origin effects, not direct maternal effects. That SNP is located near the CTCF binding sites that influence expression of the maternally-imprinted IGF2 and paternally-imprinted H19 locus, and there are statistically significant and independent opposite effects of the same rs4929984 allele, depending on the parent from which it was inherited.

Background Knowledge of how structural genome differences among microorganisms lead to variation in gene regulation is fundamentally important for our understanding of the functioning of gene regulatory pathways and their individual components. This knowledge is also necessary for our better understanding of the genomic changes leading to adaptation to diverse and changing environments. Our research focuses on Geobacteraceae, a metal-reducing family of delta-Proteobacteria, which are capable of harvesting electricity from organic matter and environmental bioremediation of organic and metal pollutants. We are investigating molecular mechanisms which allow these species to adapt and regulate their responses to environmental stimuli, which result in energy production and removal of environmental pollutants. Materials and methods In this presentation, we describe computational analysis of gene regulation in multiple species from this family. Our ongoing analyses include cataloguing and integrating information about gene regulation, in silico prediction of transcription factor binding sites, and investigation of functional effects of genome-scale and single nucleotide and amino acid level changes in transcription factors, operons, and regulatory sequence elements in Geobacteraceae. Specifically, we discuss our computational pipeline for comparative analyses of variation in regulatory organization among species and strains of Geobacteraceae, which allows us to investigate changes in operon organization and to track the effects of operon rearrangements and individual single nucleotide base pair level changes on regulatory sequence elements. We also describe our computational analyses of two systems of gene expression, one of gene regulation by the PilR enhancer binding protein and another by the TetR family of transcriptional regulators. Finally, we describe our ongoing efforts to catalog available information on gene regulation and operon organization of Geobacter sulfurreducens, a model representative of the Geobacteraceae family.

Address: 1Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA, 2Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA, 3Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA, 4Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS 39216, USA and 5Department of Obstetrics and Gynecology, Naval Medical Center at Portsmouth, VA 23708, USA

To determine whether the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene is associated with lung injury in children with community-acquired pneumonia.A prospective cohort of children diagnosed with community-acquired pneumonia.Two pediatric hospitals.Eight hundred fifty pediatric patients with community-acquired pneumonia were enrolled.Genotyping of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene was performed on DNA isolated from whole blood.The requirement for positive pressure ventilation or the diagnosis of acute lung injury or acute respiratory distress syndrome were the main outcomes of the study. Children (14 days-19 yrs) with community-acquired pneumonia (850) were enrolled; analysis was limited to African American (515) and Caucasian (232) patients. Of the 82 patients requiring positive pressure ventilation, 44 were diagnosed with acute lung injury or acute respiratory distress syndrome. Multivariate logistic regression analyses indicated that children without a copy of the A1 allele of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene were more likely to need positive pressure ventilation compared to those with one or two copies of this allele (odds ratio = 2.65, confidence interval, 1.02-6.90). In addition, the absence of the A1 allele also appeared to be associated with the development of community-acquired pneumonia-induced acute lung injury/acute respiratory distress syndrome (odds ratio = 3.1, confidence interval, 0.99-9.67).In children with community-acquired pneumonia, absence of the A1 allele at the interleukin-1 receptor antagonist intron 2 polymorphic site is associated with increased risk for more severe lung injury, as measured by the need for positive pressure ventilation or the development of acute lung injury or acute respiratory distress syndrome. Conversely, presence of the A1 allele is associated with decreased risk for more severe lung injury in this patient population.

Address: 1Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA, 2Department of Microbiology, University of Massachusetts, Amherst, MA 01003, USA, 3Departamento de Ingenieria Celular y Biocatalisis, Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico, Cuernavaca 62271, Mexico, 4Department of Molecular Microbiology, Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico, Cuernavaca 62271, Mexico and 5Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA

Background Aberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation and other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth. Results We used a bioinformatics tool, the Transcriptional Pharmacology Workbench, to analyze temporal changes in gene expression among epigenetic regulators of DNA methylation and demethylation, and one-carbon metabolism genes in response to cancer drug treatment. We analyzed gene expression information from the NCI-60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in gene expression of multiple pathway components across the cell lines. Expression changes of FOLR2, SMUG1, GART, GADD45A, MBD1, MTR, MTHFD1, and CTH were significantly correlated with chemosensitivity to some of the agents. Among many genes with concerted expression response to individual antitumor agents were genes encoding DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, epigenetic and DNA repair factors MGMT, GADD45A, and MBD1, and one-carbon metabolism pathway members MTHFD1, TYMS, DHFR, MTR, MAT2A, SLC19A1, ATIC, and GART. Conclusions These transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0240-3) contains supplementary material, which is available to authorized users.