Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies.

Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

A Web Application for Predicting Drug Combination Efficacy Using Monotherapy Data and IDACombo.

We recently reported a computational method (IDACombo) designed to predict the efficacy of cancer drug combinations using monotherapy response data and the assumptions of independent drug action. Given the strong agreement between IDACombo predictions and measured drug combination efficacy in vitro and in clinical trials, we believe IDACombo can be of immediate use to researchers who are working to develop novel drug combinations. While we previously released our method as an R package, we have now created an R Shiny application to allow researchers without programming experience to easily utilize this method. The app provides a graphical interface which enables users to easily generate efficacy predictions with IDACombo using provided data from several high-throughput cell line screens or using custom, user-provided data.

Simplicity: web-based visualization and analysis of high-throughput cancer cell line screens.

High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatic skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high-throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicity's outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/.

Simplicity: Web-Based Visualization and Analysis of High-Throughput Cancer Cell Line Screens.

High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatics skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high- throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicity's outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/.

Oncogene or tumor suppressor? Long noncoding RNAs role in patient's prognosis varies depending on disease type.

Functional studies of long noncoding RNAs (lncRNAs) are often performed in the context of only a single cancer type. However, the tissue-specific expression patterns of lncRNAs raise the question of whether lncRNA associations identified in one cancer type are relevant to other cancer types. Here, we examine the relationships between the expression levels of 50 cancer-related lncRNAs and survival data from 24 types of cancer in The Cancer Genome Atlas (TCGA) with the goal of identifying prognosis related lncRNAs. Our results suggest that high expression levels of certain lncRNAs are consistently associated with worse/better survival in a number of cancers, while other lncRNAs have different prognostic roles in different types of cancer. Our analysis also identifies 20 novel unadjusted associations that have not been reported before. In addition, in low-grade glioma (LGG), prognostic-related lncRNAs are identified after conditioning on known clinical biomarker and common therapy, revealing that 2 lncRNAs, FOXP4-AS1, and NEAT1, are associated with temozolomide response-a standard-of-care in LGG. Pathway analysis suggests NF-kB/STAT3 signaling pathway enrichment in LGG patients with high NEAT1 expression and DNA repair/myc gene set enrichment in LGG patients with high expression of FOXP4-AS1. Our work demonstrates the context dependency of lncRNAs across cancer types and highlights a number of lncRNAs as potential novel cancer prognosis markers.

Exiguobacterium himgiriensis sp. nov. a novel member of the genus Exiguobacterium, isolated from the Indian Himalayas.

The taxonomic position of an orange coloured bacterium, strain K22-26(T) isolated from a soil sample was studied using a polyphasic approach. The organism had phenotypic and chemotaxonomic properties consistent with its allocation into the genus Exiguobacterium. Phylogenetic analysis of the 16S rRNA gene sequence showed that strain K22-26(T) belongs to the genus Exiguobacterium and was related to Exiguobacterium aurantiacum DSM 6208(T) (99.0 %) Exiguobacterium mexicanum DSM 16483(T) (98.6 %), Exiguobacterium aquaticum (98.6 %), Exiguobacterium aestuarii DSM 16306(T) (98.1 %), Exiguobacterium profundum DSM 17289(T) (98.1 %) and Exiguobacterium marinum DSM 16483(T) (97.9 %), whereas sequence similarity values with respect to other Exiguobacterium species with validly published names were between 92.5-94.0 %. The major polar lipids detected were phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. The major menaquinone was determined to be MK-7 (83 %) whereas MK-8 (11 %) and MK-6 (6 %) occur in smaller amounts. The peptidoglycan of the strain was found to contain L-lysine as the diagnostic diamino acid. The major fatty acids detected were iso C13:0 (11.2 %), anteiso C13:0 (15.4 %), iso C15:0 (13.2 %) and iso C17:0 (16.1 %). However, analysis of the DNA-DNA relatedness confirmed that strain K22-26(T) belongs to a novel species. The G + C content of the strain K22-26(T) was determined to be 50.1 mol %. The novel strain was distinguished from closely related type species of the genus Exiguobacterium using DNA-DNA relatedness and phenotypic data. Based on these differences, the strain K22-26(T) should be classified as a novel species of the genus Exiguobacterium, for which the name Exiguobacterium himgiriensis sp. nov. strain K22-26(T) (= MTCC 7628(T) = JCM 14260(T)) is proposed.

Nitratireductor lucknowense sp. nov., a novel bacterium isolated from a pesticide contaminated soil.

A straw-yellow pigmented bacterium, strain IITR-21(T) was isolated from a pesticide contaminated site and characterized by using a polyphasic taxonomic approach. The organism had morphological and chemotaxonomic properties consistent with its classification in the genus Nitratireductor. Phylogenetic analysis of the 16S rRNA gene sequence showed that the strain IITR-21(T) belongs to the genus Nitratireductor and was moderately related to Nitratireductor indicus C115(T) (97.7%) and Nitratireductor pacificus pht-3B(T) (97.4%), whereas sequence similarity value with the other species including the type species of the genus Nitratireductor, Nitratireductor aquibiodomus showed less than 97.0% similarity. However, the DNA-DNA relatedness values between strain IITR-21(T) and the moderately related taxa N. indicus (59.1%) and N. pacificus (40.4%) were well below the 70% threshold value recommended for the delineation of bacterial species. The G+C content of the DNA was 62.4 mol%. Based on physiological, biochemical tests and genotypic differences between the strain IITR-21(T) and the other two validly published species of the genus Nitratireductor, it is proposed that the strain be classified as a new species of Nitratireductor as Nitratireductor lucknowense sp. nov. The type strain is IITR-21(T) (=MTCC 8354(T )= DSM 24322(T)).

Exiguobacterium aquaticum sp. nov., a member of the genus Exiguobacterium.

A Gram-positive, motile, short rod-shaped, orange pigmented bacterium, designated strain IMTB-3094(T), was isolated from a water sample collected from Tikkar Tal Lake, Haryana, and subjected to detailed polyphasic taxonomic analysis. Strain IMTB-3094(T) possessed most of the phenotypic and chemotaxonomic properties of the genus Exiguobacterium and, based on 16S rRNA gene sequence analysis, was assigned to this genus. Strain IMTB-3094(T) exhibited the highest 16S rRNA gene sequence similarity to Exiguobacterium mexicanum MTCC 7759(T) (99.5 %) followed by Exiguobacterium aurantiacum MTCC 6414(T) (99.1 %), Exiguobacterium aestuarii MTCC 7750(T) (98.0 %), Exiguobacterium profundum MTCC 10851(T) (98.0 %) and Exiguobacterium marinum MTCC 7751(T) (98.0 %). The G+C content of the genomic DNA of strain IMTB-3094(T) was 53.2 mol% and a DNA-DNA relatedness study confirmed that it represents a novel species. The major fatty acids of strain IMTB-3094(T) were iso-C(17 : 0) (16.1 %), anteiso-C(13 : 0) (19.0 %), iso-C(13 : 0) (11.9 %), iso-C(15 : 0) (9.8 %) and iso-C(17 : 1) (12.7 %). The predominant quinones were MK-7 (55.0 %) and MK-6 (26.0 %) with minor amounts of MK-8 (12.0 %). Based on phenotypic, chemotaxonomic and phylogenetic analyses, strain IMTB-3094(T) represents a novel species of the genus Exiguobacterium, for which the name Exiguobacterium aquaticum sp. nov. is proposed. The type strain is IMTB-3094(T) (= MTCC 10958(T) = JCM 17977(T)).