Background: Drug-induced liver injury (DILI) is a serious concern during drug development and the treatment of human disease. The ability to accurately predict DILI risk could yield significant improvements in drug attrition rates during drug development, in drug withdrawal rates, and in treatment outcomes. In this paper, we outline our approach to predicting DILI risk using gene-expression data from Build 02 of the Connectivity Map (CMap) as part of the 2018 Critical Assessment of Massive Data Analysis CMap Drug Safety Challenge. Results: First, we used seven classification algorithms independently to predict DILI based on gene-expression values for two cell lines. Similar to what other challenge participants observed, none of these algorithms predicted liver injury on a consistent basis with high accuracy. In an attempt to improve accuracy, we aggregated predictions for six of the algorithms (excluding one that had performed exceptionally poorly) using a soft-voting method. This approach also failed to generalize well to the test set. We investigated alternative approaches-including a multisample normalization method, dimensionality-reduction techniques, a class-weighting scheme, and expanding the number of hyperparameter combinations used as inputs to the soft-voting method. We met limited success with each of these solutions. Conclusions: We conclude that alternative methods and/or datasets will be necessary to effectively predict DILI in patients based on RNA expression levels in cell lines. Reviewers: This article was reviewed by Paweł P Labaj and Aleksandra Gruca (both nominated by David P Kreil).

Background:Kolaviron (KV) (biflavonoid from Garcinia kola) and extract of Curcuma longa (CL) are frequently used in folk medicine for treatment of hypertension. One of their mechanisms of action is to enhance antioxidant properties in animals. NG- nitro- l- arginine methyl- ester (L- NAME) is L- arginine analogue, which by binding to Nitric Oxide Synthase (NOS) may induce hypertension partly due to increase in tissues oxidative stress.Objectives:To investigate the effect of L- NAME on some biochemical indices and the possible protective effect of KV or CL.Materials and Methods:Four groups consisting of 6 rats each were used. One group served as control, second group received L- NAME (40 mg/kg/day). Third and fourth groups were treated with KV and CL, respectively and also received L- NAME. KV and CL were given at a dose of 200 mg/kg/day.Results:L- NAME caused a significant (P <0.05) increase in the levels of serum urea, creatine kinase and alanine aminotransferase relative to controls. L- NAME treated rats had markedly decreased hepatic catalase (CAT), superoxide dismutase (SOD), glutathione- S- transferase (GST) and reduced glutathione (GSH) levels. Precisely, L- NAME decreased CAT, SOD, GST and GSH by 48, 52, 76 and 40%, respectively. L- NAME intoxication significantly decreased (P <0.05) renal GSH and SOD levels. Also, L- NAME caused a significant (P <0.05) induction of lipid peroxidation (LPO) in the animals. Administration of KV or CL with L- NAME caused significant (P <0.05) inhibition of LPO and augments tissue antioxidant indices.Conclusion:These results confirm the adverse effect of L- NAME on biochemical indices and, the ability of kolaviron or Curcuma longa to ameliorate the alterations.

Erwinia amylovora is a plant pathogen belonging to the Enterobacteriaceae family, a family containing many plant and animal pathogens. Herein, we announce nine genome sequences of E. amylovora bacteriophages isolated from infected apple trees along the Wasatch Front in Utah.

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Objectives: Paucity of data on populations of African Ancestry in clinical trials continues to limit our ability to design and implement innovative solutions to narrow the breast cancer survival gap amongst Africans, African Americans, and European Americans. We have developed a cross-continent research infrastructure to examine the spectrum of genomic alterations in breast tumors from West Africa and subsequently, to compare them to tumors from African American women and women of European Ancestry in The Cancer Genome Atlas (TCGA) database. Methods: Consecutive women with breast cancer presenting for treatment at the University College Hospital, Ibadan and at Lagos State University Teaching Hospital, Lagos, Nigeria gave informed consent and were recruited to the West African Breast Cancer Study (WABCS) between 2013-2016. Tumor-normal pairs were subjected to exome and/or high-depth (90x) genome sequencing. High confidence somatic mutations (substitutions, insertions/deletions and structural variants) were obtained by using multiple variant callers. Furthermore, 1,089 exomic and 80 genomic breast tumor-normal pairs from TCGA were harmonized with WABCS samples, resulting in a cohort of 147 West Africans (147 exome; 40 genome), 154 African Americans (154 exome; 31 genome), and 776 Caucasians (776 exome; 43 genome). Results: Across the exomes, genes commonly altered in breast cancer in TCGA are also altered in women of African ancestry, but the mutational spectrum is quite different, demonstrating overrepresentation of tumors with aggressive phenotypes. Overall, TP53 (65%), ERBB2 (27%), and GATA3 (17%) showed statistically significant higher alteration frequencies in West Africans and African Americans. In contrast, PIK3CA (24%) was less frequently mutated. Of note, GATA3 mutation was statistically significantly more frequent in Nigerians (39%) and African Americans (16.7%) compared to Caucasians (10.5%), in ER-positive cancers. Analysis on Structural Variants (SV), on the other hand, has shown that the genome-wide SV counts among three populations are comparable in ER-negative cancers, while Nigerians have significantly more SV counts compared to African Americans (P=0.0013) or European Americans (P=2.9x10-5) in ER-positive cancers. Similarly, genome-wide substitution patterns in ER+ and ER- cancers varied widely by race/ethnicity. In ER- cases, West Africans carried the highest proportion of canonical APOBEC-associated substitutions, particularly C&gt;T transitions. Conversely, European Americans with ER+ disease showed a higher proportion of C&gt;T than both West Africans (Welch t-test P = 0.044) and African Americans (Welch t-test P = 0.011). Mutation signature analyses highlighted multiple APOBEC signatures, with notable contribution differences across ancestry and ER status. A signature likely corresponding to DNA damage repair correlated with the proportion of genetic ancestry, being most prevalent in European Americans and least common in Nigerians, particularly in ER-negative cancers, with African Americans showing a degree of this signature's contribution in between the two populations (linear model adjusted for age, P=1.0x10-10). Conclusions: Overall, our data suggests mutation spectra differences in across race/ethnicity and geography. Identification of molecular characteristics such as higher rates of HER2 enriched tumors and higher rates of GATA3 mutations in ER positive tumors are beginning to reveal the genomic basis of race-associated phenotypes and outcomes in breast cancer. Population differences in frequency and spectrum of mutations should now inform the design of innovative clinical trials that improve health equity and accelerate Precision Oncology care in diverse populations. Citation Format: Olopade OI, Pitt JJ, Riester M, Odetunde A, Yoshimatsu T, Labrot E, Ademola A, Sanni A, Okedere B, Mahan S, Nwosu I, Leary R, Ajani M, Johnson RS, Sveen E, Zheng Y, Wang S, Fitzgerald DJ, Grundstad J, Tuteja J, Clayton W, Khramtsova G, Oludara M, Omodele F, Benson O, Adeoye A, Morhason-Bello O, Ogundiran T, Babalola C, Popoola A, Morrissey M, Chen L, Huo D, Falusi A, Winckler W, Obafunwa J, Papoutsakis D, Ojengbede O, White KP, Ibrahim N, Oluwasola O, Barretina J. Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD8-05.