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Purpose: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. Thus, we sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with suspected or known IEI. Methods: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. Results: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novochanges. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one patient with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5%. Conclusion: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

BackgroundA DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encodingPlasmodium falciparum(Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection.MethodologyThis was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method.ResultsIn both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-γ FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection.ConclusionsThis study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.

Toxicology information systems have evolved swiftly from early, library-based bibliographic tools to advanced packages utilizing sophisticated computer and telecommunication technologies. These systems have evolved concurrently with the rapid expansion of the science of toxicology itself. Bibliographic files such as TOXLINE represent first attempts to handle the toxicology literature through online retrieval. Subsequent approaches applied the use of computers to provide literature-derived data, as in the HSDB or RTECS databanks, or to capture data directly from the laboratory. More advanced systems are utilizing computational and analytical approaches to extract knowledge from the laboratory data to predict outcomes. Societal concerns about hazardous substances, manifested in legislation and regulations, have been responsible for the generation of much toxicity information and the impetus to systematically collect and disseminate these data. Scientific progress in molecular biology, chemistry, and bioinformatics combined with advances in information technologies are also impacting the supply of toxicology information. The amount of information has risen dramatically over the years and it is more accessible and current than ever before. However, in order to derive meaning from the mounds of data and information, the field must rise to the challenge of fostering data accessibility, promoting data standards, and ensuring data quality.

Molecular, cellular, and biochemical toxicology is an extremely broad field encompassing most, if not all, in vitro and mechanistic aspects of current toxicological science. Textbooks covering key aspects, modern methods and techniques, and issues of major concern are listed. Although articles devoted to this field can be found within almost any toxicology journal, several are exclusively devoted to articles detailing molecular, cellular, and biochemical toxicology. The following list of books, journals, journal articles, organizations, and databases serves as an introduction to the complex field of molecular, cellular, and biochemical toxicology.