Feasibility of monitoring peripheral blood to detect emerging clones in children with acute lymphoblastic leukemia†

Relapse‐enriched somatic variants drive drug resistance in childhood acute lymphoblastic leukemia. We used digital droplet‐based polymerase chain reaction to establish whether relapse‐enriched mutations in emerging subclones could be detected in peripheral blood samples before frank relapse. Although limitations in sensitivity for some probes hindered detection of certain variants, we successfully detected variants in NT5C2 and PRPS1 at a fractional abundance of 0.005% to 0.3%, 41 to 116 days before relapse. As mutations in both these genes confer resistance to thiopurines, early detection protocols using peripheral blood could be implemented to preemptively alter maintenance therapy to extinguish resistant clones before overt relapse.     

Comparison of PC and iPad administrations of the Cogstate Brief Battery in the Mayo Clinic Study of Aging: Assessing cross-modality equivalence of computerized neuropsychological tests

Objective: Computerized neuropsychological assessments are increasingly used in clinical practice, population studies of cognitive aging and clinical trial enrichment. Subtle, but significant, performance differences have been demonstrated across different modes of test administration and require further investigation.

Method: Participants included cognitively unimpaired adults aged 50 and older from the Mayo Clinic Study of Aging who completed the Cogstate Brief Battery and Cogstate’s Groton Maze Learning Test (GMLT) on an iPad or a personal computer (PC) in the clinic. Mode of administration differences and test–retest reliability coefficients were examined across 3 cohorts: a demographically matched test–retest cohort completing PC and iPad administrations the same day (N?=?168); a test naïve cohort comparing baseline PC (n?=?1820) and iPad (n?=605) performance; and a demographically matched longitudinal cohort completing 3 Cogstate visits over 15 months on either the PC (n?=63) or iPad (n?=63).

Results: Results showed a small but statistically significant and consistent finding for faster performance on PC relative to iPad for several Cogstate Brief Battery measures. Measures of accuracy generally did not differ or differences were very small. The GMLT showed faster performance and higher total errors on iPad. Most Cogstate variables showed no difference in the rate of change across PC and iPad administrations.

Conclusions: There are small, but significant, differences in performance when giving the same cognitive tests on a PC or an iPad. Future studies are needed to better understand if these small differences impact the clinical interpretation of results and research outcomes.     

Predictions of genotoxic potential,mode of action,molecular targets,and potency via a tiered multiflow® assay data analysis strategy

The in vitro MultiFlow® DNA Damage Assay multiplexes γH2AX, p53, phospho-histone H3, and polyploidization biomarkers into a single flow cytometric analysis. The current report describes a tiered sequential data analysis strategy based on data generated from exposure of human TK6 cells to a previously described 85 chemical training set and a new pharmaceutical-centric test set (n = 40). In each case, exposure was continuous over a range of closely spaced concentrations, and cell aliquots were removed for analysis following 4 and 24 hr of treatment. The first data analysis step focused on chemicals' genotoxic potential, and for this purpose, we evaluated the performance of a machine learning (ML) ensemble, a rubric that considered fold increases in biomarkers against global evaluation factors (GEFs), and a hybrid strategy that considered ML and GEFs. This first tier further used ML output and/or GEFs to classify genotoxic activity as clastogenic and/or aneugenic. Test set results demonstrated the generalizability of the first tier, with particularly good performance from the ML ensemble: 35/40 (88%) concordance with a priori genotoxicity expectations and 21/24 (88%) agreement with expected mode of action (MoA). A second tier applied unsupervised hierarchical clustering to the biomarker response data, and these analyses were found to group certain chemicals, especially aneugens, according to their molecular targets. Finally, a third tier utilized benchmark dose analyses and MultiFlow biomarker responses to rank genotoxic potency. The relevance of these rankings is supported by the strong agreement found between benchmark dose values derived from MultiFlow biomarkers compared to those generated from parallel in vitro micronucleus analyses. Collectively, the results suggest that a tiered MultiFlow data analysis pipeline is capable of rapidly and effectively identifying genotoxic hazards while providing additional information that is useful for modern risk assessments—MoA, molecular targets, and potency. Environ. Mol. Mutagen. 60:513–533, 2019. © 2019 Wiley Periodicals, Inc.     

The Neurocognitive Performance of Female Veterans With Posttraumatic Stress Disorder

Neurocognitive problems are common with posttraumatic stress disorder (PTSD) and are important to understand because of their association with the success of PTSD treatment and its potential neural correlates. To our knowledge, this is the first neurocognitive study in an all‐female U.S. veteran sample, some of whom had PTSD. We examined neurocognitive performance and assessed whether learning deficits, common in PTSD, were associated with executive functioning. Veterans with PTSD (n = 56) and without (n = 53) were evaluated for psychiatric and neurocognitive status. The PTSD group had a lower estimated IQ (d = 0.53) and performed more poorly on all neurocognitive domains (d range = 0.57–0.88), except verbal retention (d = 0.04). A subset of the 2 groups that were matched on IQ and demographics similarly demonstrated poorer performance for the PTSD group on all neurocognitive domains (d range = 0.52–0.79), except verbal retention (d = 0.15). Within the PTSD group, executive functioning accounted for significant variance in verbal learning over and above IQ and processing speed (ΔR² = .06), as well as depression (ΔR² = .07) and PTSD severity (ΔR² = .06). This study demonstrated that female veterans with PTSD performed more poorly than females without PTSD on several neurocognitive domains, including verbal learning, processing speed, and executive functioning. Replication of these results using a control group of veterans with more similar trauma exposure, history of mild traumatic brain injury, and psychiatric comorbidities would solidify these findings.     

The Adverse Cardiac Effects of Di(2-ethylhexyl)phthalate and Bisphenol A

The ubiquitous nature of plastics has raised concerns pertaining to continuous exposure to plastic polymers and human health risks. Of particular concern is the use of endocrine-disrupting chemicals in plastic production, including di(2-ethylhexyl)phthalate (DEHP) and bisphenol A (BPA). Widespread and continuous exposure to DEHP and BPA occurs through dietary intake, inhalation, dermal and intravenous exposure via consumer products and medical devices. This article reviews the literature examining the relationship between DEHP and BPA exposure and cardiac toxicity. In vitro and in vivo experimental reports are outlined, as well as epidemiological studies which examine the association between these chemicals and cardiovascular outcomes. Gaps in our current knowledge are also discussed, along with future investigative endeavors that may help resolve whether DEHP and/or BPA exposure has a negative impact on cardiovascular physiology.