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Identifying the mechanisms mediating cisplatin response is essential for improving patient response. Previous research has identified base excision repair (BER) and mismatch repair (MMR) activity in sensitizing cells to cisplatin. Cisplatin forms DNA adducts including interstrand cross-links (ICLs) that distort the DNA helix, forcing adjacent cytosines to become extrahelical. These extrahelical cytosines provide a substrate for cytosine deaminases. Herein, we show that APOBEC3 (A3) enzymes are capable of deaminating the extrahelical cytosines to uracils and sensitizing breast cancer cells to cisplatin. Knockdown of A3s results in resistance to cisplatin and induction of A3 expression in cells with low A3 expression increases sensitivity to cisplatin. We show that the actions of A3s are epistatic with BER and MMR. We propose that A3-induced cytosine deamination to uracil at cisplatin ICLs results in repair of uracils by BER, which blocks ICL DNA repair and enhances cisplatin efficacy and improves breast cancer outcomes.

Background Remote monitoring is associated with improved patient outcomes; however, adoption and adherence to remote monitoring via home-based consoles remains suboptimal. BlueSync technology in new generation pacemaker and CRT-P models enables the implanted device to communicate directly with patient-owned, Bluetooth-equipped smartphones/tablets and an app (MyCareLink Heart). The app can automatically retrieve information from the cardiac device and transmit the data to the remote network, eliminating the need for traditional remote monitoring consoles. Objectives To characterize the communication process between implanted pacemakers and smart device remote monitoring apps by assessing the success of prescheduled remote transmissions in the first month of follow-up. Additionally, to assess the feedback of both patients and clinicians about the process of device pairing. Methods Enrollment in the BlueSync Field Evaluation began in April 2018 and was completed November 2018. Follow-up is ongoing. Prior to enrollment in the evaluation, patients completed the device pairing process with the app using their own compatible smartphone or tablet. Patient and clinician questionnaires were completed at the time of the device pairing process. After enrollment, successful completion of scheduled transmissions occurring in the first month were analyzed. Results Preliminary data includes 241 enrolled patients with mean age of 64.7±15.5 yrs (min 20, max 90 yrs), who completed device pairing between their implanted device and their smart device app. Of enrolled patients, 79% felt that the device paring was easy to do, 85% were satisfied with the amount of time it took to complete it, and 93% felt that they would be comfortable using the app. Clinicians reported that 67% of the device pairings took less than 20 minutes and 78% felt patients would be able to use the app independently. At the time of analysis 174 patients had at least one scheduled transmission within the first month, and collectively had a total of 322 scheduled transmissions. Out of these, 309 (96%, 95% CI: 93%-98%) were successfully completed. MyCareLink Heart App Conclusions Initial experience with the world's first app based remote monitoring system for Bluetooth enabled pacemakers demonstrated success to scheduled transmissions in the first month across a wide range of patient ages. Patients and clinicians reported high satisfaction with this novel technology. Acknowledgement/Funding Medtronic PLC

Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development.