Nanocrown electrodes for parallel and robust intracellular recording of cardiomyocytes.

Drug-induced cardiotoxicity arises primarily when a compound alters the electrophysiological properties of cardiomyocytes. Features of intracellular action potentials (iAPs) are powerful biomarkers that predict proarrhythmic risks. In the last decade, a number of vertical nanoelectrodes have been demonstrated to achieve parallel and minimally-invasive iAP recordings. However, the large variability in success rate and signal strength have hindered nanoelectrodes from being broadly adopted for proarrhythmia drug assessment. In this work, we develop vertically-aligned nanocrown electrodes that are mechanically robust and achieve > 99% success rates in obtaining intracellular access through electroporation. We validate the accuracy of nanocrown electrode recordings by simultaneous patch clamp recording from the same cell. Finally, we demonstrate that nanocrown electrodes enable prolonged iAP recording for continual monitoring of the same cells upon the sequential addition of four incremental drug doses. Our technology development provides an advancement towards establishing an iAP screening assay for preclinical evaluation of drug-induced arrhythmogenicity.

Dose-dense chemotherapy improves mechanisms of antitumor immune response.

Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are not completely clear. In this study, we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared with a maximum tolerated dose (MTD) regimen in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8(+) T-cell responses to tumors [as determined by interleukin (IL)-2 and IFN-γ secretion]. In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60-80 mg/m(2)) as the third- or fourth-line treatment. Serum was collected over the course of treatment, and serial IFN-γ and IL-2 levels were used to determine CD8(+) T-cell activation. Of the four patients with disease control, three had serum levels of IL-2 and IFN-γ associated with cytotoxic CD8(+) T-cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity, especially the antitumor CD8(+) T-cell response. Because the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment.

A noise-sensor light alarm reduces noise in the newborn intensive care unit.

This one-group pre-post test design was to evaluate sound distribution and sudden peak noise frequencies (SPNs) and the associated events after using a noise-sensor light alarm in a tertiary neonatal intensive care unit (NICU). The alarm is activated as the sound level reaches>or=65 A-weighted decibel (dBA). The environmental sound level was monitored continuously for a period of 1 week before and 1 month after using the alarm. The mean sound level in the incubator of patients receiving ventilator support before and after using the device were 58.0+/-0.6 and 56.4+/-0.7 dBA (t=8.619; p<0.001), whereas those at the radiant heated bed were 58.0+/-2.4 and 58.1+/-2.0 dBA (t=0.715; p=0.476). The percentage of observation time of sound levels<58 dBA increased by 28% in the incubator and 4% at the radiant heated bed (p<0.001). Episodes of SPN decreased from 630 to 185 times/d in the incubator and from 2069 to 748 times/d at the radiant heated bed after using the device. The noise-sensor light alarm effectively reduces sound level and episodes of SPN in the NICU. This may alleviate stress of noise for newborns with critical illness.