Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone

Alterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to β-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of β-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to β-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to β-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to β-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to β-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations

Marital Quality and Health Over 20 Years: A Growth Curve Analysis

Although there is substantial evidence linking marital quality to physical health, few studies have been longitudinal. This study examined data from the Marital Instability Over the Life Course Study; 1,681 married individuals followed for 20 years were included in these analyses. In order to control for life course effects, participants were divided into 2 cohorts: early life and midlife. On the basis of latent growth curve analysis, the results indicated that initial values of marital happiness and marital problems were significantly associated with the initial value of physical health among both cohorts. In addition, the slope of marital happiness was significantly associated with the slope of physical health among the younger cohort, and the slope of marital problems was significantly associated with the slope of physical health among the midlife cohort. These results provide evidence of the significant association between positive and negative dimensions of marital quality and physical health over the life course

Calibration strategies for use of the nanoDot OSLD in CT applications.

Aluminum oxide based optically stimulated luminescent dosimeters (OSLD) have been recognized as a useful dosimeter for measuring CT dose, particularly for patient dose measurements. Despite the increasing use of this dosimeter, appropriate dosimeter calibration techniques have not been established in the literature; while the manufacturer offers a calibration procedure, it is known to have relatively large uncertainties. The purpose of this work was to evaluate two clinical approaches for calibrating these dosimeters for CT applications, and to determine the uncertainty associated with measurements using these techniques. Three unique calibration procedures were used to calculate dose for a range of CT conditions using a commercially available OSLD and reader. The three calibration procedures included calibration (a) using the vendor-provided method, (b) relative to a 120 kVp CT spectrum in air, and (c) relative to a megavoltage beam (implemented with 60 Co). The dose measured using each of these approaches was compared to dose measured using a calibrated farmer-type ion chamber. Finally, the uncertainty in the dose measured using each approach was determined. For the CT and megavoltage calibration methods, the dose measured using the OSLD nanoDot was within 5% of the dose measured using an ion chamber for a wide range of different CT scan parameters (80-140 kVp, and with measurements at a range of positions). When calibrated using the vendor-recommended protocol, the OSLD measured doses were on average 15.5% lower than ion chamber doses. Two clinical calibration techniques have been evaluated and are presented in this work as alternatives to the vendor-provided calibration approach. These techniques provide high precision for OSLD-based measurements in a CT environment

Unicompartmental Knee Arthroplasty Is Associated with a Lower Rate of Periprosthetic Joint Infection Compared to Total Knee Arthroplasty

Background: Several studies have reported lower perioperative complications with unicompartmental knee arthroplasty (UKA) than with total knee arthroplasty (TKA). However, there is a paucity of data analyzing the incidence of periprosthetic joint infection (PJI) in similar patients undergoing UKA and TKA. As such, we sought to analyze the incidence of UKA and TKA PJI in a large matched population. Material and Methods: The Mariner data set of the PearlDiver database was queried for all patients undergoing UKA or TKA during 2010-2017. Included patients were required to have at least 2 years of database inclusion after surgery. Patients were then matched at a 1:3 ratio (UKA:TKA) on age, gender, Elixhauser Comorbidity Index, tobacco use, and obesity. Rates of PJI requiring operative intervention within 90 days and 1 year were calculated. Results: In total, 5636 patients having undergone UKA were matched to 16,890 patients having undergone TKA. Fifteen (0.27%) after UKA and 79 (0.47%) after TKA had a PJI surgically managed within 90 days (risk ratio = 0.57, 95% confidence interval = 0.33-0.99, P = .04). Thirty (0.53%) after UKA and 136 (0.81%) after TKA had a PJI surgically managed within 1 year (risk ratio = 0.66, 95% confidence interval = 0.45-0.98, P = .04). Conclusions: In a large group of rigorously matched patients, UKA was associated with a significantly lower rate of surgically managed PJI than TKA at 90 days and 1 year; however, the rate of PJI in both groups remained low at \u3c 1% at 90 days and 1 year

A Substellar Companion to a Hot Star in K2's Campaign 0 Field

The K2 mission has enabled searches for transits in crowded stellar environments very different from the original Kepler mission field. We describe here the reduction and analysis of time series data from K2's Campaign 0 superstamp, which contains the 150 Myr open cluster M35. We report on the identification of a substellar transiting object orbiting an A star at the periphery of the superstamp. To investigate this transiting source, we performed ground based follow-up observations, including photometry with the Las Cumbres Observatory telescope network and high resolution spectroscopy with Keck/High Resolution Echelle Spectrometer. We confirm that the host star is a hot, rapidly rotating star, precluding precision radial velocity measurements. We nevertheless present a statistical validation of the planet or brown dwarf candidate using speckle interferometry from the WIYN telescope to rule out false positive stellar eclipsing binary scenarios. Based on parallax and proper motion data from Gaia Data Release 2 (DR2), we conclude that the star is not likely to be a member of M35, but instead is a background star around 100 pc behind the cluster. We present an updated ephemeris to enable future transit observations. We note that this is a rare system as a hot host star with a substellar companion. It has a high potential for future follow-up, including Doppler tomography and mid-infrared secondary transit observations