The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers.

Aim: Ferroptosis is a non-apoptotic form of cell death caused by lethal lipid peroxidation. Several small molecule ferroptosis inducers (FINs) have been reported, yet little information is available regarding their interaction with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp, ABCB1) and ABCG2. We thus sought to characterize the interactions of FINs with P-gp and ABCG2, which may provide information regarding oral bioavailability and brain penetration and predict drug-drug interactions. Methods: Cytotoxicity assays with ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2 were used to determine the ability of the transporters to confer resistance to FINs; confirmatory studies were performed in OVCAR8 and NCI/ADR-RES cells. The ability of FINs to inhibit P-gp or ABCG2 was determined using the fluorescent substrates rhodamine 123 or purpuin-18, respectively. Results: P-gp overexpression conferred resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin. P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1. The FINs ML-162, GPX inhibitor 26a, and PACMA31 at 10 µM were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells. GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells. Conclusion: Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.

The Multidrug Resistance Transporter P-glycoprotein Confers Resistance to Ferroptosis Inducers.

Ferroptosis is a form of cell death caused by direct or indirect inhibition of glutathione peroxidase 4 that leads to lethal lipid peroxidation. Several small molecule ferroptosis inducers (FINs) have been reported, yet little information is available regarding resistance mechanisms, particularly their interaction with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp, ABCB1) and ABCG2. Given the role that ABC transporters play in absorption, distribution, and excretion of many drugs, characterizing these interactions could provide information regarding oral bioavailability and brain penetration and may predict drug-drug interactions. Using ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2, we found that P-gp overexpression was able to confer resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin. Results were confirmed with OVCAR8-derived NCI/ADR-RES cells that overexpress P-gp, where the P-gp inhibitor valspodar completely inhibited resistance to the FINs. P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1. At a concentration of 10 µM, the FINs ML-162, GPX inhibitor 26a, and PACMA31 were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells and GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells. Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.

Through the woods.

Many individuals find themselves taking care of a family member or loved one with a terminal illness. This narrative illustrates how my family and I navigated this caretaking process as a system and how this experience shaped my family-centered approach to care in medical settings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The MRCI with juvenile detainees: optimizing performance or emphasizing ecological validity?

The Miranda Rights Comprehension Instruments (MRCI) are intended to be administered to legally involved youths in a setting free from distractions and stressors with the explicit goal of assessing the examinee's best understanding. However, marked disparities have been observed between juveniles' MRCI performance and their unassisted recall of a representative Miranda warning. We hypothesized that youths' very strong MRCI performance might be partially due to prompts and clarifications used whenever incomplete or ambiguous answers are provided. In this archival study, we systematically re-scored three MRCI instruments from 231 legally involved youths to evaluate their original responses (i.e., non-queried scoring). This approach is viewed as more ecologically valid because actual Miranda warnings are typically provided in a routine manner without assistance following each Miranda component. For the large majority of legally involved juveniles, only small differences were noted between standard and non-queried scoring. However, some dramatic decrements were observed, especially on the Comprehension of Miranda Rights-II (CMR-II). More specifically, 15.7% of CMR-II percentiles dropped precipitously by 60% or more, when using the non-queried scores. The results are discussed within the context of optimized performances versus ecological validity as applied to Miranda evaluations.

Validity and Representative Data of the MRCI With Legally Involved Juveniles.

Recognized for nearly four decades, most juvenile suspects waive their Miranda rights and almost immediately provide self-incriminating evidence. Miranda-specific measures were eventually developed to understand their capacities and limitations. With extensive revisions, the Miranda Rights Comprehension Instruments (MRCI) were normed and validated. Beyond reliability, the current study addresses the convergent and discriminant validity of the MRCI. In response to Frumkin and Sellbom's criticism of the MRCI's norms, the current research provides representative data on 245 legally involved juveniles with percentiles to facilitate the interpretation of MRCI data. The current investigation is also the first MRCI study to link directly Miranda comprehension (i.e., the knowing prong) to Miranda reasoning (i.e., the intelligent prong) of waiver decisions.

An Examination of Juveniles' Miranda Abilities: Investigating Differences in Miranda Recall and Reasoning.

Juvenile suspects are routinely expected to possess an accurate recall of written or oral Miranda warnings. This study addresses the Miranda-related comprehension recall and reasoning of legally involved juveniles. It is the first juvenile research to compare systematically two levels of complexity for Miranda warnings with the three modalities (oral, written, or combined) of administration. Unexpectedly, easily read written warnings marginally outperformed the combined modality. In order to examine Miranda reasoning, three juvenile groups were operationalized: impaired, questionable, and likely adequate. Predictably, the impaired and questionable groups possessed significantly lower verbal abilities than the likely-adequate reasoning group. In addition, the likely-adequate group exhibited the strongest appreciation of the adversarial context in which Miranda waiver decisions are rendered. The discussion addresses the marked disparities in Miranda recall from a total recall versus component-by-component understanding of Miranda rights. It also considers more generally how crucially important Miranda misconceptions might be remedied. Copyright © 2016 John Wiley & Sons, Ltd.