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Intrinsic adaptations in OXPHOS power output and reduced tumorigenicity characterize doxorubicin resistant ovarian cancer cells
(Elsevier, 2022-11-01) Hagen, James T.; Montgomery, McLane M.; Biagioni, Ericka M.; Krassovskaia, Polina; Jevtovic, Filip; Shookster , Daniel; Sharma, Uma; Tung, Kang; Broskey, Nickolas T.; May, Linda; Huang, Hu; Brault, Jeffrey J.; Neufer, P. Darrell; Cabot, Myles C.; Fisher-Wellman, Kelsey H.; Anatomy, Cell Biology and Physiology, School of Medicine
Although the development of chemoresistance is multifactorial, active chemotherapeutic efflux driven by upregulations in ATP binding cassette (ABC) transporters are commonplace. Chemotherapeutic efflux pumps, like ABCB1, couple drug efflux to ATP hydrolysis and thus potentially elevate cellular demand for ATP resynthesis. Elevations in both mitochondrial content and cellular respiration are common phenotypes accompanying many models of cancer cell chemoresistance, including those dependent on ABCB1. The present study set out to characterize potential mitochondrial remodeling commensurate with ABCB1-dependent chemoresistance, as well as investigate the impact of ABCB1 activity on mitochondrial respiratory kinetics. To do this, comprehensive bioenergetic phenotyping was performed across ABCB1-dependent chemoresistant cell models and compared to chemosensitive controls. In doxorubicin (DOX) resistant ovarian cancer cells, the combination of both increased mitochondrial content and enhanced respiratory complex I (CI) boosted intrinsic oxidative phosphorylation (OXPHOS) power output. With respect to ABCB1, acute ABCB1 inhibition partially normalized intact basal mitochondrial respiration between chemosensitive and chemoresistant cells, suggesting that active ABCB1 contributes to mitochondrial remodeling in favor of enhanced OXPHOS. Interestingly, while enhanced OXPHOS power output supported ABCB1 drug efflux when DOX was present, in the absence of chemotherapeutic stress, enhanced OXPHOS power output was associated with reduced tumorigenicity.
The Effects of Altering Interbracket Position on Closing Loops of Similar Dimensions
(2002) Wilson, Don; Katona, Thomas R.; Baldwin, James J.; Chen, Jie; Hohlt, William F.; Shanks, James
Orthodontic closing loops offer an efficient approach to consolidate extraction spaces. They allow for efficient tooth movement by lowering the load deflection rate, increasing potential activation, and by forming posterior anchorage units that can effectively resist displacement. The closing loop under investigation is a cross-leg delta loop. No studies have been done on this unique spring and the force systems created by altering its interbracket position. It is simple to fabricate chairside and produces fairly predictable moment to force ratios (M:F). The legs are crossed so the spring is activated in the same direction as its original bends, thus giving a more uniform distribution of stress within the spring, potential permanent deformation of the spring is decreased, reduced load deflection, and a greater overall range of activation. The cross-leg delta is simpler to fabricate than the more common T-loop since it needs two fewer bends. The material chosen for loop fabrication was 0.016 x 0.022 inch stainless steel wire due to its common use in clinic and research. Allowing for patient comfort and the fact that taller loops produce greater moment to force ratios, 7mm was chosen as the height of the cross-leg delta loop. The purpose of this study was to measure the spring generated forces and moments when altering the interbracket position of the closing loop. The null hypotheses are that there will not be any differences in the forces generated in the x (Fx) and y (Fy) directions, moments about the bucco-lingual axis (Mz), and M:F ratios in the sagittal plane (Mz:Fx) will not be altered by changing the interbracket position of cross-leg delta loops of same dimensions. A total of 120 loops, grouped as four sets of loops with 30 loops in each set: L1010, Ll 109, L1208, Ll307, were fabricated. The first two digits represent the length of the mesial leg and the last two digits represent the length of the distal leg for a total of 20mm in overall length. Each sequential set had the mesial leg increased by 1mm and the distal leg decreased by 1mm such that the most asymmetric set (L1307) had a 13mm mesial and a 7mm distal leg. The testing apparatus measured forces and moments along 3 mutually perpendicular axes (x, y, and z). Horizontal activation of the loop was performed by placing measured 1mm and 2mm stops over the wire. Data were collected from each set of loops. The cross-leg delta loops with symmetric 15° gable bends were compared for differences in moments and forces using repeated measures analysis of variance (ANOVA) models. Separate analyses were performed for Fx, Fy, Mz and Mz:Fx. Since the data was not normally distributed, a rank transformation was used. Pairwise comparisons were made using the Sidak method to control the overall significance level at 5%. Altering the interbracket position of a cross-leg delta loop did not cause major changes on the anterior and posterior forces in the x direction. Statistically significant differences in vertical forces (Fy), were much more pronounced when loops were positioned asymmetrically. Posteriorly positioned loops caused a statistically significant intrusive force on the anterior and extrusive force on the posterior segment was observed. As the loop was positioned more posteriorly, moments (Mz) acting in a clockwise direction on the anterior bracket decreased. More posteriorly positioned loops caused increased moments (Mz) in a counter-clockwise direction on the posterior bracket. As the loop was positioned more posteriorly, the M:F ratios in the sagittal plane acting on the anterior bracket decreased (Mz:Fx). More posteriorly positioned loops generated increased M:F ratios on the posterior bracket in the sagittal plane (Mz:Fx). Ideally, a posteriorly positioned closing loop would be used in a deep bite case needing maximum posterior anchorage. The intrusive force and decreased M:F ratio (Mz:Fx) on the anterior segment would cause more tipping and intrusion as space closure was carried out. The posteriorly positioned loop would generate increased moments (Mz) on the posterior bracket leading to increased M:F ratios in the sagittal plane (Mz:Fx). The extusive forces on the posterior segment would open the bite while the increased M:F ratios (Mz:Fx) would cause less tipping and increased anchorage. The study showed that altering the interbracket position of a closing loop can significantly alter the M:F ratio as well as the vertical and horizontal forces on the anterior and posterior segments. These results are important because the clinician can incorporate asymmetrically positioned loops to facilitate more efficient anchorage preparation. A posteriorly positioned loop can also generate an intrusive force on the anterior segment to help control overbite while retracting individual teeth or a segment en mass.
The unexpected activist: Catholic women who donate to pro-choice causes
(Wiley, 2022-11) O'Connor, Heather A.; Philosophy, School of Liberal Arts
Social identity informs philanthropic behavior. Prior research demonstrates that donors are more likely to support individuals and groups with whom they identify. Yet individuals hold multiple social identities simultaneously. At times, these identities may be experienced as incongruent. This grounded theory study examines how the presence of incongruent identities informs philanthropic behavior by considering the experiences of Catholic women who identify as pro-choice donors and activists. Semi-structured interviews explore how participants' religious beliefs and practices influence their pro-choice philanthropy and vice versa. Findings reveal a common process that participants shared in their development from children raised in conservative, pro-life Catholic households to adults identifying as Catholic pro-choice donors and activists. The identified process extends research into social identity in donor decision-making while illustrating implications for practice by organizations representing controversial causes.
Assessing the Cost-effectiveness of a Hypothetical Disease-modifying Therapy With Limited Duration for the Treatment of Early Symptomatic Alzheimer Disease
(Elsevier, 2022-11) Boustani, Malaz; Doty, Erin G.; Garrison, Louis P., Jr.; Smolen, Lee J.; Belger, Mark; Klein, Timothy M.; Murphy, Daniel R.; Burge , Russel; Wall , J. K.; Johnston, Joseph A.; Medicine, School of Medicine
Purpose: Clinical trials have produced promising results for disease-modifying therapies (DMTs) for Alzheimer's disease (AD); however, the evidence on their potential cost-effectiveness is limited. This study assesses the cost-effectiveness of a hypothetical DMT with a limited treatment duration in AD. Methods: We developed a Markov state-transition model to estimate the cost-effectiveness of a hypothetical DMT plus best supportive care (BSC) versus BSC alone among Americans living with mild cognitive impairment (MCI) due to AD or mild AD. AD states included MCI due to AD, mild AD, moderate AD, severe AD, and death. A hypothetical DMT was assumed to confer a 30% reduction in progression from MCI and mild AD. The base case annual drug acquisition cost was assumed to be $56,000. Other medical and indirect costs were obtained from published literature or list prices. Utilities for patients and caregivers were obtained from the published literature and varied by AD state and care setting (community care or long-term care). We considered 3 DMT treatment strategies: (1) treatment administered until patients reached severe AD (continuous strategy), (2) treatment administered for a maximum duration of 18 months or when patients reached severe AD (fixed-duration strategy), and (3) 40% of patients discontinuing treatment at 6 months because of amyloid plaque clearance and the remaining patients continuing treatment until 18 months or until they reached severe AD (test-and-discontinue strategy). Incremental cost-effectiveness ratios (ICERs) were calculated as the incremental cost per quality-adjusted life-year (QALY) gained. Findings: From the health care sector perspective, continuous treatment with a hypothetical DMT versus BSC resulted in an ICER of $612,354 per QALY gained. The ICER decreased to $157,288 per QALY gained in the fixed-duration strategy, driven by large reductions in treatment costs. With 40% of patients discontinuing treatment at 6 months (test-and-discontinue strategy), the ICER was $125,631 per QALY gained. In sensitivity and scenario analyses, the ICER was the most sensitive to changes in treatment efficacy, treatment cost, and the initial population AD state distribution. From the modified societal perspective, ICERs were 6.3%, 20.4%, and 25.1% lower than those from the health care sector perspective for the continuous, fixed-duration, and test-and-discontinue strategies, respectively. Implications: Under a set of assumptions for annual treatment costs and the magnitude and duration of treatment efficacy, DMTs used for a limited duration may deliver value consistent with accepted US cost-effectiveness thresholds.