Propensity score weighting is sensitive to model misspecification and outlying weights that can unduly influence results. The authors investigated whether trimming large weights downward can improve ...the performance of propensity score weighting and whether the benefits of trimming differ by propensity score estimation method. In a simulation study, the authors examined the performance of weight trimming following logistic regression, classification and regression trees (CART), boosted CART, and random forests to estimate propensity score weights. Results indicate that although misspecified logistic regression propensity score models yield increased bias and standard errors, weight trimming following logistic regression can improve the accuracy and precision of final parameter estimates. In contrast, weight trimming did not improve the performance of boosted CART and random forests. The performance of boosted CART and random forests without weight trimming was similar to the best performance obtainable by weight trimmed logistic regression estimated propensity scores. While trimming may be used to optimize propensity score weights estimated using logistic regression, the optimal level of trimming is difficult to determine. These results indicate that although trimming can improve inferences in some settings, in order to consistently improve the performance of propensity score weighting, analysts should focus on the procedures leading to the generation of weights (i.e., proper specification of the propensity score model) rather than relying on ad-hoc methods such as weight trimming.
Traumatic brain injury triggers multiple cell death pathways, possibly including ferroptosis-a recently described cell death pathway that results from accumulation of 15-lipoxygenase-mediated lipid ...oxidation products, specifically oxidized phosphatidylethanolamine containing arachidonic or adrenic acid. This study aimed to investigate whether ferroptosis contributed to the pathogenesis of in vitro and in vivo traumatic brain injury, and whether inhibition of 15-lipoxygenase provided neuroprotection.
Cell culture study and randomized controlled animal study.
University research laboratory.
HT22 neuronal cell line and adult male C57BL/6 mice.
HT22 cells were subjected to pharmacologic induction of ferroptosis or mechanical stretch injury with and without administration of inhibitors of ferroptosis. Mice were subjected to sham or controlled cortical impact injury. Injured mice were randomized to receive vehicle or baicalein (12/15-lipoxygenase inhibitor) at 10-15 minutes postinjury.
Pharmacologic inducers of ferroptosis and mechanical stretch injury resulted in cell death that was rescued by prototypical antiferroptotic agents including baicalein. Liquid chromatography tandem-mass spectrometry revealed the abundance of arachidonic/adrenic-phosphatidylethanolamine compared with other arachidonic/adrenic acid-containing phospholipids in the brain. Controlled cortical impact resulted in accumulation of oxidized phosphatidylethanolamine, increased expression of 15-lipoxygenase and acyl-CoA synthetase long-chain family member 4 (enzyme that generates substrate for the esterification of arachidonic/adrenic acid into phosphatidylethanolamine), and depletion of glutathione in the ipsilateral cortex. Postinjury administration of baicalein attenuated oxidation of arachidonic/adrenic acid-containing-phosphatidylethanolamine, decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus, and improved spatial memory acquisition versus vehicle.
Biomarkers of ferroptotic death were increased after traumatic brain injury. Baicalein decreased ferroptotic phosphatidylethanolamine oxidation and improved outcome after controlled cortical impact, suggesting that 15-lipoxygenase pathway might be a valuable therapeutic target after traumatic brain injury.
The COVID-19 pandemic has generated a rise in psychological distress worldwide. Although fear appears to be a major contributing factor, there has been no systematic research to determine which ...specific facets of fear predict psychopathology during the coronavirus crisis. The present study is the first to examine which fear factors uniquely predict clinical levels of depressive symptoms and generalized anxiety. Data were collected from 256 adults in the United States recruited from Amazon’s Mechanical Turk (MTurk) during the coronavirus pandemic. The results from logistic regression analyses demonstrated that neuroticism, coronaphobia, and hypochondriasis were fear factors that predicted pandemic-related psychopathology in adults. These findings suggest that mental health professionals should screen individuals for this set of fear factors when choosing appropriate assessments and interventions for treating people who are suffering during the crisis.
The modular SCF (Skp1, cullin, and F box) ubiquitin ligases feature a large family of F box protein substrate receptors that enable recognition of diverse targets. However, how the repertoire of SCF ...complexes is sustained remains unclear. Real-time measurements of formation and disassembly indicate that SCFFbxw7 is extraordinarily stable, but, in the Nedd8-deconjugated state, the cullin-binding protein Cand1 augments its dissociation by one-million-fold. Binding and ubiquitylation assays show that Cand1 is a protein exchange factor that accelerates the rate at which Cul1-Rbx1 equilibrates with multiple F box protein-Skp1 modules. Depletion of Cand1 from cells impedes recruitment of new F box proteins to pre-existing Cul1 and profoundly alters the cellular landscape of SCF complexes. We suggest that catalyzed protein exchange may be a general feature of dynamic macromolecular machines and propose a hypothesis for how substrates, Nedd8, and Cand1 collaborate to regulate the cellular repertoire of SCF complexes.
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► Cand1 modulates the repertoire of SCF ubiquitin ligase complexes in cells ► Cand1 functions as an F box protein exchange factor ► FRET assay reveals real-time dynamics of SCFFbxw7 assembly and disassembly ► Cand1 accelerates the dissociation rate of SCFFbxw7 one-million-fold
Cand1 accelerates the dissociation of F box proteins from SCF ubiquitin ligases by one-million-fold. It thereby operates as a protein exchange factor to shape the cellular repertoire of SCF complexes.
Drugging the Cancers Addicted to DNA Repair Nickoloff, Jac A; Jones, Dennie; Lee, Suk-Hee ...
JNCI : Journal of the National Cancer Institute,
11/2017, Letnik:
109, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now ...appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.
Objective To compare the duration of parenteral nutrition, growth, and morbidity in extremely premature infants fed exclusive diets of either bovine milk–based preterm formula (BOV) or donor human ...milk and human milk-based human milk fortifier (HUM), in a randomized trial of formula vs human milk. Study design Multicenter randomized controlled trial. The authors studied extremely preterm infants whose mothers did not provide their milk. Infants were fed either BOV or an exclusive human milk diet of pasteurized donor human milk and HUM. The major outcome was duration of parenteral nutrition. Secondary outcomes were growth, respiratory support, and necrotizing enterocolitis (NEC). Results Birth weight (983 vs 996 g) and gestational age (27.5 vs 27.7 wk), in BOV and HUM, respectively, were similar. There was a significant difference in median parenteral nutrition days: 36 vs 27, in BOV vs HUM, respectively ( P = .04). The incidence of NEC in BOV was 21% (5 cases) vs 3% in HUM (1 case), P = .08; surgical NEC was significantly higher in BOV (4 cases) than HUM (0 cases), P = .04. Conclusions In extremely preterm infants given exclusive diets of preterm formula vs human milk, there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula. This trial supports the use of an exclusive human milk diet to nourish extremely preterm infants in the neonatal intensive care unit.
Shifts in the philosophy of the "state" and a growing emphasis on the "Big Society" have placed an increasing onus on a newly emerging organizational form, social enterprises, to deliver innovative ...solutions to ease societal issues. However, the question of how social enterprises manage the process of social innovation remains largely unexplored. Based on insights from both in-depth interviews and a quantitative empirical study of social enterprises, this research examines the role of stakeholder relationships in supporting the process of social innovation within social enterprises. We find that social enterprises are adept at working with their stakeholders in the ideation stage of social innovation. In contrast, they often fail to harness knowledge and expertise from their partners during the social innovation implementation phase. Consequently, we propose a social innovationstakeholder relationship matrix that provides social enterprises in particular with insight for developing stakeholder relationships to achieve their social innovation missions.
The psychological toll of the COVID-19 pandemic is being felt by people around the world. Persistent and disturbed thinking about the disease appears to be contributing to this mental health concern. ...Although the Obsession with COVID-19 Scale (OCS) has been shown to be a reliable and valid instrument in the U.S., it has not been examined with in Pakistan. The current study addressed this problem by examining the validity of an Urdu translated version of the OCS using online survey data from 240 university students and teachers in Pakistan. The results showed that the OCS exhibited factorial validity, as well as measurement invariance for gender. However, the OCS also showed limited evidence of construct validity in terms of showing weak positive correlations with the total scale and social dysfunction and self-confidence subscales of the General Heath Questionnaire and no correlation with the depression and anxiety subscale (GHQ-12). These findings suggest that further research is necessary before the Urdu version of the OCS is widely adopted in Pakistan.
Abstract Objective Examining covariate balance is the prescribed method for determining the degree to which propensity score methods should be successful at reducing bias. This study assessed the ...performance of various balance measures, including a proposed balance measure based on the prognostic score (similar to a disease risk score), to determine which balance measures best correlate with bias in the treatment effect estimate. Study Design and Setting The correlations of multiple common balance measures with bias in the treatment effect estimate produced by weighting by the odds, subclassification on the propensity score, and full matching on the propensity score were calculated. Simulated data were used, based on realistic data settings. Settings included both continuous and binary covariates and continuous covariates only. Results The absolute standardized mean difference (ASMD) in prognostic scores, the mean ASMD (in covariates), and the mean t -statistic all had high correlations with bias in the effect estimate. Overall, prognostic scores displayed the highest correlations with bias of all the balance measures considered. Prognostic score measure performance was generally not affected by model misspecification, and the prognostic score measure performed well under a variety of scenarios. Conclusion Researchers should consider using prognostic score–based balance measures for assessing the performance of propensity score methods for reducing bias in nonexperimental studies.
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