Defects in apoptosis signaling contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), and overexpression of antiapoptotic Bcl-2 (Bcl-2 and Bcl-XL) family proteins has been ...observed in ALL. ABT-737 is a small-molecule BH3-mimetic that inhibits the antiapoptotic Bcl-2 family proteins. We evaluated the cytotoxicity of ABT-737 in combination with vincristine, dexamethasone, and L-asparaginase (VXL) in 7 ALL cell lines. Multilog synergistic cytotoxicity was observed in all 7 cell lines with ABT-737 plus L-asparaginase or vincristine, and in 5 of 7 cell lines with ABT-737 plus dexamethasone or VXL. In leukemia cells, but not in normal lymphocytes, ABT-737 plus L-asparaginase induced greater mitochondrial depolarization (JC-1 staining); mitochondrial cytochrome c release; activation of Bax, Bid, and caspases (immunoblotting); and eventually apoptosis (annexin V staining) than did either drug alone. In mouse xenografts derived from patients with ALL at diagnosis (ALL-7) or at relapse (ALL-19), event-free survival (EFS) was significantly enhanced with ABT-737 plus VXL relative to VXL or ABT-737 alone (P ≤ .02). Thus, ABT-737 synergistically enhanced VXL cytotoxicity in ALL cell lines via a mitochondrial death pathway and enhanced EFS in VXL-treated mice bearing ALL xenografts. Combining VXL with a BH3-mimetic warrants clinical investigation in ALL at relapse and potentially in chemotherapy-resistant ALL subgroups.
Although p120-catenin regulates adherens junction (AJ) stability in cultured cells, genetic studies in lower eukaryotes have not revealed a role for this protein in vivo. Using conditional targeting ...in mice, we show that
p120 null neonatal epidermis exhibits reduced intercellular AJ components but no overt disruption in barrier function or intercellular adhesion. As the mice age, however, they display epidermal hyperplasia and chronic inflammation, typified by hair degeneration and loss of body fat. Using skin engraftments and anti-inflammatory drugs, we show that these features are not attributable to reductions in junctional cadherins and catenins, but rather NFkB activation. Both in vivo and in vitro,
p120 null epidermal cells activate nuclear NFkB, triggering a cascade of proinflammatory NFkB targets. Although the underlying mechanism is likely complex, we show that p120 affects NFkB activation and immune homeostasis in part through regulation of Rho GTPases. These findings provide important new insights into p120 function.
The analysis of relativistically broadened X-ray spectral features from the inner accretion disk provides a powerful tool for measuring the spin of supermassive black holes in active galactic nuclei ...(AGNs). However, AGN spectra are often complex and careful analysis employing appropriate and self-consistent models is required if one has to obtain robust results. In this paper, we revisit the deep 2009 July Suzaku observation of the Seyfert galaxy NGC 3783 in order to study in a rigorous manner the robustness of the inferred black hole spin parameter. Using Monte Carlo Markov chain techniques, we identify a (partial) modeling degeneracy between the iron abundance of the disk and the black hole spin parameter. We show that the data for NGC 3783 strongly require both supersolar iron abundance (Z sub(Fe) = 2-4 Z sub(middot in circle)) and a rapidly spinning black hole (a > 0.89). We discuss various astrophysical considerations that can affect the measured abundance. We note that, while the abundance enhancement inferred in NGC 3783 is modest, the X-ray analysis of some other objects has found extreme iron abundances. We introduce the hypothesis that the radiative levitation of iron ions in the innermost regions of radiation-dominated AGN disks can enhance the photospheric abundance of iron. We show that radiative levitation is a plausible mechanism in the very inner regions of high accretion rate AGN disks.
Evolutionary theory hypothesizes that intermediate virulence maximizes pathogen fitness as a result of a trade-off between virulence and transmission, but empirical evidence remains scarce. We bridge ...this gap using data from a large and long-standing HIV-1 prospective cohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data to derive evolutionary predictions based on analysis and detailed individual-based simulations. We robustly predict stabilising selection towards a low level of virulence, and rapid attenuation of the virus. Accordingly, set-point viral load, the most common measure of virulence, has declined in the last 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with both subtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads should have resulted in a 20% reduction in incidence, and a three years extension of untreated asymptomatic infection, increasing opportunities for timely treatment of infected individuals.
This manuscript proposes and tests a model that includes retailer interest as a measure of consumers’ response to a retailer. Retailer interest was found to have a significant main effect on looking ...forward to visiting the retailer again, loyalty, positive word of mouth, and a desire to learn more about the retailer, even while modeling the influence on satisfaction on these variables. Retailer interest was also found to have a significant interaction with satisfaction in predicting repatronage intentions and positive word of mouth. The implications of the retailer interest construct are discussed, as well as limitations and areas for future research.
Background:
Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these ...patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI No-MI). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA.
Methods:
Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms “MI,” “nonobstructive,” “angiography,” and “prognosis” were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran’s Q and I
2
statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI.
Results:
The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%–4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%–3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% 95% CI, 2.5%–4.1% versus 5.6% 95% CI, 4.1%–7.0%; odds ratio, 0.60 95% CI, 0.52–0.70,
P
<0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% 95% CI, 0%–5.9%) compared with No-MI (0.7% 95% CI, 0.1%–1.3%; odds ratio, 3.71 95% CI, 0.58–23.61,
P
=0.09).
Conclusions:
In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI.
Registration:
URL:
https://www.crd.york.ac.uk/PROSPERO/
; Unique identifier: CRD42020145356.
Previous studies have treated the impulse buying tendency as a generalized consumer trait consistent across product categories. This study extends previous conceptualizations and treats impulse ...buying tendency as context or product category specific. The results indicated that a product-specific conceptualization of the impulse buying behavior was a better predictor of actual impulse purchasing behavior when compared to general impulse buying tendency for two product categories. In addition, involvement was found to be an important variable impacting consumers' tendencies to purchase products of a particular product category on impulse. Implications and areas for future research are also addressed.
Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed ...genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (
,
,
,
,
, and
) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.
Theoretical and experimental studies are presented to characterize the anisotropic plastic response under torsion loading of two nominally identical aluminum Al6061-T6 extruded round bars. ...Theoretical models are developed using isotropic (Von Mises 1913) and anisotropic (Barlat 1991) yield criteria, along with isotropic strain hardening formulae, to model post-yield behavior under simple torsion loading. For the case of simple shear loading, incremental plasticity theory is used to determine the theoretical elastic, plastic, and total shear strains. A set of experiments are performed to calibrate Barlat’s 1991 yield function. Several specimens are extracted at different orientations to the longitudinal direction of each round Al6061-T6 bar and tested under uniaxial tension and simple torsion to optimally determine all anisotropic (Barlat 1991) yield function parameters. During loading, Stereo Digital Image Correlation (DIC) is used to quantify surface deformations for the torsion experiments and a baseline tension specimen to identify and correct measurement anomalies. Results show the isotropic yield model either underestimates or overestimates the experimental shear strains for both extrusions. Conversely, results using the Barlat 1991 anisotropic yield criteria are in excellent agreement with experimental measurements for both extrusions. The presence of significant differences in the anisotropic parameters for nominally similar extrusions confirms that plastic anisotropy is essential for the accurate prediction of mechanical behavior in longitudinally extruded Al6061-T6 bars.
Background:
Significant psychological impact and prevalence of posttraumatic stress disorder (PTSD) have been well documented in patients sustaining anterior cruciate ligament injury.
Purpose:
To ...examine PTSD symptomatology in baseball players after sustaining elbow ulnar collateral ligament (UCL) injury.
Study Design:
Cross-sectional study; Level of evidence, 3.
Methods:
Male baseball players of various competition levels (high school through Minor League Baseball MiLB) who underwent surgery for a UCL injury between April 2019 and June 2022 participated in the study. Before surgery, patients completed the Impact of Event Scale–Revised (IES-R) to assess PTSD symptomatology. Subgroup analysis was conducted according to level of play and player position.
Results:
A total of 104 male baseball players with a mean age of 19.4 years (range, 15-29 years) were included in the study; 32 players (30.8%) were in high school, 65 (62.5%) were in college, and 7 (6.7%) were in MiLB. There were 64 (61.5%) pitchers, 18 (17.3%) position players, and 22 (21.2%) 2-way players (both pitching and playing on the field). A total of 30 (28.8%) patients scored high enough on the IES-R to support PTSD as a probable diagnosis, and another 22 patients (21.2%) scored high enough to support PTSD as a clinical concern. Nineteen patients (18.3%) had potentially severe PTSD. Only 4 players (3.8%) were completely asymptomatic. Subgroup analysis revealed college players as significantly more symptomatic than high school players (P = .02), and 2-way players were found to be significantly less susceptible to developing symptoms of PTSD compared with pitchers (P = .04).
Conclusion:
Nearly 30% of baseball players who sustained a UCL injury qualified for a probable diagnosis of PTSD based on the IES-R. Pitchers and college athletes were at increased risk for PTSD after UCL injury compared with 2-way players and high school athletes, respectively.
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