bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDMX Recruits UbcH5c to Facilitate MDM2 E3 Ligase Activity and Subsequent p53 Degradation In Vivo
Authors: Yang Jing , Jin Aiwen , Han Jing , Chen Xin , Zheng Junnian , Zhang Yanping 
Published: December 2020

Abstract

MDM2 regulates p53 degradation by functioning as an E3 ubiquitin ligase. The role of MDMX, an MDM2 homolog that lacks E3 ligase activity, in the regulation of p53 degradation remains incompletely understood and sometime controversial. This confusion is due at least in part to studies of p53 degradation mainly carried out in in vitro settings, as elimination of either MDM2 or MDMX from mice results in p53-dependent embryonic lethality, thus obfuscating in vivo studies of the individual roles of MDM2 and MDMX in p53 degradation. To overcome this problem, we generated mice expressing an inducible p53 allele under various MDM2 and MDMX deletion and mutation statuses and studied in vivo p53 degradation. Degradation of p53 in vivo was largely prevented in mice and mouse embryonic fibroblast retaining MDM2 but lacking MDMX. Although MDM2 and MDMX interacted with p53 in the absence of each other, they bound p53 more efficiently as a heterodimer. MDMX, but not MDM2, interacted with ubiquitin-conjugating enzyme UbcH5c, an interaction that was essential for MDMX to enable MDM2 E3 ligase activity for p53 degradation. Grafting the C-terminal residues of MDMX to the C-terminus of MDM2 allowed MDM2 to interact with UbcH5c and enhanced MDM2-mediated p53 degradation in the absence of MDMX. Together, these data indicate that MDMX plays an essential role for p53 degradation in vivo by recruiting UbcH5c to facilitate MDM2 E3 ligase function.

Significance:
This study provides the first in vivo evidence of MDMX facilitating MDM2-mediated p53 degradation, clarifying its role in the regulation of this critical tumor suppressor.
KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer
Authors: Gao Lin , Zhang Wenbo , Zhang Jing , Liu Junmei , Sun Feifei , Liu Hui , Hu Jing , Wang Xin , Wang Xueli , Su Peng , Chen Shouzhen , Qu Sifeng , Shi Benkang , Xiong Xueting , Chen Weiwen , Dong Xuesen , Han Bo 
Published: December 2020

Abstract

The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target.

Significance:
These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.
Simplified Breast Risk Tool Integrating Questionnaire Risk Factors, Mammographic Density, and Polygenic Risk Score: Development and Validation
Authors: Rosner Bernard , Tamimi Rulla M. , Kraft Peter , Gao Chi , Mu Yi , Scott Christopher , Winham Stacey J. , Vachon Celine M. , Colditz Graham A. 
Published: December 2020

Abstract

Background:
Clinical use of breast cancer risk prediction requires simplified models. We evaluate a simplified version of the validated Rosner–Colditz model and add percent mammographic density (MD) and polygenic risk score (PRS), to assess performance from ages 45–74. We validate using the Mayo Mammography Health Study (MMHS).

Methods:
We derived the model in the Nurses' Health Study (NHS) based on: MD, 77 SNP PRS and a questionnaire score (QS; lifestyle and reproductive factors). A total of 2,799 invasive breast cancer cases were diagnosed from 1990–2000. MD (using Cumulus software) and PRS were assessed in a nested case–control study. We assess model performance using this case–control dataset and evaluate 10-year absolute breast cancer risk. The prospective MMHS validation dataset includes 21.8% of women age &lt;50, and 434 incident cases identified over 10 years of follow-up.

Results:
In the NHS, MD has the highest odds ratio (OR) for 10-year risk prediction: ORper SD = 1.48 [95% confidence interval (CI): 1.31–1.68], followed by PRS, ORper SD = 1.37 (95% CI: 1.21–1.55) and QS, ORper SD = 1.25 (95% CI: 1.11–1.41). In MMHS, the AUC adjusted for age + MD + QS 0.650; for age + MD + QS + PRS 0.687, and the NRI was 6% in cases and 16% in controls.

Conclusion:
A simplified assessment of QS, MD, and PRS performs consistently to discriminate those at high 10-year breast cancer risk.

Impact:
This simplified model provides accurate estimation of 10-year risk of invasive breast cancer that can be used in a clinical setting to identify women who may benefit from chemopreventive intervention.
See related commentary by Tehranifar et al., p. 587
Effect of Metabolic Health and Obesity Phenotype on the Risk of Pancreatic Cancer: A Nationwide Population-Based Cohort Study
Authors: Chung Hye Soo , Lee Ji Sung , Song Eyun , Kim Jung A , Roh Eun , Yu Ji Hee , Kim Nam Hoon , Yoo Hye Jin , Seo Ji A , Kim Sin Gon , Kim Nan Hee , Baik Sei Hyun , Choi Kyung Mook 
Published: December 2020

Abstract

Background:
Recently, a few studies have reported different results regarding the relationship between metabolic health and obesity phenotype and several cancers. We examined the effects of metabolic health and obesity phenotype on pancreatic cancer using a nationwide population-based cohort database.

Methods:
Using the Korean National Health Insurance Service–Health Screening Cohort, we enrolled 347,434 Korean adults who underwent a health examination between 2009 and 2010 and were followed until 2015. This population was divided into four groups based on metabolically healthy status and body mass index (BMI): metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO).

Results:
Over a median follow-up of 6.1 (5.5–6.5) years, 886 individuals were diagnosed with pancreatic cancer. The adjusted HRs for incident pancreatic cancer were 1.52 [95% confidence interval (CI) 1.27–1.81] and 1.34 (95% CI, 1.12–1.61) for the MUNW and MUO phenotypes (compared with the MHNW phenotype) after adjusting for various confounding factors. However, compared with the MHNW phenotype, the MHO phenotype did not show an elevated risk of pancreatic cancer. Moreover, the HR for pancreatic cancer gradually increased with an increase in number of metabolically unhealthy components, even after adjusting for BMI (Ptrend &lt; 0.001).

Conclusions:
Regardless of BMI, metabolically unhealthy phenotype demonstrated significantly increased risk of pancreatic cancer, whereas obese individuals with metabolically healthy phenotype did not.

Impact:
These findings suggest that metabolically unhealthy phenotype might represent a potential risk factor for pancreatic cancer occurrence independent of obesity.
The Histone Methyltransferase Gene G9A Is Regulated by Nuclear Receptor 4A1 in Alveolar Rhabdomyosarcoma Cells
Authors: Shrestha Rupesh , Mohankumar Kumaravel , Jin Un-ho , Martin Gregory , Safe Stephen 
Published: December 2020

Abstract
The histone methyltransferase G9A (EHMT2) gene catalyzes methylation of histone 3 lysine 9 (H3K9), and this gene silencing activity contributes to the tumor promoter–like activity of G9A in several tumor types including alveolar rhabdomyosarcoma (ARMS). Previous studies show the orphan nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in rhabdomyosarcoma and exhibits pro-oncogenic activity. In this study, we show that knockdown of NR4A1 in ARMS cells decreased expression of G9A mRNA and protein. Moreover, treatment of ARMS cells with several bis-indole–derived NR4A1 ligands (antagonists) including 1,1-bis(3′-indolyl)-1-(4-hydroxyphenyl)methane (CDIM8), 3,5-dimethyl (3,5-(CH3)2), and 3-bromo-5-methoxy (3-Br-5-OCH3) analogs also decreased G9A expression. Furthermore, NR4A1 antagonists also decreased G9A expression in breast, lung, liver, and endometrial cancer cells confirming that G9A is an NR4A1-regulated gene in ARMS and other cancer cell lines. Mechanistic studies showed that the NR4A1/Sp1 complex interacted with the GC-rich 511 region of the G9A promoter to regulate G9A gene expression. Moreover, knockdown of NR4A1 or treatment with NR4A1 receptor antagonists decreased overall H3K9me2, H3K9me2 associated with the PTEN promoter, and PTEN-regulated phospho-Akt. In vivo studies showed that the NR4A1 antagonist (3-Br-5-OCH3) inhibited tumor growth in athymic nude mice bearing Rh30 ARMS cells and confirmed that G9A was an NR4A1-regulated gene that can be targeted by NR4A1 receptor antagonists.
Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP)
Authors: Ulusan Ahmet M. , Rajendran Praveen , Dashwood Wan Mohaiza , Yavuz Omer F. , Kapoor Sabeeta , Gustafson Trace A. , Savage Michelle I. , Brown Powel H. , Sei Shizuko , Mohammed Altaf , Vilar Eduardo , Dashwood Roderick H. 
Published: December 2020

AbstractA clinical trial in patients with familial adenomatous polyposis (FAP) demonstrated that sulindac plus erlotinib (SUL+ERL) had good efficacy in the duodenum and colon, but toxicity issues raised concerns for long-term prevention. We performed a biomarker study in the polyposis in rat colon (Pirc) model, observing phosphorylated Erk inhibition in colon polyps for up to 10 days after discontinuing ERL+SUL administration. In a follow-up study lasting 16 weeks, significant reduction of colon and small intestine (SI) tumor burden was detected, especially in rats given 250 ppm SUL in the diet plus once-a-week intragastric dosing of ERL at 21 or 42 mg/kg body weight (BW). A long-term study further demonstrated antitumor efficacy in the colon and SI at 52 weeks, when 250 ppm SUL was combined with once-a-week intragastric administration of ERL at 10, 21, or 42 mg/kg BW. Tumor-associated matrix metalloproteinase-7 (Mmp7), tumor necrosis factor (Tnf), and early growth response 1 (Egr1) were decreased at 16 weeks by ERL+SUL, and this was sustained in the long-term study for Mmp7 and Tnf. Based on the collective results, the optimal dose combination of ERL 10 mg/kg BW plus 250 ppm SUL lacked toxicity, inhibited molecular biomarkers, and exhibited effective antitumor activity. We conclude that switching from continuous to once-per-week ERL, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care SUL against adenomatous polyps in the colon and SI, with clinical relevance for patients with FAP before or after colectomy.Prevention Relevance:This investigation concludes that switching from continuous to once-per-week erlotinib, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care sulindac against adenomatous polyps in the colon and small intestine, with clinical relevance for patients with FAP before or after colectomy.
Tumor-Infiltrating Natural Killer Cells
Authors: Cózar Beatriz , Greppi Marco , Carpentier Sabrina , Narni-Mancinelli Emilie , Chiossone Laura , Vivier Eric 
Published: December 2020

AbstractBecause of their potent antitumor activity and their proinflammatory role, natural killer (NK) cells are at the forefront of efforts to develop immuno-oncologic treatments. NK cells participate in immune responses to tumors by killing target cells and producing cytokines. However, in the immunosuppressive tumor microenvironment, NK cells become dysfunctional through exposure to inhibitory molecules produced by cancer cells, leading to tumor escape. We provide an overview of what is known about NK tumor infiltration and surveillance and about the mechanisms by which NK cells become dysfunctional.Significance:The functions of tumor-infiltrating NK cells may be impaired. This review aims to describe the various mechanisms by which tumors alter NK-cell functions.
Phase 1b Study to Evaluate Safety, Tolerability, and Maximum Tolerated Dose of PF-05230907 for Intracerebral Hemorrhage
Authors: Silva Blas Yolanda , Diringer Michael N. , Lo Benjamin , Masjuan Jaime , Pérez de la Ossa Natalia , Cardinal Matthew , Yong Florence , Zhu Tong , Li Gang , Arkin Steven 
Published: December 2020

Background and Purpose:
This study aimed to determine the maximum tolerated dose and to evaluate the overall safety and tolerability of single doses of PF-05230907 in subjects with acute intracerebral hemorrhage.

Methods:
Individuals presenting with intracerebral hemorrhage were enrolled in a phase 1, multicenter, open-label clinical trial. A Bayesian modified continual reassessment method design based on treatment-emergent thromboembolic or ischemic events was adopted. Sequential dosing, an external data monitoring committee, and prespecified stopping rules were incorporated as safeguards.

Results:
Twenty-one subjects received PF-05230907. The mean (±SD) age in years and intracerebral hemorrhage volume in mL at baseline were 62 (±9) and 18 (±11), respectively. Two treatment-emergent thromboembolic or ischemic events occurred (deep vein thrombosis and cerebral ischemia), in the 30 μg/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 μg/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 μg/kg, with a mean fitted dose-toxicity estimate of 11.9% (95% CI, 1.2%–27.4%).

Conclusions:
Single doses of PF-05230907 appeared to be tolerated across a range of doses in the intracerebral hemorrhage population, with thrombotic events observed only at the highest dose level tested. Recruitment within the recommended therapeutic window of opportunity remains a challenge.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02687191.
Narcissus and Echo:Reflections on an Art-Science Collaboration
Authors: Steinman Dolores A. , Coppin Peter W. , Steinman David A. 
Published: December 2020

AbstractMore than a decade ago, the authors proposed establishing a basis for scientific exploration of blood-flow dynamics intertwined with the visual arts. Here they present a case study showing how paradigms they codeveloped for visually abstracting cerebral aneurysm blood flows were extrapolated to sonification and bimodal representations, and how a close interdisciplinary partnership was effected by guiding engineering students versed in the arts and artists adept with digital technology toward final outcomes greater than the sum of their parts.
The Choreography of the Creative Process: Drawing in Time and Space
Authors: Zoran Amit Raphael , Dick Nir , Glauber Naama 
Published: December 2020

Abstract
This article provides a new perspective on the contribution of computers to visual art, exploring how the visual product’s aesthetic qualities and the making process itself can render a hybrid artistic outcome. A medium that unifies the physical product with the spirit of the making process has innovative potential for computational artistic practice. The article demonstrates various techniques to visualize artists’ motor performance in activities such as drawing and carving. The authors digitally track artists’ movements and computer graphic tools to expose expressive performance, highlight working styles and bring their strokes’ hidden paths to the artwork’s forefront. The authors discuss contextual application of this form of visualization to new domains of visual art.
World Cinema, vod Platforms and the Western Demand
Authors: Parvulescu Constantin 
Published: December 2020

Abstract
The article explores the concept of world cinema as an other to global cinema from a marketing perspective. Special attention is given to the way the world cinema universe is presented on video-on-demand platforms in Western markets. To demonstrate that the stories, scope and concerns of this universe vary according to marketing objectives, the article compares presentations on three platforms with contrasting business models and marketing algorithms: Netflix, Filmin, and FilmDoo. This leads to an important conclustion: presentations on platforms with an apparently more ethical business model are not necessarily more progressive and more advantageous to world cinema in terms of avoiding its “genre-fication”.
Evolution of intersectional perceived discrimination and internalized stigma during COVID-19 lockdown among the general population in Spain
Authors: Ugidos Carolina , López-Gómez Aída , Castellanos Miguel Ángel , Saiz Jesús , González-Sanguino Clara , Ausín Berta , Muñoz Manuel 
Published: December 2020

Background: Stigma and discrimination have been associated with different diseases and pandemics, with negative consequences for the people who suffered them and for their communities. Currently, COVID-19 has become a new source of stigmatization. Aims: The aim of the present study is to analyze longitudinally the evolution of intersectional perceived discrimination and internalized stigma among the general population of Spain, at three points in time throughout the confinement. Method: Participants completed an online survey. Results: Results show an increase in both variables from the first to the second evaluation, and a slight decrease from the second to the third evaluation. Moreover, these changes are explained by depression, anxiety and family support. Conclusions: These findings indicate the factors that need to be considered to reduce the perception of discrimination and the internalization of stigma, and their detrimental consequences, during an especially stressful event such as the current pandemic outbreak.
Global prevalence of traumatic non-fatal limb amputation
Authors: McDonald Cody L , Westcott-McCoy Sarah , Weaver Marcia R , Haagsma Juanita , Kartin Deborah 
Published: December 2020

Background:
Reliable information on both global need for prosthetic services and the current prosthetist workforce is limited. Global burden of disease estimates can provide valuable insight into amputation prevalence due to traumatic causes and global prosthetists needed to treat traumatic amputations.

Objectives:
This study was conducted to quantify and interpret patterns in global distribution and prevalence of traumatic limb amputation by cause, region, and age within the context of prosthetic rehabilitation, prosthetist need, and prosthetist education.

Study design:
A secondary database descriptive study.

Methods:
Amputation prevalence and prevalence rate per 100,000 due to trauma were estimated using the 2017 global burden of disease results. Global burden of disease estimation utilizes a Bayesian metaregression and best available data to estimate the prevalence of diseases and injuries, such as amputation.

Results:
In 2017, 57.7 million people were living with limb amputation due to traumatic causes worldwide. Leading traumatic causes of limb amputation were falls (36.2%), road injuries (15.7%), other transportation injuries (11.2%), and mechanical forces (10.4%). The highest number of prevalent traumatic amputations was in East Asia and South Asia followed by Western Europe, North Africa, and the Middle East, high-income North America and Eastern Europe. Based on these prevalence estimates, approximately 75,850 prosthetists are needed globally to treat people with traumatic amputations.

Conclusion:
Amputation prevalence estimates and patterns can inform prosthetic service provision, education and planning.
Application of Computerized Adaptive Testing to the Foot and Ankle Ability Measure
Authors: O’Neil Joseph T. , Plummer Otho R. , Raikin Steven M. 
Published: December 2020

Background: Patient-reported outcome measures are an increasingly important tool for assessing the impact of treatments orthopedic surgeons render. Despite their importance, they can present a burden. We examined the validity and utility of a computerized adaptive testing (CAT) method to reduce the number of questions on the Foot and Ankle Ability Measure (FAAM), a validated anatomy-specific outcome measure. Methods: A previously developed FAAM CAT system was applied to the responses of patients undergoing foot and ankle evaluation and treatment over a 3-year period (2017-2019). A total of 15 902 responses for the Activities of Daily Living (ADL) subscale and a total of 14 344 responses for the Sports subscale were analyzed. The accuracy of the CAT to replicate the full-form score was assessed. Results: The CAT system required 11 questions to be answered for the ADL subscale in 85.1% of cases (range, 11-12). The number of questions answered on the Sports subscale was 6 (range, 5-6) in 66.4% of cases. The mean difference between the full FAAM ADL subscale and CAT was 0.63 of a point. The mean difference between the FAAM Sports subscale and CAT was 0.65 of a point. Conclusion: The FAAM CAT was able to reduce the number of responses a patient would need to answer by nearly 50%, while still providing a valid outcome score. This measure can therefore be directly correlated with previously obtained full FAAM scores in addition to providing a foot/ankle-specific measure, which previously reported CAT systems are not able to do. Level of Evidence: Level IV, case series.