bluuebunny/crossref_metadata_2025_split huggingface dataset:
YAP-Mediated Recruitment of YY1 and EZH2 Represses Transcription of Key Cell-Cycle Regulators
Authors: Hoxha Sany , Shepard Alyssa , Troutman Scott , Diao Huitian , Doherty Joanne R. , Janiszewska Michalina , Witwicki Robert M. , Pipkin Matthew E. , Ja William W. , Kareta Michael S. , Kissil Joseph L. 
Published: May 2020

Abstract

The Hippo pathway regulates cell proliferation and organ size through control of the transcriptional regulators YAP (yes-associated protein) and TAZ. Upon extracellular stimuli such as cell–cell contact, the pathway negatively regulates YAP through cytoplasmic sequestration. Under conditions of low cell density, YAP is nuclear and associates with enhancer regions and gene promoters. YAP is mainly described as a transcriptional activator of genes involved in cell proliferation and survival. Using a genome-wide approach, we show here that, in addition to its known function as a transcriptional activator, YAP functions as a transcriptional repressor by interacting with the multifunctional transcription factor Yin Yang 1 (YY1) and Polycomb repressive complex member enhancer of zeste homologue 2 (EZH2). YAP colocalized with YY1 and EZH2 on the genome to transcriptionally repress a broad network of genes mediating a host of cellular functions, including repression of the cell-cycle kinase inhibitor p27, whose role is to functionally promote contact inhibition. This work unveils a broad and underappreciated aspect of YAP nuclear function as a transcriptional repressor and highlights how loss of contact inhibition in cancer is mediated in part through YAP repressive function.

Significance:
This study provides new insights into YAP as a broad transcriptional repressor of key regulators of the cell cycle, in turn influencing contact inhibition and tumorigenesis.
Arginine Depletion Therapy with ADI-PEG20 Limits Tumor Growth in Argininosuccinate Synthase–Deficient Ovarian Cancer, Including Small-Cell Carcinoma of the Ovary, Hypercalcemic Type
Authors: Ji Jennifer X. , Cochrane Dawn R. , Tessier-Cloutier Basile , Chen Shary Yutin , Ho Germain , Pathak Khyatiben V. , Alcazar Isabel N. , Farnell David , Leung Samuel , Cheng Angela , Chow Christine , Colborne Shane , Negri Gian Luca , Kommoss Friedrich , Karnezis Anthony , Morin Gregg B. , McAlpine Jessica N. , Gilks C. Blake , Weissman Bernard E. , Trent Jeffrey M. , Hoang Lynn , Pirrotte Patrick , Wang Yemin , Huntsman David G. 
Published: May 2020

Abstract

Purpose:
Many rare ovarian cancer subtypes, such as small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), have poor prognosis due to their aggressive nature and resistance to standard platinum- and taxane-based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes.

Experimental Design:
We compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype, high-grade serous ovarian cancer (HGSC), to identify potential therapeutic targets. IHC of tissue microarrays was used as validation of arginosuccinate synthase (ASS1) deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient-derived xenograft mouse models representing SCCOHT.

Results:
Global proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared with HGSC. Low ASS1 levels were validated through IHC in large patient cohorts. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 12 of 31 cases, and expressed in less than 5% of the tumor cells in 9 of 31 cases. ASS1-deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient-derived mouse xenograft model of SCCOHT, once-a-week treatment with ADI-PEG20 (30 mg/kg and 15 mg/kg) inhibited tumor growth in vivo.

Conclusions:
Preclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT.
Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development
Authors: Chu Nina J. , Anders Robert A. , Fertig Elana J. , Cao Minwei , Hopkins Alexander C. , Keenan Bridget P. , Popovic Aleksandra , Armstrong Todd D. , Jaffee Elizabeth M. , Zimmerman Jacquelyn W. 
Published: May 2020

Abstract
Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. In vivo miR-21 inhibition improved survival in established PDA. Importantly, early systemic miR-21 inhibition completely intercepted premalignant progression. Finally, an evaluation of miR-21 expression in the PDA cohort of The Cancer Genome Atlas identified a correlation between tumor epithelial cell content and miR-21 expression in human tumors providing further rationale for conducting human studies. Thus, miR-21 may be useful for early PanIN detection, and for intercepting developing premalignant pancreatic lesions and other KRAS-driven premalignancies.
In Vitro Lineage-Specific Differentiation of Vascular Smooth Muscle Cells in Response to SMAD3 Deficiency
Authors: Gong Jian , Zhou Dong , Jiang Longtan , Qiu Ping , Milewicz Dianna M. , Chen Y. Eugene , Yang Bo 
Published: May 2020

Objective:
SMAD3 pathogenic variants are associated with the development of thoracic aortic aneurysms. We sought to determine the role of SMAD3 in lineage-specific vascular smooth muscle cells (VSMCs) differentiation and function.

Approach and Results:

SMAD3
c.652delA, a frameshift mutation and nonsense-mediated decay, was introduced in human-induced pluripotent stem cells using CRISPR-Cas9. The wild-type and
SMAD3
−/−
(c.652delA) human-induced pluripotent stem cells were differentiated into cardiovascular progenitor cells or neural crest stem cells and then to lineage-specific VSMCs. Differentiation, contractility, extracellular matrix synthesis, and TGF-β (transforming growth factor-β) signaling of the differentiated VSMCs were analyzed. The homozygous frameshift mutation resulted in SMAD3 deficiency and was confirmed in human-induced pluripotent stem cells by Sanger sequencing and immunoblot analysis. In cardiovascular progenitor cell-VSMCs, SMAD3 deletion significantly disrupted canonical TGF-β signaling and decreased gene expression of VSMC markers, including SM α-actin, myosin heavy chain 11, calponin-1, SM22α, and key controlling factors, SRF and myocardin, but increased collagen expression. The loss of SMAD3 significantly decreased VSMC contractility. In neural crest stem cells-VSMCs, SMAD3 deficiency did not significantly affect the VSMC differentiation but decreased ELN (elastin) expression and increased phosphorylated SMAD2. Expression of mir-29 was increased in
SMAD3
−/−
VSMCs, and inhibition of mir-29 partially rescued ELN expression.

Conclusions:

SMAD3-dependent TGF-β signaling was essential for the differentiation of cardiovascular progenitor cell-VSMCs but not for the differentiation of neural crest stem cell-VSMCs. The lineage-specific TGF-β responses in human VSMCs may potentially contribute to the development of aortic root aneurysms in patients with
SMAD3
mutations.
Effects of a Hypercaloric and Hypocaloric Diet on Insulin-Induced Microvascular Recruitment, Glucose Uptake, and Lipolysis in Healthy Lean Men
Authors: Emanuel Anna L. , Meijer Rick I. , Woerdeman Jorn , van Raalte Daniel H. , Diamant Michaela , Kramer Mark H.H. , Serlie Mireille J. , Eringa Etto C. , Serné Erik H. 
Published: May 2020

Objective:
In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis.

Approach and Results:

Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after the hypercaloric diet in study participants and controls (n=5). The hypercaloric diet increased body weight (3.5 kg;
P
<0.001) and fat percentage (3.5%;
P
<0.001) but did not affect glucose uptake nor lipolysis. The hypercaloric diet increased adipose tissue microvascular recruitment (
P
=0.041) and decreased the ratio between skeletal muscle and adipose tissue microvascular blood volume during hyperinsulinemia (
P
=0.019). Insulin-induced vasodilation of isolated skeletal muscle arterioles was significantly lower in participants compared with controls (
P
<0.001). The hypocaloric diet reversed all of these changes, except the increase in adipose tissue microvascular recruitment.

Conclusions:
In lean men, short-term overfeeding reduces insulin-induced vasodilation of skeletal muscle resistance arteries and shifts the distribution of tissue perfusion during hyperinsulinemia from skeletal muscle to adipose tissue without affecting glucose uptake and lipolysis.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02628301.
Abstract 282: Long Term Exercise And Women With Heart Disease
Authors: Behnke Lyn M , Pattison Kelley 
Published: May 2020

A sedentary lifestyle has long been recognized as a risk factor for heart disease. Although little data exists on the relationship of exercise based on gender in the risk factor analysis, most guidelines support the importance of exercise in the prevention and treatment of heart disease. Bach (2020) published the American Heart Association scientific statement of long-term exercise and cardiovascular events that provides guidance for clinicians recommending exercise.
A recent survey of 395 women living with varying types of heart disease revealed that although many had been referred to cardiac rehabilitation, many did not exercise on a routine basis.
Interestingly, the barriers to attending cardiac rehab were relatively sparse. Eleven (3%) women who met criteria identified that their insurance wouldn’t cover cardiac rehab. Travel was a barrier for nine(3 %) patients, 21 (6%) patients identified distance as a barrier and eight(2%) couldn’t get off work to attend.
The worrisome component is that now, only 27.86% of the participants exercise on a routine basis. This has implications for morbidity in the future as Mediano, Leifer, Cooper, et al (2018) identify in the evaluation of baseline physical activity and outcomes in heart failure.
In this population, living in both suburban and rural areas are not conducive to exercise. Although the number of urban participants who exercise is higher than the other geographic areas, the percentage is still unsatisfactory.

The next steps for clinicians: •Develop a realistic evidence-based exercise prescription
OR
•Develop an interdisciplinary team of exercise physiologists, nurses, respiratory therapists and physical therapists who can identify specific exercise plans that meet the needs and resources of the female patient with heart disease. •Participate with communities to develop a mindset for exercise. •Participate in developing infrastructure for exercise facilities, trails, and other resources needing development, especially in rural areas.
Automatic Triage of 12‐Lead ECGs Using Deep Convolutional Neural Networks
Authors: van de Leur Rutger R. , Blom Lennart J. , Gavves Efstratios , Hof Irene E. , van der Heijden Jeroen F. , Clappers Nick C. , Doevendans Pieter A. , Hassink Rutger J. , van Es René 
Published: May 2020

BACKGROUND

The correct interpretation of the
ECG
is pivotal for the accurate diagnosis of many cardiac abnormalities, and conventional computerized interpretation has not been able to reach physician‐level accuracy in detecting (acute) cardiac abnormalities. This study aims to develop and validate a deep neural network for comprehensive automated
ECG
triage in daily practice.

METHODS AND RESULTS

We developed a 37‐layer convolutional residual deep neural network on a data set of free‐text physician‐annotated 12‐lead
ECG
s. The deep neural network was trained on a data set with 336.835 recordings from 142.040 patients and validated on an independent validation data set (n=984), annotated by a panel of 5 cardiologists electrophysiologists. The 12‐lead
ECG
s were acquired in all noncardiology departments of the University Medical Center Utrecht. The algorithm learned to classify these
ECG
s into the following 4 triage categories: normal, abnormal not acute, subacute, and acute. Discriminative performance is presented with overall and category‐specific concordance statistics, polytomous discrimination indexes, sensitivities, specificities, and positive and negative predictive values. The patients in the validation data set had a mean age of 60.4 years and 54.3% were men. The deep neural network showed excellent overall discrimination with an overall concordance statistic of 0.93 (95%
CI
, 0.92–0.95) and a polytomous discriminatory index of 0.83 (95%
CI
, 0.79–0.87).

CONCLUSIONS

This study demonstrates that an end‐to‐end deep neural network can be accurately trained on unstructured free‐text physician annotations and used to consistently triage 12‐lead
ECG
s. When further fine‐tuned with other clinical outcomes and externally validated in clinical practice, the demonstrated deep learning–based
ECG
interpretation can potentially improve time to treatment and decrease healthcare burden.
Expanding or Accepting
Authors: Li Jiangyu 
Published: May 2020

Abstract
The Confucius Institute (CI), one vehicle for promoting a new narrative of Chinese national identity, has been controversial since its establishment. In contrast with political scientists who discuss the CI from a macro-perspective and argue that it is a state apparatus, this article focuses on micro- and meso-aspects of CI teachers’ everyday lives and social engagement in their locality, Thailand. When Chinese nationness meets Thainess, CI teachers made their own calculations as to how much Chineseness and Thainess they should dip in and out of to accomplish their nation-work. Nation-work is a synthesised concept that includes the way CI teachers are “saying,” “doing,” and “otherising” the nations. By employing “Chinese and Thais are like one family,” CI teachers reproduced the Sino-Thai “brotherhood.” For staying in Thailand “peacefully,” they invented their own “tradition.” Cultural activities become a nuanced way to “overcommunicate” Chineseness on the stage, with uneven quality.
Taxonomic assessment and distribution of common toads (Bufo bufo and B. verrucosissimus) in Turkey based on morphological and molecular data
Authors: Özdemir Nurhayat , Dursun Cantekin , Üzüm Nazan , Kutrup Bilal , Gül Serkan 
Published: May 2020

Abstract
The Bufo bufo species group includes four species distributed in the western Palearctic: B. bufo, B. eichwaldii, B. spinosus and B. verrucosissimus. Both B. bufo and B. verrucosissimus are known to occur in Turkey, but their range boundaries and the taxonomic status of B. verrucosissimus are still uncertain. In this study, we analyzed the variation in a set of morphological characters and in two mitochondrial and two nuclear DNA markers to address these questions. Phylogenetic analyses of sequence data support two main clades of common toads in Turkey, corresponding to B. bufo and B. verrucosissimus. The latter is subdivided into two allopatric subclades including populations along the Mediterranean and Black Sea coast, respectively. Discriminant analysis of morphological data showed separation among groups as defined by molecular analyses. We discuss these results and their implications for the evolutionary history of common toads in Turkey.
Cardiac response to stimulation and stress in the American alligator (Alligator mississippiensis)
Authors: Young Bruce A. , Potter James , Blanchard Joshua , Knoche Lucas , Kondrashova Tatyana 
Published: May 2020

Abstract
Previous descriptions of the direction (tachycardia versus bradycardia), magnitude, and duration of the cardiac stimulation/stress response of the American alligator (Alligator mississippiensis) have been contradictory. Superficial EKG leads were used to quantify heart rate while presenting a graded series of stimuli to a cohort of 5 sub-adult alligators. Only tachycardic responses were recorded. Stress (manual restraint and transport) induced a nearly 3-fold increase over the resting heart rate (∼17 bpm), which decreased only 7 bpm over 40 minutes in a stimulus-free environment. Lower-level stimulation (i.e., exposure to room light) produced a significantly smaller response than did higher-level stimulation (i.e., physical contact), both responses were transitory, lasting approximately 120 s.
The Priority of the Good and the Contrapuntal Character of Aristotle’s Politics I
Authors: Smith Thomas W. 
Published: May 2020

Abstract
Politics I has been the subject of a number of textual questions about the relation of the Ethics to the Politics. These textual questions involve us in theoretical questions about the differences between contemporary and ancient conceptions of political rule. Resolving the exegetical challenges can help us clarify the theoretical differences. A fresh approach to the textual challenges reveals that Politics I has a contrapuntal character with two reinforcing movements. One explores why and how despotic conceptions of politics fail using case studies of despotic power: slavery and money-making. Aristotle shows dialectically how this despotic approach to rule undermines the requirements for political life. The other movement explores the character of natural human associations, culminating in the polis. The two movements converge in Aristotle’s claim about the centrality of the human good for political rule. This claim challenges modern social contract theory’s understanding of the differences between despotic and political rule.
Leukoreduction in ex vivo perfusion circuits: comparison of leukocyte depletion efficiency with leukocyte filters
Authors: Fahradyan Vahe , Annunziata Michael J , Said Sayf , Rao Maya , Shah Hirsh , Ordenana Carlos , Papay Frank A , Rampazzo Antonio , Bassiri Gharb Bahar 
Published: May 2020

Background: Leukodepletion of whole blood-based perfusates remains a challenge in experimental models of ex vivo perfusion. This study investigated the leukoreduction efficacy of the commonly used LeukoGuard LG Arterial and BC2 Cardioplegia filters. Methods: Eleven liters of washed porcine blood was used to evaluate the filtration efficiency of LG (n = 6) and BC2 (n = 5) filters. Filter efficacy was tested by passing 1 L of washed blood through each filter. Complete blood count was performed to detect a reduction of white blood cells, red blood cells, and hemoglobin concentration. Results: The BC2 Cardioplegia filter showed a significant reduction in white blood cell count (13.16 ± 4.2 × 103 cells/μL pre-filtration, 0.62 ± 0.61 cells/μL post-filtration, p = 0.005), red blood cell count (9.18 ± 0.16 × 106 cells/μL pre-filtration, 9.02 ± 0.16 × 106 cells/μL post-filtration, p = 0.012) and hemoglobin concentration (15.89 ± 0.66 g/dL pre-filtration, 15.67 ± 0.83 g/dL post-filtration, p = 0.017). Platelet reduction in the LG filter group was statistically significant (13.23 ± 13.98 × 103 cells/μL pre-filtration, 7.15 ± 3.31 × 103 cells/μL post-filtration, p = 0.029), but no difference was seen in the BC2 group. There was no significant difference in white blood cell count in the LG filter group (10.12 ± 3.0 × 103 cells/μL pre-filtration, 10.32 ± 2.44 × 103 cells/μL post-filtration, p = 0.861). Conclusion: Our results suggest that the LG filter should not be used in ex vivo perfusion circuits for the purpose of leukodepletion. The BC2 filter can be used in EVP circuits with flow rates of less than 350 mL/min. Alternatively, perfusate may be leukodepleted before perfusion.
Hips With Acetabular Retroversion Can Be Safely Treated With Advanced Arthroscopic Techniques Without Anteverting Periacetabular Osteotomy: Midterm Outcomes With Propensity-Matched Control Group
Authors: Maldonado David R. , Chen Jeffery W. , Kyin Cynthia , Rosinsky Philip J. , Shapira Jacob , Karom Jarod M. , Lall Ajay C. , Domb Benjamin G. 
Published: May 2020

Background: Different options, from reverse (anteverting) periacetabular osteotomy to hip arthroscopy, have been proposed for surgical treatment of femoroacetabular impingement syndrome (FAIS) in the setting of acetabular retroversion. Purpose: (1) To report and analyze midterm patient-reported outcome scores (PROs) in patients with FAIS and labral tears in the setting of acetabular retroversion after isolated hip arthroscopy and (2) to compare these PROs with those of a propensity-matched control group without acetabular retroversion. Study Design: Cohort study; Level of evidence, 3. Methods: Prospectively collected data were retrospectively reviewed for patients who underwent hip arthroscopy for FAIS and labral tear treatment between June 2008 and March 2014. Inclusion criteria were as follows: acetabular retroversion, pre- and postoperative PROs for modified Harris Hip Score (mHHS), Non-arthritic Hip Score, Hip Outcome Score–Sports Specific Scale (HOS-SSS), and visual analog scale (VAS). Propensity score matching was utilized to identify a control group without acetabular retroversion matched 1:1 with similar age, sex, body mass index, acetabular and femoral head Outerbridge grade, preoperative lateral center-edge angle, and labral treatment. Patient acceptable symptomatic state (PASS) and/or minimal clinically important difference (MCID) for the mHHS, HOS-SSS, International Hip Outcome Tool–12, and VAS was calculated. Results: A total of 205 hips with acetabular retroversion were matched to a control group. The groups showed no difference in demographic variables. The retroversion group was composed of 139 female and 66 male hips, with a mean ± SD age of 23.81 ± 7.28 years and follow-up time of 65.24 ± 20.31 months. Intraoperative diagnostic data and procedures performed were similar between groups, except more femoroplasties were performed in the retroversion group. Significant improvements for the mHHS, Non-arthritic Hip Score, HOS-SSS, and VAS were seen for both groups at a mean 5-year follow-up. The proportion of patients who reached the PASS and MCID were similar. Conclusion: In the setting of FAIS and labral tears, patients with acetabular retroversion can be safely treated with advanced hip arthroscopic techniques without reverse (anteverting) periacetabular osteotomy in a high-volume surgeon’s hands. Patients with acetabular retroversion demonstrated favorable PROs at midterm follow-up. Furthermore, the proportion of patients reaching the MCID and PASS for several PROs were comparable with those of a propensity-matched control group without acetabular retroversion.