bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?
Authors: Sena Laura A. , Denmeade Samuel R. 
Published: June 2021

Abstract
Tumor metabolism supports the energetic and biosynthetic needs of rapidly proliferating cancer cells and modifies intra- and intercellular signaling to enhance cancer cell invasion, metastasis, and immune evasion. Prostate cancer exhibits unique metabolism with high rates of de novo fatty acid synthesis driven by activation of the androgen receptor (AR). Increasing evidence suggests that activation of this pathway is functionally important to promote prostate cancer aggressiveness. However, the mechanisms by which fatty acid synthesis are beneficial to prostate cancer have not been well defined. In this review, we summarize evidence indicating that fatty acid synthesis drives progression of prostate cancer. We also explore explanations for this phenomenon and discuss future directions for targeting this pathway for patient benefit.
MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma
Authors: Krenz Bastian , Gebhardt-Wolf Anneli , Ade Carsten P. , Gaballa Abdallah , Roehrig Florian , Vendelova Emilia , Baluapuri Apoorva , Eilers Ursula , Gallant Peter , D'Artista Luana , Wiegering Armin , Gasteiger Georg , Rosenfeldt Mathias T. , Bauer Stefan , Zender Lars , Wolf Elmar , Eilers Martin 
Published: June 2021

Abstract

Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC.

Significance:
This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.
Site-Dependent Immune Escape Due to Impaired Dendritic Cell Cross-Priming
Authors: Diamond Mark S. , Lin Jeffrey H. , Vonderheide Robert H. 
Published: June 2021

Abstract

T-cell recognition of tumor neoantigens is critical for cancer immune surveillance and the efficacy of immunotherapy. Tumors can evade host immunity by altering their antigenicity or orchestrating an immunosuppressive microenvironment, leading to outgrowth of poorly immunogenic tumors through the well-established process of cancer immunoediting. Whether cancer immune surveillance and immunoediting depend on the tissue site of origin, however, is poorly understood. Herein, we studied T-cell–mediated surveillance of antigenic, clonal murine pancreatic adenocarcinoma cells expressing neoantigen. Whereas such tumors are robustly eliminated after subcutaneous or intravenous challenge, we observed selective immune escape within the pancreas and peritoneum. Tumor outgrowth occurred in the absence of immunoediting, and antitumor immunity could not be rescued by PD-1 or CTLA-4 checkpoint blockade. Instead, tumor escape was associated with diminished CD8+ T-cell priming by type I conventional dendritic cells (cDC1). Enhancing cDC1 cross-presentation by CD40 agonist treatment restored immunologic control by promoting T-cell priming and broadening T-cell responses through epitope spread. These findings demonstrate that immune escape of highly antigenic tumors can occur without immunoediting in a tissue-restricted manner and highlight barriers to cDC1-mediated T-cell priming imposed by certain microenvironments that must be addressed for successful combination immunotherapies.
Gifted education: Perspectives and practices of school principals in Bahrain
Authors: Al-Mahdi Osama , Yaakub Abduyah Binte , Abouzeid Abdelbaky 
Published: June 2021

<span lang="EN-US">Research on giftedness and gifted education has a rich history. Researchers have consistently pointed to the educational leadership perspectives on giftedness, and inequitable identification of policies and practices in gifted education. Research suggests there is a widening gap in the level of comprehensive knowledge in gifted education that is critical for school improvement. This paper examined school principals’ (n=29) perceptions regarding giftedness among Bahraini students. The study focuses on exploring the characteristics school principals attribute to giftedness in their schools, the methods employed by schools to identify gifted students from the school principals' perspectives, and the educational provisions school principals used to support gifted students in their school. The study also searches for any significant differences among school principals in their views on these three dimensions. The study employed quantitative methodology and the analysis of the research questionnaire included descriptive and interpretive analysis (ANOVA and T-test). The findings indicate that the school principals looked at giftedness mainly from an academic and school perspective. The results indicate some dissonance between what the principals’ perceptions on giftedness are and the educational support that they provided to the gifted students in their schools.</span>
A Dimensão Política do Atual Processo de Agilização do Licenciamento Ambiental no Brasil
Authors: Carmo Aline Borges do 
Published: June 2021

Buscou-se fazer uma análise do atual processo de agilização do licenciamento ambiental no Brasil, que, embora travestido de roupagens técnico-científicas, apresenta motivações políticas, uma vez que grupos de interesse com poder de negociação têm agido no sentido de pressionar os órgãos ambientais para a rápida aprovação de pedidos de concessão de licenças ambientais. O resultado são estratégias, mais e menos visíveis através de evidências empíricas, tais quais a flexibilização de normas existentes e criação de novas normas a fim de facilitar a obtenção de licenças ambientais, bem como o aumento de tensões interinstitucionais e intrainstitucionais nos órgãos ambientais. O entendimento do momento atual, de relativo esmorecimento do movimento ambientalista e de crise global pode ajudar a compreender as reais motivações por trás destas mudanças. Entende-se que qualquer política pública ambiental que esbarre no desenvolvimento econômico enfrentará o mesmo problema, de forma que discussões sobre a questão ambiental deveriam transcender o ambiente acadêmico, demandando participação política ativa de todos os setores da sociedade, na busca da chamada justiça ambiental.
Proton Pump Inhibitors Directly Block hERG-Potassium Channel and Independently Increase the Risk of QTc Prolongation in a Large Cohort of US Veterans
Authors: Lazzerini Pietro Enea , Cartocci Alessandra , Qu Yongxia Sarah , Saponara Simona , Furini Simone , Fusi Fabio , Fabris Frank , Gamberucci Alessandra , El-Sherif Nabil , Cevenini Gabriele , Pettini Francesco , Laghi-Pasini Franco , Acampa Maurizio , Bertolozzi Iacopo , Capecchi Pier Leopoldo , Lazaro Deana , Boutjdir Mohamed 
Published: June 2021

Background:
Worldwide, there are millions of chronic proton pump inhibitor (PPI) users, often without a compelling indication. Evidence indicates that PPI treatment can increase mortality, in part, due to a higher risk of heart rate–corrected QT interval-related malignant arrhythmias. Drug-induced hypomagnesemia is currently believed to be the only underlying mechanism, and, therefore, serum magnesium monitoring is recommended to minimize arrhythmic risk. However, recent data suggest that PPIs might also directly interfere with cardiac electrophysiology. To test this hypothesis, a translational study was performed using a combination of electrophysiology, molecular dynamics simulations, and population data.

Methods:
First, the effect of different PPIs on the human ether-a-go-go-related gene potassium channel (hERG) current was evaluated in human embryonic kidney 293 cells expressing hERG. Then, free-energy calculations were performed to investigate the binding of these drugs to hERG. Finally, the impact of PPIs on the risk of heart rate–corrected QT interval prolongation was assessed in a retrospective observational cohort of 3867 US veterans, including 1289 PPI-treated subjects.

Results:
Clinically relevant concentrations of different PPIs induced a significant inhibition of the hERG current in vitro, pantoprazole and lansoprazole being the most potent compounds. Atomic simulations demonstrated that such a blocking class effect is likely due to direct PPIs binding to hERG channel pore cavity. Accordingly, in a US veterans cohort, PPI treatment was independently associated with an ≈20% to 40% increased risk of heart rate–corrected QT interval prolongation, also regardless of hypomagnesemia. Moreover, a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors was demonstrated.

Conclusions:
Altogether, this study provides, for the first time, strong evidence that PPIs can per se promote heart rate–corrected QT interval prolongation, by directly inhibiting hERG function. A careful evaluation of the benefit/risk ratio is recommended whenever PPIs are administered in subjects with other QT-prolonging risk factors, even in the absence of hypomagnesemia.
Management of Congenitally Corrected Transposition of the Great Arteries With Intact Ventricular Septum: Anatomic Repair or Palliative Treatment?
Authors: Cui Hujun , Hage Ali , Piekarski Breanna L. , Marx Gerald R. , Baird Christopher W. , del Nido Pedro J. , Emani Sitaram M. 
Published: June 2021

Background:
Management of the congenitally corrected transposition of the great arteries (ccTGA) with intact ventricular septum (IVS) is controversial and includes either anatomic repair with systemic left ventricle (morphological left ventricle) or maintenance of a systemic right ventricle (morphological right ventricle). The purpose of this study was to describe outcomes of ccTGA-IVS with either strategy.

Methods:
A single-institution, retrospective review of all patients with a diagnosis of ccTGA-IVS who either underwent double switch operation (DSO) or managed with systemic morphological right ventricle (no-DSO). The composite end points included death, heart transplantation, or development of significant systemic ventricular dysfunction or atrioventricular valve regurgitation.

Results:

Between January 1980 and October 2019, 128 patients with ccTGA-IVS underwent primary treatment at a single institution (91 no-DSO and 37 DSO). Mean age at initial presentation was younger in the DSO compared with the no-DSO cohort (2.1 versus 18.2 years;
P
<0.001). Fifty patients underwent pulmonary artery banding (35 DSO and 15 no-DSO). In the no-DSO cohort, the overall mortality was 5.5% (n=5), 17.6% (n=16) developed morphological right ventricular dysfunction, and 40.7% (n=37) required pacemaker. In the DSO cohort, mortality was 2.7% (n=1), 8.1% (n=3) developed morphological left ventricular dysfunction, and 43.6% (n=16) required pacemaker. Freedom from composite end point at 5 and 10 years was 88% and 87% in the no-DSO compared with 94% and 84% in the DSO cohort. The DSO cohort had 0.29× the hazards of developing the composite outcome compared with the no-DSO cohort (hazard ratio, 0.29 [95% CI, 0.089–0.94];
P
=0.039). Among patients with initial age at presentation ≤5 years, DSO was associated with 0.16× the hazard compared with no-DSO (hazard ratio, 0.16 [95% CI, 0.04–0.62];
P
=0.008). Pacemaker implantation was not associated with increased hazard of the composite outcome.

Conclusions:
Systemic ventricular dysfunction is a late complication of ccTGA-IVS regardless of the strategy pursued. Compared with those undergoing anatomic repair, patients with systemic morphological right ventricle may have lower long-term freedom from cardiovascular complications.
Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination
Authors: Zhao Dingsheng , Zhong Guohui , Li Jianwei , Pan Junjie , Zhao Yinlong , Song Hailin , Sun Weijia , Jin Xiaoyan , Li Yuheng , Du Ruikai , Nie Jielin , Liu Tong , Zheng Junmeng , Jia Yixin , Liu Zifan , Liu Wei , Yuan Xinxin , Liu Zizhong , Song Jinping , Kan Guanghan , Li Youyou , Liu Caizhi , Gao Xingcheng , Xing Wenjuan , Chang Yan-Zhong , Li Yingxian , Ling Shukuan 
Published: June 2021

Background:
Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to heart failure. WWP1 (WW domain–containing E3 ubiquitin protein ligase 1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload–induced cardiac remodeling and heart failure is yet to be determined.

Methods:
To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with heart failure and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography, and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay, and an in vivo mouse model via AAV9 (adeno-associated virus serotype 9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cardiac troponin T (cTnT) promoter–driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction.

Results:
The WWP1 level was significantly increased in the hypertrophic hearts from patients with heart failure and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 knockout protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and DVL2 (disheveled segment polarity protein 2). DVL2 was stabilized by WWP1-mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload–induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure.

Conclusions:
We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway.
Cerebral Small Vessel Disease Associated With Atrial Fibrillation Among Older Adults: A Population-Based Study
Authors: Ding Mozhu , Wang Rui , Kalpouzos Grégoria , Laukka Erika J. , Li Yuanjing , Johnell Kristina , Fratiglioni Laura , Qiu Chengxuan 
Published: June 2021

Background and Purpose:
Cerebral small vessel disease, as a potential mechanism underlying the association between atrial fibrillation (AF) and dementia, remains poorly investigated. In this cohort study, we sought to examine the association between AF and cerebral small vessel disease markers among older adults.

Methods:
Data on 336 participants (age ≥60 years, mean 70.2 years; 60.2% women) free of dementia, disability, and cerebral infarcts were derived from the population-based Swedish National Study on Aging and Care in Kungsholmen. Structural brain magnetic resonance imaging examinations were performed at baseline (2001–2004) and follow-ups (2004–2007 and 2007–2010). Magnetic resonance imaging markers of cerebral small vessel disease included perivascular spaces, lacunes, and volumes of white matter hyperintensities, lateral ventricles, and total brain tissue. AF was assessed at baseline and follow-ups through clinical examinations, electrocardiogram, and medical records. Data were analyzed using linear mixed-effects models.

Results:
At baseline, 18 persons (5.4%) were identified to have prevalent AF and 17 (5.6%) developed incident AF over the 6-year follow-up. After multivariable adjustment, AF was significantly associated with a faster annual increase in white matter hyperintensities volume (β coefficient=0.45 [95% CI, 0.04–0.86]) and lateral ventricular volume (0.58 [0.13–1.02]). There was no significant association of AF with annual changes in perivascular spaces number (β coefficient=0.53 [95% CI, −0.27 to 1.34]) or lacune number (−0.01 [−0.07 to 0.05]).

Conclusions:
Independent of cerebral infarcts, AF is associated with accelerated progression of white matter lesions and ventricular enlargement among older adults.
Scanning laser wave recorder with registration of “instantaneous” sea surface profiles
Authors: Sterlyadkin V.V. , Kulikovsky K.V. , Kuzmin A.V. , Sharkov E.A. , Likhacheva M.V. 
Published: June 2021

AbstractA direct optical method for measuring the “instantaneous” profile of the sea surface with an accuracy of 1 mm and a spatial resolution of 3 mm is described. Surface profile measurements can be carried out on spatial scales from units of millimeters to units of meters with an averaging time of 10−4 s. The method is based on the synchronization of the beginning of scanning a laser beam over the sea surface and the beginning of recording the radiation scattered on the surface onto the video camera matrix. The heights of all points of the profile are brought to a single point in time, which makes it possible to obtain “instantaneous” profiles of the sea surface with the frequency of video recording. The measurement technique and data processing algorithm are described. The errors of the method are substantiated. The results of field measurements of the parameters of sea waves are presented: amplitude spectra, distribution of slopes at various spatial averaging scales. The applied version of the wave recorder did not allow recording capillary oscillations, but with some modernization it will be possible. The method is completely remote, does not distort the properties of the surface, is not affected by wind, waves and sea currents, it allows you to measure the proportion of foam on the surface. The possibility of applying the proposed method at any time of the day and in a wide range of weather conditions has been experimentally proved.
Dysphagia in Pediatric Patients with Tracheostomy
Authors: Luu Kimberly , Belsky Michael A. , Dharmarajan Harish , Kaffenberger Thomas , McCoy Jennifer L. , Cangilla Kristin , Tobey Allison B. J. , Simons Jeffrey P. , Maguire Raymond , Padia Reema 
Published: June 2021

Objective: Post-tracheotomy swallowing function has not been well described in the pediatric population. This study aims to (1) determine differences in swallowing functioning pre- and post-tracheotomy and (2) examine the association between postoperative dysphagia and indication for tracheotomy, age at the time of tracheotomy, and time between tracheotomy and modified barium swallow (MBS). Methods: A retrospective chart review was performed on 752 patients who underwent a tracheotomy from 2003 to 2018 and had adequate documentation for review. Patients were included if they received a post-operative MBS. Descriptive statistics, logistic regression, and Fisher’s exact test were used to analyze the data. Results: The cohort included 233 patients. The mean age at the time of tracheotomy was 25 months (±50.5). The indications for the tracheotomy were upper airway obstruction (110/233, 47.2%), chronic respiratory failure (104/233, 44.6%), and neurologic disease (19/233, 8.2%). The mean time from tracheotomy to post-operative MBS was 224 days (±297.7). Of the patients who had documented pre- and post-tracheotomy diets, nearly half of patients had improvement in their swallowing function after tracheotomy placement (82/195; 42.1%). Post-tracheotomy MBS recommended thickened liquids in 30.9% of the patients (72/233) and 42.5% (99/233) were recommended thin liquids. The remainder (62/233, 26.6%) remained nothing by mouth (NPO). Patients with neurological disease as the indication for the tracheotomy were more likely to remain NPO ( P = .039). Conclusion: A tracheotomy can functionally and anatomically affect swallowing in pediatric patients. The majority of our studied cohort was able to resume some form of an oral diet postoperatively based on MBS. This study highlights the need for objective measurements of swallowing in the postoperative tracheotomy patient to allow for safe and timely commencement of an oral diet. Level of Evidence Level 3.
Assessment of nutritional status of the cirrhotic patients on enteral and parenteral feeding
Authors: Aslam Mahwish , Farooq Sana , Rizwan Bahisht , Asghar Ayesha 
Published: June 2021

Background: Cirrhosis is an irreversible disease that replaces healthy tissues with scar tissues. According to the Pakistan Medical Research Council’s national general population survey (2008–2014), the ratio of cirrhosis was 4.8% among the population. Objectives: To assess the nutritional status of cirrhotic patients on enteral and parenteral nutrition and to assess the degree of malnutrition among cirrhotic patients. Methods: A cross-sectional study was conducted at Shalamar and Shiekh Zayed Hospitals of Lahore from January–April 2017. The convenient sampling technique was used. Inclusion criteria were the patients with decompensated liver cirrhosis, whereas compensated patients were excluded from the study. Data were collected through the patient’s file, nurse’s, and dietitian’s notes. The nutritional status of participants was assessed based on socio-demographic characteristics, anthropometric measurements, biochemical assessment, clinical signs, and dietary recall. Variables were categorized and compared to observe the level of significance in enteral and parenteral nutrition. SPSS version 22 was used to analyze data. Results: Patients on parenteral nutrition had a higher ratio of malnutrition with a significant Child–Pugh score—61.8% of patients belonged to Class C and 35.3% Class B, while in enteral support, 7.3% belonged to Class C and 43.9% patients belonged to Class B ( p-value = 0.000). There was a definite relationship observed in the route of intake and malnutrition among cirrhotic patients. Conclusion: Enteral route of nutrition is an effective and the safest way to provide appropriate nutrients according to the patient’s demands.