bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells
Authors: Joannes Audrey , Grelet Simon , Duca Laurent , Gilles Christine , Kileztky Claire , Dalstein Véronique , Birembaut Philippe , Polette Myriam , Nawrocki-Raby Béatrice 
Published: January 2014

AbstractIn many cancers, including lung carcinomas, Fragile histidine triad (Fhit) is frequently decreased or lost. Fhit status has recently been shown to be associated with elevated in vitro and in vivo invasiveness in lung cancer. Tumor cell invasion is facilitated by epithelial–mesenchymal transition (EMT), a process by which tumor cells lose their epithelial features to acquire a mesenchymal cell-like phenotype. In this study, the mechanism underlying Fhit-regulated EMT was deciphered. Using Slug knockdown, pharmacologic inhibitors PD98059, PP1, and gefitinib as well as an anti-EGFR antibody, it was demonstrated that Fhit silencing in bronchial cells induced overexpression of two primary EMT-associated targets, MMP-9 and vimentin, to regulate cell invasion dependent on an EGFR/Src/ERK/Slug signaling pathway. Moreover, ectopic expression of Fhit in Fhit-deficient lung cancer cells downregulated this pathway. Finally, an inverse correlation was observed between Fhit and phospho-EGFR levels in a cohort of human squamous cell lung carcinoma specimens. These results demonstrate a Fhit-dependent mechanism in the control of EMT-regulated EGFR signaling.Implications: This study adds new insight into the regulatory mechanism of EMT, a process known to increase resistance to conventional and targeted therapies in lung cancer. Mol Cancer Res; 12(5); 775–83. ©2014 AACR.
CAF-Secreted Annexin A1 Induces Prostate Cancer Cells to Gain Stem Cell–like Features
Authors: Geary Lauren A. , Nash Kevin A. , Adisetiyo Helty , Liang Mengmeng , Liao Chun-Peng , Jeong Joseph H. , Zandi Ebrahim , Roy-Burman Pradip 
Published: January 2014

Abstract
Annexin A1 (AnxA1), a phospholipid-binding protein and regulator of glucocorticoid-induced inflammatory signaling, has implications in cancer. Here, a role for AnxA1 in prostate adenocarcinoma was determined using primary cultures and a tumor cell line (cE1), all derived from the conditional Pten deletion mouse model of prostate cancer. AnxA1 secretion by prostate-derived cancer-associated fibroblasts (CAF) was significantly higher than by normal prostate fibroblasts (NPF). Prostate tumor cells were sorted to enrich for epithelial subpopulations based on nonhematopoietic lineage, high SCA-1, and high or medium levels of CD49f. Compared with controls, AnxA1 enhanced stem cell–like properties in high- and medium-expression subpopulations of sorted cE1 and primary cells, in vitro, through formation of greater number of spheroids with increased complexity, and in vivo, through generation of more, larger, and histologically complex glandular structures, along with increased expression of p63, a basal/progenitor marker. The differentiated medium-expression subpopulations from cE1 and primary cells were most susceptible to gain stem cell–like properties as shown by increased spheroid and glandular formation. Further supporting this increased plasticity, AnxA1 was shown to regulate epithelial-to-mesenchymal transition in cE1 cells. These results suggest that CAF-secreted AnxA1 contributes to tumor stem cell dynamics via two separate but complementary pathways: induction of a dedifferentiation process leading to generation of stem-like cells from a subpopulation of cancer epithelial cells and stimulation of proliferation and differentiation of the cancer stem-like cells.
Implications: AnxA1 participates in a paradigm in which malignant prostate epithelial cells that are not cancer stem cells are induced to gain cancer stem cell–like properties. Mol Cancer Res; 12(4); 607–21. ©2014 AACR.
FAK Inhibition Abrogates the Malignant Phenotype in Aggressive Pediatric Renal Tumors
Authors: Megison Michael L. , Gillory Lauren A. , Stewart Jerry E. , Nabers Hugh C. , Mrozcek-Musulman Elizabeth , Beierle Elizabeth A. 
Published: January 2014

AbstractDespite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and nonosseous renal Ewing sarcoma. Children with advanced, metastatic, or relapsed disease have a poor disease-free survival rate. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading to the hypothesis that FAK contributes to pediatric kidney tumors and would affect cellular survival. In the current study, FAK was present and phosphorylated in pediatric kidney tumor specimens. Moreover, the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines were examined using a number of parallel approaches to block FAK, including RNA interference and small-molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Furthermore, small-molecule inhibition of FAK led to decreased SK-NEP-1 xenograft growth in vivo. These data deepen the knowledge of the tumorigenic process in pediatric renal tumors, and provide desperately needed therapeutic strategies and targets for these rare, but difficult to treat, malignancies.Implications: This study provides a fundamental understanding of tumorigenesis in difficult to treat renal tumors and provides an impetus for new avenues of research and potential for novel, targeted therapies. Mol Cancer Res; 12(4); 514–26. ©2014 AACR.
Targeting Estrogen Receptor-β for the Prevention of Nonmelanoma Skin Cancer
Authors: Yao Pei-Li , Gonzalez Frank J. , Peters Jeffrey M. 
Published: January 2014

Abstract
The potential for targeting estrogen receptor (ER)-β in various cancer models has been gaining considerable attention in recent years. In this issue of the journal, Chaudhary and colleagues demonstrate markedly decreased ultraviolet B (UVB)-induced skin cancer in a mouse model using a highly specific ER-β agonist, ERB-041. The mechanisms that underlie this strong inhibitory effect are mediated by inhibition of proinflammatory signaling and epithelial–mesenchymal transition (EMT). The changes in EMT were due in part to modulation of WNT/β-catenin signaling. Collectively, the results from these studies provide important new insights into the mechanisms by which the ER-β agonist ERB-041 inhibits UVB-induced skin cancer and opens the door for future studies that could examine combinatorial approaches for UVB-dependent skin cancer chemoprevention. Cancer Prev Res; 7(2); 182–5. ©2014 AACR.
Double-Stranded RNA–Dependent Protein Kinase Deficiency Protects the Heart From Systolic Overload-Induced Congestive Heart Failure
Authors: Wang Huan , Xu Xin , Fassett John , Kwak Dongmin , Liu Xiaoyu , Hu Xinli , Falls Therasa J. , Bell John C. , Li Hongliang , Bitterman Peter , Bache Robert J. , Chen Yingjie 
Published: January 2014

Background—
Double-stranded RNA–dependent protein kinase (PKR) is a eukaryotic initiation factor 2α kinase that inhibits mRNA translation under stress conditions. PKR also mediates inflammatory and apoptotic signaling independently of translational regulation. Congestive heart failure is associated with cardiomyocyte hypertrophy, inflammation, and apoptosis, but the role of PKR in left ventricular hypertrophy and the development of congestive heart failure has not been examined.

Methods and Results—
We observed increased myocardial PKR expression and translocation of PKR into the nucleus in humans and mice with congestive heart failure. To determine the impact of PKR on the development of congestive heart failure, PKR knockout and wild-type mice were exposed to pressure overload produced by transverse aortic constriction. Although heart size increased similarly in wild-type and PKR knockout mice after transverse aortic constriction, PKR knockout mice exhibited very little pulmonary congestion, well-preserved left ventricular ejection fraction and contractility, and significantly less myocardial fibrosis compared with wild-type mice. Bone marrow–derived cells from wild-type mice did not abolish the cardiac protective effect observed in PKR knockout mice, whereas bone marrow–derived cells from PKR knockout mice had no cardiac protective effect in wild-type mice. Mechanistically, PKR knockout attenuated transverse aortic constriction–induced tumor necrosis factor-α expression and leukocyte infiltration and lowered cardiac expression of proapoptotic factors (Bax and caspase-3), so that PKR knockout hearts were more resistant to transverse aortic constriction–induced cardiomyocyte apoptosis. PKR depletion in isolated cardiomyocytes also conferred protection against tumor necrosis factor-α– or lipopolysaccharide-induced apoptosis.

Conclusion—
PKR is a maladaptive factor upregulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis, and the development of congestive heart failure.
Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation
Authors: Martins Raphael P. , Kaur Kuljeet , Hwang Elliot , Ramirez Rafael J. , Willis B. Cicero , Filgueiras-Rama David , Ennis Steven R. , Takemoto Yoshio , Ponce-Balbuena Daniela , Zarzoso Manuel , O’Connell Ryan P. , Musa Hassan , Guerrero-Serna Guadalupe , Avula Uma Mahesh R. , Swartz Michael F. , Bhushal Sandesh , Deo Makarand , Pandit Sandeep V. , Berenfeld Omer , Jalife José 
Published: January 2014

Background—
Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent.

Methods and Results—

Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (Ca
V
1.2, Na
V
1.5, and K
V
4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up.

Conclusions—
In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.
Variations in Cause and Management of Atrial Fibrillation in a Prospective Registry of 15 400 Emergency Department Patients in 46 Countries
Authors: Oldgren Jonas , Healey Jeff S. , Ezekowitz Michael , Commerford Patrick , Avezum Alvaro , Pais Prem , Zhu Jun , Jansky Petr , Sigamani Alben , Morillo Carlos A. , Liu Lisheng , Damasceno Albertino , Grinvalds Alex , Nakamya Juliet , Reilly Paul A. , Keltai Katalin , Van Gelder Isabelle C. , Yusufali Afzal Hussein , Watanabe Eiichi , Wallentin Lars , Connolly Stuart J. , Yusuf Salim 
Published: January 2014

Background—
Atrial fibrillation (AF) is the most common sustained arrhythmia; however, little is known about patients in a primary care setting from high-, middle-, and low-income countries.

Methods and Results—

This prospective registry enrolled patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. Patient characteristics were compared among 9 major geographic regions. Between September 2008 and April 2011, 15 400 patients were enrolled. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America,
P
<0.001. Hypertension was globally the most common risk factor for AF, ranging in prevalence from 41.6% in India to 80.7% in Eastern Europe,
P
<0.001. Rheumatic heart disease was present in only 2.2% of North American patients, in comparison with 21.5% in Africa and 31.5% in India,
P
<0.001. The use of oral anticoagulation among patients with a CHADS
2
score of ≥2 was greatest in North America (65.7%) but was only 11.2% in China,
P
<0.001. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa,
P
<0.001.

Conclusions—
There is a large global variation in age, risk factors, concomitant diseases, and treatment of AF among regions. Improving outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings.
Intrinsic and extrinsic intentional learning: The difference made by self-determination
Authors: Hung Woei 
Published: January 2014

Intentional learning occurs in formal and informal settings throughout an individual’s life time. Intentional learning can be deemed as an ideal learning process where all the necessary elements for achieving a goal of effective learning are in place and in order. Intentional learners take an active role in and responsibility for their own learning, and they self-plan, execute, monitor and regulate their learning processes as well as learning strategies. Most importantly, intentional learners are willing and committed to reaching the learning goal. At its occurrence, intentional learning could be triggered by an external suggestion or guidance (e.g. teacher’s explanation of the importance of the subject), or internal factors (e.g. intrinsic interests or personal needs through self-evaluation and self-determination). Thus, intentional learning could be further differentiated into intrinsic or extrinsic. While both intrinsic and extrinsic intentional learning are likely to result in similar learning outcomes, cultivating students’ disposition of intrinsic intentional learning may have more beneficial long term effects than extrinsic intentional learning as it is one of the keys that sustain an individual’s lifelong learning. Also, the technology that could facilitate intrinsic intentional learning will be discussed.
Ethical issues related to caring for low birth weight infants
Authors: Webb Mary S , Passmore Denise , Cline Genieveve , Maguire Denise 
Published: January 2014

Background: Currently preterm births are the leading causes of newborn deaths and newborn mortality in developed countries. Infants born prematurely remain vulnerable to many acute complications and long-term disabilities. There is a growing concern surrounding the moral and ethical implications of the complex and technological care being provided to extremely low birth weight infants in neonatal intensive care units in the developed nations. Research purpose: The purpose of this study was to describe the ethical and moral issues that neonatal intensive care nurses experience when caring for low birth weight preterm infants and their families. Research design: A phenomenological method design was used to describe the lived experiences of nurses with ethical and moral issues encountered in the neonatal intensive care unit. One-on-one, semi-structured interviews using open-ended questions were used to gather data from the participants. Research participants: The setting for this study was a 97-bed neonatal intensive care. A total of 16 female nurses were interviewed. Ethical considerations: Approval to conduct the research study was obtained from the institutional review board of the hospital where the study was conducted. Formal signed consent was obtained from each participant. To ensure confidentiality, each participant was asked to choose a confederate name to be used in the interview and the transcriptions. Findings: The thematic analysis identified five recurring themes: (a) at the edge of viability, (b) infant pain and discomfort, (c) crucial decisions, (d) communicating with parents, and (e) letting go. Conclusion: Neonatal intensive care unit nurses indicated that they often had challenges to their own sense of morality as they struggled to protect the infant from pain and unnecessary discomfort, provide care to an infant and their family whom they thought was faced with a lifetime of challenges and poor health, accepting decisions made by parents, and feeling as if parents were not adequately informed about outcomes.
Vibration suppression of a pneumatic drive flexible manipulator using adaptive phase adjusting controller
Authors: Qiu Zhi-cheng , Zhao Zhi-li 
Published: January 2014

Generally, a low damping system has a small phase margin. One should deal with the problems of long time delay and unmodeled dynamics for active vibration control of a low damping system sometimes. For a pneumatic drive flexible manipulator system, time delay or phase lag and unmodeled nonlinear dynamics problems have raised the level of concern. It is vital but difficult to regulate the phase of vibration controller, to compensate for the time-varying phase lag or time delay due to the gas compression and parametric uncertainty of the pneumatic control system. The objective of this investigation is to formulate an active vibration control law with practical approach of phase adjusting for a pneumatic drive flexible manipulator system. A control strategy named adaptive phase adjusting control is designed and applied. The adaptive phase adjusting controller is implemented by using the phase angles as explicit parameters. These parameters are tuned online, depending on the corresponding control performance index. To evaluate the control performance of the designed adaptive phase adjusting technique, experiments are conducted on a pneumatic drive flexible manipulator experimental setup. The experimental results demonstrate the adaptive phase adjusting controller has the ability to optimize the phase angle accordingly. Vibration suppression is accomplished by using the designed adaptive phase adjusting controller, even with time delay and unmodeled dynamics in the system.
IgA nephropathy with early kidney disease is associated with increased arterial stiffness and renin–angiotensin system activity
Authors: Abdi-Ali A , Mann MC , Hemmelgarn BR , MacRae JM , Turin TC , Benediktsson H , Sola DY , Ahmed SB 
Published: January 2014

Background: IgA nephropathy is associated with increased cardiovascular risk, though whether this is due to loss of kidney function or proteinuria is unclear. Methods: For this study 10 normotensive IgA nephropathy subjects with early kidney disease (41±5 yrs, glomerular filtration rate (GFR) 87±9 ml/min, proteinuria 720±300 mg/d) and 10 gender- and blood pressure-matched healthy controls (36±1 yrs, estimated GFR 102±5 ml/min, proteinuria 70±6 mg/d) were studied in high-salt balance. Blood pressure and arterial stiffness, expressed as pulse wave velocity and aortic augmentation index, were measured at baseline and in response to 60 min of angiotensin II (AngII) infusion. Results: At baseline, IgA nephropathy subjects demonstrated similar pulse wave velocity (8.6±0.7 vs. 8.0±0.4 m/s, p=0.5) but increased aortic augmentation index (12.6±3.1 vs. 1.8±4%, p=0.04) and a trend towards increased circulating renin–angiotensin system (RAS) components (plasma renin activity, 0.55±0.18 vs. 0.21±0.05 ng/l/s, p=0.08; angiotensin II, 25±5 vs. 16±1 ng/l, p=0.08) compared with controls. However, despite similar baseline blood pressure values ( p=0.8), IgA nephropathy was associated with reduced arterial sensitivity to AngII challenge (Δmean arterial pressure: 19±4 vs. 29±1 mm Hg, p=0.05; Δpulse wave velocity: -0.06±0.6 vs. 1.5±0.3 m/s, p=0.07) compared with controls, even after multivariate analysis. Conclusion: Even in the setting of early kidney disease, IgA nephropathy is associated with increased arterial stiffness and decreased angiotensin II responsiveness, a marker of increased RAS activity.
Neutrophil to Lymphocyte Ratio Predicts Perioperative Mortality Following Open Elective Repair of Abdominal Aortic Aneurysms
Authors: Appleton N. D. , Bailey D. M. , Morris-Stiff G. , Lewis M. H. 
Published: January 2014

Objectives: This study assesses the predictive value of neutrophil to lymphocyte ratio (NLR) in relation to 30-day and overall mortality following open abdominal aortic aneurysm (AAA) repairs. In addition, it assess assesses any correlation between NLR and age, size of the AAA and gender. Methods: Patients undergoing elective or urgent open repair of their AAA by a single surgeon during a 10-year period were included. A pre-operative NLR of >5 was regarded as abnormal. Results: 350 consecutive patients underwent AAA repair. 52 had an NLR>5. 30-day mortality rate was 12/52 (23%) in the NLR>5 group and 20/298 (6.7%) in the NLR<5 group (p = 0.0007). All deaths in the NLR>5 group were due to myocardial infarction. The median NLR was higher in those that died within 30 days at 4.2 [IQR: 2.6-7.5] versus 2.8 [IQR: 2.1-3.8] (p = 0.0001). Overall mortality at 10 years, in the NLR>5 group - 26/52 (50%) was significantly greater than that of the NLR<5 group - 102/298 (34.2%) (p = 0.043). Median NLR of those dying during follow-up was significantly higher in those with a baseline NLR>5 at 3.2 (IQR 2.5-4.6) versus 2.6 (IQR: 2.0-3.6) in those surviving (p = 0.00004). No difference was found between NLR and age, aneurysm size or gender. Conclusion: Pre-operative NLR>5 appears to be a significant predictor of both 30-day mortality and long-term outcome in elective and urgent open AAA surgery. It is plausible the NLR is identifying a group with sub-clinical cardiovascular disease at risk of peri-operative myocardial infarction.