bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subversion of Cellular Autophagy Machinery by Hepatitis B Virus for Viral Envelopment
Authors: Li Jianhua , Liu Yinghui , Wang Zekun , Liu Kuancheng , Wang Yaohui , Liu Jiangxia , Ding Huanping , Yuan Zhenghong 
Published: April 2011

ABSTRACT
Autophagy is a conserved eukaryotic mechanism that mediates the removal of long-lived cytoplasmic macromolecules and damaged organelles via a lysosomal degradative pathway. Recently, a multitude of studies have reported that viral infections may have complex interconnections with the autophagic process. The findings reported here demonstrate that hepatitis B virus (HBV) can enhance the autophagic process in hepatoma cells without promoting protein degradation by the lysosome. Mutation analysis showed that HBV small surface protein (SHBs) was required for HBV to induce autophagy. The overexpression of SHBs was sufficient to induce autophagy. Furthermore, SHBs could trigger unfolded protein responses (UPR), and the blockage of UPR signaling pathways abrogated the SHB-induced lipidation of LC3-I. Meanwhile, the role of the autophagosome in HBV replication was examined. The inhibition of autophagosome formation by the autophagy inhibitor 3-methyladenine (3-MA) or small interfering RNA duplexes targeting the genes critical for autophagosome formation (Beclin1 and ATG5 genes) markedly inhibited HBV production, and the induction of autophagy by rapamycin or starvation greatly contributed to HBV production. Furthermore, evidence was provided to suggest that the autophagy machinery was required for HBV envelopment but not for the efficiency of HBV release. Finally, SHBs partially colocalized and interacted with autophagy protein LC3. Taken together, these results suggest that the host's autophagy machinery is activated during HBV infection to enhance HBV replication.
Proprioceptive deficits after ACL injury: are they clinically relevant?
Authors: Gokeler Alli , Benjaminse Anne , Hewett Timothy E , Lephart Scott M , Engebretsen Lars , Ageberg Eva , Engelhardt Martin , Arnold Markus P , Postema Klaas , Otten Egbert , Dijkstra Pieter U 
Published: April 2011

ObjectiveTo establish the clinical relevance of proprioceptive deficits reported after anterior cruciate ligament (ACL) injury.Material and methodsA literature search was done in electronic databases from January 1990 to June 2009. Inclusion criteria for studies were ACL deficient (ACL-D) and ACL reconstruction (ACL-R) articles written in English, Dutch or German and calculation of correlation(s) between proprioception tests and clinical outcome measures. Clinical outcome measures were muscle strength, laxity, hop test, balance, patient-reported outcome, objective knee score rating, patient satisfaction or return to sports. Studies included in the review were assessed on their methodological quality.ResultsIn total 1161 studies were identified of which 24 met the inclusion criteria. Pooling of all data was not possible due to substantial differences in measurement techniques and data analysis. Most studies failed to perform reliability measurements of the test device used. In general, the correlation between proprioception and laxity, balance, hop tests and patient outcome was low. Four studies reported a moderate correlation between proprioception, strength, balance or hop test.ConclusionThere is limited evidence that proprioceptive deficits as detected by commonly used tests adversely affect function in ACL-D and ACL-R patients. Development of new tests to determine the relevant role of the sensorimotor system is needed. These tests should ideally be used as screening tests for primary and secondary prevention of ACL injury.
Impact of a care pathway in acute pancreatitis
Authors: McCallum Iain J D , Hicks Gareth J , Attwood Stephen , Seymour Keith 
Published: April 2011

ABSTRACT

Background
Previous studies have shown that accurate process of care predicts quality of care. Few examples currently exist for process of care for the acute surgical patient. A recent region wide audit had identified good outcomes for patients with acute pancreatitis at our institution but aspects of care that could be improved.

Methods
For this re-audit, a simple written care pathway for the management of those presenting with acute pancreatitis was introduced in our institution from February to July 2009. The audit standards were set against the British Society of Gastroenterology (BSG) guidelines for management of acute pancreatitis and were compared with the previous region wide audit.

Results
Marked improvements were noted in the rates of abdominal imaging achieved within 24 h of diagnosis (35.2% vs 47.7%), severity stratification within 48 h of diagnosis (28.7% vs 75%), critical care admission for those classified as severe (39.3% vs 63.6%) and definitive treatment during index admission (22.2% vs 38.5%). Survival rates were 100% for this audit cycle and 95% for all patients within the region wide audit. Despite these improvements, care still does not reach the standards set out by BSG.

Conclusion
Predefined processes of care may help to recognise those developing or likely to develop severe pancreatitis, ensure accurate documentation of severity, expedite critical care review and/or admission, and help to encourage the timely management of those with a treatable underlying cause of their pancreatitis.
Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells
Authors: Kim Won Ho , Kang Kyung Hwa , Kim Mie Young , Choi Kyung Hee 
Published: April 2011

Ceramide is known to induce pRb (retinoblastoma gene product) dephosphorylation through the activation of ceramide-activated protein phosphatase (CAPP) during G1 arrest, but other molecular mechanisms linked to regulation of pRb dephosphorylation during ceramide-induced G1 arrest are poorly understood. In this paper, we investigated whether p21, a cdk (cyclin-dependent kinase) inhibitor, is involved in the induction of pRb dephosphorylation during ceramide-induced G1 arrest. In SK-Hep-1 cells, the addition of ceramide resulted in pRb dephosphorylation and G1 arrest. The activity of cdk2 was inhibited in response to ceramide during this process. p21 protein and mRNA were remarkably induced, while the protein level of p53, known as a transcriptional activator of p21, was not elevated at the same condition. p21 induction was also observed in the Hep3B cells lacking a functional p53 after exposure to ceramide. Although p21 is induced in ceramide-treated Hep3B cells, Hep3B cells do not induce G1 arrest, because Hep3B cells are deficient in a functional pRb protein. To confirm that pRb is a critical target for the induction of G1 arrest by inhibiting cdk2 activity through p53-independent p21, pRb-expressing vector was transfected into Hep3B cells. After treatment with ceramide, pRb-expressing cells (pRb+/+), but not pRb-/-cells, were arrested in G1 phase. In pRb+/+ cells, ceramide-mediated G1 arrest was accompanied by the accumulation of hypophosphorylated pRb and p21 associated with cdk2. Together, these results suggest that p21, induced through p53-independent pathway, participates in the induction of pRb dephosphorylation by inhibiting cdk2 activity during ceramide-mediated G1 arrest in hepatocarcinoma cells. Key words: C6-ceramide, G1 arrest, p21, hepatocarcinoma cells.
The static equilibrium of drag anchors in sand
Authors: Neubecker S R , Randolph M F 
Published: April 2011

This paper examines the static equilibrium of drag anchors during embedment in sand. A limit equilibrium method is developed to allow the anchor holding capacity to be predicted given a specific anchor geometry and position relative to the free surface of the sand. The method is based on the earlier approach of Le Lievre and Tabatabaee, but is extended to include a three-dimensional soil wedge, which is consistent with experimental observation. The solution procedure is also extended to be more applicable for anchors at a preultimate stage by incorporating a force behind the anchor fluke. To calibrate the method, a series of centrifuge model anchor tests has been performed in silica and calcareous sands. The static capacity of the anchor during embedment is compared with the static limit equilibrium solution and good agreement is demonstrated. Key words: drag anchor, statics, sand, limit equilibrium, ultimate holding capacity.
Mechanical and hydraulic behaviour of a soft inorganic clay treated with lime
Authors: Locat Jacques , Trembaly Hélène , Leroueil Serge 
Published: April 2011

A comprehensive series of laboratory tests was conducted on an inorganic clayey sediment in order to predict the mechanical behaviour of dredged sediments used in reclamation projects. The soil used was a Louiseville clay, which was mixed with various quantities of lime (010%) and had a varied water content (122650%). Tests were carried out with special large cells and standard oedometers to look at both the compressibility and the hydraulic conductivity. Once pozzolanic reactions are begun, for a given curing time, a linear relationship between preconsolidation pressure and lime concentration is observed. Compressibility results indicate that it is possible to define a separate compression curve for each lime concentration and curing time. Adding lime will influence the hydraulic conductivity both by flocculation and by the formation of secondary minerals. If only flocculation occurs, an increase in hydraulic conductivity follows. If enough lime is added, the resulting secondary minerals will create major changes in the micropore network and this will decrease the hydraulic conductivity by up to one order of magnitude. The development of a secondary micropore network along with the cementation of large flocs induce significant increases in both the liquid and plastic limits. This results in a significant increase in the water sorption potential and higher Atterberg limits. Key words: dredged sediments, compressibility, hydraulic conductivity, lime, stabilization, microstructure.
EZH2-Mediated Concordant Repression of Wnt Antagonists Promotes β-Catenin–Dependent Hepatocarcinogenesis
Authors: Cheng Alfred S.L. , Lau Suki S. , Chen Yangchao , Kondo Yutaka , Li May S. , Feng Hai , Ching Arthur K. , Cheung Kin F. , Wong Hoi K. , Tong Joanna H. , Jin Hongchuan , Choy Kwong W. , Yu Jun , To Ka F. , Wong Nathalie , Huang Tim H.-M. , Sung Joseph J.Y. 
Published: April 2011

Abstract
Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/β-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear β-catenin, T-cell factor–dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of β-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/β-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and β-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/β-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor. Cancer Res; 71(11); 4028–39. ©2011 AACR.
Mutationally Activated BRAFV600E Elicits Papillary Thyroid Cancer in the Adult Mouse
Authors: Charles Roch-Philippe , Iezza Gioia , Amendola Elena , Dankort David , McMahon Martin 
Published: April 2011

Abstract
Mutated BRAF is detected in approximately 45% of papillary thyroid carcinomas (PTC). To model PTC, we bred mice with adult-onset, thyrocyte-specific expression of BRAFV600E. One month following BRAFV600E expression, mice displayed increased thyroid size, widespread alterations in thyroid architecture, and dramatic hypothyroidism. Over 1 year, without any deliberate manipulation of tumor suppressor genes, all mice developed PTC displaying nuclear atypia and marker expression characteristic of the human disease. Pharmacologic inhibition of MEK1/2 led to decreased thyroid size, restoration of thyroid form and function, and inhibition of tumorigenesis. Mice with BRAFV600E-induced PTC will provide an excellent system to study thyroid tumor initiation and progression and the evaluation of inhibitors of oncogenic BRAF signaling. Cancer Res; 71(11); 3863–71. ©2011 AACR.
MST1 Is a Multifunctional Caspase-Independent Inhibitor of Androgenic Signaling
Authors: Cinar Bekir , Collak Filiz Kisaayak , Lopez Delia , Akgul Seckin , Mukhopadhyay Nishit K. , Kilicarslan Murat , Gioeli Daniel G. , Freeman Michael R. 
Published: April 2011

Abstract
The MST1 serine–threonine kinase, a component of the RASSF1-LATS tumor suppressor network, is involved in cell proliferation and apoptosis and has been implicated in cancer. However, the physiologic role of MST1 in prostate cancer (PCa) is not well understood. Here, we investigated the possibility of a biochemical and functional link between androgen receptor (AR) and MST1 signaling. We showed that MST1 forms a protein complex with AR and antagonizes AR transcriptional activity as shown by coimmunoprecipitation (co-IP), promoter reporter analysis, and molecular genetic methods. In vitro kinase and site-specific mutagenesis approaches indicate that MST1 is a potent AR kinase; however, the kinase activity of MST1 and its proapoptotic functions were shown not to be involved in inhibition of AR. MST1 was also found in AR–chromatin complexes, and enforced expression of MST1 reduced the binding of AR to a well-characterized, androgen-responsive region within the prostate-specific antigen promoter. MST1 suppressed PCa cell growth in vitro and tumor growth in mice. Because MST1 is also involved in regulating the AKT1 pathway, this kinase may be an important new link between androgenic and growth factor signaling and a novel therapeutic target in PCa. Cancer Res; 71(12); 4303–13. ©2011 AACR.
Consequences of Epidermal Growth Factor Receptor (ErbB1) Loss for Vascular Smooth Muscle Cells From Mice With Targeted Deletion of ErbB1
Authors: Schreier Barbara , Döhler Maria , Rabe Sindy , Schneider Bettina , Schwerdt Gerald , Ruhs Stefanie , Sibilia Maria , Gotthardt Michael , Gekle Michael , Grossmann Claudia 
Published: April 2011

Objective—
Pathophysiological effects of the epidermal growth factor receptor (EGFR or ErbB1) include vascular remodeling. EGFR transactivation is proposed to contribute significantly to heterologous signaling and remodeling in vascular smooth muscle cells (VSMC).

Methods and Results—

We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR (
EGFR

Δ/Δ
VSMC

→VSMC
EGFR−/−
and
EGFR

Δ/+
VSMC

→VSMC
EGFR+/−
) and the respective littermate controls (
EGFR

+/+
VSMC

→VSMC
EGFR+/+
) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca
2+
homeostasis. In VSMC
EGFR−/−
, epidermal growth factor–induced signaling was abolished; VSMC
EGFR+/−
showed an intermediate phenotype. EGFR deletion enhanced spontaneous cell death, reduced pentose phosphate pathway activity, disturbed cellular matrix homeostasis (collagen III and fibronectin), and abolished epidermal growth factor sensitivity. In VSMC
EGFR−/−
endothelin-1- or α
1
-adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca
2+
responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca
2+
signal. Oxidative stress (H
2
O
2
) induced ERK1/2 activation in VSMC
EGFR+/+
and VSMC
EGFR+/−
but not in VSMC
EGFR−/−
. The Ca
2+
signal was enhanced in VSMC
EGFR−/−
, similar to purinergic stimulation by ATP.

Conclusion—

In conclusion, EGFR was found to be important for basal VSMC homeostasis and ERK1/2 activation by the tested G-protein–coupled receptors or radical stress. Ca
2+
signaling was modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.
Evidence of Platelet Activation at Medically Used Hypothermia and Mechanistic Data Indicating ADP as a Key Mediator and Therapeutic Target
Authors: Straub Andreas , Krajewski Stefanie , Hohmann Jan David , Westein Erik , Jia Fu , Bassler Nicole , Selan Carly , Kurz Julia , Wendel Hans Peter , Dezfouli Shala , Yuan Yuping , Nandurkar Harshal , Jackson Shaun , Hickey Michael J. , Peter Karlheinz 
Published: April 2011

Objective—
Hypothermia is used in various clinical settings to inhibit ischemia-related organ damage. However, prothrombotic effects have been described as potential side effects. This study aimed to elucidate the mechanism of hypothermia-induced platelet activation and subsequent prothrombotic events and to develop preventative pharmacological strategies applicable during clinically used hypothermia.

Methods and Results—

Platelet function was investigated ex vivo and in vivo at clinically used hypothermia (28°C/18°C). Hypothermic mice demonstrated increased expression of platelet activation marker P-selectin, platelet-leukocyte aggregate formation, and thrombocytopenia. Intravital microscopy of FeCl
3
-injured murine mesenteric arteries revealed increased platelet thrombus formation with hypothermia. Ex vivo flow chamber experiments indicated increased platelet-fibrinogen adhesion under hypothermia. We show that hypothermia results in reduced ADP hydrolysis via reduction of CD39 (E-NTPDase1) activity, resulting in increased levels of ADP and subsequent augmented primary and secondary platelet activation. In vivo administration of ADP receptor P
2
Y
12
antagonists and recombinant soluble CD39 prevented hypothermia-induced thrombus formation and thrombocytopenia, respectively.

Conclusion—
The platelet agonist ADP plays a key role in hypothermia-induced platelet activation. Inhibition of receptor binding or hydrolysis of ADP has the potential to protect platelets against hypothermia-induced activation. Our findings provide a rational basis for further evaluation of novel antithrombotic strategies in clinically applied hypothermia.
Is There an Association Between External Cardioversions and Long-Term Mortality and Morbidity?
Authors: Elayi Claude S. , Whitbeck Matthew G. , Charnigo Richard , Shah Jignesh , Macaulay Tracy E. , Morales Gustavo , Gurley John C. , Kakavand Bahram , Thal Sergio , Ching Chi Keong , Khaykin Yaariv , Verma Atul , Barrett Conor , Bai Rong , Di Biase Luigi , Patwardhan Abhijit , Moliterno David J. , Natale Andrea ,   the AFFIRM Study Investigators
Published: April 2011

Background—
Cardiac electric therapies effectively terminate tachyarrhythmias. Recent data suggest a possible increase in long-term mortality associated with implantable cardioverter-defibrillator shocks. Little is known about the association between external cardioversion episodes (ECVe) and long-term mortality. We sought to assess the safety of repeated ECVe with regard to cardiovascular mortality and morbidity.

Methods and Results—

We analyzed the data of the 4060 patients from the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial. In particular, associations of ECVe with all-cause mortality, cardiovascular mortality, and hospitalizations after ECVe were studied. Over an average follow-up of 3.5 years, 660 (16.3%) patients died, 331 (8.2%) from cardiovascular causes. A total of 207 (5.1%) and 1697 (41.8%) patients had low ejection fraction and nonparoxysmal atrial fibrillation, respectively; 2460 patients received no ECVe, whereas 1600 experienced ≥1 ECVe. Death occurred in 412 (16.7%), 196 (16.5%), 39 (13.5%), and 13 (10.4%) of patients with 0, 1, 2, and ≥3 ECVe, respectively. There was no significant association between ECVe and mortality within any of the 4 subgroups defined by ejection fraction and atrial fibrillation type, although myocardial infarction, coronary artery bypass graft, and digoxin were significantly associated with death (estimated hazard ratios, 1.65, 1.59, and 1.62, respectively;
P
<0.0001). ECVe were associated with increased cardiac hospitalization reported at the next follow-up visit (39.3% versus 5.8%; estimated odds ratio, 1.39;
P
<0.0001).

Conclusions—
In the AFFIRM study, there was no significant association between ECVe and long-term mortality, even though ECVe were associated with increased hospitalizations from cardiac causes. Digoxin, myocardial infarction, and coronary artery bypass graft were significantly associated with mortality.
Sarcomere Protein Gene Mutations in Patients With Apical Hypertrophic Cardiomyopathy
Authors: Gruner Christiane , Care Melanie , Siminovitch Katherine , Moravsky Gil , Wigle E. Douglas , Woo Anna , Rakowski Harry 
Published: April 2011

Background—
Apical hypertrophic cardiomyopathy (HCM) is a unique form of HCM with left ventricular hypertrophy confined to the cardiac apex. The purpose of our study was to report genetic findings in a large series of unrelated patients with apical HCM and compare them with a nonapical HCM cohort.

Methods and Results—

Overall, 429 patients with HCM underwent genetic testing. The panel included 8 sarcomere protein genes and 3 other genes
(GLA, PRKAG2,
and
LAMP2).
Sixty-one patients were diagnosed with apical HCM. A positive genotype was found in 8 patients with apical HCM. The genotype-positive and genotype-negative patients had similar maximal wall thicknesses (17.5±3.5 mm versus 17.6±3.3 mm,
P
=0.71) and similar frequency of HCM-related events (2/8; 25% versus 13/53; 25%;
P
=0.98). Thirteen percent with apical HCM and 40% with nonapical HCM had a positive genotype (
P
<0.001) most often involving the
MYBPC3
and
MYH7
genes.

Conclusions—

In apical HCM, a positive genotype was found less frequently than in nonapical HCM, and it was most often involving
MYBPC3
and
MYH7
genes. Only 13% of patients with apical HCM were found to be genotype positive, indicating that genome-wide association studies and gene expression profiling are needed for better understanding of the genetic background of the disease. There was no significant genotype-phenotype correlation in our cohort with apical HCM.