bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transforming Growth Factor β-Induced Reactivation of Epstein-Barr Virus Involves Multiple Smad-Binding Elements Cooperatively Activating Expression of the Latent-Lytic SwitchBZLF1Gene
Authors: Iempridee Tawin , Das Shreyasi , Xu Iris , Mertz Janet E. 
Published: May 2011

ABSTRACTTransforming growth factor β (TGF-β) physiologically induces Epstein-Barr virus (EBV) lytic infection by activating the expression of EBV's latent-lytic switchBZLF1gene. Liang et al. (J. Biol. Chem.277:23345–23357, 2002) previously identified a Smad-binding element (SBE) within theBZLF1promoter, Zp; however, it accounts for only 20 to 30% of TGF-β-mediated activation of transcription from Zp. Here, we identified additional factors responsible for the rest of this activation. The incubation of EBV-positive MutuI cells with a TGF-β neutralizing antibody or inhibitors of the TGF-β type I receptor (TβRI) or Smad3 eliminated the TGF-β-induced reactivation of EBV. The coexpression of Smad2, Smad3, and Smad4 together with a constitutively active form of TβRI induced 15- to 25-fold transcription from Zp in gastric carcinoma AGS cells. By electrophoretic mobility shift assays, we identified four additional Smad-binding elements, named SBE2 to SBE5. Substitution mutations in individual SBEs reduced Smad-mediated activation of Zp by 20 to 60%; together, these mutations essentially eliminated it. Chromatin immunoprecipitation assays confirmed that Smad4 newly bound the Zp region of the EBV genome following the incubation of MutuI cells with TGF-β. SBE2 overlaps the ZEB-binding ZV silencing element of Zp. Depending upon posttranslational modifications, Smad4 either competed with ZEB1 for binding or formed a complex with ZEB1 on the Zp ZV element in a cell-free assay system. In transiently transfected cells, exogenously expressed ZEB1 inhibited Smad-mediated transcriptional activation from Zp. We conclude that TGF-β induces EBV lytic reactivation via the canonical Smad pathway by activatingBZLF1gene expression through multiple SBEs acting in concert.
Molecular Epidemiology and Phylogeny Reveal Complex Spatial Dynamics in Areas Where Canine Parvovirus Is Endemic
Authors: Clegg S. R. , Coyne K. P. , Parker J. , Dawson S. , Godsall S. A. , Pinchbeck G. , Cripps P. J. , Gaskell R. M. , Radford A. D. 
Published: May 2011

ABSTRACT
Canine parvovirus type 2 (CPV-2) is a severe enteric pathogen of dogs, causing high mortality in unvaccinated dogs. After emerging, CPV-2 spread rapidly worldwide. However, there is now some evidence to suggest that international transmission appears to be more restricted. In order to investigate the transmission and evolution of CPV-2 both nationally and in relation to the global situation, we have used a long-range PCR to amplify and sequence the full VP2 gene of 150 canine parvoviruses obtained from a large cross-sectional sample of dogs presenting with severe diarrhea to veterinarians in the United Kingdom, over a 2-year period. Among these 150 strains, 50 different DNA sequence types (S) were identified, and apart from one case, all appeared unique to the United Kingdom. Phylogenetic analysis provided clear evidence for spatial clustering at the international level and for the first time also at the national level, with the geographical range of some sequence types appearing to be highly restricted within the United Kingdom. Evolution of the VP2 gene in this data set was associated with a lack of positive selection. In addition, the majority of predicted amino acid sequences were identical to those found elsewhere in the world, suggesting that CPV VP2 has evolved a highly fit conformation. Based on typing systems using key amino acid mutations, 43% of viruses were CPV-2a, and 57% CPV-2b, with no type 2 or 2c found. However, phylogenetic analysis suggested complex antigenic evolution of this virus, with both type 2a and 2b viruses appearing polyphyletic. As such, typing based on specific amino acid mutations may not reflect the true epidemiology of this virus. The geographical restriction that we observed both within the United Kingdom and between the United Kingdom and other countries, together with the lack of CPV-2c in this population, strongly suggests the spread of CPV within its population may be heterogeneously subject to limiting factors. This cross-sectional study of national and global CPV phylogeographic segregation reveals a substantially more complex epidemic structure than previously described.
The Diversity of Torque Teno Viruses:
In Vitro
Replication Leads to the Formation of Additional Replication-Competent Subviral Molecules
Authors: de Villiers Ethel-Michele , Borkosky Silvia S. , Kimmel Romana , Gunst Karin , Fei Jian-Wei 
Published: May 2011

ABSTRACT

The family
Anelloviridae
comprises torque teno viruses (TTVs) diverse in genome structure and organization. The isolation of a large number of TTV genomes (TTV Heidelberg [TTV-HD]) of 26 TTV types is reported. Several isolates from the same type indicate sequence variation within open reading frame 1 (ORF1), resulting in considerably modified open reading frames. We demonstrate
in vitro
replication of 12 full-length genomes of TTV-HD in 293TT cells. Propagation of virus was achieved by several rounds of infections using supernatant and frozen whole cells of initially infected cells. Replication of virus was measured by PCR amplification and transcription analyses. Subgenomic molecules (μTTV), arising early during propagation and ranging in size from 401 to 913 bases, were cloned and characterized. Propagation of these μTTV in
in vitro
cultures was demonstrated in the absence of full-length genomes.
Fluorescence in situ hybridisation analysis of formalin-fixed paraffin-embedded tissue sections in the diagnostic work-up of non-Burkitt high grade B-cell non-Hodgkin's lymphoma: a single centre's experience
Authors: Foot Nicola J , Dunn Robert G , Geoghegan Helen , Wilkins Bridget S , Neat Michael J 
Published: May 2011

AimsIn recent years the genetic aberrations associated with diffuse large B-cell lymphoma and the new subtype described in the 2008 revision of the WHO classification, ‘B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma’ have been increasingly well defined. Recurrent genetic abnormalities include rearrangements involvingMYC(8q24),BCL2(18q21) andBCL6(3q27); as the prognostic and therapeutic implications associated with these abnormalities are clarified their accurate identification at diagnosis is becoming increasingly critical. We describe our experience of using a panel of fluorescence in situ hybridisation (FISH) probes on formalin-fixed paraffin-embedded tissue sections in the diagnostic work-up of 162 patients with non-Burkitt high grade B-cell non-Hodgkin's lymphomas (HG-BNHL).MethodsBCL6, IGH-BCL2andMYCstatus were determined prospectively in sequential patients presenting with HG-BNHL, with respect to the presence of rearrangements and copy number changes. Small numbers of samples were analysed retrospectively or were studied at relapse in previously untested patients.ResultsFISH analysis was successful in 160/162 (99%) cases, with abnormalities detected in 118/160 (74%).ConclusionsFISH analysis of formalin-fixed paraffin-embedded tissue sections is a highly reproducible technique with an excellent success rate for the detection of genetic abnormalities which will play an increasingly important role in improving risk stratification of patients with HG-BNHL.
Resident education and quality of gross tissue examination practices of benign uteri
Authors: Ryan Margaret S , Smith Maxwell L , Grzybicki Dana M , Raab Stephen S 
Published: May 2011

IntroductionIn the USA, most anatomical pathology residency training is based on an apprenticeship model in which residents learn directly by watching more senior personnel and then performing the examination. The level and the effect of the standardisation of resident trainee gross tissue examination practices have not been extensively evaluated.MethodsIn this apprenticeship-based training programme, a retrospective report review was performed to measure the level of standardisation of gross description (for 11 mandatory descriptors) and tissue submission (for four mandatory sections) practices for uterine specimens removed for benign conditions (n=78). Practices were examined for significant relationships with error, turnaround time (TAT), resource utilisation and postgraduate year of resident (n=25) training.ResultsResidents provided mandatory descriptors from 23.1% to 93.6% of the time and submitted mandatory sections from 82.1% to 96.2% of the time. Cases submitted by less experienced residents had a longer TAT and were associated with more errors, measured by the necessity to submit additional tissues. Less experienced residents used greater resources (submitting 9.5 tissue cassettes per case) compared with more experienced residents (7.3 cassettes per case), and a statistically significant correlation was found between the number of cassettes submitted and TAT.ConclusionsIn this training programme, the model of apprenticeship training leads to less than optimal standardisation of gross examination practices, inefficiency, active errors and a high frequency of latent conditions leading to error.
The biology of micrometastases from uveal melanoma
Authors: Borthwick Nicola J , Thombs Jasmine , Polak Marta , Gabriel F Guy , Hungerford John L , Damato Bertil , Rennie Ian G , Jager Martine J , Cree Ian A 
Published: May 2011

BackgroundThe aim of this study was to investigate the possible causes of tumour latency in uveal melanoma primarily through the analysis of micrometastases in tissue obtained from donors postmortem. Various explanations have been proposed but there is no clear answer from animal studies and few human data. The main hypotheses may be divided into several areas—immunological control of metastatic cells, lack of angiogenesis within micrometastases and reduced cell turnover.Methods196 patients were recruited to the study between 2003 and 2007. Patients were invited to take part and their relatives agreed to postmortem examination of their liver and lungs in the event of their death, including tissue sampling to assess the presence of micrometastases and their biology. Metastatic cells were detected by immunohistochemistry using a pan-melanoma antibody reagent, and by quantitative reverse transcriptase (qRT)–PCR for three melanoma-associated genes (tyrosinase Melan-A, andgp100) and a housekeeping gene (HMBS/PBGD) in samples stored in RNAlater or as formalin-fixed paraffin-embedded tissue.Results22 deaths were investigated at autopsy as part of the study. Sixteen patients died with large deposits of metastatic melanoma, while six patients died of other causes. In addition, a liver resection for hepatic adenoma provided further tissue from a case without clinical evidence of metastasis. Metastatic melanoma cells were identified by immunohistochemistry of the liver samples in one case and by qRT–PCR in two further cases without macrometastases. There was no evidence of multicellular micrometastases sufficiently large to require angiogenesis and no associated inflammation was observed.ConclusionThe most likely explanation for latency in this setting is the inability of uveal melanoma cells in metastatic sites to grow.
Diosgenin Ameliorates Cognition Deficit and Attenuates Oxidative Damage in Senescent Mice Induced by D-Galactose
Authors: Chiu Chuan-Sung , Chiu Yung-Jia , Wu Lung-Yuan , Lu Tsung-Chun , Huang Tai-Hung , Hsieh Ming-Tsuen , Lu Chung-Yen , Peng Wen-Huang 
Published: May 2011

This study attempted to access the neuroprotective effect of diosgenin on the senescent mice induced by d-galactose (D-gal). The mice in the experiments were orally administered with diosgenin (1, 5, 25 and 125 mg/kg), for four weeks from the sixth week. The learning and memory abilities of the mice in Morris water maze test and the mechanism involved in the neuroprotective effect of diosgenin on the mice brain tissue were investigated.Diosgenin (5, 25 and 125 mg/kg, p.o.) showed significantly improved learning and memory abilities in Morris water maze test compared to D-gal treated mice (200 mg/kg, ten weeks). Diosgenin also increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased the malondialdehyde (MDA) level in the brain of D-gal treated mice.These results indicated that diosgenin has the potential to be a useful treatment for cognitive impairment. In addition, the memory enhancing effect of diosgenin may be partly mediated via enhancing endogenous antioxidant enzymatic activities.
WAVES FOR A HYPERBOLIC KELLER–SEGEL MODEL AND BRANCHING INSTABILITIES
Authors: CERRETI FIAMMETTA , PERTHAME BENOÎT , SCHMEISER CHRISTIAN , TANG MIN , VAUCHELET NICOLAS 
Published: May 2011

Recent experiments for swarming of the bacteria Bacillus subtilis on nutrient-rich media show that these cells are able to proliferate and spread out in colonies exhibiting complex patterns as dendritic ramifications. Is it possible to explain this process with a model that does not use local nutrient depletion? We present a new class of models which is compatible with the experimental observations and which predict branching instabilities and does not use nutrient limitation. These conclusions are based on numerical simulations. The most complex of these models is also the biologically most accurate but the essential effects can also be obtained in simplified versions which are amenable to analysis. An example of instability mechanism is the transition from a shock wave to a rarefaction wave in a reduced two by two hyperbolic system.
A Novel Function of Junctional Adhesion Molecule-C in Mediating Melanoma Cell Metastasis
Authors: Langer Harald F. , Orlova Valeria V. , Xie Changping , Kaul Sunil , Schneider Darius , Lonsdorf Anke S. , Fahrleitner Manuela , Choi Eun Young , Dutoit Vanessa , Pellegrini Manuela , Grossklaus Sylvia , Nawroth Peter P. , Baretton Gustavo , Santoso Sentot , Hwang Sam T. , Arnold Bernd , Chavakis Triantafyllos 
Published: May 2011

AbstractHematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified junctional adhesion molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C−/− mice as well as endothelial-specific JAM-C–deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis. Cancer Res; 71(12); 4096–105. ©2011 AACR.
IL-7 Contributes to the Progression of Human T-cell Acute Lymphoblastic Leukemias
Authors: Silva Ana , Laranjeira Angelo B.A. , Martins Leila R. , Cardoso Bruno A. , Demengeot Jocelyne , Yunes J. Andrés , Seddon Benedict , Barata João T. 
Published: May 2011

Abstract
The importance of microenvironmental factors for driving progression in leukemia has been debated. Previous evidence has pointed to interleukin-7 (IL-7), a fundamental cytokine to normal T-cell development and homeostasis, as an important determinant of the viability and proliferation of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study, we report that IL-7 is also a critical determinant of T-ALL progression. T-ALL cell lines and primary T-ALL samples initiated leukemia more slowly when engrafted to immunocompromised Rag2−/−IL2rg−/− mice lacking IL-7. This effect was not related to reduced engraftment or homing of transplanted cells to the bone marrow. Instead, IL-7 deficiency diminished expansion of leukemia cells in the bone marrow and delayed leukemia-associated death of transplanted mice. Moreover, infiltration of different organs by T-ALL cells, which characterizes patients with advanced disease, was more heterogeneous and generally less efficient in IL-7–deficient mice. Leukemia progression was associated with increased Bcl-2 expression and cell viability, reduced p27Kip1 expression, and decreased cell-cycle progression. Clinical measurements of IL-7 plasma levels and IL-7 receptor (IL-7R) expression in T-ALL patients versus healthy controls confirmed that IL-7 stimulates human leukemia cells. Our results establish that IL-7 contributes to the progression of human T-cell leukemia, and they offer preclinical validation of the concept that targeting IL-7/IL-7R signaling in the tumor microenvironment could elicit therapeutic effects in T-ALL. Cancer Res; 71(14); 4780–9. ©2011 AACR.
Telomere Dysfuction Promotes Metastasis in a TERC Null Mouse Model of Head and Neck Cancer
Authors: Bojovic Bojana , Crowe David L. 
Published: May 2011

Abstract
Squamous cell carcinoma arises from highly proliferative basal layer epithelial cells, which normally divide for a short time before detaching from the basement membrane and undergoing terminal differentiation. Basal layer cells in stratified epithelia express the reverse transcriptase known as telomerase. Most human cells do not express telomerase and therefore are subject to loss of telomeric DNA with age due to the inability of lagging strand synthesis to completely replicate chromosomal ends. Late generation telomerase deficient mice exhibit signs of premature aging including reduced function of proliferating cellular compartments. We examined development of squamous cell carcinoma in a telomerase deficient murine background with long and short telomeres. G1 Terc-/- mice (long telomeres) had fewer lymph node metastases, which correlated with increased numbers of apoptotic cells in these tumors compared with wild-type mice. However, G5 Terc-/- mice with short telomeres had increased metastatic tumor burden similar to wild type mice. This increased metastasis correlated with genomic instability and aneuploidy in tumor cells from G5 Terc-/- mice. A number of similarities with human SCC were noted in the mouse model, and dramatic differences in global gene expression profiles were shown between primary and metastatic tumors. We concluded that telomere shortening promotes metastatic tumor development in a Terc null mouse model of head and neck cancer. Mol Cancer Res; 9(7); 901–13. ©2011 AACR.
Prolonged Tpeak-to-Tend Interval on the Resting ECG Is Associated With Increased Risk of Sudden Cardiac Death
Authors: Panikkath Ragesh , Reinier Kyndaron , Uy-Evanado Audrey , Teodorescu Carmen , Hattenhauer Jonathan , Mariani Ronald , Gunson Karen , Jui Jonathan , Chugh Sumeet S. 
Published: May 2011

Background—
Early studies indicate that prolongation of the interval between the peak and the end of the T wave (Tpeak to Tend [TpTe]) on the 12-lead ECG is a marker of ventricular arrhythmogenesis. However, community-based studies have not been conducted.

Methods and Results—

TpTe and other ECG predictors were evaluated in the ongoing Oregon Sudden Unexpected Death Study based in the Portland, Oregon, metropolitan area using a case-control design. Cases of sudden cardiac death (SCD) (n=353; mean age, 66.6 years; 95% CI, 65.1 to 68.1 years; 67% men) were compared with living controls with coronary artery disease (n=342; mean age, 64.7 years; 95% CI, 63.4 to 66.0 years; 69% men) from the same region. Analysis of TpTe and selected ECG intervals was limited to sinus rhythm 12-lead ECGs. For cases, these were obtained before and unrelated to SCD. Independent-samples
t
tests and multiple logistic regression were used. Mean TpTe was significantly greater in cases (89.4 ms; 95% CI, 87.7 to 91.2 ms;
P
<0.0001) than in controls (76.1 ms; 95% CI, 74.8 to 77.4 ms). The other ECG intervals (corrected QT interval [QTc], QRS duration [QRSD], and TpTe/QT ratio) also were significantly prolonged among cases versus controls (
P
≤0.01). TpTe remained a significant predictor of SCD after adjusting for age, sex, QTc, QRSD, and left ventricular function. Odds of SCD increased more with a 1-SD increase in TpTe (12 ms) among subjects with prolonged QRSD (odds ratio, 3.49; 95% CI, 2.06 to 5.91) than with a 1-SD increase in TpTe among subjects with normal QRSD (odds ratio, 1.96; 95% CI, 1.65 to 2.32). TpTe remained significantly associated with SCD in subjects with normal QTc.

Conclusions—
Prolongation of the TpTe interval measured in lead V5 was independently associated with SCD, with particular utility when the QTc was normal or not measurable because of prolonged QRSD.
Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension
Authors: Kawut Steven M. , Bagiella Emilia , Lederer David J. , Shimbo Daichi , Horn Evelyn M. , Roberts Kari E. , Hill Nicholas S. , Barr R. Graham , Rosenzweig Erika B. , Post Wendy , Tracy Russell P. , Palevsky Harold I. , Hassoun Paul M. , Girgis Reda E. 
Published: May 2011

Background—
Pulmonary arterial hypertension (PAH) is a progressive disease that causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH.

Methods and Results—

We performed a randomized, double-blind, placebo-controlled 2×2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at 4 centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was 6-minute walk distance at 6 months. Sixty-five subjects had been randomized when the trial was terminated by the Data Safety and Monitoring Board after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6-minute walk distance, there was no significant difference in the 6-minute walk distance at 6 months between aspirin (n=32) and placebo (n=33; placebo-corrected difference −0.5 m, 95% confidence interval −28.4 to 27.4 m;
P
=0.97) or between simvastatin (n=32) and placebo (n=33; placebo-corrected difference −27.6 m, 95% confidence interval −59.6 to 4.3 m;
P
=0.09). There tended to be more major bleeding episodes with aspirin than with placebo (4 events versus 1 event, respectively;
P
=0.17).

Conclusions—
Neither aspirin nor simvastatin had a significant effect on the 6-minute walk distance, although patients randomized to simvastatin tended to have a lower 6-minute walk distance at 6 months. These results do not support the routine treatment of patients with PAH with these medications.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00384865.