bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two Domains of the V Protein of Virulent Canine Distemper Virus Selectively Inhibit STAT1 and STAT2 Nuclear Import
Authors: Röthlisberger Anne , Wiener Dominique , Schweizer Matthias , Peterhans Ernst , Zurbriggen Andreas , Plattet Philippe 
Published: April 2010

ABSTRACT
Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-α/β)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-α/β-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-α/β-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-α/β-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-α/β-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-α/β-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-α/β evasion among the morbilliviruses.
Semliki Forest Virus-Induced Endoplasmic Reticulum Stress Accelerates Apoptotic Death of Mammalian Cells
Authors: Barry Gerald , Fragkoudis Rennos , Ferguson Mhairi C. , Lulla Aleksei , Merits Andres , Kohl Alain , Fazakerley John K. 
Published: April 2010

ABSTRACT
The alphavirus Semliki Forest virus (SFV) and its derived vectors induce apoptosis in mammalian cells. Here, we show that apoptosis is associated with the loss of mitochondrial membrane potential followed by the activation of caspase-3, caspase-8, and caspase-9. Cell death can be partially suppressed by treatment with the pan-caspase inhibitor zVAD-fmk. To determine the role of SFV structural proteins in cell death, the temporal course of cell death was compared in cells infected with SFV and cells infected with SFV virus replicon particles (VRPs) lacking some or all of the virus structural genes. In the absence of virus structural proteins, cell death was delayed. The endoplasmic reticulum (ER) stress response, as determined by the splicing of X-box binding protein 1 (XBP1) transcripts and the activation of caspase-12, was activated in virus-infected cells but not in VRP (SFV lacking structural genes)-infected cells. The C/EBP-homologous protein (CHOP) was upregulated by both virus and VRP infections. The virus envelope proteins but not the virus capsid protein triggered ER stress. These results demonstrate that in NIH 3T3 cells, SFV envelope glycoproteins trigger the unfolded protein response of the ER and accelerate apoptotic cell death initiated by virus replicase activity.
Selective Visualization of Cyclooxygenase-2 in Inflammation and Cancer by Targeted Fluorescent Imaging Agents
Authors: Uddin Md. Jashim , Crews Brenda C. , Blobaum Anna L. , Kingsley Philip J. , Gorden D. Lee , McIntyre J. Oliver , Matrisian Lynn M. , Subbaramaiah Kotha , Dannenberg Andrew J. , Piston David W. , Marnett Lawrence J. 
Published: April 2010

Abstract
Effective diagnosis of inflammation and cancer by molecular imaging is challenging because of interference from nonselective accumulation of the contrast agents in normal tissues. Here, we report a series of novel fluorescence imaging agents that efficiently target cyclooxygenase-2 (COX-2), which is normally absent from cells, but is found at high levels in inflammatory lesions and in many premalignant and malignant tumors. After either i.p. or i.v. injection, these reagents become highly enriched in inflamed or tumor tissue compared with normal tissue and this accumulation provides sufficient signal for in vivo fluorescence imaging. Further, we show that only the intact parent compound is found in the region of interest. COX-2–specific delivery was unambiguously confirmed using animals bearing targeted deletions of COX-2 and by blocking the COX-2 active site with high-affinity inhibitors in both in vitro and in vivo models. Because of their high specificity, contrast, and detectability, these fluorocoxibs are ideal candidates for detection of inflammatory lesions or early-stage COX-2–expressing human cancers, such as those in the esophagus, oropharynx, and colon. Cancer Res; 70(9); 3618–27. ©2010 AACR.
Sustained Small Interfering RNA Delivery by Mesoporous Silicon Particles
Authors: Tanaka Takemi , Mangala Lingegowda S. , Vivas-Mejia Pablo E. , Nieves-Alicea René , Mann Aman P. , Mora Edna , Han Hee-Dong , Shahzad Mian M.K. , Liu Xuewu , Bhavane Rohan , Gu Jianhua , Fakhoury Jean R. , Chiappini Ciro , Lu Chunhua , Matsuo Koji , Godin Biana , Stone Rebecca L. , Nick Alpa M. , Lopez-Berestein Gabriel , Sood Anil K. , Ferrari Mauro 
Published: April 2010

AbstractRNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector composed of mesoporous silicon particles (stage 1 microparticles, S1MP) loaded with neutral nanoliposomes (dioleoyl phosphatidylcholine, DOPC) containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein, which is overexpressed in most cancers, including ovarian. Our delivery methods resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single i.v. administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis, and cell proliferation compared with a noncoding control siRNA alone (SKOV3ip1, 54%; HeyA8, 57%), with no significant changes in serum chemistries or in proinflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms. Cancer Res; 70(9); 3687–96. ©2010 AACR.
Estrogen Receptor Mutations and Changes in Downstream Gene Expression and Signaling
Authors: Barone Ines , Brusco Lauren , Fuqua Suzanne A.W. 
Published: April 2010

Abstract
Estrogens play a crucial role in regulating the growth and differentiation of breast cancers, with approximately two thirds of all breast tumors expressing the estrogen receptor alpha (ERα). Therefore, therapeutic strategies directed at inhibiting the action of ERα by using anti-estrogens such as tamoxifen, or reducing estrogens levels by using aromatase inhibitors, such as letrozole, anastrozole, or exemestane, are the standard treatments offered to women with ERα-positive cancer. However, not all patients respond to endocrine therapies (termed de novo resistance), and a large number of patients who do respond will eventually develop disease progression or recurrence while on therapy (acquired resistance). Recently, variant forms of the receptor have been identified owing to alternative splicing or gene mutation. This article reviews these variant receptors and their clinical relevance in resistance to endocrine therapy, by addressing their molecular cross-talk with growth factor receptors and signaling components. Understanding the complexity of receptor-mediated signaling has promise for new combined therapeutic options that focus on more efficient blockade of receptor cross-talk. Clin Cancer Res; 16(10); 2702–8. ©2010 AACR.
Antagonism of P2Y12 or GPIIb/IIIa receptors reduces platelet-mediated myocardial injury after ischaemia and reperfusion in isolated rat hearts
Authors: Barrabés José A. , Inserte Javier , Mirabet Maribel , Quiroga Adoración , Hernando Víctor , Figueras Jaume , Garcia-Dorado David 
Published: April 2010

SummaryPlatelets activated during experimental acute myocardial infarction (AMI) contribute to myocardial injury. This study aimed to investigate whether platelets from patients with AMI increase myocardial injury after ischaemia and reperfusion in isolated rat hearts and the modification of this effect by the P2Y12 receptor antagonist cangrelor and the glycoprotein IIb/IIIa receptor blocker abciximab. Isolated rat hearts were subjected to 40 minutes of global ischaemia and 60 minutes of reperfusion. Hearts (four simultaneous experiments per patient) were infused with platelets from nine AMI patients (seven thrombolysed, all on aspirin), untreated or incubated with 10 μM cangrelor or 5 μg/ml abciximab. Control experiments were performed using platelets from healthy volunteers and platelet-poor plasma. P-selectin expression on isolated platelets was higher in AMI patients than in controls and was not modified by the treatments. Control platelets or platelet-poor plasma did mild or no harm. In contrast, platelets from AMI patients significantly augmented myocardial injury, as demonstrated by worse left ventricular (LV) developed pressure, higher maximal LV end-diastolic pressure and coronary resistance, and greater lactate dehydrogenase release and infarct size. Both cangrelor and abciximab greatly attenuated these effects. In conclusion, activated platelets from AMI patients increase myocardial injury after ischaemia and reperfusion, and cangrelor and abciximab attenuate this effect. The results support the notion that very early antiplatelet treatment might reduce infarct size by direct effects on reperfused myocardium in these patients.
In vitro factor XIII supplementation increases clot firmness in Rotation Thromboelastometry (ROTEM®)
Authors: Asmis Lars , Seifert Burkhardt , Spahn Donat , Theusinger Oliver , Baulig Werner 
Published: April 2010

SummaryFactor XIII (F XIII) is an essential parameter for final clot stability. The purpose of this study was to determine the impact of the addition of factor (F)XIII on clot stability as assessed by Rotation Thromboelastometry (ROTEM®). In 90 intensive care patients ROTEM® measurements were performed after in vitro addition of F XIII 0.32 IU, 0.63 IU, 1.25 IU and compared to diluent controls (DC; aqua injectabile) resulting in approximate F XIII concentrations of 150, 300 and 600%. Baseline measurements without any additions were also performed. The following ROTEM® parameters were measured in FIBTEM and EXTEM tests: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), maximum lysis (ML), maximum clot elasticity (MCE) and α-angle (αA). Additionally, laboratory values for FXIII, fibrinogen (FBG), platelets and haematocrit were contemporaneously determined. In the perioperative patient population mean FBG concentration was elevated at 5.2 g/l and mean FXIII concentration was low at 62%. The addition of FXIII led to a FBG concentration-dependent increase in MCF both in FIBTEM and EXTEM. Mean increases in MCF (FXIII vs. DC) of approximately 7 mm and 6 mm were observed in FIBTEM and EXTEM, respectively. F XIII addition also led to decreased CFT, increased αA, and reduced ML in FIBTEM and EXTEM. In vitro supplementation of FXIII to supraphysiologic levels increases maximum clot firmness, accelerates clot formation and increases clot stability in EXTEM and FIBTEM as assayed by ROTEM® in perioperative patients with high fibrinogen and low FXIII levels.
Global Administrative Law Perspective of the WTO Aid for Trade Initiative
Authors: Illy Ousseni , Marceau Gabrielle 
Published: April 2010

AbstractThe emerging Global Administrative Law (GAL) study has brought into the legal frontlines the need to hold global governance bodies more accountable for their rulings and activities, and how these institutions are adapting their actions to better respond to new global challenges as their legitimacy depends on their effectiveness in coping with them. The legitimacy challenge has become a pressing issue, forcing international organizations to open up their decision-making processes and to set up review mechanisms to oversee their actions. The recent WTO Aid for Trade (AFT) Initiative belongs to this new category of global action/forums that want to respond to legitimacy and accountability challenges. This innovative movement has provided the WTO Director General with the responsibility to launch and institutionalize an initiative to allow poorer countries to derive more benefit from the Multilateral Trading System. It has brought together a wide range of stakeholders including international aid-donor states, beneficiary states, international financial and development institutions, regional banks and regional institutions, private sector, NGOs etc. to discuss and shape the best way to achieve this aim. This article tries to assess the AFT Initiative against the principles advocated by GAL, in particular those related to participation, transparency, accountability and review.
Emergency Action by the WTO Director-General: Global Administrative Law and the WTO's Initial Response to the 2008–09 Financial Crisis
Authors: Berman Ayelet , Pauwelyn Joost 
Published: April 2010

AbstractThe WTO's initial reaction to the 2008–2009 financial crisis was taken mainly by its managerial arm, that is, by the Director-General (DG) and the Secretariat and not by its legislative or judicial bodies. This is a novelty for the WTO and illustrates the emergence, even at the otherwise hard-law WTO, of informal administrative actions that go beyond the traditional member-dominated WTO. The actions were in two areas: The DG convened trade finance expert meetings with other organizations and private banks, and the Secretariat prepared reports on trade-related measures enacted across the globe in response to the crisis. The article examines these actions in light of certain concepts and principles of the GAL project. Overall, the Director-General was sensitive in his actions to GAL principles.
Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells
Authors: Hosokawa Kentaro , Arai Fumio , Yoshihara Hiroki , Iwasaki Hiroko , Nakamura Yuka , Gomei Yumiko , Suda Toshio 
Published: April 2010

AbstractDuring postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized microenvironments termed stem cell niches. Cell-cell and cell-extracellular matrix interactions between HSCs and their niches are critical for the maintenance of HSC properties. Here, we analyzed the function of N-cadherin in the regulation of the proliferation and long-term repopulation activity of hematopoietic stem/progenitor cells (HSPCs) by the transduction of N-cadherin shRNA. Inhibition of N-cadherin expression accelerated cell division in vitro and reduced the lodgment of donor HSPCs to the endosteal surface, resulting in a significant reduction in long-term engraftment. Cotransduction of N-cadherin shRNA and a mutant N-cadherin that introduced the silent mutations to shRNA target sequences rescued the accelerated cell division and reconstitution phenotypes. In addition, the requirement of N-cadherin for HSPC engraftment appears to be niche specific, as shN-cad–transduced lineage−Sca-1+c-Kit+ cells successfully engrafted in spleen, which lacks an osteoblastic niche. These findings suggest that N-cad–mediated cell adhesion is functionally required for the establishment of hematopoiesis in the BM niche after BM transplantation.
Retinoic acid enhances the generation of hematopoietic progenitors from human embryonic stem cell–derived hemato-vascular precursors
Authors: Yu Chen , Liu Yanxia , Miao Zhenchuan , Yin Ming , Lu Wei , Lv Yaxin , Ding Mingxiao , Deng Hongkui 
Published: April 2010

AbstractCurrent induction schemes directing hematopoietic differentiation of human embryonic stem cells (hESCs) are not well defined to mimic the sequential stages of hematopoietic development in vivo. Here, we report a 3-stage method to direct differentiation of hESCs toward hematopoietic progenitors in chemically defined mediums. In the first 2 stages, we efficiently generated T-positive primitive streak/mesendoderm cells and kinase domain receptor–positive (KDR+) platelet-derived growth factor receptor α–negative (PDGFRα−) hemato-vascular precursors sequentially. In the third stage, we found that cells in a spontaneous differentiation condition mainly formed erythroid colonies. Addition of all-trans retinoic acid (RA) greatly enhanced generation of hematopoietic progenitors in this stage while suppressing erythroid development. The RA-treated cells highly expressed definitive hematopoietic genes, formed large numbers of multilineage and myeloid colonies, and gave rise to greater than 45% CD45+ hematopoietic cells. When hematopoietic progenitors were selected with CD34 and C-Kit, greater than 95% CD45+ hematopoietic cells could be generated. In addition, we found that endogenous RA signaling at the second stage was required for vascular endothelial growth factor/basic fibroblast growth factor–induced hemato-vascular specification, whereas exogenously applied RA efficiently induced KDR−PDGFRα+ paraxial mesoderm cells. Our study suggests that RA signaling plays diverse roles in human mesoderm and hematopoietic development.
Deficiency of the dual ubiquitin/SUMO ligase Topors results in genetic instability and an increased rate of malignancy in mice
Authors: Marshall Henderson , Bhaumik Mantu , Aviv Hana , Moore Dirk , Yao Ming , Dutta Jayeeta , Rahim Hussein , Gounder Murugesan , Ganesan Shridar , Saleem Ahamed , Rubin Eric 
Published: April 2010

Abstract

Background
Topors is a nuclear protein that co-localizes with promyelocytic leukemia bodies and has both ubiquitin and SUMO E3 ligase activity. Expression studies implicated Topors as a tumor suppressor in various malignancies. To gain insight into the function of Topors, we generated a Topors-deficient mouse strain.

Results
Mice homozygous for a mutant Topors allele exhibited a high rate of perinatal mortality and decreased lifespan. In addition, heterozygotes were found to have an increased incidence of malignancy, involving a variety of tissues. Consistent with this finding, primary embryonic fibroblasts lacking Topors exhibited an increased rate of malignant transformation, associated with aneuploidy and defective chromosomal segregation. While loss of Topors did not alter sensitivity to DNA-damaging or microtubule-targeting agents, cells lacking Topors exhibited altered pericentric heterochromatin, manifested by mislocalization of HP1α and an increase in transcription from pericentric major satellite DNA. Topors-deficient cells exhibited a transcriptional profile similar to that of cells treated with histone deacetylase inhibitors, and were resistant to the anti-proliferative effects of the histone deacetylase inhibitor trichostatin A.

Conclusion
These results indicate a unique role for Topors in the maintenance of genomic stability and pericentric heterochromatin, as well as in cellular sensitivity to histone deacetylase inhibitors.
Oncological outcome and patient satisfaction with skin-sparing mastectomy and immediate breast reconstruction: a prospective observational study
Authors: Reefy Sara , Patani Neill , Anderson Anne , Burgoyne Gwyne , Osman Hisham , Mokbel Kefah 
Published: April 2010

Abstract

Background
The management of early breast cancer (BC) with skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR) is not based on level-1 evidence. In this study, the oncological outcome, post-operative morbidity and patients' satisfaction with SSM and IBR using the latissimus dorsi (LD) myocutaneous flap and/or breast prosthesis is evaluated.

Methods
137 SSMs with IBR (10 bilateral) were undertaken in 127 consecutive women, using the LD flap plus implant (n = 85), LD flap alone (n = 1) or implant alone (n = 51), for early BC (n = 130) or prophylaxis (n = 7). Nipple reconstruction was performed in 69 patients, using the trefoil local flap technique (n = 61), nipple sharing (n = 6), skin graft (n = 1) and Monocryl mesh (n = 1). Thirty patients underwent contra-lateral procedures to enhance symmetry, including 19 augmentations and 11 mastopexy/reduction mammoplasties. A linear visual analogue scale was used to assess patient satisfaction with surgical outcome, ranging from 0 (not satisfied) to 10 (most satisfied).

Results
After a median follow-up of 36 months (range = 6-101 months) there were no local recurrences. Overall breast cancer specific survival was 99.2%, 8 patients developed distant disease and 1 died of metastatic BC. There were no cases of partial or total LD flap loss. Morbidities included infection, requiring implant removal in 2 patients and 1 patient developed marginal ischaemia of the skin envelope. Chemotherapy was delayed in 1 patient due to infection. Significant capsule formation, requiring capsulotomy, was observed in 85% of patients who had either post-mastectomy radiotherapy (PMR) or prior radiotherapy (RT) compared with 13% for those who had not received RT. The outcome questionnaire was completed by 82 (64.6%) of 127 patients with a median satisfaction score of 9 (range = 5-10).

Conclusion
SSM with IBR is associated with low morbidity, high levels of patient satisfaction and is oncologically safe for T(is), T1 and T2 tumours without extensive skin involvement.
Use of platelet rich plasma to treat plantar fasciitis: design of a multi centre randomized controlled trial
Authors: Peerbooms Joost C , van Laar Wilbert , Faber Frank , Schuller Hans M , van der Hoeven Henk , Gosens Taco 
Published: April 2010

Abstract

Background
If conservative treatment for chronic plantar fasciitis fails, often a corticosteroid injection is given. Corticosteroid injection gives temporarily pain reduction, but no healing. Blood platelets initiate the natural healing rate. GPS® gives an eightfold concentrate platelets of patients own blood. Injection of these platelets in the attachment of the fascia to the os calcis might induce a healing rate.

Methods and design
A randomized controlled multi centre trial will be performed. The study population consists of 120 patients of 18 years and older. Patients with chronic plantar fasciitis will be allocated randomly to have a steroid injection or an autologous platelet concentrate injections. Data will be collected before the procedure, 4,8,12,26 weeks and 1 year after the procedure.
The main outcome measures of this study are pain and function measured with questionnaires.

Conclusion
Recent literature show positive effects for the treatment of tendinosis with autologous platelet injections. The forthcoming trial will compare treatment for chronic plantar fasciitis with a steroid injection versus an autologous platelet injection. Our results will be published as soon as they become available.

Trial Registration
Trial registration number: http://www.clinicaltrials.gov NCT00758641.