bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation
Authors: Valentine Robert , Dawson Christopher W , Hu Chunfang , Shah Khilan M , Owen Thomas J , Date Kathryn L , Maia Sonia P , Shao Jianyong , Arrand John R , Young Lawrence S , O'Neil John D 
Published: January 2010

Abstract

Background
The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all EBV-associated tumours, including undifferentiated nasopharyngeal carcinoma (NPC), where it is indispensable for viral replication, genome maintenance and viral gene expression. EBNA1's transcription factor-like functions also extend to influencing the expression of cellular genes involved in pathways commonly dysregulated during oncogenesis, including elevation of AP-1 activity in NPC cell lines resulting in enhancement of angiogenesis in vitro. In this study we sought to extend these observations by examining the role of EBNA1 upon another pathway commonly deregulated during carcinogenesis; namely NF-κB.

Results
In this report we demonstrate that EBNA1 inhibits the canonical NF-κB pathway in carcinoma lines by inhibiting the phosphorylation of IKKα/β. In agreement with this observation we find a reduction in the phosphorylation of IκBα and reduced phosphorylation and nuclear translocation of p65, resulting in a reduction in the amount of p65 in nuclear NF-κB complexes. Similar effects were also found in carcinoma lines infected with recombinant EBV and in the EBV-positive NPC-derived cell line C666-1. Inhibition of NF-κB was dependent upon regions of EBNA1 essential for gene transactivation whilst the interaction with the deubiquitinating enzyme, USP7, was entirely dispensable. Furthermore, in agreement with EBNA1 inhibiting p65 NF-κB we demonstrate that p65 was exclusively cytoplasmic in 11 out of 11 NPC tumours studied.

Conclusions
Inhibition of p65 NF-κB in murine and human epidermis results in tissue hyperplasia and the development of squamous cell carcinoma. In line with this, p65 knockout fibroblasts have a transformed phenotype. Inhibition of p65 NF-κB by EBNA1 may therefore contribute to the development of NPC by inducing tissue hyperplasia. Furthermore, inhibition of NF-κB is employed by viruses as an immune evasion strategy which is also closely linked to oncogenesis during persistent viral infection. Our findings therefore further implicate EBNA1 in playing an important role in the pathogenesis of NPC.
Placental thrombomodulin expression in recurrent miscarriage
Authors: Stortoni Piergiorgio , Cecati Monia , Giannubilo Stefano R , Sartini Davide , Turi Angelo , Emanuelli Monica , Tranquilli Andrea L 
Published: January 2010

Abstract

Background
Early pregnancy loss can be associated with trophoblast insufficiency and coagulation defects. Thrombomodulin is an endothelial-associated anticoagulant protein involved in the control of hemostasis and inflammation at the vascular beds and it's also a cofactor of the protein C anticoagulant pathway.

Discussion
We evaluate the Thrombomodulin expression in placental tissue from spontaneous recurrent miscarriage and voluntary abortion as controls. Thrombomodulin mRNA was determined using real-time quantitative polymerase chain reaction. Reduced expression levels of thrombomodulin were found in recurrent miscarriage group compared to controls (1.82-fold of reduction), that corresponds to a reduction of 45% (from control group Delta CT) of thrombomodulin expression in spontaneous miscarriage group respect the control groups.

Summary
We cannot state at present the exact meaning of a reduced expression of Thrombomodulin in placental tissue. Further studies are needed to elucidate the biological pathway of this important factor in the physiopathology of the trophoblast and in reproductive biology.
Fast prediction of RNA-RNA interaction
Authors: Salari Raheleh , Backofen Rolf , Sahinalp S Cenk 
Published: January 2010

Abstract

Background
Regulatory antisense RNAs are a class of ncRNAs that regulate gene expression by prohibiting the translation of an mRNA by establishing stable interactions with a target sequence. There is great demand for efficient computational methods to predict the specific interaction between an ncRNA and its target mRNA(s). There are a number of algorithms in the literature which can predict a variety of such interactions - unfortunately at a very high computational cost. Although some existing target prediction approaches are much faster, they are specialized for interactions with a single binding site.

Methods
In this paper we present a novel algorithm to accurately predict the minimum free energy structure of RNA-RNA interaction under the most general type of interactions studied in the literature. Moreover, we introduce a fast heuristic method to predict the specific (multiple) binding sites of two interacting RNAs.

Results
We verify the performance of our algorithms for joint structure and binding site prediction on a set of known interacting RNA pairs. Experimental results show our algorithms are highly accurate and outperform all competitive approaches.
The F-box protein Cdc4/Fbxw7 is a novel regulator of neural crest development in Xenopus laevis
Authors: Almeida Alexandra D , Wise Helen M , Hindley Christopher J , Slevin Michael K , Hartley Rebecca S , Philpott Anna 
Published: January 2010

Abstract
Background
The neural crest is a unique population of cells that arise in the vertebrate ectoderm at the neural plate border after which they migrate extensively throughout the embryo, giving rise to a wide range of derivatives. A number of proteins involved in neural crest development have dynamic expression patterns, and it is becoming clear that ubiquitin-mediated protein degradation is partly responsible for this.

Results
Here we demonstrate a novel role for the F-box protein Cdc4/Fbxw7 in neural crest development. Two isoforms of Xenopus laevis Cdc4 were identified, and designated xCdc4α and xCdc4β. These are highly conserved with vertebrate Cdc4 orthologs, and the Xenopus proteins are functionally equivalent in terms of their ability to degrade Cyclin E, an established vertebrate Cdc4 target. Blocking xCdc4 function specifically inhibited neural crest development at an early stage, prior to expression of c-Myc, Snail2 and Snail.

Conclusions
We demonstrate that Cdc4, an ubiquitin E3 ligase subunit previously identified as targeting primarily cell cycle regulators for proteolysis, has additional roles in control of formation of the neural crest. Hence, we identify Cdc4 as a protein with separable but complementary functions in control of cell proliferation and differentiation.
Evaluation of biodistribution and safety of adenovirus vector containing MDR1 in mice
Authors: Zhao ZhenZhen , Liu Wei , Su YuXi , Zhu Jin , Zheng GaiHuan , Luo Qing , Jin XianQing 
Published: January 2010

Abstract

Background
The aim of this study is to examine the safety and distribution of Ad-EGFP-MDR1, an adenovirus encoding human multidurg resistance gene (human MDR1), in the mice colon carcinoma model.

Methods
After bone marrow cells (BMCs) were infected with Ad-EGFP-MDR1, they were administered by intra bone marrow-bone marrow transplantation (IBM-BMT). Total adenovirus antibody and serum adenovirus neutralizing factor (SNF) were determined. Biodistribution of Ad-EGFP-MDR1 was detected by in situ hybridization and immunohistochemistry. The peripheral hematocyte white blood cell (WBC), haemoglobin (Hb), red blood cell (RBC) and platelet (Plt) counts were analyzed.

Results
Neither total adenovirus antibody nor SNF increased weeks after BMT. In situ hybridization and immunohistochemistry demonstrated concordant expression of human MDR1 and P-gp which were found in lung, intestine, kidney and BMCs after BMT, but not detected in liver, spleen, brain and tumor. No significant abnormality of the recovery hematocyte was observed on Day 30 after treatment.

Conclusion
The results indicate that IBM-BMT administration of a replication defective adenovirus is a feasible mode of delivery, allowing exogenous transference. The findings in this study are conducted for the future long-term studies of safety assessment of Ad-EGFP-MDR1.
Acute kidney injury in severe trauma assessed by RIFLE criteria: a common feature without implications on mortality?
Authors: Gomes Ernestina , Antunes Rui , Dias Cláudia , Araújo Rui , Costa-Pereira Altamiro 
Published: January 2010

Abstract

Background
Acute kidney injury (AKI) has been hard to assess due to the lack of standard definitions. Recently, the Risk, Injury, Failure, Loss and End-Stage Kidney (RIFLE) classification has been proposed to classify AKI in a number of clinical settings. This study aims to estimate the frequency and levels of severity of AKI and to study its association with patient mortality and length of stay (LOS) in a cohort of trauma patients needing intensive care.

Methods
Between August 2001 and September 2007, 436 trauma patients consecutively admitted to a general intensive care unit (ICU), were assessed using the RIFLE criteria. Demographic data, characteristics of injury, and severity of trauma variables were also collected.

Results
Half of all ICU trauma admissions had AKI, which corresponded to the group of patients with a significantly higher severity of trauma. Among patients with AKI, RIFLE class R (Risk) comprised 47%, while I (Injury) and F (Failure) were, 36% and 17%, respectively. None of these patients required renal replacement therapy. No significant differences were found among these three AKI classes in relation to patient's age, gender, type and mechanism of injury, severity of trauma or mortality. Nevertheless, increasing severity of acute renal injury was associated with a longer ICU stay.

Conclusions
AKI is a common feature among trauma patients requiring intensive care. Although the development of AKI is associated with an increased LOS it does not appear to influence patient mortality.
Choice in mental health: participation and recovery
Authors: Sugarman Philip , Ikkos George , Bailey Sue 
Published: January 2010

SummaryThe Royal College of Psychiatrists has established a Working Group on Choice in Mental Health and held a conference to include service users in formulating a challenging view of the choice agenda for mental health. This is set out here to stimulate wider interest. Choice-based practice develops in a climate of trust and information, and goes beyond simple variety or individual consumerism. For some service users, limited initial areas of choice can be of great importance, but a true culture of choice requires the widespread participation of service users and carers in service improvement. It is important that psychiatrists champion the empowerment of their patients through choice, in policy and training, and in clinical practice.
Bortezomib As Induction Before Autologous Transplantation, Followed by Lenalidomide As Consolidation-Maintenance in Untreated Multiple Myeloma Patients
Authors: Palumbo Antonio , Gay Francesca , Falco Patrizia , Crippa Claudia , Montefusco Vittorio , Patriarca Francesca , Rossini Fausto , Caltagirone Simona , Benevolo Giulia , Pescosta Norbert , Guglielmelli Tommasina , Bringhen Sara , Offidani Massimo , Giuliani Nicola , Petrucci Maria Teresa , Musto Pellegrino , Liberati Anna Marina , Rossi Giuseppe , Corradini Paolo , Boccadoro Mario 
Published: January 2010

Purpose To evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients. Patients and Methods Newly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m2 on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate). Results A total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). Conclusion Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.
Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2
Authors: Spratlin Jennifer L. , Cohen Roger B. , Eadens Matthew , Gore Lia , Camidge D. Ross , Diab Sami , Leong Stephen , O'Bryant Cindy , Chow Laura Q.M. , Serkova Natalie J. , Meropol Neal J. , Lewis Nancy L. , Chiorean E. Gabriela , Fox Floyd , Youssoufian Hagop , Rowinsky Eric K. , Eckhardt S. Gail 
Published: January 2010

Purpose To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. Patients and Methods Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. Conclusion Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
Transformation to Aggressive Lymphoma in Nodular Lymphocyte-Predominant Hodgkin's Lymphoma
Authors: Al-Mansour Mubarak , Connors Joseph M. , Gascoyne Randy D. , Skinnider Brian , Savage Kerry J. 
Published: January 2010

Purpose Prior observations suggest a higher risk of transformation of nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), than in classical Hodgkin's lymphoma. We evaluated the frequency of transformation in all patients diagnosed with NLPHL at the British Columbia Cancer Agency with long-term follow-up. Patients and Methods The Lymphoid Cancer Database of the British Columbia Cancer Agency was searched to identify all patients diagnosed with NLPHL between 1965 and 2006. After pathologic review, 95 patients with NLPHL were confirmed. Results Patients with NLPHL had the following characteristics at diagnosis: median age of 37 years, 73% male, and 68% stage I or II disease. With a median follow-up time for living patients of 6.5 years (range, 2.5 to 33 years), 13 patients (14%) experienced transformation to aggressive lymphoma (median time to transformation, 8.1 years; range, 0.35 to 20.3 years). The actuarial risk of transformation to aggressive lymphoma was 7% and 30% at 10 and 20 years, respectively. Transformation was more likely in patients with initial splenic involvement (P = .006) at the time of diagnosis of NLPHL. The 10-year progression-free and overall survival rates in patients with transformed lymphoma were 52% and 62%, respectively. Conclusion The risk of transformation in patients with NLPHL to DLBCL is substantial and underappreciated. Because transformation can occur years after the primary diagnosis of NLPHL, long-term follow-up of these individuals is necessary to accurately estimate the risk of development of secondary DLBCL.
Circulating Serum Free Light Chains As Predictive Markers of AIDS-Related Lymphoma
Authors: Landgren Ola , Goedert James J. , Rabkin Charles S. , Wilson Wyndham H. , Dunleavy Kieron , Kyle Robert A. , Katzmann Jerry A. , Rajkumar S. Vincent , Engels Eric A. 
Published: January 2010

Purpose HIV-infected persons have an elevated risk of developing non-Hodgkin's lymphoma (NHL); this risk remains increased in the era of effective HIV therapy. We evaluated serum immunoglobulin (Ig) proteins as predictors of NHL risk among HIV-infected individuals. Patients and Methods By using three cohorts of HIV-infected persons (from 1982 to 2005), we identified 66 individuals who developed NHL and 225 matched (by cohort, sex, ethnicity, age, and CD4 count), HIV-infected, lymphoma-free controls who had available stored prediagnostic blood samples. Serum/plasma samples obtained 0 to 2 years and 2 to 5 years before diagnosis/selection were assayed for IgG, IgM, and IgA levels; monoclonal (M) Igs; and κ and λ free light chain (FLC) levels. Patients and matched controls were compared by using conditional logistic regression. Results The κ and λ FLCs were both significantly higher in patients (eg, in 2- to 5-year window: median κ, 4.24 v 3.43 mg/dL; median λ, 4.04 v 3.09 mg/dL) and strongly predicted NHL in a dose-response manner up to 2 to 5 years before diagnosis/selection (eg, NHL risk 3.76-fold higher with κ concentration at least 2.00 times the upper limit of normal, and 8.13-fold higher with λ concentration at least 2.00 times the upper limit of normal compared with normal levels). In contrast, IgG, IgM, and IgA levels were similar in patients and controls. M proteins were detected in only two patients with NHL (3%) and in nine controls (4%), and they were not significantly associated with NHL risk. Conclusion Elevated FLCs may represent sensitive markers of polyclonal B-cell activation and dysfunction and could be useful for identifying HIV-infected persons at increased NHL risk.
Golimumab: A Tumor Necrosis Factor Alpha Inhibitor for the Treatment of Rheumatoid Arthritis
Authors: McCluggage Lauren K , Scholtz Jean M 
Published: January 2010

OBJECTIVE To review the pharmacologic, pharmacokinetic, efficacy, and safety data of golimumab, an anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody. DATA SOURCES A search of MEDLINE (1950-September 2009) was performed to identify any published clinical trials or review articles pertaining to golimumab. Key search terms included golimumab, rheumatoid arthritis, CNTO 148, and anti-TNF-α inhibitors. Bibliographies of selected articles were reviewed to identify other relevant citations. Abstracts from national and international meetings and information from the manufacturer were also reviewed. STUDY SELECTION AND DATA EXTRACTION All available published articles and abstracts describing golimumab's pharmacologic or pharmacokinetic profile, efficacy, and safety were included. DATA SYNTHESIS Golimumab is a fully humanized TNF-α monoclonal antibody that is specific for human TNF-α. Trials have investigated the use of golimumab in patients who have rheumatoid arthritis (RA) and are on methotrexate, are methotrexate-naïve, and have previously tried TNF-α inhibition therapy. When used in combination with methotrexate or another disease-modifying antirheumatic drug, golimumab therapy results in improvements of clinical outcomes including the American College of Rheumatology parameters in all of the aforementioned populations. Although multiple doses and dosing regimens have been studied, the Food and Drug Administration-approved dose is 50 mg subcutaneously every 4 weeks. The most common adverse effects include injection site erythema, headaches, and nausea. There were a limited number of incidences of serious infection or malignancy. CONCLUSIONS With 4 TNF-α monoclonal antibodies currently on the market, it is unclear what golimumab's place in therapy for RA will be. Some benefits include monthly injections, proven efficacy after previous TNF-α inhibitor therapy, and limited antibody development during therapy. However, with a lack of longer-term trials assessing efficacy and safety compared with other TNF-α inhibitors, golimumab should be reserved for use after other therapies fail.
Improvement of the cardiac marker N-terminal-pro brain natriuretic peptide through adjustment for renal function: a stratified multicenter trial
Authors: Luchner Andreas , Weidemann Alexander , Willenbrock Roland , Philipp Sebastian , Heinicke Norbert , Rambausek Matthias , Mehdorn Uta , Frankenberger Burkhard , Heid Iris M. , Eckardt Kai-Uwe , Holmer Stephan R. 
Published: January 2010

Abstract

Background: N-terminal-pro brain natriuretic peptide (NT-proBNP) is a useful cardiac marker that is also influenced by renal dysfunction. It was our objective to assess the relationship between NT-proBNP concentrations in plasma and worsening renal function, and to attempt adjustment of NT-proBNP for renal dysfunction in a prospective, stratified multi-center study.

Methods: We stratified 203 male patients according to their cardiac status and the estimated glomerular filtration rate (eGFR). Cardiac disease was assessed by medical history, physical examination and standardized echocardiography. Patients were stratified according to the following: absence of cardiac history and abnormalities (control, CTRL, n=66), cardiac history without left ventricular hypertrophy (LVH) or left ventricular systolic dysfunction (LVD) (history, n=30), LVH without systolic dysfunction (LVH, n=68), and LVD [ejection fraction (EF) <40%, LVD, n=39]. Renal disease was stratified according to the eGFR: 15–30 mL/min (n=52), 31–75 mL/min (n=99), and >75 mL/min (n=52).

Results: NT-proBNP was correlated with eGFR in the entire study population and for all levels of cardiac disease (all p<0.01). Regression analysis allowed adjustment of NT-proBNP for eGFR in a continuous manner, and this adjustment significantly improved the predictive value (receiver operating characteristic curve for symptomatic LVD from 0.80 to 0.86, p<0.01; sensitivity from 74% to 83% and specificity from 68% to 79%).

Conclusions: NT-proBNP correlates inversely and significantly with eGFR throughout all levels of cardiac strata. We propose for the first time a continuous adjustment algorithm which markedly improves the predictive values of NT-proBNP in male patients with impaired renal function.
Clin Chem Lab Med 2010;48:121–8.