bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating angiopoietin-1 and angiopoietin-2 in critically ill patients: development and clinical application of two new immunoassays
Authors: Lukasz Alexander , Hellpap Julian , Horn Rüdiger , Kielstein Jan T , David Sascha , Haller Hermann , Kümpers Philipp 
Published: July 2008

Abstract
Introduction
In critically ill patients, the massive release of angiopoietin-2 (Ang-2) from endothelial Weibel–Palade bodies interferes with constitutive angiopoietin-1 (Ang-1)/Tie2 signaling in endothelial cells, thus leading to vascular barrier breakdown followed by leukocyte transmigration and capillary leakage. The use of circulating Ang-1 and Ang-2 as novel biomarkers of endothelial integrity has therefore gained much attention. The preclinical characteristics and clinical applicability of angiopoietin immunoassays, however, remain elusive.

Methods
We developed sandwich immunoassays for human Ang-1 (immunoradiometric sandwich assay/immunoluminometric sandwich assay) and Ang-2 (ELISA), assessed preanalytic characteristics, and determined circulating Ang-1 and Ang-2 concentrations in 30 healthy control individuals and in 94 critically ill patients. In addition, Ang-1 and Ang-2 concentrations were measured in 10 patients during a 24-hour time course with respect to interference by intravenous antibiotic treatment and by extended daily dialysis.

Results
The assays had detection limits of 0.12 ng/ml (Ang-1) and 0.2 ng/ml (Ang-2). Inter-assay and intra-assay imprecision was ≤8.8% and 3.7% for Ang-1 and was ≤4.6% and 5.2% for Ang-2, respectively. Angiopoietins were stable for 24 hours and were resistant to four freeze–thaw cycles. Angiopoietin concentrations were not associated with age, body mass index or renal function in healthy individuals. Ang-1 and Ang-2 concentrations correlated with severity of illness in critically ill patients. Angiopoietin concentrations were not influenced by antibiotic treatment or by extended daily dialysis.

Conclusion
Ang-1 and Ang-2 might serve as a novel class of biomarker in critically ill patients. According to preclinical and clinical validation, circulating Ang-1 and Ang-2 can be reliably assessed by novel immunoassays in the intensive care unit setting.
The IL-10 and IFN-γ pathways are essential to the potent immunosuppressive activity of cultured CD8+NKT-like cells
Authors: Zhou Li , Wang Hongjie , Zhong Xing , Jin Yulan , Mi Qing-Sheng , Sharma Ashok , McIndoe Richard A , Garge Nikhil , Podolsky Robert , She Jin-Xiong 
Published: July 2008

Abstract
Background
CD8+ NKT-like cells are naturally occurring but rare T cells that express both T cell and natural killer cell markers. These cells may play key roles in establishing tolerance to self-antigens; however, their mechanism of action and molecular profiles are poorly characterized due to their low frequencies. We developed an efficient in vitro protocol to produce CD8+ T cells that express natural killer cell markers (CD8+ NKT-like cells) and extensively characterized their functional and molecular phenotypes using a variety of techniques.

Results
Large numbers of CD8+ NKT-like cells were obtained through culture of naïve CD8+ T cells using anti-CD3/anti-CD28-coated beads and high dose IL-2. These cells possess potent activity in suppressing the proliferation of naïve responder T cells. Gene expression profiling suggests that the cultured CD8+ NKT-like cells and the naïve CD8+ T cells differ by more than 2-fold for about 3,000 genes, among which 314 are upregulated by more than 5-fold and 113 are upregulated by more than 10-fold in the CD8+ NKT-like cells. A large proportion of the highly upregulated genes are soluble factors or surface markers that have previously been implicated in immune suppression or are likely to possess immunosuppressive properties. Many of these genes are regulated by two key cytokines, IL-10 and IFN-γ. The immunosuppressive activities of cells cultured from IL-10-/- and IFN-γ-/- mice are reduced by about 70% and about 50%, respectively, compared to wild-type mice.

Conclusion
Immunosuppressive CD8+ NKT-like cells can be efficiently produced and their immunosuppressive activity is related to many surface and soluble molecules regulated by IL-10 and IFN-γ.
An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo
Authors: Handel Tracy M , Johnson Zoë , Rodrigues David H , dos Santos Adriana C , Cirillo Rocco , Muzio Valeria , Riva Simona , Mack Matthias , Déruaz Maud , Borlat Frédéric , Vitte Pierre-Alain , Wells Timothy N C , Teixeira Mauro M , Proudfoot Amanda E I 
Published: July 2008

AbstractWe demonstrated recently that P8A-CCL2, a monomeric variant of the chemokine CCL2/MCP-1, is unable to induce cellular recruitment in vivo, despite full activity in vitro. Here, we show that this variant is able to inhibit CCL2 and thioglycollate-mediated recruitment of leukocytes into the peritoneal cavity and recruitment of cells into lungs of OVA-sensitized mice. This anti-inflammatory activity translated into a reduction of clinical score in the more complex inflammatory model of murine experimental autoimmune encephalomyelitis. Several hypotheses for the mechanism of action of P8A-CCL2 were tested. Plasma exposure following s.c. injection is similar for P8A-CCL2 and wild-type (WT) CCL2, ruling out the hypothesis that P8A-CCL2 disrupts the chemokine gradient through systemic exposure. P8A-CCL2 and WT induce CCR2 internalization in vitro and in vivo; CCR2 then recycles to the cell surface, but the cells remain refractory to chemotaxis in vitro for several hours. Although the response to P8A-CCL2 is similar to WT, this finding is novel and suggests that despite the presence of the receptor on the cell surface, coupling to the signaling machinery is retarded. In contrast to CCL2, P8A-CCL2 does not oligomerize on glycosaminoglycans (GAGs). However, it retains the ability to bind GAGs and displaces endogenous JE (murine MCP-1) from endothelial surfaces. Intravital microscopy studies indicate that P8A-CCL2 prevents leukocyte adhesion, while CCL2 has no effect, and this phenomenon may be related to the mechanism. These results suggest that oligomerization-deficient chemokines can exhibit anti-inflammatory properties in vivo and may represent new therapeutic modalities.
Phase III Study of R-CVP Compared With Cyclophosphamide, Vincristine, and Prednisone Alone in Patients With Previously Untreated Advanced Follicular Lymphoma
Authors: Marcus Robert , Imrie Kevin , Solal-Celigny Philippe , Catalano John V. , Dmoszynska Anna , Raposo João C. , Offner Fritz C. , Gomez-Codina José , Belch Andrew , Cunningham David , Wassner-Fritsch Elisabeth , Stein George 
Published: July 2008

Purpose To compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP. Patients and Methods Patients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n = 159) or CVP alone (n = 162). The median follow-up period was 53 months. Results The primary end point—time to treatment failure (TTF), which included patients without a response after four cycles as an event—was significantly prolonged in patients receiving R-CVP versus CVP (P < .0001). Improvements in all other end points, including overall and complete response rates (P < .0001), time to progression (TTP; P < .0001), response duration (P < .0001), time to next antilymphoma treatment (P < .0001), and overall survival (OS; P = .029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone. Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease. By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect. Conclusion Analysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.
Addition of Rituximab to Standard Chemotherapy Improves the Survival of Both the Germinal Center B-Cell–Like and Non–Germinal Center B-Cell–Like Subtypes of Diffuse Large B-Cell Lymphoma
Authors: Fu Kai , Weisenburger Dennis D. , Choi William W.L. , Perry Kyle D. , Smith Lynette M. , Shi Xinlan , Hans Christine P. , Greiner Timothy C. , Bierman Philip J. , Bociek R. Gregory , Armitage James O. , Chan Wing C. , Vose Julie M. 
Published: July 2008

Purpose Diffuse large B-cell lymphoma (DLBCL) includes at least two prognostically important subtypes (ie, germinal center B-cell–like [GCB] and activated B-cell–like [ABC] DLBCL), which initially were characterized by gene expression profiling and subsequently were confirmed by immunostaining. However, with the addition of rituximab to standard chemotherapy, the prognostic significance of this subclassification of DLBCL is unclear. Patients and Methods We studied 243 patient cases of de novo DLBCL, which included 131 patient cases treated with rituximab plus standard chemotherapy (rituximab group) and 112 patient cases treated with only standard chemotherapy (control group). The cases were assigned to GCB or non-GCB subgroups (the latter of which included both ABC DLBCL and unclassifiable DLBCL) on the basis of immunophenotype by using the Hans method. Clinical characteristics and survival outcomes of the two patient groups were compared. Results The clinical characteristics of the patients in the rituximab and the control groups were similar. Compared with the control group, addition of rituximab improved the 3-year overall survival (OS; 42% v 77%; P < .001) of patients with DLBCL. Rituximab-treated patients in either the GCB or the non-GCB subgroups also had a significantly improved 3-year OS compared with their respective subgroups in the control group (P < .001). In the rituximab group, the GCB subgroup had a significantly better 3-year OS than the non-GCB subgroup (85% v 69%; P = .032). Multivariate analyses confirmed that rituximab treatment was predictive for survival in both the GCB and the non-GCB subgroups. Conclusion In this retrospective study, we have shown that the subclassification of DLBCL on the basis of the cell of origin continues to have prognostic importance in the rituximab era.
Effect of Molecular Disease Subsets on Disease-Free Survival in Randomized Adjuvant Chemotherapy Trials for Estrogen Receptor–Positive Breast Cancer
Authors: Pusztai Lajos , Broglio Kristine , Andre Fabrice , Symmans W. Fraser , Hess Kenneth R. , Hortobagyi Gabriel N. 
Published: July 2008

Purpose The majority of estrogen receptor (ER)–positive cancers are sensitive to endocrine therapy and may not derive much further benefit from chemotherapy, but a subset are potentially chemotherapy sensitive. Molecular diagnostic tests allow the identification of these various subsets with some accuracy. The goal of the current analysis was to examine how the proportion of cases in the various risk (recurrence score [RS]) categories of a commercially available multigene assay influences the power of randomized trials to show benefit from adjuvant chemotherapy. Methods We modeled 10-year disease-free survival (DFS) for hypothetical, two-arm clinical trials that randomly assigned patients with ER-positive breast cancer to endocrine therapy alone or endocrine therapy plus chemotherapy. We varied the proportion of patients in low, intermediate, and high RS categories and used DFS estimates for each risk group based on results from the Southwest Oncology Group 8814 study. Results The probability of observing significant improvement in DFS as a result of chemotherapy decreases as the proportion of patients in the low RS category increases. For example, if a trial is designed with 80% power and the actual proportion of low RS patients accrued to the study increases from 40% to 60%, the power drops to 63%. Conclusion Variable accrual of low RS patients into different randomized adjuvant chemotherapy trials may partly explain contradictory results in the literature. Studies can be underpowered to detect improvement with chemotherapy as a result of inclusion of too many patients with low RS. Future adjuvant studies for ER-positive breast cancer will need to consider stratifying patients by molecular subtype.
Establishing a Reference Interval for Bone Turnover Markers in 637 Healthy, Young, Premenopausal Women From the United Kingdom, France, Belgium, and the United States
Authors: Glover Sarah J , Gall Martin , Schoenborn-Kellenberger Oliver , Wagener Michael , Garnero Patrick , Boonen Steven , Cauley Jane A , Black Dennis M , Delmas Pierre D , Eastell Richard 
Published: July 2008

Abstract
Robust reference intervals are needed for the interpretation of bone turnover markers in large phase III fracture trials. The objectives of the study were to (1) estimate reference intervals for serum bone alkaline phosphatase (bone ALP), serum procollagen type I N propeptide (PINP), serum β cross-linked C-telopeptides of type I collagen (S-βCTX), and urinary cross-linked N-telopeptides of type I collagen (U-NTX) in healthy young premenopausal women; (2) examine geographical differences on bone turnover markers; and (3) assess factors known to influence bone turnover and test whether these explain any regional differences. We studied 637 eligible women from four countries that participated in the Horizon-PFT study (United Kingdom, France, Belgium, United States). The women were 30–39 yr of age (mean, 34.6 yr), with regular cyclic menses. Subjects completed a medical and lifestyle questionnaire. Two-sided 95% reference intervals were estimated on transformed values and transformed back to the original scale using the proposed methodology of the International Federation of Clinical Chemistry. S-βCTX was significantly higher in France relative to the United Kingdom (p = 0.01), and PINP was higher in France (p &lt; 0.001) and Belgium (p = 0.02) relative to the United Kingdom and significantly higher in France relative to the United States (p &lt; 0.01) by ANOVA. Overall, one could associate low bone turnover markers with nonsmoking, use of a contraceptive pill, exercise, being close to the time of ovulation, and having high 25-hydroxyvitamin D levels. Countries differed by these characteristics, and once allowed for in the statistical model, any country differences were attenuated or removed.
High-Resolution pQCT Analysis at the Distal Radius and Tibia Discriminates Patients With Recent Wrist and Femoral Neck Fractures
Authors: Vico Laurence , Zouch Mohamed , Amirouche Adel , Frère Delphine , Laroche Norbert , Koller Bruno , Laib Andres , Thomas Thierry , Alexandre Christian 
Published: July 2008

Abstract
We depict a fragility bone state in two primitive osteoporosis populations using 3D high-resolution peripheral in vivo QCT (HR-pQCT). Postmenopausal women (C, controls, n = 54; WF, wrist, n = 50; HF, hip, n = 62 recent fractured patients) were analyzed for lumbar and hip DXA areal BMD (aBMD), cancellous and cortical volumetric BMD (vBMD), and microstructural and geometric parameters on tibia and radius by HR-pQCT. Principal component analysis (PCA) allowed extracting factors that best represent bone variables. Comparison between groups was made by analysis of covariance (ANCOVA). Two factors (&gt;80% of the entire variability) are extracted by PCA: at the radius, the first is a combination of trabecular parameters and the second of cortical parameters. At the tibia, we found the reverse. Femoral neck aBMD is decreased in WF (8.6%) and in HF (18%) groups (no lumbar difference). WF showed a ∼20% reduction in radius trabecular vBMD and number. Radius cortical vBMD and thickness decrease by 6% and 14%, respectively. At the tibia, only the cortical compartment is affected, with ∼20% reduction in bone area, thickness, and section modulus and 6% reduction in vBMD. HF showed same radius trabecular alterations than WF, but radius cortical parameters are more severely affected than WF with reduced bone area (25%), thickness (28.5%), and vBMD (11%). At the tibia, trabecular vBMD and number decrease by 26% and 17.5%, respectively. Tibia cortical bone area, thickness, and section modulus showed a &gt;30% decrease, whereas vBMD reduction reached 13%. Geometry parameters at the tibia displayed the greatest differences between healthy and fractured patients and between wrist and hip fractures.
Bioactive Nanofibers Instruct Cells to Proliferate and Differentiate During Enamel Regeneration
Authors: Huang Zhan , Sargeant Timothy D , Hulvat James F , Mata Alvaro , Bringas Pablo , Koh Chung-Yan , Stupp Samuel I , Snead Malcolm L 
Published: July 2008

Abstract
During tooth development, ectoderm-derived ameloblast cells create enamel by synthesizing a complex protein mixture serving to control cell to matrix interactions and the habit of hydroxyapatite crystallites. Using an in vitro cell and organ culture system, we studied the effect of artificial bioactive nanostructures on ameloblasts with the long-term goal of developing cell-based strategies for tooth regeneration. We used branched peptide amphiphile molecules containing the peptide motif Arg-Gly-Asp, or “RGD” (abbreviated BRGD-PA), known to self-assemble in physiologic environments into nanofibers that display on their surfaces high densities of this biological signal. Ameloblast-like cells (line LS8) and primary enamel organ epithelial (EOE) cells were cultured within PA hydrogels, and the PA was injected into the enamel organ epithelia of mouse embryonic incisors. The expression of amelogenin, ameloblastin, integrin α5, and integrin α6 was detected by quantitative real-time PCR and immunodetection techniques. We performed cell proliferation assay using BrdU labeling and a biomineralization assay using Alizarin red S staining with quantitative Ca2+ measurements. In the cell culture model, ameloblast-like cells (LS8) and primary EOE cells responded to the BRGD-PA nanostructures with enhanced proliferation and greater amelogenin, ameloblastin, and integrin expression levels. At the site of injection of the BRGD-PA in the organ culture model, we observed EOE cell proliferation with differentiation into ameloblasts as evidenced by their expression of enamel specific proteins. Ultrastructural analysis showed the nanofibers within the forming extracellular matrix, in contact with the EOE cells engaged in enamel formation and regeneration. This study shows that BRGD-PA nanofibers present with enamel proteins participate in integrin-mediated cell binding to the matrix with delivery of instructive signals for enamel formation.
Hormone Therapy Improves Femur Geometry Among Ethnically Diverse Postmenopausal Participants in the Women's Health Initiative Hormone Intervention Trials
Authors: Chen Zhao , Beck Thomas J , Cauley Jane A , Lewis Cora E , LaCroix Andrea , Bassford Tamsen , Wu Guanglin , Sherrill Duane , Going Scott 
Published: July 2008

Abstract
Loss of bone strength underlies osteoporotic fragility fractures. We hypothesized that hormone interventions significantly improve the structural geometry of proximal femur cross-sections. Study participants were from the Women's Health Initiative hormone intervention trials: either the conjugated equine estrogen (CEE) only (Nplacebo = 447, NCEE = 422) trial or the estrogen (E) plus progestin (P) (Nplacebo = 441, NE+P = 503) trial, who were 50–79 yr old at baseline and were followed up to 6 yr. BMD scans by DXA were conducted at baseline, year 1, year 3, and year 6. Femur geometry was derived from hip DXA scans using the hip structural analysis (HSA) method. Mixed effects models with the intent-to-treat analysis approach were used. There were no significant differences in treatment effects between the E-alone and the E + P trial, so the analyses were conducted with participants combined from both trials. Treatment benefits (p &lt; 0.05) on femur geometry were observed as early as 1 yr after the intervention. From baseline to year 6, section modulus (a measure of maximum bending stress) was preserved, and buckling ratio (an index of cortical instability under compression) was reduced by hormone interventions (p &lt; 0.05); the differences in the percent changes from baseline to year 6 between women on hormone intervention versus women on placebo were 2.3–3.6% for section modulus and –5.3% to – 4.3% for buckling ratio. Hormone interventions led to favorable changes in femur geometry, which may help explain the reduced fracture risk observed in hormone interventions.
Site-Specific Deterioration of Trabecular Bone Architecture in Men and Women With Advancing Age
Authors: Lochmüller Eva-Maria , Matsuura Maiko , Bauer Jan , Hitzl Wolfgang , Link Thomas M , Müller Ralph , Eckstein Felix 
Published: July 2008

Abstract
We tested the hypothesis that the age dependence of trabecular bone microstructure differs between men and women and is specific to skeletal site. Furthermore, we aimed to investigate the microstructural pattern of bone loss in aging. Microstructural properties of trabecular bone were measured in vitro in 75 men and 75 age-matched women (age, 52–99 yr) using μCT. Trabecular bone samples were scanned at a 26-μm isotropic resolution at seven anatomical sites (i.e., distal radius, T10 and L2 vertebrae, iliac crest, femoral neck and trochanter, and calcaneus). DXA measurements were obtained at the distal radius and proximal femur and QCT was used at T12. No significant decrease in bone density or structure with age was found in men using μCT, DXA, or QCT at any of the anatomical sites. In women, a significant age-dependent decrease in BV/TV was observed at most sites, which was strongest at the iliac crest and weakest at the distal radius. At most sites, the reduction in BV/TV was associated with an increase in structure model index, decrease in Tb.N, and an increase in Tb.Sp. Only in the calcaneus was it associated with a significant decrease in Tb.Th. In conclusion, a significant, site-specific correlation of trabecular bone microstructure with age was found in women but not in men of advanced age. The microstructural basis by which a loss of BV/TV occurs with age can vary between anatomical sites.