bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic efficacy of intra-articular adrenomedullin injection in antigen-induced arthritis in rabbits
Authors: Okura Toshiyuki , Marutsuka Kousuke , Hamada Hiroaki , Sekimoto Tomohisa , Fukushima Tsuyoshi , Asada Yujiro , Kitamura Kazuo , Chosa Etsuo 
Published: November 2008

Abstract
Introduction
Adrenomedullin is a potent vasodilatory and hypotensive peptide as well as an endogenous immunomodulatory factor with predominantly anti-inflammatory effects. The purpose of the present study was to evaluate the therapeutic effects of adrenomedullin in rabbits with antigen-induced arthritis, an experimental model of rheumatoid arthritis.

Methods
Following the induction of arthritis in both knee joints by ovalbumin injection into the joint spaces of pre-immunized rabbits, increasing daily doses of adrenomedullin were injected into the knee joint spaces or saline was injected into the contralateral knee joint spaces as the control. For time-course experiments, adrenomedullin and saline were injected into the knee joint spaces daily for 7 days and 20 days. The degree of joint swelling and the histological change in the knee joints injected with adrenomedullin were compared with the control knee joints. Histological evaluation of the infrapatellar fat pads and synovial tissue was performed. TNFα, IL-6, vascular endothelial growth factor and transforming growth factor-beta mRNA levels in the synovial tissue were measured using real-time quantitative PCR.

Results
Daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis decreased joint swelling. Histological examination revealed that adrenomedullin reduced edematous changes and the infiltration of inflammatory cells in the synovial tissues. Analysis of mRNA levels showed that adrenomedullin significantly reduced TNFα mRNA expression by 21% to 49% in a dose-dependent manner, and dose-dependently increased IL-6 mRNA expression by 45% to 121%.

Conclusions
These results suggest that daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis ameliorated the inflammatory response in arthritic joints. Adrenomedullin may thus be useful as a treatment for rheumatoid arthritis; however, the effect of adrenomedullin on IL-6 production in the synovial tissue may be an undesirable adverse effect in rheumatoid arthritis therapy.
Collagen-specific T-cell repertoire in blood and synovial fluid varies with disease activity in early rheumatoid arthritis
Authors: Ria Francesco , Penitente Romina , De Santis Maria , Nicolò Chiara , Di Sante Gabriele , Orsini Massimiliano , Arzani Dario , Fattorossi Andrea , Battaglia Alessandra , Ferraccioli Gian Franco 
Published: November 2008

Abstract
Introduction
Type II collagen is a DR4/DR1 restricted target of self-reactive T cells that sustain rheumatoid arthritis. The aim of the present study was to analyze the T-cell receptor repertoire at the onset of and at different phases in rheumatoid arthritis.

Methods
We used the CDR3 BV-BJ spectratyping to study the response to human collagen peptide 261–273 in 12 patients with DR4+ rheumatoid arthritis (six at the onset of disease and six during the course of disease) and in five healthy DR4+ relatives.

Results
The collagen-specific T-cell repertoire is quite restricted at the onset of disease, involving approximately 10 rearrangements. Within the studied collagen-specific rearrangements, nearly 75% is shared among patients. Although the size of the repertoire used by control individuals is comparable to that of patients, it is characterized by different T-cell receptors. Part of the antigen-specific T-cell repertoire is spontaneously enriched in synovial fluid. The specific T-cell repertoire in the periphery was modulated by therapy and decreased with the remission of the disease. Failure of immunoscopy to detect this repertoire was not due to suppression of collagen-driven proliferation in vitro by CD4+ CD25+ T cells. Clinical relapse of the disease was associated with the appearance of the original collagen-specific T cells.

Conclusions
The collagen-specific T-cell receptor repertoire in peripheral blood and synovial fluid is restricted to a limited number of rearrangements in rheumatoid arthritis. The majority of the repertoire is shared between patients with early rheumatoid arthritis and it is modulated by therapy.
Proteomics studies confirm the presence of alternative protein isoforms on a large scale
Authors: Tress Michael L , Bodenmiller Bernd , Aebersold Ruedi , Valencia Alfonso 
Published: November 2008

Abstract
Background
Alternative splicing of messenger RNA permits the formation of a wide range of mature RNA transcripts and has the potential to generate a diverse spectrum of functional proteins. Although there is extensive evidence for large scale alternative splicing at the transcript level, there have been no comparable studies demonstrating the existence of alternatively spliced protein isoforms.

Results
Recent advances in proteomics technology have allowed us to carry out a comprehensive identification of protein isoforms in Drosophila. The analysis of this proteomic data confirmed the presence of multiple alternative gene products for over a hundred Drosophila genes.

Conclusions
We demonstrate that proteomics techniques can detect the expression of stable alternative splice isoforms on a genome-wide scale. Many of these alternative isoforms are likely to have regions that are disordered in solution, and specific proteomics methodologies may be required to identify these peptides.
Escherichia colitype 1 pili trigger late IL-8 production by neutrophil-like differentiated PLB-985 cells through a Src family kinase- and MAPK-dependent mechanism
Authors: Sémiramoth Nicolas , Gleizes Aude , Turbica Isabelle , Sandré Catherine , Gorges Roseline , Kansau Imad , Servin Alain , Chollet-Martin Sylvie 
Published: November 2008

AbstractThe innate immune response to enteropathogenic bacteria includes chemokine-induced polymorphonuclear neutrophil (PMN) migration across mucosal epithelia leading to bacterial clearance and resolution of infection. Among these bacteria, diffusely adherent Escherichia coli expressing Afa/Dr fimbriae (Afa/Dr DAEC), causing childhood diarrhea, can promote IL-8-dependent PMN transmigration across cultured intestinal epithelial cell monolayers via MAPK pathway activation. However, interactions between PMN and Afa/Dr DAEC are poorly documented and constitute the aim of the present study. Using the human PLB-985 cell line differentiated into fully mature PMN, we described the coordinated response to various E. coli. The rapid and strong release of reactive oxygen species and preformed intragranular mediators (myeloperoxidase and IL-8) is followed by a later TNF-α, IL-1β, and IL-8 synthesis. The use of wild-type (IH11128, C1845, LF82), control (AAEC185), and recombinant (AAEC185 bearing Dr or F1845 fimbriae, AdLF82, or type 1 pili) bacterial strains allowed us to demonstrate that late IL-8 hyperproduction is triggered by type 1 pili but not by Dr or F1845 fimbriae; MAPKs (p38, ERK, Src) and NF-κB activations are implicated in this response. Thus, in the course of Afa/Dr DAEC intestinal infection, epithelium- and neutrophil-derived IL-8 could, at least in part, control the flow of neutrophils through the lamina propria. Afa/Dr DAEC-induced IL-8 hyperproduction by PMN might thus be important for inducing and perpetuating local inflammation, and this self-amplifying loop might play a role in the pathogenesis of inflammatory bowel diseases such as Crohn’s disease.
Relationship of Treatment-Related Cytopenias and Response to Lenalidomide in Patients With Lower-Risk Myelodysplastic Syndromes
Authors: Sekeres Mikkael A. , Maciejewski Jaroslaw P. , Giagounidis Aristotle A.N. , Wride Kenton , Knight Robert , Raza Azra , List Alan F. 
Published: November 2008

Purpose Patients with myelodysplastic syndromes (MDS) often require treatment with growth factors (GFs) or non-GF therapies. One non-GF drug, lenalidomide, is particularly effective at achieving transfusion independence (TI) in patients with lower-risk MDS with the del(5q) cytogenetic abnormality. However, approximately half of del(5q) patients and one quarter of non–del(5q) patients treated with lenalidomide experience significant cytopenias. Lenalidomide-induced cytopenias occurring early in treatment may serve as a surrogate marker of clonal suppression and, therefore, may be predictive of a TI response. Patients and Methods We analyzed 362 low-risk, transfusion-dependent patients with MDS, with or without the del(5q) abnormality, enrolled in two phase II studies (MDS-003 and MDS-002) to determine whether treatment-related cytopenias are correlated with lenalidomide response. Cytopenias were assessed during the first 8 weeks of therapy, and response was defined as TI; response predictors were explored in univariate and multivariate analyses. Results Among patients with del(5q), 70% of those whose platelet count decreased by ≥ 50% achieved TI, as compared with 42% of those whose platelet count remained stable or declined by less than 50% (P = .01). Among patients without baseline neutropenia, 82% of those whose absolute neutrophil count (ANC) decreased by ≥ 75% achieved TI, as compared with 51% whose ANC remained stable or decreased by less than 75% (P = .02). These relationships were consistent in multivariate analyses. No relationship between the development of cytopenias and response could be established for lower-risk patients with MDS without del(5q). Conclusion These findings support the hypothesis that a direct cytotoxic effect of lenalidomide specific to the del(5q) clone may be indicative of a TI response.
Phase I/II Study of Ipilimumab for Patients With Metastatic Melanoma
Authors: Weber Jeffrey S. , O’Day Steven , Urba Walter , Powderly John , Nichol Geoff , Yellin Michael , Snively Jolie , Hersh Evan 
Published: November 2008

Purpose The primary objective of this phase I/II study was to determine the safety and pharmacokinetic profile of either transfectoma- or a hybridoma-derived ipilimumab. Secondary objectives included determination of a maximum-tolerated dose and assessment of clinical activity. Patients and Methods Eighty-eight patients with unresectable stage III or IV melanoma with at least one measurable lesion were treated. Mean age was 59 years, with 65% male and 35% female patients, and 79% of patients had received prior systemic therapy. Single doses of ipilimumab up to 20 mg/kg (group A, single dose), multiple doses up to 5 mg/kg (group A, multiple dose), and multiple doses up to 10 mg/kg (group B) were administered. Results Single dosing up to 20 mg/kg of transfectoma antibody was well tolerated, as were multiple doses up to 10 mg/kg without a maximum-tolerated dose. In group B, dose-limiting toxicity was seen in six of 23 melanoma patients. Grade 3 or 4 immune-related adverse events (irAEs) were observed in 14% of patients (12 of 88 patients), and grade 1 or 2 irAEs were seen in an additional 58%. The half-life of ipilimumab was 359 hours. In group B, there was one partial response (23+ months), one complete response (21+ months), and seven patients with stable disease (SD), for a disease control rate of 39%. Two patients in group B with SD had slow, steady decline in tumor burden that was ongoing at 1 year of observation. Conclusion Ipilimumab has activity in patients with metastatic melanoma. Late responses were observed in patients with prolonged SD.
[18F]Fluorodeoxyglucose Positron Emission Tomography in Nonseminomatous Germ Cell Tumors After Chemotherapy: The German Multicenter Positron Emission Tomography Study Group
Authors: Oechsle Karin , Hartmann Michael , Brenner Winfried , Venz Stephan , Weissbach Lothar , Franzius Christiane , Kliesch Sabine , Mueller Stephan , Krege Susanne , Heicappell Ruediger , Bares Roland , Bokemeyer Carsten , de Wit Maike 
Published: November 2008

Purpose In patients with metastatic nonseminomatous germ cell cancer (NSGCT), residual masses after chemotherapy (CTX) can consist of vital carcinoma, mature teratoma, or necrosis. This prospective trial has evaluated the accuracy of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the prediction of histology compared with computed tomography (CT) and serum tumor markers (STM). Patients and Methods A total of 121 patients with stage IIC or III NSGCT scheduled for secondary resection after cisplatin-based CTX were included. FDG-PET was performed after completion of CTX. All results were confirmed by histopathology and correlated to STM and CT. Results Prediction of tumor viability with FDG-PET was correct in 56%, which did not reach the expected clinically relevant level of 70%, and was not better than the accuracy of CT (55%) or STM (56%). Sensitivity and specificity of FDG-PET were 70% and 48%. The positive predictive values were not significantly different (55%, 61%, and 59% for CT, STM, and PET, respectively). Judging only vital carcinoma as a true malignant finding, the negative predictive value increased to 83% for FDG-PET. Conclusion The presence of vital carcinoma and mature teratoma is common (55%) in residual masses in patients with NSGCT, and CT and STM cannot reliably predict absence of disease. In contrast to prior studies, this prospective trial, which is the only with histologic confirmation in all patients, demonstrated that FDG-PET is unable to give a clear additional clinical benefit to the standard diagnostic procedures, CT and STM, in the prediction of tumor viability in residual masses.
JNK Activity Is Essential for Atf4 Expression and Late-Stage Osteoblast Differentiation
Authors: Matsuguchi Tetsuya , Chiba Norika , Bandow Kenjiro , Kakimoto Kyoko , Masuda Akio , Ohnishi Tomokazu 
Published: November 2008

Abstract
Osteoblasts differentiate from mesodermal progenitors and play a pivotal role in bone formation and mineralization. Several transcription factors including runt-related transcription factor 2 (RUNX2), Osterix (OSX), and activating transcription factor4 (ATF4) are known to be crucial for the process, whereas the upstream signal transduction controlling the osteoblast differentiation sequence is largely unknown. Here, we explored the role of c-jun N-terminal kinase (JNK) in osteoblast differentiation using in vitro differentiation models of primary osteoblasts and MC3T3-E1 cells with ascorbic acid/β-glycerophosphate treatment. Terminal osteoblast differentiation, represented by matrix mineralization, was significantly inhibited by the inactivation of JNK with its specific inhibitor and exogenous overexpression of MKP-M (MAP kinase phosphatase isolated from macrophages), which preferentially inactivates JNK. Conversely, enhanced mineral deposition was observed by inducible overexpression of p54JNK2, whereas it was not observed by the overexpression of p46JNK1 or p46JNK2, indicating a distinct enhancing role of p54JNK2 in osteoblast differentiation. Inactivation of JNK significantly inhibited late-stage molecular events of osteoblast differentiation, including gene expression of osteocalcin (Ocn) and bone sialoprotein (Bsp). In contrast, earlier differentiation events including alkaline phosphatase (ALP) activation and osteopontin (Opn) expression were not inhibited by JNK inactivation. Although the expression levels of two transcription factor genes, Runx2 and Osx, were not significantly affected by JNK inactivation, induction of Atf4 mRNA during osteoblast differentiation was significantly inhibited. Taken together, these data indicate that JNK activity is specifically required for the late-stage differentiation events of osteoblasts.
Hip Fractures and the Contribution of Cortical Versus Trabecular Bone to Femoral Neck Strength
Authors: Holzer Gerold , von Skrbensky Gobert , Holzer Lukas A , Pichl Wolfgang 
Published: November 2008

Abstract
Osteoporotic fractures are caused by both cortical thinning and trabecular bone loss. Both are seen to be important for bone fragility. The relative contributions of cortical versus trabecular bone have not been established. The aim of this study was to test the contribution of cortical versus trabecular bone to femoral neck stability in bone strength. In one femur from each pair of 18 human cadaver femurs (5 female; 4 male), trabecular bone was completely removed from the femoral neck, providing one bone with intact and the other without any trabecular structure in the femoral neck. Geometrical, X-ray, and DXA measurements were carried out before biomechanical testing (forces to fracture). Femoral necks were osteotomized, slices were analyzed for cross-sectional area (CSA) and cross-sectional moment of inertia (CSMI), and results were compared with biomechanical testing data. Differences between forces needed to fracture excavated and intact femurs (ΔF/F mean) was 7.0% on the average (range, 4.6–17.3%). CSA of removed spongiosa did not correlate with difference of fracture load (ΔF/F mean), nor did BMD. The relative contribution of trabecular versus cortical bone in respect to bone strength in the femoral neck seems to be marginal and seems to explain the subordinate role of trabecular bone and its changes in fracture risk and the effects of treatment options in preventing fractures.
Denosumab, a Fully Human Monoclonal Antibody to RANKL, Inhibits Bone Resorption and Increases BMD in Knock-In Mice That Express Chimeric (Murine/Human) RANKL
Authors: Kostenuik Paul J , Nguyen Hung Q , McCabe James , Warmington Kelly S , Kurahara Carol , Sun Ning , Chen Ching , Li Luke , Cattley Russ C , Van Gwyneth , Scully Shelia , Elliott Robin , Grisanti Mario , Morony Sean , Tan Hong Lin , Asuncion Frank , Li Xiaodong , Ominsky Michael S , Stolina Marina , Dwyer Denise , Dougall William C , Hawkins Nessa , Boyle William J , Simonet William S , Sullivan John K 
Published: November 2008

Abstract
RANKL is a TNF family member that mediates osteoclast formation, activation, and survival by activating RANK. The proresorptive effects of RANKL are prevented by binding to its soluble inhibitor osteoprotegerin (OPG). Recombinant human OPG-Fc recognizes RANKL from multiple species and reduced bone resorption and increased bone volume, density, and strength in a number of rodent models of bone disease. The clinical development of OPG-Fc was discontinued in favor of denosumab, a fully human monoclonal antibody that specifically inhibits primate RANKL. Direct binding assays showed that denosumab bound to human RANKL but not to murine RANKL, human TRAIL, or other human TNF family members. Denosumab did not suppress bone resorption in normal mice or rats but did prevent the resorptive response in mice challenged with a human RANKL fragment encoded primarily by the fifth exon of the RANKL gene. To create mice that were responsive to denosumab, knock-in technology was used to replace exon 5 from murine RANKL with its human ortholog. The resulting “huRANKL” mice exclusively express chimeric (human/murine) RANKL that was measurable with a human RANKL assay and that maintained bone resorption at slightly reduced levels versus wildtype controls. In young huRANKL mice, denosumab and OPG-Fc each reduced trabecular osteoclast surfaces by 95% and increased bone density and volume. In adult huRANKL mice, denosumab reduced bone resorption, increased cortical and cancellous bone mass, and improved trabecular microarchitecture. These huRANKL mice have potential utility for characterizing the activity of denosumab in a variety of murine bone disease models.
The Heritability of HbA1c and Fasting Blood Glucose in Different Measurement Settings
Authors: Simonis-Bik Annemarie M. C. , Eekhoff Elisabeth M. W. , Diamant Michaela , Boomsma Dorret I. , Heine Rob J. , Dekker Jacqueline M. , Willemsen Gonneke , van Leeuwen Marieke , de Geus Eco J. C. 
Published: November 2008

AbstractIn an extended twin study we estimated the heritability of fasting HbA1c and blood glucose levels. Blood glucose was assessed in different settings (at home and in the clinic). We tested whether the genetic factors influencing fasting blood glucose levels overlapped with those influencing HbA1c and whether the same genetic factors were expressed across different settings. Fasting blood glucose was measured at home and during two visits to the clinic in 77 healthy families with same-sex twins and siblings, aged 20 to 45 years. HbA1c was measured during the first clinic visit. A 4-variate genetic structural equation model was used that estimated the heritability of each trait and the genetic correlations among traits. Heritability explained 75% of the variance in HbA1c. The heritability of fasting blood glucose was estimated at 66% at home and lower in the clinic (57% and 38%). Fasting blood glucose levels were significantly correlated across settings (0.34 <r< 0.54), mostly due to a common set of genes that explained between 53% and 95% of these correlations. Correlations between HbA1c and fasting blood glucoses were low (0.11 <r< 0.23) and genetic factors influencing HbA1c and fasting glucose were uncorrelated. These results suggest that in healthy adults the genes influencing HbA1c and fasting blood glucose reflect different aspects of the glucose metabolism. As a consequence these two glycemic parameters can not be used interchangeably in diagnostic procedures or in studies attempting to find genes for diabetes. Both contribute unique (genetic) information.
Effects of Densification on Permeable Friction Course Mixtures
Authors: Alvarez Allex E. , Martin Amy Epps , Estakhri Cindy 
Published: November 2008

Abstract
Compaction of permeable or porous friction course (PFC) mixtures is generally considered a process without major issues, and field density requirements (or corresponding total air voids [AV] content) are not currently specified for this type of hot mix asphalt. However, proper densification is one of the most important aspects to control during construction to prevent raveling, the distress most frequently reported as the cause of failure in these mixtures. This paper presents an evaluation of the effect of densification on PFC mixtures. This evaluation included both the study of the internal structure of compacted mixtures and a comparison of performance based on macroscopic response. Results from this study showed that differences encountered in the internal structure of road cores and specimens compacted using the Superpave Gyratory Compactor limit the use of these laboratory compacted specimens in durability and functionality evaluations of PFC mixtures. In addition, changes in densification, after reaching stone-on-stone contact, modified the mixture properties and performance. The magnitude of these modifications provided evidence of the ease of verifying not only stone-on-stone contact during mix design, but also of the importance of controlling the density during construction to ensure an equilibrium density that guarantees the balance between mixture durability and mixture functionality.