bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro-collagenase activation as a critical step for collagenolysis
Authors: Milner Jennifer M , Rowan Andrew D , Cawston Tim E , Young David A 
Published: August 2006

AbstractExcess proteolysis of the extracellular matrix (ECM) of articular cartilage is a key characteristic of arthritis. The main enzymes involved belong to the metalloproteinase family, specifically the matrix metalloproteinases (MMPs) and a group of proteinases with a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS). Chondrocytes are the only cell type embedded in the cartilage ECM, and cell-matrix interactions can influence gene expression and cell behaviour. Thus, although the use of monolayer cultures can be informative, it is essential to study chondrocytes encapsulated within their native environment, cartilage, to fully assess cellular responses. The aim of this study was to profile the temporal gene expression of metalloproteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and α2-macroglobulin (α2M), in actively resorbing cartilage. The addition of the pro-inflammatory cytokine combination of interleukin-1 (IL-1) + oncostatin M (OSM) to bovine nasal cartilage induces the synthesis and subsequent activation of pro-metalloproteinases, leading to cartilage resorption. We show that IL-1+OSM upregulated the expression of MMP-1, -2, -3, -9, 12, -13, -14, TIMP-1, and ADAMTS-4, -5, and -9. Differences in basal expression and the magnitude of induction were observed, whilst there was no significant modulation of TIMP-2, -3, RECK, or ADAMTS-15 gene expression. IL-1+OSM downregulated MMP-16,TIMP-4, and α2M expression. All IL-1+OSM-induced metalloproteinases showed marked upregulation early in the culture period, whilst inhibitor expression was reduced throughout the stimulation period such that metalloproteinase production would be in excess of inhibitors. Moreover, although pro-collagenases were upregulated and synthesized early (by day 5), collagenolysis became apparent later with the presence of active collagenases (day 10) when inhibitor levels were low. These findings indicate that the activation cascades for pro-collagenases are delayed relative to collagenase expression, further confirm the coordinated regulation of metalloproteinases in actively resorbing cartilage, and support the use of bovine nasal cartilage as a model system to study the mechanisms that promote cartilage degradation.
Comparison of gene expression profiles in core biopsies and corresponding surgical breast cancer samples
Authors: Zanetti-Dällenbach Rosanna , Vuaroqueaux Vincent , Wight Edward , Labuhn Martin , Singer Gad , Urban Patrick , Eppenberger Urs , Holzgreve Wolfgang , Eppenberger-Castori Serenella 
Published: August 2006

Abstract
Introduction
Gene expression profiling has been successfully used to classify breast cancer into clinically distinct subtypes, and to predict the risk of recurrence and treatment response. The aim of this study was to investigate whether the gene expression profile (GEP) detected in a core biopsy (CB) is representative for the entire tumor, since CB is an important tool in breast cancer diagnosis. Moreover, we investigated whether performing CBs prior to the surgical excision could influence the GEP of the respective tumor.

Methods
We quantified the RNA expression of 60 relevant genes by quantitative real-time PCR in paired CBs and surgical specimens from 22 untreated primary breast cancer patients. Subsequently, expression data were compared with independent GEPs obtained from tumors of 317 patients without preceding CB.

Results
In 82% of the cases the GEP detected in the CB correlated very well with the corresponding profile in the surgical sample (rs ≥ 0.95, p < 0.001). Gene-by-gene analysis revealed four genes significantly elevated in the surgical sample compared to the CB; these comprised genes mainly involved in inflammation and the wound repair process as well as in tumor invasion and metastasis.

Conclusion
A GEP detected in a CB are representative for the entire tumor and is, therefore, of clinical relevance. The observed alterations of individual genes after performance of CB deserve attention since they might impact the clinical interpretation with respect to prognosis and therapy prediction of the GEP as detected in the surgical specimen following CB performance.
Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding – a European perspective
Authors: Vincent Jean-Louis , Rossaint Rolf , Riou Bruno , Ozier Yves , Zideman David , Spahn Donat R 
Published: August 2006

Abstract
Introduction
Our aim was to develop consensus guidelines for use of recombinant activated factor VII (rFVIIa) in massive hemorrhage.

Methods
A guidelines committee derived the recommendations using clinical trial and case series data identified through searches of available databases. Guidelines were graded on a scale of A to E (with A being the highest) according to the strength of evidence available. Consensus was sought among the committee members for each recommendation.

Results
A recommendation for the use of rFVIIa in blunt trauma was made (grade B). rFVIIa might also be beneficial in post-partum hemorrhage (grade E), uncontrolled bleeding in surgical patients (grade E), and bleeding after cardiac surgery (grade D). rFVIIa could not be recommended for use in the following: in penetrating trauma (grade B); prophylactically in elective surgery (grade A) or liver surgery (grade B); or in bleeding episodes in patients with Child–Pugh A cirrhosis (grade B). Efficacy of rFVIIa was considered uncertain in bleeding episodes in patients with Child–Pugh B and C cirrhosis (grade C). Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), while thromboembolic adverse events are a cause for concern. rFVIIa should not be administered to patients considered unsalvageable by the treating medical team.

Conclusion
There is a rationale for using rFVIIa to treat massive bleeding in certain indications, but only adjunctively to the surgical control of bleeding once conventional therapies have failed. Lack of data from randomized, controlled clinical trials, and possible publication bias of the case series data, limits the strength of the recommendations that can be made.
A research algorithm to improve detection of delirium in the intensive care unit
Authors: Pisani Margaret A , Araujo Katy LB , Van Ness Peter H , Zhang Ying , Ely E Wesley , Inouye Sharon K 
Published: August 2006

Abstract
Introduction
Delirium is a serious and prevalent problem in intensive care units (ICUs). The purpose of this study was to develop a research algorithm to enhance detection of delirium in critically ill ICU patients using chart review to complement a validated clinical delirium instrument.

Methods
A prospective cohort study was conducted in 178 patients aged 60 years and older who were admitted to the medical ICU. The Confusion Assessment Method for the ICU (CAM-ICU) and a validated chart review method for detecting delirium were performed daily. We assessed the diagnostic accuracy of the chart-based delirium method using the CAM-ICU as the 'gold standard'. We then used an algorithm to detect delirium first using the CAM-ICU ratings and then chart review when the CAM-ICU was unavailable.

Results
When using both the CAM-ICU and the chart-based review, the prevalence of delirium was found to be 80% of patients (143 out of 178) or 64% of patient-days (929 out of 1,457). Of these patient-days, 292 were classified as delirium by the CAM-ICU. The remainder (637 patient-days) were classified as delirium by the validated chart review method when CAM-ICU was missing because the assessment was conducted for weekends or holidays (404 patient-days), when CAM-ICU was not performed because of stupor or coma (205 patient-days), and when the CAM-ICU was negative (28 patient-days). Sensitivity of the chart-based method was 64% and specificity was 85%. Overall agreement between chart and the CAM-ICU was 72%.

Conclusion
Eight out of 10 patients in this cohort study developed delirium in the ICU. Although use of a validated delirium instrument with frequent direct observations is recommended for clinical care, this approach may not always be feasible, especially in a research setting. The algorithm proposed here comprises a more comprehensive method for detecting delirium in a research setting, taking into account the fluctuation that occurs with delirium, which is a key component of accurate determination of delirium status. Improving detection of delirium is of paramount importance both to advance delirium research and to enhance clinical care and patient safety.
Exposure to LPS suppresses CD4+ T cell cytokine production inSalmonella-infected mice and exacerbates murine typhoid
Authors: Srinivasan Aparna , McSorley Stephen J 
Published: August 2006

AbstractA number of studies have documented suppression of lymphocyte activation in mice infected with Salmonella. Here, we describe incomplete activation of CD4+ T cells following intravenous injection of specific peptide and LPS into Salmonella-infected mice. Although antigen-specific CD4+ T cells were activated by peptide/LPS to increase surface CD69 expression, they did not produce IL-2 or TNF-α. Suppression of cytokine production did not require prolonged exposure of the T cells to the Salmonella-infected environment, was not antigen specific, but was dependent upon the presence of LPS during stimulation. These data suggest that Salmonella-infected mice are exquisitely sensitive to the generation of a suppressive environment following innate immune stimulation with LPS. In agreement with this interpretation, repeated low-dose administration of LPS caused uncontrolled replication of attenuated Salmonella in vivo.
Defining Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy: A Proposal for a Standardized Definition
Authors: Stephenson Andrew J. , Kattan Michael W. , Eastham James A. , Dotan Zohar A. , Bianco Fernando J. , Lilja Hans , Scardino Peter T. 
Published: August 2006

Purpose Prostate-specific antigen (PSA) defined biochemical recurrence (BCR) of prostate cancer is widely used for reporting the outcome of radical prostatectomy (RP). A standardized BCR definition is lacking, and overall progression-free probability and risk of subsequent metastatic disease progression may vary greatly depending on the PSA criterion used. Ten definitions of BCR were evaluated to identify the one that best explains metastatic progression. Methods Of 3,125 patients who underwent RP at our institution since 1985, 75 developed distant metastasis during a median follow-up of 49 months. To predict metastasis progression, we modeled the clinical information using multivariable Cox regression analysis. BCR was included in the model as a time-dependent covariate, and separate models were developed for each definition. A goodness-of-fit (R2) statistic was used to determine the Cox model (and thereby the BCR definition) that best explained metastatic progression. Results The 10-year progression-free probability ranged from 63% to 79%, depending on the BCR definition. The model containing BCR defined as a PSA of at least 0.4 ng/mL followed by another increase best explained metastatic progression (R2 = 0.21). This definition was also associated with a high probability of subsequent secondary therapy, continued PSA progression, and rapid PSA doubling time. Conclusion BCR defined as a PSA value of at least 0.4 ng/mL followed by another increase best explains the development of distant metastasis among 10 candidate definitions, after controlling for clinical variables and the use of secondary therapy. On the basis of this evidence, we propose that this definition be adopted as the standard for reporting the outcome of RP.
Phase III Trial of Carmustine and Cisplatin Compared With Carmustine Alone and Standard Radiation Therapy or Accelerated Radiation Therapy in Patients With Glioblastoma Multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials
Authors: Buckner Jan C. , Ballman Karla V. , Michalak John C. , Burton Gary V. , Cascino Terrence L. , Schomberg Paula J. , Hawkins Roland B. , Scheithauer Bernd W. , Sandler Howard M. , Marks Randolph S. , O'Fallon Judith R. 
Published: August 2006

Purpose In patients with newly diagnosed glioblastoma multiforme, to determine whether cisplatin plus carmustine (BCNU) administered before and concurrently with radiation therapy (RT) improves survival compared with BCNU and RT and whether survival using accelerated RT (ART) is equivalent to survival using standard RT (SRT). Patients and Methods After surgery, patients were stratified by age, performance score, extent of surgical resection, and histology (glioblastoma v gliosarcoma) and then randomly assigned to arm A (BCNU plus SRT), arm B (BCNU plus ART), arm C (cisplatin plus BCNU plus SRT), or arm D (cisplatin plus BCNU plus ART). Results Four hundred fifty-one patients were randomly assigned, and 401 were eligible. Frequent toxicities included myelosuppression, vomiting, sensory neuropathy, and ototoxicity and were worse with cisplatin. There was no difference in toxicity between SRT and ART. Median survival times and 2-year survival rates for patients who received BCNU plus RT (arms A and B) compared with cisplatin, BCNU, and RT (arms C and D) were 10.1 v 11.5 months, respectively, and 11.5% v 13.7%, respectively (P = .19). Median survival times and 2-year survival rates for patients who received SRT (arms A and C) compared with ART (arms B and D) were 11.2 v 10.5 months, respectively, and 13.8% v 11.4%, respectively (P = .33). Conclusion Cisplatin administered concurrently with BCNU and RT resulted in more toxicity but provided no significant improvement in survival. SRT and ART produced similar toxicity and survival.
Early Compared With Late Radiotherapy in Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group Multicenter Randomized Clinical Trial and Meta-Analysis
Authors: Spiro Stephen G. , James Lindsay E. , Rudd Robin M. , Trask Colin W. , Tobias Jeffrey S. , Snee Michael , Gilligan David , Murray Philip A. , de Elvira Mary Carmen Ruiz , O'Donnell Katy M. , Gower Nicole H. , Harper Peter G. , Hackshaw Allan K. 
Published: August 2006

Purpose To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). Patients and Methods Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. Results TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). Conclusion This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.
Analysis of Prognostic Factors in Patients With Nonmetastatic Rhabdomyosarcoma Treated on Intergroup Rhabdomyosarcoma Studies III and IV: The Children's Oncology Group
Authors: Meza Jane L. , Anderson James , Pappo Alberto S. , Meyer William H. 
Published: August 2006

Purpose The outcome for localized rhabdomyosarcoma (RMS) or undifferentiated sarcoma (UDS) is affected by age, histology, primary anatomic site, extent of disease, and therapy. Patients and Methods We evaluated patient and disease characteristics for their ability to predict outcome for patients with nonmetastatic RMS or UDS treated on Intergroup Rhabdomyosarcoma Study (IRS) -III (1984 to 1991) or IRS-IV (1991 to 1997). Results The estimated 5-year failure-free survival (FFS) rate was 90% for patients with embryonal RMS (ERMS) stage 1, group I or IIa; stage 2, group I; or group III orbit. The estimated 5-year FFS rate was 87% for patients with ERMS stage 1, group IIb or IIc; stage 1, group III nonorbit; stage 2, group II; and stage 3, group I or II; and 73% for patients with ERMS stage 2 or 3, group III. The estimated 5-year FFS rate was poor for patients with stage 2 or 3, group III ERMS with invasive (T2) tumors who were age younger than 1 year or 10 years or older (56%) and patients with stage 2 or 3, group III extremity primary tumors (43%). Overall, outcomes for patients with alveolar RMS (ARMS) or UDS were worse than for patients with ERMS. However, the 5-year FFS rate was good for patients with ARMS/UDS at favorable sites with group I or II (80%) or group III (76%) disease. The FFS rate was poorer for patients with ARMS/UDS at unfavorable sites with group I or II (66%) or group III (45%) disease. The estimated 5-year FFS rate was 31% for patients with group III ARMS/UDS at unfavorable sites with regional lymph node disease, which is similar to metastatic RMS. Conclusion Patient and disease characteristics identify distinct subsets with different outcomes, allowing the Soft Tissue Sarcoma Committee of the Children's Oncology Group to refine risk-adapted therapy assignment.
Adverse Event Reporting in Publications Compared With Sponsor Database for Cancer Clinical Trials
Authors: Scharf Orit , Colevas A. Dimitrios 
Published: August 2006

Purpose Prospectively planned collection and analysis of adverse event (AE) data are essential parts of well-conducted clinical trials. The AE data in a trial sponsor's database should be comparable with what is stipulated in the protocol and with the AE data published. We examined whether the published AE data differ from those in the sponsor's database and from the data collection requirements stated in study protocols. Methods We searched the National Cancer Institute (NCI) Clinical Data Update System (CDUS) for studies that used the Common Toxicity Criteria version 2.0 and for which a final study publication was available. We extracted from the protocols information pertaining to AE collection and reporting methods and compared it with the methods cited in the article. We also compared the AE data in the trial publication with the AE data submitted by the investigators to CDUS. Results We identified 22 studies meeting the criteria for this review. There was considerable inconsistency between AE collection and reporting methods cited in the protocols versus final publications. AE data in the article and CDUS were not identical. Twenty-seven percent of article high-grade AEs could not be matched to agent-attributable AEs in the CDUS. Twenty-eight percent of CDUS high-grade AEs could not be matched to AEs in the corresponding article. In 14 of 22 articles, the number of high-grade AEs in CDUS differed from the number in the articles by 20% or more. Conclusion Lack of consistency in and reporting of AEs are associated with NCI database and trial publication AE data discrepancy.
Further Analysis of Trials With Azacitidine in Patients With Myelodysplastic Syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B
Authors: Silverman Lewis R. , McKenzie David R. , Peterson Bercedis L. , Holland James F. , Backstrom Jay T. , Beach C.L. , Larson Richard A. 
Published: August 2006

Purpose Within the last two decades, a new understanding of the biology of myelodysplastic syndrome (MDS) has developed. With this understanding, new classification systems, such as the WHO diagnostic criteria, and the International Prognostic Scoring System and response criteria guidelines reported by the International Working Group (IWG) have been developed. We report the combined results of three previously reported clinical trials (n = 309) with azacitidine using the WHO classification system for MDS and acute myeloid leukemia (AML) and IWG criteria for response. Patients and Methods Data from three sequential Cancer and Leukemia Group B trials with azacitidine were recollected and reanalyzed as part of the New Drug Application process. The trials were conducted with either intravenous or subcutaneous azacitidine (75 mg/m2/d for 7 days every 28 days). Results Complete remissions were seen in 10% to 17% of azacitidine-treated patients; partial remissions were rare; 23% to 36% of patients had hematologic improvement (HI). The median number of cycles to first response was three, and 90% of responses were seen by cycle 6. Using current WHO criteria, 103 patients had AML at baseline; 35% to 48% had HI or better responses. The median survival time for the 27 AML patients randomly assigned to azacitidine was 19.3 months compared with 12.9 months for the 25 patients assigned to observation. Furthermore, azacitidine did not increase the rate of infection or bleeding above the rate caused by underlying disease. Conclusion Azacitidine provides important clinical benefits for patients with high-risk MDS.
Impact of High-Dose Busulfan Plus Melphalan As Consolidation in Metastatic Ewing Tumors: A Study by the Société Française des Cancers de l'Enfant
Authors: Oberlin Odile , Rey Annie , Desfachelles Anne Sophie , Philip Thierry , Plantaz Dominique , Schmitt Claudine , Plouvier Emmanuel , Lejars Odile , Rubie Hervé , Terrier Philippe , Michon Jean 
Published: August 2006

Purpose To improve the prognosis for patients with metastatic Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) using conventional chemotherapy and consolidation high-dose chemotherapy (HDCT) containing busulfan and melphalan. Patients and Methods Ninety-seven unselected patients with newly diagnosed metastatic ES/PNET received induction chemotherapy that included five cycles of cyclophosphamide 150 mg/m2/d for 7 days, doxorubicin 35 mg/m2/d once, followed by two cycles of ifosfamide 1.8 g/m2/d for 5 days, and etoposide 100 mg/m2/d for 5 days. Patients in complete or very good partial remission received HDCT with busulfan total dose 600 mg/m2 and melphalan 140 mg/m2 followed by autologous blood stem cells. Local therapy (surgery and/or radiation therapy) was performed before or after HDCT. Results Ninety-seven patients were enrolled from 1991 to 1999 (median age, 12.3 years; range, 0.2 to 25 years). Among them, 75 received HDCT. The 5-year event-free survival (EFS) rate for all 97 patients was 37% and the overall survival (OS) rate was 38%. The EFS after HDCT was 47%. The EFS for the 44 patients with lung-only metastases was 52%, whereas it was 36% for patients with bone metastases without bone marrow involvement. Among the 23 patients with bone marrow metastases, only one survived. The multivariate analysis for both EFS and for OS identified three independent prognostic factors: age, fever at diagnosis, and bone marrow involvement. Conclusion Compared with conventional chemotherapy, HDCT may yield benefits for patients with lung-only metastases or bone metastases. These results warrant confirmation in a randomized trial and provide part of the background data for the ongoing Euro-Ewing study.