bluuebunny/crossref_metadata_2025_split huggingface dataset:
2003 Canadian Asthma Consensus Guidelines Executive Summary
Authors: Becker Allan , Lemière Catherine , Bérubé Denis , Boulet Louis-Philippe , Ducharme Francine , FitzGerald Mark , Kovesi Thomas 
Published: May 2010

AbstractBackgroundGuidelines for the diagnosis and management of asthma have been published over the last 15 years; however, there has been little focus on issues relating to asthma in childhood. Since the last revision of the 1999 Canadian Asthma Consensus Report, important new studies, particularly in children, have highlighted the need to incorporate new information into the asthma guidelines. The objectives of this article are to review the literature on asthma published between January 2000 and June 2003 and to evaluate the influence of new evidence on the recommendations made in the 1999 Canadian Asthma Consensus Report and its 2001 update, with a major focus on pediatric issues.MethodsThe diagnosis of asthma in young children and prevention strategies, pharmacotherapy, inhalation devices, immunotherapy, and asthma education were selected for review by small expert resource groups. The reviews were discussed in June 2003 at a meeting under the auspices of the Canadian Network For Asthma Care and the Canadian Thoracic Society. Data published through December 2004 were subsequently reviewed by the individual expert resource groups.ResultsThis report evaluates early-life prevention strategies and focuses on treatment of asthma in children, emphasizing the importance of early diagnosis and preventive therapy, the benefits of additional therapy, and the essential role of asthma education.ConclusionWe generally support previous recommendations and focus on new issues, particularly those relevant to children and their families. This document is a guide for asthma management based on the best available published data and the opinion of health care professionals, including asthma experts and educators.
The Difficult-to-Control Asthmatic: A Systematic Approach
Authors: Le Annie V , Simon Ronald A 
Published: May 2010

AbstractWith the judicious use of inhaled corticosteroids, β2agonists, and leukotriene modifiers, most patients with asthma are easily controlled and managed. However, approximately 5% of asthmatics do not respond to standard therapy and are classified as "difficult to control." [1] Typically, these are patients who complain of symptoms interfering with daily living despite long-term treatment with inhaled corticosteroids in doses up to 2,000 μg daily. Many factors can contribute to poor response to conventional therapy, and especially for these patients, a systematic approach is needed to identify the underlying causes. First, the diagnosis of asthma and adherence to the medication regimen should be confirmed. Next, potential persisting exacerbating triggers need to be identified and addressed. Concomitant disorders should be discovered and treated. Lastly, the impact and implications of socioeconomic and psychological factors on disease control can be significant and should be acknowledged and discussed with the individual patient. Less conventional and novel strategies for treating corticosteroid-resistant asthma do exist. However, their use is based on small studies that do not meet evidence-based criteria; therefore, it is essential to sort through and address the above issues before reverting to other therapy.
Renal oncocytoma: a comparative clinicopathologic study and fluorescent in-situ hybridization analysis of 73 cases with long-term follow-up
Authors: Dvorakova Marie , Dhir Rajiv , Bastacky Sheldon I , Cieply Kathleen M , Acquafondata Marie B , Sherer Carol R , Mercuri Tracy L , Parwani Anil V 
Published: May 2010

Abstract
Clinical studies have confirmed that renal oncocytoma (RO) is a benign neoplasm with excellent prognosis. In diagnostically challenging cases of renal oncocytic epithelial neoplasms, fluorescent in-situ hybridization (FISH) is increasingly being used and its ability to distinguish RO from chromophobe renal cell carcinoma (ChRCC) has been documented. In this study, we evaluated the differential diagnostic contribution of FISH in cases of RO.
Clinicopathologic data and glass slides from 73 patients with RO were reviewed; 20 cases of ChRCC were included for comparison. FISH analysis of formalin-fixed, paraffin-embedded sections was performed using centromeric probes for chromosomes 1, 2, 7 and 17. FISH analysis revealed ROs had frequent loss of signal for chromosome 1 (56%) and 17 (44%). Tumors with more than one loss were common (41%) and 10% cases showed loss of all chromosomes examined. A total of 18% cases did not show any abnormality.
Our study shows that chromosomal abnormalities in both ROs and ChRCCs are common with frequent loss of chromosomes 1 and 17. No association was found between overall patient survival and the extent of chromosomal abnormalities. FISH results, even those showing significant chromosomal abnormalities, should not alter the primarily morphology-based diagnosis of RO.
Reconstruction of the yeast protein-protein interaction network involved in nutrient sensing and global metabolic regulation
Authors: Nandy Subir K , Jouhten Paula , Nielsen Jens 
Published: May 2010

Abstract

Background
Several protein-protein interaction studies have been performed for the yeast Saccharomyces cerevisiae using different high-throughput experimental techniques. All these results are collected in the BioGRID database and the SGD database provide detailed annotation of the different proteins. Despite the value of BioGRID for studying protein-protein interactions, there is a need for manual curation of these interactions in order to remove false positives.

Results
Here we describe an annotated reconstruction of the protein-protein interactions around four key nutrient-sensing and metabolic regulatory signal transduction pathways (STP) operating in Saccharomyces cerevisiae. The reconstructed STP network includes a full protein-protein interaction network including the key nodes Snf1, Tor1, Hog1 and Pka1. The network includes a total of 623 structural open reading frames (ORFs) and 779 protein-protein interactions. A number of proteins were identified having interactions with more than one of the protein kinases. The fully reconstructed interaction network includes all the information available in separate databases for all the proteins included in the network (nodes) and for all the interactions between them (edges). The annotated information is readily available utilizing the functionalities of network modelling tools such as Cytoscape and CellDesigner.

Conclusions
The reported fully annotated interaction model serves as a platform for integrated systems biology studies of nutrient sensing and regulation in S. cerevisiae. Furthermore, we propose this annotated reconstruction as a first step towards generation of an extensive annotated protein-protein interaction network of signal transduction and metabolic regulation in this yeast.
Candidate gene study of HOXB1 in autism spectrum disorder
Authors: Muscarella Lucia A , Guarnieri Vito , Sacco Roberto , Curatolo Paolo , Manzi Barbara , Alessandrelli Riccardo , Giana Grazia , Militerni Roberto , Bravaccio Carmela , Lenti Carlo , Saccani Monica , Schneider Cindy , Melmed Raun , D'Agruma Leonardo , Persico Antonio M 
Published: May 2010

Abstract

Background

HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies.

Methods
Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios.

Results
We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)χ2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01).

Conclusions

HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.
Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor α but not estrogen receptor β
Authors: Dulos John , Vijn Peter , van Doorn Cindy , Hofstra Claudia L , Veening-Griffioen Desiree , de Graaf Jan , Dijcks Fred A , Boots Annemieke MH 
Published: May 2010

Abstract
Introduction
The immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)α and β. The contribution of ERα and ERβ to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritis

Methods
ER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ERβ agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERα selective agonist (ERA-63) and a selective ERβ agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERα - or ERβ-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction.

Results
EE was found to suppress clinical signs and symptoms in rat AA. The selective ERβ agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERα agonist ERA-63 suppressed the TT-specific swelling response in WT and ERβKO mice but not in ERαKO mice. As seen in the AA model, the selective ERβ agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints.

Conclusions
ERα, but not ERβ, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease.
Mechanical signals control SOX-9, VEGF, and c-Mycexpression and cell proliferation during inflammation via integrin-linked kinase, B-Raf, and ERK1/2-dependent signaling in articular chondrocytes
Authors: Perera Priyangi M , Wypasek Ewa , Madhavan Shashi , Rath-Deschner Birgit , Liu Jie , Nam Jin , Rath Bjoern , Huang Yan , Deschner James , Piesco Nicholas , Wu Chuanyue , Agarwal Sudha 
Published: May 2010

Abstract
Introduction
The importance of mechanical signals in normal and inflamed cartilage is well established. Chondrocytes respond to changes in the levels of proinflammatory cytokines and mechanical signals during inflammation. Cytokines like interleukin (IL)-1β suppress homeostatic mechanisms and inhibit cartilage repair and cell proliferation. However, matrix synthesis and chondrocyte (AC) proliferation are upregulated by the physiological levels of mechanical forces. In this study, we investigated intracellular mechanisms underlying reparative actions of mechanical signals during inflammation.

Methods
ACs isolated from articular cartilage were exposed to low/physiologic levels of dynamic strain in the presence of IL-1β. The cell extracts were probed for differential activation/inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade. The regulation of gene transcription was examined by real-time polymerase chain reaction.

Results
Mechanoactivation, but not IL-1β treatment, of ACs initiated integrin-linked kinase activation. Mechanical signals induced activation and subsequent C-Raf-mediated activation of MAP kinases (MEK1/2). However, IL-1β activated B-Raf kinase activity. Dynamic strain did not induce B-Raf activation but instead inhibited IL-1β-induced B-Raf activation. Both mechanical signals and IL-1β induced ERK1/2 phosphorylation but discrete gene expression. ERK1/2 activation by mechanical forces induced SRY-related protein-9 (SOX-9), vascular endothelial cell growth factor (VEGF), and c-Myc mRNA expression and AC proliferation. However, IL-1β did not induce SOX-9, VEGF, and c-Myc gene expression and inhibited AC cell proliferation. More importantly, SOX-9, VEGF, and Myc gene transcription and AC proliferation induced by mechanical signals were sustained in the presence of IL-1β.

Conclusions
The findings suggest that mechanical signals may sustain their effects in proinflammatory environments by regulating key molecules in the MAP kinase signaling cascade. Furthermore, the findings point to the potential of mechanosignaling in cartilage repair during inflammation.
Novel design principles enable specific targeting of imaging and therapeutic agents to necrotic domains in breast tumors
Authors: Goldshaid Liat , Rubinstein Efrat , Brandis Alexander , Segal Dadi , Leshem Noa , Brenner Ori , Kalchenko Vyacheslav , Eren Doron , Yecheskel Tamar , Salitra Yoseph , Salomon Yoram , Scherz Avigdor 
Published: May 2010

Abstract
Introduction
Necrosis at the tumor center is a common feature of aggressive breast cancers and has been associated with poor prognosis. It is commonly identified by means of invasive histopathology, which often correlates with morbidity and potential tumor cell dissemination, and limits the reconstruction of the whole necrotic domain. In this study we hypothesized that non covalent association to serum albumin (SA) and covalent binding to ligands for tumor-abundant cell receptors should synergistically drive selective accumulation and prolonged retention of imaging and therapeutic agents in breast tumor necrotic domains enabling in vivo identification, imaging and possibly treatment of such tumors.

Methods
Cyclo-Arg-Gly-Asp-D-Phe-Lys (c(RGDfK)) were conjugated to bacteriochlorophyll-derivatives (Bchl-Ds), previously developed as photodynamic agents, fluorescent probes and metal chelators in our lab. The c(RGDfK) component drives ligation to αVβ3 integrin receptors over-expressed by tumor cells and neo-vessels, and the Bchl-D component associates to SA in a non-covalent manner. STL-6014, a c(RGDfK)-Bchl-D representative, was i.v. injected to CD-1, nude female mice bearing necrotic and non-necrotic human MDA-MB-231-RFP breast cancer tumors. The fluorescence signals of the Bchl-Ds and RFP were monitored over days after treatment, by quantitative whole body imaging and excised tumor/tissue samples derived thereof. Complementary experiments included competitive inhibition of STL-6014 uptake by free c(RGDfK), comparative pharmacokinetics of nonconjugated c(RGDfK) Bchl-D (STL-7012) and of two human serum albumin (HSA) conjugates: HSA-STL-7012 and HSA-STL-6014.

Results
STL-6014 and STL-7012 formed complexes with HSA (HSA/STL-6014, HSA/STL-7012). STL-6014, HSA-STL-7012 and HSA-STL-6014, selectively accumulated at similar rates, in tumor viable regions over the first 8 h post administration. They then migrated into the necrotic tumor domain and presented tumor half lifetimes (T1/2) in the range of days where T1/2 for HSA-STL-6014 > STL-6014 > HSA-STL-7012. No accumulation of STL-7012 was observed. Pre-injection of c(RGDfK) excess, prevented the uptake of STL-6014 in the small, but not in the large tumors.

Conclusions
Non-covalent association to SA and covalent binding to c(RGDfK), synergistically enable the accumulation and prolonged retention of Bchl-Ds in the necrotic regions of tumors. These findings provide novel guidelines and strategy for imaging and treatment of necrotic tumors.
Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Hematologic Malignancies After Dose-Escalated Treosulfan/Fludarabine Conditioning
Authors: Casper Jochen , Wolff Daniel , Knauf Wolfgang , Blau Igor W. , Ruutu Tapani , Volin Liisa , Wandt Hannes , Schäfer-Eckart Kerstin , Holowiecki Jerzy , Giebel Sebastian , Aschan Johan , Zander Axel R. , Kröger Nicolaus , Hilgendorf Inken , Baumgart Joachim , Mylius Heidrun A. , Pichlmeier Uwe , Freund Mathias 
Published: May 2010

PurposeTreosulfan was introduced recently as a conditioning agent for allogeneic blood stem-cell transplantation. The favorable nonhematologic toxicity profile at 3 × 10 g/m2was the basis for dose escalation in this prospective, multicenter trial.Patients and MethodsFifty-six patients with various hematologic malignancies who were not eligible for standard conditioning were treated with one of three doses: 10 g/m2, 12 g/m2, or 14 g/m2of intravenous treosulfan, which was administered on days −6 to −4 combined with fludarabine 30 mg/m2on days −6 to −2. Patients in complete remission (CR; 42%) or non-CR (58%) received grafts from matched related (47%) or matched unrelated (51%) donors; one patient had a mismatched related donor (2%).ResultsNo engraftment failure occurred. Overall, extramedullary toxicity and the nonrelapse mortality rate at 2 years (20%) were low and did not increase with dose. Cumulative incidence of relapse/progression reached 31%. The overall survival and progression-free survival rates were 64% and 49%, respectively, in the total study population. An inverse dose dependency of relapse incidence was indicated in the subgroup receiving transplantations from matched related donors (P = .0568).ConclusionTreosulfan-based conditioning was feasible at all three doses. The 3 × 14 g/m2dose was selected for additional studies, because it combines desired characteristics of low toxicity and a low relapse rate.
Comparison of Anticancer Drug Coverage Decisions in the United States and United Kingdom: Does the Evidence Support the Rhetoric?
Authors: Mason Anne , Drummond Michael , Ramsey Scott , Campbell Jonathan , Raisch Dennis 
Published: May 2010

Purpose In contrast to the United States, several European countries have health technology assessment programs for drugs, many of which assess cost effectiveness. Coverage decisions that consider cost effectiveness may lead to restrictions in access. Methods For a purposive sample of five decision-making bodies, we analyzed US and United Kingdom coverage decisions on all anticancer drugs approved by the US Food and Drug Administration (FDA) from 2004 to 2008. Data sources for the timing and outcome of licensing and coverage decisions included published and unpublished documentation, Web sites, and personal communication. Results The FDA approved 59 anticancer drugs over the study period, of which 46 were also approved by the European Medicines Agency. In the United States, 100% of drugs were covered, mostly without restriction. However, the United Kingdom bodies made positive coverage decisions for less than half of licensed drugs (National Institute for Health and Clinical Excellence [NICE]: 39%; Scottish Medicines Consortium [SMC]: 43%). Whereas the Centers for Medicare and Medicaid Services (CMS) and the Department of Veterans Affairs (VA) covered all 59 drugs from the FDA license date, delays were evident for some Regence Group decisions that were informed by cost effectiveness (median, 0 days; semi-interquartile range [SIQR], 122 days; n = 22). Relative to the European Medicines Agency license date, median time to coverage was 783 days (SIQR, 170 days) for NICE and 231 days (SIQR, 129 days) for the SMC. Conclusion Anticancer drug coverage decisions that consider cost effectiveness are associated with greater restrictions and slower time to coverage. However, this approach may represent an explicit alternative to rationing achieved through the use of patient copayments.
Epidermal Growth Factor Receptor Inhibitor Gefitinib Added to Chemoradiotherapy in Locally Advanced Head and Neck Cancer
Authors: Cohen Ezra E.W. , Haraf Daniel J. , Kunnavakkam Rangesh , Stenson Kerstin M. , Blair Elizabeth A. , Brockstein Bruce , Lester Eric P. , Salama Joseph K. , Dekker Allison , Williams Rosalyn , Witt Mary Ellyn , Grushko Tatyana A. , Dignam James J. , Lingen Mark W. , Olopade Olufunmilayo I. , Vokes Everett E. 
Published: May 2010

Purpose Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations. Patients and Methods Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization. Results Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02). Conclusion Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.