bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phospholipase D2 acts as an essential adaptor protein in the activation of Syk in antigen-stimulated mast cells
Authors: Lee Jun Ho , Kim Young Mi , Kim Nam Wook , Kim Jie Wan , Her Erk , Kim Bo Kyung , Kim Jong Hyun , Ryu Sung Ho , Park Jong Woo , Seo Dong Wan , Han Jeung Whan , Beaven Michael A. , Choi Wahn Soo 
Published: March 2006

AbstractMast cells are responsible for IgE-mediated allergic reactions. Phospholipase D1 (PLD1) and PLD2 regulate mast cell activation, but the mechanisms remain unclear. Here we show that PLD2 associates with and promotes activation of Syk, a key enzyme in mast cell activation. Antigen stimulation resulted in increased association and colocalization of Syk with PLD2 on the plasma membrane as indicated by coimmunoprecipitation and confocal microscopy. This association was dependent on tyrosine phosphorylation of Syk but not on PLD2 activity. In vitro, PLD2 interacted via its Phox homology (PX) domain with recombinant Syk to induce phosphorylation and activation of Syk. Furthermore, overexpression of PLD2 or catalytically inactive PLD2K758R enhanced antigen-induced phosphorylations of Syk and its downstream targets, the adaptor proteins LAT and SLP-76, while expression of a PLD2 siRNA blocked these phosphorylations. Apparently, the interaction of PLD2 with Syk is an early critical event in the activation of mast cells.
Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin
Authors: Khan Zia A. , Melero-Martin Juan M. , Wu Xiao , Paruchuri Sailaja , Boscolo Elisa , Mulliken John B. , Bischoff Joyce 
Published: March 2006

Abstract
Infantile hemangiomas are composed of endothelial cells (ECs), endothelial progenitor cells (EPCs), as well as perivascular and hematopoietic cells. Our hypothesis is that hemangioma-derived EPCs (HemEPCs) differentiate into the mature ECs that comprise the major compartment of the tumor. To test this, we isolated EPCs (CD133+/Ulex europeus– I+) and mature ECs (CD133–/Ulex europeus–I+) from proliferating hemangiomas and used a previously described property of hemangioma-derived ECs (HemECs), enhanced migratory activity in response to the angiogenesis inhibitor endostatin, to determine if HemEPCs share this abnormal behavior. Umbilical cord blood–derived EPCs (cbEPCs) were analyzed in parallel as a normal control. Our results show that HemEPCs, HemECs, and cbEPCs exhibit increased adhesion, migration, and proliferation in response to endostatin. This angiogenic response to endostatin was consistently expressed by HemEPCs over several weeks in culture, whereas HemECs and cbEPCs shifted toward the mature endothelial response to endostatin. Similar mRNA-expression patterns among HemEPCs, HemECs, and cbEPCs, revealed by microarray analyses, provided further indication of an EPC phenotype. This is the first demonstration that human EPCs, isolated from blood or from a proliferating hemangioma, are stimulated by an angiogenesis inhibitor. These findings suggest that EPCs respond differently from mature ECs when exposed to angiogenic or antiangiogenic signals.
Differential regulation by leukotrienes and calcium of Fcγ receptor-induced phagocytosis and Syk activation in dendritic cells versus macrophages
Authors: Canetti Claudio , Aronoff David M , Choe Mun , Flamand Nicolas , Wettlaufer Scott , Toews Galen B , Chen Gwo-Hsiao , Peters-Golden Marc 
Published: March 2006

Abstract
Macrophage (MØ) phagocytosis via the Fc receptor for immunoglobulin G (FcγR) requires the spleen tyrosine kinase (Syk) and serves an important antimicrobial function. We have reported previously that FcγR-mediated ingestion and Syk activation in MØ are amplified by and depend on the proinflammatory lipid mediator leukotriene B4 (LTB4). Although FcγR-mediated ingestion is also important for antigen uptake, there is no information about LTB4 regulation of these processes in dendritic cells (DCs). In this study, we compared murine bone marrow (BM)-derived DCs to MØ from BM, peritoneum, and the pulmonary alveolar space. Neither phagocytosis nor Syk activation in DCs was influenced by exogenous LTB4. Unlike the various MØ populations, Syk activation in DCs was likewise unaffected by pharmacologic or genetic strategies to inhibit endogenous LTB4 synthesis or to block the high-affinity LTB4 receptor BLT1. DCs were refractory to regulation by LTB4 despite the fact that they expressed BLT1 and mobilized intracellular calcium in response to its ligation. This resistance to LTB4 in DCs instead reflected the fact that in contrast to MØ, Syk activation in DCs was itself entirely independent of calcium. These results identify a fundamental difference in FcγR signaling between DCs and MØ, which may relate to the divergent, functional consequences of target ingestion in the two cell types.
CD8 T cells expressing killer Ig-like receptors and NKG2A are present in cord blood and express a more naïve phenotype than their counterparts in adult blood
Authors: Warren Hilary S , Rana Purna M , Rieger Duncan T , Hewitt Kimberly A , Dahlstrom Jane E , Kent Alison L 
Published: March 2006

Abstract
We report that natural killer receptors (NKR) for major histocompatibility complex (MHC) class I molecules (MHC-NKR), the inhibitory killer immunoglobulin-like receptors (KIR), and the CD94/NKG2A receptor are present on a small proportion of CD8 T cells in cord blood. On average, 1.67% of CD8 T cells in cord blood express KIR, and 0.74% expresses NKG2A, approximately fivefold less than in adult blood. CD8 T cells expressing MHC-NKR were present at similar levels in cord blood from preterm and term infants, and it is important that their presence was independent of placental pathology or infection. Cord blood CD8 T cells expressing MHC-NKR were relatively homogeneous and entirely CD27+, mostly CC chemokine receptor 7− and granzyme B−, with a majority being CD45RA+ and with no evidence for a skewed distribution of T cell receptor-Vβ when tested in KIR+ cells. This contrasted with adult blood, which was more heterogeneous, and where a majority of CD8 T cells expressing MHC-NKR was CD27− and granzyme B+. Functional studies revealed that cord blood KIR+ CD8 T cells were as capable as KIR− CD8 T cells in their ability to proliferate in response to CD3 ligation, yet it is interesting that they were more capable than KIR− CD8 T cells in their ability to secrete interferon-γ. These data suggest that cord blood CD8 T cells expressing MHC-NKR are a unique subset of cells, distinct from those in adult blood, and may represent a less-differentiated population.
Adenoviral-encoded antigens are presented efficiently by a subset of dendritic cells expressing high levels of αvβ3 integrins
Authors: Harui Airi , Roth Michael D , Vira Darshni , Sanghvi Mihir , Mizuguchi Hiroyuki , Basak Saroj K 
Published: March 2006

Abstract
Dendritic cells (DC) play a central role in antigen presentation and are often targeted by adenoviral (Ad)-based gene therapy. However, DC lack the coxsackie-Ad receptor, and little is known about the process by which they acquire and present Ad-encoded antigens. We examined the expression of ανβ3 integrins (CD51/CD61) on mouse bone marrow-derived DC (BM-DC) and their susceptibility to transduction by Ad vectors. Less than 10% of BM-DC precursors expressed CD51, but expression increased over time in culture with granulocyte macrophage-colony stimulating factor (GM-CSF)/interleukin (IL)-4. After 7 days, 28 ± 1.7% of CD11c+ DC expressed high levels of CD51 (CD51hi), and the remaining DC expressed low levels of CD51 (CD51lo). CD51hi CD express higher major histocompatibility complex type 1 (MHC I); however, both of the DC subsets expressed similar levels of MHC II and costimulatory molecules. When exposed to a first-generation Ad vector, transgene expression was restricted to the CD51hi DC subset and blocked by soluble peptides expressing an arginine, glycine, aspartic acid (RGD) sequence, confirming the role of integrins in viral entry. Consistent with this, a modified Ad expressing an RGD-binding sequence in its fiber knob (Ad-RGD) transduced the CD51hi DC subset with significantly higher efficiency. When BM-DC were transduced with an Ad-expressing ovalbumin (Ad-OVA), the CD51hi subset proved superior in activating OT-I (T cell receptor-OVA) T cells. Similar to in vitro effects, systemic administration of GM-CSF/IL-4 increased the expression of CD51 on splenic DC and rendered these cells susceptible to Ad transduction. These results suggest that a limited subset of DC expressing high levels of ανβ3 integrins is preferentially transduced by Ad vectors and activates CD8+ T cell responses against Ad-encoded antigens.
Psychotherapy plus antidepressant for panic disorder with or without agoraphobia
Authors: Furukawa Toshi A. , Watanabe Norio , Churchill Rachel 
Published: April 2006

BackgroundPanic disorder can be treated with psychotherapy, pharmacotherapy or a combination of both.AimsTo summarise the evidence concerning the short- and long-term benefits and adverse effects of a combination of psychotherapy and antidepressant treatment.MethodMeta-analyses and meta-regressions were undertaken using data from all relevant randomised controlled trials identified by a comprehensive literature search. The primary outcome was relative risk (RR) of response.ResultsWe identified 23 randomised comparisons (21 trials involving a total of 1709 patients). In the acute-phase treatment, the combined therapy was superior to antidepressant pharmacotherapy (RR=1.24, 95% CI 1.02–1.52) or psychotherapy (RR=1.16, 95%CI 1.03–1.30). After termination of the acute-phase treatment, the combined therapy was more effective than pharmacotherapy alone (RR=1.61, 95% CI 1.23–2.11) and was as effective as psychotherapy (RR=0.96, 95% CI 0.79–1.16).ConclusionsEither combined therapy or psychotherapy alone may be chosen as first-line treatment for panic disorder with or without agoraphobia, depending on the patient's preferences.
Cost-utility of brief psychological treatment for depression and anxiety
Authors: Hakkaart-Van Roijen Leona , Van Straten Annemieke , Al Maiwenn , Rutten Frans , Donker Marianne 
Published: March 2006

BackgroundThe cost-utility of brief therapy compared with cognitive–behavioural therapy (CBT) and care as usual in the treatment of depression and anxiety has not yet been determined.AimsTo assess the cost-utility of brief therapy compared with CBT and care as usual.MethodA pragmatic randomised controlled trial involving 702 patients was conducted at 7 Dutch mental healthcare centres (MHCs). Patients were interviewed at baseline and then every 3 months over a period of 1.5 years, during which time data were collected on direct costs, indirect costs and quality of life.ResultsThe mean direct costs of treatment at the MHCs were significantly lower for brief therapy than for CBT and care as usual. However, after factoring in other healthcare costs and indirect costs, no significant differences between the treatment groups could be detected. We found no significant differences in quality-adjusted life-years between the groups.ConclusionsCost-utility did not differ significantly between the three treatment groups.
Ethnic differences among patients in high-security psychiatric hospitals in England
Authors: Leese Morven , Thornicroft Graham , Shaw Jenny , Thomas Stuart , Mohan Rajesh , Harty Mari Anne , Dolan Mairead 
Published: April 2006

BackgroundBlack (Black Caribbean and Black African) patients are over-represented in admissions to general adult and medium-security psychiatric services in England.AimsTo describe the socio-demographic, clinical and offence characteristics of patients in high-security psychiatric hospitals (HSPHs) in England, and to compare admission rates and unmet needs by ethnic group.MethodA total of 1255 in-patients were interviewed, and their legal status, socio-demographic characteristics and individual treatment needs were assessed.ResultsBlack patients in HSPHs are over-represented by 8.2 times (range 3.2–24.4, 95% CI 7.1–9.3), are more often male (P=0.037), and are more often diagnosed with a mental illness and less often diagnosed with a personality disorder or learning disability (P< 0.001) than White patients. Unmet needs were significantly less common among White than among Black patients (mean values of 2.22v.2.62, difference=0.40, 95% CI 0.06–0.73).ConclusionsCompared with the proportion of Black patients in the general population in their region of origin, a much higher proportion of Black patients were admitted to HSPHs, and fewer of their needs were met.
Has the referral of older adults with dementia changed since the availability of acetylcholinesterase inhibitors and the NICE guidelines?
Authors: O'Loughlin Christopher , Darley Jon 
Published: March 2006

Aims and MethodTo investigate whether patients with dementia are referred to specialist services earlier in the disease since the launch of acetylcholinesterase inhibitors and the publication of the National Institute for Clinical Excellence (NICE) guidelines for the use of these drugs. All referrals to old age psychiatry services in two 6-month periods in 1996 and 2003 were surveyed retrospectively for diagnosis, Mini-Mental State Examination (MMSE) score and use of acetylcholinesterase inhibitors.ResultsThe mean MMSE score at referral increased from 18.8 to 21.5 (P=0.0005) between 1996 and 2003. Acetylcholinesterase inhibitors were prescribed for 35% of all patients and 58% of patients that would be suitable according to NICE guidelines in the 2003 group.Clinical ImplicationsThe earlier referral of patients with dementia to mental health services is encouraging.
Drug services in England and Wales: a survey of treatment providers and their medical leads
Authors: Airey Nick , McLaren Stuart 
Published: April 2006

Aims and MethodWe undertook a postal questionnaire survey of drug action teams in England and Wales with the aim of clarifying the nature of statutory specialist drug services.ResultsOf 159 drug action teams, 110 (69%) responded; 64 (58%) reported that mental health trusts exclusively provided their specialist drug services. Other providers were primary care and acute trusts, the non-statutory sector and social services. The majority of medical leads were psychiatrists (123 senior posts with 20% vacant/occupied by a locum), then general practitioners (GPs) (42) and other specialists (4).Clinical ImplicationsSpecialist drug services are offered by a range of treatment providers, with the medical lead being taken by GPs and other specialists in some areas. In view of the current difficulty in recruiting psychiatrists, we propose that alternative training pathways are considered for addiction specialists.
Service innovations: a dedicated drug treatment service for dementia
Authors: Sheehan Bart , Saad Karim 
Published: April 2006

Aims and MethodTo describe a targeted domiciliary drug treatment service for dementia and to establish clinical outcomes for its patients. All new referrals in a 6-month period were included. Data on clinical and demographic background, service performance and cognitive, functional and behavioural outcomes were recorded.ResultsOf 96 patients initiated on antidementia drugs, most had dementia of mild to moderate severity, and had heterogenous diagnoses. Significant improvements in cognition, behaviour and function were found.Clinical ImplicationsA dedicated domiciliary drug treatment service for dementia achieved high levels of clinical activity and outcomes at least as good as clinical trials. This service model may be an attractive choice.
Development of an Emergency Department Work Score to Predict Ambulance Diversion
Authors: Epstein Stephen K. , Tian Lu 
Published: March 2006

Abstract
Objectives:
The authors sought to develop and validate an emergency department (ED) work score that could be used in real time to quantify crowding and staff workload in an ED. This work score could be used by public health officials to direct ambulance traffic based on an objective measure of ED status and to track ED conditions over time. In addition, the authors sought to determine which portion of ED care was most responsible for crowding.
Methods:
The setting was a tertiary teaching hospital with an emergency medicine residency. A number of ED parameters were measured throughout 2003 and then matched to times that an ED was on diversion status. Odd months of the year were used to develop the standard and even months to validate the standard. A marginal logistic regression analysis was used to develop the standard. The decision to divert ambulances was used as the criterion for ED crowding.
Results:
The logistic regression demonstrated excellent correlation between the work score and diversion status. At the point of maximum inflection of the receiver operating characteristic curve, the work score predicted diversion status with 86% sensitivity and 80% specificity. Conclusions: An ED work score was successfully developed and internally validated. External validation should be performed before widespread use.
Association of High-Level MRP1 Expression With Poor Clinical Outcome in a Large Prospective Study of Primary Neuroblastoma
Authors: Haber Michelle , Smith Janice , Bordow Sharon B. , Flemming Claudia , Cohn Susan L. , London Wendy B. , Marshall Glenn M. , Norris Murray D. 
Published: March 2006

Purpose We have previously shown in a retrospective study that expression of the multidrug transporter gene MRP1 (ABCC1) is associated with outcome in neuroblastoma. We have now undertaken a prospective analysis to examine the independent prognostic significance of MRP1 expression in a large cohort of primary untreated neuroblastomas. Patients and Methods Two hundred nine diagnostic neuroblastoma samples from patients prospectively enrolled onto the Pediatric Oncology Group biology protocol 9047 were analyzed for expression of the MRP1, MDR1, MYCN, and TRKA genes using real-time polymerase chain reaction. Expression levels were correlated with established prognostic indicators and disease outcome. Results MRP1 expression was detected in all tumors analyzed, and levels were significantly higher in tumors with versus without MYCN amplification (P < .0001). High levels of MRP1 were highly predictive of both event-free survival (EFS; P < .001) and overall survival (OS; P < .001). High-level MYCN and low-level TRKA were also predictive of poor outcome. MDR1 expression demonstrated no prognostic significance. After adjustment for the effect of statistically significant prognostic indicators in multivariate models, MRP1 expression retained significant prognostic value for both EFS (hazard ratio = 3.0; P = .0011) and OS (hazard ratio = 2.5; P = .0095), whereas MYCN amplification did not have prognostic significance. Conclusion The results of this prospective study confirm our earlier findings and support a clinically relevant role for MRP1 gene expression in neuroblastoma. These findings have implications for the biology, prognosis, and treatment of this disease and provide evidence that MRP1 is a bone fide molecular target for reversing chemotherapy resistance in aggressive drug-refractory neuroblastoma.
Phase I Clinical Evaluation of Weekly Administration of the Novel Vascular-Targeting Agent, ZD6126, in Patients With Solid Tumors
Authors: Beerepoot Laurens V. , Radema Sandra A. , Witteveen Els O. , Thomas Tawnie , Wheeler Catherine , Kempin Sanford , Voest Emile E. 
Published: March 2006

Purpose ZD6126 is a novel vascular-targeting agent that induces selective effects on the morphology of endothelial cells by disrupting the tubulin cytoskeleton. This leads to cell detachment and tumor vessel congestion, resulting in extensive central necrosis in a range of tumor xenograft models. Results from a phase I dose-escalation study of ZD6126 are reported. Patients and Methods Thirty-two patients with advanced cancer received weekly ZD6126 infusion (5 to 28 mg/m2). Assessments for safety and pharmacokinetics were performed. Circulating endothelial cells (CECs) were quantified as a pharmacodynamic marker of vascular damage. Results Maximum concentrations of the active species were observed 5 to 25 minutes from the start of infusion, and decayed in a biexponential manner with a half-life of 1 to 3 hours. Maximum serum concentration and area under the time-concentration curve increased with dose in a linear fashion across the dose range of 5 to 28 mg/m2. One patient treated at 10 mg/m2 with a history of ischemic heart disease experienced acute myocardial infarction 2 weeks after drug discontinuation. Four others had asymptomatic creatine phosphokinase–muscle-brain elevation. Maximum-tolerated dose (MTD) was reached at 20 mg/m2/wk. Dose-limiting toxicities at 28 mg/m2 were hypoxia caused by pulmonary embolism and an asymptomatic decrease in left ventricular ejection fraction. No objective antitumor responses were observed. CEC levels increased in the hours after infusion, indicating potential effect of the compound on the vasculature. Conclusion ZD6126 administered as a weekly infusion was clinically well tolerated. The MTD was reached at 20 mg/m2.
Predictive Factors for Outcome in a Phase II Study of Gefitinib in Second-Line Treatment of Advanced Esophageal Cancer Patients
Authors: Janmaat Maarten L. , Gallegos-Ruiz Mariëlle I. , Rodriguez José A. , Meijer Gerrit A. , Vervenne Walter L. , Richel Dick J. , Van Groeningen Cees , Giaccone Giuseppe 
Published: March 2006

Purpose The efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib was assessed in a phase II study in patients with advanced esophageal cancer. Several biologic features were investigated as potential markers of gefitinib activity. Patients and Methods Patients with advanced esophageal cancer, who had failed one line of prior chemotherapy, were administered gefitinib 500 mg/d. Response was evaluated every 8 weeks. Tumor material obtained before gefitinib treatment was investigated for gene mutations in EGFR, k-ras, and PIK3CA; protein expression levels of EGFR, p-Akt, and p-Erk; and EGFR gene amplification. Results Of the 36 enrolled patients, one (2.8%) achieved a partial response, 10 (27.8%) had stable disease, 17 (47.2%) experienced progression on treatment, and eight (22.2%) were not assessable for response. The progression-free survival time was 59 days, and the median overall survival time was 164 days. Although EGFR or PIK3CA mutations were absent, k-ras mutations were found in two patients with progressive disease. High EGFR gene copy number was identified in two patients experiencing partial response or progressive disease. A higher disease control rate (response plus stable disease) was observed in females (P = .038) and in patients with squamous cell carcinoma (SCC; P = .013) or high EGFR expression (P = .002). Conclusion Gefitinib has a modest activity in second-line treatment of advanced esophageal cancer. However, the patient outcome was significantly better in female patients and in patients demonstrating high EGFR expression or SCC histology. The selection of esophageal cancer patients for future studies with EGFR-TKIs based on the level of EGFR expression in their tumors or SCC histology should be considered.