bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myrtucommulone, a natural acylphloroglucinol, inhibits microsomal prostaglandin E2 synthase‐1
Authors: Koeberle A , Pollastro F , Northoff H , Werz O 
Published: March 2009

Background and purpose:  The selective inhibition of prostaglandin (PG)E2 formation via interference with microsomal PGE2 synthase (mPGES)‐1 could have advantages in the treatment of PGE2‐associated diseases, such as inflammation, fever and pain, compared with a general suppression of all PG biosynthesis, provided by inhibition of cyclooxygenase (COX)‐1 and 2. Here, we addressed whether the naturally occurring acylphloroglucinol myrtucommulone (MC) from Myrtus communis L. (myrtle) affected mPGES‐1.Experimental approach:  The effect of MC on PGE2 formation was investigated in a cell‐free assay by using microsomal preparations of interleukin‐1β‐stimulated A549 cells as the source of mPGES‐1, in intact A549 cells, and in lipopolysaccharide‐stimulated human whole blood. Inhibition of COX‐1 and COX‐2 activity in cellular and cell‐free assays was assessed by measuring 12(S)‐hydroxy‐5‐cis‐8,10‐trans‐heptadecatrienoic acid and 6‐oxo PGF1α formation.Key results:  MC concentration‐dependently inhibited cell‐free mPGES‐1‐mediated conversion of PGH2 to PGE2 (IC50 = 1 µmol·L−1). PGE2 formation was also diminished in intact A549 cells as well as in human whole blood at low micromolar concentrations. Neither COX‐2 activity in A549 cells nor isolated human recombinant COX‐2 was significantly affected by MC up to 30 µmol·L−1, and only moderate inhibition of cellular or cell‐free COX‐1 was evident (IC50 > 15 µmol·L−1).Conclusions and implications:  MC is the first natural product to inhibit mPGES‐1 that efficiently suppresses PGE2 formation without significant inhibition of the COX enzymes. This provides an interesting pharmacological profile suitable for interventions in inflammatory disorders, without the typical side effects of coxibs and non‐steroidal anti‐inflammatory drugs.
Notes on the origins of Epilepsia and the International League Against Epilepsy
Authors: Shorvon Simon D. , Weiss Giselle , Goodkin Howard P. 
Published: March 2009

SummaryThe recent discovery of archival material has shed interesting light on the origins of Epilepsia and also the International League Against Epilepsy (ILAE). The idea of an international journal devoted to epilepsy seems first to have arisen from talks between Dr. L. J. J. Muskens and Dr. W. Aldren Turner in 1905. A protracted series of subsequent letters between Muskens and a Haarlem publisher show how the idea slowly took shape. The committee of patronage, editorial board, and editorial assistants was probably first approached at the First International Congress of Psychiatry, Neurology, Psychology, and Nursing of the Insane, held in Amsterdam in 1907. At this meeting, the concept of an international organization to fight epilepsy (to become the ILAE) was also first proposed in public, again by Muskens. The concept of the ILAE was clearly modeled on another international organization—the International Commission for the Study of the Causes of Mental Diseases and Their Prophylaxis. This Commission had been first publicly proposed in 1906 by Ludwig Frank, at the Second International Congress for the Care and Treatment of the Insane. The proposed Commission and ILAE shared many features, aims, and personnel. Despite an auspicious start, the International Commission was prevented by personal and political differences from ever actually coming into being. However, the first issue of Epilepsia appeared in March 1909 and the ILAE was inaugurated in August 1909; and both have flourished and celebrate their centenaries this year.
A Randomized, Double‐Blind, Placebo‐Controlled Study of Preemptively Administered Intravenous Parecoxib: Effect on Anxiety Levels and Procedural Pain During Epidural Catheter Placement for Surgical Operations or for Chronic Pain Therapy
Authors: Vadalouca Athina , Moka Eleni , Chatzidimitriou Anna , Siafaka Ioanna , Sikioti Panayiota , Argyra Erifilli 
Published: March 2009

AbstractBackground:  The effect of parecoxib, when used perioperatively or during interventional techniques, is well demonstrated in the literature. Little is known about its effects on anxiety levels before the analgesic technique application. The aim of this prospective, randomized, double‐blind, placebo‐controlled, clinical study is to investigate whether parecoxib, preemptively administrated, has an effect on anxiety levels reported prior to an epidural puncture, and if it influences the reported pain of the interventional technique itself.Material and Methods:  The study protocol involved 110 patients, scheduled for epidural catheter placement for chronic pain therapy—Group I, as well as 112 patients scheduled for orthopedic operations under epidural anesthesia—Group II. Patients in each group were randomly allocated into two subgroups in relation to parecoxib/placebo administration before epidural catheter placement: Group Ia, parecoxib 40 mg i.v. (n = 54), Group Ib, placebo (n = 56), Group IIa, parecoxib 40 mg i.v. (n = 57), Group IIb, placebo (n = 55). Patients were given a self‐administered inventory to measure the anxiety level of the presurgical/preprocedural state (State‐Trait Spielberger Anxiety Inventory) and anxiety levels were recorded 1 hour before epidural puncture, 20 minutes postdosing, and 1 hour after epidural catheter placement. Anxiety levels were also measured and recorded using visual analog scale (VAS). One hour after epidural puncture, reported procedural pain was recorded (VAS). One hour and 6 hours postepidural, patients' satisfaction was also recorded, on a 4‐point scale.Results:  All four subgroups were similar regarding demographic, operative/procedural data, and coexisting diseases. Preprocedural anxiety levels were significantly decreased with parecoxib administration in comparison with placebo in both groups (P < 0.05). Reported VAS regarding pain from epidural puncture was lower in Groups IA and Ib. Patients' satisfaction was greater with parecoxib in comparison with placebo.Conclusion:  The levels of anxiety have been investigated in several medical procedures and early, in the study of pain. The higher the expectation of pain and the anxiety are, the higher the intensity of the pain. Parecoxib seems to exert positive influence on pain and anxiety levels of interventional procedure. Further studies are needed to elucidate the actual mechanisms that are involved.
Depression in Chronic Pain Patients: Prevalence and Measurement
Authors: Poole Helen , White Susie , Blake Chantal , Murphy Peter , Bramwell Ros 
Published: March 2009

AbstractThis study aimed to: (1) determine prevalence of depression in patients referred to specialist pain services using the Structured Clinical Interview (SCID) diagnostic interview, (2) compare results on the Beck Depression Inventory II (BDI‐II) with the SCID to determine the utility of the BDI‐II as a screening tool in this population.Thirty‐six participants were recruited, mainly women, with a mean age = 47.83 years (standard deviation = 12.85 years), who were heterogeneous with regard to their pain. All completed the BDI‐II and SCID. The SCID diagnosed 26 (72%) cases of depression. BDI‐II scores showed 31 (86%) that reported at least mild depression. Agreement between BDI‐II scores over threshold for mild depression and SCID diagnosis were assessed by Cohen's kappa (= 0.6). ROC analysis for BDI‐II scores against SCID diagnosis gave a large area under the curve (0.97, 95% confidence interval 0.93 to 1.02), suggesting BDI‐II is an excellent screen for this population, although the curve was unusual in that sensitivity was high even when the false positive rate was zero. ROC analysis suggested 22 or above as an optimum cut‐off score for depression on the BDI‐II—higher than for a general population sample.It has been suggested that the BDI overestimates incidence of depression in pain patients, but this study confirmed through diagnostic interview the very high incidence of depression in this population. It is therefore questionable whether there is value in screening referrals for depression. When using BDI‐II for screening, audit or evaluation purposes with a pain clinic population, we suggest a cut‐off of 22 or above.
Array‐Based Genomics in Glioma Research
Authors: Idbaih Ahmed , Crinière Emmanuelle , Ligon Keith L. , Delattre Olivier , Delattre Jean‐Yves 
Published: March 2009

AbstractOver the years, several relevant biomarkers with a potential clinical interest have been identified in gliomas using various techniques, such as karyotype, microsatellite analysis, fluorescent in situ hybridization and chromosome comparative genomic hybridization. Despite their pivotal contribution to our understanding of gliomas biology, clinical application of these approaches has been limited by technological and clinical complexities. In contrast, genomic arrays (array‐based comparative genomic hybridization and single nucleotide polymorphisms array) have emerged as promising technologies for clinical use in the setting of gliomas. Indeed, their feasibility and reliability have been rigorously assessed in gliomas and are discussed in this review. The well‐known genomic biomarkers in gliomas are in fact readily and reliably identified using genomic arrays. Moreover, it detects a multitude of new cryptic genomic markers, with potential biological and/or clinical significances. The main studies dedicated to genomic characterization of gliomas using genomic arrays are reviewed here. Interestingly, several recurrent genomic signatures have been reported by different teams, suggesting the validity of these genomic patterns. In light of this, genomic arrays are relatively simple and cost‐effective techniques whose implementation in molecular diagnostic laboratories should be encouraged as a valuable clinical tool for management of glioma patients.
Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy
Authors: Kortylewski Marcin , Kujawski Maciej , Herrmann Andreas , Yang Chunmei , Wang Lin , Liu Yong , Salcedo Rosalba , Yu Hua 
Published: March 2009

Abstract
Although toll-like receptor (TLR) agonists, such as CpG, are used as immunotherapeutic agents in clinical trials for cancer and infectious diseases, their effects are limited and the underlying mechanism(s) that restrains CpG efficacy remains obscure. Here, we show that signal transducer and activator of transcription 3 (Stat3) plays a key role in down-modulating immunostimulatory effects of CpG. In the absence of interleukin-6 (IL-6) and IL-10 induction, CpG directly activates Stat3 within minutes through TLR9. Ablating Stat3 in hematopoietic cells results in rapid activation of innate immunity by CpG, with enhanced production of IFN-γ, tumor necrosis factor-α, IL-12, and activation of macrophages, neutrophils, and natural killer cells marked with Stat1 activation. Innate immune responses induced by CpG in mice with a Stat3-ablated hematopoietic system cause potent antitumor effects, leading to eradication of large (&gt;1 cm) B16 melanoma tumors within 72 h. Moreover, ablating Stat3 in myeloid cells increases CpG-induced dendritic cell maturation, T-cell activation, generation of tumor antigen–specific T cells, and long-lasting antitumor immunity. A critical role of Stat3 in mediating immunosuppression by certain cytokines and growth factors in the tumor microenvironment has been recently documented. By demonstrating direct and rapid activation of Stat3 by TLR agonists, we identify a second level of Stat3-mediated immunosuppression. Our results further suggest that targeting Stat3 can drastically improve CpG-based immunotherapeutic approaches. [Cancer Res 2009;69(6):2497–505]
Relationship Between Angiotensin-Converting Enzyme Gene Polymorphism and Body Composition, Functional Performance, and Blood Biomarkers in Advanced Cancer Patients
Authors: Vigano Antonio , Trutschnigg Barbara , Kilgour Robert D. , Hamel Nancy , Hornby Laura , Lucar Enriqueta , Foulkes William , Tremblay Michel L. , Morais José A. 
Published: March 2009

Abstract
Purpose: Nutritional and functional outcome measures have been shown to vary in patients with chronic diseases according to the polymorphic alleles of angiotensin-converting enzyme (ACE), but little is known about the associations between ACE gene polymorphism (ACEGP) and the components of body composition, strength, and selected blood markers in advanced cancer patients (ACP).
Experimental Design: Data were collected from an inception cohort of 172 newly diagnosed ACP with gastrointestinal and non–small cell lung cancer. ACEGP status was defined by the presence of one of the following three combinations of alleles: insertion/insertion, insertion/deletion, and deletion/deletion. Body composition measurements using Dual-energy X-ray Absorptiometry comprised of the following: total fat mass, percent body fat, lean body mass, and appendicular lean mass. Body mass index; handgrip force by Jamar dynamometry; subjective recording of nutrition and performance status as per patient-generated subjective global assessment; cell blood count and differential, serum albumin, ACE, and C-reactive protein were also recorded.
Results: Multiple regression analysis, controlling for gender, age, diagnosis, treatments (radio/chemo), survival, and medication use (ACE inhibitors, anti-inflammatories, statins) revealed the following significant (P ≤ 0.05) relationships in the insertion/deletion compared with insertion/insertion group: higher hemoglobin (Hb; β, 6.39 g/dl; 95% confidence interval, 0.01-12.78), lower total fat mass (−5.78 kg; −11.62 to 0.07), percent body fat (−6.04%; −12.20 to 0.12), and lean body mass (−3.26 kg; −6.78 to 0.26). When comparing the DD to the II group, higher serum ACE (9.10; 1.96-16.25), Hb (6.25 g/dl; −0.63 to 13.12), and handgrip force by Jamar (6.85 lbs; 0.78-12.93) were found.
Conclusion: Of the variables studied, ACEGP seems to be primarily associated with differences in body composition, Hb, and muscle strength in ACP. Further data are needed to determine the clinical effect of ACEGP in cancer cachexia.
A Population Pharmacokinetic Meta-analysis of Sunitinib Malate (SU11248) and Its Primary Metabolite (SU12662) in Healthy Volunteers and Oncology Patients
Authors: Houk Brett E. , Bello Carlo L. , Kang Dongwoo , Amantea Michael 
Published: March 2009

Abstract
Purpose: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor. Following administration, sunitinib is metabolized by cytochrome P450 3A4 to an active metabolite (SU12662). The objective of this analysis was to assess sunitinib and SU12662 pharmacokinetics and to identify covariates that might explain variability in exposure following oral administration.
Experimental Design: Data from 590 subjects (73 volunteers and 517 patients) in 14 studies were analyzed. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and gender, race, age, weight, creatinine clearance, Eastern Cooperative Oncology Group score, and tumor type. Simulations were done to determine the predicted effect of these covariates on exposure.
Results: Separate models were developed for sunitinib and SU12662 (each a two-compartment model with first-order absorption and elimination). Sunitinib parameters were estimated as CL/F, 51.8 L/h and Vd/Fcentral, 2,030 liters. SU12662 parameters were estimated as CL/F, 29.6 L/h and Vd/Fcentral, 3,080 liters. Tumor type (except acute myeloid leukemia), Asian race, gender, body weight, and elevated Eastern Cooperative Oncology Group score described a portion of the variability in CL/F for sunitinib and metabolite; gender and body weight explained some of the variability in Vd/Fcentral for sunitinib and metabolite. Among patients, the predicted changes in sunitinib and metabolite AUC and Cmax as a result of the individual covariates ranged up to 17%.
Conclusion: The magnitude of the predicted changes in exposure with the covariates studied minimizes the necessity for dose adjustment in any of these subpopulations.
Ligand-dependent Notch Signaling Is Involved in Tumor Initiation and Tumor Maintenance in Pancreatic Cancer
Authors: Mullendore Michael E. , Koorstra Jan-Bart , Li Yue-Ming , Offerhaus G. Johan , Fan Xing , Henderson Clark M. , Matsui William , Eberhart Charles G. , Maitra Anirban , Feldmann Georg 
Published: March 2009

Abstract
Purpose: Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has not been elucidated.
Experimental Design: A panel of 20 human pancreatic cancer cell lines was profiled for the expression of Notch pathway-related ligands, receptors, and target genes. Disruption of intracellular Notch signaling, either genetically by RNA interference targeting NOTCH1 or pharmacologically by means of the γ-secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance.
Results: Striking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently JAGGED2 (18 of 20 cases, 90%) and DLL4 (10 of 20 cases, 50%). In two cell lines, genomic amplification of the DLL3 locus was observed, mirrored by overexpression of DLL3 transcripts. In contrast, coding region mutations of NOTCH1 or NOTCH2 were not observed. Genetic and pharmacologic inhibition of Notch signaling mitigated anchorage-independent growth in pancreatic cancer cells, confirming that sustained Notch activation is a requirement for pancreatic cancer maintenance. Further, transient pretreatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase–expressing subpopulation and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase–expressing cells in pancreatic cancer initiation.
Conclusions: Our studies confirm that Notch activation is almost always ligand dependent in pancreatic cancer, and inhibition of Notch signaling is a promising therapeutic strategy in this malignancy.
Using conversation analysis to study prosodic problems in a child with language impairment
Authors: Samuelsson Christina 
Published: March 2009

Prosody carries a lot of information relevant for our understanding of spoken messages. In addition, prosody plays an important role in signalling attitudes and emotions. Prosodic features also constitute an important resource that participants use to achieve mutual understanding in interaction. The aim of this study was to point to possible recurring patterns in the prosodic structure of language testing activities. A further aim was to discuss similarities between English and Swedish in these patterns. The main findings indicated a systematic use of prosody in the language testing activity. Questions are mainly posed with rising intonation and answers are produced with rising intonation. Evaluations are produced with a final fall in the intonation. There was also some support for the assumption that this pattern occurs within a similar activity involving an English-speaking child and his SLT. The results of the present study showed that analysis of conversation and prosody in its conversational context is useful in order to reveal possible functions of features that would have been overlooked with a more deficit driven perspective.
BAFF-R promotes cell proliferation and survival through interaction with IKKβ and NF-κB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells
Authors: Fu Lingchen , Lin-Lee Yen-Chiu , Pham Lan V. , Tamayo Archito T. , Yoshimura Linda C. , Ford Richard J. 
Published: March 2009

Abstract
BLyS and its major receptor BAFF-R have been shown to be critical for development and homeostasis of normal B lymphocytes, and for cell growth and survival of neoplastic B lymphocytes, but the biologic mechanisms of this ligand/receptor-derived intracellular signaling pathway(s) have not been completely defined. We have discovered that the BAFF-R protein was present in the cell nucleus, in addition to its integral presence in the plasma membrane and cytoplasm, in both normal and neoplastic B cells. BAFF-R interacted with histone H3 and IKKβ in the cell nucleus, enhancing histone H3 phosphorylation through IKKβ. Nuclear BAFF-R was also associated with NF-κB/c-Rel and bound to NF-κB targeted promoters including BLyS, CD154, Bcl-xL, IL-8, and Bfl-1/A1, promoting the transcription of these genes. These observations suggested that in addition to activating NF-κB pathways in the plasma membrane, BAFF-R also promotes normal B-cell and B-cell non-Hodgkin lymphoma (NHL-B) survival and proliferation by functioning as a transcriptional regulator through a chromatin remodeling mechanism(s) and NF-κB association. Our studies provide an expanded conceptual view of the BAFF-R signaling, which should contribute a better understanding of the physiologic mechanisms involved in normal B-cell survival and growth, as well as in the pathophysiology of aggressive B-cell malignancies and autoimmune diseases.
Antisense-mediated exon skipping to correct IL-12Rβ1 deficiency in T cells
Authors: van de Vosse Esther , Verhard Els M. , de Paus Roelof A. , Platenburg Gerard J. , van Deutekom Judith C. T. , Aartsma-Rus Annemieke , van Dissel Jaap T. 
Published: March 2009

AbstractPatients with Mendelian susceptibility to mycobacterial disease have severe, recurrent life-threatening infections with otherwise poorly pathogenic mycobacteria and salmonellae. The extreme susceptibility is the result of genetic defects in the interleukin-12/interferon-γ (IL-12/IFN-γ) pathway. The infections are difficult to treat, and therapeutic options are limited. We explored the feasibility of antisense-mediated exon skipping as therapy for Mendelian susceptibility to mycobacterial disease with cells from a complete IL-12Rβ1−/− patient. Expression constructs were first studied to determine whether IL12RB1 lacking exon 2 encodes a functional protein. The IL-12Rβ1 expression construct lacking exon 2 was expressed on T cells. On IL-12 or IL-23 stimulation, this construct phosphorylated similar amounts of STAT1, STAT3, and STAT4 and induced similar amounts of IFN-γ compared with a normal IL-12Rβ1 construct. Antisense oligonucleotides (AONs) directed at exon 2 resulted in transcripts lacking exon 2 in both controls' and patients' T cells. In IL-12Rβ1−/− cells, skipping of exon 2 led to expression of IL-12Rβ1 on the cell surface and responsiveness to IL-12. We showed that IL12RB1 lacking exon 2 encodes a functional IL-12Rβ1. We demonstrated that T cells can be highly efficiently transduced with AONs and are amenable to antisense-mediated exon skipping. Furthermore, we showed that exon skipping (partly) corrects the IL-12Rβ1 deficiency in patients' cells.