bluuebunny/crossref_metadata_2025 huggingface dataset:
Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion
Authors: Seidel P. , Merfort I. , Hughes J. M. , Oliver B. G. G. , Tamm M. , Roth M.
Published: May 2009

The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-κB and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFα-induced asthma-relevant cytokines and NF-κB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1–100 μM) and/or dexamethasone (0.0001–0.1 μM), NF-κB p65 siRNA (100 nM), the NF-κB inhibitor helenalin (1 μM) before stimulation with PDGF-BB or TNFα (10 ng/ml). Cytokine release was measured by ELISA. NF-κB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFα-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-κB p65 siRNA and/or the NF-κB inhibitor helenalin reduced PDGF-BB- and TNFα-induced cytokine expression, suggesting the involvement of NF-κB signaling. DMF inhibited TNFα-induced NF-κB p65 phosphorylation, NF-κB nuclear entry, and NF-κB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-κB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-κB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-κB but a wider range of NF-κB-linked signaling proteins, which may explain its potential beneficial effect in asthma.
In Vivo Measurements of Tumor Metabolism and Growth after Administration of Enzastaurin Using Small Animal FDG Positron Emission Tomography
Authors: Pollok Karen E. , Lahn Michael , Enas Nathan , McNulty Ann , Graff Jeremy , Cai Shanbao , Hartwell Jennifer R. , Ernstberger Aaron , Thornton Donald , Brail Les , Hutchins Gary
Published: May 2009

Background. The use of 2-[]fluoro-2-deoxy-D-glucose ([]FDG) may help to establish the antitumor activity of enzastaurin, a novel protein kinase C-beta II (PKC-II) inhibitor, in mouse xenografts.Methods. The hematologic cell line RAJI and the solid tumor cell line U87MG were each implanted in NOD/SCID mice. Standard tumor growth measurements and []FDG PET imaging were performed weekly for up to three weeks after tumor implantation and growth.Results. Concomitant with caliper measurements, []FDG PET imaging was performed to monitor glucose metabolism. Heterogeneity of glucose uptake in various areas of the tumors was observed after vehicle or enzastaurin treatment. This heterogeneity may limit the use of []FDG PET imaging to measure enzastaurin-associated changes in xenograft tumors.Conclusion. []FDG PET imaging technique does not correlate with standard caliper assessments in xenografts to assess the antitumor activity of enzastaurin. Future studies are needed to determine the use of []FDG PET imaging in preclinical models.
Aspects of Toxoplasma Infection on the Reproductive System of Experimentally Infected Rams (Ovis Aries)
Authors: Lopes Welber Daniel Zanetti , da Costa Alvimar José , Santana Luis Fernando , dos Santos Ricardo Silva , Rossanese Walter Matheus , Lopes Wilton Carlos Zanetti , Costa Gustavo Henrique Nogueira , Sakamoto Cláudio Alessandro , dos Santos Thais Rabelo
Published: May 2009

Eight reproductive rams with no prior reproductive disease were distributed into three groups of infection withT. gondii: GI, 3 rams,  P strain oocysts; GII, 3 rams,  RH strain tachyzoites; GIII, 2 control rams. Clinical parameters were measured and serological evaluations (IIF) were performed. Presence of the parasite in the semen was investigated by PCR and bioassay techniques. The rams presented clinical alterations (hyperthermia and apathy) related to toxoplasmosis in both groups infected withToxoplasma gondii. All the inoculated rams responded to antigenic stimulus, producing antibodies againstT. gondiifrom postinoculation day 5 onwards. In ovine groups I and II, the greatest titers observed were 1 : 4096 and 1 : 8192, respectively. In semen samples collected from these two groups, the presence ofT. gondiiwas detected by bioassay and PCR. This coccidian was isolated (bioassay and PCR) in tissue pools (testicles, epididymis, seminal vesicle, and prostrate) from two rams infected presenting oocysts and in one presenting tachyzoites.
Collagenous Fibroma (Desmoplastic Fibroblastoma) with Vertebral Body Erosion
Authors: Osipov Vladimir , Carrera Guillermo F.
Published: May 2009

Collagenous fibroma (desmoplastic fibroblastoma) is a recently described rare benign tumor affecting mainly males in the fifth through seventh decades. This tumor occurs predominantly in the peripheral sites, with predilection for upper and lower extremities. The patients present with a painless mass of involving subcutis, with one quarter of all cases involving skeletal muscle. Both radiographically and histologically these tumors are well-circumscribed small lesions from one to several centimeters in diameter, though lesions as large as 20 cm have been reported. We report a case of collagenous fibroma presenting symptomatically as a 2.4 cm mass within the pedicle and adjacent transverse process of the L5 vertebral segment. Bone erosion by desmoplastic fibroblastoma is very rare event. This tumor should be in the differential diagnosis of the soft tissue lesions presenting with bony erosion.
Efficacy of Artesunate + Sulphadoxine-Pyrimethamine (AS + SP) and Amodiaquine + Sulphadoxine-Pyrimethamine (AQ + SP) for UncomplicatedfalciparumMalaria in Equatorial Guinea (Central Africa)
Authors: Charle Pilar , Berzosa Pedro , Descalzo Miguel Angel , de Lucio Aida , Raso Jose , Obono Jacqueline , Lwanga Magdalena , Nlang Natividad , Nchama Araceli , Mangue Catalina , Micha Anastasio , Nsee Natividad , Mesie Rosario , Benito Agustín , Roche Jesús
Published: May 2009

Objectives. The objectives of the study were (i) to evaluate the efficacy of combination drugs, such as artesunate + sulphadoxine-pyrimethamine (AS + SP) and amodiaquine + sulphadoxine-pyripethamine (AQ + SP) in treatment of uncomplicatedfalciparummalaria (ii) to differentiate recrudescence from reinfection by analysingmsp-1andmsp-2genes ofPlasmodium falciparumin treatment failure cases.Methods. We carried out an in vivo study in the year 2005 in 206 children between 6 to 59 months age groups. Of the 206, 120 received AQ + SP, and 86 received AS + SP. A clinical and parasitological followup during 14 days was undertaken. Finger-prick blood sample from each patient was taken on Whatman filter paper (no. 3) on days 0, 7, 14 and also the day when the parasite and symptoms reappeared for PCR analysis.Results. Late treatment failure was observed in 3.5% (4/114) with AQ + SP, and 2.5% (2/79) with AS + SP. The success rate was 96.5% with AQ + SP and 97.5% with AS + SP. No deaths and severe reactions were recorded. Out of the 6 treatment failure cases, one was reinfection as observed by PCR analysis ofmsp-1 andmsp-2 genes on day 14.Discussion. Both the combinations found to be efficacious and safe and could be used as a first-line treatment for uncomplicatedfalciparummalaria in Equatorial Guinea.
Bayesian Inference for Nonnegative Matrix Factorisation Models
Authors: Cemgil Ali Taylan
Published: May 2009

We describe nonnegative matrix factorisation (NMF) with a Kullback‐Leibler (KL) error measure in a statistical framework, with a hierarchical generative model consisting of an observation and a prior component. Omitting the prior leads to the standard KL‐NMF algorithms as special cases, where maximum likelihood parameter estimation is carried out via the Expectation‐Maximisation (EM) algorithm. Starting from this view, we develop full Bayesian inference via variational Bayes or Monte Carlo. Our construction retains conjugacy and enables us to develop more powerful models while retaining attractive features of standard NMF such as monotonic convergence and easy implementation. We illustrate our approach on model order selection and image reconstruction.
Circadian Rhythm in Rest and Activity: A Biological Correlate of Quality of Life and a Predictor of Survival in Patients with Metastatic Colorectal Cancer
Authors: Innominato Pasquale F. , Focan Christian , Gorlia Thierry , Moreau Thierry , Garufi Carlo , Waterhouse Jim , Giacchetti Sylvie , Coudert Bruno , Iacobelli Stefano , Genet Dominique , Tampellini Marco , Chollet Philippe , Lentz Marie-Ange , Mormont Marie-Christine , Lévi Francis , Bjarnason Georg A. ,   for the Chronotherapy Group of the European Organization for Research and Treament of Cancer
Published: May 2009

The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer. Moreover, the main CircAct parameters correlated with several health-related quality of life (HRQoL) scales. In this prospective study, we attempted to extend these results to an independent cohort of chemotherapy-naive metastatic colorectal cancer patients participating in an international randomized phase III trial (European Organisation for Research and Treatment of Cancer 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin, and oxaliplatin as first-line treatment for metastatic colorectal cancer. Patients from nine institutions completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and wore a wrist accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I<O and r24) were used to estimate CircAct. Of 130 patients with baseline CircAct assessments, 96 had baseline HRQoL data. I |0.25|; P < 0.01). I<O further independently predicted for overall survival with a hazard ratio of 0.94 (P < 0.0001). The associations between CircAct parameters, HRQoL, and survival, which were shown in this international study involving previously untreated metastatic colorectal cancer patients, confirm prior single-institution findings in mostly pretreated metastatic colorectal cancer patients. The circadian timing system constitutes a novel therapeutic target. Interventions that normalize circadian timing system dysfunction may affect quality of life and survival in cancer patients. [Cancer Res 2009;69(11):4700–7]
Abrogating Drug Resistance in Malignant Peripheral Nerve Sheath Tumors by Disrupting Hyaluronan-CD44 Interactions with Small Hyaluronan Oligosaccharides
Authors: Slomiany Mark G. , Dai Lu , Bomar Paul A. , Knackstedt Thomas J. , Kranc D. Alex , Tolliver Lauren , Maria Bernard L. , Toole Bryan P.
Published: May 2009

Malignant peripheral nerve sheath tumors (MPNST) develop in ∼10% of neurofibromatosis type-1 patients and are a major contributing factor to neurofibromatosis-1 patient mortality and morbidity. MPNSTs are multidrug resistant, and thus long-term patient survival rates are poor after standard doxorubicin or multiagent chemotherapies. We show that the hyaluronan receptor CD44 forms complexes with multidrug transporters, BCRP (ABCG2) and P-glycoprotein (ABCB1), in the plasma membrane of human MPNST cells. Small hyaluronan oligosaccharides antagonize hyaluronan-CD44–mediated processes and inhibit hyaluronan production. Treatment of MPNST cells with the hyaluronan oligomers causes disassembly of CD44-transporter complexes and induces internalization of CD44, BCRP, and P-glycoprotein. Consequently, the oligomers suppress drug transporter activity and increase sensitivity to doxorubicin treatment in culture. In vivo, systemic administration of hyaluronan oligomers inhibits growth of MPNST xenografts. Moreover, the oligomers and doxorubicin act synergistically in vivo, in that combined suboptimal doses induce tumor regression to a greater extent than the additive effects of each agent alone. These findings indicate that constitutive hyaluronan-CD44 interactions contribute to drug transporter localization and function at the plasma membrane, and that attenuating hyaluronan-CD44 interactions sensitizes MPNSTs to doxorubicin in vitro and in vivo. These results also show the potential efficacy of hyaluronan oligomers, which are nontoxic and nonimmunogenic, as an adjuvant for chemotherapy in MPNST patients. [Cancer Res 2009;69(12):4992–8]
Mechanism of Regulation and Suppression of Melanoma Invasiveness by Novel Retinoic Acid Receptor-γ Target Gene Carbohydrate Sulfotransferase 10
Authors: Zhao Xiansi , Graves Carole , Ames Sarah J. , Fisher David E. , Spanjaard Remco A.
Published: May 2009

Retinoic acid (RA) induces growth arrest and differentiation of S91 murine melanoma cells and serves as a valuable model for this disease. RA acts through activation of RA receptors (RAR), which are members of the nuclear receptor superfamily of ligand-inducible transcription factors. Interestingly, differentiation is mediated by RARγ, but not by RARα or RARβ, suggesting that RARγ possesses unique and uncharacterized molecular properties. To address this question, DNA microarrays in combination with RAR isoform-specific agonists were employed to identify novel RARγ target genes that may play a role in this process. Here, we identified and validated carbohydrate sulfotransferase 10 (CHST10) as a novel RARγ target gene in S91 cells. The RARγ-inducible CHST10 promoter was obtained, and two atypical, independently functioning RA response elements were identified in a 425 bp region. Surprisingly, this fragment is bound by RARγ, but not by RARα or RARβ, thus providing a mechanism for the observed RARγ-specific regulation. CHST10 is a sulfotransferase that forms HNK-1 glycan on neural cell adhesion proteins and glycolipids, and HNK-1 is thought to modulate cell adhesion and possibly metastasis. We show that CHST10 is also regulated by RARγ in a significant subset of human melanoma cells, and three-dimensional cell culture migration assays suggest that CHST10 functions as a suppressor of invasiveness, but not proliferation, in these cells. Induction of CHST10 by RARγ-activating retinoids may present a novel therapeutic strategy to inhibit invasiveness in a subset of melanoma patients. [Cancer Res 2009;69(12):5218–25]
Hypermethylated Genes as Biomarkers of Cancer in Women with Pathologic Nipple Discharge
Authors: Fackler Mary Jo , Rivers Aeisha , Teo Wei Wen , Mangat Amrit , Taylor Evangeline , Zhang Zhe , Goodman Steve , Argani Pedram , Nayar Ritu , Susnik Barbara , Sukumar Saraswati , Khan Seema A.
Published: May 2009

Purpose: In a pilot study of women with pathologic nipple discharge (PND) undergoing ductoscopy, we tested quantitative assessment of gene promoter hypermethylation using quantitative multiplex methylation–specific PCR (QM-MSP) to enhance detection of duct carcinoma in situ (DCIS).

Experimental Design: Women with PND underwent ductoscopy; ducts with significant lesions were surgically resected (36 ducts in 33 women) and those with minimal findings were not (28 ducts in 16 women). QM-MSP was done on ductoscopy cell samples. Results were compared with cytology and tissue histology.

Results: Cells from ducts with significant lesions on ductoscopy had significantly higher levels of methylation than those with minimal findings. Furthermore, cells from ducts with DCIS displayed higher levels of methylation than those with benign lesions such as papilloma (P = 0.006); or ducts with minimal findings on ductoscopy (P = 0.0001). Cumulative RASSF1A, TWIST1, and HIN1 gene methylation accurately distinguished ducts with cancerous versus benign lesions (100% sensitivity, 72% specificity, and area under the curve of 0.91 according to receiving operating characteristic analyses). QM-MSP analysis was more informative than cytology (100% versus 29% sensitivity, respectively), for detecting DCIS. In a validation set of paraffin-embedded DCIS and papilloma samples from women presenting with PND, QM-MSP was significantly higher in DNA from DCIS than papilloma sections (P = 0.002).

Conclusion: The positive predictive value of ductoscopy was more than doubled (19% versus 47%) with the addition of QM-MSP, demonstrating the benefit of targeting ducts having both high methylation and significant abnormalities on ductoscopy for surgical excision. Future large-scale studies to validate this approach are needed.
Decitabine Effect on Tumor Global DNA Methylation and Other Parameters in a Phase I Trial in Refractory Solid Tumors and Lymphomas
Authors: Stewart David J. , Issa Jean-Pierre , Kurzrock Razelle , Nunez Maria I. , Jelinek Jaroslav , Hong David , Oki Yasuhiro , Guo Zhong , Gupta Sanjay , Wistuba Ignacio I.
Published: May 2009

Purpose: By hypomethylating genes, decitabine may up-regulate factors required for chemotherapeutic cytotoxicity. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1.

Experimental Design: Thirty-one patients with refractory malignancies received decitabine 2.5 to 10 mg/m2 on days 1 to 5, and 8 to 12 or 15 to 20 mg/m2 on days 1 to 5. Tumor was assessed for DNA methylation (by LINE assays), apoptosis, necrosis, mitoses, Ki67, DNA methyltransferase (DNMT1), CTR1, and p16.

Results: Febrile neutropenia was dose limiting. One thymoma patient responded. Decitabine decreased tumor DNA methylation (from median 51.2% predecitabine to 43.7% postdecitabine; P = 0.01, with effects at all doses) and in peripheral blood mononuclear cells (from 65.3-56.0%). There was no correlation between tumor and peripheral blood mononuclear cells. Patients starting decitabine ≤3 versus >3 months after last prior cytotoxic or targeted therapy had lower predecitabine tumor CTR1 scores (P = 0.02), higher p16 (P = 0.04), and trends (P = 0.07) toward higher tumor methylation and apoptosis. Decitabine decreased tumor DNMT1 for scores initially >0 (P = 0.04). Decitabine increased tumor apoptosis (P < 0.05), mitoses (if initially low, P = 0.02), and CTR1 (if initially low, P = 0.025, or if ≤3 months from last prior therapy, P = 0.04). Tumor CTR1 scores correlated inversely with methylation (r = −0.41, P = 0.005), but CTR1 promoter was not hypermethylated. Only three patients had tumor p16 promoter hypermethylation. P16 scores did not increase. Higher blood pressure correlated with lower tumor necrosis (P = 0.03) and a trend toward greater DNA demethylation (P = 0.10).

Conclusions: Exposure to various cytotoxic and targeted agents might generate broad pleiotropic resistance by reducing CTR1 and other transporters. Decitabine decreases DNA methylation and augments CTR1 expression through methylation-independent mechanisms.
Local Recurrence after Breast-Conserving Therapy in Relation to Gene Expression Patterns in a Large Series of Patients
Authors: Kreike Bas , Halfwerk Hans , Armstrong Nicola , Bult Peter , Foekens John A. , Veltkamp Sanne C. , Nuyten Dimitry S.A. , Bartelink Harry , van de Vijver Marc J.
Published: May 2009

Purpose: The majority of patients with early-stage breast cancer are treated with breast-conserving therapy (BCT). Several clinical risk factors are associated with local recurrence (LR) after BCT but are unable to explain all instances of LR after BCT. Here, gene expression microarrays are used to identify novel risk factors for LR after BCT.

Experimental Design: Gene expression profiles of 56 primary invasive breast carcinomas from patients who developed a LR after BCT were compared with profiles of 109 tumors from patients who did not develop a LR after BCT. Both unsupervised and supervised methods of classification were used to separate patients into groups corresponding to disease outcome. In addition, for 15 patients, the gene expression profile in the recurrence was compared with that of the primary tumor.

Results: The two main clusters found by hierarchical cluster analysis of all 165 primary invasive breast carcinomas revealed no association with LR. Predefined gene sets (molecular subtypes and “chromosomal instability” signature) are associated with LR (P = 0.0002 and 0.003, respectively). Significant analysis of microarrays revealed an association between LR and cell proliferation, not captured by histologic grading. Class prediction analysis constructed a gene classifier, which was successfully validated, cross-platform, on an independent data set of 161 patients (log-rank P = 0.041). In multivariate analysis, young age was the only independent predictor of LR.

Conclusions: We have constructed and cross-platform validated a gene expression profile predictive for LR after BCT, which is characterized by genes involved in cell proliferation but not a surrogate for high histologic grade.
Serum Peptidome Profiling Revealed Platelet Factor 4 as a Potential Discriminating Peptide Associated with Pancreatic Cancer
Authors: Fiedler Georg Martin , Leichtle Alexander Benedikt , Kase Julia , Baumann Sven , Ceglarek Uta , Felix Klaus , Conrad Tim , Witzigmann Helmut , Weimann Arved , Schütte Christof , Hauss Johann , Büchler Markus , Thiery Joachim
Published: May 2009

Purpose: Mass spectrometry–based serum peptidome profiling is a promising tool to identify novel disease-associated biomarkers, but is limited by preanalytic factors and the intricacies of complex data processing. Therefore, we investigated whether standardized sample protocols and new bioinformatic tools combined with external data validation improve the validity of peptidome profiling for the discovery of pancreatic cancer–associated serum markers.

Experimental Design: For the discovery study, two sets of sera from patients with pancreatic cancer (n = 40) and healthy controls (n = 40) were obtained from two different clinical centers. For external data validation, we collected an independent set of samples from patients (n = 20) and healthy controls (n = 20). Magnetic beads with different surface functionalities were used for peptidome fractionation followed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). Data evaluation was carried out by comparing two different bioinformatic strategies. Following proteome database search, the matching candidate peptide was verified by MALDI-TOF MS after specific antibody-based immunoaffinity chromatography and independently confirmed by an ELISA assay.

Results: Two significant peaks (m/z 3884; 5959) achieved a sensitivity of 86.3% and a specificity of 97.6% for the discrimination of patients and healthy controls in the external validation set. Adding peak m/z 3884 to conventional clinical tumor markers (CA 19-9 and CEA) improved sensitivity and specificity, as shown by receiver operator characteristics curve analysis (AUROCcombined = 1.00). Mass spectrometry–based m/z 3884 peak identification and following immunologic quantitation revealed platelet factor 4 as the corresponding peptide.

Conclusions: MALDI-TOF MS-based serum peptidome profiling allowed the discovery and validation of platelet factor 4 as a new discriminating marker in pancreatic cancer.
Estrogen Receptor Subtype– and Promoter-Specific Modulation of Aryl Hydrocarbon Receptor–Dependent Transcription
Authors: Wihlén Björn , Ahmed Shaimaa , Inzunza José , Matthews Jason
Published: May 2009

In this study, we examined the role of estrogen receptors (ER) in aryl hydrocarbon receptor (AHR)–dependent transactivation. Chromatin immunoprecipitation assays showed that AHR agonists differentially induced recruitment of ERα to the AHR target genes CYP1A1 and CYP1B1. Cotreatment with 17β-estradiol significantly increased β-naphthoflavone (BNF)– and 2,3,7,8-tetrachlorodibenzo-p-dioxin–induced recruitment of ERα to CYP1A1, whereas 3,3′-diindolylmethane induced promoter occupancy of ERα at CYP1A1 that was unaffected by cotreatment with 17β-estradiol. Cyclical recruitment of AHR and ERα to CYP1A1 was only observed in cells treated with BNF. Stable and subtype-specific knockdown of ERα or ERβ using shRNA showed that suppression of ERα significantly reduced, whereas knockdown of ERβ significantly enhanced, AHR agonist–induced Cyp1a1 expression in HC11 mouse mammary epithelial cells. AHR agonist–induced Cyp1b1 expression was reduced by ERβ knockdown but unaffected by ERα knockdown. The siRNA-mediated knockdown of ERα in MCF-7 human breast cancer cells did not affect 2,3,7,8-tetrachlorodibenzo-p-dioxin–dependent regulation of CYP1A1 and CYP1B1 mRNA expression. In agreement with our in vitro findings in the HC11 cells, ERα knockout mice exhibit reduced BNF-dependent induction of Cyp1a1 mRNA. These results establish ligand- and promoter-specific influences on the cyclical recruitment patterns for AHR and show ER species-, subtype-, and promoter-specific modulation of AHR-dependent transcription. (Mol Cancer Res 2009;7(6):977–86)
Development of Dietary Phytochemical Chemopreventive Agents: Biomarkers and Choice of Dose for Early Clinical Trials
Authors: Scott Edwina N. , Gescher Andreas J. , Steward William P. , Brown Karen
Published: May 2009

In view of safety concerns surrounding the use of pharmaceuticals such as nonsteroidal anti-inflammatory drugs and tamoxifen as cancer chemopreventive agents, potentially innocuous phytochemicals derived from the diet are considered attractive alternatives. However, results from cancer chemoprevention trials of dietary agents have been disappointing to date, as promising activities observed in rodent models and cells in vitro have not translated into clinical success. This may be partly due to the development process for these agents, which is complex for a number of reasons; the definitive end point, inhibition of carcinogenesis, requires large numbers of individuals followed-up over many years. Furthermore, whereas biomarkers are frequently used as surrogate efficacy end points to expedite the process, biomarker assessment and validation has proven difficult because dietary agents exert multiple actions with an unknown hierarchy of biological importance. These factors have made determining the dose for clinical investigation extremely challenging, and at present, there are no defined strategies for rationally identifying the most appropriate doses. In this commentary, the complexities involved in the development of dietary chemoprevention agents are discussed, and a tentative route towards selection of the optimal clinical dose is proposed. The approach highlights the need to conduct long-term preclinical studies with realistic concentrations that are achievable in human tissues and the importance of efficacy biomarkers that are intrinsically linked to the key mechanisms of action. A more logical design of studies should increase the likelihood that the encouraging preclinical results observed for many phytochemicals translate into tangible clinical benefit.
Full-Field Electroretinography Obtained Using a Contact Lens Electrode with Built-In High-Intensity White-Light-Emitting Diodes Can Be Utilized in Toxicological Assessments in Rats
Authors: Yamashita Haruhiro , Yamasaki Kiyo , Sugihara Kazunari , Miyata Hiroto , Tsutsumi Shunsuke , Iwaki Yoshinobu
Published: May 2009

Full-field electroretinography (ERG) using contact lenses with built-in LED was performed on albino rats, and used to evaluate the visual toxicity of sodium iodate (NaIO3). Experiment 1 was carried out to determine the optimal conditions in rats relating to stimulus intensity, background illumination, and light adaptation period. As a result, we found that a full-field ERG was recorded under the following conditions: stimulus intensity: –3.5 log cd s/m2 in rod response; background intensity and light adaptation period: 10 cd/m2 and 10 min in cone and flicker responses. Experiment 2 was carried out to confirm the usefulness of full-field ERG using rats with retinal toxicities induced by NaIO3. Male rats were given NaIO3 intravenously at a dose of 50 mg/kg. ERG was recorded before administration and after 3, 8, 24 h, and 7 days of administration, and histopathological analysis was conducted after 8 h of administration. The rod response disappeared completely at 3 h, based on a reduced maximal response and oscillatory potentials. On the other hand, cone and flicker responses were still present at 8 h. All responses disappeared on the 7th day. These findings indicate that the retinal toxicity induced by NaIO3 was expressed first in rods, followed by cones. There were no microscopical changes after 8 h of administration, although the rod responses had completely disappeared by this time. These results suggest that full-field ERG in rats using an LED contact lens is useful for the separate evaluation of toxic effects on rods and cones.
Elevated Plasma Levels of C3a Complement Compound in the Exudative Form of Age-Related Macular Degeneration
Authors: Machalińska Anna , Dziedziejko Violetta , Mozolewska-Piotrowska Katarzyna , Karczewicz Danuta , Wiszniewska Barbara , Machaliński Bogusław
Published: May 2009

Aim: Recent findings suggest that chronic inflammatory processes play a role in the progression of age-related macular degeneration (AMD). Here we asked whether the development of different forms of AMD is connected with the elevation of plasma C3a-desArg concentration. Methods: We recruited 30 subjects with a clinical diagnosis of exudative AMD with newly diagnosed choroidal neovascularization (CNV), 30 subjects with dry AMD and 30 age- and sex-matched volunteers without AMD. The concentration of C3a-desArg complement compound was measured in the subjects’ peripheral blood. We evaluated the association between the level of C3a-desArg and age, sex, smoking, atherosclerosis, and hypertension. Results: We found that the levels of C3a-desArg were significantly elevated in patients with exudative AMD compared to the control group. The concentrations of C3a-desArg in patients with dry AMD were similar to those of controls. Additionally, patients and controls with documented atherosclerosis (AS) displayed significantly higher levels of C3a-desArg compared to subjects without AS. Conclusions: Our results suggest an association between systemic complement activation and the development of CNV. Moreover, we found an association of complement activation with atherosclerosis and confirmed the hypothesis that AMD can be a local manifestation of systemic disease.
Influence of Early Nutritional Components on the Development of Murine Autoimmune Diabetes
Authors: Mueller Daniela B. , Koczwara Kerstin , Mueller Andreas S. , Pallauf Josef , Ziegler Anette-G. , Bonifacio Ezio
Published: May 2009

Background/Aims: Infant diet is suggested to modify autoimmune diabetes risk. The aim of this study was to determine whether infant food components affect diabetes development in the nonobese autoimmune diabetes (NOD) mouse. Methods: A basal low-diabetogenic diet was identified by feeding litter-matched female NOD mice standardized diets with and without casein and wheat proteins after weaning. In subsequent trials, basal diet with supplements of wheat (5, 10 and 30%), gluten, wheat globulin/albumin, corn (5%), potato (5%), apple (5%) or carrot (5%) was fed to litter-matched female NOD mice after weaning. Mice were followed for diabetes development and insulin autoantibodies. Results: A casein- and wheat-free diet was associated with the lowest rate of diabetes development (37% by age 25 weeks). Increased diabetes rates were observed when the basal diet was supplemented with 5% wheat (71% by age 25 weeks; p = 0.023) and 5% corn (57% by age 25 weeks; p = 0.05). Increasing wheat concentrations returned diabetes development to that in basal diet-fed mice. Other food supplements had no or minimal effects on diabetes development. Conclusions: Early supplementation of a basal low-diabetogenic diet with low concentrations of the cereals wheat or corn is associated with a moderate increase in the rate of diabetes. Removal of cereals, however, does not abrogate diabetes development in NOD mice.
Intravitreal and Orbital Floor Triamcinolone Acetonide Injections in Noninfectious Uveitis: A Comparative Study
Authors: Roesel Martin , Gutfleisch Matthias , Heinz Carsten , Heimes Britta , Zurek-Imhoff Beatrix , Heiligenhaus Arnd
Published: May 2009

Purpose: To compare the effect of orbital floor (OFTA) or intravitreal (IVTA) administration of triamcinolone acetonide on visual acuity and chronic cystoid macular edema (CME) in patients with uveitis. Methods: Retrospective study of patients suffering from chronic noninfectious uveitis in whom CME (n = 97) did not respond to systemic corticosteroids and/or immunosuppression combined with acetazolamide. Patients received a single injection of either IVTA (n = 48, group 1) or OFTA (n = 49, group 2). Best-corrected visual acuity, macular edema (fluorescein angiography), uveitis activity, ocular hypertension, and cataract formation were analyzed over the course of 1 year. Results: Improvement in visual acuity (≥2 lines, LogMAR) was noted in 50% (IVTA) and 34% (OFTA) after 3 months (p = 0.23), and in 18% (IVTA) and 20% (OFTA) after 12 months. CME improved in 100% (IVTA) and 76% (OFTA) of the eyes within the first month postoperatively (p = 0.36). Macular edema was reduced in 100% (group 1) and 20% (group 2) after 3 months (p < 0.01). At 1 year, cataract progression was noted in 68% (IVTA) and 27% (OFTA) (p < 0.01). Increased intraocular pressure (>21 mm Hg) was detected in 21% (IVTA) and 0% (OFTA) at 4 weeks (p < 0.01) after injection. Conclusion: Uveitic CME and visual acuity not responding to systemic immunosuppression and acetazolamide may improve after an IVTA and OFTA injection. The effect is mostly transient. While the IVTA injections were more effective for improving CME, ocular hypertension and cataracts developed more often.
Ventilator Gas Flow Rates Affect Inspiratory Time and Ventilator Efficiency Index in Term Lambs
Authors: Bach Katinka P. , Kuschel Carl A. , Oliver Mark H. , Bloomfield Frank H.
Published: May 2009

Background: Despite increasing survival in the smallest preterm infants, the incidence of chronic lung disease has not decreased. Research into ventilatory strategies has concentrated on minimising barotrauma, volutrauma and atelectotrauma, but little attention has been paid to the role of bias gas flow rates and the potential for rheotrauma or shear stress injury. Ventilated preterm infants frequently receive relatively high gas flow rates. Objectives: We hypothesised that altering bias gas flow rates would change the efficiency of ventilation and thereby affect ventilatory parameters. Methods: We tested this hypothesis using an artificial lung followed by ventilation of 8 term lambs. Results: Between flows of 2 and 15 l/min, inflation time (Ti) in the artificial lung was inversely related to the bias gas flow rate. In the ventilated lambs, Ti was inversely related to flow rates up to 10 l/min, with no statistically significant effect at flow rates >10 l/min. There were no adverse effects on gas exchange or cardiovascular parameters until a flow rate of 3 l/min was used, when inadequate gas exchange occurred. Conclusions: Ti is inversely associated with the bias gas flow rate. Flow rates much lower than those used in many neonatal units seem to provide adequate ventilation. We suggest that the role of ventilator gas flow rates, which may potentially influence shear stress in ventilator-induced lung injury, merits further investigation.
Aminosäurenaufnahme und -abgabe kolorektaler Karzinome des Menschen
Authors: Striebel J.-P. , Saeger H.-D. , Ritz R. , Leweling H. , Holm E.
Published: May 2009

Über den Aminosäurenaustausch menschlicher Tumoren informieren nur wenige Arbeiten. Um diesen Austausch in vivo zu kennzeichnen, wurden 21 Patienten mit resezierbaren kolorektalen Karzinomen wäh-rend kurativer Operationen untersucht. Bezüglich der Aminosäurenaufnahme und -abgabe seitens der peripheren Gewebe dienten 20 Patienten ohne Tumoren als Kontrollen. Die Probanden beider Kollektive befanden sich – nach anthropometrischen und biochemischen Variablen beurteilt – in einem normalen bzw. guten Ernährungszustand. Bei den Karzinomkranken kanülierten wir jeweils eine periphere Arterie und Vene sowie eine zentrale tumordrainierende Vene und die Pfortader. Die Konzentrationen und Konzentrationsdifferenzen der Plasmaaminosäuren wurden in μmol/l und als Prozentwerte der Aminosäuren-Gesamtmengen bestimmt. Die periphere Glutamataufnahme pro Liter Plasma war bei den Karzinompatienten reduziert (p = 0,02). In diesem Kollektiv enthielt die tumordrainierende Vene weniger Glutamin (p = 0,002) und mehr Glutamat (p = 0,002) als die periphere Vene. Von den Tumoren wurde Glutamin häufiger aufgenommen als abgegeben, während die transtumorale Glutamat-Bilanz in 18 Fallen negativ war. Die qualitativen Unterschiede zwischen den peripheren Geweben und den Tumoren hinsichtlich des Glutamin- und Glutamat-Austausches erreichten ein hohes Signifikanzniveau (p = 0,002 für beide Aminosäuren). Im übrigen setzten die Tumoren mehr Glyzin, Ornithin und Tyrosin frei als die Peripherie. Der Glutamin- und Glutamatstoffwechsel der Tumoren unterschied sich signifikant von dem der portal drainierten Organe (p≤0,05). Die Diskussion der Resultate hebt die Einflüsse der Peripherie und des Tumors auf das Plasmaaminogramm besonders hervor. Des weiteren wird ausgeführt, daβ Glutamin potentiell eine sehr bedeutende Energiequelle für neoplastische Gewebe darstellt.
Adjuvante künstliche Ernährung in der Tumorchirurgie
Authors: Müller J.M. , Keller H.W. , Brenner U. , Walter M. , Holzmüller W.
Published: May 2009

Die Mangelernährung ist eine quantitiv erfaβbare Gröβe, die das Ergebnis einer Karzinomoperation negativ beeinflussen kann. Durch eine geeignete präoperative Ernährungstherapie kann der Ausgangszustand von Karzinompatienten verbessert werden. Dies führt insbesondere bei ausgedehnten Eingriffen am oberen Gastrointestinaltrakt zu einer signifikanten Senkung der postoperativen Morbidität und Mortalität. Der Wert der postoperativen Ernährungstherapie kann im Tierexperiment durch forcierte Ernährung stimuliert werden, im klinischchirurgischen Bereich dürfte dem jedoch keine wesentliche Bedeutung zukommen.
A Randomized Trial on the Effect of Isotonic Amino Acid Infusion on Postoperative Complications and Short Life Plasma Protein Concentrations
Authors: Sitges-Serra A. , Figueras-Felip J. , Alastrue-Vidal A. , Jaurrieta-Mas E. , Rafecas-Renau A.
Published: May 2009

In a randomized clinical study 30 patients with high risk surgical procedures were distributed to receive either standard fluid-therapy (n= 14) or an isotonic amino acid solution (n = 16) during five days. The patients were evaluated pre- and postoperatively using: anthropometric parameters: body weight, biceps and triceps skin-fold thickness, and mid arm circumference; biochemical parameters: albumin, prealbumin, transferrin, retinol-binding protein, total iron-binding capacity, and cholesterol; and delayed cutaneous hypersensitivity. Clinical outcome and complications were also recorded. Positive ketonuria was obtained soon in the treatment group after 24 h. Mean daily nitrogen balance was better in the protein sparing group (–3.8 g vs –9.3 g) p < 0.02. No differences were observed between both groups in the postoperative plasma protein levels. There were no significant differences in delayed cutaneous reactivity nor anthropometric parameters between both groups; and mortality and morbidity were similar. The present study lends little support for substituting the routine D5W and saline postoperative fluid regime. No clinical advantage of amino acids over standard fluids could be appreciated indicating that the much less expensive conventional solutions should not be replaced by amino acids, at least in routine postoperative cases.
Aminosäurenzufuhr beim akuten, noch kompensierten Nierenversagen in der posttraumatischen Phase
Authors: Bock E.
Published: May 2009

Zur Auswertung kamen 3 Patientengruppen, die im kompensierten akuten Nierenversagen nach vorangegangener Operation isokalorisch (1700 kcal) und annähernd isonitrogen (33–36 g Aminosäuren), jedoch mit verschiedenen Aminosäurengemischen, ernährt wurden. Neben der einheitlichen täglichen Energiezufuhr von 750 ml Invert-zucker 40% und 250 ml Lipofundin®S 20% betrug die tägliche Aminosäureninfusion in Gruppe I (n = 13) ausschlieβlich 500 ml EAS pfrimmer (34,5 g), in Gruppe II (n = 10) 250 ml EAS pfrimmer und 250 ml Intrafusin® 7,5 % E (36 g) und in Gruppe III (n = 16) 250 ml EAS pfrimmer und 350 ml Aminofusin® Hepar (33,1 g). Bei der Auswertung der Aminogramme konnten bereits zu Beginn der Studie in alien 3 Patientengruppen unter den unteren Referenzbereich erniedrigte Ausgangswerte von Glyzin, Serin, Arginin und Histidin im Serum gemessen werden. Im Verlauf der 4tägigen Infusionstherapie zeigten sich bezüglich einer Verbesserung der Serumwerte die Patienten der Gruppe II und III denen der Gruppe I überlegen. Dagegen waren die Serumspiegel von Phenylalanin, Methionin und 3-Methyl-Histidin bereits zu Beginn auf das 2–3fache des Referenzbereiches erhöht. Bezüglich einer Senkung der hohen Einzelwerte im Serum war die Patientengruppe II der Gruppe I und III überlegen. Im klinischen Verlauf waren keine signifikanten Unterschiede zu erkennen.
Elimination of Amino Acids in Chronic Renal Failure
Authors: Druml W. , Weinberger G. , Bürger U. , Balcke P. , Laggner A. , Lenz K. , Schmidt P. , Zazgornik J.
Published: May 2009

Elimination of parenterally administered amino acids was investigated in patients with chronic renal failure (CRF) (10 on conservative treatment = CT, 13 on regular hemodialysis therapy = HD). In a bolus injection protocol 0.1 g amino acids as a 10% solution containing essential and nonessential amino acids were infused and pharmacokinetic parameters of 17 amino acids were calculated. The mean elimination half life was increased by 40 % in CT and 87 % in HD (p < 0.001 CT and HD versus controls). Total clearance was reduced in CT (p < 0.001 versus HD and controls). In CT clearance of phenylalanine, proline, alanine, histidine and arginine was reduced, of none of the amino acids elevated. In HD clearance of methionine, lysine, aspartic acid and serine was increased, of proline decreased. The total transfer rate was reduced in CT (p < 0.025 versus controls) and transfer of threonine, aspartic acid, glutamic acid, alanine, histidine and arginine was reduced in these patients. Mainly due to elevated basal plasma concentration transfer of methionine was elevated in CT and HD. In dialysis patients transfer of isoleucine, tryptophan, glycine and serine was increased. Despite variations of absolute values of clearance between the two groups investigated relative clearance rates of amino acids were similar because of a uniform increase of clearance of about 37 % in HD compared to CT (p < 0.001). Results indicate that the elimination of parenterally administered amino acids is grossly altered in uremia and that in patients on CT and HD a uniform elimination pattern can be observed.
Die biologische Verfügbarkeit von Glutamin aus N-Acetyl-L-Glutamin bei intravenöser Verabreichung
Authors: Neuhäuser M. , Bässler K.H.
Published: May 2009

Glutamin ist möglicherweise aufgrund seiner universellen Rolle bei Transaminierungsreaktionen insbesondere für den katabolen Stoffwechsel von Bedeutung. Aus Stabilitätsgründen ist diese Aminosäure bisher nicht in Lösungen für die parenterale Ernährung enthalten. Die biologische Verfügbarkeit von Glutamin aus der stabilen Substanz N-Acetyl-L-Glutamin wird bei langfristiger parenteraler Verabreichung anhand von Wachstum, N-Bilanz und Aminosäurenkonzentrationen in Plasma, Urin und Muskel untersucht. Hierzu werden 2 Gruppen von jungen gesunden männlichen Ratten (n = 6) 12 Tage ausschlieβlich parenteral ernährt. Beide Gruppen erhalten 0,8 g N/kg/d in Form einer Aminosäurenlösung, in der kein Glutamin enthalten ist. Nur einer der beiden Gruppen wird zusätzlich 0,4 g N als N-Acetyl-L-Glutamin infundiert. In dieser Gruppe beträgt die Gewichtszunahme 33 ± 1,5 g und die kumulative N-Bilanz 1,5 ± 0,045 g. Demgegenüber liegt die Gewichtszunahme bei der Gruppe ohne N-Acetyl-L-Glut-amin bei 27 ± 1,8 g (p < 0,05) und die kumulative N-Bilanz bei 1,16 ± 0,034 g (p < 0,001). Signifikant höhere Konzentrationen zeigen sich insbesondere für die essentiellen Aminosäuren im Plasma und im Urin bei den Tieren, die kein N-Acetyl-L-Glutamin erhalten. Die Ergebnisse lassen auf eine gute biologische Verfügbarkeit von Glutamin aus N-Acetyl-L-Glutamin bei intravenöser Verabreichung in der Ratte schlieβen.
Intrazelluläre Aminosäurenkonzentrationen bei verschiedenen Krankheitszuständen
Authors: Roth E. , Karner J.
Published: May 2009

Die Bestimmung der freien intrazellulären Aminosäuren (AS) im menschlichen Gewebe ist methodisch weitaus aufwendiger als die der Plasmaaminosäuren. Die Konzentrationen der freien AS sind im Plasma und im Gewebe (Muskel, Leber) unterschiedlich. Pathologische Zustände (Sepsis, Leberversagen, Glukagonom) führen zu spezifischen Veränderungen der Aminosäurenkonzentrationen in alien Kompartments. Die Zusammenhänge zwischen veränderten AS-Konzentrationen im Zytosol und der Proteinsynthese bzw. Hydrolyserate sind noch nicht geklärt, möglicherweise führt aber der Mangel an einzelnen freien Aminosäuren (z.B. Glutamin) zu einer «Down»-Regulation der Proteinbiosynthese.
Blutflußmessung und Kanülierungstechnik im akuten und chronischen Hundemodell
Authors: Karner J. , Roth E.
Published: May 2009

Die Bestimmung von Stoffwechselvorgängen unter In-vivo-Bedingungen erfordert öfters eine Kanülierung verschiedener Organe. Aufgrund der phylogenetischen Verwandtschaft bietet sich neben dem Schwein vor allem der Hund für Stoffwechseluntersuchungen an. Mit Hilfe von verschiedenen Farbstoffverdünnungsmethoden Indocyaningrün (ICG), Paraaminohippursäure (PAH), Bromsulphthalein (BSP) ist es möglich, über arteriovenöse Konzentrationsmessung den organspezifischen Fluß zu bestimmen. In der vorliegenden Arbeit wird eine gängige Methode zur Katheterisierung von Leber und hinteren Extremitäten beschrieben.
Untersuchungen zur Homöostase der Plasmaaminosäuren unter standardisierter parenteraler Ernährungstherapie bei akut nekrotisierender Pankreatitis
Authors: Wiedeck H.
Published: May 2009

Die vorliegende Studie untersucht die Fragestellung zur Aminosäurenhomöostase sowie der Ökonomie der Stickstoffversorgung bei Patienten mit akut nekrotisierender Pankreatitis. 10 Patienten wurden parenteral ernährt mit lg Aminosäuren/kg KG/ Tag und 6,5 g Kohlenhydrate/kg KG/Tag. Zur Charakterisierung der Patienten wurden die Kenngrößen der Homoostase gemessen, als fragestellungsspezifische Parameter die Plasmaaminosauren und die Stickstoffbilanzen ermittelt. Die Ergebnisse zeigen, daß die Kenngrößen zur Charakterisierung der Homoostase der Patienten im Bereich der physiologischen Referenz-werte liegen, und daß bei der Darstellung des relativen Aminosäuren-patterns Abweichungen vom physiologischen Referenzbereich nur bei den postoperativ üblichen Amínosäuren, wie z.B. Phenylalanin, zu beobachten waren. Daraus folgt, daß eine kontrollierte und bilanzierte parenterale Ernährungstherapie bei Patienten mit akut nekrotisierender Pankreatitis indiziert ist, wenn die für eine Ernährungstherapie üblichen Voraussetzungen erfüllt sind. Sonderdruckbestellungen an: OÄ Dr. H. Wiedeck, Zentrum für Anästhesiologie, Klinikum der Universität Ulm, Steinhövelstraße 9, D-7900 Ulm/Donau