bluuebunny/crossref_metadata_2025 huggingface dataset:
COSMOLOGICAL DEFECT AND HIGH ENERGY EXPERIMENTS
Authors: NAGASAWA MICHIYASU
Published: January 2008

The production and evolution of cosmological defects are investigated based on the standard particle physics theory such as the electroweak unified model and quantum chromodynamics. In these models, the string type solution can be obtained. Although electroweak strings and pion strings are embedded ones and topologically unstable, they would be stabilized by high temperature plasma and bring various cosmological consequences. Moreover, the production of pion strings may be observed in the LHC experiment.
R-Parity Violation and Family Symmetry
Authors: KAJIYAMA YUJI
Published: January 2008

In this talk, we investigate the implications of R-parity violating (RPV) operators in a model with family symmetry 1. Family symmetry can determine the form of RPV operators as well as the Yukawa matrices. We consider a concrete model with non-abelian discrete symmetry Q6, which has only three RPV trilinear operators with no baryon number violating terms. We find that ratios of decay rates of the lepton flavor violating processes are fixed thanks to the family symmetry, predicting [Formula: see text].
SUSY HIGGS SEARCHES AT THE LHC
Authors: KINNUNEN RITVA
Published: January 2008

Searches for the Higgs bosons of the Minimal Supersymmetric Standard Model are discussed at the LHC in the CMS and ATLAS experiments. Results are presented for the scenario which maximizes the mass of the lighter scalar Higgs boson. Low integrated luminosity is assumed.
CP VIOLATION AND A SEARCH FOR NEW PHYSICS IN LHCb
Authors:   On behalf of the LHCb collaboration., CAMILLERI LESLIE
Published: January 2008

The physics program of LHCb concerns the study of CP violation in the B system, including more precise determination of the CKM matrix parameters and in particular the determination of φs The search for new physics which could manifest itself indirectly will be a high priority. The main advantages of LHCb over the B factories are the access to the Bs system and very large B production rates. In addition, LHCb is a dedicated B physics experiment with excellent vertexing and particle identification capabilities. It is currently setting up its detector in its allocated LHC interaction region and is foreseen to be ready for data taking in November 2007 for the pilot run.
CAN THE BIG 3 OVERTAKE TOYOTA? — A STUDY BASED ON THE THEORY OF CONSTRAINTS
Authors: WU SIMON , WANG SAMUEL , BLOS MAURICIO F. , WEE H. M.
Published: January 2008

Purpose — The aim of this paper is to provide answers to two significant questions. The first question is "what is the comprehensive action for the Big 3 to overtake Toyota Company?" The second question is "Can TOC (Theory of Constraints) really deal with this kind of complicated problem effectively?"

Design/methodology/approach — In order to address this question and come out with a reasonable answer, this study uses the Theory of Constraints to discover the root causes and countermeasures for the Big 3 to break through their paradigms.

Findings — It is worthwhile to highlight that we have demonstrated that a sophisticated case in global competition of the motor market can provide solutions with only four TOC logic trees. Furthermore, it is interesting to note that the four TOC logic trees fit perfectly well with each of the four problem solving steps in two aspects: (1) It provides a shortcut through mirror imaging process and (2) It enhances the clarity of the thinking process.

Research limitations/implications — However, there remains some issues open for further exploration: (1) How can we make sure that the appropriate core problem(s) or root cause(s) has been identified in CRT (Current Reality Tree) and it is indeed the most meaningful one? (2) How can we proceed from CRT to FRT (Future Reality Tree) & further from FRT to PT (Prerequisites Tree) more effectively? (3) How can we discover key obstacles from PT and how to develop action plans from TT (Transition Tree) smoothly? (4) How to refine and integrate these feasible solution sets coming out from TT into the optimal solution scheme to be adapted in the real world?

Originality/value — This study demonstrates how TOC problem solving can help to solve the core problems and root causes of "can the Big 3 overtake Toyota?" It not only gives managerial insights for the Big 3 to break through their paradigms to fight back Toyota; but also identify how a complex problem beyond production field can be analyzed and dealt with effectively.

Paper type–Case study paper.
Identification of functional intramuscular rectal mechanoreceptors in aganglionic rectal smooth muscle from piebald lethal mice
Authors: Spencer Nick J. , Kerrin Aoife , Zagorodnyuk Vladimir P. , Hennig Grant W. , Muto Melodie , Brookes Simon J. , McDonnell Orla
Published: January 2008

The mechanosensitive endings of low-threshold, slowly adapting pelvic afferents that innervate the rectum have been previously identified as rectal intraganglionic laminar endings (rIGLEs) that lie within myenteric ganglia. We tested whether the aganglionic rectum of piebald-lethal (sl/sl) mice lacks rIGLEs and whether this could explain impaired distension-evoked reflexes from this region. Extracellular recordings were made from fine rectal nerves in C57BL/6 wild-type and sl/slmice, combined with anterograde labeling. In C57BL/6 mice, graded circumferential stretch applied to the rectum activated graded increases in firing of slowly adapting rectal mechanoreceptors. In sl/slmice, graded stretch of the aganglionic rectum activated similar graded increases in rectal afferent firing. Stretch-sensitive afferents responded at low mechanical thresholds and fired more intensely at noxious levels of stretch. They could also be activated by probing their receptive fields with von Frey hairs and by muscle contraction. Anterograde labeling from recorded rectal nerves identified the mechanoreceptors of muscular afferents in the aganglionic rectal smooth muscle. A population of afferents were also recorded in both C57BL/6 and sl/slmice that were activated by von Frey hair probing, but not stretch. In summary, the aganglionic rectum is innervated by a population of stretch-sensitive rectal afferent mechanoreceptor which develops and functions in the absence of any enteric ganglia. These results suggest that in patients with Hirschsprung's disease the inability to activate extrinsic distension reflexes from the aganglionic rectum is unlikely to be due to the absence of stretch-sensitive extrinsic mechanoreceptors.
Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes
Authors: Tzeng Huei-Ping , Fan Jinping , Vallejo Jesus G. , Dong Jian Wen , Chen Xiongwen , Houser Steven R. , Mann Douglas L.
Published: January 2008

High-mobility group box 1 (HMGB1) released from necrotic cells or macrophages functions as a late inflammatory mediator and has been shown to induce cardiovascular collapse during sepsis. Thus far, however, the effect(s) of HMGB1 in the heart are not known. We determined the effects of HMGB1 on isolated feline cardiac myocytes by measuring sarcomere shortening in contracting cardiac myocytes, intracellular Ca2+ transients by using fluo-3, and L-type calcium currents by using whole cell perforate configuration of the patch-clamp technique. Treatment of isolated myocytes with HMGB1 (100 ng/ml) resulted in a 70% decrease in sarcomere shortening and a 50% decrease in the height of the peak Ca2+ transient within 5 min ( P < 0.01). The immediate negative inotropic effects of HMGB1 on cell contractility and calcium homeostasis were partially reversible upon washout of HMGB1. A significant inhibition of the inward l-type calcium currents was also documented by the patch-clamp technique. HMGB1 induced the PKC-ε translocation, and a PKC inhibitor significantly attenuated the negative inotropic effects of HMGB1. These studies show for the first time that HMGB1 impairs sarcomere shortening by decreasing calcium availability in cardiac myocytes through modulating membrane calcium influx and suggest that HMGB1 maybe acts as a novel myocardial depressant factor during cardiac injury.
Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts
Authors: Gélinas Roselle , Labarthe François , Bouchard Bertrand , Mc Duff Janie , Charron Guy , Young Martin E. , Des Rosiers Christine
Published: January 2008

Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA β-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in the myocardial utilization of CHOs for energy production and anaplerosis in 12-wk-old peroxisome proliferator-activating receptor-α (PPARα) null mice (a model of FA β-oxidation defects). Carbon-13 methodology was used to assess substrate flux through energy-yielding pathways in hearts perfused ex vivo at two workloads with a physiological substrate mixture mimicking the fed state, and real-time RT-quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. When compared with that from control C57BL/6 mice, isolated working hearts from PPARα null mice displayed an impaired capacity to withstand a rise in preload (mimicking an increased venous return as it occurs during exercise) as reflected by a 20% decline in the aortic flow rate. At the metabolic level, beyond the expected shift from FA (5-fold down) to CHO (1.5-fold up; P < 0.001) at both preloads, PPARα null hearts also displayed 1) a significantly greater contribution of exogenous lactate and glucose and/or glycogen (2-fold up) to endogenous pyruvate formation, whereas that of exogenous pyruvate remained unchanged and 2) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was affected differently by preloads in control and PPARα null mouse hearts, suggesting a restricted reserve for the latter hearts to enhance glycolysis when the energy demand is increased. Alterations in the expression of some glycolysis-related genes suggest potential mechanisms involved in this defective CHO metabolism. Collectively, our data highlight the importance of metabolic alterations in CHO metabolism associated with FA oxidation defects as a factor that may predispose the heart to decompensation under stress conditions even in the fed state.
Stability of hemoglobin mass over 100 days in active men
Authors: Eastwood Annette , Hopkins Will G. , Bourdon Pitre C. , Withers Robert T. , Gore Christopher J.
Published: January 2008

The purpose of this study was to investigate the suggestion in a recent meta-analysis that variability in hemoglobin mass increases when time between measurements increases from days to months. Hemoglobin mass of six active men was measured with the carbon monoxide method every 1–6 days for 100–114 days (42 ± 3 measurements, mean ± SD). Measurement error for each individual's series was estimated from the standard deviation of consecutive pairwise changes and compared with his total error (standard deviation of all values). Linear trends and periodicities in each series were quantified by regression and spectral analysis. Series with known random error and periodicity were also simulated and analyzed. There were clear differences in the pairwise error of measurement between subjects (range 1.4–2.7%). For five men, there was little difference between the total and pairwise errors; their mean ratio (1.06, 90% confidence limits 0.96–1.17) was less than ratios for simulated sinusoidal series with random error of 2%, amplitude of 2%, and periods of 20–100 days (ratios 1.13–1.21). Spectral analysis clearly revealed such periodicities in the simulated series but not in the series of these subjects. The sixth man, who had donated blood 12 days before commencing measurements, showed errors, trend, and periodicity consistent with gradual restoration of hemoglobin mass. Measurement error of hemoglobin mass does not increase over 100 days. Consequently, hemoglobin mass may be suitable for long-term monitoring of small changes that might occur with training or erythropoietin abuse, taking into consideration the small differences between athletes in errors and trends.
Effects of IL-10 and age on IL-6, IL-1β, and TNF-α responses in mouse skeletal and cardiac muscle to an acute inflammatory insult
Authors: Meador B. M. , Krzyszton C. P. , Johnson R. W. , Huey K. A.
Published: January 2008

Exaggerated proinflammatory cytokine responses can be observed with aging, and reduced levels of the anti-inflammatory cytokine IL-10 may contribute to these responses. IL-10 can reduce IL-6, IL-1β, and TNF-α expression in nonmuscle tissues; however, no studies have examined the combined effects of IL-10 and age on cytokine responses in skeletal and cardiac muscle. These experiments tested the hypothesis that the absence of IL-10, in vivo, is associated with greater IL-6, TNF-α, and IL-1β responses to an inflammatory challenge in skeletal and cardiac muscle and that aging exaggerates these responses. We compared IL-6, IL-1β, and TNF-α mRNA and protein levels in skeletal and cardiac muscle of young (4 mo) and mature (10–11 mo) wild-type (IL-10+/+) and IL-10 deficient (IL-10−/−) mice following LPS. Skeletal and cardiac IL-6 mRNA and protein were elevated by LPS for IL-10+/+and IL-10−/−mice with greater responses in the IL-10−/−mice ( P < 0.01). In skeletal muscle these effects were greater in mature than young mice ( P < 0.01). IL-1β mRNA and protein responses to LPS were greater in cardiac muscle of young but not mature IL-10−/−mice compared with IL-10+/+( P < 0.01). However, IL-1β responses were greater in mature than young mice, but only in IL-10+/+groups ( P < 0.05). The absence of IL-10 was associated with higher TNF-α protein levels in cardiac muscle ( P < 0.05). The results provide the first in vivo evidence that the absence of IL-10 is associated with a greater IL-6 response to LPS in skeletal and cardiac muscles, and in skeletal muscle aging further exaggerates these responses.
A maximal exercise bout increases the number of circulating CD34+/KDR+ endothelial progenitor cells in healthy subjects. Relation with lipid profile
Authors: Van Craenenbroeck Emeline M. F. , Vrints Christiaan J. , Haine Steven E. , Vermeulen Katrien , Goovaerts Inge , Van Tendeloo Viggo F. I. , Hoymans Vicky Y. , Conraads Viviane M. A.
Published: January 2008

Mobilization of bone marrow-derived endothelial progenitor cells (EPC) might explain exercise-induced improvement of endothelial function. We assessed whether a maximal exercise bout could alter the number of circulating EPC in healthy subjects and whether this effect is related to their cardiovascular risk profile. Additionally, we investigated possible mediators of this effect, namely nitric oxide (NO) bioavailability and vascular endothelial growth factor (VEGF) release. Healthy subjects ( group 1, n = 11; group 2, n = 14) performed a symptom-limited cardiopulmonary exercise test on a bicycle ergometer. Numbers of CD34+/kinase insert domain receptor (KDR)+ cells were determined by flow-cytometric analysis, either after magnetic separation of CD34+ cells ( group 1) or starting from whole blood ( group 2). Serum concentrations of VEGF and NO metabolites were measured by using ELISA. Following exercise, EPC increased by 76% (15.4 ± 10.7 cells/ml vs. 27.2 ± 13.7 cells/ml; P = 0.01) in group 1 and by 69% in group 2 (30.9 ± 14.6 cells/ml vs. 52.5 ± 42.6 cells/ml; P = 0.03). The increase in EPC correlated positively with LDL and total cholesterol/HDL ratio and negatively with peak oxygen consumption and oxygen consumption at anaerobic threshold. VEGF levels increased with exercise, with a strong trend toward significance ( P = 0.055). NO levels remained unchanged. The present study demonstrates that a maximal bout of exercise induces a significant shift in CD34+ cells toward CD34+/KDR+ cells. This response was larger in subjects with a less favorable lipid profile.
Erythropoietin receptor in human skeletal muscle and the effects of acute and long-term injections with recombinant human erythropoietin on the skeletal muscle
Authors: Lundby Carsten , Hellsten Ylva , Jensen Mie B. F. , Munch Anders S. , Pilegaard Henriette
Published: January 2008

The presence and potential physiological role of the erythropoietin receptor (Epo-R) were examined in human skeletal muscle. In this study we demonstrate that Epo-R is present in the endothelium, smooth muscle cells, and in fractions of the sarcolemma of skeletal muscle fibers. To study the potential effects of Epo in human skeletal muscle, two separate studies were conducted: one to study the acute effects of a single Epo injection on skeletal muscle gene expression and plasma hormones and another to study the effects of long-term (14 wk) Epo treatment on skeletal muscle structure. Subjects ( n = 11) received a single Epo injection of 15,000 IU (double blinded, cross over, placebo). A single Epo injection reduced myoglobin and increased transferrin receptor and MRF-4 mRNA content within 10 h after injection. Plasma hormones remained unaltered. Capillarization and fiber hypertrophy was studied in subjects ( n = 8) who received long-term Epo administration, and muscle biopsies were obtained before and after. Epo treatment did not alter mean fiber area (0.84 ± 0.2 vs. 0.72 ± 0.3 mm2), capillaries per fiber (4.3 ± 0.5 vs. 4.4 ± 1.3), or number of proliferating endothelial cells. In conclusion, the Epo-R is present in the vasculature and myocytes in human skeletal muscle, suggesting a role in both cell types. In accordance, a single injection of Epo regulates myoglobin, MRF-4, and transferrin receptor mRNA levels. However, in contrast to our hypothesis, prolonged Epo administration had no apparent effect on capillarization or muscle fiber hypertrophy.
Transcription factors and the genetic organization of brain stem respiratory neurons
Authors: Gray Paul A.
Published: January 2008

Breathing is a genetically determined behavior generated by neurons in the brain stem. Transcription factors, in part, determine the basic developmental identity of neurons, but the relationships between these genes and the neural populations generating and modulating respiration are unclear. The diversity of brain stem populations has been proposed to result from a combinatorial code of transcription factor expression corresponding to the anterior-posterior (A-P) and dorsal-ventral (D-V) location of a neuron's birth. I provide a schematic of transcription factor coding identifying at least 15 genetically distinct D-V subdivisions of brain stem neurons that, combined with A-P patterning, may provide a genetic organization of the brain stem in general, with the eventual goal of describing respiratory populations in particular. Using a combination of fate mapping in transgenic mouse lines and immunohistochemistry, we confirm the parabrachial nuclei are derived from a subset of Atoh1 expression progenitor neurons. I hypothesize the Kölliker-Fuse nucleus can be uniquely defined in the neonate mouse by the coexpression of the transcription factor FoxP2 in Atoh1-derived neurons of rhombomere 1.
In vivo and Microarray Analysis of Rexinoid-Responsive Anaplastic Thyroid Carcinoma
Authors: Klopper Joshua P. , Berenz Andrew , Hays William R. , Sharma Vibha , Pugazhenthi Umarani , Janssen Jennifer , Singh Meenakshi , Bissonnette Reid P. , Haugen Bryan R.
Published: January 2008

Purpose: Anaplastic thyroid carcinoma is rare, yet lethal despite aggressive therapy. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid X receptor–selective agonist, as a novel treatment. In this report, we describe the efficacy of LGD1069 in anaplastic thyroid carcinoma in vitro and assess the in vivo treatment effects on a responsive cancer. Additionally, we explore potential mediators of the rexinoid effect on a responsive anaplastic thyroid cancer using comparative microarray analysis.

Experimental Design: Anaplastic thyroid cancer cell lines DRO, ARO, and FRO were treated with LGD1069 in vitro. Responsive DRO xenograft tumors were treated with control chow or chow containing a low dose (30 mg/kg/d) or a high dose (100 mg/kg/d) of LGD1069. Comparative microarray analysis of DRO cells treated with LGD1069 compared with volume-equivalent control was assessed after 24 h of treatment to evaluate early gene expression changes.

Results: DRO xenograft tumor growth was inhibited by LGD1069 treatment in a dose-dependent manner. Comparative microarray analysis showed that 80 genes had a significant increase in expression and 29 genes had a decrease in expression after 24 h of treatment with LGD1069. Expression of angiopoietin-like 4 (ANGPTL4) mRNA was increased 6.5-fold. A trend towards an increase in ANGPTL4 mRNA (not statistically significant) was seen in treated tumors in vivo and this correlated with decreased tumor vascularity and increased necrosis.

Conclusions: LGD1069 therapy decreases proliferation in an anaplastic thyroid cancer cell line that expresses retinoid X receptor-γ, and this effect is confirmed with decreased tumor size in vivo in a nude mouse model. ANGPTL4 is increased in DRO in response to LGD1069 and may be a potential mediator of the effects of rexinoid treatment.
Overexpression of Cellular Iron Import Proteins Is Associated with Malignant Progression of Esophageal Adenocarcinoma
Authors: Boult Jessica , Roberts Keith , Brookes Matthew J. , Hughes Sharon , Bury Jonathan P. , Cross Simon S. , Anderson Gregory J. , Spychal Robert , Iqbal Tariq , Tselepis Chris
Published: January 2008

Purpose: There is growing evidence that iron is important in esophageal adenocarcinoma, a cancer whose incidence is rising faster than any other in the Western world. However, how iron mediates carcinogenesis at the molecular level remains unclear. In this study, we investigated the expression of iron transport proteins involved in cellular iron import, export, and storage in the premalignant lesion Barrett's metaplasia and esophageal adenocarcinoma.

Experimental Design: Perls' staining was used to examine iron deposition in tissue. mRNA expression in samples of Barrett's metaplasia matched with esophageal adenocarcinoma and samples of Barrett's metaplasia without evidence of adenocarcinoma were examined by real-time PCR. Semiquantitative immunohistochemistry was used to examine cellular localization and protein levels. The effect of iron loading on cellular proliferation and iron transporter expression was determined in esophageal cell lines OE33 and SEG-1 using a bromodeoxyuridine assay and real-time PCR, respectively.

Results: In the progression of Barrett's metaplasia to adenocarcinoma, there was overexpression of divalent metal transporter 1 (DMT1), transferrin receptor 1, duodenal cytochrome b, ferroportin, and H-ferritin, and these changes were associated with increased iron deposition. Overexpression of DMT1 was further associated with metastatic adenocarcinoma. Iron loading OE33 and SEG-1 cells caused increased cellular proliferation, which was associated with increased H-ferritin and decreased transferrin receptor 1 and DMT1 expression.

Conclusions: Progression to adenocarcinoma is associated with increased expression of iron import proteins. These events culminate in increased intracellular iron and cellular proliferation. This may represent a novel mechanism of esophageal carcinogenesis.
Imatinib Mesylate Enhances Therapeutic Effects of Gemcitabine in Human Malignant Mesothelioma Xenografts
Authors: Bertino Pietro , Piccardi Federica , Porta Camillo , Favoni Roberto , Cilli Michele , Mutti Luciano , Gaudino Giovanni
Published: January 2008

Purpose: Platelet-derived growth factor receptor β (PDGFRβ), frequently activated in malignant mesothelioma, is a promising cancer therapeutic target. Imatinib mesylate (STI571; Glivec) is a selective inhibitor of tyrosine kinases as bcr-abl, c-kit, c-fms, and PDGFRβ and enhances tumor drug uptake by reducing the interstitial fluid pressure. We previously showed that imatinib mesylate synergizes with gemcitabine and pemetrexed in PDGFRβ-positive mesothelioma cells. Here, we aimed at investigating these combined treatments in a novel mesothelioma model.

Experimental Design: REN mesothelioma cells, infected with a lentiviral vector carrying the luciferase gene, were injected in the peritoneum of severe combined immunodeficient mice. This model allowed imaging of live animals treated with pemetrexed or gemcitabine chemotherapeutics, or with imatinib mesylate alone, as well as with a combination of gemcitabine and imatinib mesylate.

Results: We show here that, consistent with our previous in vitro studies, gemcitabine inhibited tumor growth, whereas pemetrexed was ineffective, even at the highest dosage tested. Compared with monotreatment, the combination of gemcitabine with imatinib mesylate led to a further tumor growth inhibition and improved mice survival, by a decrease rate of tumor cell proliferation and an increase in number of apoptotic tumor cells.

Conclusions: Imatinib mesylate enhances the therapeutic response to gemcitabine, in accordance with our previous in vitro data. These in vivo results validate imatinib mesylate and gemcitabine as a combination treatment of malignant mesothelioma, also in view of its known positive effects on tumor drug uptake. These evidences provide the rationale for the currently ongoing clinical trials.
Dose and Schedule Study of Panitumumab Monotherapy in Patients with Advanced Solid Malignancies
Authors: Weiner Louis M. , Belldegrun Arie S. , Crawford Jeffrey , Tolcher Anthony W. , Lockbaum Pamela , Arends Rosalin H. , Navale Lynn , Amado Rafael G. , Schwab Gisela , Figlin Robert A.
Published: January 2008

Purpose: This phase 1 study evaluated the safety, pharmacokinetics, and activity of panitumumab, a fully human, IgG2 monoclonal antibody that targets the epidermal growth factor receptor in patients with previously treated epidermal growth factor receptor–expressing advanced solid tumors.

Experimental Design: Sequential cohorts were enrolled to receive four i.v. infusions of panitumumab monotherapy at various doses and schedules. Safety was continuously monitored. Serum samples for pharmacokinetic, immunogenicity, and chemistry assessments were drawn at preset intervals. Tumor response was assessed at week 8.

Results: Ninety-six patients received panitumumab. Median (range) age was 61 years (32-79 years), and 72 (75%) patients were male. Tumor types were 41% colorectal cancer, 22% prostate, 16% renal, 15% non–small cell lung, 3% pancreatic, 3% esophageal/gastroesophageal, and 1% anal. The overall incidence of grade 3 or 4 adverse events was 32% and 7%, respectively. The incidence of skin-related toxicities was dose dependent. No maximum tolerated dose was reached. No human anti-panitumumab antibodies were detected. No investigator-determined panitumumab infusion-related reactions were reported. Serum panitumumab concentrations were similar in the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks dose cohorts. Five of 39 patients (13%) with colorectal cancer had a confirmed partial response, and 9 of 39 patients (23%) with colorectal cancer had stable disease.

Conclusions: Panitumumab was well tolerated with comparable exposure and safety profiles for the weekly, every 2 weeks, and every 3 weeks administration schedules. Rash and dry skin occurred more frequently in the dose cohorts receiving ≥2.5 mg/kg weekly dose. Panitumumab has single-agent antitumor activity, most notably in patients with advanced colorectal cancer.
Vascular Endothelial Growth Factor Genotypes, Haplotypes, Gender, and the Risk of Non–Small Cell Lung Cancer
Authors: Zhai Rihong , Liu Geoffrey , Zhou Wei , Su Li , Heist Rebecca Suk , Lynch Thomas J. , Wain John C. , Asomaning Kofi , Lin Xihong , Christiani David C.
Published: January 2008

Purpose: The vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving tumor growth and metastasis. Polymorphisms in the VEGF gene may regulate VEGF production. In this large case-control study, we investigated whether functional polymorphisms (−460C/T, +405C/G, +936C/T) in the VEGF gene are associated with the risk of non–small cell lung cancer (NSCLC).

Experimental Design:VEGF genotypes and haplotypes were determined in 1,900 Caucasian patients with NSCLC and 1,458 healthy controls. The results were analyzed using logistic regression models, adjusting for age, gender, smoking status, pack-years of smoking, and years since smoking cessation (for ex-smokers). The false-positive report probability was estimated for the observed odds ratios (OR).

Results: There were no overall associations between individual VEGF genotypes and the risk of NSCLC. Stratified analysis suggested that the combined +405CC+CG genotype was significantly associated with increased risk of lung adenocarcinoma in males (adjusted OR, 1.40; 95% confidence interval, 1.03-1.87). In haplotype analysis, haplotypes were globally associated with differences between cases and controls in males (P = 0.03). Specifically, the −460T/+405G/+936C haplotype was significantly (P = 0.02) associated with decreased risk of adenocarcinoma in males when compared with the most common CGC haplotype (adjusted OR, 0.76; 95% confidence interval, 0.50-0.98). None of the VEGF genotypes and haplotypes studied significantly influenced the susceptibility to NSCLC in females.

Conclusions: Polymorphisms of −460C/T, +405C/G, and +936C/T in the VEGF gene do not play a major role in NSCLC risk. However, we could not exclude a minor role for the +405CC+CG genotypes and the 460T/+405G/+936C haplotype in lung adenocarcinogenesis in male Caucasians.
Unique Cell Surface Expression of Receptor Tyrosine Kinase ROR1 in Human B-Cell Chronic Lymphocytic Leukemia
Authors: Baskar Sivasubramanian , Kwong Ka Yin , Hofer Thomas , Levy Jessica M. , Kennedy Michael G. , Lee Elinor , Staudt Louis M. , Wilson Wyndham H. , Wiestner Adrian , Rader Christoph
Published: January 2008

Purpose: Gene expression profiling identified receptor tyrosine kinase ROR1, an embryonic protein involved in organogenesis, as a signature gene in B-cell chronic lymphocytic leukemia (B-CLL). To assess the suitability of ROR1 as a cell surface antigen for targeted therapy of B-CLL, we carried out a comprehensive analysis of ROR1 protein expression.

Experimental Design: Peripheral blood mononuclear cells, sera, and other adult tissues from B-CLL patients and healthy donors were analyzed qualitatively and quantitatively for ROR1 protein expression by flow cytometry, cell surface biotinylation, Western blotting, and ELISA.

Results: ROR1 protein is selectively expressed on the surface of B-CLL cells, whereas normal B cells, other normal blood cells, and normal adult tissues do not express cell surface ROR1. Moreover, cell surface expression of ROR1 is uniform and constitutive, i.e., independent of anatomic niches, independent of biological and clinical heterogeneity of B-CLL, independent of B-cell activation, and found at similar levels in all B-CLL samples tested. The antibody binding capacity of B-CLL cell surface ROR1 was determined to be in the range of 103 to 104 molecules per cell. A portion of B-CLL cell surface ROR1 was actively internalized upon antibody binding. Soluble ROR1 protein was detectable in sera of <25% of B-CLL patients and a similar fraction of healthy donors at concentrations below 200 ng/mL.

Conclusions: The restricted, uniform, and constitutive cell surface expression of ROR1 protein in B-CLL provides a strong incentive for the development of targeted therapeutics such as monoclonal antibodies.
Sprycel for Chronic Myeloid Leukemia and Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Resistant to or Intolerant of Imatinib Mesylate
Authors: Brave Michael , Goodman Vicki , Kaminskas Edvardas , Farrell Ann , Timmer William , Pope Sarah , Harapanhalli Ravi , Saber Haleh , Morse David , Bullock Julie , Men Angela , Noory Carol , Ramchandani Roshni , Kenna Leslie , Booth Brian , Gobburu Joga , Jiang Xiaoping , Sridhara Rajeshwari , Justice Robert , Pazdur Richard
Published: January 2008

Purpose: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval.

Experimental Design: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph+ ALL was major hematologic response.

Results: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph+ ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph+ ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention.

Conclusions: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph+ ALL based on the rates and durability of cytogenetic and hematologic responses.
Tumor Necrosis Factor-Alpha and Interleukin-10 in Whole Blood Is Associated with Disease Progression in Pulmonary Mulitdrug-Resistant Tuberculosis Patients
Authors: Eum Seok-Yong , Jeon Bo-Young , Min Jin-Hong , Kim Seung-Cheol , Cho Sungae , Park Seung-Kyu , Cho Sang-Nae
Published: January 2008

Background: Cytokine production profiles may reflect the clinical pictures of patients with tuberculosis (TB). Objective: We examined the relationship between cytokine levels and clinical parameters indicating the state of disease in active pulmonary TB patients. Methods: We measured interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-10 levels in whole blood after stimulation with culture filtrate protein of Mycobacterium tuberculosis in 33 multi-drug resistant (MDR)-TB and 51 non-MDR-TB patients. Results: No significant difference was found in IFN-γ production between non-MDR-TB and MDR-TB patients, but there was a marked reduction in TNF-α production in MDR-TB patients accompanied by a moderate increase in IL-10 levels. In contrast, the presence of cavity was associated with a significant increase in IFN-γ, whereas no difference in TNF-α between the cavity and non-cavity group was observed. Those who have TB lesions in the left lung showed lower levels of IFN-γ and TNF-α and higher IL-10 levels than the patients with lesions on the right side. IFN-γ levels were significantly increased in those with moderate or advanced lesions compared with patients with mild lesions. TNF-α and IL-10 levels did not change with disease severity. The number of M. tuberculosis bacilli in sputum was closely associated with TNF-α levels. The patient group with high value (+++) of sputum culture acid-fast bacilli produced significantly reduced levels of TNF-α compared with medium (++) and low (+) values. Conclusion: These findings suggest that IFN-γ, TNF-α or IL-10 production patterns in whole blood are associated with disease progression in active pulmonary TB.
Estrogen and Progesterone Modulate [35S]GTPγS Binding to Nociceptin Receptors
Authors: Quesada Arnulfo , Micevych Paul
Published: January 2008

Sex steroids modulate reproduction by altering the response of steroid-activated opioid circuits in the hypothalamus and limbic system, by inducing release of endogenous opioids and activation of their cognate receptors. Many studies have concentrated on steroid regulation of exogenous opioid peptides, but steroids also have important actions on opioid receptors inducing receptor trafficking. Opioid receptors are G protein-coupled receptors and their activation catalyzes the exchange of GTP for GDP initiating intracellular signaling cascades. Kinetics of G protein activation were studied using [35S]GTPγS binding. Catalytic amplification, the number of G proteins activated per occupied receptor, was used as a measure of receptor/transducer amplification. The present study examined whether estrogen and progesterone treatment altered the kinetics of nociceptin opioid receptor (ORL1) in plasma membranes from the medial preoptic area and mediobasal hypothalamus. These hypothalamic regions are important in the gonadal steroid hormone regulation of sexual receptivity. In the mediobasal hypothalamus, estrogen increased ORL1 (Bmax) receptor number 2-fold and maximal GTPγS binding (Emax) 3.9-fold. Subsequent progesterone treatment further increased ORL1 Emax 6.9-fold above baseline, despite a 2-fold decrease in the catalytic amplification factor. In the medial preoptic area, estrogen alone did not increase Emax, but both estrogen and progesterone were able to increase ORL1 Bmax 2.2-fold and Emax 3-fold, despite having a 3-fold decrease in the catalytic amplification factor. These effects are interesting because they indicate actions of steroids that increase the number of ORL1 but decrease the catalytic amplification suggesting that the steroid effects on opioid receptors are complex and may involve modulation by other signals.
Sperm dimorphism in the free-living marine nematode Terschellingia glabricutis (Nematoda: Monhysterida: Linhomoeidae)
Authors: Yushin Vladimir
Published: January 2008

The structure and development of the dimorphic spermatozoa of the free-living marine nematode Terschellingia glabricutis (Monhysterida, Linhomoeina, Linhomoeidae) were studied with transmission electron microscope (TEM). The linhomoeid pattern of spermatozoa includes absence of fibrous bodies (FB) in spermatocytes and their appearance in spermatids as spindle-shaped bodies never associating with membranous organelles (MO); presence of centrioles near the sperm nucleus; occurrence of filopodia in the spermatids and immature spermatozoa; unpolarised concentric structure of the mature spermatozoa; microtubule-like elements in spermatids and spermatozoa. The linhomoeins differ from their closest relatives, monhysterins (Xyalidae, Sphaerolaimidae), by total absence of MO at all the stages of spermatogenesis. This peculiarity is also found in the sperm development of some chromadorids, desmodorids and tylenchomorphs. In T. glabricutis the anterior testis produces large (20 μm) 'macrospermatozoa' of the linhomoeid pattern; the posterior testis produces much smaller (10 μm) 'microspermatozoa' of simplified structure. The female genital tubes also contain two types of amoeboid spermatozoa of different size and internal structure. Thus, T. glabricutis demonstrates a pattern of sperm dimorphism in which each testis of the diorchic male produces its own type of spermatozoa. Both types are found in the genital tube of fertilised females. Such sperm dimorphism is known from light microscope observations for several distantly related marine species although the biological significance of this dimorphism is obscure.
Quality damage on carrots (Daucus carota L.) caused by the root-knot nematode Meloidogyne chitwoodi
Authors: Moens Maurice , Wesemael Wim
Published: January 2008

In the Belgian provinces Antwerp and Limburg, the root-knot nematode, Meloidogyne chitwoodi, is widespread. These regions are important production areas of carrot, Daucus carota, for the processing industry. Nineteen carrot cultivars were screened for potential resistance for M. chitwoodi. Egg masses of M. chitwoodi were found on all cultivars. However, there were no egg masses on more than 80% of plants of cvs Berlanda, Bolero, Chantenay, Nantucket and Parmex. By contrast, on cvs ABK, Douceur, Maxi and Merida egg masses were formed on all of the tested plants. To gain information about the damage caused by M. chitwoodi, carrots were grown in soil infected with different densities of nematodes. There was no effect of M. chitwoodi on the length, width and weight of the carrot taproot. Damage caused by M. chitwoodi was manifested by severe galling near the lenticels. Inoculation of nematodes 6 weeks after the carrots emerged resulted in a higher percentage of infected carrots and damaged taproots compared with earlier inoculation times. The effect of the time of harvest on nematode infection and damage was examined. When harvested 100 days after sowing in soil with low nematode densities (two second-stage juveniles (J2)/100 g soil), no damage was reported. Harvesting 120 and 140 days after sowing resulted in 10 and 20% damaged carrots, respectively. With initial M. chitwoodi densities of 25 J2/100 g soil, the percentage of damaged taproots increased from 10% when harvested 100 days after sowing to 70% when harvested 140 days after sowing. In a field trial, 11.5% of the carrots were damaged after a field period of 139 days and the initial M. chitwoodi population increased from 3 to 111 J2/100 g soil. It is recommended that growing carrots in M. chitwoodi-infested fields should be avoided. However, damage can be limited in fields with low initial nematode populations when the growing period is reduced.
Teratorhabditis synpapillata Sudhaus, 1985 (Rhabditida: Rhabditidae) is an associate of the red palm weevil, Rhynchophorus ferrugineus (Coleoptera: Curculionidae)
Authors: Fitch David , Soné Koichi , Kanzaki Natsumi , Abe Fukiko , Giblin-Davis Robin , Kiontke Karin , Hata Kunihiko
Published: January 2008

Teratorhabditis synpapillata, originally described from cow dung in Bali, was isolated from the red palm weevil, Rhynchophorus ferrugineus, in Japan. Dauer juveniles were isolated from beneath the elytra of five specimens of R. ferrugineus that had emerged from a dead Canary Island date palm, Phoenix canariensis, in Kagoshima, Japan. The dauer juveniles were cultured on a NGM agar plate and the adult nematodes observed and measured with the aid of light microscopy. The full length of the ribosomal small subunit (SSU) and D2/D3 expansion segment of the ribosomal large subunit (LSU) were sequenced for molecular identification. Based upon morphology, molecular profile and a hybridisation test, the nematode was confirmed as T. synpapillata. A comparison of morphology and morphometrics suggests that the only other nematode reported from R. ferrugineus (= 'Pelodera rhynchophori') is also conspecific with T. synpapillata. A phylogenetic analysis using SSU and LSU rRNA gene sequences fully resolves the relationships of four Teratorhabditis and six outgroup species and demonstrates a sister group relationship of T. synpapillata and T. palmarum, another associate of palm weevils.
Competitive interaction between Bursaphelenchus xylophilus and the closely related species Bursaphelenchus mucronatus
Authors: Altemayer Valérie , Vincent Bruno , Naves Pedro , Lieutier François , Roux-Morabito Géraldine , Sousa Edmundo
Published: January 2008

Bursaphelenchus xylophilus is an invasive pest of pines. When introduced accidentally into a new geographic area, it will share the same ecological niche as the closely related indigenous species, B. mucronatus. Competition between native and introduced species may affect the spread of invasive species, so we investigated the possible competitive interaction between these two nematode species transmitted by the same insect-vector, Monochamus galloprovincialis. In order to understand how the two species interacted, we compared, under laboratory conditions, their growth on fungi and pines, their ability to board M. galloprovincialis, and their competitive interaction in situations of double boarding. Bursaphelenchus xylophilus showed greater rates of growth than B. mucronatus in single and mixed treatments. The invasive species was competitively superior to the indigenous species in mixed treatments (fungi and pines). This competitive advantage in pines, prior to the beetles' infestation, could explain the greater abundance of the invasive (68%) species over the indigenous in the insect vector M. galloprovincialis. The indigenous species had no effect on beetle boarding of the invasive species. The occurrence of B. mucronatus in France and its wide distribution on numerous pine species could have an effect on B. xylophilus invasion in the initial steps of an invasion process. Nevertheless, due to the superior competitiveness of B. xylophilus, we cannot state that B. mucronatus will be efficient as a factor to decrease propagation of this invasive species.
Better Place: Performing the Urbanisms of Hope
Authors: Davey Andrew
Published: January 2008

An increasing awareness of the urbanized reality of our world through experience and the burgeoning field of urban studies provides a critical challenge to those concerned with the development of an urban public theology. A key strand within urban studies is concerned with an 'urbanism of hope' promoting an open participatory understanding of urban politics in community. A performative approach to theology promotes an understanding of the church's engagement in informal urban politics, and the embodiment of a transfigured city.
Making Oneself at Home in Environments of Urban Amnesia: Religion and Theology in City Space
Authors: Bergmann Sigurd
Published: January 2008

How is urban space to be developed as a habitable place, and what could religion and theology contribute to it? This article explores the question in three sections. First, urbanization is considered as a religious phenomenon, and examples from Mayan sacred geography, Swedish landscape architecture and the medieval European Hansa city are presented and discussed. Then, the human dimension, and the human capacity 'to make oneself at home', are elaborated clearly in articulating the need for a more plastic critical urban theory. The challenge to public theology in this context is to reflect deeply about how the Spirit is taking place in urban space. The final section investigates the dynamics of the space between oblivion, amnesia and remembrance and its significance for urban transformation. The design of places for remembering the sufferings of the past and the differences between strangers and residents are thereby outlined as a necessary condition for a city where humans can make themselves at home.