bluuebunny/crossref_metadata_2025 huggingface dataset:
Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Promote Malignant Growth of Cells from Head and Neck Squamous Cell Carcinomas In vivo
Authors: Gutschalk Claudia M. , Herold-Mende Christel C. , Fusenig Norbert E. , Mueller Margareta M.
Published: August 2006

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are used to ameliorate cancer therapy-induced neutropenia and mucositis. Yet, first data in head and neck squamous cell carcinoma (HNSCC) indicate an impaired long-term prognosis on G-CSF treatment, and previous studies showed a contribution of both factors to the progression of human epithelial tumors. Therefore, we investigate the role of G-CSF and GM-CSF in progression of tumor cells from human HNSCC. Both factors stimulated proliferation and migration of tumor cell lines established from patient tumors expressing G-CSF and GM-CSF and/or their receptors. Blockade of G-CSF and GM-CSF inhibited tumor cell invasion in a three-dimensional organotypic culture model. The contribution of both factors to tumor malignancy was further confirmed in nude mouse transplants in vivo. Invasive and malignant growth yielding a similar tumor phenotype as the original patient tumor was exclusively observed in G-CSF- and GM-CSF-expressing tumors and was associated with enhanced and persistent angiogenesis and enhanced inflammatory cell recruitment. Although factor-negative tumors grew somewhat faster, they were characterized by lack of invasion, reduced and transient angiogenesis, and large necrotic areas. These data provide evidence for a progression-promoting effect of G-CSF and GM-CSF in human HNSCC and suggest further detailed evaluation of their use in the therapy of these tumors. (Cancer Res 2006; 66(16): 8026-36)
Different Lineages of P1A-Expressing Cancer Cells Use Divergent Modes of Immune Evasion for T-Cell Adoptive Therapy
Authors: Bai Xue-Feng , Liu Jin-Qing , Joshi Pramod S. , Wang Lizhong , Yin Lijie , Labanowska Jadwiga , Heerema Nyla , Zheng Pan , Liu Yang
Published: August 2006

Tumor evasion of T-cell immunity remains a significant obstacle to adoptive T-cell therapy. It is unknown whether the mode of immune evasion is dictated by the cancer cells or by the tumor antigens. Taking advantage of the fact that multiple lineages of tumor cells share the tumor antigen P1A, we adoptively transferred transgenic T cells specific for P1A (P1CTL) into mice with established P1A-expressing tumors, including mastocytoma P815, plasmocytoma J558, and fibrosarcoma Meth A. Although P1CTL conferred partial protection, tumors recurred in almost all mice. Analysis of the status of the tumor antigen revealed that all J558 tumors underwent antigenic drift whereas all P815 tumors experienced antigenic loss. Interestingly, although Meth A cells are capable of both antigenic loss and antigenic drift, the majority of recurrent Meth A tumors retained P1A antigen. The ability of Meth A to induce apoptosis of P1CTL in vivo alleviated the need for antigenic drift and antigenic loss. Our data showed that, in spite of their shared tumor antigen, different lineages of cancer cells use different mechanisms to evade T-cell therapy. (Cancer Res 2006; 66(16):8241-9)
Tip60 Protein Isoforms and Altered Function in Skin and Tumors that Overexpress Ornithine Decarboxylase
Authors: Hobbs Cheryl A. , Wei Gang , DeFeo Karen , Paul Barry , Hayes Candace S. , Gilmour Susan K.
Published: August 2006

Elevated expression of ornithine decarboxylase (ODC) and increased synthesis of polyamines are hallmarks of epithelial tumorigenesis. The skin and tumors of K6/ODC and ODC/Ras transgenic mice, in which overexpression of ODC has been targeted to hair follicles, were found to exhibit intrinsically high histone acetyltransferase (HAT) activity. We identified Tip60 as a candidate enzyme for contributing significantly to this abnormally high HAT activity. Compared with normal littermate controls, the levels of Tip60 protein and an alternative splice variant Tip53 were found to be greater in K6/ODC mouse skin. Furthermore, skin tumors that spontaneously develop in ODC/Ras bigenic mice typically have substantially more Tip60 protein than adjacent non–tumor-bearing skin and exhibit a unique pattern of Tip60 size variants and chemically modified protein isoforms. Steady-state Tip60 and Tip53 mRNA levels were not affected in ODC-overexpressing skin and tumors, implying novel posttranscriptional regulation by polyamines. Given the diverse roles of Tip60, the overabundance of Tip60 protein is predicted to have biological consequences. Compared with normal littermate skin, we detected altered association of Tip60 with E2F1 and a subset of newly identified Tip60-interacting transcription factors in ODC transgenic mouse skin and tumors. E2F1 was shown to be bound in greater amounts to up-regulated target genes in ODC-overexpressing skin. Thus, up-regulation of Tip60 protein, influencing the expression of Tip60-regulated genes, could play a contributing role in polyamine-mediated tumor promotion. (Cancer Res 2006; 66(16): 8116-22)
Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib
Authors: Carey Kendall D. , Garton Andrew J. , Romero Maria S. , Kahler Jennifer , Thomson Stuart , Ross Sarajane , Park Frances , Haley John D. , Gibson Neil , Sliwkowski Mark X.
Published: August 2006

We show that two commonly occurring epidermal growth factor receptor (EGFR) somatic mutations, L858R and an in-frame deletion mutant, Del(746-750), exhibit distinct enzymatic properties relative to wild-type EGFR and are differentially sensitive to erlotinib. Kinetic analysis of the purified intracellular domains of EGFR L858R and EGFR Del(746-750) reveals that both mutants are active but exhibit a higher KM for ATP and a lower Ki for erlotinib relative to wild-type receptor. When expressed in NR6 cells, a cell line that does not express EGFR or other ErbB receptors, both mutations are ligand dependent for receptor activation, can activate downstream EGFR signaling pathways, and promote cell cycle progression. As expected from the kinetic analysis, the EGFR Del(746-752) is more sensitive to erlotinib inhibition than the EGFR L858R mutant. Further characterization shows that these mutations promote ligand-dependent and anchorage-independent growth, and cells harboring these mutant receptors form tumors in immunocompromised mice. Analysis of tumor lysates reveals that the tumorigenicity of the mutant EGFR cell lines may be due to a differential pattern of mutant EGFR autophosphorylation as compared with wild-type receptor. Significant inhibition of tumor growth, in mice harboring wild-type EGFR receptors, is only observed at doses of erlotinib approaching the maximum tolerated dose for the mouse. In contrast, the growth of mutant tumors is inhibited by erlotinib treatment at approximately one third the maximum tolerated dose. These findings suggest that EGFR somatic mutations directly influence both erlotinib sensitivity and cellular transformation. (Cancer Res 2006; 66(16): 8163-71)
Epigenetic Silencing of the Tumor Suppressor Cystatin M Occurs during Breast Cancer Progression
Authors: Ai Lingbao , Kim Wan-Ju , Kim Tae-You , Fields C. Robert , Massoll Nicole A. , Robertson Keith D. , Brown Kevin D.
Published: August 2006

Cystatin M is a secreted inhibitor of lysosomal cysteine proteases. Several lines of evidence indicate that cystatin M is a tumor suppressor important in breast malignancy; however, the mechanism(s) that leads to inactivation of cystatin M during cancer progression is unknown. Inspection of the human cystatin M locus uncovered a large and dense CpG island within the 5′ region of this gene (termed CST6). Analysis of cultured human breast tumor lines indicated that cystatin M expression is either undetectable or in low abundance in several lines; however, enhanced gene expression was measured in cells cultured on the DNA demethylating agent 5-aza-2′-deoxycytidine (5-aza-dC). Increased cystatin M expression does not correlate with a cytotoxic response to 5-aza-dC; rather, various molecular approaches indicated that the CST6 gene was aberrantly methylated in these tumor lines as well as in primary breast tumors. Moreover, 60% (12 of 20) of primary tumors analyzed displayed CST6 hypermethylation, indicating that this aberrant characteristic is common in breast malignancies. Finally, preinvasive and invasive breast tumor cells were microdissected from nine archival breast cancer specimens. Of the five tumors displaying CST6 gene methylation, four tumors displayed methylation in both ductal carcinoma in situ and invasive breast carcinoma lesions and reduced expression of cystatin M in these tumors was confirmed by immunohistochemistry. In summary, this study establishes that the tumor suppressor cystatin M is a novel target for epigenetic silencing during mammary tumorigenesis and that this aberrant event can occur before development of invasive breast cancer. (Cancer Res 2006; 66(16): 7899-909)
Switching on Chromosomal Translocations
Authors: Ramiro Almudena R. , Nussenzweig Michel C. , Nussenzweig André
Published: August 2006

Activation-induced deaminase initiates three different antibody diversification reactions: class switch recombination, somatic hypermutation (SHM), and gene conversion. We have shown that, in addition to antibody diversification, activation-induced deaminase can also initiate Burkitt's lymphoma–like c-myc/IgH translocations. However, distinct DNA damage- and oncogene-induced checkpoints operate in B cells to produce a normal intrachromosomal class switch recombination event or an aberrant interchromosomal fusion. These findings open the way to study the molecular pathways taking place at the early stages of malignant transformation. (Cancer Res 2006; 66(16): 7837-9)
Disruption of Scaffold Attachment Factor B1 Leads to TBX2 Up-regulation, Lack of p19ARF Induction, Lack of Senescence, and Cell Immortalization
Authors: Dobrzycka Klaudia M. , Kang Kaiyan , Jiang Shiming , Meyer Rene , Rao Pulivarthi H. , Lee Adrian V. , Oesterreich Steffi
Published: August 2006

Scaffold attachment factor B1 (SAFB1) is a multifunctional protein, which has previously been implicated in breast cancer. Here, we show that genetic deletion of SAFB1 in mouse embryonic fibroblasts (MEF) leads to spontaneous immortalization and altered expression of two proteins involved in immortalization and escape from senescence: low levels of p19ARF and high levels of TBX2. Inactivation of TBX2 using a dominant-negative TBX2 resulted in up-regulation of p19ARF in SAFB1 knockout MEFs. SAFB1 loss also caused lack of contact inhibition, increased foci formation, and increased oncogene-induced anchorage-independent growth. These findings suggest that SAFB1 is a novel player in cellular immortalization and transformation. (Cancer Res 2006; 66(16): 7859-63)
Neutrophil Granulocytes Are Required for EffectiveBacillus Calmette-GuérinImmunotherapy of Bladder Cancer and Orchestrate Local Immune Responses
Authors: Suttmann Henrik , Riemensberger Josef , Bentien Gabriele , Schmaltz Dominik , Stöckle Michael , Jocham Dieter , Böhle Andreas , Brandau Sven
Published: August 2006

The role of polymorphonuclear neutrophil granulocytes (PMN) in antitumoral immune responses displays a striking dichotomy. Under inflammatory conditions, PMN may promote tumor growth and progression. In contrast, especially in the context of therapeutic interventions, PMN can exert important antitumor functions. However, until now, the mechanisms of PMN-mediated activation of tumor immunity are poorly defined. Based on a murine model of Bacillus Calmette-Guérin (BCG) immunotherapy of bladder cancer, we provide evidence for a novel immunoregulatory role of this leukocyte subset. PMN immigrate into the bladder after intravesical BCG instillation and depletion of PMN from tumor-bearing mice completely abrogated antitumor efficacy of BCG. PMN stimulated with BCG in vitro as well as PMN isolated from the urine of BCG-treated patients were a major source of the chemokines interleukin-8, growth-related oncogene-α, macrophage inflammatory protein-1α and of the inflammatory cytokine migration inhibitory factor. In vitro, BCG-stimulated PMN indirectly induced T-cell chemotaxis via the accessory function of activated monocytes. In vivo, depletion of PMN from BCG-treated mice significantly impaired CD4+ T-cell trafficking to the bladder. These data show that PMN direct the migration of effector cells to the bladder and by this means are indispensable for effective tumor immunotherapy. Thus, our findings provide evidence for a novel early immunoregulatory role of these innate immune cells in local antitumor immunity. (Cancer Res 2006; 66(16): 8250-7)
Presence ofEpidermal Growth Factor ReceptorGene T790M Mutation as a Minor Clone in Non–Small Cell Lung Cancer
Authors: Inukai Michio , Toyooka Shinichi , Ito Sachio , Asano Hiroaki , Ichihara Shuji , Soh Junichi , Suehisa Hiroshi , Ouchida Mamoru , Aoe Keisuke , Aoe Motoi , Kiura Katsuyuki , Shimizu Nobuyoshi , Date Hiroshi
Published: August 2006

The threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene has been reported in progressing lesions after gefitinib treatment in non–small cell lung cancer (NSCLC) that causes sensitive tumors to become resistant to gefitinib. Alternatively, the EGFR T790M mutation might be present in small fractions of tumor cells before drug treatment, and the tumor cells harboring the T790M mutation might be enriched during the proliferation after drug treatment. We developed a mutant-enriched PCR assay to detect small fractions of cells with T790M mutation and used this technique to detect mutations in 280 NSCLCs, including gefitinib-treated 95 cases. Although the direct sequencing detected only 1 T790M mutant case, the mutant-enriched PCR (confirmed to enrich one mutant out of 1 × 103 wild-type alleles) detected 9 additional cases among 280 cases. As linkage to clinicopathologic factors, the T790M mutation showed no bias for sex, smoking status, or histology but was significantly more frequent in advanced tumors (9 of 111 cases) than in early-stage tumors (1 of 169 cases; P = 0.0013). Among gefitinib-treated cases, gefitinib-sensitive mutations were found in 30 cases. The T790M mutation was present in 3 of 7 no-responders with the gefitinib-sensitive mutation and was not present in 19 responders (P = 0.014). Our results indicate that the T790M mutation is sometimes present in a minor population of tumor cells during the development of NSCLC and suggest that the detection of small fractions of T790M mutant alleles may be useful for predicting gefitinib resistance of NSCLCs with sensitive EGFR mutations. (Cancer Res 2006; 66(16): 7854-8)
Skeletonized Internal Thoracic Artery Harvest Reduces Pain and Dysesthesia and Improves Sternal Perfusion After Coronary Artery Bypass Surgery
Authors: Boodhwani Munir , Lam B. Khanh , Nathan Howard J. , Mesana Thierry G. , Ruel Marc , Zeng Wanzhen , Sellke Frank W. , Rubens Fraser D.
Published: August 2006

Background—

Observational studies suggest that skeletonization of the internal thoracic artery (ITA) can improve conduit flow and length and reduce deep sternal infections and postoperative pain. We performed a randomized, double-blind, within-patient comparison of skeletonized and nonskeletonized ITAs in patients undergoing coronary surgery.

Methods and Results—

Patients (n=48) undergoing bilateral ITA harvest were randomized to receive 1 skeletonized and 1 nonskeletonized ITA. Intraoperatively, ITA flow was assessed directly and with a Doppler flow probe before and after topical application of papaverine. ITA harvest time and conduit length were recorded. A blinded assessment of pain (visual analog scale) and dysesthesia (physical examination) was performed at discharge, at 2 weeks, and at a 3-month follow-up. Sternal perfusion was assessed with nuclear imaging (n=7). Skeletonization required longer ITA harvest times (27±1 versus 24±1 minutes;
P
=0.04). There was a trend toward increased ITA length in the skeletonized group (18.2±0.3 versus 17.7±0.3 cm;
P
=0.09). In situ ITA flow was lower in skeletonized arteries (7.4±0.9 versus 10.1±1.0 mL/min;
P
=
0.01) and increased significantly after ITA division and papaverine application. Postanastomotic flows were similar between groups. Skeletonization was associated with decreased pain at the 3-month follow-up and a reduction in major sensory deficits at the 4-week and 3-month (17% versus 50%;
P
=0.002) follow-ups. Baseline adjusted sternal perfusion was significantly greater by 17±6% (
P
=0.03) on the skeletonized side.

Conclusions—

Skeletonization results in reduced postoperative pain and dysesthesia and increased sternal perfusion at follow-up but does not produce increased conduit flow. ITA skeletonization may be a strategy for reducing morbidity after CABG.
Augmentation of Myocardial Production of 15-Epi-Lipoxin-A
4
by Pioglitazone and Atorvastatin in the Rat
Authors: Birnbaum Yochai , Ye Yumei , Lin Yu , Freeberg Sheldon Y. , Nishi Shawn P. , Martinez Juan D. , Huang Ming-He , Uretsky Barry F. , Perez-Polo Jose R.
Published: August 2006

Background—

Both statins and thiazolidinediones have antiinflammatory properties. However, the exact mechanisms underlying these effects are unknown. We investigated whether atorvastatin (ATV) and pioglitazone (PIO) increase the myocardial content of lipoxin-A
4
and 15(R)-epi-lipoxin-A
4
(15-epi-LXA
4
), both arachidonic acid products with strong antiinflammatory properties.

Methods and Results—

In experiment 1, rats received 3-day pretreatment with water; PIO 2, 5, or 10 mg · kg
−1
· d
−1
; ATV 2, 5, or 10 mg · kg
−1
· d
−1
; or PIO 10 mg · kg
−1
· d
−1
+ATV 10 mg · kg
−1
· d
−1
. In experiment 2, rats received water; PIO 10 mg · kg
−1
· d
−1
+ATV 10 mg · kg
−1
· d
−1
; PIO+ATV and valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor; PIO+ATV and zileuton, a selective 5-lipoxygenase inhibitor; or zileuton alone. There were 4 rats in each group. Hearts were harvested and analyzed for myocardial lipoxin-A
4
and 15-epi-LXA
4
levels and for COX-2 and 5-lipoxygenase protein expression. ATV and PIO at 5 and 10 mg · kg
−1
· d
−1
significantly increased myocardial 15-epi-LXA
4
levels compared with the sham-treated group (0.51±0.02 ng/mg). Myocardial 15-epi-LXA
4
were significantly higher in the PIO+ATV group (1.29±0.02 ng/mg;
P
<0.001 versus each other group). Both valdecoxib and zileuton abrogated the PIO+ATV increase in 15-epi-LXA
4
, whereas zileuton alone had no effect. PIO, ATV, and their combination resulted in a small increase in myocardial lipoxin-A
4
levels, which was not statistically significant. ATV alone or in combination with PIO markedly augmented COX-2 expression. PIO had a much smaller effect on COX-2 expression. Myocardial expression of 5-lipoxygenase was not altered by PIO, ATV, or their combination.

Conclusions—

Both PIO and ATV increase myocardial levels of 15-epi-LXA
4
, a mediator with antiinflammatory properties. This finding may explain the antiinflammatory properties of both PIO and ATV.
Risk of Thromboembolic Events After Percutaneous Left Atrial Radiofrequency Ablation of Atrial Fibrillation
Authors: Oral Hakan , Chugh Aman , Özaydın Mehmet , Good Eric , Fortino Jackie , Sankaran Sundar , Reich Scott , Igic Petar , Elmouchi Darryl , Tschopp David , Wimmer Alan , Dey Sujoya , Crawford Thomas , Pelosi Frank , Jongnarangsin Krit , Bogun Frank , Morady Fred
Published: August 2006

Background—

In patients with atrial fibrillation (AF), the risk of thromboembolic events (TEs) is variable and is influenced by the presence and number of comorbid conditions. The effect of percutaneous left atrial radiofrequency ablation (LARFA) of AF on the risk of TEs is unclear.

Methods and Results—

LARFA was performed in 755 consecutive patients with paroxysmal (n=490) or chronic (n=265) AF. Four hundred eleven patients (56%) had ≥1 risk factor for stroke. All patients were anticoagulated with warfarin for ≥3 months after LARFA. A TE occurred in 7 patients (0.9%) within 2 weeks of LARFA. A late TE occurred 6 to 10 months after ablation in 2 patients (0.2%), 1 of whom still had AF, despite therapeutic anticoagulation in both. Among 522 patients who remained in sinus rhythm after LARFA, warfarin was discontinued in 79% of 256 patients without risk factors and in 68% of 266 patients with ≥1 risk factor. Patients older than 65 years or with a history of stroke were more likely to remain anticoagulated despite a successful outcome from LARFA. None of the patients in whom anticoagulation was discontinued had a TE during 25±8 months of follow-up.

Conclusions—

The risk of a TE after LARFA is 1.1%, with most events occurring within 2 weeks after the procedure. Discontinuation of anticoagulant therapy appears to be safe after successful LARFA, both in patients without risk factors for stroke and in patients with risk factors other than age >65 years and history of stroke. Sufficient safety data are as yet unavailable to support discontinuation of anticoagulation in patients older than 65 years or with a history of stroke.
Characterising the System of the International Criminal Court: An Exploration of the Role of the Court Through the Elements of Crimes and the Crime of Genocide
Authors: McKay Leanne
Published: August 2006

This paper examines the nature of the legislative system of the International Criminal Court, as established by the Rome Statute and the Elements of Crimes. It asks, to what extent can this system be seen as self-contained and self-sustaining or is its role better described as one of global harmonisation of existing and developing international criminal law? By examining the Elements of Crimes and their operation through the case study of the crime of genocide, the paper identifies some of the contradictions and challenges facing both the judges and parties who are obliged to work within this system, and also national jurisdictions that simultaneously seek to maintain their sovereignty and be included within the International Criminal Court system.
International Sentencing Law: In Search of a Justification and Coherent Framework
Authors: Bagaric Mirko , Morss John
Published: August 2006

An international sentencing jurisprudence is emerging from the decisions by the International Criminal Tribunal for the Former Yugoslavia (ICTY or the Yugoslav tribunal) and the International Criminal Tribunal for Rwanda (ICTR or the Rwanda tribunal) (collectively, 'the tribunals'). This article examines international sentencing law and practice and discusses the justification for the practice. International sentencing law has several objectives. The main goals are reconciliation, deterrence, retribution and rehabilitation. The sentencing inquiry is marked by a high degree of discretion and has resulted in sentencers developing a large amount of aggravating and mitigating considerations, such as being in a position of authority, remorse and good character. It is argued that the current international sentencing approach is flawed – fundamentally so. Most of the stated goals of international sentencing in the form of reconciliation, retribution and rehabilitation are either highly speculative or misguided. The only justification for the practice is general deterrence. This is, however, significantly undermined by the selective and infrequent enforcement of crimes within the jurisdiction of such tribunals. The stated aggravated and mitigating considerations are not valid given that they are not justified by reference to the stated aims of sentencing and only serve to undermine the search for a penalty which is commensurate the serious of the offence. This article suggests a coherent framework for international sentencing policy and practice.
A Model of Social Organization and the Evolution of Food Sharing in Vampire Bats
Authors: Paolucci Mario , Conte Rosaria , Tosto Gennaro Di
Published: August 2006

This article is aimed at exploring the role of groups in the evolution of a well-known form of altruism: blood sharing among vampire bats. In particular, we are interested in the formation and maintenance of new social structures (roosts) from initial populations as a consequence of both demographic growth and social organization. The example of vampire bats is especially interesting because of the flexible roost-switching behavior shown by these animals in nature. The main hypothesis made in this article concerns the role of grooming networks in roost formation, and was investigated by means of simula tion grounded on ethological evidence. The use of simulation allows the discussion of generative hypotheses on the origin of roosts, which are emergent from individual behavior. Besides confirming the main expectations, the results point to the need for a natural ordering in grooming partner selection. This ordering can be obtained not only through kin-based groups but also through the maintenance of a non kin-based precedence rule.
How Learning Affects the Evolution of Strong Reciprocity
Authors: Calderón Juan Pablo , Zarama Roberto
Published: August 2006

Experiments show that humans cooperate with non-kin, including people they will never meet again, and punish non-cooperators at personal cost. This is called strong reciprocity. It has recently been sug gested, based on evolutionary simulations of an agent-based model inspired by the ultimatum game, that strong reciprocity may arise from individual selection. Ontogenic adaptations were introduced to the model to see how phenotypic plasticity affects the evolution of strong reciprocity. The influence of plasticity is explored by varying the way in which agents adapt. Simulations show that plasticity during an agent's lifetime changes the path of evolution toward interesting behaviors that better approach those observed in humans. As plasticity is increased, the average offers and acceptance threshold also increase.
A high-density consensus map of barley linking DArT markers to SSR, RFLP and STS loci and agricultural traits
Authors: Wenzl Peter , Li Haobing , Carling Jason , Zhou Meixue , Raman Harsh , Paul Edie , Hearnden Phillippa , Maier Christina , Xia Ling , Caig Vanessa , Ovesná Jaroslava , Cakir Mehmet , Poulsen David , Wang Junping , Raman Rosy , Smith Kevin P , Muehlbauer Gary J , Chalmers Ken J , Kleinhofs Andris , Huttner Eric , Kilian Andrzej
Published: August 2006

Background

Molecular marker technologies are undergoing a transition from largely serial assays measuring DNA fragment sizes to hybridization-based technologies with high multiplexing levels. Diversity Arrays Technology (DArT) is a hybridization-based technology that is increasingly being adopted by barley researchers. There is a need to integrate the information generated by DArT with previous data produced with gel-based marker technologies. The goal of this study was to build a high-density consensus linkage map from the combined datasets of ten populations, most of which were simultaneously typed with DArT and Simple Sequence Repeat (SSR), Restriction Enzyme Fragment Polymorphism (RFLP) and/or Sequence Tagged Site (STS) markers.

Results

The consensus map, built using a combination of JoinMap 3.0 software and several purpose-built perl scripts, comprised 2,935 loci (2,085 DArT, 850 other loci) and spanned 1,161 cM. It contained a total of 1,629 'bins' (unique loci), with an average inter-bin distance of 0.7 ± 1.0 cM (median = 0.3 cM). More than 98% of the map could be covered with a single DArT assay. The arrangement of loci was very similar to, and almost as optimal as, the arrangement of loci in component maps built for individual populations. The locus order of a synthetic map derived from merging the component maps without considering the segregation data was only slightly inferior. The distribution of loci along chromosomes indicated centromeric suppression of recombination in all chromosomes except 5H. DArT markers appeared to have a moderate tendency toward hypomethylated, gene-rich regions in distal chromosome areas. On the average, 14 ± 9 DArT loci were identified within 5 cM on either side of SSR, RFLP or STS loci previously identified as linked to agricultural traits.

Conclusion

Our barley consensus map provides a framework for transferring genetic information between different marker systems and for deploying DArT markers in molecular breeding schemes. The study also highlights the need for improved software for building consensus maps from high-density segregation data of multiple populations.
Identification of the ancestral killer immunoglobulin-like receptor gene in primates
Authors: Sambrook Jennifer G , Bashirova Arman , Andersen Hanne , Piatak Mike , Vernikos George S , Coggill Penny , Lifson Jeff D , Carrington Mary , Beck Stephan
Published: August 2006

Background

Killer Immunoglobulin-like Receptors (KIR) are essential immuno-surveillance molecules. They are expressed on natural killer and T cells, and interact with human leukocyte antigens. KIR genes are highly polymorphic and contribute vital variability to our immune system. Numerous KIR genes, belonging to five distinct lineages, have been identified in all primates examined thus far and shown to be rapidly evolving. Since few KIR remain orthologous between species, with only one of them,KIR2DL4, shown to be common to human, apes and monkeys, the evolution of the KIR gene family in primates remains unclear.

Results

Using comparative analyses, we have identified the ancestral KIR lineage (provisionally namedKIR3DL0) in primates. We showKIR3DL0to be highly conserved with the identification of orthologues in human (Homo sapiens), common chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla), rhesus monkey (Macaca mulatta) and common marmoset (Callithrix jacchus). We predictKIR3DL0to encode a functional molecule in all primates by demonstrating expression in human, chimpanzee and rhesus monkey. Using the rhesus monkey as a model, we further show the expression profile to be typical of KIR by quantitative measurement ofKIR3DL0from an enriched population of natural killer cells.

Conclusion

One reason whyKIR3DL0may have escaped discovery for so long is that, in human, it maps in between two related leukocyte immunoglobulin-like receptor clusters outside the known KIR gene cluster on Chromosome 19. Based on genomic, cDNA, expression and phylogenetic data, we report a novel lineage of immunoglobulin receptors belonging to the KIR family, which is highly conserved throughout 50 million years of primate evolution.
Biphasic parapharyngeal synovial sarcoma : A cytologic and immunocytologic report of a case
Authors: Khademi Bijan , Daneshbod Yahya , Negahban Shahrzad , Daneshbod Khosrow , Kaviani Massud , Mohammadianpanah Mohammad , Ashraf Mohammad J
Published: August 2006

Background:

Synovial sarcoma is a rare soft tissue sarcoma in the head and neck region and parapharyngeal space. There is no previous cytologic report of synovial sarcoma of parapharynx. The cytologic and immunocytochemical findings of a parapharyngeal biphasic synovial sarcoma together with diagnostic pitfalls are described.

Case report:

A 21-year-old girl presented with a 6-month history of progressive right arm pain, neck mass and upper aerodigestive tract obstruction. On physical examination there was a large painless mass arising from the right-sided parapharyngeal space causing airway obstruction. Initial magnetic resonance imaging (MRI) revealed a large tumor in the right-sided parapharyngeal space. Fine needle aspiration through cervical region was performed and was reported as benign spindle cell tumor. Smears were cellular and composed mostly of tight and loose clusters of spindle cells. Epitheloid cells could also be identified intermingled with them. She underwent near total resection of the tumor. Pathologic report disclosed the diagnosis of synovial sarcoma. She then received postoperative adjuvant external radiotherapy.

Conclusion:

Due to rarity of this tumor in this region and nonspecific cytologic features, we could not differentiate this tumor from the other more common spindle cell neoplasms. Considering synovial sarcoma in this region and immunocytochemistry can be helpful in rendering a correct initial diagnosis of this tumor.
Serum, urinary, and salivary nitric oxide in rheumatoid arthritis: complexities of interpreting nitric oxide measures
Authors: Weinberg J Brice , Lang Thomas , Wilkinson William E , Pisetsky David S , St Clair E William
Published: August 2006

Nitric oxide (NO) may play important roles in rheumatoid arthritis (RA). RA is an inflammatory disease involving joints and other systems including salivary glands. To assess NO production in RA patients, we compared levels of serum, urine, and salivary nitrite and nitrate (NOx) in patients with RA and normal subjects, and we examined the relationships of these measures to disease activity. Serum, urine, and NOx levels as well as renal creatinine, NOx clearance and fractional excretion rates were compared in 25 RA patients and 20 age- and gender-matched healthy controls. Subjects were hospitalized for 3 days and placed on a NOxrestricted diet. NOx was assayed using nitrate reductase and the Griess reagent. RA activity was assessed using standard clinical and laboratory measures. While consuming a restricted diet for 3 days to eliminate the effects of oral intake of NOx, 24 hour urinary NOx excretion decreased in both RA patients and healthy controls. Urine NOx levels at all time points were not significantly different between RA patients and normal subjects. Serum NOx levels also decreased during the 3 days of NOx restriction, but RA patients had higher serum NOx levels at all time points compared with the control group. Likewise, serum NOx/creatinine ratios were higher in RA patients than in controls. Although basal salivary flow rate and tear flow were lower in RA patients, salivary NOx levels did not differ between normal and RA subjects. While renal creatinine clearance was not different between the two groups, we found that RA patients had lower renal NOx clearance and lower renal NOx fractional excretion. After correction of p values for multiple comparisons, there were no significant relationships for the RA group between measures of disease activity and the urinary NOx, serum NOx, or urinary NOx clearance. Despite interest in the use of NO as a marker of disease activity, alterations in renal NOx clearance and fractional excretion in RA make it difficult to assess in vivo NO production even with strict dietary restriction of NOx intake.
Preventing autoimmune arthritis using antigen-specific immature dendritic cells: a novel tolerogenic vaccine
Authors: Popov Igor , Li Mu , Zheng Xiufen , San Hongtao , Zhang Xusheng , Ichim Thomas E , Suzuki Motohiko , Feng Biao , Vladau Costin , Zhong Robert , Garcia Bertha , Strejan Gill , Inman Robert D , Min Wei-Ping
Published: August 2006

Conventional treatments for autoimmune diseases have relied heavily on nonspecific immune suppressants, which possess a variety of adverse effects without inhibiting the autoimmune process in a specific manner. In the present study we demonstrate the effectiveness of antigen-specific, maturation-resistant, tolerogenic dendritic cells (DC) in suppressing collagen-induced arthritis, a murine model of rheumatoid arthritis. Treatment of DC progenitors with the NF-κB inhibiting agent LF 15-0195 (LF) resulted in a population of tolerogenic DC that are characterized by low expression of MHC class II, CD40, and CD86 molecules, as well as by poor allostimulatory capacity in a mixed leukocyte reaction. Administering LF-treated DC pulsed with keyhole limpet hemocyanin antigen to naïve mice resulted hyporesponsiveness specific for this antigen. Furthermore, administration of LF-treated DC to mice with collagen-induced arthritis resulted in an improved clinical score, in an inhibited antigen-specific T-cell response, and in reduced antibody response to the collagen. The efficacy of LF-treated DC in preventing arthritis was substantiated by histological examination, which revealed a significant decrease in inflammatory cell infiltration in the joints. In conclusion, we demonstrate that in vitro-generated antigen-specific immature DC may have important potential as a tolerogenic vaccine for the treatment of autoimmune arthritis.
Pivotal Advance: Francisella tularensis LVS evades killing by human neutrophils via inhibition of the respiratory burst and phagosome escape
Authors: McCaffrey Ramona L , Allen Lee-Ann H
Published: August 2006

Francisella tularensis is a Gram-negative bacterium and the causative agent of tularemia. Recent data indicate that F. tularensis replicates inside macrophages, but its fate in other cell types, including human neutrophils, is unclear. We now show that F. tularensis live vaccine strain (LVS), opsonized with normal human serum, was rapidly ingested by neutrophils but was not eliminated. Moreover, evasion of intracellular killing can be explained, in part, by disruption of the respiratory burst. As judged by luminol-enhanced chemiluminescence and nitroblue tetrazolium staining, neutrophils infected with live F. tularensis did not generate reactive oxygen species. Confocal microscopy demonstrated that NADPH oxidase assembly was disrupted, and LVS phagosomes did not acquire gp91/p22phox or p47/p67phox. At the same time, F. tularensis also impaired neutrophil activation by heterologous stimuli such as phorbol esters and opsonized zymosan particles. Later in infection, LVS escaped the phagosome, and live organisms persisted in the neutrophil cytosol for at least 12 h. To our knowledge, our data are the first demonstration of a facultative intracellular pathogen, which disrupts the oxidative burst and escapes the phagosome to evade elimination inside neutrophils, and as such, our data define a novel mechanism of virulence.
Long-Term Cardiac Tolerability of Trastuzumab in Metastatic Breast Cancer: The M.D. Anderson Cancer Center Experience
Authors: Guarneri Valentina , Lenihan Daniel J. , Valero Vicente , Durand Jean-Bernard , Broglio Kristine , Hess Kenneth R. , Michaud Laura Boehnke , Gonzalez-Angulo Ana M. , Hortobagyi Gabriel N. , Esteva Francisco J.
Published: August 2006

Purpose

To evaluate the cardiac safety of long-term trastuzumab therapy in patients with human epidermal growth receptor 2 (HER2) –overexpressing metastatic breast cancer (MBC) treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX).

Patients and Methods

Among 218 MBC patients treated with trastuzumab-based therapy for at least 1 year, 173 patients were assessable for cardiac toxicity. Cardiac events (CEs) were defined as follows: asymptomatic decrease of left ventricular ejection fraction (LVEF) below 50%; decrease of 20 percentage points in LVEF compared with the baseline; or signs or symptoms of congestive heart failure (CHF).

Results

The median cumulative time for trastuzumab administration was 21.3 months. The median follow-up was 32.6 months (range, 11.8 to 79.0 months). Forty-nine patients (28%) experienced a CE: three patients (1.7%) had an asymptomatic decrease in the LVEF of 20 percentage points, 27 patients (15.6%) experienced grade 2 cardiac toxicity, and 19 patients (10.9%) experienced grade 3 cardiac toxicity. All but three patients had improved LVEF or symptoms of CHF with trastuzumab discontinuation and appropriate therapy. There was one cardiac-related death (0.5%). Baseline LVEF was significantly associated with CE (hazard ratio, 0.94; P = .001). The hazard of a CE among patients taking concomitant taxanes was higher early in the follow-up period but declined during the course of follow-up.

Conclusion

The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function.
Influence of Windfarms on Power System Dynamic and Transient Stability
Authors: Anaya-Lara Olimpo , Hughes F. Michael , Jenkins Nicholas , Strbac Goran
Published: August 2006

The interaction between bulk windfarm generation and conventional generation and its influence on network dynamic characteristics are investigated. A simple three-generator system having characteristics that may be considered representative of the major areas of the UK network is used for the dynamic studies. Time response simulation and eigenvalue analysis are used to establish basic transient and dynamic stability characteristics. The wind generation is provided either by windfarms based on Fixed Speed Induction Generators (FSIGs) or Doubly Fed Induction Generators (DFIGs). In addition, in order to provide a base-line, against which windfarm influence on network dynamics can be judged, the case where the power is provided only by conventional synchronous generation is also considered.
Clean Energy Funds in Individual US States Provide Significant Support for Utility-Scale Wind Power
Authors: Bolinger Mark , Wiser Ryan
Published: August 2006

Federal support for wind power in the United States occurs primarily through the tax code, in the form of accelerated depreciation and a 10-year production tax credit. Support for wind power from individual States within the US, however, is much more diverse, and includes State clean-energy funds, State renewables portfolio standards, and various types of State tax incentives. This article focuses exclusively on State clean-energy funds, which exist in 14 States and in aggregate collect roughly $500 million per year to aid in the deployment of renewable energy. In 8 of these 14 States, a portion of funding has been allocated to utility-scale renewable energy projects. To date, utility-scale wind projects have been the dominant recipient of such funds, with 970 MW online through March 2006. This article reviews the experience of these 8 States in supporting utility-scale wind projects via clean-energy funds.
Fault Ride-through Testing of Wind Turbines
Authors: Mo Olve , Tande John Olav , Warland Leif , Ljøkelsøy Kjell
Published: August 2006

Grid codes concerning low-voltage fault ride-through capabilities of wind turbines are not (yet) harmonized, varying from country to country. Full-scale field testing of wind turbines with respect to all such codes may therefore not be practical.

IEC 61400-21 is currently under revision, and the last committee draft (CD 2006) presents a standardized physical test for characterizing a wind turbine's response to a voltage-dip. The results of such physical tests may be used to validate numerical models of the turbine, which in turn can be used for modelling grid code compliance assessment of particular country codes. Success with such modelled validation will provide confidence in numerical simulations.

The hypothesis of this paper is that the use of numerical models, that have been validated against the standardized tests, can reduce the number of physical full-scale tests needed.

This paper assesses to what degree a validated simulation model is capable of predicting the fault ride-through capabilities of a fixed speed induction generator. This is done by comparing measurements on a wind-turbine emulator in a laboratory with predictions from a validated simulation model of the laboratory emulator.

Simulations and laboratory measurements show excellent agreement. The validated simulation model accurately predicts the fault ride-through capability of the direct grid connected induction generator.

It is concluded that the proposed methodology is promising and thus has the potential to increase the efficiency of grid code assessments. Full-scale field tests will still be required to validate the modelling completely, but using numerical models reduces the number of field tests needed.
Optimal Econoimc Layout of Turbines on Windfarms
Authors: Attias Koby , Ladany Shaul P.
Published: August 2006

A general discrete model is formulated for the expected (i) Net Present Value (NPV) of the profit and (ii) yield of the investment (Internal Rate of Return - IRR) derived from windfarms on flat ground or over water. It is assumed that the wind-turbines are identical and of equal height, and are spaced equally along the axes of a rectangle, but not necessarily at the same equal distance along both axes. The model considers wind shadowing in the down-wind direction and the effect of wakes behind the turbines, the joint wind-direction wind-velocity probability distribution and various relevant cost and revenue factors. Using the model, the optimal layout that maximizes the expected NPV and/or IRR was derived numerically for a given data set. The calculation proceeded in stages, so determining the optimal number and separation of turbines by row and column. Sensitivity analysis has shown that minor changes in the parameters do not affect the selection of the optimal layout.
Wind Power Density Statistics Using the Weibull Model for Inner Mongolia, China
Authors: Yingni Jiang , Xiuling Yuan , Jianmei Feng , Xiaojun Cheng
Published: August 2006

The Weibull density function is used to estimate the wind energy potential of Zhurihe station (42.2°N, 112.5°E) situated in the most windy area of Inner Mongolia, China. Based on 10 years (1991–2000) measured daily-average wind-speed data, the scale and shape parameters of the Weibull model are estimated and the probability density distributions are derived from the time-series data. The wind energy potential of Zhurihe station is also evaluated by the Weibull model.
Combined Treatment of Steroids and Cyclosporine in Kimura Disease
Authors: Sato Satoshi , Kawashima Hisashi , Kuboshima Shinji , Watanabe Kiyoko , Kashiwagi Yasuyo , Takekuma Kouji , Hoshika Akinori
Published: August 2006

Kimura disease is a rare but distinctive chronic eosinophilic inflammatory disorder that is characterized by tumor-like lesions in the soft tissue and lymph nodes of the head and neck or parotid gland. Recently, many immunopathogenetic features of underlying T lymphocytes and related cytokines have been noted in Kimura disease. However, few previous studies have investigated the serial levels of cytokines in children. In this report we describe an 11-year-old Japanese boy with relapsing Kimura disease. Before the diagnosis of Kimura disease, the patient had a swelling on his left neck. Steroids were effective, but the tumor relapsed within a few months as the steroids were tapered. He was treated with steroids and cyclosporine. This treatment was done by measuring serial levels of serum soluble interleukin-2 receptor, interleukin-4, interleukin-5, and eosinophil cationic protein. These results suggest the activation of T-helper cells and T-helper 2 cytokines, that after activated B cells and eosinophilic infiltration play an important role in Kimura disease, and that cyclosporine suppresses the activity of this disease.
To Slideware or Not to Slideware: Students' Experiences with Powerpoint Vs. Lecture
Authors: Amare Nicole
Published: August 2006

This study analyzes the performance and attitudes of technical writing students in PowerPoint-enhanced and in non- PowerPoint lectures. Four classes of upper-level undergraduates ( n = 84) at a mid-sized, Southern university taking a one-semester technical writing course were surveyed at the beginning and end of the course about their perceptions of PowerPoint. Of the four sections, two classes were instructed using traditional lecture materials (teacher at podium, chalkboard, handouts); the other two sections were instructed with PowerPoint presentations. All four classes were given the same pre- and post-test to measure performance over the course of the semester. Traditional lecture or PowerPoint presentations consisted of at least 50% of the course, with the remaining time spent on exercises and small group work. Results reveal that while most students say they preferred PowerPoint, performance scores were higher in the sections with the traditional lecture format.