bluuebunny/crossref_metadata_2025 huggingface dataset:
The Best of Times, the Worst of Times
Authors: King Eden B. , Reilly Clare , Hebl Michelle
Published: July 2008

The present article explores the complexities of sexual orientation disclosure in the workplace and attempts to identify factors that may facilitate positive or exacerbate negative disclosure experiences from the perspectives of gay and lesbian employees (Study 1) and heterosexual coworkers (Study 2). Content analyses of narrative descriptions of “coming out” experiences suggest that the supportiveness of the climate of an organization may be more critical than timing or method of disclosure for gay and lesbian individuals. Reports from heterosexual individuals, however, suggest that timing of disclosure is meaningful over and above their own attitudes toward homosexuality and the organization's climate. These results indicate that both situational and contextual characteristics influence disclosure encounters and that disclosers' and recipients' experiences may differ in the extent to which they are influenced by each of these factors.
Partisan and Nonpartisan Message Content and Voter Mobilization
Authors: Panagopoulos Costas
Published: July 2008

This article reports the results of a randomized field experiment designed to compare directly the mobilization impact of partisan versus nonpartisan messages delivered via commercial phone banks. The experiment, conducted during the November 2005 municipal elections in Albany, New York, incorporates a series of design innovations to improve on extant research and to assuage skepticism about the internal and external validity of previous studies conducted along these lines. The author finds that partisan messages delivered by professional call centers are no more effective than nonpartisan messages in mobilizing voters.
Pluralism, Relativism, and Liberalism
Authors: Moore Matthew J.
Published: July 2008

One major focus of recent value-pluralist literature has been the question of what normative consequences follow from pluralism. This essay critically examines three arguments that attempt to show that either liberalism or a bounded modus vivendi is the state of affairs that pluralism makes morally preferable. All three arguments are shown to encounter the same fundamental problem—once we have agreed that values and sets of values are unrankable, any effort to claim that one such set is morally preferable will inevitably contradict value pluralism, either explicitly or implicitly. If this is correct, it seems that pluralism leads to relativism.
Alveolar Rhabdomyosarcoma With Neuroendocrine/Neuronal Differentiation: Report of 3 Cases
Authors: Houreih M. Adib , Lin Amy Y. , Eyden Brian , Menasce Lia P. , Harrison James , Jones David , Folberg Robert , Chejfec Gregorio , Banerjee S. Sankar
Published: July 2008

The aim of this study is to report the clinicopathologic characteristics of 3 cases of alveolar rhabdomyosarcoma with neuroendocrine/neuronal differentiation. Specimens of 3 cases of alveolar rhabdomyosarcoma were studied using histologic, immunohistochemical, ultrastructural, and molecular genetic techniques. The patients were a 19-year-old man with metastatic alveolar rhabdomyosarcoma in a groin lymph node, a 16-year-old girl with alveolar rhabdomyosarcoma of the perineum, and a 20-year-old man with recurrent orbital alveolar rhabdomyosarcoma. Microscopically, case 1 was composed of compact sheets of medium to large tumor cells. Cases 2 and 3 were small blue round cell tumors. Cases 1 and 3 were solid throughout, whereas case 2 demonstrated alveolar and solid architecture. By immunohistochemistry, the following markers were positive: desmin (3/3), myogenin (3/3), synaptophysin (3/3), and chromogranin (2/3). Ultrastructurally, sarcomeric filaments were seen in all cases, while neuroendocrine granules were detected only in case 1. PAX:FKHR fusion transcript was identified in case 2, case 3 had a variant PAX3 transcript, and case 1 was negative. The data presented expands the known differentiation of alveolar rhabdomyosarcoma.
Aggressive Osteoblastoma: A Case Report Involving a Unique Chromosomal Aberration
Authors: Baker Allyson C. , Rezeanu Luminita , Klein Michael J. , Pitt Michael J. , Buecker Peter , Hersh Joseph H. , Buchino John J. , Siegal Gene P.
Published: July 2008

Osteoblastomas are rare bone-producing neoplasms that generally occur in the young and can be misdiagnosed as an osteosarcoma if correlation with clinical history, radiology, and histology is not carefully considered or if the several variants of osteoblastoma are not recognized. These variants lie on a morphologic spectrum between conventional osteoblastoma and osteosarcoma. Aggressive osteoblastoma is one such subtype. As the name implies, the histologic features of aggressive osteoblastoma may appear malignant, and its biologic behavior may separate it from conventional osteoblastoma. We report a case of aggressive osteoblastoma occurring in the femoral diaphysis of a 12-year-old girl; this osetoblastoma was dyssynchronous from the radiologic appearance and a diagnostic challenge. Cytogenetic evaluation of the neoplasm revealed a pseudodiploid clone with a balanced translocation involving chromosomes 4, 7, and 14. Using the premise that cytogenetics might be useful as a diagnostic tool for a more specific classification, we reviewed the literature in order to compare our findings with known chromosomal aberrations.
Papillary Adenocarcinoma of the Thymus: Case Report and Review of the Literature
Authors: Furtado Antónia , Nogueira Rosete , Ferreira Diva , Tente David , Eisele Rogério , Parente Bárbara
Published: July 2008

A 44-year-old male with a mediastinal mass measuring 3.5 × 3.5 × 3 cm was diagnosed with papillary adenocarcinoma of the thymus. Other origins of papillary adenocarcinoma were excluded by clinical, imaging, and immunocytochemical methods before assuming this diagnosis. Residual thymus was seen under the microscope. Focal CD5 immunoreactivity was present. There was no associated thymoma. The patient underwent surgery, radiotherapy, and chemotherapy. He disclosed systemic recurrence at 18 months (subcutaneous nodule). He is alive after 24 months of follow-up with active disease. There had been only 7 cases of this rare entity published before.
Pseudoangiomatous Stromal Hyperplasia (PASH) of the Breast With Foci of Morphologic Malignancy: A Case of PASH With Malignant Transformation?
Authors: Nassar Hind , Elieff Michelle P. , Kronz Joseph D. , Argani Pedram
Published: July 2008

Pseudoangiomatous stromal hyperplasia (PASH) is a benign proliferation of the hormonally responsive, specialized mammary stroma characterized by slit-like pseudovascular spaces lined by bland spindle cells. It is usually an incidental microscopic finding but in some cases it may present as a slowly growing mass. A malignant counterpart for this lesion has not been reported. We describe a case of PASH with foci of malignant histologic features presenting as a slowly growing mass in a 30-year-old woman. The previously reported variants of PASH and the other mammary stromal lesions related to PASH are also discussed. This is perhaps the first case of PASH with foci of malignant histologic features reported in the literature and represents a rare sarcoma derived from specialized hormonally responsive mammary stroma.
Merits of the PMiT (Papillary Microtumor) Terminology in the Definition of a Subset of Incidental Papillary Microcarcinomas of the Thyroid
Authors: Asioli Sofia , Odasso Chiara , Macrì Luigia , Palestini Nicola , Bussolati Gianni
Published: July 2008

An exponential increase in the detection of papillary thyroid microcarcinomas (PTMCs) has been observed in recent times, possibly because of recent improvements in the management of thyroid lesions and extensive histological examination. However, no definitive treatment guideline has been developed for PTMC, resulting in patients undergoing overtreatment. In 2003, the term papillary microtumor of the thyroid (PMiT) was proposed for small (≤1 cm) intrathyroidal tumors with excellent prognostic prospects along with strict definition criteria. Since then, the term PMiT has been adopted by clinicians and surgeons. In this article, the authors report a series of 50 consecutive cases of PMiT collected and treated at the University Hospital of Turin, Italy. From the authors’ experience, this terminology, which demarks a subset of PTMC, should be widely adopted as it is biologically sound, well accepted by both clinicians and patients, decreases the danger of overtreatment, minimizes the psychological anxiety engendered by a diagnosis of carcinoma, and maintains the patient’s eligibility for health insurance.
Astrocyte Responses after Neonatal Ischemia: The Yin and the Yang
Authors: Villapol Sonia , Gelot Antoinette , Renolleau Sylvain , Charriaut-Marlangue Christiane
Published: July 2008

Neonatal encephalopathy is a major predictor of neurodevelopmental disability in term infants and occurs in 1 to 6 of every 1000 live term births. Despite improvements in perinatal practice during the past several decades, the incidence of cerebral palsy attributed to neonatal asphyxia remained essentially unchanged, primarily because management strategies were supportive and not targeted toward the processes of ongoing injury. Traditionally, experimental research in vivo focused on neurons, and more recently, oligodendrocytes whereas astrocytes have been more or less neglected. This review aims at dissecting possible protective as well as destructive roles of astrocytes in the immature ischemic brain to stimulate further research into this unexplored aspect of brain pathophysiology. NEUROSCIENTIST 14(4):339ndash;344, 2008. DOI: 10.1177/1073858408316003
Revenue Structure and Nonprofit Borrowing
Authors: Yan Wenli , Denison Dwight V. , Butler J.S.
Published: July 2008

The capital structure of nonprofit organizations plays a crucial role in their sustainability and development. This article explores the extent to which revenue diversification is incorporated into the leverage decision. In addition, this study investigates whether government grants have an impact on the long-term liabilities of nonprofit organizations. A model of nonprofit borrowing is proposed and examined with a national sample of arts, culture, and humanities nonprofit organizations. Model estimates show that nonprofit organizations with higher degree of revenue diversification are more likely to issue debt, but do not necessarily have higher debt ratios. Arts organizations with more government financial support are also more likely to issue debt and to have higher leverage ratios.
The Use of Corticosteroids to Treat Keloids: A Review
Authors: Roques Claude , Téot Luc
Published: July 2008

Mechanisms for keloid formation include drastic changes in growth factor actions, collagen turnover, mechanical forces applied over the skin, and genetic and immunologic contributions. The use of corticosteroids to manage keloids increases basic fibroblast growth factor production while decreasing transforming growth factor-β1 production by human dermal fibroblasts, endogenous vascular endothelial growth factor, and insulin-like growth factor-1. The use of corticosteroid injections is, to date, the core treatment available for the management of excessive tissue production in scars. Currently, the most effective and safe regimen for keloid management appears to be the use of corticotherapy—injection of intradermal steroids after a surgical excision.
The glycoprotein Ib-IX-V complex contributes to tissue factor–independent thrombin generation by recombinant factor VIIa on the activated platelet surface
Authors: Weeterings Cees , de Groot Philip G. , Adelmeijer Jelle , Lisman Ton
Published: July 2008

Several lines of evidence suggest that recombinant factor VIIa (rFVIIa) is able to activate factor X on an activated platelet, in a tissue factor-independent manner. We hypothesized that, besides the anionic surface, a receptor on the activated platelet surface is involved in this process. Here, we showed that, in an ELISA setup, a purified extracellular fragment of GPIbα bound to immobilized rFVIIa. Surface plasmon resonance established a affinity constant (Kd) of approximately 20 nM for this interaction. In addition, CHO cells transfected with the GPIb-IX-V complex could adhere to immobilized rFVIIa, whereas wild-type CHO cells could not. Furthermore, platelets sti-mulated with a combination of collagen and thrombin adhered to immobilized rFVIIa under static conditions. Platelet adhesion was inhibited by treatment with O-sialoglycoprotein endopeptidase, which specifically cleaves GPIbα from the platelet surface. In addition, rFVIIa-mediated thrombin generation on the activated platelet surface was inhibited by cleaving GPIbα from its surface. In summary, 3 lines of evidence showed that rFVIIa interacts with the GPIb-IX-V complex, and this interaction enhanced tissue factor-independent thrombin generation mediated by rFVIIa on the activated platelet surface. The rFVIIa-GPIbα interaction could contribute to cessation of bleeding after administration of rFVIIa to patients with bleeding disorders.
A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial)
Authors: Mead Graham M. , Barrans Sharon L. , Qian Wendi , Walewski Jan , Radford John A. , Wolf Max , Clawson Simon M. , Stenning Sally P. , Yule Claire L. , Jack Andrew S.
Published: July 2008

This prospective study aimed to develop reproducible diagnostic criteria for sporadic Burkitt lymphoma (BL), applicable to routine practice, and to evaluate the efficacy of dose-modified (dm) CODOX-M/IVAC in patients diagnosed using these criteria. The study was open to patients with an aggressive B-cell lymphoma with an MKI67 fraction approaching 100%. Immunophenotype and fluorescent in situ hybridization (FISH) were used to separate BL from other aggressive B-cell lymphomas. BL was characterized by the presence of a cMYC rearrangement as a sole cytogenetic abnormality occurring in patients with a germinal center phenotype with absence of BCL-2 expression and abnormal TP53 expression. A total of 128 patients were eligible for the study, of whom 58 were considered to have BL and 70 to have diffuse large B-cell lymphoma (DLBCL). There were 110 clinically fit patients who received dmCODOX-M (methotrexate, dose 3 g/m2) with or without IVAC according to risk group. The 2-year progression-free survival was 64% (95% confidence interval [CI] 51%-77%) for BL, 55% (95% CI 42%-66%) for DLBCL, 85% (95% CI 73%-97%) for low risk, and 49% (95% CI 38%-60%) for high-risk patients. The observed differences in outcome and other clinical features validate the proposed diagnostic criteria. Compared with the previous trial LY06 with full-dose methotrexate (6.7 g/m2), there was a reduction in toxicity with comparable outcomes. This study was registered at www.clinicaltrials.gov as NCT00040690.
EVI1activation in blast crisis CML due to juxtaposition to the rare 17q22 partner region as part of a 4-way variant translocation t(9;22)
Authors: De Weer An , Poppe Bruce , Cauwelier Barbara , Carlier Andre , Dierick Jan , Verhasselt Bruno , Philippé Jan , Van Roy Nadine , Speleman Frank
Published: July 2008

Background

Variant translocations t(9;22) occur in 5 to 10% of newly diagnosed CMLs and additional genetic changes are present in 60–80% of patients in blast crisis (BC). Here, we report on a CML patient in blast crisis presenting with a four-way variant t(9;22) rearrangement involving the EVI1 locus.

Methods

Dual-colour Fluorescence In Situ Hybridisation was performed to unravel the different cytogenetic aberrations. Expression levels of EVI1 and BCR/ABL1 were investigated using real-time quantitative RT-PCR.

Results

In this paper we identified a patient with a complex 4-way t(3;9;17;22) which, in addition to BCR/ABL1 gene fusion, also resulted in EVI1 rearrangement and overexpression.

Conclusion

This report illustrates how a variant t(9;22) translocation can specifically target a second oncogene most likely contributing to the more aggressive phenotype of the disease. Molecular analysis of such variants is thus warranted to understand the phenotypic consequences and to open the way for combined molecular therapies in order to tackle the secondary oncogenic effect which is unresponsive to imatinib treatment.
The effect on the extracellular matrix of the deep fascia in response to leg lengthening
Authors: Wang Hai-Qiang , Li Xin-Kui , Wu Zi-Xiang , Wei Yi-Yong , Luo Zhuo-Jing
Published: July 2008

Background

Whereas the alterations of diverse tissues in cellular and molecular levels have been investigated during leg lengthening via microscopy and biochemical studies, little is known about the response of deep fascia. This study aims to investigate the changes of the extracellular matrix in deep fascia in response to leg lengthening.

Methods

Animal model of leg lengthening was established in New Zealand white rabbits. Distraction was initiated at a rate of 1 mm/day and 2 mm/day in two steps, and preceded until increases of 10% and 20% in the initial length of tibia had been achieved. Alcian blue stain and picrosirius-polarization method were used for the study of the extracellular matrix of deep fascia samples. Leica DM LA image analysis system was used to investigate the quantitative changes of collagen type I and III.

Results

Alcian blue stain showed that glycosaminoglycans of fascia of each group were composed of chondroitin sulphate and heparin sulphate, but not of keratan sulphate. Under the polarization microscopy, the fascia consisted mainly of collagen type I. After leg lengthening, the percentage of collagen type III increased. The most similar collagen composition of the fascia to that of the normal fascia was detected at a 20% increase in tibia length achieved via a distraction rate of 1 mm/d.

Conclusion

The changes in collagen distribution and composition occur in deep fascia during leg lengthening. Although different lengthening schemes resulted in varied matrix changes, the most comparable collagen composition to be demonstrated under the scheme of a distraction rate of 1 mm/day and 20% increase in tibia length. Efficient fascia regeneration is initiated only in certain combinations of the leg load parameters including appropriate intensity and duration time, e.g., either low density distraction that persist a relatively short time or high distraction rates.
Modulation of microtubule assembly by the HIV-1 Tat protein is strongly dependent on zinc binding to Tat
Authors: Egelé Caroline , Barbier Pascale , Didier Pascal , Piémont Etienne , Allegro Diane , Chaloin Olivier , Muller Sylviane , Peyrot Vincent , Mély Yves
Published: July 2008

Background

During HIV-1 infection, the Tat protein plays a key role by transactivating the transcription of the HIV-1 proviral DNA. In addition, Tat induces apoptosis of non-infected T lymphocytes, leading to a massive loss of immune competence. This apoptosis is notably mediated by the interaction of Tat with microtubules, which are dynamic components essential for cell structure and division. Tat binds two Zn2+ ions through its conserved cysteine-rich region in vitro, but the role of zinc in the structure and properties of Tat is still controversial.

Results

To investigate the role of zinc, we first characterized Tat apo- and holo-forms by fluorescence correlation spectroscopy and time-resolved fluorescence spectroscopy. Both of the Tat forms are monomeric and poorly folded but differ by local conformational changes in the vicinity of the cysteine-rich region. The interaction of the two Tat forms with tubulin dimers and microtubules was monitored by analytical ultracentrifugation, turbidity measurements and electron microscopy. At 20°C, both of the Tat forms bind tubulin dimers, but only the holo-Tat was found to form discrete complexes. At 37°C, both forms promoted the nucleation and increased the elongation rates of tubulin assembly. However, only the holo-Tat increased the amount of microtubules, decreased the tubulin critical concentration, and stabilized the microtubules. In contrast, apo-Tat induced a large amount of tubulin aggregates.

Conclusion

Our data suggest that holo-Tat corresponds to the active form, responsible for the Tat-mediated apoptosis.
A broad spectrum, one-step reverse-transcription PCR amplification of the neuraminidase gene from multiple subtypes of influenza A virus
Authors: Alvarez Alejandra Castillo , Brunck Marion EG , Boyd Victoria , Lai Richard , Virtue Elena , Chen Wenbin , Bletchly Cheryl , Heine Hans G , Barnard Ross
Published: July 2008

Background

The emergence of high pathogenicity strains of Influenza A virus in a variety of human and animal hosts, with wide geographic distribution, has highlighted the importance of rapid identification and subtyping of the virus for outbreak management and treatment. Type A virus can be classified into subtypes according to the viral envelope glycoproteins, hemagglutinin and neuraminidase. Here we review the existing specificity and amplification of published primers to subtype neuraminidase genes and describe a new broad spectrum primer pair that can detect all 9 neuraminidase subtypes.

Results

Bioinformatic analysis of 3,337 full-length influenza A neuraminidase segments in the NCBI database revealed semi-conserved regions not previously targeted by primers. Two degenerate primers with M13 tags, NA8F-M13 and NA10R-M13 were designed from these regions and used to generate a 253 bp cDNA product. One-step RT-PCR testing was successful in 31/32 (97%) cases using a touchdown protocol with RNA from over 32 different cultured influenza A virus strains representing the 9 neuraminidase subtypes. Frozen blinded clinical nasopharyngeal aspirates were also assayed and were mostly of subtype N2. The region amplified was direct sequenced and then used in database searches to confirm the identity of the template RNA. The RT-PCR fragment generated includes one of the mutation sites related to oseltamivir resistance, H274Y.

Conclusion

Our one-step RT-PCR assay followed by sequencing is a rapid, accurate, and specific method for detection and subtyping of different neuraminidase subtypes from a range of host species and from different geographical locations.
The Last Universal Common Ancestor: emergence, constitution and genetic legacy of an elusive forerunner
Authors: Glansdorff Nicolas , Xu Ying , Labedan Bernard
Published: July 2008

Background

Since the reclassification of all life forms in three Domains (Archaea, Bacteria, Eukarya), the identity of their alleged forerunner (Last Universal Common Ancestor or LUCA) has been the subject of extensive controversies: progenote or already complex organism, prokaryote or protoeukaryote, thermophile or mesophile, product of a protracted progression from simple replicators to complex cells or born in the cradle of "catalytically closed" entities? We present a critical survey of the topic and suggest a scenario.

Results

LUCA does not appear to have been a simple, primitive, hyperthermophilic prokaryote but rather a complex community of protoeukaryotes with a RNA genome, adapted to a broad range of moderate temperatures, genetically redundant, morphologically and metabolically diverse. LUCA's genetic redundancy predicts loss of paralogous gene copies in divergent lineages to be a significant source of phylogenetic anomalies, i.e. instances where a protein tree departs from the SSU-rRNA genealogy; consequently, horizontal gene transfer may not have the rampant character assumed by many. Examining membrane lipids suggest LUCA hadsn1,2ester fatty acid lipids from which Archaea emerged from the outset as thermophilic by "thermoreduction," with a new type of membrane, composed ofsn2,3ether isoprenoid lipids; this occurred without major enzymatic reconversion. Bacteria emerged by reductive evolution from LUCA and some lineages further acquired extreme thermophily by convergent evolution. This scenario is compatible with the hypothesis that the RNA to DNA transition resulted from different viral invasions as proposed by Forterre. Beyond the controversy opposing "replication first" to metabolism first", the predictive arguments of theories on "catalytic closure" or "compositional heredity" heavily weigh in favour of LUCA's ancestors having emerged as complex, self-replicating entities from which a genetic code arose under natural selection.

Conclusion

Life was born complex and the LUCA displayed that heritage. It had the "body "of a mesophilic eukaryote well before maturing by endosymbiosis into an organism adapted to an atmosphere rich in oxygen. Abundant indications suggest reductive evolution of this complex and heterogeneous entity towards the "prokaryotic" Domains Archaea and Bacteria. The word "prokaryote" should be abandoned because epistemologically unsound.

Reviewers

This article was reviewed by Anthony Poole, Patrick Forterre, and Nicolas Galtier.
Accumulation of GC donor splice signals in mammals
Authors: Churbanov Alexander , Winters-Hilt Stephen , Koonin Eugene V , Rogozin Igor B
Published: July 2008

The GT dinucleotide in the first two intron positions is the most conserved element of the U2 donor splice signals. However, in a small fraction of donor sites, GT is replaced by GC. A substantial enrichment of GC in donor sites of alternatively spliced genes has been observed previously in human, nematode and Arabidopsis, suggesting that GC signals are important for regulation of alternative splicing. We used parsimony analysis to reconstruct evolution of donor splice sites and inferred 298 GT > GC conversion events compared to 40 GC > GT conversion events in primate and rodent genomes. Thus, there was substantive accumulation of GC donor splice sites during the evolution of mammals. Accumulation of GC sites might have been driven by selection for alternative splicing.

Reviewers

This article was reviewed by Jerzy Jurka and Anton Nekrutenko. For the full reviews, please go to the Reviewers' Reports section.
Characterization of seed nuclei in glucagon aggregation using light scattering methods and field-flow fractionation
Authors: Hoppe Cindy C , Nguyen Lida T , Kirsch Lee E , Wiencek John M
Published: July 2008

Background

Glucagon is a peptide hormone with many uses as a therapeutic agent, including the emergency treatment of hypoglycemia. Physical instability of glucagon in solution leads to problems with the manufacture, formulation, and delivery of this pharmaceutical product. Glucagon has been shown to aggregate and form fibrils and gels in vitro. Small oligomeric precursors serve to initiate and nucleate the aggregation process. In this study, these initial aggregates, or seed nuclei, are characterized in bulk solution using light scattering methods and field-flow fractionation.

Results

High molecular weight aggregates of glucagon were detected in otherwise monomeric solutions using light scattering techniques. These aggregates were detected upon initial mixing of glucagon powder in dilute HCl and NaOH. In the pharmaceutically relevant case of acidic glucagon, the removal of aggregates by filtration significantly slowed the aggregation process. Field-flow fractionation was used to separate aggregates from monomeric glucagon and determine relative mass. The molar mass of the large aggregates was shown to grow appreciably over time as the glucagon solutions gelled.

Conclusion

The results of this study indicate that initial glucagon solutions are predominantly monomeric, but contain small quantities of large aggregates. These results suggest that the initial aggregates are seed nuclei, or intermediates which catalyze the aggregation process, even at low concentrations.
At-TAX: a whole genome tiling array resource for developmental expression analysis and transcript identification in Arabidopsis thaliana
Authors: Laubinger Sascha , Zeller Georg , Henz Stefan R , Sachsenberg Timo , Widmer Christian K , Naouar Naïra , Vuylsteke Marnik , Schölkopf Bernhard , Rätsch Gunnar , Weigel Detlef
Published: July 2008

Gene expression maps for model organisms, including Arabidopsis thaliana, have typically been created using gene-centric expression arrays. Here, we describe a comprehensive expression atlas, Arabidopsis thaliana Tiling Array Express (At-TAX), which is based on whole-genome tiling arrays. We demonstrate that tiling arrays are accurate tools for gene expression analysis and identified more than 1,000 unannotated transcribed regions. Visualizations of gene expression estimates, transcribed regions, and tiling probe measurements are accessible online at the At-TAX homepage.
Induction of human CD4+ regulatory T cells by mycophenolic acid-treated dendritic cells
Authors: Lagaraine Christine , Lemoine Roxane , Baron Christophe , Nivet Hubert , Velge-Roussel Florence , Lebranchu Yvon
Published: July 2008

Depending on their degree of maturation, costimulatory molecule expression, and cytokine secretion, dendritic cells (DC) can induce immunity or tolerance. DC treated with mycophenolic acid during their maturation (MPA-DC) have a regulatory phenotype and may therefore provide a new approach to induce allograft tolerance. Purified CD4+ T cells stimulated in a human in vitro model of mixed culture by allogeneic MPA-DC displayed much weaker proliferation than T cells activated by mature DC and were anergic. This hyporesponsiveness was alloantigen-specific. Interestingly, T cells stimulated by MPA-DC during long-term coculture in four 7-day cycles displayed potent, suppressive activity, as revealed by marked inhibition of the proliferation of naive and preactivated control T cells. These regulatory T cells (Tregs) appeared to have antigen specificity and were contact-dependent. Tregs induced by MPA-DC were CD25+glucocorticoid-induced TNFR+CTLA-4+CD95+, secreted IL-5 and large amounts of IL-10 and TGF-β, and displayed enhanced forkhead box p3 expression. These results obtained in vitro demonstrate that human MPA-DC can induce allospecific Tregs that may be exploited in cell therapy to induce allograft tolerance.
Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells
Authors: Varga Georg , Ehrchen Jan , Tsianakas Athanasios , Tenbrock Klaus , Rattenholl Anke , Seeliger Stephan , Mack Matthias , Roth Johannes , Sunderkoetter Cord
Published: July 2008

Glucocorticoids (GC) are still the most widely used immunosuppressive agents in clinical medicine. Surprisingly, little is known about the mechanisms of GC action on monocytes, although these cells exert pro- and anti-inflammatory effects. We have shown recently that GC induce a specific monocyte phenotype with anti-inflammatory properties in humans. We now investigated whether this also applies for the murine system and how this subset would relate to recently defined murine subtypes. After treatment with dexamethasone for 48 h, monocytes up-regulated scavenger receptor CD163 and Gr-1, down-regulated CX3CR1, and shared with human GC-treated monocytes functional features such as low adhesiveness but high migratory capacity. They specifically up-regulated anti-inflammatory IL-10, but not TGF-β, and in contrast to their human counterparts, they down-regulated IL-6. Although GC-induced monocytes down-regulated CX3CR1, a distinctive marker for classical/proinflammatory human and murine monocytes (CX3CR1loCCR2+Ly6Chi), they differed from this physiologically occurring subset, as they remained Ly6Cmed and unactivated (CD62 ligand++). In addition to their immunosuppressive effects, they were CD11b+Gr-1+ and expressed the IL-4Rα chain (CD124), a recently described, signature molecule of tumor-induced myeloid-derived suppressor cells (MDSC). We therefore generated murine MDSC in B16 melanoma-bearing mice and indeed found parallel up-regulation of CD11b+Gr-1+ and CD124 on GC-induced monocytes and MDSC. These data allow us to speculate that the GC-induced subtype shares with inflammatory monocytes the ability to migrate quickly into inflamed tissue, where they, however, exert anti-inflammatory effects and that similarities between GC-induced monocytes and MDSC may be involved in progression of some tumors observed in patients chronically treated with GC.
Prevalence of Adenomas and Hyperplastic Polyps in Mismatch Repair Mutation Carriers Among CAPP2 Participants: Report by the Colorectal Adenoma/Carcinoma Prevention Programme 2
Authors: Liljegren Annelie , Barker Gail , Elliott Faye , Bertario Lucio , Bisgaard Marie Luise , Eccles Diana , Evans Gareth , Macrae Finlay , Maher Eamonn , Lindblom Annika , Rotstein Samuel , Nilsson Bo , Mecklin Jukka-Pekka , Möslein Gabriela , Jass Jeremy , Fodde Riccardo , Mathers John , Burn John , Bishop D. Timothy
Published: July 2008

Purpose

To determine the prevalence of adenomatous and hyperplastic polyps in a large cohort of individuals with a germline mutation in a mismatch repair (MMR) gene, the major genetic determinant of hereditary nonpolyposis colorectal cancer (HNPCC). These prevalences have been estimated previously in smaller studies, and the results have been found to be variable.

Patients and Methods

Colorectal Adenoma/Carcinoma Prevention Programme 2 trial is a chemoprevention trial in people classified as having HNPCC. The 695 patients with a proven germline MMR mutation and documented screening history before the chemoprevention study were the focus of this study. The number, histology, size, and location of polyps found at the participants' first ever colonoscopy were analyzed in a cross-sectional study.

Results

Seventy-four patients (10.6%) were found to have at least one adenoma at first colonoscopy, whereas 37 (5.3%) had at least one hyperplastic polyp. The frequency of an adenoma at first colonoscopy increased from 5.0% (95% CI, 2.8% to 8.3%) in patients younger than 35 years old to 18.9% (95% CI, 9.4% to 32.0%) in patients age at least 55 years (P = .0001 for trend). No such trend was observed for hyperplastic polyps. No sex differences were found for either type of polyp. A marginal association was found between the co-occurrence of adenomas and hyperplastic polyps. Adenomas tended to be more proximally distributed through the colon, whereas hyperplastic polyps tended to be located in the distal colon.

Conclusion

Adenoma prevalence increases with age among MMR mutation carriers, whereas hyperplastic polyp prevalence is consistent. No sex differences were observed for either type of lesion.
Increased EGFR Gene Copy Number Detected by Fluorescent In Situ Hybridization Predicts Outcome in Non–Small-Cell Lung Cancer Patients Treated With Cetuximab and Chemotherapy
Authors: Hirsch Fred R. , Herbst Roy S. , Olsen Christine , Chansky Kari , Crowley John , Kelly Karen , Franklin Wilbur A. , Bunn Paul A. , Varella-Garcia Marileila , Gandara David R.
Published: July 2008

Purpose

Epidermal growth factor receptor (EGFR) gene copy number detected by fluorescent in situ hybridization (FISH) has proven to be useful for selection of non–small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors. Here, we evaluate EGFR FISH as a predictive marker in NSCLC patients receiving the EGFR monoclonal antibody inhibitor cetuximab plus chemotherapy.

Patients and Methods

Two hundred twenty-nine chemotherapy-naive patients with advanced-stage NSCLC were enrolled onto a phase II selection trial evaluating sequential or concurrent chemotherapy (paclitaxel plus carboplatin) with cetuximab.

Results

EGFR FISH was assessable in 76 patients with available tumor tissue and classified as positive (four or more gene copies per cell in ≥ 40% of the cells or gene amplification) in 59.2%. Response (complete response/partial response) was numerically higher in FISH-positive (45%) versus FISH-negative (26%) patients (P = .14), whereas disease control rate (complete response/partial response plus stable disease) was statistically superior (81% v 55%, respectively; P = .02). Patients with FISH-positive tumors had a median progression-free survival time of 6 months compared with 3 months for FISH-negative patients (P = .0008). Median survival time was 15 months for the FISH-positive group compared with 7 months for patients who were FISH negative. (P = .04). Furthermore, survival favored FISH-positive patients receiving concurrent therapy.

Conclusion

These results are the first to suggest that EGFR FISH is a predictive factor for selection of NSCLC patients for cetuximab plus chemotherapy. Prospective validation of these findings is warranted.
Phase II Evaluation of Imatinib Mesylate in the Treatment of Recurrent or Persistent Epithelial Ovarian or Primary Peritoneal Carcinoma: A Gynecologic Oncology Group Study
Authors: Schilder Russell J. , Sill Michael W. , Lee Roger B. , Shaw Tanya J. , Senterman Mary K. , Klein-Szanto Andres J. , Miner Zoe , Vanderhyden Barbara C.
Published: July 2008

Purpose

This phase II trial assessed the activity and tolerability of an oral dose of imatinib mesylate 400 mg twice daily in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma. The association between the expression of certain markers and clinical outcome was investigated.

Patients and Methods

Primary measure of clinical efficacy was progression-free survival (PFS) at 6 months. Mutational analysis of KIT, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay for markers (KIT, platelet-derived growth factor [PDGF] receptor [-R], AKT2, phosphorylated AKT [p-AKT], stem cell factor [SCF], and PDGF) were performed.

Results

Fifty-six eligible patients were evaluated. Nine patients were progression free for at least 6 months including one complete responder. The median PFS and survival were 2 and 16 months, respectively. The most common grade 3 and 4 toxicities were neutropenia, GI, dermatologic effects, pain, and electrolyte disturbances. At least one target of imatinib (KIT, PDGFR-α, or PDGFR-β) was expressed in all tumors, and most tumors expressed all three receptors. Higher expression of p-AKT and PDGFR-β were associated with shorter PFS, and higher IHC scores (% immunopositive cells × staining intensity) of SCF and p-AKT were associated with decreased overall survival. No sequence mutations were detected in the KIT gene. Higher pretreatment plasma concentrations of PDGF-AB, PDGF-BB, and vascular endothelial growth factor (VEGF) were individually associated with shorter PFS and survival.

Conclusion

Imatinib mesylate was well tolerated but had minimal single-agent activity in patients with recurrent ovarian or primary peritoneal carcinoma. No marker was identified that would predict activity of imatinib; however, tumor p-AKT and plasma VEGF levels were associated with poor outcome.
Disclosure of Incurable Illness to Spouses: Do They Want to Know? A Swedish Population-Based Follow-Up Study
Authors: Dahlstrand Hanna , Hauksdóttir Arna , Valdimarsdóttir Unnur , Fürst Carl-Johan , Bergmark Karin , Steineck Gunnar
Published: July 2008

Purpose

Awareness of the cancer patient's terminal state decreases the risk of psychological morbidity of the bereaved. We wanted to determine whether male spouses of cancer patients who died from their disease had received information that the illness was incurable and to determine their preferences of disclosure.

Participants and Methods

The study included 907 widowers whose wives had died of cancer. In an anonymous questionnaire, we asked whether the widower had received information that his wife's illness was incurable and about his attitudes towards receiving this information.

Results

Six hundred ninety-one widowers (76%) participated. Eighty percent of the widowers reported that they were told that the wife's cancer was incurable, and 21% reported that they had been informed within 1 week before the patient's death. Although 14% of the widowers did not think the next of kin should be told immediately when the patient's cancer is beyond cure, 39% of the men did not want the patient to be immediately informed. Furthermore, 71% of the men who were never informed about the incurable illness believed that the next of kin should receive that information immediately.

Conclusion

Although a large majority of men prefer an immediate disclosure about the incurable stage of their wife's illness, 41% of the husbands received this information during the last week of the patient's life or not at all. These findings indicate that there is room for improvement in the level of communication between health providers and the husbands of women with incurable cancer.
Nocturnal Glucose Metabolism after Bedtime Injection of Insulin Glargine or Neutral Protamine Hagedorn Insulin in Patients with Type 2 Diabetes
Authors: Linn Thomas , Fischer Britta , Soydan Nedim , Eckhard Michael , Ehl Julia , Kunz Clemens , Bretzel Reinhard G.
Published: July 2008

Aims/Hypothesis: Insulin glargine is a long-acting human insulin analog often administered at bedtime to patients with type 2 diabetes. It reduces fasting blood glucose levels more efficiently and with less nocturnal hypoglycemic events compared with human neutral protamine Hagedorn (NPH) insulin. Therefore, bedtime injections of insulin glargine and NPH insulin were compared overnight and in the morning.

Methods: In 10 type 2 diabetic patients, euglycemic clamps were performed, including [6,6′]2H2 glucose, to study the rate of disappearance (Rd) and endogenous production (EGP) of glucose during the night. On separate days at bedtime (2200 h), patients received a sc injection of insulin glargine, NPH insulin, or saline in a randomized, double-blind fashion.

Results: Similar doses of both insulins had different metabolic profiles. NPH insulin had a greater effect on both Rd and EGP in the night compared with insulin glargine. By contrast, in the morning, insulin glargine was more effective, increasing Rd by 5.8 μmol/kg−1·min−1 (95% confidence interval 4.7–6.9) and reducing EGP −5.7 (−5.0 to −6.4) compared with NPH insulin. Nearly 80% of the glucose lowering effect in the morning was due to insulin glargine’s reduction of EGP. Its injection was associated with one-third lower morning glucagon levels compared with NPH insulin (P = 0.021).

Conclusion/Interpretation: Nocturnal variations of EGP and Rd explain the reduced incidence of hypoglycemia and lower fasting glucose levels reported for insulin glargine compared with human NPH insulin.
Insulin-Like Factor 3 Levels in Second-Trimester Amniotic Fluid
Authors: Bay Katrine , Cohen Arieh S. , Jørgensen Finn Stener , Jørgensen Connie , Lind Anne Marie , Skakkebæk Niels E. , Andersson Anna-Maria
Published: July 2008

Background: According to animal studies, the testicular Leydig cell hormone insulin-like factor 3 (Insl3) exerts a fundamental role in abdominal testis translocation, which occurs in the beginning of the second trimester in humans. Despite this, human prenatal INSL3 production has been poorly investigated.

Methods: Amniotic fluid from 91 pregnant women undergoing amniocentesis was analyzed for INSL3 and testosterone (T) levels. Data were related to gestational age (15–25 wk) at amniocentesis and to sex (45 males and 48 females).

Results: INSL3 was present in amniotic fluid from all but one of the investigated male fetuses (range: <0.02–0.36 ng/ml; mean ± sd: 0.12 ± 0.07), whereas the hormone was undetectable in the female fetuses. T was significantly higher in male (range: 0.54–1.71 nmol/liter; mean ± sd: 1.04 ± 0.30) as compared with in female amniotic fluid (range: 0.19–0.50 nmol/liter; mean ± sd: 0.34 ± 0.06) (P < 0.001). In males there was no correlation between INSL3 and T. A statistically borderline negative association was found between INSL3 and gestational age (P = 0.07), whereas the corresponding association was not significant for T (P = 0.12). In contrast, T in females correlated positively with gestational age (P = 0.02).

Conclusions: INSL3 is clearly present in human male amniotic fluid in the second trimester, where abdominal testis translocation takes place. In contrast, the hormone is undetectable in female amniotic fluid. The prenatal presence of INSL3 supports the hypothesis that this hormone is essential for testicular descent in humans.
Risk of Thyroid Disease in Individuals with Celiac Disease
Authors: Elfström Peter , Montgomery Scott M. , Kämpe Olle , Ekbom Anders , Ludvigsson Jonas F.
Published: July 2008

Background: It has been suggested that celiac disease is associated with thyroid disease. Earlier studies, however, have been predominately cross-sectional and have often lacked controls. There is hence a need for further research. In this study, we estimated the risk of thyroid disease in individuals with celiac disease from a general population cohort.

Methods: A total of 14,021 individuals with celiac disease (1964–2003) and a matched reference population of 68,068 individuals were identified through the Swedish national registers. Cox regression estimated the risk of thyroid disease in subjects with celiac disease. Analyses were restricted to individuals with a follow-up of more than 1 yr and with no thyroid disease before study entry or within 1 yr after study entry. Conditional logistic regression estimated the odds ratio for subsequent celiac disease in individuals with thyroid disease.

Results: Celiac disease was positively associated with hypothyroidism [hazard ratio (HR) = 4.4; 95% confidence interval (CI) = 3.4–5.6; P < 0.001], thyroiditis (HR = 3.6; 95% CI =1.9–6.7; P < 0.001) and hyperthyroidism (HR = 2.9; 95% CI = 2.0–4.2; P < 0.001). The highest risk estimates were found in children (hypothyroidism, HR = 6.0 and 95% CI = 3.4–10.6; thyroiditis, HR = 4.7 and 95% CI = 2.1–10.5; hyperthyroidism, HR = 4.8 and 95% CI = 2.5–9.4). In post hoc analyses, where the reference population was restricted to inpatients, the adjusted HR was 3.4 for hypothyroidism (95% CI = 2.7–4.4; P < 0.001), 3.3 for thyroiditis (95% CI = 1.5–7.7; P < 0.001), and 3.1 for hyperthyroidism (95% CI = 2.0–4.8; P < 0.001).

Conclusion: Celiac disease is associated with thyroid disease, and these associations were seen regardless of temporal sequence. This indicates shared etiology and that these individuals are more susceptible to autoimmune disease.