bluuebunny/crossref_metadata_2025 huggingface dataset:
Haplotype specific-sequencing reveals MBL2 association with asymptomatic Plasmodium falciparum infection
Authors: Boldt Angelica BW , Messias-Reason Iara J , Lell Bertrand , Issifou Saadou , Pedroso Maria Lucia Alves , Kremsner Peter G , Kun Jürgen FJ
Published: May 2009

Background

Mannose binding lectin (MBL) has an important role in the activation of the complement system and opsonization of pathogenic microorganisms. Frequent polymorphisms found in theMBL2gene affect the concentration and functionality of the protein and are associated with enhanced susceptibility to severe malaria in African children. MostMBL2typing strategies were designed to the analysis of selected variants, the significance of whole haplotypes is poorly known. In this work, a new typing strategy was developed and validated in an association analysis ofMBL2with adult asymptomatic infection.

Methods

MBL2allele-specific fragments of 144 healthy Gabonese adults were amplified by using haplotype-specific sequencing (HSS), a new strategy that combines sequence-specific PCR and sequence-based typing. The Gabonese were investigated for the presence ofPlasmodium falciparumparasitaemia by the amplification of parasite genes, immunochromatographic antigen detection and microscopic analysis. HSS results were also compared with a previously used real-time PCR (RT-PCR) method in 72 Euro-Brazilians.

Results

Fourteen polymorphisms were identified beside the commonly investigated promoter (H, L;X, Y;P, Q) and exon 1 (A, O;O=B,CorD) variants. TheMBL2*LYPA/LYPAgenotype was associated with the absence of asymptomatic infection (P = 0.017), whereas theMBL2*LYQChaplotype andYA/YO+YO/YOgenotypes were associated with positive parasite counts in asymptomatic adults (P = 0.033 and 0.018, respectively). The associations were specific toLYPA(identical to the reference sequence Y16577) andLYQC(Y16578) and would not have been revealed by standard genotyping, as there was no association withLYPAandLYQChaplotypes carrying new polymorphisms defined by sequence-based typing. In contrast, HSS and RT-PCR produced very similar results in the less diverse European-derived population.

Conclusion

In this work, a new typing strategy for a highly polymorphic gene was developed and validated focusing on the asymptomatic status ofP. falciparum-infected adults. In populations with high nucleotide diversity, it allowed for the identification of associations with fine-scaled haplotypes that would not have been found using common typing techniques. In this preliminary study,MBL2haplotypes or SNPs linked to them were found associated with susceptibility to infection and parasitaemia control of asymptomatic adults.
PfeIK1, a eukaryotic initiation factor 2α kinase of the human malaria parasite Plasmodium falciparum, regulates stress-response to amino-acid starvation
Authors: Fennell Clare , Babbitt Shalon , Russo Ilaria , Wilkes Jonathan , Ranford-Cartwright Lisa , Goldberg Daniel E , Doerig Christian
Published: May 2009

Background

Post-transcriptional control of gene expression is suspected to play an important role in malaria parasites. In yeast and metazoans, part of the stress response is mediated through phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which results in the selective translation of mRNAs encoding stress-response proteins.

Methods

The impact of starvation on the phosphorylation state of PfeIF2α was examined. Bioinformatic methods were used to identify plasmodial eIF2α kinases. The activity of one of these, PfeIK1, was investigated using recombinant protein with non-physiological substrates and recombinant PfeIF2α. Reverse genetic techniques were used to disrupt the pfeik1 gene.

Results

The data demonstrate that the Plasmodium falciparum eIF2α orthologue is phosphorylated in response to starvation, and provide bioinformatic evidence for the presence of three eIF2α kinases in P. falciparum, only one of which (PfPK4) had been described previously. Evidence is provided that one of the novel eIF2α kinases, PfeIK1, is able to phosphorylate the P. falciparum eIF2α orthologue in vitro. PfeIK1 is not required for asexual or sexual development of the parasite, as shown by the ability of pfeik1
- parasites to develop into sporozoites. However, eIF2α phosphorylation in response to starvation is abolished in pfeik1
- asexual parasites

Conclusion

This study strongly suggests that a mechanism for versatile regulation of translation by several kinases with a similar catalytic domain but distinct regulatory domains, is conserved in P. falciparum.
Assessment of methods and analysis of outcomes for comprehensive optimization of nucleofection
Authors: Bradburne Christopher , Robertson Kelly , Thach Dzung
Published: May 2009

Background

Nucleofection is an emerging technology for delivery of nucleic acids into both the cytoplasm and nucleus of eukaryotic cells with high efficiency. This makes it an ideal technology for gene delivery and siRNA applications. A 96-well format has recently been made available for high-throughput nucleofection, however conditions must be optimized for delivery into each specific cell type. Screening each 96-well plate can be expensive, and descriptions of methods and outcomes to determine the best conditions are lacking in the literature. Here we employ simple methods, including cell counting, microscopy, viability and cytotoxicity assays to describe the minimal experimental methods required to optimize nucleofection conditions for a given cell line.

Methods

We comprehensively measured and analyzed the outcomes of the 96-well nucleofection of pmaxGFP plasmids encoding green fluorescent protein (GFP) into the A-549 human lung epithelial cell line. Fluorescent microscopy and a plate reader were used to respectively observe and quantify green fluorescence in both whole and lysed cells. Cell viability was determined by direct counting/permeability assays, and by both absorbance and fluorescence-based plate reader cytotoxicity assays. Finally, an optimal nucleofection condition was used to deliver siRNA and gene specific knock-down was demonstrated.

Results

GFP fluorescence among conditions ranged from non-existent to bright, based upon the fluorescent microscopy and plate reader results. Correlation between direct counting of cells and plate-based cytotoxicity assays were from R = .81 to R = .88, depending on the assay. Correlation between the GFP fluorescence of lysed and unlysed cells was high, ranging from R = .91 to R = .97. Finally, delivery of a pooled sample of siRNAs targeting the gene relA using an optimized nucleofection condition resulted in a 70–95% knock down of the gene over 48 h with 90–97% cell viability.

Conclusion

Our results show the optimal 96-well nucleofection conditions for the widely-used human cell line, A-549. We describe simple, effective methods for determining optimal conditions with high confidence, providing a useful road map for other laboratories planning optimization of specific cell lines or primary cells. Our analysis of outcomes suggests the need to only measure unlysed, whole-cell fluorescence and cell metabolic activity using a plate reader cytotoxicity assay to determine the best conditions for 96-well nucleofection.
In vitro host range, multiplication and virion forms of recombinant viruses obtained from co-infection in vitro with a vaccinia-vectored influenza vaccine and a naturally occurring cowpox virus isolate
Authors: Okeke Malachy Ifeanyi , Nilssen Øivind , Moens Ugo , Tryland Morten , Traavik Terje
Published: May 2009

Background

Poxvirus-vectored vaccines against infectious diseases and cancer are currently under development. We hypothesized that the extensive use of poxvirus-vectored vaccine in future might result in co-infection and recombination between the vaccine virus and naturally occurring poxviruses, resulting in hybrid viruses with unpredictable characteristics. Previously, we confirmed that co-infecting in vitro a Modified vaccinia virus Ankara (MVA) strain engineered to express influenza virus haemagglutinin (HA) and nucleoprotein (NP) genes with a naturally occurring cowpox virus (CPXV-NOH1) resulted in recombinant progeny viruses (H Hansen, MI Okeke, Ø Nilssen, T Traavik, Vaccine 23: 499–506, 2004). In this study we analyzed the biological properties of parental and progeny hybrid viruses.

Results

Five CPXV/MVA progeny viruses were isolated based on plaque phenotype and the expression of influenza virus HA protein. Progeny hybrid viruses displayed in vitro cell line tropism of CPXV-NOH1, but not that of MVA. The HA transgene or its expression was lost on serial passage of transgenic viruses and the speed at which HA expression was lost varied with cell lines. The HA transgene in the progeny viruses or its expression was stable in African Green Monkey derived Vero cells but became unstable in rat derived IEC-6 cells. Hybrid viruses lacking the HA transgene have higher levels of virus multiplication in mammalian cell lines and produced more enveloped virions than the transgene positive progenitor virus strain. Analysis of the subcellular localization of the transgenic HA protein showed that neither virus strain nor cell line have effect on the subcellular targets of the HA protein. The influenza virus HA protein was targeted to enveloped virions, plasma membrane, Golgi apparatus and cytoplasmic vesicles.

Conclusion

Our results suggest that homologous recombination between poxvirus-vectored vaccine and naturally circulating poxviruses, genetic instability of the transgene, accumulation of non-transgene expressing vectors or hybrid virus progenies, as well as cell line/type specific selection against the transgene are potential complications that may result if poxvirus vectored vaccines are extensively used in animals and man.
Undiagnosed osteoid osteoma of the spine presenting as painful scoliosis from adolescence to adulthood: a case report
Authors: Sapkas George , Efstathopoulos Nicolas E , Papadakis Michael
Published: May 2009

Presented here is a case of a young woman, with an undiagnosed osteoid osteoma of the spine, which presented with painful scoliosis in adolescence and was treated by bracing until her accession to adulthood. A more thorough investigation, years after the initial one, revealed the tumor. Surgical excision and stabilization offered the long-awaited cure. Misdiagnosis resulted in intractable pain for years, deformity, the discomfort of brace therapy, and the frustration of a prolonged yet ineffective treatment.
Interactions between innexins UNC-7 and UNC-9 mediate electrical synapse specificity in the Caenorhabditis elegans locomotory nervous system
Authors: Starich Todd A , Xu Ji , Skerrett I Martha , Nicholson Bruce J , Shaw Jocelyn E
Published: May 2009

Background

Approximately 10% of Caenorhabditis elegans nervous system synapses are electrical, that is, gap junctions composed of innexins. The locomotory nervous system consists of several pairs of interneurons and three major classes of motor neurons, all with stereotypical patterns of connectivity that include gap junctions. Mutations in the two innexin genes unc-7 and unc-9 result in identical uncoordinated movement phenotypes, and their respective gene products were investigated for their contribution to electrical synapse connectivity.

Results

unc-7 encodes three innexin isoforms. Two of these, UNC-7S and UNC-7SR, are functionally equivalent and play an essential role in coordinated locomotion. UNC-7S and UNC-7SR are widely expressed and co-localize extensively with green fluorescent protein-tagged innexin UNC-9 in the ventral and dorsal nerve cords. A subset of UNC-7S/SR expression visualizes gap junctions formed between the AVB forward command interneurons and their B class motor neuron partners. Experiments indicate that expression of UNC-7S/SR in AVB and expression of UNC-9 in B motor neurons is necessary for these gap junctions to form. In Xenopus oocyte pairs, both UNC-7S and UNC-9 form homomeric gap junctions, and together they form heterotypic channels. Xenopus oocyte studies and co-localization studies in C. elegans suggest that UNC-7S and UNC-9 do not heteromerize in the same hemichannel, leading to the model that hemichannels in AVB:B motor neuron gap junctions are homomeric and heterotypic.

Conclusion

UNC-7S and UNC-9 are widely expressed and contribute to a large number of the gap junctions identified in the locomotory nervous system. Proper AVB:B gap junction formation requires UNC-7S expression in AVB interneurons and UNC-9 expression in B motor neurons. More broadly, this illustrates that innexin identity is critical for electrical synapse specificity, but differential (compartmentalized) innexin expression cannot account for all of the specificity seen in C. elegans, and other factors must influence the determination of synaptic partners.
Regulation of dopamine transporter activity by carboxypeptidase E
Authors: Zhang Heping , Li Shupeng , Wang Min , Vukusic Brian , Pristupa Zdenek B , Liu Fang
Published: May 2009

Background

The dopamine transporter (DAT) plays a critical role in terminating the action of dopamine by rapid reuptake into the presynaptic neuron. Previous studies have revealed that the DAT carboxyl terminus (DAT-CT) can directly interact with other cellular proteins and regulate DAT function and trafficking.

Results

Here, we have identified that carboxypeptidase E (CPE), a prohormone processing exopeptidase and sorting receptor for the regulated secretory pathway, interacts with the DAT-CT and affects DAT function. Mammalian cell lines coexpressing CPE and DAT exhibited increased DAT-mediated dopamine uptake activity compared to cells expressing DAT alone. Moreover, coexpression of an interfering DAT-CT minigene inhibited the effects of CPE on DAT. Functional changes caused by CPE could be attributed to enhanced DAT expression and subsequent increase in DAT cell surface localization, due to decreased DAT degradation. In addition, CPE association could reduce the phosphorylation state of DAT on serine residues, potentially leading to reduced internalization, thus stabilizing plasmalemmal DAT localization.

Conclusion

Taken together, our results reveal a novel role for CPE in the regulation of DAT trafficking and DAT-mediated DA uptake, which may provide a novel target in the treatment of dopamine-governed diseases such as drug addiction and obesity.
MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neureceptor status in breast cancer
Authors: Lowery Aoife J , Miller Nicola , Devaney Amanda , McNeill Roisin E , Davoren Pamela A , Lemetre Christophe , Benes Vladimir , Schmidt Sabine , Blake Jonathon , Ball Graham , Kerin Michael J
Published: May 2009

Introduction

Breast cancer is a heterogeneous disease encompassing a number of phenotypically diverse tumours. Expression levels of the oestrogen, progesterone and HER2/neu receptors which characterize clinically distinct breast tumours have been shown to change during disease progression and in response to systemic therapies. Mi(cro)RNAs play critical roles in diverse biological processes and are aberrantly expressed in several human neoplasms including breast cancer, where they function as regulators of tumour behaviour and progression. The aims of this study were to identify miRNA signatures that accurately predict the oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor status of breast cancer patients to provide insight into the regulation of breast cancer phenotypes and progression.

Methods

Expression profiling of 453 miRNAs was performed in 29 early-stage breast cancer specimens. miRNA signatures associated with ER, PR and HER2/neu status were generated using artificial neural networks (ANN), and expression of specific miRNAs was validated using RQ-PCR.

Results

Stepwise ANN analysis identified predictive miRNA signatures corresponding with oestrogen (miR-342, miR-299, miR-217, miR-190, miR-135b, miR-218), progesterone (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and HER2/neu (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) receptor status. MiR-342 and miR-520g expression was further analysed in 95 breast tumours. MiR-342 expression was highest in ER and HER2/neu-positive luminal B tumours and lowest in triple-negative tumours. MiR-520g expression was elevated in ER and PR-negative tumours.

Conclusions

This study demonstrates that ANN analysis reliably identifies biologically relevant miRNAs associated with specific breast cancer phenotypes. The association of specific miRNAs with ER, PR and HER2/neu status indicates a role for these miRNAs in disease classification of breast cancer. Decreased expression of miR-342 in the therapeutically challenging triple-negative breast tumours, increased miR-342 expression in the luminal B tumours, and downregulated miR-520g in ER and PR-positive tumours indicates that not only is dysregulated miRNA expression a marker for poorer prognosis breast cancer, but that it could also present an attractive target for therapeutic intervention.
On the estimation of local slopes
Authors: Schleicher J. , Costa J. C. , Santos L. T. , Novais A. , Tygel M.
Published: May 2009

Current time-processing algorithms often are based on one-parameter or multiparameter coherency analysis (semblance) schemes applied to the data. Such procedures, besides being computationally expensive, lead to significant uncertainties in the searched parameters. Conventional semblance methods can be avoided for a number of imaging tasks if local slopes can be extracted directly from prestack data—for example, by filtering schemes. Although the idea is not new, it has revived for various purposes, such as velocity analysis, [Formula: see text] imaging, migration to zero offset, and time migration. We propose a simple, straightforward correction to linear plane-wave destructors based on the observation that in addition to the local slope, its inverse can be extracted from the data in a fully analogous way. Combining the information of both extractions yields a simple yet effective correction to the local slopes. The naive application of linear plane-wave destructors with our correction produces high-quality results, even with a high noise level and interfering events.
Biologic Cost of Caring for a Cancer Patient: Dysregulation of Pro- and Anti-Inflammatory Signaling Pathways
Authors: Rohleder Nicolas , Marin Teresa J. , Ma Roy , Miller Gregory E.
Published: May 2009

Purpose

Caring for a family member with cancer is a psychologically demanding experience. However, it remains unclear whether the distress that caregiving provokes also takes a physiologic toll on the body. This study observed familial caregivers of patients with brain cancer for a year after diagnosis and tracked changes in neurohormonal and inflammatory processes.

Patients and Methods

Eighteen caregivers (age 50.4 ± 3.5 years) and 19 controls (age 50.2 ± 2.6 years) were assessed four times during a year (before and after radiotherapy, as well as 6 weeks and 4 months thereafter). Salivary biomarkers of hypothalamus-pituitary-adrenal axis and sympathetic nervous system (SNS) activity were collected, and blood was drawn for assessment of the systemic inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6). Blood was also used to monitor in vitro IL-6 production by endotoxin-stimulated leukocytes and expression of mRNA for pro- and anti-inflammatory signaling molecules.

Results

Caregivers showed marked changes over time in diurnal output of salivary amylase, a marker of SNS activity, whereas secretions in controls were stable during follow-up. Cortisol output was similar in caregivers and controls. During the year, caregivers showed a profound linear increase in systemic inflammation, as indexed by CRP. At the same time, they displayed a linear decline in mRNA for anti-inflammatory signaling molecules and diminished in vitro glucocorticoid sensitivity.

Conclusion

These preliminary data show that familial caregivers of patients with cancer experience marked changes in neurohormonal and inflammatory processes in the year after diagnosis. These changes may place them at risk for morbidity and mortality from diseases fostered by excessive inflammation.
Cognitive Deficits and Predictors 3 Years After Diagnosis of a Pilocytic Astrocytoma in Childhood
Authors: Aarsen Femke K. , Paquier Philippe F. , Arts Willem-Frans , Van Veelen Marie-Lise , Michiels Erna , Lequin Maarten , Catsman-Berrevoets Coriene E.
Published: May 2009

Purpose

To prospectively study cognitive deficits and predictors 3 years after diagnosis in a large series of pediatric patients treated for pilocytic astrocytoma (PA).

Patients and Methods

Sixty-one of 67 children were grouped according to infratentorial, supratentorial midline, and supratentorial hemispheric site. Intelligence, memory, attention, language, visual-spatial, and executive functions were assessed. Included predictors were sex, age, relapse, diagnosis-assessment interval, hydrocephalus, kind of treatment, and tumor variables.

Results

All children with PA had problems with sustained attention and speed. In the infratentorial group, there also were deficits in verbal intelligence, visual-spatial memory, executive functioning, and naming. Verbal intelligence and verbal memory problems occurred in the brainstem tumor group. The supratentorial hemispheric tumor group had additional problems with selective attention and executive functioning, and the supratentorial midline tumor group displayed no extra impairments. More specifically, the dorsal supratentorial midline tumor group displayed problems with language and verbal memory. Predictors for lower cognitive functioning were hydrocephalus, radiotherapy, residual tumor size, and age; predictors for better functioning were chemotherapy or treatment of hydrocephalus. Almost 60% of children had problems with academic achievement, for which risk factors were relapse and younger age at diagnosis.

Conclusion

Despite normal intelligence at long-term follow-up, children treated for PA display invalidating cognitive impairments. Adequate treatment of hydrocephalus is important for a more favorable long-term cognitive outcome. Even children without initial severe deficits may develop cognitive impairments years after diagnosis, partly because of the phenomenon of growing into deficit, which has devastating implications for academic achievement and quality of life (QOL).
Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma: A Phase III Randomized Controlled Trial of Health-Related Quality of Life and Symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group
Authors: Bottomley Andrew , Coens Corneel , Suciu Stefan , Santinami Mario , Kruit Willem , Testori Alessandro , Marsden Jeremy , Punt Cornelis , Salès François , Gore Martin , MacKie Rona , Kusic Zvonko , Dummer Reinhard , Patel Poulam , Schadendorf Dirk , Spatz Alain , Keilholz Ulrich , Eggermont Alexander
Published: May 2009

Purpose

Interferon (IFN) -based adjuvant therapy in melanoma is associated with significant side effects, which necessitates evaluation of health-related quality of life (HRQOL). Our trial examined the HRQOL effects of adjuvant pegylated IFN-α-2b (PEG-IFN-α-2b) versus observation in patients with stage III melanoma.

Methods

A total of 1,256 patients with stage III melanoma were randomly assigned after full lymphadenectomy to receive either observation (n = 629) or PEG-IFN-α-2b (n = 627): induction 6 μg/kg/wk for 8 weeks then maintenance 3 μg/kg/wk for an intended total duration of 5 years. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 was used to assess HRQOL.

Results

At 3.8 years of median follow-up, for the primary end point, recurrence-free survival (RFS), risk was reduced by 18% (hazard rate = 0.82; P = .01) in the PEG-IFN-α-2b arm compared with observation. Significant and clinically meaningful differences occurred with the PEG-IFN-α-2b treatment arm compared with the observation group, showing decreased global HRQOL at month 3 (−11.6 points; 99% CI, −8.2 to −15.0) and year 2 (−10.5 points; 99% CI, −6.6 to −14.4). Many of the other scales showed statistically significant differences between scores when comparing the two arms. From a clinical point of view, important differences were found for five scales: two functioning scales (social and role functioning) and three symptom scales (appetite loss, fatigue, and dyspnea), with the PEG-IFN-α-2b arm being most impaired.

Conclusion

PEG-IFN-α-2b leads to a significant and sustained improvement in RFS. There is an expected negative effect on global HRQOL and selected symptoms when patients undergo PEG-IFN-α-2b treatment.
Phase III Study by the Norwegian Lung Cancer Study Group: Pemetrexed Plus Carboplatin Compared With Gemcitabine Plus Carboplatin As First-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer
Authors: Grønberg Bjørn H. , Bremnes Roy M. , Fløtten Øystein , Amundsen Tore , Brunsvig Paal Fr. , Hjelde Harald H. , Kaasa Stein , von Plessen Christian , Stornes Frøydis , Tollåli Terje , Wammer Finn , Aasebø Ulf , Sundstrøm Stein
Published: May 2009

Purpose

To compare pemetrexed/carboplatin with a standard regimen as first-line therapy in advanced non–small-cell lung cancer NSCLC.

Patients and Methods

Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were randomly assigned to receive pemetrexed 500 mg/m2 plus carboplatin area under the curve (AUC) = 5 (Calvert's formula) on day 1 or gemcitabine 1,000 mg/m2 on days 1 and 8 plus carboplatin AUC = 5 on day 1 every 3 weeks for up to four cycles. The primary end point was health-related quality of life (HRQoL) defined as global quality of life, nausea/vomiting, dyspnea, and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer–specific module LC13 during the first 20 weeks. Secondary end points were overall survival and toxicity.

Results

Four hundred thirty-six eligible patients were enrolled from April 2005 to July 2006. Patients who completed the baseline questionnaire were analyzed for HRQoL (n = 427), and those who received ≥ one cycle of chemotherapy were analyzed for toxicity (n = 423). Compliance of HRQoL questionnaires was 87%. There were no significant differences for the primary HRQoL end points or in overall survival between the two treatment arms (pemetrexed/carboplatin, 7.3 months; gemcitabine/carboplatin, 7.0 months; P = .63). The patients who received gemcitabine/carboplatin had more grade 3 to 4 hematologic toxicity than patients who received pemetrexed/carboplatin, including leukopenia (46% v 23%, respectively; P < .001), neutropenia (51% v 40%, respectively; P = .024), and thrombocytopenia (56% v 24%, respectively; P < .001). More patients on the gemcitabine/carboplatin arm received transfusions of RBCs and platelets, whereas the frequencies of neutropenic infections and thrombocytopenic bleedings were similar on both arms.

Conclusion

Pemetrexed/carboplatin provides similar HRQoL and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care.
Prospective Randomized Multicenter Adjuvant Dermatologic Cooperative Oncology Group Trial of Low-Dose Interferon Alfa-2b With or Without a Modified High-Dose Interferon Alfa-2b Induction Phase in Patients With Lymph Node–Negative Melanoma
Authors: Hauschild Axel , Weichenthal Michael , Rass Knuth , Linse Ruthild , Ulrich Jens , Stadler Rudolf , Volkenandt Matthias , Grabbe Stephan , Proske Ulrike , Schadendorf Dirk , Brockmeyer Norbert , Vogt Thomas , Rompel Rainer , Kaufmann Roland , Kaatz Martin , Näher Helmut , Mohr Peter , Eigentler Thomas , Livingstone Elisabeth , Garbe Claus
Published: May 2009

Purpose

Interferon alfa (IFN-α) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-α (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen.

Patients and Methods

In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node–negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m2 IFN-α-2b IV for 2 weeks and 5 times weekly 10 MU/m2 IFN-α-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-α-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B.

Results

Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B).

Conclusion

The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-α-2b treatment schedule did not improve the clinical outcome.
Application of the Film–Pore Diffusion Model to the Sorption of Phenol onto Activated Carbons Prepared from Peanut Shells
Authors: Gonzo Elio E. , Gonzo Luis F.
Published: May 2009

In this work, the film–pore diffusion model was applied to the adsorption of phenol onto peanut shell activated carbon in a batch stirred vessel. This two-resistance model was applied to predict the phenol concentration decay curves for different initial phenol concentrations, carbon particle sizes and dosages. The predicted concentration decay curves were compared with the experimental findings. The optimum best-fit values of the external mass-transfer coefficient and effective diffusion coefficients were found by minimizing the difference between the experimental and model-predicted phenol solution concentration. It was found that, under the experimental conditions employed in this study, the influence of the external mass-transfer resistance was low. A single value of the mass transport coefficient, kf, of (4.8 ± 1.3) × 10−3 (cm/s) described the whole range of system conditions. The difference between the corresponding values of the effective diffusivity, Deff, was not statistically significant. Consequently, a constant value of the effective pore diffusivity of (4.1 ± 0.4) × 10−6 (cm2/s) was sufficient to provide an accurate correlation of the decay concentration curve.
Modular Spatial Structure Applied to a Single-Story Industrial Building
Authors: Ferran J. Javier , Torregrosa J. Bautista , Ferrer Carlos , Ferrer Carlos M. , Redon Miguel , Sanchez Francisco J.
Published: May 2009

Horticultural warehouses with large and open floorspace requirements call for new typologies of steel structures. Faced with this problem, and after a comparison of various structural alternatives, a pseudo-folded sheet was adopted as a final design solution. A modulated spatial structure was designed for an agro-industrial warehouse in Valencia, Spain. Bending forces in the element's roof cover are transformed into axial stresses, thereby improving structural performance. A detailed analysis was performed in setting the geometric and structural behaviour of the different steel elements. Finally, we consider issues such as joint connectivity, global stability, and the erection process.
Weighted Graph Products for Configuration Processing of Planar and Space Structures
Authors: Kaveh A. , Nouri M.
Published: May 2009

In this paper three graph products and three weighted graph products are presented for the formation of structural models. The graph products are extensively used in graph theory and combinatorial optimization, however, the weighted products defined in this paper are more suitable for the formation of practical structural models. Here, the simple and weighted products are employed for the configuration processing of space structures. This application can easily be extended to the formation of finite element models.
Experimental Research and Analysis on Encased Steel Box Concrete Beams
Authors: Zheng Wen-Zhong , Xie Heng-Yan
Published: May 2009

A encased steel box concrete beam (ESBCB) is light because it is hollow. In order to investigate the mechanical behavior of ESBCBs, 5 simple ESBCBs and 4 continuous ESBCBs have been tested. The test results reported include distribution of cracks, deformation, failure characteristics, strength and ultimate load. That the bending capacity of this kind of beam can be calculated in accordance with the plane section assumption was verified, and the formula for calculating crack width and stiffness are given. The formula for calculating the length of an equivalent plastic hinge for continuous ESBCBs is presented. A design method for moment modification is put forward, in which, the difference between the elastic calculated moment of critical section at the intermediate support and the moment subjected by the steel box is modified, and in the calculation formula, the variable is the relative plastic rotation.
A Degree-Based Clustering Technique for VLSI Placement
Authors: Huang Jie , Behjat Laleh , Rakai Logan , Li Jianhua
Published: May 2009

In this paper, clustering for the circuit placement problem is examined from the perspective of wire length contribution from groups of nets. First, the final wire length data of groups of nets with different degrees are extracted and studied. It is illustrated that nets with high-degree contribute a high percentage to the total wire length. To remedy this problem, a clustering algorithm for placement is proposed that focuses on clustering nets with high-degree. This new clustering algorithm is implemented as a preprocessing step in the placement stage. ICCAD04 benchmark circuits abstracted from IBM are used to validate the placement quality by using four academic placers with and without the proposed preprocessing step. Experiments show that the overall placement results can be improved by up to 5%.
Structural Optimization Using the Simultaneous Perturbation Stochastic Approximation Algorithm
Authors: Hamidian D. , Seyedpoor S.M.
Published: May 2009

This paper presents an application of the simultaneous perturbation stochastic approximation (SPSA) method to size optimization of structures. This method can predict a gradient approximation that needs only two measurements of the objective function regardless of optimization problem dimension. This characteristic is very promising in reducing the computational cost of optimization process, especially in problems with a large number of variables to be optimized. Furthermore, the stochastic nature of SPSA can enhance the convergence of the method to achieve the global optimum. Some test examples are considered to demonstrate the effectiveness of the method when compared with the other optimization methods found in the literature. Numerical results reveal the computational merits of the SPSA-based method for structural optimization.
Dinogunellins A-D: Putative ichthyootoxic phospholipids of northern blenny Stichaeus grigorjewi eggs
Authors: Matsunaga Shigeki , Takahashi Nobutaka , Fusetani Nobuhiro
Published: May 2009

Dinogunellins A-D, ichthyootoxic phospholipids, have been isolated from the mature eggs of the northern blenny Stichaeus grigorjewi. Their structures were determined based on spectral and chemical methods as a mixture of 2’- or 3’-acylated adenosine 5’-phosphate linked to the α-carboxyl group of L-asparagine through a P-N bond.
Die Rechtsstellung des Unterhaltsgläubigers im Insolvenz(plan)-verfahren
Authors: Paul Uwe
Published: May 2009

Zum Unterhalt in der Insolvenz finden sich in der InsO Regelungen aus zwei Blickrichtungen: Während §§ 100, 101 Abs. 1 Satz 3 InsO thematisieren, ob und in welchem Umfange dem Schuldner bzw. dem vertretungsberechtigten persönlich haftenden Gesellschafter eines Schuldners Unterhalt aus der Insolvenzmasse zu gewähren ist, befassen sich §§ 38, 40 Satz 1 InsO mit der Konstellation, dass der Insolvenzschuldner sich selbst Unterhaltsansprüchen von Gläubigern ausgesetzt sieht. Gegenstand dieses Beitrags sind allein die Unterhaltsverpflichtungen des Schuldners und deren Behandlung in der Insolvenz.
Recent developments in EU competition law (2006–2008): Single-firm dominance and the interpretation of Article 82
Authors: Schweitzer Heike
Published: May 2009

In December 2008, the Commission published a ‘Guidance on the Commission's Enforcement Priorities in Applying Article 82 EC Treaty to Abusive Exclusionary Conduct by Dominant Undertakings’. The communication appears to conclude a debate on a ‘more economic approach’ towards Article 82 which has occupied the competition law community for the last three years. This article reviews the proposals contained in the ‘Priorities Paper’ in the light of the important judgments on the abuse of single-firm dominance which the CFI and the ECJ have issued between 2006 and 2008, including the Microsoft judgment. It strives to ascertain the current state of the law on Article 82, and the room it leaves for a ‘more economic approach’.
Hyperinsulinismus bei Säuglingen und Kindern: wenn ein Insulinspiegel nicht immer ausreicht / Hyperinsulinism in infancy and childhood: when an insulin level is not always enough1)
Authors: Palladino Andrew A. , Bennett Michael J. , Stanley Charles A.
Published: May 2009

Hypoglykämie bei Säuglingen und Kindern kann zu Krampfanfällen, Entwicklungsverzögerungen und anhaltenden Hirnschäden führen. Häufigste Ursache sowohl transienter als auch permanenter Hypoglykämien ist ein Hyperinsulinismus (HI). Der HI ist durch eine fehlregulierte Insulinsekretion gekennzeichnet, die zu einer persistierenden milden bis schweren Hypoglykämie führt. Die verschiedenen Formen des HI stellen eine Gruppe klinisch, genetisch und morphologisch heterogener Erkrankungen dar.

Kongenitaler Hyperinsulinismus steht mit Mutationen der Gene für SUR-1 und Kir6.2, Glukokinase, Glutamatdehydrogenase, kurzkettige 3-Hydroyacyl-CoA-Dehydrogenase sowie mit einer ektopischen Expression vonSLC16A1auf der Plasmamembran der β-Zelle im Zusammenhang. Ein Hyperinsulinismus kann mit perinatalem Stress, wie Geburtsasphyxie, mütterlicher Toxinämie, Frühgeburtlichkeit oder einer intrauterinen Wachstumsretardierung assoziiert sein, was zu einer prolongierten anhaltenden neonatalen Hypoglykämie führt. Zu den Mimikris eines Hyperinsulinismus gehören neonataler Panhypopituitarismus, medikamenteninduzierte Hypoglykämie, ein Insulinom, Anti-Insulin- und Insulin-Rezeptor-stimulierende Antikörper, das Beckwith-Wiedemann-Syndrom sowie angeborene Erkrankungen der Glykosylierung. Laboratoriumsuntersuchungen bei einem Hyperinsulinismus umfassen die Bestimmung des Blutzuckers, der Konzentrationen von Insulin, β-Hydroxybutyrat, Fettsäuren, Ammoniak und des Acylcarnitin-Profils im Plasma sowie die Untersuchung auf organische Säuren im Urin. Über Speziallaboratorien stehen genetische Untersuchungen der bekannten, mit Hyperinsulinismus assoziierten Gene zur Verfügung. Bestimmungen der akuten Insulinantwort (AIR) sind nützlich für eine phänotypische Charakterisierung. Bildgebende Verfahren und histologische Methoden stehen für eine Diagnose und Klassifizierung des Hyperinsulinismus ebenfalls zur Verfügung. Das Ziel der Behandlung bei Säuglingen mit Hyperinsulinismus ist die Prävention von hypoglykämiebedingten Hirnschäden durch Aufrechterhaltung eines Blutzuckerspiegels von über 700 mg/L (70 mg/dL) mit einer medikamentösen oder operativen Therapie.

Das Management des Hyperinsulinismus erfordert einen multidisziplinären Ansatz, an dem pädiatrische Endokrinologen, Radiologen, Chirurgen und Pathologen, beteiligt werden sollten, die mit der Diagnosestellung, Klassifizierung und Behandlung eines Hyperinsulinismus vertraut sind.
Multiparametrische Diagnostik in der Pathologie / Multiparametric diagnostic methods in pathology
Authors: Cullen Paul , Funke Harald , Klein Hanns-Georg , Langmann Thomas , Miethke Thomas , Neumaier Michael , Sauter Guido
Published: May 2009

Die Arbeitsgruppen Chipdiagnostik und Bioinformatik der DGKL haben sich bei ihrer Jahrestagung 2008 mit Anwendungen der arraybasierten Technologie in der Pathologie beschäftigt. Hauptthemen waren neue Entwicklungen auf dem Feld der Gewebematrices oder Multigewebeblöcken (engl. tissue arrays), Anwendungen der multiparametrischen Analytik in der epigenetischen Regulation der Genaktivität, sowie die arraybasierte vergleichende genomische Hybridisierungstechnologie (engl. array comparative genomic hybridization oder Array-CGH). Diese Methoden finden bereits heute besonders in der Charakterisierung von Tumorzellen und -gewebe einen breiten Einsatz und haben die Krebsdiagnostik erheblich vorangebracht. Eine wichtiges Ergebnis der Tagung war die Erkenntnis, dass bei der hochparallelen Analytik die technischen Möglichkeiten der klinischen Anwendung voraus sind. Deshalb besteht ein erheblicher Bedarf vor allem an begleitender klinischer Forschung, um die Anwendbarkeit und die Bedeutung dieser Diagnostik zu präzisieren.
Changes in Fluid Penetrability and Mechanical Properties of Concrete due to High Temperature Exposure
Authors: Recalde Juan José , Leming Michael L.
Published: May 2009

This paper examines the relationship between changes in mechanical properties and fluid penetrability of a conventional and a high strength concrete mixture resulting from exposure to temperatures of 150°C, 300°C, or both, using a unique experimental technique. Measurements were taken before and after exposure on 100 mm diameter disks, approximately 25 mm thick. The dynamic modulus of elasticity (Ed) was measured using resonant frequency techniques. Fluid penetrability of the disks was characterized by air permeability index (API) and rate of water absorption (sorptivity). The nondestructive nature of these tests allowed multiple testing on the same samples. The changes in API and Ed of high strength concrete disks were greater than those of conventional strength. Damaged high strength concrete was found to have a lower residual rate of water absorption than damaged conventional strength concrete. However, the rate of water absorption of high strength concrete did not show as large an increase as was found with air permeability. The API identified differences between high strength concrete specimens exposed to both 150°C and 300°C compared to similar specimens exposed to 300°C only. This difference was also identified by changes in Ed, but was not identified using the rate of water absorption. The test methods for API and Ed described in this paper are simple and easy to conduct, and appear to provide useful information in studying changes in microstructure of concrete exposed to elevated temperatures.
Multiple Metal Cations as Spray Deposit Tracers and Evaluation of the AGDISP Ground Boom Spray Drift Model
Authors: Zabkiewicz J. A. , Steele K. D. , Connell R. J.
Published: May 2009

The determination of spray drift by agrichemicals in field applications is laborious and expensive. Dyes have been used as tracers to reduce workloads and costs, but these methods have technical drawbacks. Metal cations have also been used as tracers and this method is promising, especially if a number of distinct cations from consecutive spray applications can be collected cumulatively by the same collectors. This study evaluated the use of various water soluble metal cation salts and plastic tape as a cost-effective collector for spray drift deposits. Measured deposit values were compared with calculated outputs from the AGDISP ground boom spray drift model. The comparisons showed that AGDISP over estimated downwind deposition and under estimated deposition within the last swathe in the spray block. Increasing boom height above the canopy improved within spray block deposition estimates. Varying wind direction had negligible effect; increasing relative humidity gave greater deposition closer to the spray block. These trends are discussed, together with the pros and cons of the metal cation and plastic tape collector system.
Buchbesprechung
Authors: Moser Michael
Published: May 2009

LAADA BILANIUK, Contested Tongues: Language Politics and Cultural Correction in Ukraine. Ithaca and London: Cornell University Press 2005. XIV + 230 S. ISBN 978-0801443497
The histone deacetylase inhibitor scriptaid enhances nascent mRNA production and rescues full-term development in cloned inbred mice
Authors: Van Thuan Nguyen , Bui Hong-Thuy , Kim Jin-Hoi , Hikichi Takafusa , Wakayama Sayaka , Kishigami Satoshi , Mizutani Eiji , Wakayama Teruhiko
Published: May 2009

Since the birth of Cumulina, the first mouse clone produced by somatic cell nuclear transfer (SCNT), the success rate of cloning in mice has been extremely low compared with other species and most of the inbred mouse strains have never been cloned. Recently, our laboratory has found that treatment of SCNT mouse embryos with trichostatin A, a histone deacetylase inhibitor (HDACi), improved the full-term development of B6D2F1 mouse clones significantly. However, this was not effective for the inbred strains. Here, we show for the first time that by treating SCNT embryos with another HDACi, scriptaid, all the important inbred mouse strains can be cloned, such as C57BL/6, C3H/He, DBA/2, and 129/Sv. Moreover, the success of somatic nuclear reprogramming and cloning efficiency via nuclear transfer technique is clearly linked to the competent de novo synthesis of nascent mRNA in cloned mouse embryos.
Genomewide Analysis Reveals Novel Pathways Affecting Endoplasmic Reticulum Homeostasis, Protein Modification and Quality Control
Authors: Čopič Alenka , Dorrington Mariana , Pagant Silvere , Barry Justine , Lee Marcus C S , Singh Indira , Hartman John L , Miller Elizabeth A
Published: May 2009

To gain new mechanistic insight into ER homeostasis and the biogenesis of secretory proteins, we screened a genomewide collection of yeast mutants for defective intracellular retention of the ER chaperone, Kar2p. We identified 87 Kar2p-secreting strains, including a number of known components in secretory protein modification and sorting. Further characterization of the 73 nonessential Kar2p retention mutants revealed roles for a number of novel gene products in protein glycosylation, GPI-anchor attachment, ER quality control, and retrieval of escaped ER residents. A subset of these mutants, required for ER retrieval, included the GET complex and two novel proteins that likely function similarly in membrane insertion of tail-anchored proteins. Finally, the variant histone, Htz1p, and its acetylation state seem to play an important role in maintaining ER retrieval pathways, suggesting a surprising link between chromatin remodeling and ER homeostasis.
Mecânica Relacional: A Propósito de uma Resenha
Authors: Escobar O. , Pleitez V.
Published: May 2009

Neste artigo fazemos uma análise crítica à proposta da Mecânica Relacional tal como apresentada no livro de mesmo nome, objeto de uma resenha recente nesta revista.
Produção de Filmes Didáticos de Curta Metragem e CD-ROMs para o Ensino de Física
Authors: Rohling Jurandir Hillmann , Neves Marcos Cesar Danhoni , Savi Arlindo Antonio , Sakai Fabio Sussumi , Raniero Leandro José , Bernabe Hilton Souza
Published: May 2009

Este artigo procurar mostrar o programa do Laboratório de Criação Visual do Departamento de Física da Universidade Estadual de Maringá na produção e divulgação de filmes educativos de física em curta-metragem.
Uma Demonstração de como o Método da Função Zeta para o Potencial Efetivo Elimina as Divergências
Authors: Nogueira José Alexandre , Maia Jr. Adolfo
Published: May 2009

O cálculo do potencial efetivo usando o método da função zeta é extremamente vantajoso, porque a função zeta é regular em s = 0, e nós obtemos imediatamente um resultado finito para o potencial efetivo sem a necessidade de subtração de qualquer pólo ou a adição de contratermos infinitos. O propósito deste artigo é mostrar explicitamente como ocorre o cancelamento das divergências e que o método da função zeta implicitamente usa o mesmo procedimento usado por Bollini-Giambiagi e Salam-Strathdee para obter a parte finita de funções com um pólo simples.