bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation of in situ (Fe,Cr)7C3/Fe composite coating by centrifugal casting
Authors: Niu L , Xu Y , Wu H , Wang W
Published: June 2010

Using chromium wires as starting material, an iron based composite coating reinforced by in situ (Fe,Cr)7C3 particles, with a thickness of 4·0 mm, was fabricated on the surface of the ductile cast iron substrate, by means of a centrifugal casting technique. The microstructure and properties of the composite coating were investigated by optical microscope, X-ray diffraction, scanning electron micrograph, energy dispersive spectrum, microhardness tester and pin on disc wear tester. Results show that the composite coating consists of primary (Fe,Cr)7C3 carbides as the reinforcing phase and interdendritic (Fe,Cr)7C3/ γ eutectics accompanied by negligible graphite nodules as the matrix. The composite coating is metallurgically bonded to the ductile cast iron substrate. Under the condition of dry sliding with loads, the composite coating offers virtually a unique wear resistant behaviour compared with that of unreinforced ductile cast iron material.
Preparation of improved hydroxyapatite coating on HT-C/C by modified induction heating deposition/hydrothermal treatment technologies
Authors: Xiong X-B , Zeng X-R , Zou J-Z , Xie S-H
Published: June 2010

Monetite coatings were produced on H2O2 treated carbon/carbon composites by induction heating deposition in the presence or absence of ultrasonic agitation of the bath and then converted to hydroxyapatite coatings undoped with other cations by ammonia hydrothermal treatment. The phase, morphology and chemical composition of the as achieved monetite and hydroxyapatite coatings in the presence/absence of ultrasound were characterised by XRD, SEM and TR-XRF. The adhesion of monetite and hydroxyapatite to the H2O2 treated carbon/carbon substrates was evaluated by a scratch test. The results showed that no obvious differences in the phase and composition for the as obtained coatings were found. However, ultrasonic bath could produce denser and better bonded coatings. The ultrasonicated coatings showed an average critical load of 38 N, which is nearly three times as high as that of the hydroxyapatite coating without ultrasonic bath. The failure position of the hydroxyapatite coating occurred in the coating, and no delamination was observed.
Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis
Authors: White Thomas A. , Johnson Tucker , Zarzhevsky Natalia , Tom Cindy , Delacroix Sinny , Holroyd Eric W. , Maroney Susan A. , Singh Ripudamanjit , Pan Shuchong , Fay William P. , van Deursen Jan , Mast Alan E. , Sandhu Gurpreet S. , Simari Robert D.
Published: June 2010

The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPIFlox) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPITie2) and myelomonocytic (TFPILysM) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPITie2 (71% ± 0.9%, P < .001) and TFPILysM (19% ± 0.6%, P < .001) compared with TFPIFlox littermate controls. Tail and cuticle bleeding were unaffected. However, TFPITie2 mice but not TFPILysM mice had increased ferric chloride–induced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial- and myelomonocytic-derived TFPI.
Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state
Authors: den Hollander Jürgen , Rimpi Sara , Doherty Joanne R. , Rudelius Martina , Buck Andreas , Hoellein Alexander , Kremer Marcus , Graf Nikolas , Scheerer Markus , Hall Mark A. , Goga Andrei , von Bubnoff Nikolas , Duyster Justus , Peschel Christian , Cleveland John L. , Nilsson Jonas A. , Keller Ulrich
Published: June 2010

Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.
Recurrent BRAF mutations in Langerhans cell histiocytosis
Authors: Badalian-Very Gayane , Vergilio Jo-Anne , Degar Barbara A. , MacConaill Laura E. , Brandner Barbara , Calicchio Monica L. , Kuo Frank C. , Ligon Azra H. , Stevenson Kristen E. , Kehoe Sarah M. , Garraway Levi A. , Hahn William C. , Meyerson Matthew , Fleming Mark D. , Rollins Barrett J.
Published: June 2010

Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen–activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.
Right and left heart failure in severe H1N1 influenza A infection
Authors: Brown S.M. , Pittman J. , Miller R.R. , Horton K.D. , Markewitz B. , Hirshberg E. , Jones J. , Grissom C.K.
Published: June 2010

Influenza infection can affect cardiac function. The recent pandemic of H1N1 influenza A provided an opportunity to study echocardiographic findings in critically ill infected patients.

We hypothesised that critically ill patients with H1N1 infection would have a higher incidence of right and left heart failure than is seen in unselected populations of patients with septic shock and/or acute respiratory distress syndrome (ARDS).

We retrospectively studied all patients admitted to four intensive care units at three hospitals in Salt Lake County, UT, USA, with laboratory-confirmed H1N1 infection in whom a clinical echocardiogram was available.

23 out of 48 patients had qualifying echocardiograms. Right ventricular (RV) dilatation (50–80%) and at least moderate systolic impairment (23%) were common, higher than the range described in general populations with ARDS. Left ventricular systolic dysfunction was present in 17% of patients. No single echocardiographic parameter was associated with 28-day mortality or ventilator-free days to 28 days.

Critically ill patients with H1N1 infection frequently exhibit right heart dilatation and failure. RV basal dilatation was extremely common. These patients have less left heart failure than expected on the basis of prior descriptions of influenza myopericarditis or of general populations of septic patients.
Super-sparse principal component analyses for high-throughput genomic data
Authors: Lee Donghwan , Lee Woojoo , Lee Youngjo , Pawitan Yudi
Published: June 2010

Background

Principal component analysis (PCA) has gained popularity as a method for the analysis of high-dimensional genomic data. However, it is often difficult to interpret the results because the principal components are linear combinations of all variables, and the coefficients (loadings) are typically nonzero. These nonzero values also reflect poor estimation of the true vector loadings; for example, for gene expression data, biologically we expect only a portion of the genes to be expressed in any tissue, and an even smaller fraction to be involved in a particular process. Sparse PCA methods have recently been introduced for reducing the number of nonzero coefficients, but these existing methods are not satisfactory for high-dimensional data applications because they still give too many nonzero coefficients.

Results

Here we propose a new PCA method that uses two innovations to produce an extremely sparse loading vector: (i) a random-effect model on the loadings that leads to an unbounded penalty at the origin and (ii) shrinkage of the singular values obtained from the singular value decomposition of the data matrix. We develop a stable computing algorithm by modifying nonlinear iterative partial least square (NIPALS) algorithm, and illustrate the method with an analysis of the NCI cancer dataset that contains 21,225 genes.

Conclusions

The new method has better performance than several existing methods, particularly in the estimation of the loading vectors.
Copine A plays a role in the differentiation of stalk cells and the initiation of culmination in Dictyostelium development
Authors: Smith Tasha S , Pineda Jaimie M , Donaghy Alex C , Damer Cynthia K
Published: June 2010

Background

Copines are calcium-dependent phospholipid-binding proteins found in diverse eukaryotic organisms. We are studying the function of copines in Dictyostelium discoideum, a single-celled amoeba that undergoes cell differentiation and morphogenesis to form multicellular fruiting bodies when placed in starvation conditions. Previously, we showed that Dictyostelium cells lacking the copine A (cpnA) gene are not able to complete the developmental cycle, arresting at the slug stage. The aim of this study is to further characterize the developmental defect of the cpnA- cells.

Results

Time-lapse imaging revealed that cpnA- cells exhibited delayed aggregation and made large mounds that formed one large slug as compared to the smaller slugs of the wild-type cells. While the prespore cell patterning appeared to be normal within the cpnA- slugs, the prestalk cell patterning was different from wild-type. When cpnA- cells were mixed with a small percentage of wild-type cells, chimeric fruiting bodies with short stalks formed. When a small percentage of cpnA- cells was mixed with wild-type cells, the cpnA- cells labeled with GFP were found located throughout the chimeric slug and in both the stalk and sporehead of the fruiting bodies. However, there appeared to be a small bias towards cpnA- cells becoming spore cells. When cpnA- cells were developed in buffer containing EGTA, they were also able to differentiate into either stalk or spore cells to form fruiting bodies with short stalks.

Conclusions

Our results indicate that CpnA is involved in the regulation of aggregation, slug size, and culmination during Dictyostelium development. More specifically, CpnA appears to be involved in the function and differentiation of prestalk cells and plays a role in a calcium-regulated signaling pathway critical to triggering the initiation of culmination.
Asymmetrical hippocampal connectivity in mesial temporal lobe epilepsy: evidence from resting state fMRI
Authors: Pereira Fabrício RS , Alessio Andréa , Sercheli Maurício S , Pedro Tatiane , Bilevicius Elizabeth , Rondina Jane M , Ozelo Helka FB , Castellano Gabriela , Covolan Roberto JM , Damasceno Benito P , Cendes Fernando
Published: June 2010

Background

Mesial temporal lobe epilepsy (MTLE), the most common type of focal epilepsy in adults, is often caused by hippocampal sclerosis (HS). Patients with HS usually present memory dysfunction, which is material-specific according to the hemisphere involved and has been correlated to the degree of HS as measured by postoperative histopathology as well as by the degree of hippocampal atrophy on magnetic resonance imaging (MRI). Verbal memory is mostly affected by left-sided HS, whereas visuo-spatial memory is more affected by right HS. Some of these impairments may be related to abnormalities of the network in which individual hippocampus takes part. Functional connectivity can play an important role to understand how the hippocampi interact with other brain areas. It can be estimated via functional Magnetic Resonance Imaging (fMRI) resting state experiments by evaluating patterns of functional networks. In this study, we investigated the functional connectivity patterns of 9 control subjects, 9 patients with right MTLE and 9 patients with left MTLE.

Results

We detected differences in functional connectivity within and between hippocampi in patients with unilateral MTLE associated with ipsilateral HS by resting state fMRI. Functional connectivity resulted to be more impaired ipsilateral to the seizure focus in both patient groups when compared to control subjects. This effect was even more pronounced for the left MTLE group.

Conclusions

The findings presented here suggest that left HS causes more reduction of functional connectivity than right HS in subjects with left hemisphere dominance for language.
Tobramycin at subinhibitory concentration inhibits the RhlI/R quorum sensing system in a Pseudomonas aeruginosaenvironmental isolate
Authors: Babić Fedora , Venturi Vittorio , Maravić-Vlahoviček Gordana
Published: June 2010

Background

Antibiotics are not only small molecules with therapeutic activity in killing or inhibiting microbial growth, but can also act as signaling molecules affecting gene expression in bacterial communities. A few studies have demonstrated the effect of tobramycin as a signal molecule on gene expression at the transcriptional level and its effect on bacterial physiology and virulence. These have shown that subinhibitory concentrations (SICs) of tobramycin induce biofilm formation and enhance the capabilities of P. aeruginosa to colonize specific environments.

Methods

Environmental P. aeruginosa strain PUPa3 was grown in the presence of different concentrations of tobramycin and it was determined at which highest concentration SIC, growth, total protein levels and translation efficiency were not affected. At SIC it was then established if phenotypes related to cell-cell signaling known as quorum sensing were altered.

Results

In this study it was determined whether tobramycin sensing/response at SICs was affecting the two independent AHL QS systems in an environmental P. aeruginosa strain. It is reasonable to assume that P. aeruginosa encounters tobramycin in nature since it is produced by niche mate Streptomyces tenebrarius. It was established that SICs of tobramycin inhibited the RhlI/R system by reducing levels of C4-HSL production. This effect was not due to a decrease of rhlI transcription and required tobramycin-ribosome interaction.

Conclusions

Tobramycin signaling in P. aeruginosa occurs and different strains can have a different response. Understanding the tobramycin response by an environmental P. aeruginosa will highlight possible inter-species signalling taking place in nature and can possible also have important implications in the mode of utilization for human use of this very important antibiotic.
Effects of bevacizumab plus irinotecan on response and survival in patients with recurrent malignant glioma: a systematic review and survival-gain analysis
Authors: Xu Tao , Chen Juxiang , Lu Yicheng , Wolff Johannes EA
Published: June 2010

Background

The combination of bevacizumab and irinotecan is a new chemotherapy protocol increasingly used for recurrent malignant glioma. Results from phase II trials suggest this drug combination is beneficial to patients, but no conclusive comparisons between this and other treatment protocols have been published.

Methods

We performed a systematic review and survival gain analysis of phase II studies to evaluate the efficacy and safety of bevacizumab plus irinotecan treatment. To do this, we utilized a preexisting database from which the mean overall survival and response rate of patients could be predicted. Survival gain, which characterized the influence of treatment, was defined as the difference between observed and predicted mean overall survival. Response gain was calculated similarly.

Results

741 cohorts were enrolled in the database. Among them, 282 cohorts were based on recurrent adult HGG, mean reported median overall survival was 10.96 ± 8.4 months, and mean response rate was 18.9% ± 20.5. We found that compared with other treatment protocols, bevacizumab plus irinotecan largely improved response rates (P = 0.00002) and had a possible moderate effect on overall survival time (P = 0.024). Hemorrhage, thromboembolic complications, and gastrointestinal toxicities were the most frequently reported side effects.

Conclusion

The combination of bevacizumab and irinotecan might improve outcome in patients with recurrent malignant glioma. Randomized controlled trials are recommended to evaluate this treatment protocol and the additional value of irinotecan.
AlignMiner: a Web-based tool for detection of divergent regions in multiple sequence alignments of conserved sequences
Authors: Guerrero Darío , Bautista Rocío , Villalobos David P , Cantón Francisco R , Claros M Gonzalo
Published: June 2010

Background

Multiple sequence alignments are used to study gene or protein function, phylogenetic relations, genome evolution hypotheses and even gene polymorphisms. Virtually without exception, all available tools focus on conserved segments or residues. Small divergent regions, however, are biologically important for specific quantitative polymerase chain reaction, genotyping, molecular markers and preparation of specific antibodies, and yet have received little attention. As a consequence, they must be selected empirically by the researcher. AlignMiner has been developed to fill this gap in bioinformatic analyses.

Results

AlignMiner is a Web-based application for detection of conserved and divergent regions in alignments of conserved sequences, focusing particularly on divergence. It accepts alignments (protein or nucleic acid) obtained using any of a variety of algorithms, which does not appear to have a significant impact on the final results. AlignMiner uses different scoring methods for assessing conserved/divergent regions, being the method that provides the highest number of regions with the greatest length, and being the most restrictive. Conserved/divergent regions can be generated either with respect to the consensus sequence or to one master sequence. The resulting data are presented in a graphical interface developed in AJAX, which provides remarkable user interaction capabilities. Users do not need to wait until execution is complete and can.even inspect their results on a different computer. Data can be downloaded onto a user disk, in standard formats. In silico and experimental proof-of-concept cases have shown that AlignMiner can be successfully used to designing specific polymerase chain reaction primers as well as potential epitopes for antibodies. Primer design is assisted by a module that deploys several oligonucleotide parameters for designing primers "on the fly".

Conclusions

AlignMiner can be used to reliably detect divergent regions via several scoring methods that provide different levels of selectivity. Its predictions have been verified by experimental means. Hence, it is expected that its usage will save researchers' time and ensure an objective selection of the best-possible divergent region when closely related sequences are analysed. AlignMiner is freely available at http://www.scbi.uma.es/alignminer.
Natural killer cells control a T-helper 1 response in patients with Behçet's disease
Authors: Yamaguchi Yukie , Takahashi Hayato , Satoh Takashi , Okazaki Yuka , Mizuki Nobuhisa , Takahashi Kazuo , Ikezawa Zenro , Kuwana Masataka
Published: June 2010

Introduction

Behçet's disease (BD) is a multisystem inflammatory disorder, in which a T-helper 1 (Th1)-polarized immune response plays a major role in the pathogenic process. We evaluated the regulatory role of natural killer (NK) cells in Th1-biased immune responses in patients with BD.

Methods

We studied 47 patients with BD, including 10 with active disease (aBD) and 37 with inactive disease (iBD), and 29 healthy controls. The activation status and cytotoxic activity of NK cells were examined by flow cytometry. The levels of mRNAs for immune modulatory and cytotoxic molecules in NK cells were determined by quantitative PCR. The IL-12 signal strength in NK cells was determined by assessing the phosphorylation state of its downstream component, signal transducer and activator of transduction 4, by immunoblotting. Finally, NK cells' ability to modulate the Th1 response was evaluated by co-culturing NK cells and T cells without cell contact.

Results

CD69+-activated NK cells were significantly increased in aBD compared with iBD or control samples, although their cytotoxic activities were similar. The iBD NK cells showed downregulated IL-12 receptor β2 mRNA levels compared with aBD or control NK cells. The increased IL-13 expression was detected in a subset of BD patients: most of them had iBD. The IL-13 expression level in iBD patients was significantly higher than the level in controls, but was not statistically different compared with the level in aBD patients. The gene expression profile in iBD patients was consistent with the NK type 2 phenotype, and the shift to NK type 2 was associated with disease remission. NK cells from iBD patients showed impaired IL-12-induced signal transducer and activator of transduction 4 phosphorylation. Finally, iBD, but not control, NK cells suppressed IFNγ expression by aBD-derived CD4+ T cells in vitro.

Conclusions

NK cells may control disease flare/remission in BD patients via NK type 2-mediated modulation of the Th1 response.
Phase II Proof-of-Concept Study of Pazopanib Monotherapy in Treatment-Naive Patients With Stage I/II Resectable Non–Small-Cell Lung Cancer
Authors: Altorki Nasser , Lane Maureen E. , Bauer Thomas , Lee Paul C. , Guarino Michael J. , Pass Harvey , Felip Enriqueta , Peylan-Ramu Nili , Gurpide Alfonso , Grannis Frederic W. , Mitchell John D. , Tachdjian Sabrina , Swann R. Suzanne , Huff Anne , Roychowdhury Debasish F. , Reeves Anthony , Ottesen Lone H. , Yankelevitz David F.
Published: June 2010

Purpose

Patients with early-stage, resectable, non–small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC.

Patients and Methods

Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients.

Results

Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction ≥ 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment.

Conclusion

Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned.
Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer
Authors: Monk Bradley J. , Herzog Thomas J. , Kaye Stanley B. , Krasner Carolyn N. , Vermorken Jan B. , Muggia Franco M. , Pujade-Lauraine Eric , Lisyanskaya Alla S. , Makhson Anatoly N. , Rolski Janusz , Gorbounova Vera A. , Ghatage Prafull , Bidzinski Mariusz , Shen Keng , Ngan Hextan Yuen-Sheung , Vergote Ignace B. , Nam Joo-Hyun , Park Youn Choi , Lebedinsky Claudia A. , Poveda Andrés M.
Published: June 2010

Purpose

The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy.

Patients and Methods

Women ≥ 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m2followed by a 3-hour infusion of trabectedin 1.1 mg/m2every 3 weeks or PLD 50 mg/m2every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment.

Results

Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone.

Conclusion

When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.
Accumulation of Segmental Alterations Determines Progression in Neuroblastoma
Authors: Schleiermacher Gudrun , Janoueix-Lerosey Isabelle , Ribeiro Agnès , Klijanienko Jerzy , Couturier Jérôme , Pierron Gaëlle , Mosseri Véronique , Valent Alexander , Auger Nathalie , Plantaz Dominique , Rubie Hervé , Valteau-Couanet Dominique , Bourdeaut Franck , Combaret Valérie , Bergeron Christophe , Michon Jean , Delattre Olivier
Published: June 2010

Purpose

Neuroblastoma is characterized by two distinct types of genetic profiles, consisting of either numerical or segmental chromosome alterations. The latter are associated with a higher risk of relapse, even when occurring together with numerical alterations. We explored the role of segmental alterations in tumor progression and the possibility of evolution from indolent to aggressive genomic types.

Patients and Methods

Array-based comparative genomic hybridization data of 394 neuroblastoma samples were analyzed and linked to clinical data.

Results

Integration of ploidy and genomic data indicated that pseudotriploid tumors with mixed numerical and segmental profiles may be derived from pseudotriploid tumors with numerical alterations only. This was confirmed by the analysis of paired samples, at diagnosis and at relapse, as in tumors with a purely numerical profile at diagnosis additional segmental alterations at relapse were frequently observed. New segmental alterations at relapse were also seen in patients with segmental alterations at diagnosis. This was not linked to secondary effects of cytotoxic treatments since it occurred even in patients treated with surgery alone. A higher number of chromosome breakpoints were correlated with advanced age at diagnosis, advanced stage of disease, with a higher risk of relapse, and a poorer outcome.

Conclusion

These data provide further evidence of the role of segmental alterations, suggesting that tumor progression is linked to the accumulation of segmental alterations in neuroblastoma. This possibility of genomic evolution should be taken into account in treatment strategies of low- and intermediate-risk neuroblastoma and should warrant biologic reinvestigation at the time of relapse.
Clinical Relevance of Microsatellite Instability in Colorectal Cancer
Authors: de la Chapelle Albert , Hampel Heather
Published: June 2010

Microsatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. It arises in tumors with deficient mismatch repair due to the inactivation of one of the four mismatch repair genes: MSH2, MLH1, MSH6, and PMS2. In order to determine the MSI status of a tumor, microdissection and polymerase chain reaction–based detection strategies are required. For practical purposes, MSI is equivalent to the loss of staining by immunohistochemistry (IHC) of one of the mismatch repair genes since both signify an abnormality in mismatch repair. Of all colorectal cancers (CRCs), 15% to 20% display MSI or abnormal IHC (often referred to as microsatellite instability [MIN] pathway). The remaining 80% to 85% of CRCs are microsatellite stable but most are characterized by chromosomal instability (CIN pathway). Almost all Lynch syndrome tumors have MSI or abnormal IHC and they account for up to one third of all MIN CRCs (3% to 5% of all CRCs). The remaining MIN tumors are sporadic as a result of somatic inactivation of the MLH1 gene caused by methylation of its promoter. Thus, the presence of a MSI/IHC abnormality prompts further investigations to diagnose Lynch syndrome, whereas its absence excludes Lynch syndrome. We recommend screening all CRC tumors for IHC or MSI. MIN tumors have a more favorable outcome than CIN tumors, and fluorouracil-based adjuvant chemotherapy does not improve the outcome of stage II or stage III MIN tumors. More data are needed to determine how best to treat patients with stage II and stage III MIN CRCs.
Integrated Positron Emission Tomography/Computed Tomography May Render Bone Scintigraphy Unnecessary to Investigate Suspected Metastatic Breast Cancer
Authors: Morris Patrick G. , Lynch Colleen , Feeney John N. , Patil Sujata , Howard Jane , Larson Steven M. , Dickler Maura , Hudis Clifford A. , Jochelson Maxine , McArthur Heather L.
Published: June 2010

Purpose

Although the accurate detection of osseous metastases in the evaluation of patients with suspected metastatic breast cancer (MBC) has significant prognostic and therapeutic implications, the ideal diagnostic approach is uncertain. In this retrospective, single-institution study, we compare the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BSc) in women with suspected MBC.

Patients and Methods

Women with suspected MBC evaluated with PET/CT and BSc (within 30 days) between January 1, 2003 and June 30, 2008, were identified through institutional databases. Electronic medical records were reviewed, and radiology reports were classified as positive/negative/equivocal for osseous metastases. A nuclear medicine radiologist (blinded to correlative and clinical end points) reviewed all equivocal PET/CT and BSc images and reclassified some reports. Final PET/CT and BSc classifications were compared. Baseline patient/tumor characteristics and bone pathology were recorded and compared to the final imaging results.

Results

We identified 163 women who had a median age of 52 years (range, 30 to 90 years); 32% had locally advanced breast cancer, 42% had been diagnosed with breast cancer less than 12 weeks before identification. Twenty studies were originally deemed equivocal (five with PET/CT, and 15 with BSc), and 13 (65%) of these studies were reclassified after radiology review. Overall, PET/CT and BSc were highly concordant for reporting osseous metastases with 132 paired studies (81%); 32 (20%) were positive, and 100 (61%) were negative. Thirty-one occurrences (19%) were discordant. Twelve of these (39%) had pathology confirming osseous metastases: nine (of 18) were PET/CT positive and BSc negative; one (of three) was PET/CT positive and BSc equivocal; and two (of two) were PET/CT equivocal and BSc negative.

Conclusion

This study supports the use of PET/CT in detecting osseous metastases for suspected MBC. Whether PET/CT may supplant BSc in this setting is unknown.
Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non–Small-Cell Lung Cancer
Authors: Felip Enriqueta , Rosell Rafael , Maestre José Antonio , Rodríguez-Paniagua José Manuel , Morán Teresa , Astudillo Julio , Alonso Guillermo , Borro José Manuel , González-Larriba José Luis , Torres Antonio , Camps Carlos , Guijarro Ricardo , Isla Dolores , Aguiló Rafael , Alberola Vicente , Padilla José , Sánchez-Palencia Abel , Sánchez José Javier , Hermosilla Eduardo , Massuti Bartomeu
Published: June 2010

Purpose

To address whether preoperative chemotherapy plus surgery or surgery plus adjuvant chemotherapy prolongs disease-free survival compared with surgery alone among patients with resectable non–small-cell lung cancer.

Patients and Methods

In this phase III trial, 624 patients with stage IA (tumor size > 2 cm), IB, II, or T3N1 were randomly assigned to surgery alone (212 patients), three cycles of preoperative paclitaxel-carboplatin followed by surgery (201 patients), or surgery followed by three cycles of adjuvant paclitaxel-carboplatin (211 patients). The primary end point was disease-free survival.

Results

In the preoperative arm, 97% of patients started the planned chemotherapy, and radiologic response rate was 53.3%. In the adjuvant arm, 66.2% started the planned chemotherapy. Ninety-four percent of patients underwent surgery; surgical procedures and postoperative mortality were similar across the three arms. Patients in the preoperative arm had a nonsignificant trend toward longer disease-free survival than those assigned to surgery alone (5-year disease-free survival 38.3% v 34.1%; hazard ratio [HR] for progression or death, 0.92; P = .176). Five-year disease-free survival rates were 36.6% in the adjuvant arm versus 34.1% in the surgery arm (HR 0.96; P = .74).

Conclusion

In early-stage patients, no statistically significant differences in disease-free survival were found with the addition of preoperative or adjuvant chemotherapy to surgery. In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment.
US Intelligence at the Crossroads
Authors: Ellis William W.
Published: June 2010

US intelligence activities have changed in recent years because of changing global political conditions. Using sophisticated technologies, intelligence agencies now conduct surveillance of a wide variety of organizations and an enormous number of people, including many US citizens. This has generated a vast amount of data that these agencies have not been able to use productively, in spite of the expenditure of many billions of dollars, mostly with private firms. Some 70 percent of the approximately $75 billion spent on intelligence annually is spent on these firms. The author discusses a number of serious problems with these developments.
The Euro-Atlantic Brand
Authors: Binder David
Published: June 2010

“Euro-Atlantic” as a political power brand name was employed possibly for the first time in a 1985 speech by Bettino Craxi, then president of the European Council, when he spoke about “Italy's Euro-Atlantic role.” Its political usage was codified in the label Euro-Atlantic Partnership Council (EAPC), a group formed in 1997 and which now numbers fifty “partner” governments. EAPC is the successor to the North Atlantic Cooperation Council. (The NACC was created as an adjunct to NATO six years earlier in the first flush of post–Cold War Europe.) Among EAPC partners are not only eleven far-flung (and non-Atlantic-riparian) governments of the former Soviet Union—from Armenia to Uzbekistan—but also the six republics of the former Yugoslavia. Russia itself is listed among the partners, although its leaders remain highly suspicious of the NATO parent.
As the World Constricts: Kader Attia’s Pictures of Spacelessness
Authors: Feldman Hannah
Published: June 2010

Kader Attia is a French Algerian artist who now divides his time among Berlin, Algiers, and Paris. This article surveys his sculptural and photographic practice since his provocative Piste d’atterrissage (1997). It argues that Attia’s invocation of modernist urbanism, religious custom, and the aftermath of human migration combine across the arc of his production to present a dystopic picture of globalization that critiques both postcolonial theories of hybridity and the cultural and architectural homogenization against which they were originally formulated. Crucially, this picture is grounded in the particularities of the displacement and destruction generated first by the Algerian War of Independence and then by the Algerian Civil War. Yet the degree to which Attia is expanding his focus beyond the specifics of this experience marks his investment in probing the claims of universalism that originally underlay the colonialist premise. The article also explores the ways in which Attia’s focus on the spatial and pictorial exclusion of migrant and exiled subjects engages the art world’s celebration of its own purported global reach.
Bat3 promotes the membrane integration of tail-anchored proteins
Authors: Leznicki Pawel , Clancy Anne , Schwappach Blanche , High Stephen
Published: June 2010

The membrane integration of tail-anchored proteins at the endoplasmic reticulum (ER) is post-translational, with different tail-anchored proteins exploiting distinct cytosolic factors. For example, mammalian TRC40 has a well-defined role during delivery of tail-anchored proteins to the ER. Although its Saccharomyces cerevisiae equivalent, Get3, is known to function in concert with at least four other components, Get1, Get2, Get4 and Get5 (Mdy2), the role of additional mammalian proteins during tail-anchored protein biogenesis is unclear. To this end, we analysed the cytosolic binding partners of Sec61β, a well-defined substrate of TRC40, and identified Bat3 as a previously unknown interacting partner. Depletion of Bat3 inhibits the membrane integration of Sec61β, but not of a second, TRC40-independent, tail-anchored protein, cytochrome b5. Thus, Bat3 influences the in vitro membrane integration of tail-anchored proteins using the TRC40 pathway. When expressed in Saccharomyces cerevisiae lacking a functional GET pathway for tail-anchored protein biogenesis, Bat3 associates with the resulting cytosolic pool of non-targeted chains and diverts it to the nucleus. This Bat3-mediated mislocalisation is not dependent upon Sgt2, a recently identified component of the yeast GET pathway, and we propose that Bat3 either modulates the TRC40 pathway in higher eukaryotes or provides an alternative fate for newly synthesised tail-anchored proteins.
Medicine and music: A note on John Hunter (1728–93) and Joseph Haydn (1732–1809)
Authors: Fu Louis
Published: June 2010

Joseph Haydn was a central figure in the development and growth of the European classical musical tradition in its transition from the Baroque period. John Hunter as the Founder of Scientific Surgery was a dominant figure in 18th-century British medical science. Anne Hunter née Home (1742–1821) was in her own right a figure of some eminence in the literary circles of 18th-century London. Attracted to the burgeoning medical and musical scenes of London, John Hunter married Anne Home and became a famous surgeon; Haydn became acquainted with the Hunters. The people, the opportunities and the circumstances had coincided.
European 18th-century obstetrical pioneers in Japan: a new light in the Empire of the Sun
Authors: van der Weiden R M F , Uhlenbeck G C
Published: June 2010

From the second half of the 18th century, Japanese physicians incorporated concepts of European medicine in their publications. Dutch physicians had a pivotal role in this process, facilitated by their trade relations in Deshima, near Nagasaki. This paper focuses on the influence of later Dutch editions (probably the 1765 edition) of Hendrik van Deventer's pioneer work Nieuw Ligt ( a New Light) on Japanese obstetrics, especially on Katakura Kakuryō's publication in 1799 of Sanka Hatsumō ( Enlightenment of Obstetrics).
The Role of Ondansetron in the Treatment of Schizophrenia
Authors: Bennett Allison C , Vila Tania M
Published: June 2010

Objective:

To evaluate the efficacy of ondansetron for the treatment of schizophrenia.

Data Sources:

Searches of MEDLINE (1950–March 2010) and Google Scholar were performed. Key search terms included ondansetron, Zofran, serotonin antagonists, 5-HT, serotonin receptor, and schizophrenia.

Study Selection and Data Extraction:

All articles published in English identified from the data sources were evaluated. All studies and case reports evaluating ondansetron for the treatment of schizophrenia were reviewed.

Data Synthesis:

Six clinical trials, including 3 double-blind, randomized trials, and 2 case reports pertinent to ondansetron use in schizophrenia, were identified. Ondansetron daily doses ranged from 4 to 16 mg, with doses administered once or twice daily. Ondansetron was used as monotherapy in 3 trials and as an adjunct to therapy with clozapine, haloperidol, or risperidone, respectively, in 3 trials. Studies were of varying durations, ranging from a single-dose study with a 3-hour follow-up to three 12-week studies. Most studies evaluated ondansetron's efficacy in treating schizophrenia as measured with changes in Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale, and Clinical Global Impression scale scores. In the 2 largest trials, with a combined patient population of 151, treatment with adjunctive ondansetron resulted in statistically significant improvement in negative symptoms as assessed with PANSS. In all studies, ondansetron was well tolerated, with no severe adverse reactions reported.

Conclusions:

Ondansetron may be effective as an adjunct to antipsychotics for the treatment of schizophrenia, specifically negative symptoms, as assessed with PANSS. Due to the variation in concurrent therapies and dosing regimens, it is difficult to establish an optimal dose from the reviewed trials. Further large, randomized, double-blind, active-controlled studies would be helpful in determining the role of ondansetron in the treatment of schizophrenia.
Amoxicillin-Induced Hemolytic Anemia in a Child with Glucose 6-Phosphate Isomerase Deficiency
Authors: Rossi Francesca , Ruggiero Simona , Gallo Mariapina , Simeone Gelsomina , Maria Sofia , Matarese Rosaria , Nobili Bruno
Published: June 2010

Objective:

To describe the first case of amoxicillin-induced nonimmune hemolytic anemia in a child with glucose-6-phosphate isomerase (GPI) deficiency.

Case Summary:

A 3-year-old boy with GPI deficiency was admitted for upper respiratory tract infection and fever. The patient was treated with a standard dose of amoxicillin (50 mg/kg/day). On hospital admission, the child had a chronic moderately low hemoglobin level (8.6 g/dL), but within 24 hours of the first amoxicillin dose, the hemoglobin level markedly decreased (5.8 g/dL), the reticulocyte level increased (58%), and the urine darkened. Results of the direct and indirect Coomb's tests were negative and the acute hemolytic phase ended spontaneously 8 days after amoxicillin withdrawal (hemoglobin 9.5 g/dL, reticulocytes 22%).

Discussion:

All previous cases of amoxicillin-induced hemolytic anemia have been attributed to an immune mechanism. Given the absence of anti-reticulocyte antibodies (Coomb's test), we suggest that the amoxicillin-induced hemolytic anemia in our patient occurred via a nonimmune mechanism favored by the child's GPI deficiency. Based on a MEDLINE search, we believe this to be the first report of amoxicillin-induced nonimmune hemolytic anemia in a child with GPI deficiency. GPI deficiency has been associated with well-compensated chronic hemolytic anemia that can become clinically relevant consequent to the administration of drugs. GPI deficiency can lead to impairment of the system that removes free radicals generated by amoxicillin, thereby resulting in oxidation of hemoglobin and destabilization of red cell membranes, with acute hemolysis and severe hemoglobinuria. The Naranjo probability score was consistent with a probable relationship between the hemolytic anemia and amoxicillin therapy.

Conclusions:

This report reinforces the hypothesis that a drug-sensitivity reaction is closely related to a genetically transmitted enzyme deficiency.
Psychiatric Symptoms in Adults With Down Syndrome and Alzheimer's Disease
Authors: Urv Tiina K. , Zigman Warren B. , Silverman Wayne
Published: June 2010

Changes in psychiatric symptoms related to specific stages of dementia were investigated in 224 adults 45 years of age or older with Down syndrome. Findings indicate that psychiatric symptoms are a prevalent feature of dementia in the population with Down syndrome and that clinical presentation is qualitatively similar to that seen in Alzheimer's disease within the general population. Psychiatric symptoms related to Alzheimer's disease vary by the type of behavior and stage of dementia, but do not seem to be influenced by sex or level of premorbid intellectual impairment. Some psychiatric symptoms may be early indicators of Alzheimer's disease and may appear prior to substantial changes in daily functioning. Improvements in understanding the progression of dementia in individuals with Down syndrome may lead to improved diagnosis and treatment.
Comparisons Between Individuals With Autism Spectrum Disorders and Individuals With Down Syndrome in Adulthood
Authors: Esbensen Anna J. , Bishop Somer , Seltzer Marsha Mailick , Greenberg Jan S. , Taylor Julie Lounds
Published: June 2010

Differences between 70 adults with autism spectrum disorders and intellectual disability and 70 age-matched adults with Down syndrome were examined on variables indicative of independence in adult life. Adults with autism spectrum disorder had less residential independence and social contact with friends, had more limited functional abilities and literacy, exhibited more behavior problems, had more unmet service needs, and received fewer services as compared to adults with Down syndrome. Reflecting these differences, adults with autism spectrum disorder were less likely to be classified as having high or moderate levels of independence in adult life as compared to adults with Down syndrome. Predictors of independence in adult life differed for adults with autism spectrum disorder as compared with adults who have Down syndrome. Implications for service delivery are discussed.