bluuebunny/crossref_metadata_2025 huggingface dataset:
FUNYBASE: a FUNgal phYlogenomic dataBASE
Authors: Marthey Sylvain , Aguileta Gabriela , Rodolphe François , Gendrault Annie , Giraud Tatiana , Fournier Elisabeth , Lopez-Villavicencio Manuela , Gautier Angélique , Lebrun Marc-Henri , Chiapello Hélène
Published: October 2008

Background

The increasing availability of fungal genome sequences provides large numbers of proteins for evolutionary and phylogenetic analyses. However the heterogeneity of data, including the quality of genome annotation and the difficulty of retrieving true orthologs, makes such investigations challenging. The aim of this study was to provide a reliable and integrated resource of orthologous gene families to perform comparative and phylogenetic analyses in fungi.

Description

FUNYBASE is a database dedicated to the analysis of fungal single-copy genes extracted from available fungal genomes sequences, their classification into reliable clusters of orthologs, and the assessment of their informative value for phylogenetic reconstruction based on amino acid sequences. The current release of FUNYBASE contains two types of protein data: (i) a complete set of protein sequences extracted from 30 public fungal genomes and classified into clusters of orthologs using a robust automated procedure, and (ii) a subset of 246 reliable ortholog clusters present as single copy genes in 21 fungal genomes. For each of these 246 ortholog clusters, phylogenetic trees were reconstructed based on their amino acid sequences. To assess the informative value of each ortholog cluster, each was compared to a reference species tree constructed using a concatenation of roughly half of the 246 sequences that are best approximated by the WAG evolutionary model. The orthologs were classified according to a topological score, which measures their ability to recover the same topology as the reference species tree. The full results of these analyses are available on-line with a user-friendly interface that allows for searches to be performed by species name, the ortholog cluster, various keywords, or using the BLAST algorithm. Examples of fruitful utilization of FUNYBASE for investigation of fungal phylogenetics are also presented.

Conclusion

FUNYBASE constitutes a novel and useful resource for two types of analyses: (i) comparative studies can be greatly facilitated by reliable clusters of orthologs across sets of user-defined fungal genomes, and (ii) phylogenetic reconstruction can be improved by identifying genes with the highest informative value at the desired taxonomic level.
Biclustering via optimal re-ordering of data matrices in systems biology: rigorous methods and comparative studies
Authors: DiMaggio Peter A , McAllister Scott R , Floudas Christodoulos A , Feng Xiao-Jiang , Rabinowitz Joshua D , Rabitz Herschel A
Published: October 2008

Background

The analysis of large-scale data sets via clustering techniques is utilized in a number of applications. Biclustering in particular has emerged as an important problem in the analysis of gene expression data since genes may only jointly respond over a subset of conditions. Biclustering algorithms also have important applications in sample classification where, for instance, tissue samples can be classified as cancerous or normal. Many of the methods for biclustering, and clustering algorithms in general, utilize simplified models or heuristic strategies for identifying the "best" grouping of elements according to some metric and cluster definition and thus result in suboptimal clusters.

Results

In this article, we present a rigorous approach to biclustering, OREO, which is based on the Optimal RE-Ordering of the rows and columns of a data matrix so as to globally minimize the dissimilarity metric. The physical permutations of the rows and columns of the data matrix can be modeled as either a network flow problem or a traveling salesman problem. Cluster boundaries in one dimension are used to partition and re-order the other dimensions of the corresponding submatrices to generate biclusters. The performance of OREO is tested on (a) metabolite concentration data, (b) an image reconstruction matrix, (c) synthetic data with implanted biclusters, and gene expression data for (d) colon cancer data, (e) breast cancer data, as well as (f) yeast segregant data to validate the ability of the proposed method and compare it to existing biclustering and clustering methods.

Conclusion

We demonstrate that this rigorous global optimization method for biclustering produces clusters with more insightful groupings of similar entities, such as genes or metabolites sharing common functions, than other clustering and biclustering algorithms and can reconstruct underlying fundamental patterns in the data for several distinct sets of data matrices arising in important biological applications.
Splice-mediated Variants of Proteins (SpliVaP) – data and characterization of changes in signatures among protein isoforms due to alternative splicing
Authors: Floris Matteo , Orsini Massimiliano , Thanaraj Thangavel Alphonse
Published: October 2008

Background

It is often the case that mammalian genes are alternatively spliced; the resulting alternate transcripts often encode protein isoforms that differ in amino acid sequences. Changes among the protein isoforms can alter the cellular properties of proteins. The effect can range from a subtle modulation to a complete loss of function.

Results

(i) We examined human splice-mediated protein isoforms (as extracted from a manually curated data set, and from a computationally predicted data set) for differences in the annotation for protein signatures (Pfam domains and PRINTS fingerprints) and we characterized the differences & their effects on protein functionalities. An important question addressed relates to the extent of protein isoforms that may lack any known function in the cell. (ii) We present a database that reports differences in protein signatures among human splice-mediated protein isoform sequences.

Conclusion

(i) Characterization: The work points to distinct sets of alternatively spliced genes with varying degrees of annotation for the splice-mediated protein isoforms. Protein molecular functions seen to be often affected are those that relate to: binding, catalytic, transcription regulation, structural molecule, transporter, motor, and antioxidant; and the processes that are often affected are nucleic acid binding, signal transduction, and protein-protein interactions. Signatures are often included/excluded and truncated in length among protein isoforms; truncation is seen as the predominant type of change. Analysis points to the following novel aspects: (a) Analysis using data from the manually curated Vega indicates that one in 8.9 genes can lead to a protein isoform of no "known" function; and one in 18 expressed protein isoforms can be such an "orphan" isoform; the corresponding numbers as seen with computationally predicted ASD data set are: one in 4.9 genes and one in 9.8 isoforms. (b) When swapping of signatures occurs, it is often between those of same functional classifications. (c) Pfam domains can occur in varying lengths, and PRINTS fingerprints can occur with varying number of constituent motifs among isoforms – since such a variation is seen in large number of genes, it could be a general mechanism to modulate protein function. (ii) Data: The reported resource (at http://www.bioinformatica.crs4.org/tools/dbs/splivap/) provides the community ability to access data on splice-mediated protein isoforms (with value-added annotation such as association with diseases) through changes in protein signatures.
RAId_DbS: mass-spectrometry based peptide identification web server with knowledge integration
Authors: Alves Gelio , Ogurtsov Aleksey Y , Yu Yi-Kuo
Published: October 2008

Background

Existing scientific literature is a rich source of biological information such as disease markers. Integration of this information with data analysis may help researchers to identify possible controversies and to form useful hypotheses for further validations. In the context of proteomics studies, individualized proteomics era may be approached through consideration of amino acid substitutions/modifications as well as information from disease studies. Integration of such information with peptide searches facilitates speedy, dynamic information retrieval that may significantly benefit clinical laboratory studies.

Description

We have integrated from various sources annotated single amino acid polymorphisms, post-translational modifications, and their documented disease associations (if they exist) into one enhanced database per organism. We have also augmented our peptide identification software RAId_DbS to take into account this information while analyzing a tandem mass spectrum. In principle, one may choose to respect or ignore the correlation of amino acid polymorphisms/modifications within each protein. The former leads to targeted searches and avoids scoring of unnecessary polymorphism/modification combinations; the latter explores possible polymorphisms in a controlled fashion. To facilitate new discoveries, RAId_DbS also allows users to conduct searches permitting novel polymorphisms as well as to search a knowledge database created by the users.

Conclusion

We have finished constructing enhanced databases for 17 organisms. The web link to RAId_DbS and the enhanced databases is http://www.ncbi.nlm.nih.gov/CBBResearch/qmbp/RAId_DbS/index.html. The relevant databases and binaries of RAId_DbS for Linux, Windows, and Mac OS X are available for download from the same web page.
Cloning of the cytochrome p450 reductase (crtR) gene and its involvement in the astaxanthin biosynthesis of Xanthophyllomyces dendrorhous
Authors: Alcaíno Jennifer , Barahona Salvador , Carmona Marisela , Lozano Carla , Marcoleta Andrés , Niklitschek Mauricio , Sepúlveda Dionisia , Baeza Marcelo , Cifuentes Víctor
Published: October 2008

Background

The yeast Xanthophyllomyces dendrorhous synthesizes astaxanthin, a carotenoid with high commercial interest. The proposed biosynthetic route in this organism is isopentenyl-pyrophosphate (IPP) → geranyleranyl pyrophosphate (GGPP) → phytoene → lycopene → β-carotene → astaxanthin. Recently, it has been published that the conversion of β-carotene into astaxanthin requires only one enzyme, astaxanthin synthase or CrtS, encoded by crtS gene. This enzyme belongs to the cytochrome P450 protein family.

Results

In this work, a crtR gene was isolated from X. dendrorhous yeast, which encodes a cytochrome P450 reductase (CPR) that provides CrtS with the necessary electrons for substrate oxygenation. We determined the structural organization of the crtR gene and its location in the yeast electrophoretic karyotype. Two transformants, CBSTr and T13, were obtained by deleting the crtR gene and inserting a hygromycin B resistance cassette. The carotenoid composition of the transformants was altered in relation to the wild type strain. CBSTr forms yellow colonies because it is unable to produce astaxanthin, hence accumulating β-carotene. T13 forms pale colonies because its astaxanthin content is reduced and its β-carotene content is increased.

Conclusion

In addition to the crtS gene, X. dendrorhous requires a novel gene, crtR, for the conversion of β-carotene to astaxanthin.
Heat shock protein90 in lobular neoplasia of the breast
Authors: Zagouri Flora , Nonni Afrodite , Sergentanis Theodoros N , Papadimitriou Christos A , Michalopoulos Nikolaos V , Lazaris Andreas C , Patsouris Efstratios , Zografos George C
Published: October 2008

Background

Heat shock protein 90 (Hsp90) overexpression has been implicated in breast carcinogenesis, with putative prognostic and therapeutic implications. The purpose of this study is to evaluate the immunohistochemical expression of Hsp90 and to examine whether Hsp90 expression is associated with estrogen receptor alpha (ER-alpha) and beta (ER-beta) immunostaining in lobular neoplasia (LN) of the breast.

Methods

Tissue specimens were taken from 44 patients with LN. Immunohistochemical assessment of Hsp90, ER-alpha and ER-beta was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. As far as Hsp90 evaluation is concerned: i) the percentage of positive cells, and ii) the intensity was separately analyzed. Additionally, the Allred score was adopted and calculated. Accordingly, Allred score was separately evaluated for ER-alpha and ER-beta. The intensity was treated as an ordinal variable-score (0: negative, low: 1, moderate: 2, high: 3). Statistical analysis followed.

Results

Hsp90 immunoreactivity was mainly cytoplasmic in both the epithelial cells of normal breast (ducts and lobules) and LN. Some epithelial cells of LN also showed nuclear staining, but all the LN foci mainly disclosed a positive cytoplasmic immunoreaction for Hsp90. In addition, rare intralobular inflammatory cells showed a slight immunoreaction. The percentage of Hsp90 positive cells in the LN areas was equal to 67.1 ± 12.2%, whereas the respective percentage in the normal adjacent breast tissue was 69.1 ± 11.6%; the difference was not statistically significant. The intensity score of Hsp90 staining was 1.82 ± 0.72 in LN foci, while in the normal adjacent tissue the intensity score was 2.14 ± 0.64. This difference was statistically significant (p = 0.029, Wilcoxon matched-pairs signed-ranks test). The Hsp90 Allred score was 6.46 ± 1.14 in the LN foci, significantly lower than in the normal adjacent tissue (6.91 ± 0.92, p = 0.049, Wilcoxon matched-pairs signed-ranks test). Within the LN foci, the Hsp90 Allred score was neither associated with ER-alpha, nor with ER-beta percentage.

Conclusion

Hsp90 was lower in LN foci both at the level of intensity and Allred score, a finding contrary to what might have been expected, given that high Hsp90 expression is detected in invasive breast carcinomas. Hsp90 deregulation does not seem to be a major event in LN pathogenesis.
Risk factors for methamphetamine use in youth: a systematic review
Authors: Russell Kelly , Dryden Donna M , Liang Yuanyuan , Friesen Carol , O'Gorman Kathleen , Durec Tamara , Wild T Cameron , Klassen Terry P
Published: October 2008

Background

Methamphetamine (MA) is a potent stimulant that is readily available. Its effects are similar to cocaine, but the drug has a profile associated with increased acute and chronic toxicities. The objective of this systematic review was to identify and synthesize literature on risk factors that are associated with MA use among youth.

More than 40 electronic databases, websites, and key journals/meeting abstracts were searched. We included studies that compared children and adolescents (≤ 18 years) who used MA to those who did not. One reviewer extracted the data and a second checked for completeness and accuracy. For discrete risk factors, odds ratios (OR) were calculated and when appropriate, a pooled OR with 95% confidence intervals (95% CI) was calculated. For continuous risk factors, mean difference and 95% CI were calculated and when appropriate, a weighted mean difference (WMD) and 95% CI was calculated. Results were presented separately by comparison group: low-risk (no previous drug abuse) and high-risk children (reported previous drug abuse or were recruited from a juvenile detention center).

Results

Twelve studies were included. Among low-risk youth, factors associated with MA use were: history of heroin/opiate use (OR = 29.3; 95% CI: 9.8–87.8), family history of drug use (OR = 4.7; 95% CI: 2.8–7.9), risky sexual behavior (OR = 2.79; 95% CI: 2.25, 3.46) and some psychiatric disorders. History of alcohol use and smoking were also significantly associated with MA use. Among high-risk youth, factors associated with MA use were: family history of crime (OR = 2.0; 95% CI: 1.2–3.3), family history of drug use (OR = 4.7; 95% CI: 2.8–7.9), family history of alcohol abuse (OR = 3.2; 95% CI: 1.8–5.6), and psychiatric treatment (OR = 6.8; 95% CI: 3.6–12.9). Female sex was also significantly associated with MA use.

Conclusion

Among low-risk youth, a history of engaging in a variety of risky behaviors was significantly associated with MA use. A history of a psychiatric disorder was a risk factor for MA for both low- and high-risk youth. Family environment was also associated with MA use. Many of the included studies were cross-sectional making it difficult to assess causation. Future research should utilize prospective study designs so that temporal relationships between risk factors and MA use can be established.
Correlates of illicit methadone use in New York City: A cross-sectional study
Authors: Ompad Danielle C , Fuller Crystal M , Chan Christina A , Frye Victoria , Vlahov David , Galea Sandro
Published: October 2008

Background

Despite growing concern about illicit methadone use in the US and other countries, there is little data about the prevalence and correlates of methadone use in large urban areas. We assessed the prevalence and examined correlates of lifetime and recent illicit methadone use in New York City (NYC).

Methods

1,415 heroin, crack, and cocaine users aged 15–40 years were recruited in NYC between 2000 and 2004 to complete interviewer-administered questionnaires.

Results

In multivariable logistic regression, non-injection drug users who used illicit methadone were more likely to be heroin dependent, less than daily methamphetamine users and to have a heroin using sex partner in the last two months. Injection drug users who used illicit methadone were more likely to use heroin daily, share injection paraphernalia and less likely to have been in a detoxification program and to have not used marijuana in the last six months.

Conclusion

The results overall suggest that illicit (or street) methadone use is likely not a primary drug of choice, but is instead more common in concert with other illicit drug use.
Expression of the metalloproteases MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, TIMP-1 and TIMP-2 in angiocentric midfacial lymphomas
Authors: Meneses-García Abelardo , Betancourt Alejandro Mohar , Abarca Jorge Herrera , Montes Adriana Becerril , Roa Lourdes Suarez , Ruíz-Godoy Luz
Published: October 2008

Background

Extranodal T/NK cell lymphomas possess distinctive clinico-pathological characteristics: they are angiocentric, exhibit extensive necrosis. Prognosis is poor in the short term. The objective is to explore the expression of different MMPs in the cells and stroma which are around of the blood vessels damaged and their correlation with clinico-pathological parameters.

Patients and methods

Twenty cases of this type of lymphomas were studied and collected patient clinical data. The expressions of MMP-1, 2, 3, 9, 11, 13 and TIMP-1, 2 were studied by immunohistochemistry. Ultrastructural studies were performed in two cases. Statistical analysis was done with Fisher's exact test, Chi2test.

Results

Of the 20 patients, 13 were men with median age of 43 years. In 13 patients the primary tumor was localized in the nasal cavity. Treatment was combined chemotherapy and radiotherapy in 60%. The 55% advanced clinical stages, 70% died from the disease. There were neoplastic cell and peritumoral fibroblasts positivity to MMP-1 and MMP-11 in most of the cases. The MMPs-2, 3 and 9 were expressed in neoplastic cell between 30 to 65%of the cases. TIMP-1 was presented mainly in the epithelium and TIMP-2 was poor expressed of the all cases.

Conclusion

There were no statistical significance between the different enzymes used and the clinical parameters, besides status and survival of the patients. It is necessary to study more enzymes and focus them to quantify and determine their activity, in order to have a better correlation with histological features in this type of neoplasm.
Sequence analysis of dolphin ferritin H and L subunits and possible iron-dependent translational control of dolphin ferritin gene
Authors: Takaesu Azusa , Watanabe Kiyotaka , Takai Shinji , Sasaki Yukako , Orino Koichi
Published: October 2008

Background

Iron-storage protein, ferritin plays a central role in iron metabolism. Ferritin has dual function to store iron and segregate iron for protection of iron-catalyzed reactive oxygen species. Tissue ferritin is composed of two kinds of subunits (H: heavy chain or heart-type subunit; L: light chain or liver-type subunit). Ferritin gene expression is controlled at translational level in iron-dependent manner or at transcriptional level in iron-independent manner. However, sequencing analysis of marine mammalian ferritin subunits has not yet been performed fully. The purpose of this study is to reveal cDNA-derived amino acid sequences of cetacean ferritin H and L subunits, and demonstrate the possibility of expression of these subunits, especially H subunit, by iron.

Methods

Sequence analyses of cetacean ferritin H and L subunits were performed by direct sequencing of polymerase chain reaction (PCR) fragments from cDNAs generated via reverse transcription-PCR of leukocyte total RNA prepared from blood samples of six different dolphin species (Pseudorca crassidens, Lagenorhynchus obliquidens, Grampus griseus, Globicephala macrorhynchus, Tursiops truncatus, and Delphinapterus leucas). The putative iron-responsive element sequence in the 5'-untranslated region of the six different dolphin species was revealed by direct sequencing of PCR fragments obtained using leukocyte genomic DNA.

Results

Dolphin H and L subunits consist of 182 and 174 amino acids, respectively, and amino acid sequence identities of ferritin subunits among these dolphins are highly conserved (H: 99–100%, (99→98) ; L: 98–100%). The conserved 28 bp IRE sequence was located -144 bp upstream from the initiation codon in the six different dolphin species.

Conclusion

These results indicate that six different dolphin species have conserved ferritin sequences, and suggest that these genes are iron-dependently expressed.
From protein interactions to functional annotation: graph alignment in Herpes
Authors: Kolář Michal , Lässig Michael , Berg Johannes
Published: October 2008

Background

Sequence alignment is a prolific basis of functional annotation, but remains a challenging problem in the 'twilight zone' of high sequence divergence or short gene length. Here we demonstrate how information on gene interactions can help to resolve ambiguous sequence alignments. We compare two distant Herpes viruses by constructing a graph alignment, which is based jointly on the similarity of their protein interaction networks and on sequence similarity. This hybrid method provides functional associations between proteins of the two organisms that cannot be obtained from sequence or interaction data alone.

Results

We find proteins where interaction similarity and sequence similarity are individually weak, but together provide significant evidence of orthology. There are also proteins with high interaction similarity but without any detectable sequence similarity, providing evidence of functional association beyond sequence homology. The functional predictions derived from our alignment are consistent with genomic position and gene expression data.

Conclusion

Our approach shows that evolutionary conservation is a powerful filter to make protein interaction data informative about functional similarities between the interacting proteins, and it establishes graph alignment as a powerful tool for the comparative analysis of data from highly diverged species.
Spatial and temporal plasticity of chromatin during programmed DNA-reorganization in Stylonychia macronuclear development
Authors: Postberg Jan , Heyse Katharina , Cremer Marion , Cremer Thomas , Lipps Hans J
Published: October 2008

Background:

In this study we exploit the unique genome organization of ciliates to characterize the biological function of histone modification patterns and chromatin plasticity for the processing of specific DNA sequences during a nuclear differentiation process. Ciliates are single-cell eukaryotes containing two morphologically and functionally specialized types of nuclei, the somatic macronucleus and the germline micronucleus. In the course of sexual reproduction a new macronucleus develops from a micronuclear derivative. During this process specific DNA sequences are eliminated from the genome, while sequences that will be transcribed in the mature macronucleus are retained.

Results:

We show by immunofluorescence microscopy, Western analyses and chromatin immunoprecipitation (ChIP) experiments that each nuclear type establishes its specific histone modification signature. Our analyses reveal that the early macronuclear anlage adopts a permissive chromatin state immediately after the fusion of two heterochromatic germline micronuclei. As macronuclear development progresses, repressive histone modifications that specify sequences to be eliminated are introduced de novo. ChIP analyses demonstrate that permissive histone modifications are associated with sequences that will be retained in the new macronucleus. Furthermore, our data support the hypothesis that a PIWI-family protein is involved in a transnuclear cross-talk and in the RNAi-dependent control of developmental chromatin reorganization.

Conclusion:

Based on these data we present a comprehensive analysis of the spatial and temporal pattern of histone modifications during this nuclear differentiation process. Results obtained in this study may also be relevant for our understanding of chromatin plasticity during metazoan embryogenesis.
Antisense inhibition of ATM gene enhances the radiosensitivity of head and neck squamous cell carcinoma in mice
Authors: Zou Jian , Qiao Xiaoming , Ye Huiping , Yang Yuqiong , Zheng Xuelian , Zhao Houyu , Liu Shixi
Published: October 2008

Background

Treatment failure after radiotherapy of head and neck squamous cell carcinoma (HNSCC) could be a significant problem. Our objective is to sensitize SCCVII cells to ionizing radiation in vitro and in vivo through inhibiting ATM expression using antisense oligodeoxynucleotides (AS-ODNs), and investigate the potential mechanism of radiosensitization.

Methods

We designed and synthesized AS-ODNs that target ATM mRNA to reduce the ATM expression. The influence on the expression of ATM mRNA and protein in SCCVII cells were analysed by real-time quantitative PCR and western blotting respectively. Clonogenic survival assay was performed to detect the survival ability of SCCVII cells after irradiation, while flow cytometry used to analyse the cell cycle and apoptosis. The volume of solid tumors generated with SCCVII cells was measured, and cell apoptosis was analysed by TUNEL assay after irradiation.

Results

The relative ATM mRNA and protein expression in SCCVII cells treated with ATM AS-ODNs were decreased to 25.7 ± 3.1% and 24.1 ± 2.8% of that in untreated cells respectively (P < 0.05). After irradiation, the survival fraction (SF) of cells treated with ATM AS-ODNs was lower than that of other groups at the same dose of radiation (P < 0.05), while the percentage of cells in G2/M phase decreased and apoptotic rate of cells increased(P < 0.05). The inhibition rate in SCCVII cells solid tumor exposed to X-ray alone was 23.2 ± 2.7%, while it was 56.1 ± 3.8% in the group which irradiated in combination with the treatment of ATM AS-ODNs (P < 0.05). The apoptotic index for the group irradiated in combination with ATM AS-ODNs injection was 19.6 ± 3.2, which was significantly higher than that of others (P < 0.05)

Conclusion

Inhibition of ATM expression sensitized SCCVII cells to ionizing radiation in vitro and in vivo. The potential mechanism should be the defective G2/M cell cycle checkpoint control and enhanced radiation-induced apoptosis.
Benign retropneumoperitoneum developed after endoscopic sphincterotomy and large balloon dilation of biliary sphincter for removal of large biliary stones: a case report
Authors: Katsinelos Panagiotis , Chatzimavroudis Grigoris , Pilpilidis Ioannis , Zavos Christos , Lazaraki Georgia , Tzilves Dimitris , Paroutoglou George , Kountouras Jannis
Published: October 2008

Biliary endoscopic sphincterotomy (ES) followed by biliary orifice dilation (BOD) with large-diameter balloons (> 12 mm) is a relative new technique for extraction of large biliary stones. However, the safety and the potential complications of this combined technique are not known yet. We present a patient who developed benign retroperitoneum after ES plus BOD with large-diameter balloon for removal of a large biliary stone, which was successfully treated conservatively. To the best of our knowledge this is the first report of such a complication after introduction of this method to clinical practice.
Serial analysis of gene expression of lobular carcinoma in situ identifies down regulation of claudin 4 and overexpression of matrix metalloproteinase 9
Authors: Cao Dengfeng , Polyak Kornelia , Halushka Marc K , Nassar Hind , Kouprina Nina , Iacobuzio-Donahue Christine , Wu Xinyan , Sukumar Saraswati , Hicks Jessica , De Marzo Angelo , Argani Pedram
Published: October 2008

Introduction

Although lobular carcinoma in situ (LCIS) has traditionally been viewed as a marker of breast cancer risk, recent clinical, pathological and genetic analyses have supported the concept that LCIS is a low risk, direct precursor of invasive lobular carcinoma. Global gene expression profiling of LCIS has not been performed.

Methods

We analysed the comprehensive gene expression profile of a unique case of mass-forming LCIS using serial analysis of gene expression (SAGE). This SAGE library is publicly available online. By comparing the gene expression profile of LCIS to that of benign breast epithelium and stroma, we identified several genes up and down regulated in LCIS. Differential expression of selected genes not previously studied in LCIS was validated at the protein level by immunohistochemistry and at the RNA level by quantitative reverse transcriptase PCR (RT-PCR).

Results

We identified down regulation of claudin 4 and overexpression of matrix metalloproteinase 9 in LCIS relative to normal breast epithelium and stroma. We validated these findings by immunohistochemistry in a separate series of 11 and 19 LCIS cases, respectively. Overexpression of matrix metalloproteinase 9 was further confirmed by quantitative RT-PCR analysis of the index case.

Conclusions

We have created the first global gene expression profile of LCIS, and demonstrated down regulation of cell junction proteins (an expected result) and overexpression of matrix metalloproteinase 9 (an unexpected result). Additional analysis of this data made available as an online resource should facilitate further molecular characterisation of LCIS.
Functional architecture of Escherichia coli: new insights provided by a natural decomposition approach
Authors: Freyre-González Julio A , Alonso-Pavón José A , Treviño-Quintanilla Luis G , Collado-Vides Julio
Published: October 2008

Background

Previous studies have used different methods in an effort to extract the modular organization of transcriptional regulatory networks. However, these approaches are not natural, as they try to cluster strongly connected genes into a module or locate known pleiotropic transcription factors in lower hierarchical layers. Here, we unravel the transcriptional regulatory network of Escherichia coli by separating it into its key elements, thus revealing its natural organization. We also present a mathematical criterion, based on the topological features of the transcriptional regulatory network, to classify the network elements into one of two possible classes: hierarchical or modular genes.

Results

We found that modular genes are clustered into physiologically correlated groups validated by a statistical analysis of the enrichment of the functional classes. Hierarchical genes encode transcription factors responsible for coordinating module responses based on general interest signals. Hierarchical elements correlate highly with the previously studied global regulators, suggesting that this could be the first mathematical method to identify global regulators. We identified a new element in transcriptional regulatory networks never described before: intermodular genes. These are structural genes that integrate, at the promoter level, signals coming from different modules, and therefore from different physiological responses. Using the concept of pleiotropy, we have reconstructed the hierarchy of the network and discuss the role of feedforward motifs in shaping the hierarchical backbone of the transcriptional regulatory network.

Conclusions

This study sheds new light on the design principles underpinning the organization of transcriptional regulatory networks, showing a novel nonpyramidal architecture composed of independent modules globally governed by hierarchical transcription factors, whose responses are integrated by intermodular genes.
Neutrophil-derived azurocidin alarms the immune system
Authors: Soehnlein Oliver , Lindbom Lennart
Published: October 2008

Azurocidin (heparin-binding protein/cationic antimicrobial protein of 37 kD) is a protein that is mobilized rapidly from emigrating polymorphonuclear leukocytes (PMN). Initially, this inactive serine protease was recognized for its antimicrobial effects. However, it soon became apparent that azurocidin may act to alarm the immune system in different ways and thus serve as an important mediator during the initiation of the immune response. Azurocidin, released from PMN secretory vesicles or primary granules, acts as a chemoattractant and activator of monocyte and macrophages. The functional consequence is enhancement of cytokine release and bacterial phagocytosis, allowing for a more efficient bacterial clearance. Leukocyte activation by azurocidin is mediated via β2-integrins, and azurocidin-induced chemotaxis is dependent on formyl-peptide receptors. In addition, azurocidin activates endothelial cells leading to vascular leakage and edema formation. For these reasons, targeting azurocidin release and its actions may have therapeutic potential in inflammatory disease conditions.
Seismic Analysis of Conventional and Isolated LNG Tanks Using Mechanical Analogs
Authors: Christovasilis Ioannis P. , Whittaker Andrew S.
Published: October 2008

The seismic response of a conventional and an isolated vertical, cylindrical, Liquefied Natural Gas (LNG) tank is computed using a mechanical analog and a finite element code to judge the utility of the analog for preliminary design and of the effectiveness of seismic isolation. Data reported and statistically sorted include base shear, global overturning moment, and wave height in the tank. The results obtained from the two numerical models are in good agreement and demonstrate that the mechanical analog can be used with confidence for the preliminary analysis and design of conventional and isolated LNG tanks that have similar dimensions to the sample tank of this study. The base shear and overturning moment in the seismically isolated LNG tank are 10% to 15% of the values computed for the conventional tank; the wave heights are unaffected by the introduction of a seismic isolation system.
Nonlinear Pushover Analysis of Bridge Columns Supported on Full-Moment Connection CISS Piles on Clays
Authors: Silva Pedro F. , Manzari Majid T.
Published: October 2008

This paper summarizes results from a static pushover analysis on the inelastic response of bridge columns supported on pile groups and consisting of full moment connection cast-in-place steel shell piles. The analytical models considered the nonlinear actions that develop in the column, the supporting piles and the soil. Parametric studies were then carried out under different sets of column height to diameter or aspect ratios and soil–structure interaction, and included variations in: (a) nonlinear soil–structure horizontal interaction and (b) nonlinear soil–structure vertical interaction. Parametric studies confirmed that variations in the horizontal and vertical soil stiffness can affect the pile cap lateral deflection and rotation, respectively. As importantly, results from this analysis indicate that for columns with aspect ratios lower than six, the contribution of soil–structure interaction is significant; however, for columns with higher aspect ratios and for stiffer soils, the effects of soil–structure interaction are almost negligible regarding the lateral response of the system. Detailed results from this study are presented and discussed in this paper.
Recommendations for Collection and Handling of Specimens From Group Breast Cancer Clinical Trials
Authors: Leyland-Jones Brian R. , Ambrosone Christine B. , Bartlett John , Ellis Matthew J.C. , Enos Rebecca A. , Raji Adekunle , Pins Michael R. , Zujewski Jo Anne , Hewitt Stephen M. , Forbes John F. , Abramovitz Mark , Braga Sofia , Cardoso Fatima , Harbeck Nadia , Denkert Carsten , Jewell Scott D.
Published: October 2008

Recommendations for specimen collection and handling have been developed for adoption across breast cancer clinical trials conducted by the Breast International Group (BIG)-sponsored Groups and the National Cancer Institute (NCI)-sponsored North American Cooperative Groups. These recommendations are meant to promote identifiable standards for specimen collection and handling within and across breast cancer trials, such that the variability in collection/handling practices that currently exists is minimized and specimen condition and quality are enhanced, thereby maximizing results from specimen-based diagnostic testing and research. Three working groups were formed from the Cooperative Group Banking Committee, BIG groups, and North American breast cancer cooperative groups to identify standards for collection and handling of (1) formalin-fixed, paraffin-embedded (FFPE) tissue; (2) blood and its components; and (3) fresh/frozen tissue from breast cancer trials. The working groups collected standard operating procedures from multiple group specimen banks, administered a survey on banking practices to those banks, and engaged in a series of discussions from 2005 to 2007. Their contributions were synthesized into this document, which focuses primarily on collection and handling of specimens to the point of shipment to the central bank, although also offers some guidance to central banks. Major recommendations include submission of an FFPE block, whole blood, and serial serum or plasma from breast cancer clinical trials, and use of one fixative and buffer type (10% neutral phosphate-buffered formalin, pH 7) for FFPE tissue across trials. Recommendations for proper handling and shipping were developed for blood, serum, plasma, FFPE, and fresh/frozen tissue.
Randomized Comparison of Cooked and Noncooked Diets in Patients Undergoing Remission Induction Therapy for Acute Myeloid Leukemia
Authors: Gardner Alison , Mattiuzzi Gloria , Faderl Stefan , Borthakur Gautam , Garcia-Manero Guillermo , Pierce Sherry , Brandt Mark , Estey Elihu
Published: October 2008

Purpose

A neutropenic diet is often used to prevent infection in patients with acute myeloid leukemia (AML). Although such a diet potentially entails inconvenience, its value is uncertain.

Patients and Methods

One hundred fifty-three patients admitted to a high-efficiency particulate air–filtered room (protected environment [PE]) to receive induction therapy for newly diagnosed AML were randomly assigned to a diet containing no raw fruits or vegetables (cooked diet) or to a diet containing fresh fruit and fresh vegetables (raw diet). Stratification was based on the patients’ early risk of mortality (ERM) score. All patients received antibacterial and antifungal prophylaxis and remained on study until they were discharged from the PE. The outcomes of principal interest were major infection (pneumonia, bacteremia, or fungemia) and death; if the true probability of either event was 20% on the cooked arm and 40% on the raw arm, then the probability that the cooked arm would be selected as superior was 83%.

Results

Seventy-eight patients were randomly assigned to the cooked arm, and 75 were assigned to the raw arm. The two groups were similar with respect to age, ERM, chemotherapy received, and days at risk. Twenty-nine percent of patients in the cooked group and 35% of patients in the raw group developed a major infection (P = .60). Time to major infection and survival time were similar in the two groups. Fever of unknown origin occurred in 51% of the cooked group and 36% of the raw group.

Conclusion

In patients treated in a PE, a neutropenic diet did not prevent major infection or death.
Correlation of Kinase Genotype and Clinical Outcome in the North American Intergroup Phase III Trial of Imatinib Mesylate for Treatment of Advanced Gastrointestinal Stromal Tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group
Authors: Heinrich Michael C. , Owzar Kouros , Corless Christopher L. , Hollis Donna , Borden Ernest C. , Fletcher Christopher D.M. , Ryan Christopher W. , von Mehren Margaret , Blanke Charles D. , Rankin Cathryn , Benjamin Robert S. , Bramwell Vivien H. , Demetri George D. , Bertagnolli Monica M. , Fletcher Jonathan A.
Published: October 2008

Purpose

Imatinib mesylate is standard treatment for patients who have advanced gastrointestinal stromal tumor (GIST), but not all patients benefit equally. In previous studies, GIST genotype correlated with treatment outcome and optimal imatinib dosing.

Patients and Methods

We examined the relationship between kinase genotype and treatment outcome for 428 patients enrolled on the North American phase III study SWOG S0033/CALGB 150105 and treated with either 400 mg or 800 mg daily doses of imatinib.

Results

The presence of KIT exon 11–mutant genotype (n = 283) correlated with improved treatment outcome when compared with KIT exon 9–mutant (n = 32) and wild-type (WT; n = 67) genotypes for objective response (complete response [CR]/partial response [PR], 71.7% v 44.4% [P = .007]; and 44.6% [P = .0002], respectively); time to tumor progression (TTP; median 24.7 months v 16.7 and 12.8 months, respectively); and overall survival (OS; median 60.0 months v 38.4 and 49.0 months, respectively). The survival outcomes for patients with exon 9–mutant, exon 11–mutant or WT GIST were not affected by imatinib dose. However, there was evidence of improved response rates for patients with exon 9–mutant tumors treated with imatinib 800 mg versus 400 mg (CR/PR, 67% v 17%; P = .02). Patients who had CD117-negative GIST had similar TTP but inferior OS compared with patients who had CD117-positive disease, which suggests that patients who have CD117-negative GIST may benefit from imatinib treatment. In addition, we identified novel but rare mutations of the KIT extracellular domain (exons 8 and 9).

Conclusion

We confirmed the favorable impact of KIT exon 11 genotype when compared with KIT exon 9 and wild-type genotype for patients with advanced GIST who are treated with imatinib.
Prevalence of Secondary Causes of Bone Loss Among Breast Cancer Patients With Osteopenia and Osteoporosis
Authors: Camacho Pauline M. , Dayal Amit S. , Diaz Josefina L. , Nabhan Fadi A. , Agarwal Monica , Norton John G. , Robinson Patricia A. , Albain Kathy S.
Published: October 2008

Purpose

To determine the prevalence of secondary causes of bone loss among patients with breast cancer with osteopenia and osteoporosis.

Patients and Methods

All women referred to a bone health clinic over a 6-year period for bone evaluation were included in this retrospective study and stratified based on presence or absence of a breast cancer history. The prevalence of secondary causes of bone loss in the two groups was compared.

Results

Of the 238 women identified, 64 women had breast cancer. The non–breast cancer group (n = 174) was significantly older (P = .015), had a lower mean weight (P = .019), lower 25 hydroxy-vitamin D level (P = .019), and greater degree of bone loss in both the spine and hip (P < .001 and 0.004, respectively). The presence of at least one secondary cause of bone loss, excluding cancer-related therapies, was seen in 78% of the breast cancer patient group and in 77% of the non–breast cancer group (P = not significant). Newly diagnosed metabolic bone disorders were seen in 58% of the breast cancer population. The most common was vitamin D deficiency, seen in 38% of patients in the breast cancer group and 51% of patients in the non–breast cancer group. Idiopathic hypercalciuria was diagnosed in 15.6%, primary hyperparathyroidism in 1.6%, and normocalcemic hyperparathyroidism in 3.1% of the breast cancer population.

Conclusion

A high prevalence of secondary causes of bone loss among patients with breast cancer supports a comprehensive evaluation in these patients, particularly those considering therapy with an aromatase inhibitor.
Chemotherapy Use for Hormone Receptor–Positive, Lymph Node–Negative Breast Cancer
Authors: Hassett Michael J. , Hughes Melissa E. , Niland Joyce C. , Edge Stephen B. , Theriault Richard L. , Wong Yu-Ning , Wilson John , Carter W. Bradford , Blayney Douglas W. , Weeks Jane C.
Published: October 2008

Purpose

To describe the frequency of chemotherapy use for hormone receptor (HR)–positive, lymph node (LN)–negative breast cancer from 1997 to 2004 at eight National Comprehensive Cancer Network institutions, to explore whether chemotherapy use varied over time and between institutions, and to identify factors associated with the decision to forego chemotherapy.

Patients and Methods

Among women younger than age 70 years with HR-positive, LN-negative breast cancer measuring more than 1 cm, we analyzed the frequency of chemotherapy use on a yearly basis. A multivariable logistic regression model assessed the relationship between receipt of chemotherapy and year of diagnosis, institution, tumor features, and patient characteristics. Interaction terms were added to the model, and stratified analyses were conducted to further explore the determinants of chemotherapy use.

Results

Fifty-five percent of 3,190 women received chemotherapy. Chemotherapy use was less common for patients with 1.1- to 2-cm tumors than for patients tumors greater 2 cm (47% v 87%, respectively; P < .01) and for women age 60 to 69 years versus women younger than age 50 years (24% v 76%, respectively; P < .01). On multivariable analysis, predictors independently associated with receiving chemotherapy included larger tumor size, higher grade, human epidermal growth factor receptor 2 overexpression, younger age, and institution (P < .01 for all). Institutions exhibited dramatically different rates of chemotherapy use (from 46% to 65%) and patterns of change in chemotherapy use over time (from a 79% relative increase to a 22% relative decrease).

Conclusion

Although institutions seemed to agree that not all women with HR-positive, LN-negative breast cancer need chemotherapy, there did not seem to be consensus regarding which women should get chemotherapy. Only prospective randomized controlled trials will conclusively establish which subtypes of HR-positive, LN-negative breast cancer benefit from chemotherapy.