bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational prediction of host-pathogen protein–protein interactions
Authors: Dyer Matthew D. , Murali T. M. , Sobral Bruno W.
Published: July 2007

Motivation: Infectious diseases such as malaria result in millions of deaths each year. An important aspect of any host-pathogen system is the mechanism by which a pathogen can infect its host. One method of infection is via protein–protein interactions (PPIs) where pathogen proteins target host proteins. Developing computational methods that identify which PPIs enable a pathogen to infect a host has great implications in identifying potential targets for therapeutics.

Results: We present a method that integrates known intra-species PPIs with protein-domain profiles to predict PPIs between host and pathogen proteins. Given a set of intra-species PPIs, we identify the functional domains in each of the interacting proteins. For every pair of functional domains, we use Bayesian statistics to assess the probability that two proteins with that pair of domains will interact. We apply our method to the Homo sapiens – Plasmodium falciparum host-pathogen system. Our system predicts 516 PPIs between proteins from these two organisms. We show that pairs of human proteins we predict to interact with the same Plasmodium protein are close to each other in the human PPI network and that Plasmodium pairs predicted to interact with same human protein are co-expressed in DNA microarray datasets measured during various stages of the Plasmodium life cycle. Finally, we identify functionally enriched sub-networks spanned by the predicted interactions and discuss the plausibility of our predictions.

Availability: Supplementary data are available at http://staff.vbi.vt.edu/dyermd/publications/dyer2007a.html

Contact: dyermd@vbi.vt.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
A geometric approach for the alignment of liquid chromatography—mass spectrometry data
Authors: Lange Eva , Gröpl Clemens , Schulz-Trieglaff Ole , Leinenbach Andreas , Huber Christian , Reinert Knut
Published: July 2007

Motivation: Liquid chromatography coupled to mass spectrometry (LC-MS) and combined with tandem mass spectrometry (LC-MS/MS) have become a prominent tool for the analysis of complex proteomic samples. An important step in a typical workflow is the combination of results from multiple LC-MS experiments to improve confidence in the obtained measurements or to compare results from different samples. To do so, a suitable mapping or alignment between the data sets needs to be estimated. The alignment has to correct for variations in mass and elution time which are present in all mass spectrometry experiments.

Results: We propose a novel algorithm to align LC-MS samples and to match corresponding ion species across samples. Our algorithm matches landmark signals between two data sets using a geometric technique based on pose clustering. Variations in mass and retention time are corrected by an affine dewarping function estimated from matched landmarks. We use the pairwise dewarping in an algorithm for aligning multiple samples. We show that our pose clustering approach is fast and reliable as compared to previous approaches. It is robust in the presence of noise and able to accurately align samples with only few common ion species. In addition, we can easily handle different kinds of LC-MS data and adopt our algorithm to new mass spectrometry technologies.

Availability: This algorithm is implemented as part of the OpenMS software library for shotgun proteomics and available under the Lesser GNU Public License (LGPL) at www.openms.de

Contact: lange@inf.fu-berlin.de
A statistical method for alignment-free comparison of regulatory sequences
Authors: Kantorovitz Miriam R. , Robinson Gene E. , Sinha Saurabh
Published: July 2007

Motivation: The similarity of two biological sequences has traditionally been assessed within the well-established framework of alignment. Here we focus on the task of identifying functional relationships between cis-regulatory sequences that are non-orthologous or greatly diverged. ‘Alignment-free’ measures of sequence similarity are required in this regime.

Results: We investigate the use of a new score for alignment-free sequence comparison, called the score. It is based on comparing the frequencies of all fixed-length words in the two sequences. An important, novel feature of the score is that it is comparable across sequence pairs drawn from arbitrary background distributions. We present a method that gives quadratic improvement in the time complexity of calculating the score, over the naïve method. We then evaluate the score on several tissue-specific families of cis-regulatory modules (in Drosophila and human). The new score is highly successful in discriminating functionally related regulatory sequences from unrelated sequence pairs. The performance of the score is compared to five other alignment-free similarity measures, and shown to be consistently superior to all of these measures.

Availability: Our implementation of the score will be made freely available as source code, upon publication of this article, at: http://veda.cs.uiuc.edu/d2z/

Contact: sinhas@cs.uiuc.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Using genome-context data to identify specific types of functional associations in pathway/genome databases
Authors: Green Michelle L. , Karp Peter D.
Published: July 2007

Background: Hundreds of genes lacking homology to any protein of known function are sequenced every day. Genome-context methods have proved useful in providing clues about functional annotations for many proteins. However, genome-context methods detect many biological types of functional associations, and do not identify which type of functional association they have found.

Results: We have developed two new genome-context-based algorithms. Algorithm 1 extends our previous algorithm for identifying missing enzymes in predicted metabolic pathways (pathway holes) to use genome-context features. The new algorithm has significantly improved scope because it can now be applied to pathway reactions to which sequence similarity methods cannot be applied due to an absence of known sequences for enzymes catalyzing the reaction in other organisms. The new method identifies at least one known enzyme in the top ten hits for 58% of EcoCyc reactions that lack enzyme sequences in other organisms. Surprisingly, the addition of genome-context features does not improve the accuracy of the algorithm when sequences for the enzyme do exist in other organisms. Algorithm 2 uses genome-context methods to predict three distinct types of functional relationships between pairs of proteins: pairs that occur in the same protein complex, the same pathway, or the same operon. This algorithm performs with varying degrees of accuracy on each type of relationship, and performs best in predicting pathway and protein complex relationships.

Contact: pkarp@ai.sri.com
Inferring protein–DNA dependencies using motif alignments and mutual information
Authors: Mahony Shaun , Auron Philip E. , Benos Panayiotis V.
Published: July 2007

Motivation: Mutual information can be used to explore covarying positions in biological sequences. In the past, it has been successfully used to infer RNA secondary structure conformations from multiple sequence alignments. In this study, we show that the same principles allow the discovery of transcription factor amino acids that are coevolving with nucleotides in their DNA-binding targets.

Results: Given an alignment of transcription factor binding domains, and a separate alignment of their DNA target motifs, we demonstrate that mutually covarying base-amino acid positions may indicate possible protein–DNA contacts. Examples explored in this study include C2H2 zinc finger, homeodomain and bHLH DNA-binding motif families, where a number of known base-amino acid contacting positions are identified. Mutual information analyses may aid the prediction of base-amino acid contacting pairs for particular transcription factor families, thereby yielding structural insights from sequence information alone. Such inference of protein–DNA contacting positions may guide future experimental studies of DNA recognition.

Contact: shaun.mahony@ccbb.pitt.edu or benos@pitt.edu
Bayesian association of haplotypes and non-genetic factors to regulatory and phenotypic variation in human populations
Authors: Huang Jim C. , Kannan Anitha , Winn John
Published: July 2007

Motivation: With the recent availability of large-scale data sets profiling single nucleotide polymorphisms (SNPs) and quantitative traits data across different human subpopulations, there has been much attention directed towards discovering patterns of genetic variation and their connection to gene regulation and the onset/progression of disease. While previous work has focused primarily on correlating individual SNP markers with gene expression and disease, it has been suggested that using haplotype blocks instead of individual markers can significantly increase statistical power.

Results: We present BlockMapper, a probabilistic generative model for genotype data and quantitative traits data, such as gene expression or phenotype measurements. BlockMapper discovers the block structure of genotype data and associates these inferred blocks to patterns of variation in quantitative traits data, whilst accounting for non-genetic factors. Our model achieves high accuracy for predicting Crohn's disease phenotype in Chromosome 5q31 and reveals novel cis-associations between two haplotype blocks in the ENm006 genomic region and GDI1, a gene implicated in X-linked mental retardation. Our results underscore the importance of accounting for the influence of large sets of SNPs on patterns of regulatory/phenotypic variation and represent a step towards an understanding of human genetic variation.

Contact: jwinn@microsoft.com
Continuous hidden process model for time series expression experiments
Authors: Shi Yanxin , Klustein Michael , Simon Itamar , Mitchell Tom , Bar-Joseph Ziv
Published: July 2007

Motivation: When analyzing expression experiments, researchers are often interested in identifying the set of biological processes that are up-or down-regulated under the experimental condition studied. Current approaches, including clustering expression profiles and averaging the expression profiles of genes known to participate in specific processes, fail to provide an accurate estimate of the activity levels of many biological processes.

Results: We introduce a probabilistic continuous hidden process Model (CHPM) for time series expression data. CHPM can simultaneously determine the most probable assignment of genes to processes and the level of activation of these processes over time. To estimate model parameters, CHPM uses multiple time series datasets and incorporates prior biological knowledge. Applying CHPM to yeast expression data, we show that our algorithm produces more accurate functional assignments for genes compared to other expression analysis methods. The inferred process activity levels can be used to study the relationships between biological processes. We also report new biological experiments confirming some of the process activity levels predicted by CHPM.

Availability: A Java implementation is available at http:\\www.cs.cmu.edu\~yanxins\chpm

Contact: zivbj@cs.cmu.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Modeling recurrent DNA copy number alterations in array CGH data
Authors: Shah Sohrab P. , Lam Wan L. , Ng Raymond T. , Murphy Kevin P.
Published: July 2007

Motivation: Recurrent DNA copy number alterations (CNA) measured with array comparative genomic hybridization (aCGH) reveal important molecular features of human genetics and disease. Studying aCGH profiles from a phenotypic group of individuals can determine important recurrent CNA patterns that suggest a strong correlation to the phenotype. Computational approaches to detecting recurrent CNAs from a set of aCGH experiments have typically relied on discretizing the noisy log ratios and subsequently inferring patterns. We demonstrate that this can have the effect of filtering out important signals present in the raw data. In this article we develop statistical models that jointly infer CNA patterns and the discrete labels by borrowing statistical strength across samples.

Results: We propose extending single sample aCGH HMMs to the multiple sample case in order to infer shared CNAs. We model recurrent CNAs as a profile encoded by a master sequence of states that generates the samples. We show how to improve on two basic models by performing joint inference of the discrete labels and providing sparsity in the output. We demonstrate on synthetic ground truth data and real data from lung cancer cell lines how these two important features of our model improve results over baseline models. We include standard quantitative metrics and a qualitative assessment on which to base our conclusions.

Availability: http://www.cs.ubc.ca/~sshah/acgh

Contact: sshah@cs.ubc.ca
Systematic discovery of functional modules and context-specific functional annotation of human genome
Authors: Huang Yu , Li Haifeng , Hu Haiyan , Yan Xifeng , Waterman Michael S. , Huang Haiyan , Zhou Xianghong Jasmine
Published: July 2007

Motivation: The rapid accumulation of microarray datasets provides unique opportunities to perform systematic functional characterization of the human genome. We designed a graph-based approach to integrate cross-platform microarray data, and extract recurrent expression patterns. A series of microarray datasets can be modeled as a series of co-expression networks, in which we search for frequently occurring network patterns. The integrative approach provides three major advantages over the commonly used microarray analysis methods: (1) enhance signal to noise separation (2) identify functionally related genes without co-expression and (3) provide a way to predict gene functions in a context-specific way.

Results: We integrate 65 human microarray datasets, comprising 1105 experiments and over 11 million expression measurements. We develop a data mining procedure based on frequent itemset mining and biclustering to systematically discover network patterns that recur in at least five datasets. This resulted in 143 401 potential functional modules. Subsequently, we design a network topology statistic based on graph random walk that effectively captures characteristics of a gene's local functional environment. Function annotations based on this statistic are then subject to the assessment using the random forest method, combining six other attributes of the network modules. We assign 1126 functions to 895 genes, 779 known and 116 unknown, with a validation accuracy of 70%. Among our assignments, 20% genes are assigned with multiple functions based on different network environments.

Availability: http://zhoulab.usc.edu/ContextAnnotation

Contact: xjzhou@usc.edu
Efficient parameter estimation for RNA secondary structure prediction
Authors: Andronescu Mirela , Condon Anne , Hoos Holger H. , Mathews David H. , Murphy Kevin P.
Published: July 2007

Motivation: Accurate prediction of RNA secondary structure from the base sequence is an unsolved computational challenge. The accuracy of predictions made by free energy minimization is limited by the quality of the energy parameters in the underlying free energy model. The most widely used model, the Turner99 model, has hundreds of parameters, and so a robust parameter estimation scheme should efficiently handle large data sets with thousands of structures. Moreover, the estimation scheme should also be trained using available experimental free energy data in addition to structural data.

Results: In this work, we present constraint generation (CG), the first computational approach to RNA free energy parameter estimation that can be efficiently trained on large sets of structural as well as thermodynamic data. Our CG approach employs a novel iterative scheme, whereby the energy values are first computed as the solution to a constrained optimization problem. Then the newly computed energy parameters are used to update the constraints on the optimization function, so as to better optimize the energy parameters in the next iteration. Using our method on biologically sound data, we obtain revised parameters for the Turner99 energy model. We show that by using our new parameters, we obtain significant improvements in prediction accuracy over current state of-the-art methods.

Availability: Our CG implementation is available at http://www.rnasoft.ca/CG/

Contact: andrones@cs.ubc.ca
Multiple alignment by aligning alignments
Authors: Wheeler Travis J. , Kececioglu John D.
Published: July 2007

Motivation: Multiple sequence alignment is a fundamental task in bioinformatics. Current tools typically form an initial alignment by merging subalignments, and then polish this alignment by repeated splitting and merging of subalignments to obtain an improved final alignment. In general this form-and-polish strategy consists of several stages, and a profusion of methods have been tried at every stage. We carefully investigate: (1) how to utilize a new algorithm for aligning alignments that optimally solves the common subproblem of merging subalignments, and (2) what is the best choice of method for each stage to obtain the highest quality alignment.

Results: We study six stages in the form-and-polish strategy for multiple alignment: parameter choice, distance estimation, merge-tree construction, sequence-pair weighting, alignment merging, and polishing. For each stage, we consider novel approaches as well as standard ones. Interestingly, the greatest gains in alignment quality come from (i) estimating distances by a new approach using normalized alignment costs, and (ii) polishing by a new approach using 3-cuts. Experiments with a parameter-value oracle suggest large gains in quality may be possible through an input-dependent choice of alignment parameters, and we present a promising approach for building such an oracle. Combining the best approaches to each stage yields a new tool we call Opal that on benchmark alignments matches the quality of the top tools, without employing alignment consistency or hydrophobic gap penalties.

Availability: Opal, a multiple alignment tool that implements the best methods in our study, is freely available at http://opal.cs.arizona.edu

Contact: twheeler@cs.arizona.edu
Connecting quantitative regulatory-network models to the genome
Authors: Pan Yue , Durfee Tim , Bockhorst Joseph , Craven Mark
Published: July 2007

Motivation: An important task in computational biology is to infer, using background knowledge and high-throughput data sources, models of cellular processes such as gene regulation. Nachman et al. have developed an approach to inferring gene-regulatory networks that represents quantitative transcription rates, and simultaneously estimates both the kinetic parameters that govern these rates and the activity levels of unobserved regulators that control them. This approach is appealing in that it provides a more detailed and realistic description of how a gene's regulators influence its level of expression than alternative methods. We have developed an extension to this approach that involves representing and learning the key kinetic parameters as functions of features in the genomic sequence. The primary motivation for our approach is that it provides a more mechanistic representation of the regulatory relationships being modeled.

Results: We evaluate our approach using two Escherichia coli gene-expression data sets, with a particular focus on modeling the networks that are involved in controlling how E.coli regulates its response to the carbon source(s) available to it. Our results indicate that our sequence-based models provide predictive accuracy that is better than similar models without sequence-based parameters, and substantially better than a simple baseline. Moreover, our approach results in models that offer more explanatory power and biological insight than models without sequence-based parameters.

Contact: ypan@cs.wisc.edu
Manual curation is not sufficient for annotation of genomic databases
Authors: Baumgartner William A. , Cohen K. Bretonnel , Fox Lynne M. , Acquaah-Mensah George , Hunter Lawrence
Published: July 2007

Motivation: Knowledge base construction has been an area of intense activity and great importance in the growth of computational biology. However, there is little or no history of work on the subject of evaluation of knowledge bases, either with respect to their contents or with respect to the processes by which they are constructed. This article proposes the application of a metric from software engineering known as the found/fixed graph to the problem of evaluating the processes by which genomic knowledge bases are built, as well as the completeness of their contents.

Results: Well-understood patterns of change in the found/fixed graph are found to occur in two large publicly available knowledge bases. These patterns suggest that the current manual curation processes will take far too long to complete the annotations of even just the most important model organisms, and that at their current rate of production, they will never be sufficient for completing the annotation of all currently available proteomes.

Contact: larry.hunter@uchsc.edu
Swallowing Outcomes After Microvascular Head and Neck Reconstruction: A Prospective Review of 191 Cases
Authors: Khariwala Samir S. , Vivek Prashant P. , Lorenz Robert R. , Esclamado Ramon M. , Wood Benjamin , Strome Marshall , Alam Daniel S.
Published: July 2007

Background: The use of microvascular free tissue flaps tailored specifically to the ablative surgical defects has allowed precise anatomic reconstructions to be performed and, in turn, has improved patient outcomes. We report here the postoperative swallowing outcomes of patients undergoing microvascular reconstructions for a range of head and neck defects at the Cleveland Clinic.

Methods: The study includes 191 consecutive reconstructions for varied defects. All patients were reconstructed with four specific microvascular flaps based on their surgical defect, and postoperative swallowing outcomes were evaluated and recorded on a prospectively maintained database. Pre‐ and postoperative swallowing was graded on an ordinal scale. Data were simultaneously collected on the precise anatomic ablative defect in each patient, subdividing the head and neck into 16 subsites. The data were analyzed using a multivariate analysis accounting for comorbid factors, type of flap used, and subsite of defect.

Results: The findings are summarized as follows. There were no flap failures. The percent of patients who were able to swallow and maintain an exclusively oral diet postoperatively was 78.5%. Only 16.8% were unable to have an oral diet (NPO) and dependent on a gastric tube (G‐tube) for feeding. The factors that predicted an inability to swallow include tongue resection, preoperative radiation therapy, and hypopharyngeal defects. In contrast, floor of mouth, mandibular, and pharyngeal defects, regardless of size, had excellent long‐term swallowing outcomes. Most patients with these defects were able to tolerate at least a soft solid diet.

Conclusions: In summary, we report excellent postoperative swallowing outcomes after microvascularreconstructions at our institution that compare favorably with outcomes with pedicled flaps and historic controls. The type of flap used and the size of defect had minimal effects on swallowing outcomes. The most difficult subsites to reconstruct were tongue defects, which strongly correlated with poor swallowing outcomes. The other factor that strongly impacted outcomes was preoperative radiation treatment. We believe these results highlight the utility of free flaps in recreating the precise anatomy required to maintain swallowing function. These data will hopefully support numerous previous studies that have established the use of microvascular reconstruction as standard of care for ablative surgical defects in the head and neck.
Estimating Subglottal Pressure via Airflow Redirection
Authors: Baggott Christopher D. , Yuen Alexander K. , Hoffman Matthew R. , Zhou Liang , Jiang Jack J.
Published: July 2007

Subglottal pressure (SGP) is a valuable parameter in the research and clinical assessment of laryngeal function. The lungs serve as a constant pressure source during sustained phonation, and that pressure, SGP, can be used to determine the efficiency with which the larynx converts aerodynamic power to acoustic power. As the larynx serves as an aerodynamic transducer, the vocal efficiency (Ve) coefficient, defined as acoustic power (dB) divided by aerodynamic power (SGP × glottal airflow) has been shown to reliably reflect vocal health. However, current SGP measurement techniques are hesitantly used because of either an invasive nature or the requirement of intensive patient training. This study tests a novel device that has been designed to noninvasively estimate SGP through mechanical airflow redirection, producing a numeric output on completion of the trial, which lasts only a few seconds. The novelty of this design lies in the ease of use for both the patient and the clinician. Multiple mechanical airflow redirections occlude the airway for only 135 ms, which is predicted to limit the effect of confounding laryngeal reflexes that may occur during the trials. Additionally, the airflow redirection into a retention device allows for the pneumatic in‐trial comparison of the estimated SGP with the pressure achieved by the patient, providing a numeric output to the clinician on completion.
Effects of Dexamethasone on the Expression of Transforming Growth Factor‐β in the Mouse Model of Allergic Rhinitis
Authors: Lee Seung‐Sin , Won Tae‐Bin , Kim Jeong‐Whun , Rhee Chae‐Seo , Lee Chul‐Hee , Hong Seok‐Chan , Min Yang‐Gi
Published: July 2007

Objectives/Hypothesis: This study aimed to evaluate the effect of dexamethasone on the expression of transforming growth factor (TGF)‐β in the mouse model of allergic rhinitis.

Study Design: Female BALB/c mice were randomly assigned to four groups, including two control groups and two treatment groups.

Methods: General sensitization and local challenge were performed with ovalbumin (OVA). In the treatment groups, dexamethasone was injected intraperitoneally 3 hours before general sensitization or local challenge. Symptom score, eosinophil infiltration, and immunostaining for TGF‐β1 and CD4 in nasal mucosa, and TGF‐β1 and OVA‐specific immunoglobulin E (IgE) in sera were analyzed.

Results: Dexamethasone administration before general sensitization reduced the symptom score, OVA‐specific IgE, and eosinophil infiltration and increased the serum level of TGF‐β1 significantly. Dexamethasone administration before local challenge reduced only the eosinophil infiltration significantly. Immunoreactivity of TGF‐β1 and CD4 was lower in both treatment groups.

Conclusion: These results suggest that dexamethasone may play an important role in the regulation of allergic reactions by at least two mechanisms; one by suppressing allergic sensitization through decrease of CD4+ T cells and increase of TGF‐β, and the other by suppressing late allergic reactions through the inhibition of proliferation and chemotaxis of inflammatory cells such as eosinophils.
Pediatric Salivary Gland Obstructive Swelling: Sialendoscopic Approach
Authors: Faure Frederic , Querin Stephanie , Dulguerov Pavel , Froehlich Patrick , Disant Francois , Marchal Francis
Published: July 2007

Objective: To assess the efficacy of sialendoscopy as a diagnostic and interventional procedure for salivary ductal pathologies of children.

Design: Prospective case series study.

Setting: Tertiary care teaching hospitals.

Patients: Eight children were investigated under general anesthesia by sialendoscopy for recurring salivary gland swellings between 2003 to 2004 in two university centers.

Intervention: Diagnostic sialendoscopy was used for classifying ductal lesions as sialolithiasis or stenosis. Interventional sialendoscopy was used to treat these disorders. Different variables were analyzed: type of endoscope used, intraoperative findings, type of device used for sialoliths fragmentation or extraction, total number of procedures, and size and number of sialoliths removed.

Results: Five cases of parotid and three cases of submandibular gland recurring swellings were included in the present study. Diagnostic sialendoscopy was possible in all cases. Salivary stones were found in six patients and parotid ductal stenosis in the remaining two. Multiple stones were seen in two cases. Interventional sialendoscopy was also possible in all cases, allowing an intraductal retrieval of the stones in three cases, and a marsupialization of the duct in two cases. Two cases required laser fragmentation of the stone. No major complications occurred intraoperatively or during follow‐up (mean 18 months).

Conclusion: Diagnostic sialendoscopy is a new technique allowing a reliable evaluation of salivary ductal disorders in children, with low morbidity. Interventional sialendoscopy allows early treatment of pediatric sialoliths and stenosis in most cases, avoiding classical open surgery.
Prevalence of Laryngopharyngeal Reflux in a Population With Gastroesophageal Reflux
Authors: Groome Maximillian , Cotton James P. , Borland Marina , McLeod Shirley , Johnston David A. , Dillon John F.
Published: July 2007

Objective: Laryngopharyngeal reflux (LPR) is a syndrome associated with a constellation of symptoms usually treated by ENT surgeons. It is believed to be caused by the retrograde flow of stomach contents into the laryngopharynx, this being a supra‐esophageal manifestation of gastroesophageal reflux disease (GERD). It has been cited that LPR and GERD can be considered separate entities. Our hypothesis was that LPR is a supra‐esophageal manifestation of GERD and therefore that patients with GERD should have a degree of symptoms suggestive of LPR because of the reflux of the gastric contents. We examined a population of patients with both upper gastrointestinal endoscopy and symptom‐proven GERD and, using a questionnaire, looked at their existing symptoms to help assess the prevalence of LPR. We also looked at whether, with more severe GERD (suggestive of increased gastric content reflux), the degree of symptoms suggestive of LPR would be increased, as would be expected.

Methods: A population of patients with endoscopically proven GERD were recruited and divided into groups depending on the severity of their reflux disease. A questionnaire was then administered that examined both LPR and GERD scoring criteria. The relationship between GERD and LPR was then analyzed.

Results: We recruited 1,383 subjects with GERD; those with severe GERD had significantly higher LPR scores compared with those with mild (P < .01), moderate (P < .05), or inactive disease (P < .001).

Conclusions: The condition of LPR is likely to represent a supra‐esophageal manifestation of GERD. This study examined a large number of patients with endoscopically proven GERD and has demonstrated a correlation between the severity of GERD and the prevalence of LPR. LPR and GERD are common and interlinked conditions. The subsequent prevalence of LPR in the population with GERD is therefore likely to be dramatically underestimated.
Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression
Authors: Moustakas Aristidis , Heldin Carl‐Henrik
Published: July 2007

Epithelial–mesenchymal transition (EMT) describes the differentiation switch between polarized epithelial cells and contractile and motile mesenchymal cells, and facilitates cell movements and generation of new tissue types during embryogenesis. Many secreted polypeptides are implicated in the EMT process and their corresponding intracellular transduction pathways form highly interconnected networks. Transforming growth factor‐β, Wnt, Notch and growth factors acting through tyrosine kinase receptors induce EMT and often act in a sequential manner. Such growth factors orchestrate the concerted regulation of an elaborate gene program and a complex protein network, needed for establishment of new mesenchymal phenotypes after disassembly of the main elements of epithelial architecture, such as desmosomes, as well as tight, adherens and gap junctions. EMT of tumor cells occurs during cancer progression and possibly generates cell types of the tumor stroma, such as cancer‐associated myofibroblasts. EMT contributes to new tumor cell properties required for invasiveness and vascular intravasation during metastasis. Here we present some of the current mechanisms that mediate the process of EMT and discuss their relevance to cancer progression. (Cancer Sci 2007; 98: 1512–1520)
HLA class I antigen expression is associated with a favorable prognosis in early stage non‐small cell lung cancer
Authors: Kikuchi Eiki , Yamazaki Koichi , Torigoe Toshihiko , Cho Yasushi , Miyamoto Masaki , Oizumi Satoshi , Hommura Fumihiro , Dosaka‐Akita Hirotoshi , Nishimura Masaharu
Published: July 2007

Human leukocyte antigen (HLA) class I displays a repertoire of endogenously processed peptides to CD8+ T lymphocytes. The present study assessed correlations between HLA class I expression, clinicopathologic factors, and tumor‐infiltrating immune cells in human non‐small cell lung cancers (NSCLC). Expression of HLA class I was assessed in 161 resected primary NSCLC by immunohistochemistry using EMR8–5, a novel monoclonal anti‐pan HLA class I heavy chain antibody. Expression of HLA class I was classified into three categories: strongly positive, weakly positive, or negative. Tumor‐infiltrating CD8+ lymphocytes and CD56+ natural killer cells within cancer nests and stroma were also counted. Expression of HLA class I was strongly positive in 50 tumors, weakly positive in 57 tumors, and negative in 54 tumors. Down‐regulation of HLA class I was significantly correlated with male sex, history of smoking, non‐adenocarcinoma histology, and moderate‐/low‐grade differentiation. The density of cancer nest‐infiltrating CD8+ cells in HLA class I‐negative tumors was significantly decreased compared to that in HLA class I strongly positive tumors (P < 0.01). Kaplan–Meier analysis revealed a significant favorable influence on overall survival for patients displaying tumors with strongly positive expression of HLA class I (P < 0.01). Multivariate analysis revealed down‐regulation of HLA class I as an independent factor of poor prognosis in pathological stage I patients, but not in late‐stage patients. These results suggest that down‐regulation of HLA class I expression in NSCLC is a marker of poor prognosis, and this may play a critical role in immune surveillance of patients with NSCLC. (Cancer Sci 2007; 98: 1424–1430)
Lipoxygenase inhibitors induce death receptor 5/TRAIL‐R2 expression and sensitize malignant tumor cells to TRAIL‐induced apoptosis
Authors: Yoshida Tatsushi , Shiraishi Takumi , Horinaka Mano , Nakata Susumu , Yasuda Takashi , Goda Ahmed E. , Wakada Miki , Mizutani Yoichi , Miki Tsuneharu , Nishikawa Akiyoshi , Sakai Toshiyuki
Published: July 2007

Lipoxygenases induce malignant tumor progression and lipoxygenase inhibitors have been considered as promising anti‐tumor agents. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. Combined treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, and TRAIL markedly induced apoptosis in Jurkat T‐cell leukemia cells at suboptimal concentrations for each agent. The combined treatment efficiently activated caspase‐3, ‐8 and ‐10, and Bid. The underling mechanism by which NDGA enhanced TRAIL‐induced apoptosis was examined. NDGA did not change the expression levels of anti‐apoptotic factors, Bcl‐xL, Bcl‐2, cIAP‐1, XIAP and survivin. The expression of death receptor‐related genes was investigated and it was found that NDGA specifically up‐regulated the expression of death receptor 5 (DR5) at mRNA and protein levels. Down‐regulation of DR5 by small interfering RNA prevented the sensitizing effect of NDGA on TRAIL‐induced apoptosis. Furthermore, NDGA sensitized prostate cancer and colorectal cancer cells to TRAIL‐induced apoptosis. In contrast, NDGA neither enhanced TRAIL‐induced apoptosis nor up‐regulated DR5 expression in normal peripheral blood mononuclear cells. Another lipoxygenase inhibitor, AA861, also up‐regulated DR5 and sensitized Jurkat and DU145 cells to TRAIL. These results indicate that lipoxygenase inhibitors augment the apoptotic efficiency of TRAIL through DR5 up‐regulation in malignant tumor cells, and raise the possibility that the combination of lipoxygenase inhibitor and TRAIL is a promising strategy for malignant tumor treatment. (Cancer Sci 2007; 98: 1417–1423)
Involvement of cyclooxygenase‐2 in the tumor site‐dependent production of parathyroid hormone‐related protein in colon 26 carcinoma
Authors: Saito Hidemi , Inagaki Yukiko , Tsunenari Toshiaki , Ura Masako , Mizuno Hideaki , Fujimoto‐Ouchi Kaori , Onuma Etsuro , Sato Koh , Ogata Etsuro , Yamada‐Okabe Hisafumi
Published: July 2007

It has been shown that in the mouse colon 26 tumor model, tumors grown in the subcutis (subcutis colon 26) caused early onset of cachectic syndromes, whereas those in the liver (liver colon 26) did not. Both interleukin (IL)‐6 and parathyroid hormone‐related protein (PTHrP) were involved in the development of cachectic syndromes in this tumor model. However, whether expression of PTHrP and IL‐6 is differently regulated in the tumor microenvironment is unclear. In the present study, culturing the colon 26 cells under different conditions in vitro revealed that IL‐6 production was increased by monolayer culture under a low‐glucose condition but not by spheroid culture. In contrast, PTHrP production was increased by spheroid culture but not by monolayer culture, even under a low‐glucose condition. Gene expression profiling revealed that the expression of cyclooxygenase (COX)‐2 was up‐regulated in both subcutis colon 26 and spheroid cultures, and that COX‐2 inhibitor NS‐398 suppressed PTHrP production in spheroid cultures. Furthermore, administration of NS‐398 decreased the PTHrP level without affecting the tumor growth in mice bearing subcutis colon 26. These results demonstrate that production of PTHrP and IL‐6 largely depends on the microenvironments in which tumors are developed or metastasized and that up‐regulation of COX‐2 in a necrobiotic environment leads to PTHrP production, thereby causing cachectic syndromes. (Cancer Sci 2007; 98: 1563–1569)
Epigenetic silencing of claudin‐6 promotes anchorage‐independent growth of breast carcinoma cells
Authors: Osanai Makoto , Murata Masaki , Chiba Hideki , Kojima Takashi , Sawada Norimasa
Published: July 2007

Cancer cells often exhibit loss of functional tight junctions (TJ), and disruption of the TJ structure is associated with cancer development. However, whether loss of a certain type of claudin, an integral membrane protein of TJ, is involved in malignant phenotypes remains to be clarified. Based on a report that claudin‐6 functions as a tumor suppressor for breast cancer, the authors show here that suppression of claudin‐6 expression results in increased resistance to various apoptogens, and causally enhances anchorage‐independent growth properties. Because claudin‐6 expression is partially silenced by promoter CpG island hypermethylation in MCF7 breast carcinoma cells, a synergistic effect of a demethylator and histone deacetylase inhibitor up‐regulates the expression of endogenous claudin‐6, which is sufficient for apoptotic sensitization and abrogation of colony‐forming efficacy. In addition, decreased expression of claudin‐6 promotes cellular invasiveness and transendothelial migration, accompanied by an increase in matrix metalloproteinase activity. These data suggest that the methylator phenotype of claudin‐6 may at least partially contribute to enhanced tumorigenic and invasive properties of breast carcinoma cells. (Cancer Sci 2007; 98: 1557–1562)
Reducing alcohol‐related damage in populations: rethinking the roles of education and persuasion interventions
Authors: Giesbrecht Norman
Published: July 2007

Aim In order to potentially enhance the impact of most effective policies and interventions in reducing the population level damage from alcohol, a new perspective with regard to education and persuasion interventions is offered.

Methods Recent studies were examined on the global burden of alcohol and also those focusing on the links between overall consumption and high‐risk drinking, on one hand, and drinking‐related damage on the other hand. A synopsis of main findings from reviews and other analysis provides the basis for conclusions about the impacts of education and persuasion interventions.

Results There is a relative absence of evidence of the effectiveness of education and persuasion in reducing consumption, curtailing high‐risk drinking or reducing damage from alcohol. This is in contrast to the rising levels of damage from alcohol, and also to the demonstrated effectiveness of certain alcohol policies and interventions, as summarized in Baboret al.

Conclusions Given that only a small fraction of education and persuasion interventions have any positive impact, generating ‘more of the same’ is not an impact‐effective and cost‐efficient approach. Therefore, interventions that have not been shown to be effective need to be phased out and those most effective and of widest scope should receive more attention and enhanced resources. A reframing of the roles and foci of persuasion interventions is advised, including, for example, focusing on informing policy‐makers, and stimulating public discussions about the rationale of alcohol policies and the roles that citizens can play in promoting and supporting these policies.
Does smoking in adolescence affect body mass index, waist or height? Findings from a longitudinal study
Authors: Fidler Jennifer A. , West Robert , Van Jaarsveld Cornelia H. M. , Jarvis Martin J. , Wardle Jane
Published: July 2007

Aim  To assess the effect of smoking uptake on body mass index (BMI), waist circumference and height during adolescence.

Design  Five‐year longitudinal study.

Setting  Thirty‐six schools in South London, England, selected by a stratified random sampling procedure designed to ensure ethnic and socio‐economic diversity.

Participants  A total of 5863 students took part in the HABITS (Health and Behaviour in Teenagers) Study between 1999 and 2003.

Measurements  Self‐reported smoking behaviour, saliva cotinine concentrations and measured weight, waist circumference and height were obtained, along with information on gender, ethnicity, socio‐economic deprivation, pubertal status, self‐reported exercise and dieting. Students were examined annually from school year 7 (ages 11–12) to year 11 (ages 15–16), with response rates ranging from 74 to 84%. A total of 2665 never smokers at year 7 with complete data for years 7 and 11 were included in the analyses.

Findings  Adjusting for year 7 BMI and other potential confounders, regular smokers (more than six cigarettes a week) at year 11 had significantly lower BMI (P = 0.002) than other students. Smokers defined by a cotinine above 15 ng/ml also had lower BMI (P < 0.0001). Waist circumferences were lower in regular smokers (P = 0.014) and cotinine‐defined smokers (P < 0.011). No consistent association was found between smoking and height. The adjusted difference in weight between regular smokers and other students amounted to 1.8 kg (95% CI, 0.52–3.17) for an average‐height student.

Conclusion  Taking up regular smoking during adolescence may result in a lower BMI, but the effect is small and of uncertain significance.
Cost‐effectiveness of prize‐based contingency management in methadone maintenance treatment programs
Authors: Sindelar Jody L. , Olmstead Todd A. , Peirce Jessica M.
Published: July 2007

Aim To determine if prize‐based contingency management (CM), which has been shown to improve treatment outcomes over usual care (UC) alone, is cost‐effective.

Design A cost‐effectiveness study of a multi‐site clinical trial. Data on the outcome measures came from the original effectiveness trial. Cost data were gathered by clinic survey specifically for this cost‐effectiveness analysis.

Setting Six methadone maintenance community clinics participating in the National Drug Abuse Treatment Clinical Trials Network.

Participants Participants were recruited from six methadone maintenance community treatment programs. The study sample consisted of 388 participants: 190 in the UC condition and 198 in the CM condition. Participants were randomized at each site to either the UC or the CM condition based on the presence of stimulants (cocaine, amphetamine or methamphetamine) and opioids in their baseline urine sample.

Intervention Prize‐based contingency management added to usual care.

Measurements Longest duration of abstinence (LDA), number of stimulant‐negative urine samples and costs of treatment.

Findings Compared to usual care, the incremental cost of using prize‐based CM to lengthen the LDA by 1 week was $141 [95% confidence interval (CI), $105–$193]. The incremental cost to obtain an additional stimulant‐negative urine sample was $70 (95% CI, $53–$117).

Conclusions By comparing this study to a companion study, we found that adding prize‐based CM to usual care may be more cost‐effective in methadone maintenance clinics than in counseling‐based drug‐free clinics.
HIV risk behavior among injection drug users in Tehran, Iran
Authors: Razani Nooshin , Mohraz Minoo , Kheirandish Parastoo , Malekinejad Mohsen , Malekafzali Hossein , Mokri Azarakhsh , McFarland Willi , Rutherford George
Published: July 2007

Aims  Iran faces parallel human immunodeficiency virus (HIV) and injection drug use epidemics; more than 62% of known HIV cases occur among injection drug users (IDU). We conducted a formative study of IDU in Tehran to explore risk behavior in the wake of the recent harm reduction efforts.

Participants and design  Key informant interviews (n = 40), focus group discussions (nine groups of IDU, n = 66) and a review of existing published and unpublished literature were conducted. Participants included IDU, physicians, policy makers, police, IDU advocates and their families. IDU were diverse in gender, education, income and neighborhood of residence. Interviews were transcribed and analyzed using grounded theory. A typology of IDUs in Tehran, categorized according to self‐defined networks as well as HIV risks, is presented. This categorization is based on the groups identified by IDUs, compared to those identified by other key informants, and on a secondary data review.

Findings  Homeless, female, young IDU and users of a more potent form of heroin were identified as having increased risks for HIV. Participants described shortening transitions from smoked opium to injected opiates. Whereas a majority of participants considered needle sharing less common than previously, sharing continues in locations of group injection, and in states of withdrawal or severe addiction. System‐wise barriers to harm reduction were discussed, and include the cost or stigma of purchasing needles from pharmacies, over‐burdened clinics, irregular enforcement of laws protecting IDU and lack of efforts to address the sexual risks of IDU.

Conclusions  This research is one of the first to describe a diversity of IDU, including women and higher socio‐economic class individuals, in Tehran. While efforts in harm reduction in Iran to date have been notable, ongoing risks point to an urgent need for targeted, culturally acceptable interventions.