bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities
Authors: Toole Bryan P.
Published: December 2009

Hyaluronan is a prominent component of the micro-environment in most malignant tumors and can be prognostic for tumor progression. Extensive experimental evidence in animal models implicates hyaluronan interactions in tumor growth and metastasis, but it is also evident that a balance of synthesis and turnover by hyaluronidases is critical. CD44, a major hyaluronan receptor, is commonly but not uniformly associated with malignancy, and is frequently used as a marker for cancer stem cells in human carcinomas. Multivalent interactions of hyaluronan with CD44 collaborate in driving numerous tumor-promoting signaling pathways and transporter activities. It is widely accepted that hyaluronan-CD44 interactions are crucial in both malignancy and resistance to therapy, but major challenges for future research in the field are the mechanism of activation of hyaluronan-CD44 signaling in cancer cells, the relative importance of variant forms of CD44 and other hyaluronan receptors, e.g., Rhamm, in different tumor contexts, and the role of stromal versus tumor cell production and turnover of hyaluronan. Despite these caveats, it is clear that hyaluronan-CD44 interactions are an important target for translation into the clinic. Among the approaches that show promise are antibodies and vaccines to specific variants of CD44 that are uniquely expressed at critical stages of progression of a particular cancer, hyaluronidase-mediated reduction of barriers to drug access, and small hyaluronan oligosaccharides that attenuate constitutive hyaluronan-receptor signaling and enhance chemosensitivity. In addition, hyaluronan is being used to tag drugs and delivery vehicles for targeting of anticancer agents to CD44-expressing tumor cells. (Clin Cancer Res 2009;15(24):7462–8)
A Phase I Clinical Trial of CHT-25 a 131I-Labeled Chimeric Anti-CD25 Antibody Showing Efficacy in Patients with Refractory Lymphoma
Authors: Dancey Gairin , Violet John , Malaroda Alessandra , Green Alan J. , Sharma Surinder K. , Francis Roslyn , Othman Shokri , Parker Sweta , Buscombe John , Griffin Natalie , Chan Pei-San , Malhotra Anmol , Woodward Nicholas , Ramsay Alan , Ross Philip , Lister T. Andrew , Amlot Peter , Begent Richard , McNamara Christopher
Published: December 2009

Purpose: There is a need for new treatments for Hodgkin and T-cell lymphoma due to the development of drug resistance in a proportion of patients. This phase I study of radioimmunotherapy used CHT-25, a chimeric antibody to the α-chain of the interleukin-2 receptor, CD25, conjugated to iodine-131 (131I) in patients with refractory CD25-positive lymphomas.

Experimental Design: Fifteen patients were treated (Hodgkin lymphoma, 12; angioimmunoblastic T-cell lymphoma, 1; adult T-cell leukemia/lymphoma, 2). Tumor was monitored by computed tomography and in all but two patients by 18F-fluorodeoxyglucose positron emission tomography.

Results: There were no grade 3 or 4 infusion reactions. At the maximum tolerated dose of 1,200 MBq/m2, the major side effect was delayed myelotoxicity with the nadir for platelets at 38 days and for neutrophils at 53 days. One patient treated with 2,960 MBq/m2 developed prolonged grade 4 neutropenia and thrombocytopenia and died of Pneumocystis jiroveci pneumonia. Nonhematologic toxicity was mild. Single photon emission computer tomography imaging showed tumor-specific uptake and retention of 131I and no excessive retention in normal organs. Of nine patients receiving ≥1,200 MBq/m2, six responded (three complete response and three partial response); one of six patients with administered radioactivity of ≤740 MBq/m2 had a complete response.

Conclusions: CHT-25 is well tolerated with 1,200 MBq/m2 administered radioactivity and shows clinical activity in patients who are refractory to conventional therapies. Phase II studies are justified to determine efficacy and toxicity in a broader range of clinical scenarios. (Clin Cancer Res 2009;15(24):7701–10)
Inhibition of Vascular Endothelial Growth Factor Receptor-1/Wnt/β-catenin Crosstalk Leads to Tumor Cell Death
Authors: Zeitlin Benjamin D. , Ellis Lee M. , Nör Jacques E.
Published: December 2009

Two genes are considered synthetic lethal if mutation of either alone allows cell viability, whereas simultaneous mutation leads to cell death. A synthetic lethal screen unveiled the dependency of Wnt/β-catenin-addicted colorectal cancer cells on vascular endothelial growth factor receptor-1 kinase activity and suggested a novel therapeutic approach for this malignancy. (Clin Cancer Res 2009;15(24):7453–5)
Induction of Hypertension and Peripheral Inflammation by Reduction of Extracellular Superoxide Dismutase in the Central Nervous System
Authors: Lob Heinrich E. , Marvar Paul J. , Guzik Tomasz J. , Sharma Shraya , McCann Louise A. , Weyand Cornelia , Gordon Frank J. , Harrison David G.
Published: December 2009

The circumventricular organs (CVOs) lack a well-formed blood-brain barrier and produce superoxide in response to angiotensin II and other hypertensive stimuli. This increase in central superoxide has been implicated in the regulation of blood pressure. The extracellular superoxide dismutase (SOD3) is highly expressed in cells associated with CVOs and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVOs in blood pressure regulation, we performed intracerebroventricular injection an adenovirus encoding Cre-recombinase (5×10
8
particles per milliliter) in mice with loxP sites flanking the SOD3 coding region (SOD3
loxp/loxp
mice). An adenovirus encoding red-fluorescent protein was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg per day), whereas intracerebroventricular injection of adenovirus encoding red-fluorescent protein had minimal effects on these parameters. Adenovirus encoding Cre-recombinase–treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production, and T-cell activation as characterized by increased circulating CD69
+
/CD3
+
cells. Deletion of CVO SOD3 also markedly increased vascular T-cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in the regulation of blood pressure, and its loss promotes T-cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli, such as angiotensin II.
Impacts of Historic Climate Variability on Seasonal Soil Frost in the Midwestern United States
Authors: Sinha Tushar , Cherkauer Keith A. , Mishra Vimal
Published: December 2009

The present study examines the effects of historic climate variability on cold-season processes, including soil temperature, frost depth, and the number of frost days and freeze–thaw cycles. Considering the importance of spatial and temporal variability in cold-season processes, the study was conducted in the midwestern United States using both observations and model simulations. Model simulations used the Variable Infiltration Capacity (VIC) land surface model (LSM) to reconstruct and to analyze changes in the long-term (i.e., 1917–2006) means of soil frost variables. The VIC model was calibrated using observed streamflow records and near-surface soil temperatures and then evaluated for streamflow, soil temperature, frost depth, and soil moisture before its application at the regional scale. Soil frost indicators—such as the number of frost days and freeze–thaw cycles—were determined from observed records and were tested for the presence of significant trends. Overall trends in extreme and mean seasonal soil temperature from 1967 onward indicated a warming of soil temperatures at a depth of 10 cm—specifically in northwest Indiana, north-central Illinois, and southeast Minnesota—leading to a reduction in the number of soil frost days. Model simulations indicated that by the late-century period (1977–2006), soil frost duration decreased by as much as 36 days compared to the midcentury period (1947–76). Spatial averages for the study area in warm years indicated shallower frost penetration by 15 cm and greater soil temperatures by about 3°C at 10-cm soil depth than in the cold years.
A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment)
Authors: Passamonti Francesco , Cervantes Francisco , Vannucchi Alessandro Maria , Morra Enrica , Rumi Elisa , Pereira Arturo , Guglielmelli Paola , Pungolino Ester , Caramella Marianna , Maffioli Margherita , Pascutto Cristiana , Lazzarino Mario , Cazzola Mario , Tefferi Ayalew
Published: December 2009

Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 × 109/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.
EEVD motif of heat shock cognate protein 70 contributes to bacterial uptake by trophoblast giant cells
Authors: Watanabe Kenta , Tachibana Masato , Kim Suk , Watarai Masahisa
Published: December 2009

Background

The uptake of abortion-inducing pathogens by trophoblast giant (TG) cells is a key event in infectious abortion. However, little is known about phagocytic functions of TG cells against the pathogens. Here we show that heat shock cognate protein 70 (Hsc70) contributes to bacterial uptake by TG cells and the EEVD motif of Hsc70 plays an important role in this.

Methods

Brucella abortus and Listeria monocytogenes were used as the bacterial antigen in this study. Recombinant proteins containing tetratricopeptide repeat (TPR) domains were constructed and confirmation of the binding capacity to Hsc70 was assessed by ELISA. The recombinant TPR proteins were used for investigation of the effect of TPR proteins on bacterial uptake by TG cells and on pregnancy in mice.

Results

The monoclonal antibody that inhibits bacterial uptake by TG cells reacted with the EEVD motif of Hsc70. Bacterial TPR proteins bound to the C-terminal of Hsc70 through its EEVD motif and this binding inhibited bacterial uptake by TG cells. Infectious abortion was also prevented by blocking the EEVD motif of Hsc70.

Conclusions

Our results demonstrate that surface located Hsc70 on TG cells mediates the uptake of pathogenic bacteria and proteins containing the TPR domain inhibit the function of Hsc70 by binding to its EEVD motif. These molecules may be useful in the development of methods for preventing infectious abortion.
Developmental expression of BK channels in chick cochlear hair cells
Authors: Li Yi , Atkin Graham M , Morales Marti M , Liu Li Qian , Tong Mingjie , Duncan R Keith
Published: December 2009

Background

Cochlear hair cells are high-frequency sensory receptors. At the onset of hearing, hair cells acquire fast, calcium-activated potassium (BK) currents, turning immature spiking cells into functional receptors. In non-mammalian vertebrates, the number and kinetics of BK channels are varied systematically along the frequency-axis of the cochlea giving rise to an intrinsic electrical tuning mechanism. The processes that control the appearance and heterogeneity of hair cell BK currents remain unclear.

Results

Quantitative PCR results showed a non-monotonic increase in BK α subunit expression throughout embryonic development of the chick auditory organ (i.e. basilar papilla). Expression peaked near embryonic day (E) 19 with six times the transcript level of E11 sensory epithelia. The steady increase in gene expression from E11 to E19 could not explain the sudden acquisition of currents at E18-19, implicating post-transcriptional mechanisms. Protein expression also preceded function but progressed in a sequence from diffuse cytoplasmic staining at early ages to punctate membrane-bound clusters at E18. Electrophysiology data confirmed a continued refinement of BK trafficking from E18 to E20, indicating a translocation of BK clusters from supranuclear to subnuclear domains over this critical developmental age.

Conclusions

Gene products encoding BK α subunits are detected up to 8 days before the acquisition of anti-BK clusters and functional BK currents. Therefore, post-transcriptional mechanisms seem to play a key role in the delayed emergence of calcium-sensitive currents. We suggest that regulation of translation and trafficking of functional α subunits, near voltage-gated calcium channels, leads to functional BK currents at the onset of hearing.
A high-density collection of EMS-induced mutations for TILLING in Landsberg erecta genetic background of Arabidopsis
Authors: Martín Beatriz , Ramiro Mercedes , Martínez-Zapater José M , Alonso-Blanco Carlos
Published: December 2009

Background

Arabidopsis thaliana is the main model species for plant molecular genetics studies and world-wide efforts are devoted to identify the function of all its genes. To this end, reverse genetics by TILLING (Targeting Induced Local Lesions IN Genomes) in a permanent collection of chemically induced mutants is providing a unique resource in Columbia genetic background. In this work, we aim to extend TILLING resources available in A. thaliana by developing a new population of ethyl methanesulphonate (EMS) induced mutants in the second commonest reference strain. In addition, we pursue to saturate the number of EMS induced mutations that can be tolerated by viable and fertile plants.

Results

By mutagenizing with different EMS concentrations we have developed a permanent collection of 3712 M2/M3 independent mutant lines in the reference strain Landsberg erecta (Ler) of A. thaliana. This population has been named as the Arabidopsis TILLer collection. The frequency of mutations per line was maximized by using M1 plants with low but sufficient seed fertility. Application of TILLING to search for mutants in 14 genes identified 21 to 46 mutations per gene, which correspond to a total of 450 mutations. Missense mutations were found for all genes while truncations were selected for all except one. We estimated that, on average, these lines carry one mutation every 89 kb, Ler population providing a total of more than five million induced mutations. It is estimated that TILLer collection shows a two to three fold higher EMS mutation density per individual than previously reported A. thaliana population.

Conclusions

Analysis of TILLer collection demonstrates its usefulness for large scale TILLING reverse genetics in another reference genetic background of A. thaliana. Comparisons with TILLING populations in other organisms indicate that this new A. thaliana collection carries the highest chemically induced mutation density per individual known in diploid species.
'Who's who' in two different flower types of Calluna vulgaris (Ericaceae): morphological and molecular analyses of flower organ identity
Authors: Borchert Thomas , Eckardt Katrin , Fuchs Jörg , Krüger Katja , Hohe Annette
Published: December 2009

Background

The ornamental crop Calluna vulgaris is of increasing importance to the horticultural industry in the northern hemisphere due to a flower organ mutation: the flowers of the 'bud-flowering' phenotype remain closed i.e. as buds throughout the total flowering period and thereby maintain more colorful flowers for a longer period of time than the wild-type. This feature is accompanied and presumably caused by the complete lack of stamens. Descriptions of this botanical particularity are inconsistent and partially conflicting. In order to clarify basic questions of flower organ identity in general and stamen loss in detail, a study of the wild-type and the 'bud-flowering' flower type of C. vulgaris was initiated.

Results

Flowers were examined by macro- and microscopic techniques. Organ development was investigated comparatively in both the wild-type and the 'bud-flowering' type by histological analyses. Analysis of epidermal cell surface structure of vegetative tissues and perianth organs using scanning electron microscopy revealed that in wild-type flowers the outer whorls of colored organs may be identified as sepals, while the inner ones may be identified as petals. In the 'bud-flowering' type, two whorls of sepals are directly followed by the gynoecium. Both, petals and stamens, are completely missing in this flower type. The uppermost whorl of green leaves represents bracts in both flower types.

In addition, two MADS-box genes (homologs of AP3/DEF and SEP1/2) were identified in C. vulgaris using RACE-PCR. Expression analysis by qRT-PCR was conducted for both genes in leaves, bracts, sepals and petals. These experiments revealed an expression pattern supporting the organ classification based on morphological characteristics.

Conclusions

Organ identity in both wild-type and 'bud-flowering' C. vulgaris was clarified using a combination of microscopic and molecular methods. Our results for bract, sepal and petal organ identity are supported by the 'ABCDE model'. However, loss of stamens in the 'bud-flowering' phenotype is an exceptional flower organ modification that cannot be explained by modified spatial expression of known organ identity genes.
ATP stimulates chemokine production via a store-operated calcium entry pathway in C6 glioma cells
Authors: Jantaratnotai Nattinee , Choi Hyun B , McLarnon James G
Published: December 2009

Background

Glioma present as one of the most challenging cancers to treat, however, understanding of tumor cell biology is not well understood. Extracellular adenosine triphosphate (ATP) could serve as a critical signaling molecule regulating tumor development. This study has examined pharmacological modulation of calcium (Ca2+) entry through store-operated channels (SOC) on cellular expression and production of immune-cell mobilizing chemokines in ATP-stimulated C6 glioma cells.

Methods

Calcium spectrofluorometry was carried out to measure mobilization of intracellular Ca2+ [Ca2+]i following ATP stimulation of rat C6 glioma cells. Pretreatment with two inhibitors of SOC, SKF96365 or gadolinium, was used to examine for effects on [Ca2+]i. RT-PCR was performed to determine effects of purinergic stimulation on C6 cell expression of metabotropic P2Y receptors (P2YR) and the chemokines, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8). ELISA was carried out to measure production of MCP-1 and IL-8 with ATP stimulation of glioma cells.

Results

Application of ATP (at 100 μM) to C6 glioma induced an increase in [Ca2+]i with the response exhibiting two components of decay. In the presence of the SOC inhibitors, SKF96365 or gadolinium, or with Ca2+-free solution, ATP responses lacked a slow phase suggesting the secondary component was due to SOC-mediated influx of Ca2+. RT-PCR confirmed expression of purinergic P2Y-subtype receptors in C6 cells which would serve as a precursor to activation of SOC. In addition, ATP-stimulated C6 cells showed enhanced expression of the chemokines, MCP-1 and IL-8, with SKF96365 or gadolinium effective in reducing chemokine expression. Gadolinium treatment of ATP-stimulated C6 cells was also found to inhibit the production of MCP-1 and IL-8.

Conclusion

These results suggest ATP-induced Ca2+ entry, mediated by activation of SOC in C6 glioma, as a mechanism leading to increased cellular expression and release of chemokines. Elevated levels of MCP-1 and IL-8 are predicted to enhance the mobility of tumor cells and promote recruitment of microglia into developing tumors thereby supporting tumor growth.
Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: implications for modelling human cancers
Authors: Veliça Pedro , Davies Nicholas J , Rocha Pedro P , Schrewe Heinrich , Ride Jonathan P , Bunce Chris M
Published: December 2009

Background

Over recent years, enzymes of the aldo-keto reductase (AKR) 1C subfamily have been implicated in the progression of prostate, breast, endometrial and leukemic cancers. This is due to the ability of AKR1C enzymes to modify androgens, estrogens, progesterone and prostaglandins (PGs) in a tissue-specific manner, regulating the activity of nuclear receptors and other downstream effects. Evidence supporting a role for AKR1C enzymes in cancer derives mostly from studies with isolated primary cells from patients or immortalized cell lines. Mice are ideal organisms for in vivo studies, using knock-out or over-expression strains. However, the functional conservation of AKR1C enzymes between human and mice has yet to be described.

Results

In this study, we have characterized and compared the four human (AKR1C1,-1C2, -1C3 and -1C4) and the eight murine (AKR1C6, -1C12, -1C13, -1C14, -1C18, -1C19, -1C20 and -1C21) isoforms in their phylogeny, substrate preference and tissue distribution. We have found divergent evolution between human and murine AKR1C enzymes that was reflected by differing substrate preference. Murine enzymes did not perform the 11β-ketoreduction of prostaglandin (PG) D2, an activity specific to human AKR1C3 and important in promoting leukemic cell survival. Instead, murine AKR1C6 was able to perform the 9-ketoreduction of PGE2, an activity absent amongst human isoforms. Nevertheless, reduction of the key steroids androstenedione, 5α-dihydrotestosterone, progesterone and estrone was found in murine isoforms. However, unlike humans, no AKR1C isoforms were detected in murine prostate, testes, uterus and haemopoietic progenitors.

Conclusions

This study exposes significant lack of phylogenetic and functional homology between human and murine AKR1C enzymes. Therefore, we conclude that mice are not suitable to model the role of AKR1C in human cancers and leukemia.
SWiss Atorvastatin and Interferon Beta-1b Trial In Multiple Sclerosis (SWABIMS) - rationale, design and methodology
Authors: Kamm Christian P , Mattle Heinrich P ,   SWABIMS Study Group
Published: December 2009

Background

Statins have anti-inflammatory and immunomodulatory properties in addition to their lipid-lowering effects. Currently, the effects of statins on multiple sclerosis are still controversial. Therefore, randomized clinical trials are needed to provide better evidence on the therapeutic potential of statins in multiple sclerosis. The SWiss Atorvastatin and Interferon Beta-1b trial in Multiple Sclerosis (SWABIMS) evaluates the efficacy, safety and tolerability of atorvastatin 40 mg per os daily and subcutaneous interferon beta-1b every other day compared to monotherapy with subcutaneous interferon beta-1b every other day in patients with relapsing-remitting multiple sclerosis.

Methods/Design

SWABIMS is a multi-centre, randomized, parallel-group, rater-blinded, Phase IIb-study conducted in eight hospitals in Switzerland. 80 treatment naïve patients with relapsing-remitting forms of multiple sclerosis will receive subcutaneous interferon beta-1b for three months. Afterwards, they are randomized into two equal-sized parallel arms, receiving atorvastatin 40 mg/d or not in addition to interferon beta-1b for another 12 months. Disease activity measured by the proportion of patients with new T2 lesions is the primary endpoint.

Discussion

SWABIMS is designed to give further information about the therapeutic effect of atorvastatin 40 mg per os daily as add-on therapy to interferon beta-1b in patients with relapsing-remitting multiple sclerosis. Furthermore important safety and tolerability data will be generated.

Trial Registration

http://www.clinicaltrials.gov. Identifier: NCT00942591; Swissmedic reference number: 2005DR2119
A method to correct for population structure using a segregation model
Authors: Feng Qingfu , Abraham Joseph , Feng Tao , Song Yeunjoo , Elston Robert C , Zhu Xiaofeng
Published: December 2009

To overcome the "spurious" association caused by population stratification in population-based association studies, we propose a principal-component based method that can use both family and unrelated samples at the same time. More specifically, we adapt the multivariate logistic model, which is often used in segregation analysis and can allow for the family correlation structure, for association analysis. To correct the effect of hidden population structure, the first ten principal-components calculated from the matrix of marker genotype data are incorporated as covariates in the model. To test for the association, the marker of interest is also incorporated as a covariate in the model. We applied the proposed method to the second generation (i.e., the Offspring Cohort), in the Genetic Analysis Workshop 16 Framingham Heart Study 50 k data set to evaluate the performance of the method. Although there may have been difficulty in the convergence while maximizing the likelihood function as indicated by a flat likelihood, the distribution of the empirical p-values for the test statistic does show that the method has a correct type I error rate whenever the variance-covariance matrix of the estimates can be computed.
A genome-wide association analysis of Framingham Heart Study longitudinal data using multivariate adaptive splines
Authors: Zhu Wensheng , Cho Kelly , Chen Xiang , Zhang Meizhuo , Wang Minghui , Zhang Heping
Published: December 2009

The Framingham Heart Study is a well known longitudinal cohort study. In recent years, the community-based Framingham Heart Study has embarked on genome-wide association studies. In this paper, we present a Framingham Heart Study genome-wide analysis for fasting triglycerides trait in the Genetic Analysis Workshop16 Problem 2 using multivariate adaptive splines for the analysis of longitudinal data (MASAL). With MASAL, we are able to perform analysis of genome-wide data with longitudinal phenotypes and covariates, making it possible to identify genes, gene-gene, and gene-environment (including time) interactions associated with the trait of interest. We conducted a permutation test to assess the associations between MASAL selected markers and triglycerides trait and report significant gene-gene and gene-environment interaction effects on the trait of interest.
Gene hunting of the Genetic Analysis Workshop 16 rheumatoid arthritis data using rough set theory
Authors: Aporntewan Chatchawit , Ballard David H , Lee Ji Young , Lee Joon Sang , Wu Zheyang , Zhao Hongyu
Published: December 2009

We propose to use the rough set theory to identify genes affecting rheumatoid arthritis risk from the data collected by the North American Rheumatoid Arthritis Consortium. For each gene, we employ generalized dynamic reducts in the rough set theory to select a subset of single-nucleotide polymorphisms (SNPs) to represent the genetic information from this gene. We then group the study subjects into different clusters based on their genotype similarity at the selected markers. Statistical association between disease status and cluster membership is then studied to identify genes associated with rheumatoid arthritis. Based on our proposed approach, we are able to identify a number of statistically significant genes associated with rheumatoid arthritis. Aside from genes on chromosome 6, our identified genes include known disease-associated genes such as PTPN22 and TRAF1. In addition, our list contains other biologically plausible genes, such as ADAM15 and AGPAT2. Our findings suggest that ADAM15 and AGPAT2 may contribute to a genetic predisposition through abnormal angiogenesis and adipose tissue.
Effect of population stratification on the identification of significant single-nucleotide polymorphisms in genome-wide association studies
Authors: Sarasua Sara M , Collins Julianne S , Williamson Dhelia M , Satten Glen A , Allen Andrew S
Published: December 2009

The North American Rheumatoid Arthritis Consortium case-control study collected case participants across the United States and control participants from New York. More than 500,000 single-nucleotide polymorphisms (SNPs) were genotyped in the sample of 2000 cases and controls. Careful adjustment for the confounding effect of population stratification must be conducted when analyzing these data; the variance inflation factor (VIF) without adjustment is 1.44. In the primary analyses of these data, a clustering algorithm in the program PLINK was used to reduce the VIF to 1.14, after which genomic control was used to control residual confounding. Here we use stratification scores to achieve a unified and coherent control for confounding. We used the first 10 principal components, calculated genome-wide using a set of 81,500 loci that had been selected to have low pair-wise linkage disequilibrium, as risk factors in a logistic model to calculate the stratification score. We then divided the data into five strata based on quantiles of the stratification score. The VIF of these stratified data is 1.04, indicating substantial control of stratification. However, after control for stratification, we find that there are no significant loci associated with rheumatoid arthritis outside of the HLA region. In particular, we find no evidence for association of TRAF1-C5 with rheumatoid arthritis.
Simultaneous genome-wide association studies of anti-cyclic citrullinated peptide in rheumatoid arthritis using penalized orthogonal-components regression
Authors: Lin Yanzhu , Zhang Min , Wang Libo , Pungpapong Vitara , Fleet James C , Zhang Dabao
Published: December 2009

Genome-wide associations between single-nucleotide polymorphisms and clinical traits were simultaneously conducted using penalized orthogonal-components regression. This method was developed to identify the genetic variants controlling phenotypes from a massive number of candidate variants. By investigating the association between all single-nucleotide polymorphisms to the phenotype of antibodies against cyclic citrullinated peptide using the rheumatoid arthritis data provided by Genetic Analysis Workshop 16, we identified genetic regions which may contribute to the pathogenesis of rheumatoid arthritis. Bioinformatic analysis of these genomic regions showed most of them harbor protein-coding gene(s).
Haplotype association analysis of North American Rheumatoid Arthritis Consortium data using a generalized linear model with regularization
Authors: Guo Wei , Liang Chin-yuan , Lin Shili
Published: December 2009

The Genetic Analysis Workshop 16 rheumatoid arthritis data include a set of 868 cases and 1194 controls genotyped at 545,080 single-nucleotide polymorphisms (SNPs) from the Illumina 550 k chip. We focus on investigating chromosomes 6 and 18, which have 35,574 and 16,450 SNPs, respectively. Association studies, including single SNP and haplotype-based analyses, were applied to the data on those two chromosomes. Specifically, we conducted a generalized linear model with regularization (rGLM) approach for detecting disease-haplotype association using unphased SNP data. A total of 444 and 43 four-SNP tests were found to be significant at the Bonferroni corrected 5% significance level on chromosome 6 and 18, respectively.
Evaluation of genetic risk scores for lipid levels using genome-wide markers in the Framingham Heart Study
Authors: Piccolo Stephen R , Abo Ryan P , Allen-Brady Kristina , Camp Nicola J , Knight Stacey , Anderson Jeffrey L , Horne Benjamin D
Published: December 2009

Background

Multiple single-nucleotide polymorphisms have been associated with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels. In this paper, we evaluate a weighted and an unweighted approach for estimating the combined effect of multiple markers (using genotypes and haplotypes) on lipid levels for a given individual.

Methods

Using data from the Framingham Heart Study SHARe genome-wide association study, we tested genome-wide genotypes and haplotypes for association with lipid levels and constructed genetic risk scores (GRS) based on multiple markers that were weighted according to their estimated effects on LDL-C, HDL-C, and TG. These scores (GRS-LDL, GRS-HDL, and GRS-TG) were then evaluated for associations with LDL-C, HDL-C, and TG, and compared with results of an unweighted method based on risk-allele counts. For comparability of metrics, GRS variables were divided into quartiles.

Results

GRS-LDL quartiles were associated with LDL-C levels (p = 2.1 × 10-24), GRS-HDL quartiles with HDL-C (p = 5.9 × 10-22), and GRS-TG quartiles with TG (p = 5.4 × 10-25). In comparison, these p-values were considerably lower than those for the associations of the unweighted GRS quartiles for LDL-C (p = 3.6 × 10-7), HDL-C (p = 6.4 × 10-16), and TG (p = 4.1 × 10-10).

Conclusion

GRS variables were highly predictive of LDL-C, HDL-C, and TG measurements, especially when weighted based on each marker's individual association with those intermediate risk phenotypes. The allele-count GRS approach that does not weight the GRS by individual marker associations was considerably less predictive of lipid and lipoprotein measures when the same genetic markers were utilized, suggesting that substantially more risk-associated genetic marker information is encapsulated by the weighted GRS variables.
Assessment of genotype imputation methods
Authors: Biernacka Joanna M , Tang Rui , Li Jia , McDonnell Shannon K , Rabe Kari G , Sinnwell Jason P , Rider David N , de Andrade Mariza , Goode Ellen L , Fridley Brooke L
Published: December 2009

Several methods have been proposed to impute genotypes at untyped markers using observed genotypes and genetic data from a reference panel. We used the Genetic Analysis Workshop 16 rheumatoid arthritis case-control dataset to compare the performance of four of these imputation methods: IMPUTE, MACH, PLINK, and fastPHASE. We compared the methods' imputation error rates and performance of association tests using the imputed data, in the context of imputing completely untyped markers as well as imputing missing genotypes to combine two datasets genotyped at different sets of markers. As expected, all methods performed better for single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium with genotyped SNPs. However, MACH and IMPUTE generated lower imputation error rates than fastPHASE and PLINK. Association tests based on allele "dosage" from MACH and tests based on the posterior probabilities from IMPUTE provided results closest to those based on complete data. However, in both situations, none of the imputation-based tests provide the same level of evidence of association as the complete data at SNPs strongly associated with disease.
ACPA: automated cluster plot analysis of genotype data
Authors: Schillert Arne , Schwarz Daniel F , Vens Maren , Szymczak Silke , König Inke R , Ziegler Andreas
Published: December 2009

Genome-wide association studies have become standard in genetic epidemiology. Analyzing hundreds of thousands of markers simultaneously imposes some challenges for statisticians. One issue is the problem of multiplicity, which has been compared with the search for the needle in a haystack. To reduce the number of false-positive findings, a number of quality filters such as exclusion of single-nucleotide polymorphisms (SNPs) with a high missing fraction are employed. Another filter is exclusion of SNPs for which the calling algorithm had difficulties in assigning the genotypes. The only way to do this is the visual inspection of the cluster plots, also termed signal intensity plots, but this approach is often neglected. We developed an algorithm ACPA (automated cluster plot analysis), which performs this task automatically for autosomal SNPs. It is based on counting samples that lie too close to the cluster of a different genotype; SNPs are excluded when a certain threshold is exceeded. We evaluated ACPA using 1,000 randomly selected quality controlled SNPs from the Framingham Heart Study data that were provided for the Genetic Analysis Workshop 16. We compared the decision of ACPA with the decision made by two independent readers. We achieved a sensitivity of 88% (95% CI: 81%-93%) and a specificity of 86% (95% CI: 83%-89%). In a screening setting in which one aims at not losing any good SNP, we achieved 99% (95% CI: 98%-100%) specificity and still detected every second low-quality SNP.
Rheumatoid arthritis-associated gene-gene interaction network for rheumatoid arthritis candidate genes
Authors: Huang Chien-Hsun , Cong Lei , Xie Jun , Qiao Bo , Lo Shaw-Hwa , Zheng Tian
Published: December 2009

Rheumatoid arthritis (RA, MIM 180300) is a chronic and complex autoimmune disease. Using the North American Rheumatoid Arthritis Consortium (NARAC) data set provided in Genetic Analysis Workshop 16 (GAW16), we used the genotype-trait distortion (GTD) scores and proposed analysis procedures to capture the gene-gene interaction effects of multiple susceptibility gene regions on RA. In this paper, we focused on 27 RA candidate gene regions (531 SNPs) based on a literature search. Statistical significance was evaluated using 1000 permutations. HLADRB1 was found to have strong marginal association with RA. We identified 14 significant interactions (p < 0.01), which were aggregated into an association network among 12 selected candidate genes PADI4, FCGR3, TNFRSF1B, ITGAV, BTLA, SLC22A4, IL3, VEGF, TNF, NFKBIL1, TRAF1-C5, and MIF. Based on our and other contributors' findings during the GAW16 conference, we further studied 24 candidate regions with 336 SNPs. We found 23 significant interactions (p-value < 0.01), nine interactions in addition to our initial findings, and the association network was extended to include candidate genes HLA-A, HLA-B, HLA-C, CTLA4, and IL6. As we will discuss in this paper, the reported possible interactions between genes may suggest potential biological activities of RA.
Genome-wide association study of rheumatoid arthritis by a score test based on wavelet transformation
Authors: Jiang Renfang , Dong Jianping , Dai Yilin
Published: December 2009

Background

We have conducted a genome-wide association study on the Genetic Analysis Workshop (GAW) 16 rheumatoid arthritis data using a multilocus score test based on wavelet transform proposed recently by the authors. The wavelet-based test automatically adjusts for the amount of noise suppressed from the data. The power of the test is also increased by using the genetic information contained in the spatial ordering of single-nucleotide polymorphisms on a chromosome.

Results

After adjusting for the effect of population stratification, the test identified some previously discovered rheumatoid arthritis susceptibility loci (HLA-DRB1 and rs3761847) as well as some loci (rs2076530 and rs3130340) known to have association with sarcoidosis and bone mineral density. It was previously reported that patients with rheumatoid arthritis have elevated prevalence of sarcoidosis and have reduced bone mass.

Conclusion

This new test provides a useful tool in genome-wide association studies.
A transcriptomic computational analysis of mastic oil-treated Lewis lung carcinomas reveals molecular mechanisms targeting tumor cell growth and survival
Authors: Moulos Panagiotis , Papadodima Olga , Chatziioannou Aristotelis , Loutrari Heleni , Roussos Charis , Kolisis Fragiskos N
Published: December 2009

Background

Mastic oil from Pistacia lentiscus variation chia, a blend of bioactive terpenes with recognized medicinal properties, has been recently shown to exert anti-tumor growth activity through inhibition of cancer cell proliferation, survival, angiogenesis and inflammatory response. However, no studies have addressed its mechanisms of action at genome-wide gene expression level.

Methods

To investigate molecular mechanisms triggered by mastic oil, Lewis Lung Carcinoma cells were treated with mastic oil or DMSO and RNA was collected at five distinct time points (3-48 h). Microarray expression profiling was performed using Illumina mouse-6 v1 beadchips, followed by computational analysis. For a number of selected genes, RT-PCR validation was performed in LLC cells as well as in three human cancer cell lines of different origin (A549, HCT116, K562). PTEN specific inhibition by a bisperovanadium compound was applied to validate its contribution to mastic oil-mediated anti-tumor growth effects.

Results

In this work we demonstrated that exposure of Lewis lung carcinomas to mastic oil caused a time-dependent alteration in the expression of 925 genes. GO analysis associated expression profiles with several biological processes and functions. Among them, modifications on cell cycle/proliferation, survival and NF-κB cascade in conjunction with concomitant regulation of genes encoding for PTEN, E2F7, HMOX1 (up-regulation) and NOD1 (down-regulation) indicated some important mechanistic links underlying the anti-proliferative, pro-apoptotic and anti-inflammatory effects of mastic oil. The expression profiles of Hmox1, Pten and E2f7 genes were similarly altered by mastic oil in the majority of test cancer cell lines. Inhibition of PTEN partially reversed mastic oil effects on tumor cell growth, indicating a multi-target mechanism of action. Finally, k-means clustering, organized the significant gene list in eight clusters demonstrating a similar expression profile. Promoter analysis in a representative cluster revealed shared putative cis-elements suggesting a common regulatory transcription mechanism.

Conclusions

Present results provide novel evidence on the molecular basis of tumor growth inhibition mediated by mastic oil and set a rational basis for application of genomics and bioinformatic methodologies in the screening of natural compounds with potential cancer chemopreventive activities.
Mucosa associated lymphoid tissue lymphoma of the colon: a case report
Authors: Gezen Cem , Kement Metin , Oncel Mustafa , Tuncay Erhan , Sahlepci Taflan , Alkan Serdar
Published: December 2009

A 65-year-old man had suffered from rectal bleeding during defecation for a few weeks, admitted to our department. Laboratory findings were normal except a slight elevation in the level of alkaline phosphatase. Multiple polypoid lesions were observed in colonoscopic examination. The histological and immunochemical evaluation showed atypical lymphoid cell proliferation and lymphoepithelial lesions on the colonic mucosa, staining with CD20 (CD20 × 100). After the diagnosis had been confirmed as low grade mucosa associated lymphoid tissue lymphoma. Abdominal computed tomography revealed polypoid lesions throughout the colon and multiple milimetrics lymphadenopathies in the mesentery. The patient was treated with a chemotherapy regimen. During the follow-up, colonoscopic examination and blind biopsies were repeated in every 6 months, revealed endoscopically and pathologically normal mucosa each time. The patient is still alive without any recurrence of the disease 36 months after the diagnosis.
Accelerating 3D Fourier migration with graphics processing units
Authors: Zhang Jin-Hai , Wang Shu-Qin , Yao Zhen-Xing
Published: December 2009

Computational cost is a major factor that inhibits the practical application of 3D depth migration. We have developed a fast parallel scheme to speed up 3D wave-equation depth migration on a parallel computing device, i.e., on graphics processing units (GPUs). The third-order optimized generalized-screen propagator is used to take advantage of the built-in software implementation of the fast Fourier transform. The propagator is coded as a sequence of kernels that can be called from the computer host for each frequency component. Moving the wavefield extrapolation for each depth level to the GPUs allows handling a large 3D velocity model, but this scheme can be speeded up to a limited degree over the CPU implementation because of the low-bandwidth data transfer between host and device. We have created further speedup in this extrapolation scheme by minimizing the low-bandwidth data transfer, which is done by storing the 3D velocity model and imaged data in the device memory, and reducing half the memory demand by compressing the 3D velocity model and imaged data using integer arrays instead of float arrays. By incorporating a 2D tapered function, time-shift propagator, and scaling of the inverse Fourier transform into a compact kernel, the computation time is reduced greatly. Three-dimensional impulse responses and synthetic data examples have demonstrated that the GPU-based Fourier migration typically is 25 to 40 times faster than the CPU-based implementation. It enables us to image complex media using 3D depth migration with little concern for computational cost. The macrovelocity model can be built in a much shorter turnaround time.
Nonlinear multitrace genetic inversion applied on seismic data across the Shtokman field, offshore northern Russia
Authors: Veeken Paul C. , Priezzhev Ivan I. , Shmaryan Leo E. , Shteyn Yan I. , Barkov Alexander Y. , Ampilov Yuri P.
Published: December 2009

Seismic inversion is an important processing step for characterizing reservoirs with properties predicted away from well controls. A new approach to inversion and reservoir modeling is based on a nonlinear multitrace seismic inversion algorithm. Neural-network solutions for the inversion problem exist, whereby a multiattribute analysis increases output reliability. A more robust 3D working method is proposed that uses a simple nonlinear operator. The method is fast, user friendly, and cost effective. Initial input is formed by poststack seismic data and relevant well logs (e.g., acoustic impedance). The latter serve as a training and control point set to calculate optimized weights in the neural-network scheme. The nonlinear output operator trans-forms the seismic data into the desired log-response equivalent. Crucial is finding a real regional minimum for the difference between the computed synthetic and the recorded seismic traces at the target location. Intelligent data decimation eliminates the number of unknown coefficients in the operator computation. Moreover, it speeds up the true 3D minicube processing. Genetic inversion can be applied to properties other than acoustic impedance. However, these attributes should have a meaningful physical relationship to the seismic data, e.g., porosity, density, and saturation. Geologic modeling constitutes the last step of the inversion workflow. The geologic model is populated stochastically with relevant reservoir properties. The capabilities of the genetic inversion were tested on a semicontrolled seismic example and a real case study across the Shtokman gas field, Russia.