bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of type I error for multiple test corrections in large single-nucleotide polymorphism studies using principal components versus haplotype blocking algorithms
Authors: Nicodemus Kristin K , Liu Wenlei , Chase Gary A , Tsai Ya-Yu , Fallin M Daniele 
Published: December 2005

Abstract
Although permutation testing has been the gold standard for assessing significance levels in studies using multiple markers, it is time-consuming. A Bonferroni correction to the nominal p-value that uses the underlying pair-wise linkage disequilibrium (LD) structure among the markers to determine the number of effectively independent tests has recently been proposed. We propose using the number of independent LD blocks plus the number of independent single-nucleotide polymorphisms for correction. Using the Collaborative Study on the Genetics of Alcoholism LD data for chromosome 21, we simulated 1,000 replicates of parent-child trio data under the null hypothesis with two levels of LD: moderate and high. Assuming haplotype blocks were independent, we calculated the number of independent statistical tests using 3 haplotype blocking algorithms. We then compared the type I error rates using a principal components-based method, the three blocking methods, a traditional Bonferroni correction, and the unadjusted p-values obtained from FBAT. Under high LD conditions, the PC method and one of the blocking methods were slightly conservative, whereas the 2 other blocking methods exceeded the target type I error rate. Under conditions of moderate LD, we show that the blocking algorithm corrections are closest to the desired type I error, although still slightly conservative, with the principal components-based method being almost as conservative as the traditional Bonferroni correction.
Haplotype sharing correlation of alcohol dependence on chromosomes 1–6 in 93 nuclear families
Authors: Qian Dajun 
Published: December 2005

Abstract
Haplotype data contain signatures of ancestral alleles and increased information for mapping genes associated with complex traits. The motivation of this paper is to test the feasibility of a recently developed haplotype reconstruction algorithm and to perform haplotype-sharing correlation (HSC) analysis in nuclear families using data provided by the Genetic Analysis Workshop 14 and the Collaborative Study of the Genetics of Alcoholism. As an exemplary analysis, haplotype data on chromosomes 1–6 were reconstructed from genotype data in 93 nuclear families by minimizing both the recombinants in within-family haplotypes and the tree distance in between-family haplotypes. HSC analysis was performed using the best set of reconstructed haplotypes, and chromosome-wide significance was evaluated using a permutation procedure. Three markers were found to have significant haplotype associations with DSM-IV alcohol dependence that exceeded the 0.05 level of chromosome-wide significance: marker rs895941 at 36.7 cM on chromosome 3 (p = 0.03), marker rs1631833 at 109.1 cM on chromosome 4 (p = 0.008), and marker rs953887 at 74.2 cM on chromosome 6 (p = 0.02). These results indicated the usefulness of HSC analysis and provided further evidence on chromosome regions associated with alcohol dependence.
Genome-wide linkage analysis for alcohol dependence: a comparison between single-nucleotide polymorphism and microsatellite marker assays
Authors: Ma Qianli , Yu Yi , Meng Yan , Farrell John , Farrer Lindsay A , Wilcox Marsha A 
Published: December 2005

Abstract
Both theoretical and applied studies have proven that the utility of single nucleotide polymorphism (SNP) markers in linkage analysis is more powerful and cost-effective than current microsatellite marker assays. Here we performed a whole-genome scan on 115 White, non-Hispanic families segregating for alcohol dependence, using one 10.3-cM microsatellite marker set and two SNP data sets (0.33-cM, 0.78-cM spacing). Two definitions of alcohol dependence (ALDX1 and ALDX2) were used. Our multipoint nonparametric linkage analysis found alcoholism was nominal linked to 12 genomic regions. The linkage peaks obtained by using the microsatellite marker set and the two SNP sets had a high degree of correspondence in general, but the microsatellite marker set was insufficient to detect some nominal linkage peaks. The presence of linkage disequilibrium between markers did not significantly affect the results. Across the entire genome, SNP datasets had a much higher average linkage information content (0.33 cM: 0.93, 0.78 cM: 0.91) than did microsatellite marker set (0.57). The linkage peaks obtained through two SNP datasets were very similar with some minor differences. We conclude that genome-wide linkage analysis by using approximately 5,000 SNP markers evenly distributed across the human genome is sufficient and might be more powerful than current 10-cM microsatellite marker assays.
Accuracy of haplotype estimation in a region of low linkage disequilibrium
Authors: Avery Christy L , Martin Lisa J , Williams Jeff T , North Kari E 
Published: December 2005

Abstract
We compared the accuracy of haplotype inferences at a 6 Mb region on chromosome 7 where significant linkage between a brain oscillation phenotype and a cholinergic muscarinic receptor gene was previously reported. Individual haplotype assignments and haplotype frequencies were estimated using 5, 10, and 14 consecutive Illumina single-nucleotide polymorphisms (SNPs) within the 1-LOD unit support interval of the chromosome 7 linkage peak. Initially, haplotypes were constructed incorporating phase information provided by relatives using the pedigree analysis package MERLIN. Population-based haplotypes were inferred using the haplotype estimation software HAPLO.STATS and PHASE, using unrelated individuals.
The 14 SNPs within this region exhibited markedly low linkage disequilibrium, and the average D' estimate between SNPs was 0.18 (range: 0.01–0.97). In comparison to the family-based haplotypes calculated in MERLIN, the computational inferences of individual haplotype assignments were most accurate when considering 5 consecutive SNPs, but decayed dramatically when considering 10 or 14 SNPs in both PHASE and HAPLO.STATS. When comparing the two haplotype inference methods, both PHASE and HAPLO.STATS performed poorly. These analyses underscore the difficulties of haplotype estimation in the presence of low linkage disequilibrium and stress the importance of careful consideration of confidence measures when using estimated haplotype frequencies and individual assignments in biomedical research.
An exploration of sex-specific linkage disequilibrium on chromosome X in Caucasians from the COGA study
Authors: Cox Miranda E , Campbell Joel K , Langefeld Carl D 
Published: December 2005

Abstract
This paper explores the decay of linkage disequilibrium (LD) on the autosomes and chromosome X. The extent of marker-marker LD is important for both linkage and association studies. The analysis of the Caucasian sample from the Collaborative Study on the Genetics of Alcoholism study revealed the expected negative relationship between the magnitude of the marker-marker LD and distance (cM), with the male and female subgroups exhibiting similar patterns of LD. The observed extent of LD in females was less across the pseudoautosomal markers relative to the heterosomal region of chromosome X. Marked differences in LD patterns were also observed between chromosomes X and the 22 autosomes in both males and females.
Bias of allele-sharing linkage statistics in the presence of intermarker linkage disequilibrium
Authors: Goode Ellen L , Badzioch Michael D , Jarvik Gail P 
Published: December 2005

Abstract
Current genome-wide linkage-mapping single-nucleotide polymorphism (SNP) panels with densities of 0.3 cM are likely to have increased intermarker linkage disequilibrium (LD) compared to 5-cM microsatellite panels. The resulting difference in haplotype frequencies versus that predicted may affect multipoint linkage analysis with ungenotyped founders; a common haplotype may be assumed to be rare, leading to inflation of identical-by-descent (IBD) allele-sharing estimates and evidence for linkage. Using data simulated for the Genetic Analysis Workshop 14, we assessed bias in allele-sharing measures and nonparametric linkage (NPLall) and Kong and Cox LOD (KC-LOD) scores in a targeted analysis of regions with and without LD and with and without genes. Using over 100 replicates, we found that if founders were not genotyped, multipoint IBD estimates and δ parameters were modestly inflated and NPLall and KC-LOD scores were biased upwards in the region with LD and no gene; rather than centering on the null, the mean NPLall and KC-LOD scores were 0.51 ± 0.91 and 0.19 ± 0.38, respectively. Reduction of LD by dropping markers reduced this upward bias. These trends were not seen in the non-LD region with no gene. In regions with genes (with and without LD), a slight loss in power with dropping markers was suggested. These results indicate that LD should be considered in dense scans; removal of markers in LD may reduce false-positive results although information may also be lost. Methods to address LD in a high-throughput manner are needed for efficient, robust genomic scans with dense SNPs.
The efficacy of short tandem repeat polymorphisms versus single-nucleotide polymorphisms for resolving population structure
Authors: Kauwe John SK , Bertelsen Sarah , Bierut Laura Jean , Dunn Gerald , Hinrichs Anthony L , Jin Carol H , Suarez Brian K 
Published: December 2005

Abstract
Accurately resolving population structure in a sample is important for both linkage and association studies. In this study we investigated the power of single-nucleotide polymorphisms (SNPs) in detecting population structure in a sample of 286 unrelated individuals. We varied the number of SNPs to determine how many are required to approach the degree of resolution obtained with the Collaborative Study on the Genetics of Alcoholism (COGA) short tandem repeat polymorphisms (STRPs). In addition, we selected SNPs with varying minor allele frequencies (MAFs) to determine whether low or high frequency SNPs are more efficient in resolving population structure. We conclude that a set of at least 100 evenly spaced SNPs with MAFs of 40–50% is required to resolve population structure in this dataset. If SNPs with lower MAFs are used, then more than 250 SNPs may be required to obtain reliable results.
Action potential repolarization enabled by Ca++ channel deactivation in PSpice simulation of smooth muscle propagation
Authors: Ramasamy Lakshminarayanan , Sperelakis Nicholas 
Published: December 2005

Abstract

Background
Previously, only the rising phase of the action potential (AP) in cardiac muscle and smooth muscle could be simulated due to the instability of PSpice upon insertion of a second black box (BB) into the K+ leg of the basic membrane unit. This restriction was acceptable because only the transmission of excitation from one cell to the next was investigated.

Methods
In the current work, the repolarization of the AP was accomplished by inserting a second BB into the Ca++ leg of the basic membrane unit. Repolarization of the AP was produced, not through an activation of the K+ channel conductance, but rather through a mimicking of the deactivation of the Ca++ channel conductance. Propagation of complete APs was studied in a chain (strand) of 10 smooth muscle cells, in which various numbers of gap-junction (gj) channels (assumed to be 100 pS each) were inserted across the cell junctions.

Results
The shunt resistance across the junctions produced by the gj-channels (Rgj) was varied from 100,000 MΩ (0 gj-channels) to 10,000 MΩ (1 gj-channel), to 1,000 MΩ (10 channels), to 100 MΩ (100 channels), to 10 MΩ (1000 channels), and to 1.0 MΩ (10,000 channels). Velocity of propagation (θ, in cm/sec) was calculated from the measured total propagation time (TPT, the time difference between when the AP rising phase of the first cell and the last cell crossed -20 mV), assuming a constant cell length of 200 μm. When there were no gj-channels, or only one, the transmission of excitation between cells was produced by the electric field (EF), i.e., the negative junctional cleft potential, that is generated in the narrow junctional clefts (e.g., 100 A) when the prejunctional membrane fires an AP (a fraction of a millisecond before the adjacent surface membrane). There were significant end-effects at the termination of the strand, such that the last cell (cell #10) failed to fire, or fired after a prolonged delay. This end-effect was abolished when the strand termination resistance (Rbt) was increased from 1.0 KΩ to 600 MΩ. When there were 1000 or 10,000 gj-channels, the transmission of excitation was produced by local-circuit current flow from one cell to the next through the gj-channels.

Discussion
In summary, it is now possible to simulate complete APs in smooth muscle cells that could propagate along a single chain of 10 cells, even when there were no gj-channels between the cells.
Surgical resection for gastrointestinal stromal tumors (GIST): experience on 25 patients
Authors: Boni Luigi , Benevento Angelo , Dionigi Gianlorenzo , Rovera Francesca , Dionigi Renzo 
Published: December 2005

Abstract

Background
Gastrointestinal stromal tumors (GIST) are infrequent and diagnosis and prognosis could be troublesome. We present short and long term results of surgical resection for GIST at the Department of Surgery, University of Insubria, during a period of 17 years.

Materials and methods
All patients' data, tumor characteristics, surgical procedure and survival data were analyzed retrospectively. Tumors were divided in risk classes using the classification proposed by Fletcher, based on tumor size and number of mitosis.

Results
Between 1987 and 2004, 25 patients underwent surgical resection for GIST. Stomach was the most common site of localization. Complete resection was achieved in 88% cases, while in 12% radical resection was not possible. The mean tumor size was 9.2 cm (1.2 – 30 cm): <5 cm diameter in 14/25 cases (56%), 5–10 cm in 5/25 (20%) and >10 cm in 6/25 (24%). Mitotic count was <10/50 HPF in 68% (17/25) and >10/50 in 32% (8/25). Using Fletcher's classification, tumors were divided in very low (11/25, 44%), low (4/25, 16%), intermediate (6/25, 24%) and high-risk (4/25, 16%) groups. The 5-year overall survival was 65% and 34% respectively with a statistically significant difference between tumors <5 cm and >10 cm in diameter and between complete and incomplete resection. High-risk tumors had a significantly shorter survival than low or very low risk.

Conclusion
Our experience confirms that GIST's are uncommon and aggressive cancers. The prognosis is strictly related to tumor size and number of mitosis. Although significant advances on new chemotherapeutic regimes have been made, to date, only radical surgery offers the chance of long-term survival.
17beta-estradiol suppresses TLR3-induced cytokine and chemokine production in endometrial epithelial cells
Authors: Lesmeister Margaret J , Jorgenson Rebecca L , Young Steven L , Misfeldt Michael L 
Published: December 2005

AbstractBackgroundThe human endometrium is an important site for contact between the host and pathogens ascending the reproductive tract, and thus plays an important role in female reproductive tract immunity. Previous work in our laboratory has suggested that Toll-like receptors (TLRs) are involved in endometrial epithelial recognition of pathogens and that ligation of endometrial TLRs results in the production of cytokines and chemokines important for both immune and reproductive functions of the endometrium. We have also demonstrated cyclic regulation of TLR3 mRNA and protein expression in human endometrium, suggesting that steroid hormones might play a role in the expression and function of TLR3. In this study, the effects of 17beta-estradiol (E2) and progesterone (P) on TLR3 expression and function in endometrial cell lines were investigated.MethodsEndometrial epithelial cell lines were cultured and examined for the presence of TLR3 and hormone receptors by endpoint RT-PCR. For hormonal studies, cells were pre-treated with ethanol vehicle, 10^(-8) M E2, and/or 10^(-7) M P. For antagonist assays, cells were treated with the ER antagonist, ICI 182, 780, or the PR antagonist, RU486, for two hours prior to treatment with hormones. Following hormone or hormone/antagonist pre-treatment, cells were stimulated with vehicle, the synthetic TLR3 ligand, polyinosinic-polycytidylic acid (Poly I:C), a negative dsDNA control, or a positive control. Cytokine and chemokine production post-stimulation was measured by ELISA. The effects of E2 and P on TLR3 mRNA and protein expression were measured using Real Time RT-PCR and FACS analysis, respectively.ResultsStimulation of TLR3-expressing cells with the synthetic TLR3 ligand, Poly I:C, resulted in the production of cytokines and chemokines important for endometrial function and regulation. Suppression of Poly I:C-induced cytokine and chemokine production by cells treated with 10^(-8) M E2, but not cells treated with 10^(-7) M P, was observed in endometrial epithelial cell lines expressing TLR3 and estrogen receptor alpha (ERalpha). The effects of E2 were not observed on cells which did not express ERalpha or in cells pre-treated with the ER antagonist, ICI 182, 780. Treatment with E2 did not affect TLR3 mRNA or protein expression. However, treatment with E2 did suppress cytokine and chemokine production resulting from TLR3 stimulation with Poly I:C, suggesting that E2 modulates TLR3 function.ConclusionThe data presented in this study are the first indication that E2 can markedly alter the innate immune response to dsRNA, providing a previously unreported process by which E2 can alter immune responses.
Harnessing information and communication technologies to leverage scarce resources for cancer education, research and practice in developing countries
Authors: Andela Valentine B 
Published: January 2006

Abstract
In developing countries, low levels of awareness, cost and organizational constraints on access to specialized care contribute to inadequate patient help-seeking behavior. As much as 95% of cancer patients in developing countries are diagnosed at late to end stage disease. Consequently, treatment outcome is dismally poor and a vicious cycle sets in, with public mystification of cancer and the admonishment of cancer medicine as a futile effort, all, to the further detriment of patient help-seeking behavior and treatment engagement. The situation spirals down, when the practice of cancer medicine is not gratifying to the medical practitioner and does not appeal as a medical specialty to those in training. The future of cancer medicine in developing countries thus hinges on the demystification of cancer through positive information, coupled to an effective organization that allows for the optimal use of available resources, facilitates access to specialized care and promotes the flow of knowledge and technology amongst various stakeholders. This paper strives to make a cogent argument and highlight the capital importance of information and communication technologies in organizing and leveraging scarce resources for cancer education, research and practice in developing countries.
Immature monocyte derived dendritic cells gene expression profile in response to Virus-Like Particles stimulation
Authors: Aricò Eleonora , Wang Ena , Tornesello Maria Lina , Tagliamonte Maria , Lewis George K , Marincola Francesco M , Buonaguro Franco M , Buonaguro Luigi 
Published: December 2005

AbstractWe have recently developed a candidate HIV-1 vaccine model based on HIV-1 Pr55gag Virus-Like Particles (HIV-VLPs), produced in a baculovirus expression system and presenting a gp120 molecule from an Ugandan HIV-1 isolate of the clade A (HIV-VLPAs).The HIV-VLPAs induce in Balb/c mice systemic and mucosal neutralizing Antibodies as well as cytotoxic T lymphocytes, by intra-peritoneal as well as intra-nasal administration. Moreover, we have recently shown that the baculovirus-expressed HIV-VLPs induce maturation and activation of monocyte-derived dendritic cells (MDDCs) which, in turn, produce Th1- and Th2-specific cytokines and stimulatein vitroa primary and secondary response in autologous CD4+ T cells.In the present manuscript, the effects of the baculovirus-expressed HIV-VLPAs on the genomic transcriptional profile of MDDCs obtained from normal healthy donors have been evaluated. The HIV-VLPAstimulation, compared to both PBS and LPS treatment, modulate the expression of genes involved in the morphological and functional changes characterizing the MDDCs activation and maturation.The results of gene profiling analysis here presented are highly informative on the global pattern of gene expression alteration underlying the activation of MDDCs by HIV-VLPAs at the early stages of the immune response and may be extremely helpful for the identification of exclusive activation markers.
Attenuation of murine antigen-induced arthritis by treatment with a decoy oligodeoxynucleotide inhibiting signal transducer and activator of transcription-1 (STAT-1)
Authors: Hückel Marion , Schurigt Uta , Wagner Andreas H , Stöckigt Renate , Petrow Peter K , Thoss Klaus , Gajda Mieczyslaw , Henzgen Steffen , Hecker Markus , Bräuer Rolf 
Published: December 2005

AbstractThe transcription factor STAT-1 (signal transducer and activator of transcription-1) plays a pivotal role in the expression of inflammatory gene products involved in the pathogenesis of arthritis such as various cytokines and the CD40/CD40 ligand (CD40/CD40L) receptor-ligand dyad. The therapeutic efficacy of a synthetic decoy oligodeoxynucleotide (ODN) binding and neutralizing STAT-1 was tested in murine antigen-induced arthritis (AIA) as a model for human rheumatoid arthritis (RA). The STAT-1 decoy ODN was injected intra-articularly in methylated bovine serum albumin (mBSA)-immunized mice 4 h before arthritis induction. Arthritis was evaluated by joint swelling measurement and histological evaluation and compared to treatment with mutant control ODN. Serum levels of pro-inflammatory cytokines, mBSA-specific antibodies and auto-antibodies against matrix constituents were assessed by enzyme-linked immunosorbent assay (ELISA). The transcription factor neutralizing efficacy of the STAT-1 decoy ODN was verified in vitro in cultured synoviocytes and macrophages. Single administration of STAT-1 decoy ODN dose-dependently suppressed joint swelling and histological signs of acute and chronic arthritis. Delayed-type hypersensitivity (DTH) reaction, serum levels of interleukin-6 (IL-6) and anti-proteoglycan IgG titres were significantly reduced in STAT-1 decoy ODN-treated mice, whereas mBSA, collagen type I and type II specific immunoglobulins were not significantly affected. Intra-articular administration of an anti-CD40L (anti-CD154) antibody was similarly effective. Electrophoretic mobility shift analysis (EMSA) of nuclear extracts from synoviocytes incubated with the STAT-1 decoy ODN in vitro revealed an inhibitory effect on STAT-1. Furthermore, the STAT-1 decoy ODN inhibited the expression of CD40 mRNA in stimulated macrophages. The beneficial effects of the STAT-1 decoy ODN in experimental arthritis presumably mediated in part by affecting CD40 signalling in macrophages may provide the basis for a novel treatment of human RA.