bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling the signaling endosome hypothesis: Why a drive to the nucleus is better than a (random) walk
Authors: Howe Charles L 
Published: October 2005

Abstract

Background
Information transfer from the plasma membrane to the nucleus is a universal cell biological property. Such information is generally encoded in the form of post-translationally modified protein messengers. Textbook signaling models typically depend upon the diffusion of molecular signals from the site of initiation at the plasma membrane to the site of effector function within the nucleus. However, such models fail to consider several critical constraints placed upon diffusion by the cellular milieu, including the likelihood of signal termination by dephosphorylation. In contrast, signaling associated with retrogradely transported membrane-bounded organelles such as endosomes provides a dephosphorylation-resistant mechanism for the vectorial transmission of molecular signals. We explore the relative efficiencies of signal diffusion versus retrograde transport of signaling endosomes.

Results
Using large-scale Monte Carlo simulations of diffusing STAT-3 molecules coupled with probabilistic modeling of dephosphorylation kinetics we found that predicted theoretical measures of STAT-3 diffusion likely overestimate the effective range of this signal. Compared to the inherently nucleus-directed movement of retrogradely transported signaling endosomes, diffusion of STAT-3 becomes less efficient at information transfer in spatial domains greater than 200 nanometers from the plasma membrane.

Conclusion
Our model suggests that cells might utilize two distinct information transmission paradigms: 1) fast local signaling via diffusion over spatial domains on the order of less than 200 nanometers; 2) long-distance signaling via information packets associated with the cytoskeletal transport apparatus. Our model supports previous observations suggesting that the signaling endosome hypothesis is a subset of a more general hypothesis that the most efficient mechanism for intracellular signaling-at-a-distance involves the association of signaling molecules with molecular motors that move along the cytoskeleton. Importantly, however, cytoskeletal association of membrane-bounded complexes containing ligand-occupied transmembrane receptors and downstream effector molecules provides the ability to regenerate signals at any point along the transmission path. We conclude that signaling endosomes provide unique information transmission properties relevant to all cell architectures, and we propose that the majority of relevant information transmitted from the plasma membrane to the nucleus will be found in association with organelles of endocytic origin.
Prevalence, predisposition and prevention of type II diabetes
Authors: Cheng Dong 
Published: October 2005

Abstract
In 2000, more than 151 million people in the world are diabetic. It is predicted that by 2010, 221 million people and by 2025, 324 million will be diabetic. In the U.S., for the population born in 2000, the estimated lifetime risk for diabetes is more than 1 in 3. The economic and human cost of this disease is devastating. The current cost of diabetes in the U.S. is estimated to be at $132 billion, which includes $92 billion of direct medical costs and $40 billion of indirect costs such as disability, work loss and premature mortality. The outbreak of the current diabetic epidemic has been accompanied by a similarly drastic increase in obesity. The relation between the two is a matter of debate but presumably both are caused by changes in dietary habits and an increasingly sedentary modern lifestyle. Compelling scientific evidence indicates that lifestyle modification effectively prevents or delays the occurrence of type 2 diabetes. Recent clinical trials also demonstrate that success in the treatment of obesity, either surgically or pharmacologically, leads to the prevention of type 2 diabetes among the obese. Clinical data have also revealed that the insulin sensitizing agent troglitazone is efficacious in both β-cell preservation and delaying the onset of type 2 diabetes. Future safe and more effective anti-obesity medicines and insulin sensitizing agents that help to preserve β-cell function, in addition to efforts of lifestyle modification, thus hold promise for the overweight population with potential for reduction in the development of diabetics.
COMT genetic variation confers risk for psychotic and affective disorders: a case control study
Authors: Funke Birgit , Malhotra Anil K , Finn Christine T , Plocik Alex M , Lake Stephen L , Lencz Todd , DeRosse Pamela , Kane John M , Kucherlapati Raju 
Published: October 2005

Abstract

Background
Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls. Cases included patients with schizophrenia (n = 196), schizoaffective disorder (n = 62), bipolar disorder (n = 82), major depression (n = 30), and patients diagnosed with either psychotic disorder NOS or depressive disorder NOS (n = 24).

Results
SNP rs2097603, the Val/Met variant and SNP rs165599 were significantly associated (p = 0.004; p = 0.05; p = 0.035) with a broad "all affected" diagnosis. Haplotype analysis revealed a potentially protective G-A-A-A haplotype haplotype (-278A/G; rs737865; Val108/158Met; rs165599), which was significantly underrepresented in this group (p = 0.0033) and contained the opposite alleles of the risk haplotype previously described by Shifman et al. Analysis of diagnostic subgroups within the "all affecteds group" showed an association of COMT in patients with psychotic disorders as well as in cases with affective illness although the associated variants differed. The protective haplotype remained significantly underrepresented in most of these subgroups.

Conclusion
Our results support the view that COMT variation provides a weak general predisposition to neuropsychiatric disease including psychotic and affective disorders.
No effect of omeprazole on pH of exhaled breath condensate in cough associated with gastro-oesophageal reflux
Authors: Torrego Alfonso , Cimbollek Stefan , Hew Mark , Chung Kian Fan 
Published: October 2005

Abstract

Background
Endogenous airway acidification evaluated as pH in exhaled breath condensate (EBC) has been described in patients with chronic cough. Proton pump inhibitors improve gastro-oesophageal reflux (GOR)-associated cough.

Methods
We examined pH levels in EBC and capsaicin cough response in 13 patients with chronic cough (mean age 41 years, SD 9) associated with GOR before and after omeprazole treatment (40 mg/day for 14 days) and its relationship with clinical response.

Results
Omeprazole abolished symptoms associated with GOR. Patients with chronic cough had an EBC pH of 8.28 (SD 0.13) prior to treatment but this did not change with omeprazole treatment. There was a significant improvement in the Leicester Cough Questionnaire symptom scores from 80.8 points (SD 13.2) to 95.1 (SD 17) (p = 0.02) and in a 6-point scale of cough scores, but there was no change in capsaicin cough response.

Conclusion
An improvement in GOR-associated cough was not associated with changes in EBC pH or capsaicin cough response. These parameters are not useful markers of therapeutic response.
Expression analysis of candidate breast tumour suppressor genes on chromosome 16q
Authors: van Wezel Tom , Lombaerts Marcel , van Roon Eddy H , Philippo Katja , Baelde Hans J , Szuhai Karoly , Cornelisse Cees J , Cleton-Jansen Anne-Marie 
Published: October 2005

Abstract
Introduction
Chromosome arm 16q is the second most frequent target of loss of heterozygosity in breast cancer and is, therefore, a candidate to contain one or more classic tumour suppressor genes (TSGs). E-cadherin at 16q22 was identified as a TSG in lobular breast cancer, but TSGs in ductal breast cancer remain elusive. Several genes have been suggested as potential candidates (e.g. CBFA2T3, CTCF and WWOX) but no inactivating mutations could be identified in these genes and they thus fail to fit the classic two-hit model for a TSG. With the completion of the human transcriptome, new candidate genes can be distinguished. Besides mutational inactivation, a TSG could, at least in a subset of the tumours, be transcriptionally suppressed or even inactivated. Studying candidate genes for expression and somatic mutations could thus identify the TSGs.

Methods
Possible candidates CBFA2T3, TERF2 and TERF2IP, FBXL8 and LRRC29 and FANCA were studied for insertion and deletion mutations and for expression differences using quantitative RT-PCR in a panel of tumour cell lines and primary tumours with and without loss of 16q.

Results
None of the genes showed mutations or obvious expression differences. FANCA expression increased with tumour grade.

Conclusion
Apparently, the underlying genetics at chromosome 16q are complex or the TSGs remain to be identified. Multiple mechanisms, such as mutations, promoter hypermethylation or haploinsufficiency, might lead to the inactivation of a TSG.
Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture
Authors: Kuklin Vladimir , Sovershaev Mikhail , Andreasen Thomas , Skogen Vegard , Ytrehus Kirsti , Bjertnaes Lars 
Published: October 2005

Abstract
Introduction
We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1.

Methods
Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Cα (PKCα) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 μg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (CL) were assessed.

Results
After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and CL that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCα by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCα in the membrane fraction.

Conclusion
In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCα in the membrane fraction of lung tissue.
Do universal codon-usage patterns minimize the effects of mutation and translation error?
Authors: Marquez Roberto , Smit Sandra , Knight Rob 
Published: October 2005

Abstract
Background
Do species use codons that reduce the impact of errors in translation or replication? The genetic code is arranged in a way that minimizes errors, defined as the sum of the differences in amino-acid properties caused by single-base changes from each codon to each other codon. However, the extent to which organisms optimize the genetic messages written in this code has been far less studied. We tested whether codon and amino-acid usages from 457 bacteria, 264 eukaryotes, and 33 archaea minimize errors compared to random usages, and whether changes in genome G+C content influence these error values.

Results
We tested the hypotheses that organisms choose their codon usage to minimize errors, and that the large observed variation in G+C content in coding sequences, but the low variation in G+U or G+A content, is due to differences in the effects of variation along these axes on the error value. Surprisingly, the biological distribution of error values has far lower variance than randomized error values, but error values of actual codon and amino-acid usages are actually greater than would be expected by chance.

Conclusion
These unexpected findings suggest that selection against translation error has not produced codon or amino-acid usages that minimize the effects of errors, and that even messages with very different nucleotide compositions somehow maintain a relatively constant error value. They raise the question: why do all known organisms use highly error-minimizing genetic codes, but fail to minimize the errors in the mRNA messages they encode?
ChIPOTle: a user-friendly tool for the analysis of ChIP-chip data
Authors: Buck Michael J , Nobel Andrew B , Lieb Jason D 
Published: October 2005

AbstractChIPOTle (Chromatin ImmunoPrecipitation On Tiled arrays) takes advantage of two unique properties of ChIP-chip data: the single-tailed nature of the data, caused by specific enrichment but not specific depletion of genomic fragments; and the predictable enrichment of DNA fragments adjacent to sites of direct protein-DNA interaction. Implemented as a Microsoft Excel macro written in Visual Basic, ChIPOTle uses a sliding window approach that yields improvements in the identification of bona fide sites of protein-DNA interaction.
Minority recruitment to the Selenium and Vitamin E Cancer Prevention Trial (SELECT)
Authors: Cook Elise D , Moody-Thomas Sarah , Anderson Karen B , Campbell Russell , Hamilton Sandra J , Harrington Joseph M , Lippman Scott M , Minasian Lori M , Paskett Electra D , Craine Stephen , Arnold Kathryn B , Probstfield Jeffrey L 
Published: October 2005

Background Previous large chemoprevention studies have not recruited significant numbers of minorities. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a large phase III study evaluating the impact of selenium and vitamin E on the clinical incidence of prostate cancer. Over 400 SELECT study sites in the USA, Canada, and Puerto Rico recruited men to this trial. The SELECT recruitment goal was 24% minorities, with 20% black, 3% Hispanic, and 1% Asian participants. The goal for black participants was set at 20% because of their proportion in the United States population and their prevalence of prostate cancer. Methods The minority recruitment strategies in SELECT were to: 1) consider minority recruitment during site selection; 2) expand the eligibility criteria by lowering the age criterion for black men and including men with controlled co-morbid illnesses; 3) develop a national infrastructure; 4) give additional funds to sites with the potential to increase black enrollment; and 5) provide resources to maximize free media opportunities to promote SELECT. Results SELECT recruitment began in August 2001 and was intended to last five years, but concluded two years ahead of schedule in June 2004. Of the 35 534 participants enrolled, 21% were minorities, with 15% black, 5% Hispanic, and 1% Asian. Conclusions Careful planning, recruitment of large numbers of clinical centers and adequate resources accomplished by the combined efforts of the National Cancer Institute (NCI), Southwest Oncology Group (SWOG), SELECT Recruitment and Adherence Committee (RAC), SELECT Minority and Medically Underserved Subcommittee (MMUS), and the local SELECT sites resulted in attainment of the estimated sample size ahead of schedule and recruitment of the largest percentage of black participants ever randomized to a cancer prevention trial.
Power and sample size for clinical trials when efficacy is required in multiple endpoints: application to an Alzheimer's treatment trial
Authors: Xiong Chengjie , Yu Kai , Gao Feng , Yan Yan , Zhang Zhengjun 
Published: October 2005

Background When the efficacy of a treatment in a randomized controlled trial is required for multiple primary endpoints, trial design and analysis differ from trial requiring efficacy in only one of the multiple endpoints. Methods We consider a two-arm clinical trial requiring efficacy analysis for multiple primary endpoints, formulating the appropriate null and alternative hypotheses for the test of treatment efficacy. We study the significance level/statistical power of an intersection-union test (IUT) in this situation. We compare IUT with the intuitive approach (selecting the maximum sample size over those obtained from testing individual primary endpoints one by one) for determination of sample size. Results The proposed IUT reserves the same Type I error rate as shared by all endpoint-specific tests. The statistical power of the proposed IUT is no more than the minimum from the individual tests. The maximum sample size from multiple endpoint-specific tests is often inadequate for the test of treatment efficacy, especially when the standardized effect sizes are similar. Finally, the IUT can be applied to Alzheimer's disease treatment trials in which two primary endpoints are typically used. Conclusions The IUT is a valid method for use in the design and analysis of clinical trials requiring efficacy at multiple primary endpoints.
Reasons for high retention in pediatric clinical trials: comparison of participant and staff responses in the Correction of Myopia Evaluation Trial
Authors: Dias Lynette , Schoenfeld Elinor , Thomas Jennifer , Baldwin Catherine , Mcleod Jennifer , Smith Justin , Owens Robert , Hyman Leslie 
Published: October 2005

Background The Correction of Myopia Evaluation Trial (COMET), a randomized, multicenter clinical trial of myopia progression in children, had an exceptionally high retention rate of 98.5% (462/469) at three years of follow-up. The present investigation was designed to evaluate and compare the reasons for COMET's high retention rate according to participating families and clinical center staff. Methods Families ( n = 411) and staff ( n = 35) completed a confidential 19-item questionnaire by indicating families' levels of preference for each item, and rating its importance in keeping families in the study. The questionnaire evaluated study features in four categories: staff characteristics, operational aspects, specific study elements, and incentives. Results Results showed that most families viewed the study very favorably. Features that appealed to 90% or more families and promoted continued study participation included staff attributes such as friendliness, responsiveness and encouragement, and aspects pertaining to standard of care such as completeness of eye exam, quality of eye care and free eyeglasses. Compared to families, staff tended to underestimate the importance of the following features for retention: seeing the same staff at each visit, appointment reminders, center location, newsletters, commitment to the study, being part of a nationwide study, length of the study, association with a college of optometry, completeness of eye exam, and eye drops ( p < 0.05 by chi-square analyses). However, staff responses also revealed less preferred components of the study protocol (e.g., eye drops), to which families might have been reluctant to respond unfavorably. Conclusions Our findings highlight the importance of intangible factors such as staff attributes and participants' study commitment in maintaining high retention rates, and the usefulness of surveying both families and staff.
Maximum information designs
Authors: Lachin John M 
Published: October 2005

Background Expressions to determine the sample size N needed to provide power 1 to detect a difference between groups, say, involve other nuisance parameters, such as the variance of the observations for a test or means, or the control group probability for a test of proportions or the control group hazard rate for a logrank test of event-times. Designs where N is fixed are called maximum N or duration designs because the sample size and required duration of the study can be fixed, or estimated. However, such designs are expected, but not guaranteed, to provide the desired level of power to detect the specified difference - at the study end because the true or estimated values of the nuisance parameters are unknown. Thus, the actual information to be accrued and the associated level of power are random variables with sample variation. Methods Expressions are developed to determine the amount of information needed to provide the desired level of power, regardless of the values of the nuisance parameters. Results The amount of information ( I) in the observed data is readily quantified and can often be expressed as the inverse of the variance of the test statistic. Also, the total amount of information required to provide the desired level of power 1 to detect a difference - with a test at level - is readily determined, designated as I, Under a maximum information design, the study is continued until the required total amount of information is accrued, or I I, In this case, the sample size or duration are random variables, but each can be estimated under various projections about the underlying parameters (variance, probability, hazard) in advance. The implementation of a maximum information design for two and multiple group trials is described for a test of means, proportions and event-times using the logrank test. Application to other methods of analysis is described. Conclusions A maximum information design provides greater assurance that the desired level of power will be attained. However, the exact study duration is unknown. Issues related to the implementation of such a design are discussed.
Direct likelihood analysis versus simple forms of imputation for missing data in randomized clinical trials
Authors: Beunckens Caroline , Molenberghs Geert , Kenward Michael G 
Published: October 2005

Background In many clinical trials, data are collected longitudinally over time. In such studies, missingness, in particular dropout, is an often encountered phenomenon. Methods We discuss commonly used but often problematic methods such as complete case analysis and last observation carried forward and contrast them with broadly valid and easy to implement direct-likelihood methods. We comment on alternatives such as multiple imputation and the expectation-maximization algorithm. Results We apply these methods in particular to data from a study with continuous outcomes. The outcomes are modelled using a general linear mixed-effects model. The bias with CC and LOCF is established in the case study and the advantages of the direct-likelihood approach shown. Conclusions We have established formal but easy to understand arguments for a shift towards a direct-likelihood paradigm when analysing incomplete data from longitudinal clinical trials, necessitating neither imputation nor deletion.