bluuebunny/crossref_metadata_2025_split huggingface dataset:
Handling ethical, legal and social issues in birth cohort studies involving genetic research: responses from studies in six countries
Authors: Ries Nola M , LeGrandeur Jane , Caulfield Timothy 
Published: March 2010

Abstract

Background
Research involving minors has been the subject of much ethical debate. The growing number of longitudinal, pediatric studies that involve genetic research present even more complex challenges to ensure appropriate protection of children and families as research participants. Long-term studies with a genetic component involve collection, retention and use of biological samples and personal information over many years. Cohort studies may be established to study specific conditions (e.g. autism, asthma) or may have a broad aim to research a range of factors that influence the health and development of children. Studies are increasingly intended to serve as research platforms by providing access to data and biological samples to researchers over many years.
This study examines how six birth cohort studies in North America and Europe that involve genetic research handle key ethical, legal and social (ELS) issues: recruitment, especially parental authority to include a child in research; initial parental consent and subsequent assent and/or consent from the maturing child; withdrawal; confidentiality and sample/data protection; handling sensitive information; and disclosure of results.

Methods
Semi-structured telephone interviews were carried out in 2008/09 with investigators involved in six birth cohort studies in Canada, Denmark, England, France, the Netherlands and the United States. Interviewees self-identified as being knowledgeable about ELS aspects of the study. Interviews were conducted in English.

Results
The studies vary in breadth of initial consent, but none adopt a blanket consent for future use of samples/data. Ethics review of new studies is a common requirement. Studies that follow children past early childhood recognise a need to seek assent/consent as the child matures. All studies limit access to identifiable data and advise participants of the right to withdraw. The clearest differences among studies concern handling of sensitive information and return of results. In all studies, signs of child abuse require reports to authorities, but this disclosure duty is not always stated in consent materials. Studies vary in whether they will return to participants results of routine tests/measures, but none inform participants about findings with unknown clinical significance.

Conclusions
Analysis of how cohort studies in various jurisdictions handle key ELS issues provides informative data for comparison and contrast. Consideration of these and other examples and further scholarly exploration of ELS issues provides insight on how best to address these aspects in ways that respect the well-being of participants, especially children who become research subjects at the start of their lives.
Epidermal growth factor receptor regulates β-catenin location, stability, and transcriptional activity in oral cancer
Authors: Lee Chien-Hsing , Hung Hsing-Wen , Hung Pei-Hsin , Shieh Yi-Shing 
Published: March 2010

AbstractBackgroundMany cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells.ResultsWe used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of β-catenin and GSK-3β, association of β-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, β-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of β-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of β-catenin (tyrosine) and GSK-3β(Ser-(9), resulting in a loss of β-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates β-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of β-catenin in oral cancer.ConclusionsEGFR signaling regulates β-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of β-catenin under EGFR activation is a malignancy marker of oral cancer.
Cysteine 95 and other residues influence the regulatory effects of Histidine 69 mutations on Human Immunodeficiency Virus Type 1 protease autoprocessing
Authors: Huang Liangqun , Hall Alyssa , Chen Chaoping 
Published: March 2010

Abstract

Background
Regulated autoprocessing of HIV Gag-Pol precursor is required for the production of mature and fully active protease. We previously reported that H69E mutation in a pseudo wild type protease sequence significantly (>20-fold) impedes protease maturation in an in vitro autoprocessing assay and in transfected mammalian cells.

Results
Interestingly, H69E mutation in the context of a laboratory adapted NL4-3 protease showed only moderate inhibition (~4-fold) on protease maturation. There are six point mutations (Q7K, L33I, N37S, L63I, C67A, and C95A) between the NL4-3 and the pseudo wild type proteases suggesting that the H69E effect is influenced by other residues. Mutagenesis analyses identified C95 as the primary determinant that dampened the inhibitory effect of H69E. L63 and C67 also demonstrated rescue effect to a less extent. However, the rescue was completely abolished when H69 was replaced by aspartic acid in the NL4-3 backbone. Charge substitutions of surface residues (E21, D30, E34, E35, and F99) to neutral or positively charged amino acids failed to restore protease autoprocessing in the context of H69E mutation.

Conclusions
Taken together, we suggest that residue 69 along with other amino acids such as C95 plus L63 and C67 to a less extent modulate precursor structures for the regulation of protease autoprocessing in the infected cell.
Accuracy of DXA in estimating body composition changes in elite athletes using a four compartment model as the reference method
Authors: Santos Diana A , Silva Analiza M , Matias Catarina N , Fields David A , Heymsfield Steven B , Sardinha Luís B 
Published: March 2010

AbstractBackgroundDual-energy x-ray absorptiometry (DXA) provides an affordable and practical assessment of multiple whole body and regional body composition. However, little information is available on the assessment of changes in body composition in top-level athletes using DXA. The present study aimed to assess the accuracy of DXA in tracking body composition changes (relative fat mass [%FM], absolute fat mass [FM], and fat-free mass [FFM]) of elite male judo athletes from a period of weight stability to prior to a competition, compared to a four compartment model (4C model), as the criterion method.MethodsA total of 27 elite male judo athletes (age, 22.2 ± 2.8 yrs) athletes were evaluated. Measures of body volume by air displacement plethysmography, bone mineral content assessed by DXA, and total-body water assessed by deuterium dilution were used in a 4C model. Statistical analyses included examination of the coefficient of determinant (r2), standard error of estimation (SEE), slope, intercept, and agreement between models.ResultsAt a group level analysis, changes in %FM, FM, and FFM estimates by DXA were not significantly different from those by the 4C model. Though the regression between DXA and the 4C model did not differ from the line of identity DXA %FM, FM, and FFM changes only explained 29%, 36%, and 38% of the 4C reference values, respectively. Individual results showed that the 95% limits of agreement were -3.7 to 5.3 for %FM, -2.6 to 3.7 for FM, and -3.7 to 2.7 for FFM. The relation between the difference and the mean of the methods indicated a significant trend for %FM and FM changes with DXA overestimating at the lower ends and underestimating at the upper ends of FM changes.ConclusionsOur data indicate that both at group and individual levels DXA did not present an expected accuracy in tracking changes in adiposity in elite male judo athletes.
Distinguishing between hot-spots and melting-pots of genetic diversity using haplotype connectivity
Authors: Nguyen Binh , Spillner Andreas , Emerson Brent C , Moulton Vincent 
Published: March 2010

Abstract
We introduce a method to help identify how the genetic diversity of a species within a geographic region might have arisen. This problem appears, for example, in the context of identifying refugia in phylogeography, and in the conservation of biodiversity where it is a factor in nature reserve selection. Complementing current methods for measuring genetic diversity, we analyze pairwise distances between the haplotypes of a species found in a geographic region and derive a quantity, called haplotype connectivity, that aims to capture how divergent the haplotypes are relative to one another. We propose using haplotype connectivity to indicate whether, for geographic regions that harbor a highly diverse collection of haplotypes, diversity evolved inside a region over a long period of time (a "hot-spot") or is the result of a more recent mixture (a "melting-pot"). We describe how the haplotype connectivity for a collection of haplotypes can be computed efficiently and briefly discuss some related optimization problems that arise in this context. We illustrate the applicability of our method using two previously published data sets of a species of beetle from the genus Brachyderes and a species of tree from the genus Pinus.
Simultaneous determination of three major bioactive saponins of Panax notoginseng using liquid chromatography-tandem mass spectrometry and a pharmacokinetic study
Authors: Chen Wei , Dang Yunjie , Zhu Chunyan 
Published: March 2010

Abstract

Background
Panax notoginseng saponins (PNS), the main active components of Radix Notoginseng, has been used for treating atherosclerosis, cerebral infarction, and cerebral ischemia. Ginsenosides Rg1, ginsenoside Rb1, and notoginsenoside R1 are the main contributors of biological activities, determination of these three saponins is very important for the in vivo evaluation of PNS. The present study aims to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ginsenosides Rg1, ginsenoside Rb1, and notoginsenoside R1. The use of this method was exemplified in pharmacokinetic study of beagle dog plasma after oral administration of PNS.

Methods
Liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was combined with solid-phase extraction (SPE). This setup was used to determine simultaneously the three major PNS (ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1) in beagle dog plasma. Tandem mass spectrometry was performed using electrospray ionization in the positive ion mode.

Results
The lower limits of quantification were 0.5 ng/mL for notoginsenoside R1, 0.82 ng/mL for ginsenoside Rg1, and 1.10 ng/mL for ginsenoside Rb1. The calibration curves for the three saponins were linear over the concentration ranges 2.64-264 ng/mL (r2 = 0.9967, P = 0.003), 3.6-360 ng/mL (r2 = 0.9941, P = 0.004), and 18.7-1870 ng/mL (r2 = 0.9912, P = 0.004) for notoginsenoside R1, ginsenoside Rg1, and ginsenoside Rb1, respectively. Within these concentration ranges, the relative standard deviation (RSD) of intra- and interday assays for the three PNS from beagle dog plasma samples were less than 12%.

Conclusions
This LC/MS/MS method in combination with SPE is useful in the pharmacokinetic study of PNS, such as the simultaneous determination of saponins in beagle dog plasma after oral administration.
Thyroid function in children with growth hormone (GH) deficiency during the initial phase of GH replacement therapy - clinical implications
Authors: Smyczynska Joanna , Hilczer Maciej , Stawerska Renata , Lewinski Andrzej 
Published: March 2010

AbstractBackgroundNormal thyroid hormone secretion or appropriate L-thyroxine (L-T4) substitution is necessary for the optimal effect of the growth hormone (GH) administration on growth rate. The decrease of free thyroxine (FT4) levels at recombinant human GH (rhGH) therapy onset has been reported in several studies. The aim of the present study was to evaluate the effect of rhGH administration on thyrotropin (TSH) and FT4serum concentrations in children with GH deficiency (GHD) during the 1st year of therapy, as well as to assess potential indications to thyroid hormone supplementation in them.Patients and methodsThe analysis involved data of 75 children (59 boys, 16 girls) with disorders of GH secretion (GHD, neurosecretory dysfunction - NSD) and partial GH inactivity (inactGH), who were treated with rhGH for - at least - one year. In all the children, body height and height velocity (HV) were assessed before and after 1 year of therapy, while TSH, FT4, IGF-I and IGFBP-3 before treatment and after 3-6 months and 1 year of treatment. In the patients, who revealed hypothyroidism (HypoT), an appropriate L-T4substitution was introduced immediately. The incidence of HypoT, occurring during the initial phase of rhGH therapy, was assessed, as well as its influence on the therapy effectiveness.ResultsBefore rhGH substitution, there were no significant differences in either auxological indices or TSH and FT4secretion, or IGF-I concentration and its bioavailability among the groups of patients. During the initial 3-6 months of rhGH administration, a significant decrease of FT4serum concentration, together with a significant increase of IGF-I SDS and IGF-I/IGFBP-3 molar ratio was observed in all the studied groups. In 17 children, HypoT was diagnosed and L-T4substitution was administered. Despite similar IGF-I secretion increase, the improvement of HV presented significantly lower in children with HypoT than in those who remained euthyroid all the time.ConclusionsThe incidence of HypoT during the initial phase of GH treatment in children with GHD and the negative effect of even transient thyroid hormone deficiency on the growth rate should be taken into account.
"Idiopathic" mental retardation and new chromosomal abnormalities
Authors: Galasso Cinzia , Lo-Castro Adriana , El-Malhany Nadia , Curatolo Paolo 
Published: March 2010

Abstract
Mental retardation is a heterogeneous condition, affecting 1-3% of general population. In the last few years, several emerging clinical entities have been described, due to the advent of newest genetic techniques, such as array Comparative Genomic Hybridization. The detection of cryptic microdeletion/microduplication abnormalities has allowed genotype-phenotype correlations, delineating recognizable syndromic conditions that are herein reviewed. With the aim to provide to Paediatricians a combined clinical and genetic approach to the child with cognitive impairment, a practical diagnostic algorithm is also illustrated. The use of microarray platforms has further reduced the percentage of "idiopathic" forms of mental retardation, previously accounted for about half of total cases. We discussed the putative pathways at the basis of remaining "pure idiopathic" forms of mental retardation, highlighting possible environmental and epigenetic mechanisms as causes of altered cognition.
Interferon-γ inhibits interleukin-1β-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritis
Authors: Page Charlotte E , Smale Shaun , Carty Sara M , Amos Nicholas , Lauder Sarah N , Goodfellow Rhian M , Richards Peter J , Jones Simon A , Topley Nicholas , Williams Anwen S 
Published: March 2010

Abstract
Introduction
The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis.

Methods
We studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)).

Results
IFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA.

Conclusions
Early therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis.
Nomogram to Predict Subsequent Brain Metastasis in Patients With Metastatic Breast Cancer
Authors: Graesslin Olivier , Abdulkarim Bassam S. , Coutant Charles , Huguet Florence , Gabos Zsolt , Hsu Limin , Marpeau Olivier , Uzan Serge , Pusztai Lajos , Strom Eric A. , Hortobagyi Gabriel N. , Rouzier Roman , Ibrahim Nuhad K. 
Published: March 2010

Purpose Brain metastasis is usually a fatal event in patients with stage IV breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of enriched patient populations for prevention trials. Patients and Methods Electronic medical records of patients with metastatic breast cancer were retrospectively reviewed for the period between January 2000 and February 2007 under a study approved by the institutional review board. A multivariate logistic regression analysis of selected prognostic features was done. A nomogram to predict brain metastasis was constructed and validated in a cohort of 128 patients with brain metastasis treated at the Cross Cancer Institute (Edmonton, Alberta, Canada). Results Of 2,136 patients with breast cancer, 362 developed subsequent brain metastasis. Age, grade, negative status of estrogen receptor and human epidermal growth factor receptor 2, number of metastatic sites (one v > one), and short disease-free survival were significantly and independently associated with subsequent brain metastasis. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.68 (95% CI, 0.66 to 0.69) in the training set. The validation set showed a good discrimination with an AUC of 0.74 (95% CI, 0.70 to 0.79). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities. Conclusion We have developed a robust tool that is able to predict subsequent brain metastasis in patients with breast cancer with nonbrain metastatic disease. Selection of an enriched patient population at high risk for brain metastasis will facilitate the design of trials aiming at its prevention.
Safety, Pharmacokinetics, and Preliminary Clinical Activity of Inotuzumab Ozogamicin, a Novel Immunoconjugate for the Treatment of B-Cell Non-Hodgkin's Lymphoma: Results of a Phase I Study
Authors: Advani Anjali , Coiffier Bertrand , Czuczman Myron S. , Dreyling Martin , Foran James , Gine Eva , Gisselbrecht Christian , Ketterer Nicolas , Nasta Sunita , Rohatiner Ama , Schmidt-Wolf Ingo G.H. , Schuler Martin , Sierra Jorge , Smith Mitchell R. , Verhoef Gregor , Winter Jane N. , Boni Joseph , Vandendries Erik , Shapiro Mark , Fayad Luis 
Published: March 2010

Purpose Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22+ B-cell non-Hodgkin's lymphoma (NHL). Patients and Methods Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m2. Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival. Results Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m2. Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively. Conclusion Inotuzumab ozogamicin has demonstrated efficacy against CD22+ B-cell NHL, with reversible thrombocytopenia as the main toxicity.
Influencing expert judgment: Attributions of crime causality
Authors: Murray Jennifer , Thomson Mary E. , Cooke David J. , Charles Kathy E. 
Published: March 2010

Purpose. The present research aimed to investigate the effects of attribution on expert clinical judgment in comparison to semi‐experts and laypeople. Two research questions were addressed. First, would experts be less subject to attributional manipulations, in terms of their perceived ratings of dangerousness, than would semi‐experts or laypeople? Second, would experts be less subject to attributional manipulations, in terms of their assessments of offender responsibility, than would semi‐experts or laypeople? Method. A 3×3×2 mixed groups design was implemented. Participants read nine crime scenarios that had been internally or externally manipulated. For each scenario, participants were asked to rate offender dangerousness, offender responsibility, and the seriousness of the crime and to suggest a suitable sentence length. Targeted recruitment was employed, yielding 12 experts, 21 semi‐experts, and 22 laypeople. Results. Offenders were considered to be more responsible for their actions and more dangerous to others in the internal manipulations than in the external ones across all crime types and by all levels of expertise. Findings indicate that semi‐experts are less subject to the influence of attributional manipulations than both experts and laypeople. Marked similarities in the pattern of expert and lay person judgments can be observed from the present analyses. Conclusions. The current findings lend support to previous research in the area in that similarities between expert and lay person judgment were observed. However, through expanding and clarifying the levels of expertise investigated, the current findings highlight the need for greater research into the distinct ‘semi‐expert’ group.