bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multidrug Resistance Protein 2 Is an Important Determinant of Paclitaxel Pharmacokinetics
Authors: Lagas Jurjen S. , Vlaming Maria L. , van Tellingen Olaf , Wagenaar Els , Jansen Robert S. , Rosing Hilde , Beijnen Jos H. , Schinkel Alfred H. 
Published: October 2006

AbstractPurpose: P-glycoprotein (P-gp; ABCB1) efficiently transports lipophilic amphipathic drugs, including the widely used anticancer drug paclitaxel (Taxol). We found previously that human multidrug resistance protein 2 (MRP2; ABCC2) also transports paclitaxel in vitro, and although we expected that paclitaxel pharmacokinetics would be dominated by P-gp, the effect of Mrp2 was tested in vivo.Experimental Design: We generated and characterized Mdr1a/1b/Mrp2−/− mice, allowing assessment of the distinct roles of Mrp2 and Mdr1a/1b P-gp in paclitaxel pharmacokinetics.Results: Surprisingly, the effect of Mrp2 on i.v. administration of paclitaxel was as great as that of P-gp. The area under plasma concentration-time curve (AUC)i.v. in both Mrp2−/− and Mdr1a/1b−/− mice was 1.3-fold higher than in wild-type mice, and in Mdr1a/1b/Mrp2−/− mice, a 1.7-fold increase was found. In spite of this similar effect, Mrp2 and P-gp had mostly complementary functions in paclitaxel elimination. Mrp2 dominated the hepatobiliary excretion, which was reduced by 80% in Mrp2−/− mice. In contrast, P-gp dominated the direct intestinal excretion, with a minor role for Mrp2. The AUCoral of paclitaxel was 8.5-fold increased by Mdr1a/1b deficiency but not affected by Mrp2 deficiency. However, in the absence of Mdr1a/1b P-gp, additional Mrp2 deficiency increased the AUCoral another 1.7-fold.Conclusions: Thus far, Mrp2 was thought to mainly affect organic anionic drugs in vivo. Our data show that Mrp2 can also be a major determinant of the pharmacokinetic behavior of highly lipophilic anticancer drugs, even in the presence of other efficient transporters. Variation in MRP2 activity might thus directly affect the effective exposure to paclitaxel, on i.v. administration, but also on oral administration, especially when P-gp activity is inhibited.
The Hedgehog Signaling Pathway in Cancer
Authors: Evangelista Marie , Tian Hua , de Sauvage Frederic J. 
Published: October 2006

AbstractThe Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is crucial for proper development. At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. Hh signaling is most active during embryogenesis, and aberrant reactivation of the pathway in adult tissue can lead to the development of cancer. A comprehensive understanding of Hh signaling during development will undoubtedly shed light into the mechanism of Hh in cancer progression and identify potential targets for therapeutic intervention.
Myocardial Infarct–Sparing Effect of Adenosine A2AReceptor Activation Is due to Its Action on CD4+T Lymphocytes
Authors: Yang Zequan , Day Yuan-Ji , Toufektsian Marie-Claire , Xu Yaqin , Ramos Susan I. , Marshall Melissa A. , French Brent A. , Linden Joel 
Published: October 2006

Background—We previously used adenosine A2Areceptor (A2AR) knockout (KO) mice and bone marrow transplantation to show that the infarct-sparing effect of A2AR activation at reperfusion is primarily due to effects on bone marrow–derived cells. In this study we show that CD4+but not CD8+T lymphocytes contribute to myocardial ischemia/reperfusion injury.Method and Results—After a 45-minute occlusion of the left anterior descending coronary artery and reperfusion, T cells accumulate in the infarct zone within 2 minutes. Addition of 10 μg/kg of the A2AR agonist ATL146e 5 minutes before reperfusion produces a significant reduction in T-cell accumulation and a significant reduction in infarct size (percentage of risk area) measured at 24 hours. In Rag1 KO mice lacking mature lymphocytes, infarct size is significantly smaller than in C57BL/6 mice. Infarct size in Rag1 KO mice is increased to the level of B6 mice by adoptive transfer of 50 million CD4+T lymphocytes derived from C57BL/6 or A2AR KO but not interferon-γ KO mice. ATL146e completely blocked the increase in infarct size in Rag1 KO mice reconstituted with B6 but not A2AR KO CD4+T cells. The number of neutrophils in the reperfused heart at 24 hours after infarction correlated well with the number of lymphocytes and infarct size.Conclusions—These results strongly suggest that the infarct-sparing effect of A2AR activation is primarily due to inhibition of CD4+T-cell accumulation and activation in the reperfused heart.
Sexual health services and education: Young people’s experiences and preferences
Authors: Reeves C , Whitaker R , Parsonage R K , Robinson C A , Swale K , Bayley L 
Published: October 2006

Objective To examine young people’s requirements and perceptions of sexual health services and education in the context of their experience of sexual relationships and knowledge of sexual health. Design A questionnaire based cohort study. Setting Three hundred and sixty Year 11 students (aged 15-16 years) surveyed in three Secondary Schools. Method The study received ethical approval from The North Wales Central Ethics Committee. School nurses distributed questionnaires in classroom conditions to all students present on the survey day. Results Eighty-six per cent of the cohort responded. Those young people who reported being sexually active (153, 45 per cent) thought most sexual education topics should be taught around six months earlier than non-sexually active respondents. Of those accessing sexual health services, 90 per cent were happy with the services received, however, only 44 per cent of sexually active males and 76 per cent of sexually active females had sought advice. That clinics had a ‘friendly atmosphere and staff easy to talk to’ ranked highest and ‘only people of your own age using the clinic’ ranked lowest on a list of important features for a sexual health clinic. Conclusion Planners should consult young people and develop services in line with their needs. Sexual health education should be taught earlier in the school curriculum, with flexibility over when some information is accessed. There is little evidence for the assumption upon which much work in this field is based; that most young people prefer a specifically young person’s sexual health clinic.
Challenges in the design and conduct of a randomized study of two interventions for liquid aspiration
Authors: Brandt Diane K , Hind Jacqueline A , Robbins JoAnne , Lindblad Anne S , Gensler Gary , Gill Gary , Baum Herb , Lilienfeld David , Logemann Jeri A ,   Communication Sciences and Disorders Clinical Trials Research Group (CSDRG)
Published: October 2006

Background Liquid aspiration during swallowing has been linked to pneumonia, the most common cause of infectious death in the elderly. This paper examines the key issues in the design and implementation of the first multisite, randomized behavioral trial in dysphagia in an aging population. The study evaluated two commonly used treatments with respect to short-term and long-term management of liquid aspiration and subsequent pneumonia in dysphagic geriatric participants with dementia and/or Parkinson's disease. Methods Discussed are lessons learned during the conduct of this trial and include (1) ethical and methodological design issues, (2) pragmatic implementation of procedures and forms, (3) importance of multiple communication and monitoring strategies, (4) response to funding issues, and (5) changes in staff and facilities. Results In order to complete this trial the researchers were required to provide more support than anticipated in tasks such as completion of regulatory requirements by sites, supplementing site staff to identify potential study participants using a ‘circuit rider’ approach, continued recruitment of new sites and staff throughout the course of the trial, adapting forms and procedures and managing within economic constraints in a changing trial environment. Limitations Many of the challenges faced by the researchers were not anticipated when the study began. Successful strategies are described for these unanticipated difficulties, based on retrospective evaluation. Conclusions Successful conduct of clinical trials in long-term care environments that are heavily impacted by changes extraneous to the trial design and with staff typically new to clinical trials is possible but success depends on logistical flexibility.
Centralized medical monitoring in phase III clinical trials: the National Surgical Adjuvant Breast and Bowel Project (NSABP) experience
Authors: Soran A , Nesbitt L , Mamounas E P , Lembersky B , Bryant J , Anderson S , Brown A , Passarello M 
Published: October 2006

Background There is a need for data quality assurance procedures in phase III cancer trials. At the National Surgical Adjuvant Breast and Bowel Project (NSABP) ‘real-time’ systems have been developed for quality assurance and study monitoring: (1) manual review and triage of data forms by data managers at the time of submission; (2) computerized edit checking of all submitted data forms; (3) systematic review of eligibility, treatment compliance and toxicity in the first 100 patients of a new protocol; (4) prospective centralized medical review of all reported serious adverse events, treatment failures, second primary cancers and deaths; (5) quarterly review and approval of study summary data files by project statistician; and (6) on-site auditing. Purpose To assess the utility of an additional final comprehensive review of all patient records to confirm eligibility, disease status and vital status prior to manuscript submission. Methods Four phase III NSABP studies, which had been monitored using the triagebased quality assurance program described above, were selected for analysis ( n = 7972). Charts for 5965 patients were identified that had not been previously medically reviewed for protocol events of recurrence, second primary cancer or death. Submitted source documents and data forms of these 5965 NSABP patient records underwent medical review to verify patient eligibility, disease status and vital status. Results This final comprehensive review found no additional treatment failures or deaths, identified seven additional cases of ineligibility, was time-intensive requiring enormous use of expensive resources, and was therefore judged not to add significantly to the integrity of the database. Limitations Our findings are influenced by the procedures the NSABP employs for quality assurance and study monitoring for Phase III clinical trials and may have limited generalizability to other settings. Conclusion In the presence of multiple quality assurance and data monitoring systems, the rare discrepancies found between the data forms and source documentation does not support the routine use of a final comprehensive chart review for phase III trials at the NSABP Biostatistical Center.
Impact of on-site initiation visits on patient recruitment and data quality in a randomized trial of adjuvant chemotherapy for breast cancer
Authors: Liénard J-L , Quinaux E , Fabre-Guillevin E , Piedbois P , Jouhaud A , Decoster G , Buyse M , on behalf of the European Association for Research in Oncolo  
Published: October 2006

Purpose To provide empirical evidence on the impact of on-site initiation visits on the following outcomes: patient recruitment, quantity and quality of data submitted to the trial coordinating office, and patients' follow-up time. Patients and methods This methodological study was performed as part of a randomized trial comparing two combination chemotherapies for adjuvant treatment of breast cancer. Centers participating to the trial were randomized to either receive systematic on-site visits (Visited group), or not (Non-visited group). Results The study was terminated after two years, while the main randomized trial continued. Of the 135 centers that had expressed an interest in the trial, only 69 randomized at least one patient (35/68 in the Visited group, 34/67 in the Nonvisited group). Almost two-thirds of the patients were entered by 17 centers (10 in the Visited group, seven in the Non-visited group) that accrued more than 10 patients each. None of the prespecified outcomes favored the group of centers submitted to on-site initiation visits (ie, mean number of queries par patient: 6.1 ± 9.7 versus 5.4 ± 6.4, respectively for the Visited and Non-visited groups). Spontaneous transmittal of case report forms, although required by protocol, was low in both randomized groups (mean number of pages per patient: 1.5 ± 2.0 versus 2.1 ± 2.3, respectively), with investigators submitting about one-third of the expected forms on time (29% and 39%, respectively). Limitations This study could not evaluate the impact of repeated on-site visits on clinical outcomes. Conclusion Systematic on-site initiation visits did not contribute significantly to this clinical trial.
Reasons for participation and non-participation in a randomized controlled trial: postal questionnaire surveys of women eligible for TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears)
Authors: Sharp L , Cotton S C , Alexander L , Williams E , Gray N M , Reid J M 
Published: October 2006

Background Better understanding of motivators for, and barriers to, participation in randomized controlled trials (RCTs) in different study populations and settings has the potential to improve participation of historically under-represented groups (eg, women) in future trials. Purpose To investigate reasons why women agreed, or declined, to participate in a RCT. Methods In two postal questionnaire-based studies, we investigated women's reasons for participation or non-participation in TOMBOLA, a RCT comparing management policies for low-grade cervical abnormalities. Four-hundred and ninety-two TOMBOLA participants (response rate 56%) completed questionnaires on reasons for participation. One-hundred and thiry-seven women (38%) who declined TOMBOLA participation completed questionnaires on reasons for this. Results Eighty percent of women reported that one of their reasons for attending their TOMBOLA recruitment appointment was worries about their smear result. Ninety-four percent participated in the RCT because it was a worthwhile contribution to the cervical screening programme and other women; for 70% this was the most important reason. These proportions did not vary by socio-demographic factors. Thirty-two percent thought participation would result in better care. The most common reason for non-participation was preference for follow-up from the woman's GP. Logistical issues (eg, inconvenient appointments, travel time, arranging time off work or child-care) were commonly cited. Fourteen percent were too frightened to participate; this was unrelated to the grade of the recruitment smear. Limitations Response rates were not high, but there was little evidence of response bias. Structured questionnaires were used. Conclusions Future research should address how best to deliver information to ensure different social groups appreciate potential benefits of RCT participation and provide reassurance regarding fears about participation. Simple strategies (eg, appealing to the altruism of potential participants or offering flexible recruitment clinic locations and times) might enhance RCT recruitment rates. This in turn would ensure best use of research resources thus bringing the greatest benefits to participants and the population.
Kamphaugite-(Y) from La Cabrera massif, Spain: a low-temperature hydrothermal Y-REE carbonate
Authors: González del Tánago J. , La Iglesia A. , Delgado A. 
Published: October 2006

AbstractKamphaugite-(Y) occurs as white to cream-coloured spherical to semi-spherical aggregates of radial crystals in the La Cabrera granitic pluton (Spanish Central System). It mainly occurs on the free surfaces of alkali feldspar, quartz, calcite, kainosite-(Y) and laumontite, and inside miarolitic cavities. La Cabrera kamphaugite-(Y) has an average composition of Ca0.94Y0.89REE0.21(CO3)2 [F0.05(OH)0.95]·1.19H2O. Negative δ13CV-PDB values (–14 to –15‰) indicate a meteoric carbon source. Textural relations between kamphaugite-(Y) and coexisting minerals, its relatively high δ18OV-SMOW values (+25 to +26‰), and the occurrence of laumontite inclusions in kamphaugite-(Y), point to a genesis at < 50°C during very low-temperature post-magmatic hydrothermal activity.
Sazhinite-(La), Na3LaSi6O15(H2O)2, a new mineral from the Aris phonolite, Namibia: Description and crystal structure
Authors: Cámara F. , Ottolini L. , Devouard B. , Garvie L. A. J. , Hawthorne F. C. 
Published: October 2006

AbstractSazhinite-(La) is a new mineral from the Aris phonolite, Windhoek, Namibia. It occurs in vesicles within the phonolite, together with other species crystallized from late-stage hydrothermal fluids: natrolite, aegirine, microcline, apophyllite, sphalerite, analcime, fluorite, villiaumite, hydroxylapatite, galena, makatite, quartz, eudialyte, kanemite, tuperssuatsiaite and korobitsynite. Sazhinite-(La) forms small euhedral crystals up to 1 mm long and 0.4 mm wide, elongated along [001] and flattened on (010), exhibiting the forms {h0l}, {100} and {001}. It has good cleavage parallel to {010} and {001}. Twinning was not observed. Crystals are brittle with a Mohs hardness of 3, creamy white with a white streak, vitreous to pearly lustre, and translucent to transparent. In plane-polarized light, crystals are colourless with a = Z, b = Y, c = X. It is biaxial positive with α = 1.524, β = 1.528, γ = 1.544, all ±0.002, 2Vz(obs) = 46(1)°, and 2Vz(calc.) = 53.6°.Sazhmite-(La) is orthorhombic Pmm2, a = 7.415(2), b = 15.515(3), c = 7.164(1) Å, and V = 824.2 Å3. One crystal was studied by X-ray diffraction, electron microprobe and secondary ion mass spectrometry (SIMS) microanalysis, leading to the average composition (Na2.87K0.02Sr0.01)Σ2.90 [La0.41Ce0.35Pr0.02Nd0.04(Sm,Gd,Dy,Er,Yb)Σ0.01Th0.09U0.01Y0.01Zr0.01Ca0.08Li0.01]Σ1.04 (S15.87S0.06B0.01) (O14.86F0.14).(H2O)2.Weighted full-matrix least-squares refinement on 3369 reflections yielded Rall = 3.8%. The structure is built of corrugated [Si6O15]6- layers linked by [7]-coordinated REE and R4+ cations. This framework leaves channels that contain three [5]- and [6]-coordinated Na cations per formula unit that compensate for the residual charge on the silicate layers. The SIMS analyses confirm a Na content of 3 atoms per formula unit, leading to an ideal formula of Na3LaSi6O15(H2O)2. The third Na atom is bonded to H2O groups and therefore the total content of both Na and H2O may be reduced to 2 and 1 per formula, respectively. The depletion in Na allows for the entrance of high-charge cations such as Th4+.
The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules
Authors: Chintala Sreenivasulu , Tan Jian , Gautam Rashi , Rusiniak Michael E. , Guo Xiaoli , Li Wei , Gahl William A. , Huizing Marjan , Spritz Richard A. , Hutton Saunie , Novak Edward K. , Swank Richard T. 
Published: October 2006

Abstract
Platelet dense granules are lysosome-related organelles which contain high concentrations of several biologically important low-molecular-weight molecules. These include calcium, serotonin, adenine nucleotides, pyrophosphate, and polyphosphate, which are necessary for normal blood hemostasis. The synthesis of dense granules and other lysosome-related organelles is defective in inherited diseases such as Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HPS and CHS mutations in 8 human and at least 16 murine genes have been identified. Previous studies produced contradictory findings for the function of the murine ashen (Rab27a) gene in platelet-dense granules. We have used a positional cloning approach with one line of ashen mutants to establish that a new mutation in a second gene, Slc35d3, on mouse chromosome 10 is the basis of this discrepancy. The platelet-dense granule defect is rescued in BAC transgenic mice containing the normal Slc35d3 gene. Thus, Slc35d3, an orphan member of a nucleotide sugar transporter family, specifically regulates the contents of platelet-dense granules. Unlike HPS or CHS genes, it has no apparent effect on other lysosome-related organelles such as melanosomes or lysosomes. The ash-Roswell mouse mutant is an appropriate model for human congenital-isolated delta-storage pool deficiency.
ProFAT: a web-based tool for the functional annotation of protein sequences
Authors: Bradshaw Charles Richard , Surendranath Vineeth , Habermann Bianca 
Published: October 2006

Abstract

Background
The functional annotation of proteins relies on published information concerning their close and remote homologues in sequence databases. Evidence for remote sequence similarity can be further strengthened by a similar biological background of the query sequence and identified database sequences. However, few tools exist so far, that provide a means to include functional information in sequence database searches.

Results
We present ProFAT, a web-based tool for the functional annotation of protein sequences based on remote sequence similarity. ProFAT combines sensitive sequence database search methods and a fold recognition algorithm with a simple text-mining approach. ProFAT extracts identified hits based on their biological background by keyword-mining of annotations, features and most importantly, literature associated with a sequence entry. A user-provided keyword list enables the user to specifically search for weak, but biologically relevant homologues of an input query. The ProFAT server has been evaluated using the complete set of proteins from three different domain families, including their weak relatives and could correctly identify between 90% and 100% of all domain family members studied in this context. ProFAT has furthermore been applied to a variety of proteins from different cellular contexts and we provide evidence on how ProFAT can help in functional prediction of proteins based on remotely conserved proteins.

Conclusion
By employing sensitive database search programs as well as exploiting the functional information associated with database sequences, ProFAT can detect remote, but biologically relevant relationships between proteins and will assist researchers in the prediction of protein function based on remote homologies.