bluuebunny/crossref_metadata_2025_split huggingface dataset:
Motivating the unmotivated for health behavior change: a randomized trial of cessation induction for smokers
Authors: Carpenter Matthew J , Alberg Anthony J , Gray Kevin M , Saladin Michael E 
Published: March 2010

Background Many smokers remain unwilling or unable to make a quit attempt. For these smokers, novel strategies to induce quit attempts are necessary to achieve further reductions in smoking prevalence. Purpose This article describes the design and methods of an ongoing nationwide telephone-based clinical trial for cessation induction, the principal aim of which is to test the hypothesis that samples of nicotine replacement therapy (NRT), can induce quit attempts among smokers otherwise unmotivated to quit. Methods Smokers are recruited proactively through online channels. A ‘behavioral filter’ is used to identify and separate motivated versus unmotivated smokers, the latter of whom (N = 750) are formally entered into the clinical trial. Participants are randomized to one of two treatment conditions designed to promote self-efficacy and motivation to quit: (1) practice quit attempt (PQA) or (2) PQA plus NRT sampling. The primary outcome measure tested over a 6-month follow-up is the incidence of additional quit attempts as well as hypothesized mediators of treatment effects. Results This study details the challenges of identifying and treating smokers who are unmotivated to quit. Strengths include a novel treatment approach, tested among a group of proactively recruited smokers nationwide, with a unique method of identifying cessation-resistant smokers. Limitations The omission of a true control group, testing the effect of the PQA itself, is an inherent limitation to the study design. Online recruitment presents additional study challenges, all of which are discussed in detail. Conclusions The study has translational potential to guide both clinical and policy recommendations for cessation induction. Further, while the focus is on smoking, this trial may serve as an example to researchers and clinicians who focus on other health behaviors, and who themselves are challenged with motivating people who are unmotivated for change. Clinical Trials 2010; 7: 157—166. http://ctj.sagepub.com
Barriers and opportunities for implementation of adaptive designs in pharmaceutical product development
Authors: Quinlan Judith , Gaydos Brenda , Maca Jeff , Krams Michael 
Published: March 2010

Background This review discusses barriers to implementing adaptive designs in a pharmaceutical R&D environment and provides recommendations on how to overcome challenges. A summary of findings from a survey conducted through PhRMA’s working group on adaptive designs is followed by a report based on our experience as statistical and clinical consultants to project teams charged with establishing the clinical development strategy for investigational compounds and interested in applying innovative approaches. Findings and recommendations Adaptive designs require additional work in that clinical trial simulations are needed to develop the design. Some project teams, due to time and resource constraints, are unable to invest the additional effort required to conduct necessary scenario analyses of options through simulation. We recommend formally integrating the planning time for scenario analyses and to incentivize optimal designs (e.g., designs offering the highest information value per resource unit invested). Regardless of the trial design ultimately chosen, quantitatively comparing alternative trial design options through simulation will enable earlier and better decision making in the context of the overall clinical development plan. Adhering to ‘Good Adaptive Practices’ will be key to achieving this goal. Outlook Implementing adaptive designs efficiently requires top—down and bottom— up support and the willingness to invest into integrated process and information technology infrastructures. Success is conditional on the willingness of the R&D environment to embrace the implementation of adaptive designs as a Change Management Initiative in the spirit of the Critical Path of the Food and Drug Administration. Clinical Trials 2010; 7: 167—173. http://ctj.sagepub.com
Regional differences in multinational clinical trials: anticipating chance variation
Authors: Marschner Ian C 
Published: March 2010

Background Multinational clinical trials efficiently pool resources and provide treatment comparisons across diverse populations. However, they may be difficult to interpret when there are larger than expected differences in region-specific treatment effects, such as a positive study that includes regions favoring the control arm. Purpose This article investigates the extent of chance variation that can be expected in regional treatment effects from multinational studies. It advocates studying this expected variation during the design stage, hence limiting the potential for surprises and misinterpretations at the end of the study. Methods The theory of order statistics was used to quantify chance variation between regions, assuming a homogeneous treatment effect. The expected values of the smallest and largest treatment difference were used to calculate the expected range of regional effects. This range was supplemented by the probability of observing at least one regional effect favoring the control arm. Results Chance variation led to a wide range of expected regional effects. For a study with five regions and 80% power, the expected regional treatment effects ranged from no difference to double the true difference, while the probability of observing a region favoring the control was approximately 50%. With 10 regions this probability exceeded 85% and the expected range of regional effects extended to values substantially favoring the control. Increasing the power of the study to 90% or more offered little protection against wide variation in regional effects. Limitations The proposed approach does not replace heterogeneity testing at the end of the study, but provides useful supporting information for interpreting such tests. Conclusions Large differences between regions should be anticipated in multinational studies. The expected range of treatment effects should be assessed during study design in order to inform stakeholders and calibrate expectations. Clinical Trials 2010; 7: 147—156. http://ctj.sagepub.com
Routine data from hospital information systems can support patient recruitment for clinical studies
Authors: Dugas Martin , Lange Matthias , Müller-Tidow Carsten , Kirchhof Paulus , Prokosch Hans-Ulrich 
Published: March 2010

Background Delayed patient recruitment is a common problem in clinical studies. Hospital information systems (HIS) contain data items relevant for inclusion or exclusion criteria of these studies. Purpose We developed and assessed a system to support patient recruitment using HIS data. Methods We developed a workflow integrated in our HIS to notify study physicians about potential trial subjects. Automatic HIS database queries based on inclusion and exclusion criteria for each clinical study are performed regularly and generate e-mail notifications via a communication server. Study physicians can verify eligibility with a specific HIS study module. The system performance was assessed with a survey addressing utility, usability, stability, change in recruitment rate, and estimated time savings. Results During 10 months of operation, 1328 notifications were generated and 329 enrollments (25%) were documented for seven studies. Precision of alerts depends on availability of appropriate HIS items. Utility and usability were assessed as good, and stability as excellent. Users reported an increased patient recruitment rate for three studies. Three studies reported an estimated time saving of 10 min per recruited patient. The main perceived benefit was systematic identification of potentially eligible patients without time-consuming patient screening procedures in the different parts of the hospital. Limitations Notifications about potentially eligible patients depend on HIS data quality regarding inclusion/exclusion criteria, in particular, completeness, timeliness, and validity. Conclusions Routine HIS data can support patient recruitment for clinical studies by means of an automated notification workflow and efficient access to clinical data. Clinical Trials 2010; 7: 183-189. http://ctj.sagepub.com
AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2
Authors: Wang Wei , Schwemmers Sven , Hexner Elizabeth O. , Pahl Heike L. 
Published: March 2010

Abstract
The transcription factor NF-E2 is overexpressed in the majority of patients with polycythemia vera (PV). Concomitantly, 95% of these patients carry the JAK2V617F mutation. Although NF-E2 levels correlate with JAK2V671F allele burden in some PV cohorts, the molecular mechanism causing aberrant NF-E2 expression has not been described. Here we show that NF-E2 expression is also increased in patients with essential thrombocythemia and primary myelofibrosis independent of the presence of the JAK2V617F mutation. Characterization of the NF-E2 promoter revealed multiple functional binding sites for AML1/RUNX-1. Chromatin immunoprecipitation demonstrated AML1 binding to the NF-E2 promoter in vivo. Moreover, AML1 binding to the NF-E2 promoter was significantly increased in granulocytes from PV patients compared with healthy controls. AML1 mRNA expression was elevated in patients with PV, essential thrombocythemia, and primary myelofibrosis both in the presence and absence of JAK2V617F. In addition, AML1 and NF-E2 expression were highly correlated. RNAi-mediated suppression of either AML1 or of its binding partner CBF-β significantly decreased NF-E2 expression. Moreover, expression of the leukemic fusion protein AML/ETO drastically decreased NF-E2 protein levels. Our data identify NF-E2 as a novel AML1 target gene and delineate a role for aberrant AML1 expression in mediating elevated NF-E2 expression in MPN patients.
Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study
Authors: Mitchell Lesley , Lambers Moritz , Flege Silke , Kenet Gili , Li-Thiao-Te Valerie , Holzhauer Susanne , Bidlingmaier Christoph , Frühwald Michael C. , Heller Christine , Schmidt Wolfgang , Pautard Brigitte , Nowak-Göttl Ulrike 
Published: March 2010

Abstract
Among risk factors for developing thromboembolism (VTE) in children with acute lymphoblastic leukemia were Escherichia coli asparaginase, concomitant steroid use, presence of central venous lines, and thrombophilic abnormalities. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to high-risk groups (HRGs). Predictive variables were incorporated into a risk assessment model, which was evaluated in 456 children and then validated in 339 patients. VTE risk by score was no greater than 2.5 for low-risk group (LRG) and greater than 2.5 for HRG. VTE rates at 3.5 months (validation cohorts) were 2.5% in LRG and 64.7% in HRG. In multivariate analysis adjusted for age, duration of asparaginase administration, enoxaparin prophylaxis, and T-immunophenotype, the HRG was significantly associated with VTE compared with the LRG (hazard/95% confidence interval [CI], 8.22/1.85-36.53). Model specificity was 96.2% and sensitivity was 63.2%. As secondary objective we investigated the use of enoxaparin for VTE prophylaxis in the HRG. HRG patients without enoxaparin prophylaxis showed a significantly reduced thrombosis-free survival compared with children on low-molecular-weight heparin (LMWH). On the basis of the high specificity, the model may identify children with leukemia at risk of VTE. LMWH may help prevent VTE in the HRG; this warrants assessment in larger cooperative clinical trials.
Reduced representation of protein structure: implications on efficiency and scope of detection of structural similarity
Authors: Zhang Zong Hong , Lee Hwee Kuan , Mihalek Ivana 
Published: March 2010

Abstract

Background
Computational comparison of two protein structures is the starting point of many methods that build on existing knowledge, such as structure modeling (including modeling of protein complexes and conformational changes), molecular replacement, or annotation by structural similarity. In a commonly used strategy, significant effort is invested in matching two sets of atoms. In a complementary approach, a global descriptor is assigned to the overall structure, thus losing track of the substructures within.

Results
Using a small set of geometric features, we define a reduced representation of protein structure, together with an optimizing function for matching two representations, to provide a pre-filtering stage in a database search. We show that, in a straightforward implementation, the representation performs well in terms of resolution in the space of protein structures, and its ability to make new predictions.

Conclusions
Perhaps unexpectedly, a substantial discriminating power already exists at the level of main features of protein structure, such as directions of secondary structural elements, possibly constrained by their sequential order. This can be used toward efficient comparison of protein (sub)structures, allowing for various degrees of conformational flexibility within the compared pair, which in turn can be used for modeling by homology of protein structure and dynamics.
Moara: a Java library for extracting and normalizing gene and protein mentions
Authors: Neves Mariana L , Carazo José-María , Pascual-Montano Alberto 
Published: March 2010

Abstract

Background
Gene/protein recognition and normalization are important preliminary steps for many biological text mining tasks, such as information retrieval, protein-protein interactions, and extraction of semantic information, among others. Despite dedication to these problems and effective solutions being reported, easily integrated tools to perform these tasks are not readily available.

Results
This study proposes a versatile and trainable Java library that implements gene/protein tagger and normalization steps based on machine learning approaches. The system has been trained for several model organisms and corpora but can be expanded to support new organisms and documents.

Conclusions
Moara is a flexible, trainable and open-source system that is not specifically orientated to any organism and therefore does not requires specific tuning in the algorithms or dictionaries utilized. Moara can be used as a stand-alone application or can be incorporated in the workflow of a more general text mining system.
The function and regulation of the bHLH gene, cato, in Drosophila neurogenesis
Authors: zur Lage Petra I , Jarman Andrew P 
Published: March 2010

Abstract
Background
bHLH transcription factors play many roles in neural development. cousin of atonal (cato) encodes one such factor that is expressed widely in the developing sensory nervous system of Drosophila. However, nothing definitive was known of its function owing to the lack of specific mutations.

Results
We characterised the expression pattern of cato in detail using newly raised antibodies and GFP reporter gene constructs. Expression is predominantly in sensory lineages that depend on the atonal and amos proneural genes. In lineages that depend on the scute proneural gene, cato is expressed later and seems to be particularly associated with the type II neurons. Consistent with this, we find evidence that cato is a direct target gene of Atonal and Amos, but not of Scute. We generated two specific mutations of cato. Mutant embryos show several defects in chordotonal sensory lineages, most notably the duplication of the sensory neuron, which appears to be caused by an extra cell division. In addition, we show that cato is required to form the single chordotonal organ that persists in atonal mutant embryos.

Conclusions
We conclude that although widely expressed in the developing PNS, cato is expressed and regulated very differently in different sensory lineages. Mutant phenotypes correlate with cato's major expression in the chordotonal sensory lineage. In these cells, we propose that it plays roles in sense organ precursor maintenance and/or identity, and in controlling the number of cell divisions in the neuronal branch of the lineage arising from these precursors.
Population dynamic of the extinct European aurochs: genetic evidence of a north-south differentiation pattern and no evidence of post-glacial expansion
Authors: Mona Stefano , Catalano Giulio , Lari Martina , Larson Greger , Boscato Paolo , Casoli Antonella , Sineo Luca , Di Patti Carolina , Pecchioli Elena , Caramelli David , Bertorelle Giorgio 
Published: March 2010

AbstractBackgroundThe aurochs (Bos primigenius) was a large bovine that ranged over almost the entirety of the Eurasian continent and North Africa. It is the wild ancestor of the modern cattle (Bos taurus), and went extinct in 1627 probably as a consequence of human hunting and the progressive reduction of its habitat. To investigate in detail the genetic history of this species and to compare the population dynamics in different European areas, we analysedBos primigeniusremains from various sites across Italy.ResultsFourteen samples provided ancient DNA fragments from the mitochondrial hypervariable region. Our data, jointly analysed with previously published sequences, support the view that Italian aurochsen were genetically similar to modern bovine breeds, but very different from northern/central European aurochsen. Bayesian analyses and coalescent simulations indicate that the genetic variation pattern in both Italian and northern/central European aurochsen is compatible with demographic stability after the last glaciation. We provide evidence that signatures of population expansion can erroneously arise in stable aurochsen populations when the different ages of the samples are not taken into account.ConclusionsDistinct groups of aurochsen probably inhabited Italy and northern/central Europe after the last glaciation, respectively. On the contrary, Italian and Fertile Crescent aurochsen likely shared several mtDNA sequences, now common in modern breeds. We argue that a certain level of genetic homogeneity characterized aurochs populations in Southern Europe and the Middle East, and also that post-glacial recolonization of northern and central Europe advanced, without major demographic expansions, from eastern, and not southern, refugia.
The response to unfolded protein is involved in osmotolerance of Pichia pastoris
Authors: Dragosits Martin , Stadlmann Johannes , Graf Alexandra , Gasser Brigitte , Maurer Michael , Sauer Michael , Kreil David P , Altmann Friedrich , Mattanovich Diethard 
Published: March 2010

AbstractBackgroundThe effect of osmolarity on cellular physiology has been subject of investigation in many different species. High osmolarity is of importance for biotechnological production processes, where high cell densities and product titers are aspired. Several studies indicated that increased osmolarity of the growth medium can have a beneficial effect on recombinant protein production in different host organisms. Thus, the effect of osmolarity on the cellular physiology ofPichia pastoris, a prominent host for recombinant protein production, was studied in carbon limited chemostat cultures at different osmolarities. Transcriptome and proteome analyses were applied to assess differences upon growth at different osmolarities in both, a wild type strain and an antibody fragment expressing strain. While our main intention was to analyze the effect of different osmolarities onP. pastorisin general, this was complemented by studying it in context with recombinant protein production.ResultsIn contrast to the model yeastSaccharomyces cerevisiae, the main osmolyte inP. pastoriswas arabitol rather than glycerol, demonstrating differences in osmotic stress response as well as energy metabolism. 2D Fluorescence Difference Gel electrophoresis and microarray analysis were applied and demonstrated that processes such as protein folding, ribosome biogenesis and cell wall organization were affected by increased osmolarity. These data indicated that upon increased osmolarity less adaptations on both the transcript and protein level occurred in aP. pastorisstrain, secreting the Fab fragment, compared with the wild type strain. No transcriptional activation of the high osmolarity glycerol (HOG) pathway was observed at steady state conditions. Furthermore, no change of the specific productivity of recombinant Fab was observed at increased osmolarity.ConclusionThese data point out that the physiological response to increased osmolarity is different to S.cerevisiae. Increased osmolarity resulted in an unfolded protein response (UPR) like response inP. pastorisand lead to pre-conditioning of the recombinant Fab producing strain ofP. pastoristo growth at high osmolarity. The current data demonstrate a strong similarity of environmental stress response mechanisms and recombinant protein related stresses. Therefore, these results might be used in future strain and bioprocess engineering of this biotechnologically relevant yeast.
First insights into the genetic diversity of Mycobacterium tuberculosis isolates from HIV-infected Mexican patients and mutations causing multidrug resistance
Authors: Lopez-Alvarez Rocio , Badillo-Lopez Claudia , Cerna-Cortes Jorge F , Castillo-Ramirez Ivan , Rivera-Gutierrez Sandra , Helguera-Repetto Addy C , Aguilar Diana , Hernandez-Pando Rogelio , Samper Sofia , Gonzalez-y-Merchand Jorge A 
Published: March 2010

Abstract

Background
The prevalence of infections with Mycobacterium tuberculosis (MTb) and nontuberculous mycobacteria (NTM) species in HIV-infected patients in Mexico is unknown. The aims of this study were to determine the frequency of MTb and NTM species in HIV-infected patients from Mexico City, to evaluate the genotypic diversity of the Mycobacterium tuberculosis complex strains, to determine their drug resistance profiles by colorimetric microplate Alamar Blue assay (MABA), and finally, to detect mutations present in kat G, rpo B and inh A genes, resulting in isoniazid (INH) and rifampin (RIF) resistance.

Results
Of the 67 mycobacterial strains isolated, 48 were identified as MTb, 9 as M. bovis, 9 as M. avium and 1 as M. intracellulare. IS6110-RFLP of 48 MTb strains showed 27 profiles. Spoligotyping of the 48 MTb strains yielded 21 patterns, and 9 M. bovis strains produced 7 patterns. Eleven new spoligotypes patterns were found. A total of 40 patterns were produced from the 48 MTb strains when MIRU-VNTR was performed. Nineteen (39.6%) MTb strains were resistant to one or more drugs. One (2.1%) multidrug-resistant (MDR) strain was identified. A novel mutation was identified in a RIF-resistant strain, GAG → TCG (Glu → Ser) at codon 469 of rpo B gene.

Conclusions
This is the first molecular analysis of mycobacteria isolated from HIV-infected patients in Mexico, which describe the prevalence of different mycobacterial species in this population. A high genetic diversity of MTb strains was identified. New spoligotypes and MIRU-VNTR patterns as well as a novel mutation associated to RIF-resistance were found. This information will facilitate the tracking of different mycobacterial species in HIV-infected individuals, and monitoring the spread of these microorganisms, leading to more appropriate measures for tuberculosis control.