bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Bayesian adaptive design with biomarkers for targeted therapies
Authors: Eickhoff Jens C , KyungMann Kim  , Beach Jason , Kolesar Jill M , Gee Jason R 
Published: June 2010

Background Targeted therapies are becoming increasingly important for the treatment of various diseases. Biomarkers are a critical component of a targeted therapy as they can be used to identify patients who are more likely to benefit from a treatment. Targeted therapies, however, have created major challenges in the design, conduct, and analysis of clinical trials. In traditional clinical trials, treatment effects for various biomarkers are typically evaluated in an exploratory fashion and only limited information about the predictive values of biomarkers obtained. Purpose New study designs are required, which effectively evaluate both the diagnostic and the therapeutic implication of biomarkers. Methods The Bayesian approach provides a useful framework for optimizing the clinical trial design by directly integrating information about biomarkers and clinical outcomes as they become available. We propose a Bayesian covariate-adjusted response-adaptive randomization design, which utilizes individual biomarker profiles and patient’s clinical outcomes as they become available during the course of the trial, to assign the most efficacious treatment to individual patients. Predictive biomarker subgroups are determined adaptively using a partial least squares regression approach. Results A series of simulation studies were conducted to examine the operating characteristics of the proposed study design. The simulation studies show that the proposed design efficiently identifies patients who benefit most from a targeted therapy and that there are substantial savings in the sample size requirements when compared to alternative designs. Limitations The design does not control for the type I error in the traditional sense and a positive result should be confirmed by conducting an independent phase III study focusing on the selected biomarker profile groups. Conclusions We conclude that the proposed design may serve a useful role in the early efficacy phase of targeted therapy development. Clinical Trials 2010; 7: 546—556. http://ctj.sagepub.com
Evaluation of an automated method to assist with error detection in the ACCORD central laboratory
Authors: Strylewicz Gregory , Doctor Jason 
Published: June 2010

Background Errors in clinical laboratory data are rare but their potential high cost both in terms of harm to the subject as well as diluted statistical power results in a significant workload for experts, who must review large volumes of data in the search for these errors. Purpose The current research objective is to develop and evaluate a method to assist in detecting potential errors in laboratory data for an interventional clinical trial, such as Action to Control Cardiovascular Risk in Diabetes, where treatment effects may be influenced by errors in the data. Methods Utilizing data from a clinical trial investigating the effect of intensive glycemic control on major cardiovascular disease events, we constructed an algorithm that conducts probabilistic error detection called a ‘Bayesian network’. Using a synthetic error model, errors were introduced into a testing dataset, and the Bayesian network’s performance in identifying those errors was compared to laboratory experts. For each laboratory result we used the Bayesian network to compute the probability, the measured value was erroneous. This probability was then used to compute a receiver operating characteristic (ROC) curve. Three laboratory experts were recruited and took a survey consisting of 200 laboratory results. The task was to evaluate if these results were erroneous or not and to provide a confidence rating on a 6-point subjective probability scale. Results The Bayesian network’s overall area under the ROC curve was calculated to be 0.79, whereas the three laboratory experts had areas under the ROC curve of 0.73, 0.73, and 0.72. Perfect error prediction and random guessing yield a ROC of 1.00 and 0.50, respectively. This difference in performance was statistically significant for all three experts. Human experts were also generally overconfident in their ability to detect errors. Limitations The model is, by design, specific to a novel intervention in a specific diabetic population and, therefore, the specific Bayesian network discussed may not generalize to other interventions and populations. In addition, the study is limited by the small number of expert eligible to complete the survey. Conclusions The results of this study suggest that continuous Bayesian networks, suitably constructed, may serve as an effective tool to assist experts in the review of voluminous laboratory data by flagging unlikely results for more thorough review. Clinical Trials 2010; 7: 380—389. http://ctj.sagepub.com
Successful subject recruitment for a prostate cancer behavioral intervention trial
Authors: Heiney Sue P , Arp Adams Swann , Drake Bettina F , Bryant Lisa H , Bridges Lynne , Hebert James R 
Published: June 2010

Background Inadequate participant recruitment, which may lead to unrepresentative study samples that threaten a study’s validity, is often a major challenge in the conduct of research studies. Purpose The purpose of this article is to describe the development and implementation of a recruitment plan and evaluate the different recruitment strategies for a prostate cancer behavioral intervention trial. Methods Our recruitment plan was based on a framework (The Heiney—Adams Recruitment Model) that we developed, which combines relationship building and social marketing. We evaluated the success of our model using several different recruitment sources including: mailed letters, physician referral, and self-referral. Results Recruitment rates ranged from 67% for a support services department mailing to 100% for physician referral. While our original list of contacted patients was comprised of only 13% African American (AA) men, 22% of our recruited participants were AA. Limitations One of the strongest barriers to recruitment was strict patient eligibility. Another significant barrier was the lack of electronic records systems to allow for the identification of large numbers of potential participants. Conclusions In conclusion, our model incorporating social marketing and relationship building was quite successful in recruiting for a prostate cancer behavioral study, particularly AA participants. In developing strategies, future researchers should attend to issues of staffing, financial resources, physician support, and eligibility criteria in the light of study accrual. Clinical Trials 2010; 7: 411—417. http://ctj.sagepub.com
Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation
Authors: Milner Joshua D. , Orekov Tatyana , Ward Jerrold M. , Cheng Lily , Torres-Velez Fernando , Junttila Ilkka , Sun Guangping , Buller Mark , Morris Suzanne C. , Finkelman Fred D. , Paul William E. 
Published: June 2010

AbstractErythrophagocytosis and inflammation from activated macrophages occur in distinct clinical scenarios. The presence of CD8+ T cells and interferon-γ (IFN-γ) production is required to induce disease in mouse models of hemophagocytic lymphohistiocytosis. We investigated the roles of a different class of proinflammatory cytokines, interleukin-4 (IL-4) and IL-13, in the induction of inflammatory tissue macrophage accumulation and/or hemophagocytosis. We found that large amounts of IL-4, but not IL-13, delivered via an implanted mini-pump or IL-4/anti–IL-4 complexes, lead to substantial YM1+ tissue macrophage accumulation, erythrophagocytosis within the liver, spleen, and bone marrow, decreased hemoglobin and platelet levels, and acute weight loss. This effect is not dependent on the presence of antibody or T cells, as treatment of Rag2−/− mice leads to similar disease, and IFN-γ neutralization during IL-4 treatment had no effect. IL-4 treatment results in suppression of IL-12, elevation of serum IFN-γ, IL-10, and the murine IL-8 homolog KC, but not IL-6, IL-1β, or tumor necrosis factor-α. Finally, mice transgenic for IL-4 production developed tissue macrophage accumulation, disruption of splenic architecture, bone marrow hypocellularity, and extramedullary hematopoiesis. These data describe a novel pathophysiologic pathway for erythrophagocytosis in the context of tissue macrophage accumulation and inflammation involving elevations in IL-4 and alternative macrophage activation.
Regulation of fibrinogen production by microRNAs
Authors: Fort Alexandre , Borel Christelle , Migliavacca Eugenia , Antonarakis Stylianos E. , Fish Richard J. , Neerman-Arbez Marguerite 
Published: June 2010

AbstractElevated levels of fibrinogen are associated with increased risk of cardiovascular disease, whereas low fibrinogen can lead to a bleeding disorder. We investigated whether microRNAs (miRNAs), known to act as post-transcriptional regulators of gene expression, regulate fibrinogen production. Using transfection of a library of 470 annotated human miRNA precursor molecules in HuH7 hepatoma cells and quantitative measurements of fibrinogen production, we identified 23 miRNAs with down-regulating (up to 64% decrease) and 4 with up-regulating effects (up to 129% increase) on fibrinogen production. Among the down-regulating miRNAs, we investigated the mechanism of action of 3 hsa-miR-29 family members and hsa-miR-409-3p. Overexpression of hsa-miR-29 members led to decreased steady-state levels of all fibrinogen gene (FGA, FGB, and FGG) transcripts in HuH7 cells. Luciferase reporter gene assays demonstrated that this was independent of miRNA-fibrinogen 3′-untranslated region interactions. In contrast, overexpression of hsa-miR-409-3p specifically lowered fibrinogen Bβ mRNA levels, and this effect was dependent on a target site in the fibrinogen Bβ mRNA 3′-untranslated region. This study adds to the known mechanisms that control fibrinogen production, points toward a potential cause of variable circulating fibrinogen levels, and demonstrates that a screening approach can identify miRNAs that regulate clinically important proteins.
Mantle cell lymphoma activation enhances bortezomib sensitivity
Authors: Brennan Sarah K. , Meade Brooke , Wang Qiuju , Merchant Akil A. , Kowalski Jeanne , Matsui William 
Published: June 2010

AbstractPatients with mantle cell lymphoma (MCL) typically respond to initial treatment but subsequently relapse. This pattern suggests that a population of MCL cells is both drug resistant and capable of clonogenic growth. The intracellular enzyme retinaldehyde dehydrogenase (ALDH) provides resistance to several toxic agents. ALDH can also identify stem cells in normal adult tissues and tumorigenic cancer stem cells in several human malignancies. We studied ALDH expression in MCL and found small populations of ALDH+ cells that were highly clonogenic. Moreover, ALDH+ MCL cells were relatively quiescent and resistant to a wide range of agents. Normal B cells can be activated by specific unmethylated cytosine-phosphate-guanosine (CpG) DNA motifs through toll-like receptor 9, and we found that the synthetic CpG oligonucleotide 2006 (CpG) reduced the frequency of quiescent ALDH+ MCL cells, induced terminal plasma cell differentiation, and limited tumor formation in vitro and in vivo. Treatment with CpG also significantly enhanced the activity of the proteasome inhibitor bortezomib that was associated with induction of the unfolded protein response. Our data suggest that CpG may target clonogenic and resistant ALDH+ cells as well as improve the activity of proteasome inhibitors in MCL.
The dominant-negative von Willebrand factor gene deletion p.P1127_C1948delinsR: molecular mechanism and modulation
Authors: Casari Caterina , Pinotti Mirko , Lancellotti Stefano , Adinolfi Elena , Casonato Alessandra , De Cristofaro Raimondo , Bernardi Francesco 
Published: June 2010

AbstractUnderstanding molecular mechanisms in the dominant inheritance of von Willebrand disease would improve our knowledge of pathophysiologic processes underlying its prevalence. Cellular models of severe type 2 von Willebrand disease, caused by a heterozygous deletion in the von Willebrand factor (VWF) gene, were produced to investigate the altered biosynthesis. Coexpression of the wild-type and in-frame deleted (p.P1127_C1948delinsR) VWF forms impaired protein secretion, high molecular weight multimer formation and function (VWF collagen-binding 1.9% ± 0.5% of wild-type), which mimicked the patient's phenotype. mRNA, protein, and cellular studies delineated the highly efficient dominant-negative mechanism, based on the key role of heterodimers as multimer terminators. The altered VWF, synthesized in large amounts with the correctly encoded “cysteine knot” domain, formed heterodimers and heterotetramers with wild-type VWF, in addition to deleted homodimers. Impaired multimerization was associated with reduced amounts of VWF in late endosomes. Correction of the dominant-negative effect was explored by siRNAs targeting the mRNA breakpoint, which selectively inhibited the in-frame deleted VWF expression. Although the small amount of the deleted protein synthesized after inhibition still exerted dominant, even though weakened, negative effects, the siRNA treatment restored secretion of large multimers with improved function (VWF collagen-binding 28.0% ± 3.3% of wild-type).
Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia
Authors: Zhou Qing , Munger Meghan E. , Highfill Steven L. , Tolar Jakub , Weigel Brenda J. , Riddle Megan , Sharpe Arlene H. , Vallera Daniel A. , Azuma Miyuki , Levine Bruce L. , June Carl H. , Murphy William J. , Munn David H. , Blazar Bruce R. 
Published: June 2010

Abstract
Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8+ cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8+ T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti–PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease.
Crosstalks between integrin alpha 5 and IGF2/IGFBP2 signalling trigger human bone marrow-derived mesenchymal stromal osteogenic differentiation
Authors: Hamidouche Zahia , Fromigué Olivia , Ringe Jochen , Häupl Thomas , Marie Pierre J 
Published: June 2010

Abstract

Background
The potential of mesenchymal stromal cells (MSCs) to differentiate into functional bone forming cells provides an important tool for bone regeneration. The identification of factors that trigger osteoblast differentiation in MSCs is therefore critical to promote the osteogenic potential of human MSCs. In this study, we used microarray analysis to identify signalling molecules that promote osteogenic differentiation in human bone marrow stroma derived MSCs.

Results
Microarray analysis and validation experiments showed that the expression of IGF2 and IGFBP2 was increased together with integrin alpha5 (ITGA5) during dexamethasone-induced osteoblast differentiation in human MSCs. This effect was functional since we found that IGF2 and IGFBP2 enhanced the expression of osteoblast phenotypic markers and in vitro osteogenic capacity of hMSCs. Interestingly, we showed that downregulation of endogenous ITGA5 using specific shRNA decreased IGF2 and IGFBP2 expression in hMSCs. Conversely, ITGA5 overexpression upregulated IGF2 and IGFBP2 expression in hMSCs, which indicates tight crosstalks between these molecules. Consistent with this concept, activation of endogenous ITGA5 using a specific antibody that primes the integrin, or a peptide that specifically activates ITGA5 increased IGF2 and IGFBP2 expression in hMSCs. Finally, we showed that pharmacological inhibition of FAK/ERK1/2-MAPKs or PI3K signalling pathways that are enhanced by ITGA5 activation, blunted IGF2 and IGFBP2 expression in hMSCs.

Conclusion
The results show that ITGA5 is a key mediator of IGF2 and IGFBP2 expression that promotes osteoblast differentiation in human MSCs, and reveal that crosstalks between ITGA5 and IGF2/IGFBP2 signalling are important mechanisms that trigger osteogenic differentiation in human bone marrow derived mesenchymal stromal cells.
A draft physical map of a D-genome cotton species (Gossypium raimondii)
Authors: Lin Lifeng , Pierce Gary J , Bowers John E , Estill James C , Compton Rosana O , Rainville Lisa K , Kim Changsoo , Lemke Cornelia , Rong Junkang , Tang Haibao , Wang Xiyin , Braidotti Michele , Chen Amy H , Chicola Kristen , Collura Kristi , Epps Ethan , Golser Wolfgang , Grover Corrinne , Ingles Jennifer , Karunakaran Santhosh , Kudrna Dave , Olive Jaime , Tabassum Nabila , Um Eareana , Wissotski Marina , Yu Yeisoo , Zuccolo Andrea , ur Rahman Mehboob , Peterson Daniel G , Wing Rod A , Wendel Jonathan F , Paterson Andrew H 
Published: June 2010

Abstract

Background
Genetically anchored physical maps of large eukaryotic genomes have proven useful both for their intrinsic merit and as an adjunct to genome sequencing. Cultivated tetraploid cottons, Gossypium hirsutum and G. barbadense, share a common ancestor formed by a merger of the A and D genomes about 1-2 million years ago. Toward the long-term goal of characterizing the spectrum of diversity among cotton genomes, the worldwide cotton community has prioritized the D genome progenitor Gossypium raimondii for complete sequencing.

Results
A whole genome physical map of G. raimondii, the putative D genome ancestral species of tetraploid cottons was assembled, integrating genetically-anchored overgo hybridization probes, agarose based fingerprints and 'high information content fingerprinting' (HICF). A total of 13,662 BAC-end sequences and 2,828 DNA probes were used in genetically anchoring 1585 contigs to a cotton consensus genetic map, and 370 and 438 contigs, respectively to Arabidopsis thaliana (AT) and Vitis vinifera (VV) whole genome sequences.

Conclusion
Several lines of evidence suggest that the G. raimondii genome is comprised of two qualitatively different components. Much of the gene rich component is aligned to the Arabidopsis and Vitis vinifera genomes and shows promise for utilizing translational genomic approaches in understanding this important genome and its resident genes. The integrated genetic-physical map is of value both in assembling and validating a planned reference sequence.
Role of type 1 and type 3 fimbriae in Klebsiella pneumoniae biofilm formation
Authors: Schroll Casper , Barken Kim B , Krogfelt Karen A , Struve Carsten 
Published: June 2010

Abstract

Background

Klebsiella pneumoniae is an important gram-negative opportunistic pathogen causing primarily urinary tract infections, respiratory infections, and bacteraemia. The ability of bacteria to form biofilms on medical devices, e.g. catheters, has a major role in development of many nosocomial infections. Most clinical K. pneumoniae isolates express two types of fimbrial adhesins, type 1 fimbriae and type 3 fimbriae. In this study, we characterized the role of type 1 and type 3 fimbriae in K. pneumoniae biofilm formation.

Results
Isogenic fimbriae mutants of the clinical K. pneumoniae isolate C3091 were constructed, and their ability to form biofilm was investigated in a flow cell system by confocal scanning laser microscopy. The wild type strain was found to form characteristic biofilm and development of K. pneumoniae biofilm occurred primarily by clonal growth, not by recruitment of planktonic cells. Type 1 fimbriae did not influence biofilm formation and the expression of type 1 fimbriae was found to be down-regulated in biofilm forming cells. In contrast, expression of type 3 fimbriae was found to strongly promote biofilm formation.

Conclusion
By use of well defined isogenic mutants we found that type 3 fimbriae, but not type 1 fimbriae, strongly promote biofilm formation in K. pneumoniae C3091. As the vast majority of clinical K. pneumoniae isolates express type 3 fimbriae, this fimbrial adhesin may play a significant role in development of catheter associated K. pneumoniae infections.
1Novel MEFV transcripts in Familial Mediterranean fever patients and controls
Authors: Medlej-Hashim Myrna , Nehme Nancy , Chouery Eliane , Jalkh Nadine , Megarbane André 
Published: June 2010

Abstract

Background
Familial Mediterranean fever is a recessive autoinflammatory disease frequently encountered in Armenians, Jews, Arabs and Turks. The MEFV gene is responsible for the disease. It encodes a protein called pyrin/marenostrin involved in the innate immune system. A large number of clinically diagnosed FMF patients carry only one MEFV mutation. This study aims at studying the MEFV gene splicing pattern in heterozygous FMF patients and healthy individuals, in an attempt to understand the mechanism underlying the disease in these patients.

Methods
RNA was extracted from peripheral blood leucocytes of 41 FMF patients and 34 healthy individuals. RT-PCR was then performed, and the amplified products were migrated on a polyacrylamide electrophoresis gel, characterized by gel extraction of the corresponding bands followed by sequencing.

Results
Five novel splicing events were observed in both patients and controls deleting either exons 3, 4 (del34), or exons 2, 3, 4 (del234), or exons 2, 3, 4, 5 (del2345) or exon7 (del7) or exons 7 and 8 (del78).

Conclusions
The observation of such qualitative variability in the expression of the MEFV gene suggests a complex transcriptional regulation. However, the expression of these novel transcripts in both patients and controls is not in favour of a severe pathogenic effect.