bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways
Authors: Sepulcre J , Masdeu JC , Goñi J , Arrondo G , Vélez de Mendizábal N , Bejarano B , Villoslada P 
Published: November 2008

Background Fatigue is one of the most frequent and disturbing symptoms in multiple sclerosis (MS), directly affecting the patient’s quality of life. However, many questions remain unclear regarding the anatomic brain correlate of MS-related fatigue. Objective To assess the relationship between fatigue and white matter lesion location and gray matter atrophy. Methods In this study, 60 patients with MS were evaluated with the Modified Fatigue Impact Scale and magnetic resonance imaging. Location of white matter lesion was analyzed using a voxel-by-voxel lesion probability mapping approach and gray matter atrophy degree and location using an optimized voxel-based morphometry method. Results We found a correlation between lesion load and fatigue score (T2 lesion load: r = 0.415, P = 0.001; T1 lesion load r = 0.328, P = 0.011). Moreover, fatigue correlated with lesions in the right parietotemporal (periatrial area, juxtaventricular white matter deep in the parietal lobe and callosal forceps) and left frontal (middle-anterior corpus callosum, anterior cingulum and centrum semiovale of the superior and middle frontal gyri) white matter regions ( P < 0.001 in all cases). Finally, fatigue score significantly correlated with gray matter atrophy in frontal regions, specifically, the left superior frontal gyrus and bilateral middle frontal gyri ( P < 0.001 in all cases). Conclusion Our results suggest that the symptom of fatigue is associated with a disruption of brain networks involved in cognitive/attentional processes.
Toward a Critical Historiography of the Episcopal Church
Authors: Harp Gillis 
Published: November 2008

ABSTRACTHistorians of the Episcopal Church of the USA face the challenge of dealing with a tradition of in house ‘self-serving’ biographies and also of a Whiggish meta-narrative which privileged the Anglo Catholic reading of the history of ECUSA. This is similar to the challenge laid out by Diarmaid MacCulloch in relation to the English Reformation. This meta-narrative often read evangelicals out of the story. My book sought in part to correct this approach through a fresh analysis of Phillips Brooks' ministry and teaching. Within a broad tradition such as Anglicanism, argument about the past is part of the contemporary debate about identity in the tradition and of priorities in the present. That is very reasonable and a more candid engagement of the differences would serve everyone better than different perspectives passing each other like ships in the night.
Hemoglobin research and the origins of molecular medicine
Authors: Schechter Alan N. 
Published: November 2008

AbstractMuch of our understanding of human physiology, and of many aspects of pathology, has its antecedents in laboratory and clinical studies of hemoglobin. Over the last century, knowledge of the genetics, functions, and diseases of the hemoglobin proteins has been refined to the molecular level by analyses of their crystallographic structures and by cloning and sequencing of their genes and surrounding DNA. In the last few decades, research has opened up new paradigms for hemoglobin related to processes such as its role in the transport of nitric oxide and the complex developmental control of the α-like and β-like globin gene clusters. It is noteworthy that this recent work has had implications for understanding and treating the prevalent diseases of hemoglobin, especially the use of hydroxyurea to elevate fetal hemoglobin in sickle cell disease. It is likely that current research will also have significant clinical implications, as well as lessons for other aspects of molecular medicine, the origin of which can be largely traced to this research tradition.
Distinctive localization of antigen-presenting cells in human lymph nodes
Authors: Angel Catherine E. , Chen Chun-Jen J. , Horlacher Oliver C. , Winkler Sintia , John Thomas , Browning Judy , MacGregor Duncan , Cebon Jonathan , Dunbar P. Rod 
Published: November 2008

AbstractProfessional antigen-presenting cells (APCs) are sentinel cells of the immune system that present antigen to T lymphocytes and mediate an appropriate immune response. It is therefore surprising that knowledge of the professional APCs in human lymph nodes is limited. Using 3-color immunohistochemistry, we have identified APCs in human lymph nodes, excluding plasmacytoid APCs, that fall into 2 nonoverlapping classes: (1) CD209+ APCs, coexpressing combinations of CD206, CD14, and CD68, that occupied the medullary cords, lined the capsule and trabeculae and were also scattered throughout the diffuse T-lymphocyte areas of the paracortex; and (2) APCs expressing combinations of CD1a, CD207, and CD208, that were always restricted to the paracortex. Surprisingly, this second class of APCs was almost entirely absent from many lymph nodes. Our data suggest that most CD208+ cells, often referred to as “interdigitating cells,” derive from migratory APCs, and that the major APC subset consistently resident in the paracortex of human lymph nodes is the CD209+ subset. All APC subsets were demonstrated to be in close contact with the fibroreticular network. The identification of 2 distinct APC populations in the paracortex of human lymph nodes has important implications for understanding T-lymphocyte responses and optimizing vaccine design.
The transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element
Authors: Cichocki Frank , Hanson Rebecca J. , Lenvik Todd , Pitt Michelle , McCullar Valarie , Li Hongchuan , Anderson Stephen K. , Miller Jeffrey S. 
Published: November 2008

Abstract
The killer cell immunoglobulin-like receptor (KIR) repertoire of natural killer (NK) cells determines their ability to detect infected or transformed target cells. Although epigenetic mechanisms play a role in KIR gene expression, work in the mouse suggests that other regulatory elements may be involved at specific stages of NK-cell development. Here we report the effects of the transcription factor c-Myc on KIR expression. c-Myc directly binds to, and promotes transcription from, a distal element identified upstream of most KIR genes. Binding of endogenous c-Myc to the distal promoter element is significantly enhanced upon interleukin-15 (IL-15) stimulation in peripheral blood NK cells and correlates with an increase in KIR transcription. In addition, the overexpression of c-Myc during NK-cell development promotes transcription from the distal promoter element and contributes to the overall transcription of multiple KIR genes. Our data demonstrate the significance of the 5′ promoter element upstream of the conventional KIR promoter region and support a model whereby IL-15 stimulates c-Myc binding at the distal KIR promoter during NK-cell development to promote KIR transcription. This finding provides a direct link between NK-cell activation signals and KIR expression required for acquisition of effector function during NK-cell education.
Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia
Authors: Phelps Mitch A. , Lin Thomas S. , Johnson Amy J. , Hurh Eunju , Rozewski Darlene M. , Farley Katherine L. , Wu Di , Blum Kristie A. , Fischer Beth , Mitchell Sarah M. , Moran Mollie E. , Brooker-McEldowney Michelle , Heerema Nyla A. , Jarjoura David , Schaaf Larry J. , Byrd John C. , Grever Michael R. , Dalton James T. 
Published: November 2008

Abstract
We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.
Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison
Authors: Cornelissen Jan J. , van der Holt Bronno , Verhoef Gregor E. G. , van 't Veer Mars B. , van Oers Marinus H. J. , Schouten Harry C. , Ossenkoppele Gert , Sonneveld Pieter , Maertens Johan , van Marwijk Kooy Marinus , Schaafsma Martijn R. , Wijermans Pierre W. , Biesma Douwe H. , Wittebol Shulamit , Voogt Paul J. , Baars Joke W. , Zachée Pierre , Verdonck Leo F. , Löwenberg Bob , Dekker Adriaan W. 
Published: November 2008

Abstract
While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio [HR], 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (± 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P = .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.
Bone marrow angiogenesis magnetic resonance imaging in patients with acute myeloid leukemia: peak enhancement ratio is an independent predictor for overall survival
Authors: Shih Tiffany Ting-Fang , Hou Hsin-An , Liu Chieh-Yu , Chen Bang-Bin , Tang Jih-Luh , Chen Hsuan-Yu , Wei Shwu-Yuan , Yao Ming , Huang Shang-Yi , Chou Wen-Chien , Hsu Szu-Chun , Tsay Woei , Yu Chih-Wei , Hsu Chao-Yu , Tien Hwei-Fang , Yang Pan-Chyr 
Published: November 2008

Abstract
Emerging evidence suggests that progression of hematologic malignancies is associated with angiogenesis. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide global and functional imaging of tumor angiogenesis. In this study, we performed bone marrow DCE-MRI prospectively at diagnosis and after induction chemotherapy in 78 de novo acute myeloid leukemia (AML) patients and correlated it with treatment outcome. An algorithm to assess bone marrow angiogenesis by measuring the DCE-MRI time-intensity curve pixel by pixel was developed using 3 distinct parameters: peak enhancement ratio (Peak) to indicate tissue blood perfusion; amplitude (Amp) to reflect vascularity; and volume transfer constant (K trans) to indicate vascular permeability. The Peak and Amp decreased significantly at remission status after induction chemotherapy. Patients with higher Peak or Amp at diagnosis had shorter overall survival and disease-free survival than others. Cox multivariate analysis identified higher Peak value (hazard ratio, 9.181; 95% confidence interval, 1.740-48.437; P = .009) as an independent predictor for overall survival in addition to unfavorable karyotype and old age. Our findings provide evidence that increased bone marrow angiogenesis measured by DCE-MRI can predict adverse clinical outcome in AML patients. DCE-MRI may help to select high-risk phenotype AML patients for tailored antiangiogenic therapy and to monitor treatment response.
Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study
Authors: Adès Lionel , Boehrer Simone , Prebet Thomas , Beyne-Rauzy Odile , Legros Laurence , Ravoet Christophe , Dreyfus François , Stamatoullas Aspasia , Pierre Chaury Marie , Delaunay Jacques , Laurent Guy , Vey Norbert , Burcheri Sara , Mbida Rose-Marie , Hoarau Natacha , Gardin Claude , Fenaux Pierre 
Published: November 2008

AbstractHigher-risk MDS with del5q carry a poor prognosis. In this phase 2 trial, 47 patients with higher-risk MDS received lenalidomide 10 mg/day. International Prognostic Scoring System was high in 60%, intermediate-2 risk in 40%. del 5q was isolated, with one additional and more than one additional abnormality in 19%, 23%, and 58% patients, respectively. Thirteen (27%) patients achieved hematologic response, including 7 hematologic complete remission (CR) (with complete [4] or partial [3] cytogenetic response), 2 marrow CR and 4 hematologic improvement erythroid, and 12 became red blood cell (RBC) transfusion independent, for a median duration of 6.5 months. Median CR duration was 11.5 months. Six of 9 (67%) patients with isolated del 5q achieved CR, versus 1 of 11 and none of 27 patients with one or more than one additional abnormality, respectively (P < .001). Seven of 20 (35%) with initial platelets more than 100 000/mm3 obtained CR, compared with none of the 27 with lower platelet counts less than 100 000/mm3 (P = .001). Our data support a potential role of lenalidomide in higher-risk MDS with isolated del 5q. This trial was registered at www.clinicaltrials.gov as NCT00424229.
Nuclear staining and relative distance for quantifying epidermal differentiation in biomarker expression profiling
Authors: Pommerencke Thora , Steinberg Thorsten , Dickhaus Hartmut , Tomakidi Pascal , Grabe Niels 
Published: November 2008

Abstract

Background
The epidermal physiology results from a complex regulated homeostasis of keratinocyte proliferation, differentiation and death and is tightly regulated by a specific protein expression during cellular maturation. Cellular in silico models are considered a promising and inevitable tool for the understanding of this complex system. Hence, we need to incorporate the information of the differentiation dependent protein expression in cell based systems biological models of tissue homeostasis. Such methods require measuring tissue differentiation quantitatively while correlating it with biomarker expression intensities.

Results
Differentiation of a keratinocyte is characterized by its continuously changing morphology concomitant with its movement from the basal layer to the surface, leading to a decreased average nuclei density throughout the tissue. Based thereon, we designed and evaluated three different mathematical measures (nuclei based, distance based, and joint approach) for quantifying differentiation in epidermal keratinocytes. We integrated them with an immunofluorescent staining and image analysis method for tissue sections, automatically quantifying epidermal differentiation and measuring the corresponding expression of biomarkers. When studying five well-known differentiation related biomarkers in an epidermal neck sample only the resulting biomarker profiles incorporating the relative distance information of cells to the tissue borders (distance based and joint approach) provided a high-resolution view on the whole process of keratinocyte differentiation. By contrast, the inverse nuclei density approach led to an increased resolution at early but heavily decreased resolution at late differentiation. This effect results from the heavy non-linear decay of DAPI intensity per area, probably caused by cytoplasmic growth and chromatin decondensation. In the joint approach this effect could be compensated again by incorporating distance information.

Conclusion
We suppose that key mechanisms regulating tissue homeostasis probably depend more on distance information rather than on nuclei reorganization. Concluding, the distance approach appears well suited for comprehensively observing keratinocyte differentiation.
The prediction of protein-protein interaction networks in rice blast fungus
Authors: He Fei , Zhang Yan , Chen Hao , Zhang Ziding , Peng You-Liang 
Published: November 2008

Abstract

Background
Protein-protein interaction (PPI) maps are useful tools for investigating the cellular functions of genes. Thus far, large-scale PPI mapping projects have not been implemented for the rice blast fungus Magnaporthe grisea, which is responsible for the most severe rice disease. Inspired by recent advances in PPI prediction, we constructed a PPI map of this important fungus.

Results
Using a well-recognized interolog approach, we have predicted 11,674 interactions among 3,017 M. grisea proteins. Although the scale of the constructed map covers approximately only one-fourth of the M. grisea's proteome, it is the first PPI map for this crucial organism and will therefore provide new insights into the functional genomics of the rice blast fungus. Focusing on the network topology of proteins encoded by known pathogenicity genes, we have found that pathogenicity proteins tend to interact with higher numbers of proteins. The pathogenicity proteins and their interacting partners in the entire network were then used to construct a subnet called a pathogenicity network. These data may provide further clues for the study of these pathogenicity proteins. Finally, it has been established that secreted proteins in M. grisea interact with fewer proteins. These secreted proteins and their interacting partners were also compiled into a network of secreted proteins, which may be helpful in constructing an interactome between the rice blast fungus and rice.

Conclusion
We predicted the PPIs of M. grisea and compiled them into a database server called MPID. It is hoped that MPID will provide new hints as to the functional genomics of this fungus. MPID is available at http://bioinformatics.cau.edu.cn/zzd_lab/MPID.html.
Comparative genomics of wild type yeast strains unveils important genome diversity
Authors: Carreto Laura , Eiriz Maria F , Gomes Ana C , Pereira Patrícia M , Schuller Dorit , Santos Manuel AS 
Published: November 2008

AbstractBackgroundGenome variability generates phenotypic heterogeneity and is of relevance for adaptation to environmental change, but the extent of such variability in natural populations is still poorly understood. For example, selectedSaccharomyces cerevisiaestrains are variable at the ploidy level, have gene amplifications, changes in chromosome copy number, and gross chromosomal rearrangements. This suggests that genome plasticity provides important genetic diversity upon which natural selection mechanisms can operate.ResultsIn this study, we have used wild-typeS. cerevisiae(yeast) strains to investigate genome variation in natural and artificial environments. We have used comparative genome hybridization on array (aCGH) to characterize the genome variability of 16 yeast strains, of laboratory and commercial origin, isolated from vineyards and wine cellars, and from opportunistic human infections. Interestingly, sub-telomeric instability was associated with the clinical phenotype, while Ty element insertion regions determined genomic differences of natural wine fermentation strains. Copy number depletion ofASP3andYRF1genes was found in all wild-type strains. Other gene families involved in transmembrane transport, sugar and alcohol metabolism or drug resistance had copy number changes, which also distinguished wine from clinical isolates.ConclusionWe have isolated and genotyped more than 1000 yeast strains from natural environments and carried out an aCGH analysis of 16 strains representative of distinct genotype clusters. Important genomic variability was identified between these strains, in particular in sub-telomeric regions and in Ty-element insertion sites, suggesting that this type of genome variability is the main source of genetic diversity in natural populations of yeast. The data highlights the usefulness of yeast as a model system to unravel intraspecific natural genome diversity and to elucidate how natural selection shapes the yeast genome.
Expression of recombinant Clostridium difficile toxin A and B in Bacillus megaterium
Authors: Yang Guilin , Zhou Boping , Wang Jufang , He Xiangyun , Sun Xingmin , Nie Weijia , Tzipori Saul , Feng Hanping 
Published: November 2008

AbstractBackgroundMajorClostridium difficilevirulence factors are the exotoxins TcdA and TcdB. Due to the large size and poor stability of the proteins, the active recombinant TcdA and TcdB have been difficult to produce.ResultsThe toxin genestcdAandtcdBwere amplified by PCR using chromosomal DNA from a toxigenic strain as a template, and cloned into a shuttle vector pHis1522. The sequences of bothtcdAandtcdBgenes in the vector have been verified by DNA sequencing. The constructs were transformed intoB. megateriumprotoplasts and the protein expression was controlled under a xylose promoter. The recombinant toxins (rTcdA and rTcdB) were purified from bacterial crude extracts. Approximately 5 – 10 mg of highly purified recombinant toxins were obtained from one liter of bacterial culture. The resulting rTcdA and rTcdB had similar molecular masses to the native toxins, and their biological activities were found to be similar to their native counterparts after an extensive examination.ConclusionWe have generated the full length and active recombinant TcdA and TcdB inBacillus megaterium.