bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression
Authors: Sridhar Kunju , Ross Douglas T. , Tibshirani Robert , Butte Atul J. , Greenberg Peter L. 
Published: October 2009

AbstractMicroarray analysis with 40 000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34+ marrow cells from myelodysplastic syndrome (MDS) patients compared with healthy persons. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS versus normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between healthy and MDS patients and between several MDS subgroups: (1) those whose disease remained stable and those who subsequently transformed (tMDS) to acute myeloid leukemia; (2) between del(5q) and other MDS patients. A 6-gene “poor risk” signature was defined, which was associated with acute myeloid leukemia transformation and provided additive prognostic information for International Prognostic Scoring System Intermediate-1 patients. Overexpression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) with the remaining MDS patients showed 1924 differentially expressed genes, with underexpression of 1014 genes, 11 of which were within the 5q31-32 commonly deleted region. These data demonstrated (1) GEPs distinguishing MDS patients from healthy and between those with differing clinical outcomes (tMDS vs those whose disease remained stable) and cytogenetics [eg, del(5q)]; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS.
Enhancing navigation in biomedical databases by community voting and database-driven text classification
Authors: Duchrow Timo , Shtatland Timur , Guettler Daniel , Pivovarov Misha , Kramer Stefan , Weissleder Ralph 
Published: October 2009

Abstract

Background
The breadth of biological databases and their information content continues to increase exponentially. Unfortunately, our ability to query such sources is still often suboptimal. Here, we introduce and apply community voting, database-driven text classification, and visual aids as a means to incorporate distributed expert knowledge, to automatically classify database entries and to efficiently retrieve them.

Results
Using a previously developed peptide database as an example, we compared several machine learning algorithms in their ability to classify abstracts of published literature results into categories relevant to peptide research, such as related or not related to cancer, angiogenesis, molecular imaging, etc. Ensembles of bagged decision trees met the requirements of our application best. No other algorithm consistently performed better in comparative testing. Moreover, we show that the algorithm produces meaningful class probability estimates, which can be used to visualize the confidence of automatic classification during the retrieval process. To allow viewing long lists of search results enriched by automatic classifications, we added a dynamic heat map to the web interface. We take advantage of community knowledge by enabling users to cast votes in Web 2.0 style in order to correct automated classification errors, which triggers reclassification of all entries. We used a novel framework in which the database "drives" the entire vote aggregation and reclassification process to increase speed while conserving computational resources and keeping the method scalable. In our experiments, we simulate community voting by adding various levels of noise to nearly perfectly labelled instances, and show that, under such conditions, classification can be improved significantly.

Conclusion
Using PepBank as a model database, we show how to build a classification-aided retrieval system that gathers training data from the community, is completely controlled by the database, scales well with concurrent change events, and can be adapted to add text classification capability to other biomedical databases.
The system can be accessed at http://pepbank.mgh.harvard.edu.
Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening
Authors: Voss Matthias , Lettau Marcus , Janssen Ottmar 
Published: October 2009

Abstract

Background -
Fas ligand is a cytotoxic effector molecule of T and NK cells which is characterized by an intracellular N-terminal polyproline region that serves as a docking site for SH3 and WW domain proteins. Several previously described Fas ligand-interacting SH3 domain proteins turned out to be crucial for the regulation of storage, expression and function of the death factor. Recent observations, however, indicate that Fas ligand is also subject to posttranslational modifications including shedding and intramembrane proteolysis. This results in the generation of short intracellular fragments that might either be degraded or translocate to the nucleus to influence transcription. So far, protein-protein interactions that specifically regulate the fate of the intracellular fragments have not been identified.

Results -
In order to further define the SH3 domain interactome of the intracellular region of Fas ligand, we now screened a human SH3 domain phage display library. In addition to known SH3 domains mediating binding to the Fas ligand proline-rich domain, we were able to identify a number of additional SH3 domains that might also associate with FasL. Potential functional implications of the new binding proteins for the death factor's biology are discussed. For Tec kinases and sorting nexins, the observed interactions were verified in cellular systems by pulldown experiments.

Conclusion -
We provide an extended list of putative Fas ligand interaction partners, confirming previously identified interactions, but also introducing several novel SH3 domain proteins that might be important regulators of Fas ligand function.
Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy
Authors: Casula Milena , Muggiano Antonio , Cossu Antonio , Budroni Mario , Caracò Corrado , Ascierto Paolo A , Pagani Elena , Stanganelli Ignazio , Canzanella Sergio , Sini MariaCristina , Palomba Grazia ,   The Italian Melanoma Intergroup (IMI), Palmieri Giuseppe 
Published: October 2009

Abstract

Background
Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease.

Methods
A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16

CDKN2A
, BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16

CDKN2A
genes.

Results
For melanoma susceptibility, investigations at germline level indicated that p16

CDKN2A
was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16

CDKN2A
gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16

CDKN2A
silencing).

Conclusion
Our findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis.
Recurrence in oral and pharyngeal cancer is associated with quantitative MGMT promoter methylation
Authors: Taioli Emanuela , Ragin Camille , Wang Xiao-hong , Chen Jiangying , Langevin Scott M , Brown Ashley R , Gollin Susanne M , Garte Seymour , Sobol Robert W 
Published: October 2009

AbstractBackgroundBiomarkers that predict clinical response, tumor recurrence or patient survival are severely lacking for most cancers, particularly for oral and pharyngeal cancer. This study examines whether gene-promoter methylation of tumor DNA correlates with survival and recurrence rates in a population of patients with oral or pharyngeal cancer.MethodsThe promoter methylation status of the DNA repair geneMGMTand the tumor suppressor genesCDKN2A and RASSF1were evaluated by methylation-specific PCR in 88 primary oral and pharyngeal tumors and correlated with survival and tumor recurrence. QuantitativeMGMTmethylation was also assessed.Results29.6% of the tumors presented withMGMTmethylation, 11.5% withCDKN2Amethylation and 12.1% withRASSF1methylation.MGMTpromoter methylation was significantly associated with poorer overall and disease-free survival. No differences in methylation status ofMGMTandRASSF1with HPV infection, smoking or drinking habits were observed. A significant inverse trend with the amount ofMGMTmethylation and overall and disease-free survival was observed (ptrend= 0.002 and 0.001 respectively).ConclusionThese results implicateMGMTpromoter methylation as a possible biomarker for oral and pharyngeal cancer prognosis. The critical role of MGMT in DNA repair suggests that defective DNA repair may be correlative in the observed association betweenMGMTpromoter methylation and tumor recurrence. Follow-up studies should include further quantitative MSP-PCR measurement, global methylation profiling and detailed analysis of downstream DNA repair genes regulated by promoter methylation.
A theoretical framework to describe communication processes during medical disability assessment interviews
Authors: van Rijssen H Jolanda , Schellart Antonius JM , Anema Johannes R , van der Beek Allard J 
Published: October 2009

Abstract

Background
Research in different fields of medicine suggests that communication is important in physician-patient encounters and influences satisfaction with these encounters. It is argued that this also applies to the non-curative tasks that physicians perform, such as sickness certification and medical disability assessments. However, there is no conceptualised theoretical framework that can be used to describe intentions with regard to communication behaviour, communication behaviour itself, and satisfaction with communication behaviour in a medical disability assessment context.

Objective
The objective of this paper is to describe the conceptualisation of a model for the communication behaviour of physicians performing medical disability assessments in a social insurance context and of their claimants, in face-to-face encounters during medical disability assessment interviews and the preparation thereof.

Conceptualisation
The behavioural model, based on the Theory of Planned Behaviour (TPB), is conceptualised for the communication behaviour of social insurance physicians and claimants separately, but also combined during the assessment interview. Other important concepts in the model are the evaluation of communication behaviour (satisfaction), intentions, attitudes, skills, and barriers for communication.

Conclusion
The conceptualisation of the TPB-based behavioural model will help to provide insight into the communication behaviour of social insurance physicians and claimants during disability assessment interviews. After empirical testing of the relationships in the model, it can be used in other studies to obtain more insight into communication behaviour in non-curative medicine, and it could help social insurance physicians to adapt their communication behaviour to their task when performing disability assessments.
Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue
Authors: Aslakson Eric , Vollmer-Conna Uté , Reeves William C , White Peter D 
Published: October 2009

Abstract

Background
Chronic fatigue syndrome (CFS) is defined by self-reported symptoms. There are no diagnostic signs or laboratory markers, and the pathophysiology remains inchoate. In part, difficulties identifying and replicating biomarkers and elucidating the pathophysiology reflect the heterogeneous nature of the syndromic illness CFS. We conducted this analysis of people from defined metropolitan, urban, and rural populations to replicate our earlier empirical delineation of medically unexplained chronic fatigue and CFS into discrete endophenotypes. Both the earlier and current analyses utilized quantitative measures of functional impairment and symptoms as well as laboratory data. This study and the earlier one enrolled participants from defined populations and measured the internal milieu, which differentiates them from studies of clinic referrals that examine only clinical phenotypes.

Methods
This analysis evaluated 386 women identified in a population-based survey of chronic fatigue and unwellness in metropolitan, urban, and rural populations of the state of Georgia, USA. We used variables previously demonstrated to effectively delineate endophenotypes in an attempt to replicate identification of these endophenotypes. Latent class analyses were used to derive the classes, and these were compared and contrasted to those described in the previous study based in Wichita, Kansas.

Results
We identified five classes in the best fit analysis. Participants in Class 1 (25%) were polysymptomatic, with sleep problems and depressed mood. Class 2 (24%) was also polysymptomatic, with insomnia and depression, but participants were also obese with associated metabolic strain. Class 3 (20%) had more selective symptoms but was equally obese with metabolic strain. Class 4 (20%) and Class 5 (11%) consisted of nonfatigued, less symptomatic individuals, Class 4 being older and Class 5 younger. The classes were generally validated by independent variables. People with CFS fell equally into Classes 1 and 2. Similarities to the Wichita findings included the same four main defining variables of obesity, sleep problems, depression, and the multiplicity of symptoms. Four out of five classes were similar across both studies.

Conclusion
These data support the hypothesis that chronic medically unexplained fatigue is heterogeneous and can be delineated into discrete endophenotypes that can be replicated. The data do not support the current perception that CFS represents a unique homogeneous disease and suggests broader criteria may be more explanatory. This replication suggests that delineation of endophenotypes of CFS and associated ill health may be necessary in order to better understand etiology and provide more patient-focused treatments.
Chemokine receptor expression and functional effects of chemokines on B cells: implication in the pathogenesis of rheumatoid arthritis
Authors: Nanki Toshihiro , Takada Kazuki , Komano Yukiko , Morio Tomohiro , Kanegane Hirokazu , Nakajima Atsuo , Lipsky Peter E , Miyasaka Nobuyuki 
Published: October 2009

Abstract
Introduction
Accumulation of B cells in the rheumatoid arthritis (RA) synovium has been reported, and it has been thought that these cells might contribute to the pathogenesis of RA by antigen presentation, autoantibody production, and/or inflammatory cytokine production. Chemokines could enhance the accumulation of B cells in the synovium. The aims of this study were to determine chemokine receptor expression by B cells both in the peripheral blood of normal donors and subjects with RA, and at the inflammatory site in RA, and the effects of chemokines on B cell activation.

Methods
Cell surface molecule expression was analyzed by flow cytometry. Cellular migration was assessed using chemotaxis chambers. Cellular proliferation was examined by 3H-thymidine incorporation. Tumor necrosis factor (TNF) production was assayed by enzyme-linked immunosorbent assay.

Results
Significant numbers of peripheral blood B cells of healthy donors and subjects with RA expressed CC chemokine receptor (CCR)5 and CXCR3, and most B cells expressed CCR6, CCR7, CXCR4 and CXCR5. CCR5 expression was more frequent on CD27+ than CD27- peripheral blood B cells of healthy donors and RA. Synovial B cells more frequently expressed CCR5, but less often expressed CCR6, CCR7 and CXCR5 compared to peripheral blood in RA. Further functional analyses were performed on peripheral blood B cells from healthy donors. Migration of peripheral blood B cells, especially CD27+ B cells, was enhanced by CC chemokine ligand (CCL)20, CCL19, CCL21 and CXCL12. All four chemokines alone induced B cell proliferation; with CCL21 being the most effective. CCL21 also enhanced the proliferation of anti-immunoglobulin (Ig)M-stimulated B cells and blockade of CCR7 inhibited this effect. CCL20, CCL21 and CXCL12 enhanced TNF production by anti-IgM mAb-stimulated B cells. Finally, stimulation with CXCL12, but not CCL20, CCL19 and CCL21, enhanced inducible costimulator-ligand (ICOSL) expression by peripheral blood B cells of healthy donors and RA, but did not increase B cell-activating factor receptor or transmembrane activator and CAML-interactor.

Conclusions
The data suggest that CCR5, CCR6, CCR7, CXCR3, CXCR4 and CXCR5 may be important for the B cell migration into the synovium of RA patients, and also their local proliferation, cytokine production and ICOSL expression in the synovium.
MethMarker: user-friendly design and optimization of gene-specific DNA methylation assays
Authors: Schüffler Peter , Mikeska Thomas , Waha Andreas , Lengauer Thomas , Bock Christoph 
Published: October 2009

AbstractDNA methylation is a key mechanism of epigenetic regulation that is frequently altered in diseases such as cancer. To confirm the biological or clinical relevance of such changes, gene-specific DNA methylation changes need to be validated in multiple samples. We have developed the MethMarker http://methmarker.mpi-inf.mpg.de/ software to help design robust and cost-efficient DNA methylation assays for six widely used methods. Furthermore, MethMarker implements a bioinformatic workflow for transforming disease-specific differentially methylated genomic regions into robust clinical biomarkers.
Draft genome sequence of the Daphnia pathogen Octosporea bayeri: insights into the gene content of a large microsporidian genome and a model for host-parasite interactions
Authors: Corradi Nicolas , Haag Karen L , Pombert Jean-François , Ebert Dieter , Keeling Patrick J 
Published: October 2009

Abstract
Background
The highly compacted 2.9-Mb genome of Encephalitozoon cuniculi placed the microsporidia in the spotlight, encoding a mere 2,000 proteins and a highly reduced suite of biochemical pathways. This extreme level of reduction is not universal across the microsporidia, with genomes known to vary up to sixfold in size, suggesting that some genomes may harbor a gene content that is not as reduced as that of Enc. cuniculi. In this study, we present an in-depth survey of the large genome of Octosporea bayeri, a pathogen of Daphnia magna, with an estimated genome size of 24 Mb, in order to shed light on the organization and content of a large microsporidian genome.

Results
Using Illumina sequencing, 898 Mb of O. bayeri genome sequence was generated, resulting in 13.3 Mb of unique sequence. We annotated a total of 2,174 genes, of which 893 encodes proteins with assigned function. The gene density of the O. bayeri genome is very low on average, but also highly uneven, so gene-dense regions also occur. The data presented here suggest that the O. bayeri proteome is well represented in this analysis and is more complex that that of Enc. cuniculi. Functional annotation of O. bayeri proteins suggests that this species might be less biochemically dependent on its host for its metabolism than its more reduced relatives.

Conclusions
The combination of the data presented here, together with the imminent annotated genome of Daphnia magna, will provide a wealth of genetic and genomic tools to study host-parasite interactions in an interesting model for pathogenesis.
Regulation of TNF-induced oxygen radical production in human neutrophils: role of δ-PKC
Authors: Kilpatrick Laurie E , Sun Shuang , Li Haiying , Vary Thomas C , Korchak Helen M 
Published: October 2009

Abstract
δ-PKC is a key regulator of early events in the assembly and activation of the NADPH oxidase elicited by TNF in adherent neutrophils.
In human neutrophils, TNF-elicited O2− production requires adherence and integrin activation. How this cooperative signaling between TNFRs and integrins regulates O2− generation has yet to be fully elucidated. Previously, we identified δ-PKC as a critical early regulator of TNF signaling in adherent neutrophils. In this study, we demonstrate that inhibition of δ-PKC with a dominant-negative δ-PKC TAT peptide resulted in a significant delay in the onset time of TNF-elicited O2− generation but had no effect on Vmax, indicating an involvement of δ-PKC in the initiation of O2− production. In contrast, fMLP-elicited O2− production in adherent and nonadherent neutrophils was δ-PKC-independent, suggesting differential regulation of O2− production. An important step in activation of the NADPH oxidase is phosphorylation of the cytosolic p47phox component. In adherent neutrophils, TNF triggered a time-dependent association of δ-PKC with p47phox, which was associated with p47phox phosphorylation, indicating a role for δ-PKC in regulating O2− production at the level of p47phox. Activation of ERK and p38 MAPK is also required for TNF-elicited O2− generation. TNF-mediated ERK but not p38 MAPK recruitment to p47phox was δ-PKC-dependent. δ-PKC activity is controlled through serine/threonine phosphorylation, and phosphorylation of δ-PKC (Ser643) and δ-PKC (Thr505) was increased significantly by TNF in adherent cells via a PI3K-dependent process. Thus, signaling for TNF-elicited O2− generation is regulated by δ-PKC. Adherence-dependent cooperative signaling activates PI3K signaling, δ-PKC phosphorylation, and δ-PKC recruitment to p47phox. δ-PKC activates p47phox by serine phosphorylation or indirectly through control of ERK recruitment to p47phox.
HIV-1 regulation of latency in the monocyte-macrophage lineage and in CD4+ T lymphocytes
Authors: Redel Laetitia , Le Douce Valentin , Cherrier Thomas , Marban Céline , Janossy Andrea , Aunis Dominique , Van Lint Carine , Rohr Olivier , Schwartz Christian 
Published: October 2009

Abstract
Review of molecular mechanisms of latency used by HIV-1 to establish viral reservoirs within CD4 T cells and/or macrophages.
The introduction in 1996 of the HAART raised hopes for the eradication of HIV-1. Unfortunately, the discovery of latent HIV-1 reservoirs in CD4+ T cells and in the monocyte-macrophage lineage proved the optimism to be premature. The long-lived HIV-1 reservoirs constitute a major obstacle to the eradication of HIV-1. In this review, we focus on the establishment and maintenance of HIV-1 latency in the two major targets for HIV-1: the CD4+ T cells and the monocyte-macrophage lineage. Understanding the cell-type molecular mechanisms of establishment, maintenance, and reactivation of HIV-1 latency in these reservoirs is crucial for efficient therapeutic intervention. A complete viral eradication, the holy graal for clinicians, might be achieved by strategic interventions targeting latently and productively infected cells. We suggest that new approaches, such as the combination of different kinds of proviral activators, may help to reduce dramatically the size of latent HIV-1 reservoirs in patients on HAART.