bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33
Authors: Pecaric-Petkovic Tatjana , Didichenko Svetlana A. , Kaempfer Sacha , Spiegl Nicole , Dahinden Clemens A. 
Published: October 2008

AbstractIn mice, interleukin-18 (IL-18) regulates Th1- or Th2-type immune responses depending on the cytokine environment and effector cells involved, and the ST2-ligand, IL-33, primarily promotes an allergic phenotype. Human basophils, major players in allergic inflammation, constitutively express IL-18 receptors, while ST2 surface expression is inducible by IL-3. Unexpectedly, freshly isolated basophils are strongly activated by IL-33, but, in contrast to mouse basophils, do not respond to IL-18. IL-33 promotes IL-4, IL-13 and IL-8 secretion in synergy with IL-3 and/or FcϵRI-activation, and enhances FcϵRI-induced mediator release. These effects are similar to that of IL-3, but the signaling pathways engaged are distinct because IL-33 strongly activates NF-κB and shows a preference for p38 MAP-kinase, while IL-3 acts through Jak/Stat and preferentially activates ERK. Eosinophils are the only other leukocyte-type directly activated by IL-33, as evidenced by screening of p38-activation in peripheral blood cells. Only upon CD3/CD28-ligation, IL-33 weakly enhances Th2 cytokine expression by in vivo polarized Th2 cells. This study on primary human cells demonstrates that basophils and eosinophils are the only direct target leukocytes for IL-33, suggesting that IL-33 promotes allergic inflammation and Th2 polarization mainly by the selective activation of these specialized cells of the innate immune system.
Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML
Authors: Zeng Zhihong , Xi Shi Yue , Samudio Ismael J. , Wang Rui-Yu , Ling Xiaoyang , Frolova Olga , Levis Mark , Rubin Joshua B. , Negrin Robert R. , Estey Elihu H. , Konoplev Sergej , Andreeff Michael , Konopleva Marina 
Published: October 2008

Abstract
SDF-1α/CXCR4 signaling plays a key role in leukemia/bone marrow microenvironment interactions. We previously reported that bone marrow–derived stromal cells inhibit chemotherapy-induced apoptosis in acute myeloid leukemia (AML). Here we demonstrate that the CXCR4 inhibitor AMD3465 antagonized stromal-derived factor 1α (SDF-1α)–induced and stroma-induced chemotaxis and inhibited SDF-1α–induced activation of prosurvival signaling pathways in leukemic cells. Further, CXCR4 inhibition partially abrogated the protective effects of stromal cells on chemotherapy-induced apoptosis in AML cells. Fetal liver tyrosine kinase-3 (FLT3) gene mutations activate CXCR4 signaling, and coculture with stromal cells significantly diminished antileukemia effects of FLT3 inhibitors in cells with mutated FLT3. Notably, CXCR4 inhibition increased the sensitivity of FLT3-mutated leukemic cells to the apoptogenic effects of the FLT3 inhibitor sorafenib. In vivo studies demonstrated that AMD3465, alone or in combination with granulocyte colony-stimulating factor, induced mobilization of AML cells and progenitor cells into circulation and enhanced antileukemic effects of chemotherapy and sorafenib, resulting in markedly reduced leukemia burden and prolonged survival of the animals. These findings indicate that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to signal transduction inhibitor– and chemotherapy-induced apoptosis in systems mimicking the physiologic microenvironment. Disruption of these interactions with CXCR4 inhibitors represents a novel strategy of sensitizing leukemic cells by targeting their protective bone marrow microenvironment.
Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells
Authors: Tolar Jakub , Ishida-Yamamoto Akemi , Riddle Megan , McElmurry Ron T. , Osborn Mark , Xia Lily , Lund Troy , Slattery Catherine , Uitto Jouni , Christiano Angela M. , Wagner John E. , Blazar Bruce R. 
Published: October 2008

AbstractThe recessive dystrophic form of epidermolysis bullosa (RDEB) is a disorder of incurable skin fragility and blistering caused by mutations in the type VII collagen gene (Col7a1). The absence of type VII collagen production leads to the loss of adhesion at the basement membrane zone due to the absence of anchoring fibrils, which are composed of type VII collagen. We report that wild-type, congenic bone marrow cells homed to damaged skin, produced type VII collagen protein and anchoring fibrils, ameliorated skin fragility, and reduced lethality in the murine model of RDEB generated by targeted Col7a1 disruption. These data provide the first evidence that a population of marrow cells can correct the basement membrane zone defect found in mice with RDEB and offer a potentially valuable approach for treatment of human RDEB and other extracellular matrix disorders.
Gene expression profiling of peripheral T-cell lymphoma including γδ T-cell lymphoma
Authors: Miyazaki Kana , Yamaguchi Motoko , Imai Hiroshi , Kobayashi Tohru , Tamaru Satoshi , Nishii Kazuhiro , Yuda Masao , Shiku Hiroshi , Katayama Naoyuki 
Published: October 2008

Abstract
The gene expression profile of peripheral γδ T-cell lymphoma (γδTCL) has not been investigated. Using oligonucleotide microarrays, we analyzed total RNA from 7 patients with γδTCL (4 hepatosplenic, 1 cutaneous, 1 intestinal, and 1 thyroidal) and 27 patients with αβTCL (11 peripheral TCL-unspecified, 15 angioimmunoblastic TCL, and 1 hepatosplenic). Unsupervised microarray analyses classified all hepatosplenic γδTCLs into a single cluster, whereas other γδTCLs were scattered within the αβTCL distribution. We identified a T-cell receptor signature gene set, which accurately classified γδTCL and αβTCL. A classifier based on gene expression under supervised analysis correctly identified γδTCL. One case of hepatosplenic αβTCL was placed in the γδTCL grouping. γδTCL signature genes included genes encoding killer cell immunoglobulin-like receptors and killer cell lectin-like receptors. Our results indicate that hepatosplenic γδTCL is a distinct form of peripheral TCL and suggest that nonhepatosplenic γδTCLs are heterogeneous in gene expression.
Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma
Authors: Ludwig Heinz , Hajek Roman , Tóthová Elena , Drach Johannes , Adam Zdenek , Labar Boris , Egyed Miklós , Spicka Ivan , Gisslinger Heinz , Greil Richard , Kuhn Ingrid , Zojer Niklas , Hinke Axel 
Published: October 2008

AbstractWe compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon α-2b thrice weekly or to 3 MU interferon α-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P = .006) and overall responses (68% vs 50%; P = .002) compared with MP. Time to progression (21.2 vs 29.1 months; P = .2), and progression-free survival was similar (16.7 vs 20.7 months; P = .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P = .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.
Severe bleeding complications caused by an autoantibody against the B subunit of plasma factor XIII: a novel form of acquired factor XIII deficiency
Authors: Ajzner Éva , Schlammadinger Ágota , Kerényi Adrienne , Bereczky Zsuzsanna , Katona Éva , Haramura Gizella , Boda Zoltán , Muszbek László 
Published: October 2008

AbstractAcquired factor XIII (FXIII) deficiency due to autoantibody against FXIII is a very rare severe hemorrhagic diathesis. Antibodies directed against the A subunit of FXIII, which interfere with different functions of FXIII, have been described. Here, for the first time, we report an autoantibody against the B subunit of FXIII (FXIII-B) that caused life-threatening bleeding in a patient with systemic lupus erythematosus. FXIII activity, FXIII-A2B2 complex, and individual FXIII subunits were undetectable in the plasma, whereas platelet FXIII activity and antigen were normal. Neither FXIII activation nor its activity was inhibited by the antibody, which bound to structural epitope(s) on both free and complexed FXIII-B. The autoantibody highly accelerated the elimination of FXIII from the circulation. FXIII supplementation combined with immunosuppressive therapy, plasmapheresis, immunoglobulin, and anti-CD20 treatment resulted in the patient's recovery. FXIII levels returned to around 20% at discharge and after gradual increase the levels stabilized above 50%.
HIV-associated lymphomas and gamma-herpesviruses
Authors: Carbone Antonino , Cesarman Ethel , Spina Michele , Gloghini Annunziata , Schulz Thomas F. 
Published: October 2008

AbstractAmong the most common HIV-associated lymphomas are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) with immunoblastic-plasmacytoid differentiation (also involving the central nervous system). Lymphomas occurring specifically in HIV-positive patients include primary effusion lymphoma (PEL) and its solid variants, plasmablastic lymphoma of the oral cavity type and large B-cell lymphoma arising in Kaposi sarcoma herpesvirus (KSHV)–associated multicentric Castleman disease. These lymphomas together with BL and DLBCL with immunoblastic-plasmacytoid differentiation frequently carry EBV infection and display a phenotype related to plasma cells. EBV infection occurs at different rates in different lymphoma types, whereas KSHV is specifically associated with PEL, which usually occurs in the setting of profound immunosuppression. The current knowledge about HIV-associated lymphomas can be summarized in the following key points: (1) lymphomas specifically occurring in patients with HIV infection are closely linked to other viral diseases; (2) AIDS lymphomas fall in a spectrum of B-cell differentiation where those associated with EBV or KSHV commonly exhibit plasmablastic differentiation; and (3) prognosis for patients with lymphomas and concomitant HIV infection could be improved using better combined chemotherapy protocols in-corporating anticancer treatments and antiretroviral drugs.
CompMoby: Comparative MobyDick for detection of cis-regulatory motifs
Authors: Chaivorapol Christina , Melton Collin , Wei Grace , Yeh Ru-Fang , Ramalho-Santos Miguel , Blelloch Robert , Li Hao 
Published: October 2008

AbstractBackgroundThe regulation of gene expression is complex and occurs at many levels, including transcriptional and post-transcriptional, in metazoans. Transcriptional regulation is mainly determined by sequence elements within the promoter regions of genes while sequence elements within the 3' untranslated regions of mRNAs play important roles in post-transcriptional regulation such as mRNA stability and translation efficiency. Identifying cis-regulatory elements, or motifs, in multicellular eukaryotes is more difficult compared to unicellular eukaryotes due to the larger intergenic sequence space and the increased complexity in regulation. Experimental techniques for discovering functional elements are often time consuming and not easily applied on a genome level. Consequently, computational methods are advantageous for genome-wide cis-regulatory motif detection. To decrease the search space in metazoans, many algorithms use cross-species alignment, although studies have demonstrated that a large portion of the binding sites for the same trans-acting factor do not reside in alignable regions. Therefore, a computational algorithm should account for both conserved and nonconserved cis-regulatory elements in metazoans.ResultsWe present CompMoby (Comparative MobyDick), software developed to identify cis-regulatory binding sites at both the transcriptional and post-transcriptional levels in metazoans without prior knowledge of the trans-acting factors. The CompMoby algorithm was previously shown to identify cis-regulatory binding sites in upstream regions of genes co-regulated in embryonic stem cells. In this paper, we extend the software to identify putative cis-regulatory motifs in 3' UTR sequences and verify our results using experimentally validated data sets in mouse and human. We also detail the implementation of CompMoby into a user-friendly tool that includes a web interface to a streamlined analysis. Our software allows detection of motifs in the following three categories: one, those that are alignable and conserved; two, those that are conserved but not alignable; three, those that are species specific. One of the output files from CompMoby gives the user the option to decide what category of cis-regulatory element to experimentally pursue based on their biological problem. Using experimentally validated biological datasets, we demonstrate that CompMoby is successful in detecting cis-regulatory target sites of known and novel trans-acting factors at the transcriptional and post-transcriptional levels.ConclusionCompMoby is a powerful software tool for systematicde novodiscovery of evolutionarily conserved and nonconserved cis-regulatory sequences involved in transcriptional or post-transcriptional regulation in metazoans. This software is freely available to users athttp://genome.ucsf.edu/compmoby/.
Identification of a small optimal subset of CpG sites as bio-markers from high-throughput DNA methylation profiles
Authors: Meng Hailong , Murrelle Edward L , Li Guoya 
Published: October 2008

Abstract

Background
DNA methylation patterns have been shown to significantly correlate with different tissue types and disease states. High-throughput methylation arrays enable large-scale DNA methylation analysis to identify informative DNA methylation biomarkers. The identification of disease-specific methylation signatures is of fundamental and practical interest for risk assessment, diagnosis, and prognosis of diseases.

Results
Using published high-throughput DNA methylation data, a two-stage feature selection method was developed to select a small optimal subset of DNA methylation features to precisely classify two sample groups. With this approach, a small number of CpG sites were highly sensitive and specific in distinguishing lung cancer tissue samples from normal lung tissue samples.

Conclusion
This study shows that it is feasible to identify DNA methylation biomarkers from high-throughput DNA methylation profiles and that a small number of signature CpG sites can suffice to classify two groups of samples. The computational method we developed in the study is efficient to identify signature CpG sites from disease samples with complex methylation patterns.
Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells
Authors: Kretlow James D , Jin Yu-Qing , Liu Wei , Zhang Wen Jie , Hong Tan-Hui , Zhou Guangdong , Baggett L Scott , Mikos Antonios G , Cao Yilin 
Published: October 2008

Abstract

Background
Bone marrow-derived mesenchymal stem cells (BMSCs) are a widely researched adult stem cell population capable of differentiation into various lineages. Because many promising applications of tissue engineering require cell expansion following harvest and involve the treatment of diseases and conditions found in an aging population, the effect of donor age and ex vivo handling must be understood in order to develop clinical techniques and therapeutics based on these cells. Furthermore, there currently exists little understanding as to how these two factors may be influenced by one another.

Results
Differences in the adipogenic, chondrogenic, and osteogenic differentiation capacity of murine MSCs harvested from donor animals of different age and number of passages of these cells were observed. Cells from younger donors adhered to tissue culture polystyrene better and proliferated in greater number than those from older animals. Chondrogenic and osteogenic potential decreased with age for each group, and adipogenic differentiation decreased only in cells from the oldest donors. Significant decreases in differentiation potentials due to passage were observed as well for osteogenesis of BMSCs from the youngest donors and chondrogenesis of the cells from the oldest donors.

Conclusion
Both increasing age and the number of passages have lineage dependent effects on BMSC differentiation potential. Furthermore, there is an obvious interplay between donor age and cell passage that in the future must be accounted for when developing cell-based therapies for clinical use.
An evolutionarily conserved intronic region controls the spatiotemporal expression of the transcription factor Sox10
Authors: Dutton James R , Antonellis Anthony , Carney Thomas J , Rodrigues Frederico SLM , Pavan William J , Ward Andrew , Kelsh Robert N 
Published: October 2008

AbstractBackgroundA major challenge lies in understanding the complexities of gene regulation. Mutation of the transcription factor SOX10 is associated with several human diseases. The disease phenotypes reflect the function of SOX10 in diverse tissues including the neural crest, central nervous system and otic vesicle. As expected, the SOX10 expression pattern is complex and highly dynamic, but little is known of the underlying mechanisms regulating its spatiotemporal pattern.SOX10expression is highly conserved between all vertebrates characterised.ResultsWe have combined in vivo testing of DNA fragments in zebrafish and computational comparative genomics to identify the first regulatory regions of the zebrafishsox10gene. Both approaches converged on the 3' end of the conserved 1stintron as being critical for spatial patterning ofsox10in the embryo. Importantly, we have defined a minimal region crucial for this function. We show that this region contains numerous binding sites for transcription factors known to be essential in early neural crest induction, including Tcf/Lef, Sox and FoxD3. We show that the identity and relative position of these binding sites are conserved between zebrafish and mammals. A further region, partially required for oligodendrocyte expression, lies in the 5' region of the same intron and contains a putative CSL binding site, consistent with a role for Notch signalling insox10regulation. Furthermore, we show that β-catenin, Notch signalling and Sox9 can induce ectopicsox10expression in early embryos, consistent with regulatory roles predicted from our transgenic and computational results.ConclusionWe have thus identified two major sites ofsox10regulation in vertebrates and provided evidence supporting a role for at least three factors in drivingsox10expression in neural crest, otic epithelium and oligodendrocyte domains.
Dual-hemisphere tDCS facilitates greater improvements for healthy subjects' non-dominant hand compared to uni-hemisphere stimulation
Authors: Vines Bradley W , Cerruti Carlo , Schlaug Gottfried 
Published: October 2008

Abstract

Background
Transcranial direct current stimulation (tDCS) is a non-invasive technique that has been found to modulate the excitability of neurons in the brain. The polarity of the current applied to the scalp determines the effects of tDCS on the underlying tissue: anodal tDCS increases excitability, whereas cathodal tDCS decreases excitability. Research has shown that applying anodal tDCS to the non-dominant motor cortex can improve motor performance for the non-dominant hand, presumably by means of changes in synaptic plasticity between neurons. Our previous studies also suggest that applying cathodal tDCS over the dominant motor cortex can improve performance for the non-dominant hand; this effect may result from modulating inhibitory projections (interhemispheric inhibition) between the motor cortices of the two hemispheres. We hypothesized that stimultaneously applying cathodal tDCS over the dominant motor cortex and anodal tDCS over the non-dominant motor cortex would have a greater effect on finger sequence performance for the non-dominant hand, compared to stimulating only the non-dominant motor cortex. Sixteen right-handed participants underwent three stimulation conditions: 1) dual-hemisphere – with anodal tDCS over the non-dominant motor cortex, and cathodal tDCS over the dominant motor cortex, 2) uni-hemisphere – with anodal tDCS over the non-dominant motor cortex, and 3) sham tDCS. Participants performed a finger-sequencing task with the non-dominant hand before and after each stimulation. The dependent variable was the percentage of change in performance, comparing pre- and post-tDCS scores.

Results
A repeated measures ANOVA yielded a significant effect of tDCS condition (F(2,30) = 4.468, p = .037). Post-hoc analyses revealed that dual-hemisphere stimulation improved performance significantly more than both uni-hemisphere (p = .021) and sham stimulation (p = .041).

Conclusion
We propose that simultaneously applying cathodal tDCS over the dominant motor cortex and anodal tDCS over the non-dominant motor cortex produced an additive effect, which facilitated motor performance in the non-dominant hand. These findings are relevant to motor skill learning and to research studies of motor recovery after stroke.
TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy
Authors: Turner Bradley J , Bäumer Dirk , Parkinson Nicholas J , Scaber Jakub , Ansorge Olaf , Talbot Kevin 
Published: October 2008

Abstract

Background
Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology. Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases. Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease. Here, we characterise TDP-43 localisation, expression levels and post-translational modifications in mouse models of ALS and spinal muscular atrophy (SMA).

Results
TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords.

Conclusion
These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.