bluuebunny/crossref_metadata_2025_split huggingface dataset:
TheIFNG(IFN-γ) Genotype Predicts Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia
Authors: Kim Dong Hwan (Dennis) , Kong Jee Hyun , Byeun Ji Young , Jung Chul Won , Xu Wei , Liu Xiangdong , Kamel-Reid Suzanne , Kim Yeo-Keyoung , Kim Hyeoung-Joon , Lipton Jeffrey H. 
Published: October 2010

AbstractPurpose: The present study analyzed treatment outcomes of imatinib therapy by interindividual genetic variants in candidate biological pathways of chronic myeloid leukemia (CML) such as apoptosis, angiogenesis, IFN-γ signaling pathways, or drug transport/metabolism of imatinib.Experimental Design: Peripheral blood DNAs were genotyped for 79 single nucleotide polymorphism markers involved in the pathways of apoptosis, angiogenesis, myeloid cell growth, xenobiotic metabolism, WT1 signaling, IFN signaling, and others in CML patients who were included in discovery (n = 229, Canada) and validation cohorts (n = 187, Korea).Results: We found several genotypes associated with complete cytogenetic response: IFNG (rs1861494, rs2069705), FASL (rs763110), FAS (rs2234767, rs2234978), VEGFR2 (rs1531289), and WT1 (rs2234590); with major molecular response: IFNG (rs1861494, rs2069705), BIRC5 (rs9904341), FAS (rs2234978), and ABCG2 (rs2231142); with loss of response: IFNG (rs2069705), IFNGR2 (rs9808753), BIRC5 (rs9904341), and ORM (rs3182041); and with treatment failure: IFNG (rs2069705), JAK3 (rs3212713), and ORM (rs3182041). External validation for the above significant genotypes confirmed that the IFNG genotype (rs2069705) was predictive of complete cytogenetic response (hazard ratio, 2.17; P &lt; 0.001) and major molecular response (hazard ratio, 1.96; P = 0.0001) in validation cohorts of Korean ethnicity.Conclusions: The IFNG genotype was predictive for response to imatinib therapy, suggesting potential involvement of the IFN-γ signaling pathway in the mechanism of action of imatinib in CML. Clin Cancer Res; 16(21); 5339–50. ©2010 AACR.
Safety and Clinical Effect of Subcutaneous Human Interleukin-21 in Patients with Metastatic Melanoma or Renal Cell Carcinoma: A Phase I Trial
Authors: Schmidt Henrik , Brown Janet , Mouritzen Ulrik , Selby Peter , Fode Kirsten , Svane Inge Marie , Cook Graham P. , Mollerup David Hal , Geertsen Poul F. 
Published: October 2010

AbstractPurpose: This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21).Experimental Design: Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 μg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks.Results: Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 μg/kg, although five of seven patients at the 300 μg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-γ, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8+ T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response.Conclusion: Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC. Clin Cancer Res; 16(21); 5312–9. ©2010 AACR.
Magnitude of Perceived Change in Natural Images May Be Linearly Proportional to Differences in Neuronal Firing Rates
Authors: Chua Pei-Ying , Troscianko Tom , Lovell P. George , Tolhurst David , Chirimuuta Mazviita , To Michelle 
Published: October 2010

AbstractWe are studying how people perceive naturalistic suprathreshold changes in the colour, size, shape or location of items in images of natural scenes, using magnitude estimation ratings to characterise the sizes of the perceived changes in coloured photographs. We have implemented a computational model that tries to explain observers' ratings of these naturalistic differences between image pairs. We model the action-potential firing rates of millions of neurons, having linear and non-linear summation behaviour closely modelled on real V1 neurons. The numerical parameters of the model's sigmoidal transducer function are set by optimising the same model to experiments on contrast discrimination (contrast 'dippers') on monochrome photographs of natural scenes. The model, optimised on a stimulus-intensity domain in an experiment reminiscent of the Weber–Fechner relation, then produces tolerable predictions of the ratings for most kinds of naturalistic image change. Importantly, rating rises roughly linearly with the model's numerical output, which represents differences in neuronal firing rate in response to the two images under comparison; this implies that rating is proportional to the neuronal response.
Motorcycle Conspicuity: Effects of Age and Daytime Running Lights
Authors: Al-Awar Smither Janan , Torrez Lorenzo I. 
Published: October 2010

Objective:This study investigated variables that may contribute to motorcycle conspicuity within a high-fidelity simulated environment. The variables included motorcycle lighting, vehicular daytime running lights (DRLs), and age of the driver of the other vehicle. Background: Research suggests that decreased levels of conspicuity associated with riding a small two-wheeled vehicle reduce the ability of other drivers to detect and respond to that vehicle effectively. This lack of conspicuity is often responsible for the frequent injuries and fatalities incurred by motorcycle riders. Method: The 75 participants who took part in this study watched a series of video clips of roadway traffic and were asked to indicate when they saw a hazardous situation, such as the presence of pedestrians, motorcycles, or traffic cones. Both motorcycle and following-vehicle lights were manipulated, and participant reaction times were collected and analyzed. Results: Analyses indicated main effects for all three variables as well as interaction effects between motorcycle lighting and vehicle-following conditions. Overall, findings showed a link between DRLs and the effective detection of motorcycles and suggested that age-related changes affect the ability to detect and respond to a motorcycle effectively. Conclusion: Although our laboratory findings corroborated previous correlational studies, further research in real-world settings, such as those with high-density traffic or under adverse environmental conditions, needs to be conducted. Application: Potential applications of this research include the assessment of appropriate lighting technology to enhance conspicuity of motorcycles and reduce the high rate of fatalities and injuries related to motorcycle crashes.
CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability
Authors: Lannutti Brian J. , Meadows Sarah A. , Herman Sarah E. M. , Kashishian Adam , Steiner Bart , Johnson Amy J. , Byrd John C. , Tyner Jeffrey W. , Loriaux Marc M. , Deininger Mike , Druker Brian J. , Puri Kamal D. , Ulrich Roger G. , Giese Neill A. 
Published: October 2010

AbstractPhosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC50] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110δ-dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101.
Deciphering the human platelet sheddome
Authors: Fong Karen P. , Barry Colin , Tran Anh N. , Traxler Elizabeth A. , Wannemacher Kenneth M. , Tang Hsin-Yao , Speicher Kaye D. , Blair Ian A. , Speicher David W. , Grosser Tilo , Brass Lawrence F. 
Published: October 2010

Abstract
Activated platelets shed surface proteins, potentially modifying platelet function as well as providing a source of bioactive fragments. Previous studies have identified several constituents of the platelet sheddome, but the full extent of shedding is unknown. Here we have taken a global approach, analyzing protein fragments in the supernate of activated platelets using mass spectroscopy and looking for proteins originating from platelet membranes. After removing plasma proteins and microparticles, 1048 proteins were identified, including 69 membrane proteins. Nearly all of the membrane proteins had been detected previously, but only 10 had been shown to be shed in platelets. The remaining 59 are candidates subject to confirmation. Based on spectral counts, protein representation in the sheddome varies considerably. As proof of principle, we validated one of the less frequently detected proteins, semaphorin 7A, which had not previously been identified in platelets. Surface expression, cleavage, and shedding of semaphorin 7A were demonstrated, as was its association with α-granules. Finally, cleavage of semaphorin 7A and 12 other proteins was substantially reduced by an inhibitor of ADAM17, a known sheddase. These results define a subset of membrane proteins as sheddome candidates, forming the basis for further studies examining the impact of ectodomain shedding on platelet function.
Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome
Authors: Kfoury Youmna , Setterblad Niclas , El-Sabban Marwan , Zamborlini Alessia , Dassouki Zeina , El Hajj Hiba , Hermine Olivier , Pique Claudine , de Thé Hugues , Saïb Ali , Bazarbachi Ali 
Published: October 2010

AbstractThe human T-lymphotropic virus type I oncoprotein Tax is critical for T-cell transformation, acting mainly through nuclear factor kappa B essential modulator (NEMO) binding and subsequent nuclear factor-κB activation. Tax localizes to Tax nuclear bodies and to the centrosome and is subjected to ubiquitylation and small ubiquitin-like modifier (SUMO)ylation, which are both necessary for complete transcriptional activation. Using the photoconvertible fluorophore Dendra-2 coupled with live video confocal microscopy, we show for the first time that the same Tax molecule shuttles among Tax nuclear bodies and between these nuclear bodies and the centrosome, depending on its posttranslational modifications. Ubiquitylation targets Tax to nuclear bodies to which NEMO is recruited and subsequently SUMOylated. We also demonstrate that Tax nuclear bodies contain the SUMOylation machinery including SUMO and the SUMO conjugating enzyme Ubc9, strongly suggesting that these nuclear bodies represent sites of active SUMOylation. Finally, both ubiquitylation and SUMOylation of Tax control NEMO targeting to the centrosome. Altogether, we are proposing a model where both ubiquitylation and SUMOylation of Tax control the shuttling of Tax and NEMO between the cytoplasmic and nuclear compartments.
Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche
Authors: Zheng Junke , Huynh HoangDinh , Umikawa Masato , Silvany Robert , Zhang Cheng Cheng 
Published: October 2010

AbstractThe physiologic roles of angiopoietin-like proteins (Angptls) in the hematopoietic system remain unknown. Here we show that hematopoietic stem cells (HSCs) in Angptl3-null mice are decreased in number and quiescence. HSCs transplanted into Angptl3-null recipient mice exhibited impaired repopulation. Bone marrow sinusoidal endothelial cells express high levels of Angptl3 and are adjacent to HSCs. Importantly, bone marrow stromal cells or endothelium deficient in Angptl3 have a significantly decreased ability to support the expansion of repopulating HSCs. Angptl3 represses the expression of the transcription factor Ikaros, whose unregulated overexpression diminishes the repopulation activity of HSCs. Angptl3, as an extrinsic factor, thus supports the stemness of HSCs in the bone marrow niche.
An inventory of the Aspergillus niger secretome by combining in silico predictions with shotgun proteomics data
Authors: Braaksma Machtelt , Martens-Uzunova Elena S , Punt Peter J , Schaap Peter J 
Published: October 2010

Abstract

Background
The ecological niche occupied by a fungal species, its pathogenicity and its usefulness as a microbial cell factory to a large degree depends on its secretome. Protein secretion usually requires the presence of a N-terminal signal peptide (SP) and by scanning for this feature using available highly accurate SP-prediction tools, the fraction of potentially secreted proteins can be directly predicted. However, prediction of a SP does not guarantee that the protein is actually secreted and current in silico prediction methods suffer from gene-model errors introduced during genome annotation.

Results
A majority rule based classifier that also evaluates signal peptide predictions from the best homologs of three neighbouring Aspergillus species was developed to create an improved list of potential signal peptide containing proteins encoded by the Aspergillus niger genome. As a complement to these in silico predictions, the secretome associated with growth and upon carbon source depletion was determined using a shotgun proteomics approach. Overall, some 200 proteins with a predicted signal peptide were identified to be secreted proteins. Concordant changes in the secretome state were observed as a response to changes in growth/culture conditions. Additionally, two proteins secreted via a non-classical route operating in A. niger were identified.

Conclusions
We were able to improve the in silico inventory of A. niger secretory proteins by combining different gene-model predictions from neighbouring Aspergilli and thereby avoiding prediction conflicts associated with inaccurate gene-models. The expected accuracy of signal peptide prediction for proteins that lack homologous sequences in the proteomes of related species is 85%. An experimental validation of the predicted proteome confirmed in silico predictions.
Genetic diversity and striatal gene networks: focus on the heterogeneous stock-collaborative cross (HS-CC) mouse
Authors: Iancu Ovidiu D , Darakjian Priscila , Walter Nicole AR , Malmanger Barry , Oberbeck Denesa , Belknap John , McWeeney Shannon , Hitzemann Robert 
Published: October 2010

Abstract
Background
The current study focused on the extent genetic diversity within a species (Mus musculus) affects gene co-expression network structure. To examine this issue, we have created a new mouse resource, a heterogeneous stock (HS) formed from the same eight inbred strains that have been used to create the collaborative cross (CC). The eight inbred strains capture > 90% of the genetic diversity available within the species. For contrast with the HS-CC, a C57BL/6J (B6) × DBA/2J (D2) F2 intercross and the HS4, derived from crossing the B6, D2, BALB/cJ and LP/J strains, were used. Brain (striatum) gene expression data were obtained using the Illumina Mouse WG 6.1 array, and the data sets were interrogated using a weighted gene co-expression network analysis (WGCNA).

Results
Genes reliably detected as expressed were similar in all three data sets as was the variability of expression. As measured by the WGCNA, the modular structure of the transcriptome networks was also preserved both on the basis of module assignment and from the perspective of the topological overlap maps. Details of the HS-CC gene modules are provided; essentially identical results were obtained for the HS4 and F2 modules. Gene ontology annotation of the modules revealed a significant overrepresentation in some modules for neuronal processes, e.g., central nervous system development. Integration with known protein-protein interactions data indicated significant enrichment among co-expressed genes. We also noted significant overlap with markers of central nervous system cell types (neurons, oligodendrocytes and astrocytes). Using the Allen Brain Atlas, we found evidence of spatial co-localization within the striatum for several modules. Finally, for some modules it was possible to detect an enrichment of transcription binding sites. The binding site for Wt1, which is associated with neurodegeneration, was the most significantly overrepresented.

Conclusions
Despite the marked differences in genetic diversity, the transcriptome structure was remarkably similar for the F2, HS4 and HS-CC. These data suggest that it should be possible to integrate network data from simple and complex crosses. A careful examination of the HS-CC transcriptome revealed the expected structure for striatal gene expression. Importantly, we demonstrate the integration of anatomical and network expression data.
Is human blood a good surrogate for brain tissue in transcriptional studies?
Authors: Cai Chaochao , Langfelder Peter , Fuller Tova F , Oldham Michael C , Luo Rui , van den Berg Leonard H , Ophoff Roel A , Horvath Steve 
Published: October 2010

Abstract

Background
Since human brain tissue is often unavailable for transcriptional profiling studies, blood expression data is frequently used as a substitute. The underlying hypothesis in such studies is that genes expressed in brain tissue leave a transcriptional footprint in blood. We tested this hypothesis by relating three human brain expression data sets (from cortex, cerebellum and caudate nucleus) to two large human blood expression data sets (comprised of 1463 individuals).

Results
We found mean expression levels were weakly correlated between the brain and blood data (r range: [0.24,0.32]). Further, we tested whether co-expression relationships were preserved between the three brain regions and blood. Only a handful of brain co-expression modules showed strong evidence of preservation and these modules could be combined into a single large blood module. We also identified highly connected intramodular "hub" genes inside preserved modules. These preserved intramodular hub genes had the following properties: first, their expression levels tended to be significantly more heritable than those from non-preserved intramodular hub genes (p < 10-90); second, they had highly significant positive correlations with the following cluster of differentiation genes: CD58, CD47, CD48, CD53 and CD164; third, a significant number of them were known to be involved in infection mechanisms, post-transcriptional and post-translational modification and other basic processes.

Conclusions
Overall, we find transcriptome organization is poorly preserved between brain and blood. However, the subset of preserved co-expression relationships characterized here may aid future efforts to identify blood biomarkers for neurological and neuropsychiatric diseases when brain tissue samples are unavailable.
Cyclosporin A increases recovery after spinal cord injury but does not improve myelination by oligodendrocyte progenitor cell transplantation
Authors: Lü He-Zuo , Wang Yan-Xia , Zhou Jian-Sheng , Wang Feng-Chao , Hu Jian-Guo 
Published: October 2010

AbstractBackgroundTransplantation of oligodendrocyte precursor cells (OPCs) is an attractive therapy for demyelinating diseases. Cyclosporin A (CsA) is one of the foremost immunosuppressive agents and has widespread use in tissue and cell transplantation. However, whether CsA affects survival and differentiation of engrafted OPCsin vivois unknown. In this study, the effect of CsA on morphological, functional and immunological aspects, as well as survival and differentiation of engrafted OPCs in injured spinal cord was explored.ResultsWe transplanted green fluorescent protein (GFP) expressed OPCs (GFP-OPCs) into injured spinal cords of rats treated with or without CsA (10 mg/kg). Two weeks after cell transplantation, more GFP-positive cells were found in CsA-treated rats than that in vehicle-treated ones. However, the engrafted cells mostly differentiated into astrocytes, but not oligodendrocytes in both groups. In the CsA-treated group, a significant decrease in spinal cord lesion volume along with increase in spared myelin and neurons were found compared to the control group. Such histological improvement correlated well with an increase in behavioral recovery. Further study suggested that CsA treatment could inhibit infiltration of T cells and activation of resident microglia and/or macrophages derived from infiltrating monocytes in injured spinal cords, which contributes to the survival of engrafted OPCs and repair of spinal cord injury (SCI).ConclusionsThese results collectively indicate that CsA can promote the survival of engrafted OPCs in injured spinal cords, but has no effect on their differentiation. The engrafted cells mostly differentiated into astrocytes, but not oligodendrocytes. The beneficial effect of CsA on SCI and the survival of engrafted cells may be attributed to its neuroprotective effect.