bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABCB5 Identifies a Therapy-Refractory Tumor Cell Population in Colorectal Cancer Patients
Authors: Wilson Brian J. , Schatton Tobias , Zhan Qian , Gasser Martin , Ma Jie , Saab Karim R. , Schanche Robin , Waaga-Gasser Ana-Maria , Gold Jason S. , Huang Qin , Murphy George F. , Frank Markus H. , Frank Natasha Y. 
Published: June 2011

Abstract
Identification and reversal of treatment resistance mechanisms of clinically refractory tumor cells is critical for successful cancer therapy. Here we show that ATP-binding cassette member B5 (ABCB5) identifies therapy-refractory tumor cells in colorectal cancer patients following fluorouracil (5-FU)–based chemoradiation therapy and provide evidence for a functional role of ABCB5 in colorectal cancer 5-FU resistance. Examination of human colon and colorectal cancer specimens revealed ABCB5 to be expressed only on rare cells within healthy intestinal tissue, whereas clinical colorectal cancers exhibited substantially increased levels of ABCB5 expression. Analysis of successive, patient-matched biopsy specimens obtained prior to and following neoadjuvant 5-FU–based chemoradiation therapy in a series of colorectal cancer patients revealed markedly enhanced abundance of ABCB5-positive tumor cells when residual disease was detected. Consistent with this finding, the ABCB5-expressing tumor cell population was also treatment refractory and exhibited resistance to 5-FU–induced apoptosis in a colorectal cancer xenograft model of 5-FU monotherapy. Mechanistically, short hairpin RNA–mediated ABCB5 knockdown significantly inhibited tumorigenic xenograft growth and sensitized colorectal cancer cells to 5-FU–induced cell killing. Our results identify ABCB5 as a novel molecular marker of therapy-refractory tumor cells in colorectal cancer patients and point to a need for consistent eradication of ABCB5-positive resistant tumor cell populations for more effective colorectal cancer therapy. Cancer Res; 71(15); 5307–16. ©2011 AACR.
MicroRNA-10b Expression Correlates with Response to Neoadjuvant Therapy and Survival in Pancreatic Ductal Adenocarcinoma
Authors: Preis Meir , Gardner Timothy B. , Gordon Stuart R. , Pipas J. Marc , Mackenzie Todd A. , Klein Erin E. , Longnecker Daniel S. , Gutmann Edward J. , Sempere Lorenzo F. , Korc Murray 
Published: June 2011

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Diagnosis and management of PDAC are hampered by the absence of sensitive and specific disease biomarkers. MicroRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC.
Experimental Design: miRNA expression was characterized by fluorescence-based in situ hybridization using locked nucleic acid–modified DNA probes against miR-10b, miR-21, miR-155, miR-196a, and miR-210, followed by codetection of proteins by immunohistochemistry on the same tissue sections. miRNA expression in surgically resected PDAC tissues and in endoscopic ultrasonography (EUS)-guided fine-needle aspirate (EUS-FNA) samples was analyzed in cytokeratin 19 (CK19)–positive epithelial cells using optical intensity analysis.
Results: In 10 resected PDAC samples, miR-10b was the most frequently and consistently overexpressed miRNA among characterized miRNAs, exhibiting a four-fold increase in the cancer cells (P = 0.012). Given this preferential overexpression of miR-10b, we sought to determine whether miR-10b expression was clinically relevant. Accordingly, miR-10b expression was examined in 106 EUS-FNA samples obtained from pancreatic lesions. miR-10b expression was increased in cancer cells compared with CK19-positive epithelial cells in benign lesions (P = 0.0001). In patients with PDACs, lower levels of miR-10b were associated with improved response to multimodality neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival.
Conclusion: miR-10b is a novel diagnostic biomarker for PDACs when assessing pancreatic lesions. Expression of miR-10b is predictive of response to neoadjuvant therapy and outcome in this disease. Clin Cancer Res; 17(17); 5812–21. ©2011 AACR.
A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance
Authors: Guerreiro Ana S. , Fattet Sarah , Kulesza Dorota W. , Atamer Abdullah , Elsing Alexandra N. , Shalaby Tarek , Jackson Shaun P. , Schoenwaelder Simone M. , Grotzer Michael A. , Delattre Olivier , Arcaro Alexandre 
Published: June 2011

Abstract
Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110γ (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110γ phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma. Mol Cancer Res; 9(7); 925–35. ©2011 AACR.
Health education and interactive drama
Authors: Robinson Daniel B , Meyer Matthew 
Published: June 2011

Objective: Within Canada, health education is generally taught by teachers who are subject generalists, or subject specialists within other disciplines, with little-to-no formal teacher training in health education. Without teacher training related to curriculum and instruction in health education, teachers are effectively required to adapt their developing pedagogies to unique health contexts. This article highlights findings from a recent study in which pre-service physical education (PE) teachers implemented interactive drama (ID) as a pedagogical practice to engage adolescent students (aged 13–16 years) in meaningful learning opportunities related to particular health education curricular outcomes. Design: The study was part of a Service Learning Project (SLP) within a secondary physical education curriculum and instruction course at Atlantic Canada University. 1 During the SLP, pre-service PE teachers ( n = 21) engaged adolescent students ( n = 162) in ID presentations and discussions. After completion of the SLP, pre-service PE teachers shared their perspectives of ID as a pedagogical practice capable of meaningfully engaging themselves and their students within health education. Setting: Atlantic Canada University has a population of approximately 5,000 students, the majority of whom come from Atlantic and Eastern Canada. The SLP occurred at Melmerby School, 2 a P-12 school with a student population of approximately 500 students. Method: Applying case study methodology, the researchers examined pre-service PE teachers’ written responses to a post-SLP survey. These data were collected so as to gain an in-depth understanding of ID as a perceived appropriate pedagogical practice for health education. Results: Three primary themes were identified through the data analysis. These were: enabling teachers; engaging students; and real-life connections. Conclusion: ID can be a beneficial pedagogical practice for health education; it has the potential to benefit both pre-service PE teachers and their adolescent students.
The Emergence of the King James Version of the Bible, 1611
Authors: Croft Pauline 
Published: June 2011

In 2011 we celebrate the four-hundredth anniversary of the publication in 1611 of the King James Version of the Bible. It is by far the best-known of all Bible translations, still used worldwide. In 1604 at the Hampton Court Conference, the more puritan wing of the Church of England pressed King James I to reform various ecclesiastical practices which they saw as abuses. He refused but agreed that there should be a new Bible translation. The article discusses this key event and traces the background, from Anglo-Saxon translations to the Reformation scholarship of men such as Tyndale and Coverdale, who used the new technology of printing to make Scripture widely available to those who knew no Latin or Greek. The process culminated in 1611 with the King James Bible, an exceptionally scholarly and readable version, at a time when expanding literacy allowed far more people to read the Scriptures for themselves.
The IDDEA project: a strategy for the detection of alpha-1 antitrypsin deficiency in COPD patients in the primary care setting
Authors: Molina Jesús , Flor Xavier , García Rosa , Timiraos Rosario , Tirado-Conde Gema , Miravitlles Marc 
Published: June 2011

Objective: Primary care provides the main route for access to health care for patients with common chronic illnesses such as chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin (AAT) deficiency is an underdiagnosed pathology associated with COPD risk which has a very low prevalence. The Information and Detection of the Deficiency of AAT (IDDEA) project was developed to identify AAT-deficient patients at primary care centres by providing adequate diagnostic tools to family doctors. Methods: Patients with COPD were identified and registered on a specially designed website. Dried blood samples were collected on filter papers and sent to the laboratory for AAT levels and AAT deficiency-related genotype determinations. Results were uploaded to the website and analysed. Results: Between January 2008 and April 2009, 596 patients were identified by 90 participating physicians. The number of patients who did not have AAT deficiency (serum concentrations ≥60 mg AAT/dl) was 549 (98.9%). Nineteen patients (3.2%) were carriers of the allelic variant Pi*Z among which two were homozygous PiZZ (one of them was an index case) and one was heterozygous PiSZ. These three newly detected cases were registered in the Spanish Registry of Patients with AAT Deficiency. An estimate of the gene frequency of the S allele was 7.65% and the severe deficiency Z allele was 1.76%. Conclusions: Results confirm that ATT deficiency is still underdiagnosed. The IDDEA system appears to be a useful tool for the detection of AAT deficiency in the primary care setting.
The critical role of agrin in the hematopoietic stem cell niche
Authors: Mazzon Cristina , Anselmo Achille , Cibella Javier , Soldani Cristiana , Destro Annarita , Kim Natalie , Roncalli Massimo , Burden Steven J. , Dustin Michael L. , Sarukhan Adelaida , Viola Antonella 
Published: June 2011

Abstract
Hematopoiesis is the process leading to the sustained production of blood cells by hematopoietic stem cells (HSCs). Growth, survival, and differentiation of HSCs occur in specialized microenvironments called “hematopoietic niches,” through molecular cues that are only partially understood. Here we show that agrin, a proteoglycan involved in the neuromuscular junction, is a critical niche-derived signal that controls survival and proliferation of HSCs. Agrin is expressed by multipotent nonhematopoietic mesenchymal stem cells (MSCs) and by differentiated osteoblasts lining the endosteal bone surface, whereas Lin−Sca1+c-Kit+ (LSK) cells express the α-dystroglycan receptor for agrin. In vitro, agrin-deficient MSCs were less efficient in supporting proliferation of mouse Lin−c-Kit+ cells, suggesting that agrin plays a role in the hematopoietic cell development. These results were indeed confirmed in vivo through the analysis of agrin knockout mice (Musk-L;Agrn−/−). Agrin-deficient mice displayed in vivo apoptosis of CD34+CD135− LSK cells and impaired hematopoiesis, both of which were reverted by an agrin-sufficient stroma. These data unveil a crucial role of agrin in the hematopoietic niches and in the cross-talk between stromal and hematopoietic stem cells.
IL-7 mediates Ebf-1–dependent lineage restriction in early lymphoid progenitors
Authors: Tsapogas Panagiotis , Zandi Sasan , Åhsberg Josefine , Zetterblad Jenny , Welinder Eva , Jönsson Jan Ingvar , Månsson Robert , Qian Hong , Sigvardsson Mikael 
Published: June 2011

Abstract
Deficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D− multipotent CLPs, the formation of the lineage restricted LY6D+ CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D+ CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D+ cells develop in Ebf-1–deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D+ CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.
Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms
Authors: Anand Shubha , Stedham Frances , Gudgin Emma , Campbell Peter , Beer Philip , Green Anthony R. , Huntly Brian J. P. 
Published: June 2011

Abstract
Myeloproliferative neoplasms (MPNs) are associated with recurrent activating mutations of signaling proteins such as Janus kinase 2 (JAK2). However, the actual downstream signaling events and how these alter myeloid homeostasis are poorly understood. We developed an assay to measure basal levels of phosphorylated signaling intermediates by flow cytometry during myeloid differentiation in MPN patients. Our study provides the first systematic demonstration of specific signaling events and their comparison with disease phenotype and JAK2 mutation status. We demonstrate increased basal signaling in MPN patients, which occurs in both early and later stages of myeloid differentiation. In addition, the pattern of signaling is not correlated with JAK2 mutation status and signaling intensity is poorly correlated with mutant JAK2 allele burden. In contrast, signaling differences are detected between different MPN disease phenotypes. Finally, we demonstrate that signaling can be inhibited by a JAK2-selective small molecule, but that this inhibition is not JAK2 V617F specific, because MPN patients with mutant JAK2, wild-type JAK2, and control patients were inhibited to a similar degree. Our data suggest that, in addition to JAK2 mutations, other factors contribute significantly to the MPN phenotype, results that are relevant to both the pathogenesis and therapy of MPN.
Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion
Authors: Morlacchi Sara , Soldani Cristiana , Viola Antonella , Sarukhan Adelaida 
Published: June 2011

Abstract
Multiple mechanisms operate to ensure T-cell tolerance toward self-antigens. Three main processes have been described: clonal deletion, anergy, and deviation to CD4+ regulatory T cells (Tregs) that suppress autoreactive T cells that have escaped the first 2 mechanisms. Although it is accepted that dendritic cells (DCs) and B cells contribute in maintaining T-cell tolerance to self-antigens, their relative contribution and the processes involved under physiologic conditions remain only partially characterized. In this study, we used different transgenic mouse models to obtain chimeras where a neo self-antigen is expressed by thymic epithelium and/or by DCs or B cells. We found that expression of cognate ligand in the thymus enhances antigen-specific FoxP3+ cells independently of whether the self-antigen is expressed on thymic epithelium or only on DCs, but not on B cells. On the contrary, self-antigen expression by B cells was very efficient in inducing FoxP3+ cells in the periphery, whereas self-antigen expression by DC led mainly to deletion and anergy of antigen-specific FoxP3− cells. The results presented in this study underline the role of B cells in Treg induction and may have important implications in clinical protocols aimed at the peripheral expansion of Tregs in patients.
CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia
Authors: Stolla Moritz , Stefanini Lucia , André Pierrette , Ouellette Timothy D. , Reilly Michael P. , McKenzie Steven E. , Bergmeier Wolfgang 
Published: June 2011

AbstractPlatelet activation via Fcγ receptor IIA (FcγRIIA) is a critical event in immune-mediated thrombocytopenia and thrombosis syndromes (ITT). We recently identified signaling by the guanine nucleotide exchange factor CalDAG-GEFI and the adenosine diphosphate receptor P2Y12 as independent pathways leading to Rap1 small GTPase activation and platelet aggregation. Here, we evaluated the contribution of CalDAG-GEFI and P2Y12 signaling to platelet activation in ITT. Mice transgenic for the human FcγRIIA (hFcR) and deficient in CalDAG-GEFI−/− (hFcR/CDGI−/−) were generated. Compared with controls, aggregation of hFcR/CDGI−/− platelets or P2Y12 inhibitor-treated hFcR platelets required more than 5-fold and approximately 2-fold higher concentrations of a FcγRIIA stimulating antibody against CD9, respectively. Aggregation and Rap1 activation were abolished in P2Y12 inhibitor-treated hFcR/CDGI−/− platelets. For in vivo studies, a novel model for antibody-induced thrombocytopenia and thrombosis was established. FcγRIIA-dependent platelet thrombosis was induced by infusion of Alexa750-labeled antibodies to glycoprotein IX (CD42a), and pulmonary thrombi were detected by near-infrared imaging technology. Anti-GPIX antibodies dose-dependently caused thrombocytopenia and pulmonary thrombosis in hFcR-transgenic but not wild-type mice. CalDAG-GEFI-deficient but not clopidogrel-treated hFcR-transgenic mice were completely protected from ITT. In summary, we established a novel mouse model for ITT, which was used to identify CalDAG-GEFI as a potential new target in the treatment of ITT.
Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures
Authors: Glomski Krzysztof , Monette Sébastien , Manova Katia , De Strooper Bart , Saftig Paul , Blobel Carl P. 
Published: June 2011

AbstractDuring vertebrate angiogenesis, Notch regulates the cell-fate decision between vascular tip cells versus stalk cells. Canonical Notch signaling depends on sequential proteolytic events, whereby interaction of Notch with membrane-anchored ligands triggers proteolytic processing, first by Adam10 and then presenilins. This liberates the Notch intracellular domain, allowing it to enter the nucleus and activate Notch-dependent genes. Here we report that conditional inactivation of Adam10 in endothelial cells (A10ΔEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling. Moreover, A10ΔEC mice have additional vascular abnormalities, including aberrant subcapsular hepatic veins, enlarged glomeruli, intestinal polyps containing endothelial cell masses, abnormal endochondral ossification, leading to stunted long bone growth and increased pathologic neovascularization following oxygen-induced retinopathy. Our findings support a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions, most likely because of its essential role in canonical Notch signaling.
Overwhelming postsplenectomy infection due to Mycoplasma pneumoniaein an asplenic cirrhotic patient: Case report
Authors: Xu Feng , Dai Chao-Liu , Wu Xing-Mao , Chu Peng 
Published: June 2011

Abstract

Background

Mycoplasma
pneumoniae infection is usually self-limited, but some fulminant cases are fatal, even when occurring in previously healthy individuals. It can also be the cause of overwhelming postsplenectomy infection (OPSI).

Case presentation
We report a case of OPSI in a 41-year-old woman with hypersplenism associated with hepatitis B cirrhosis. We detected a significant Mycoplasma pneumoniae agglutination titer, but no evidence of infection with Chlamydia pneumoniae, Legionnella spp., or any other bacterial or fungal pathogens. She eventually died despite aggressive therapy.

Conclusions

M. pneumoniae could be an underestimated cause of OPSI, and should be suspected in fulminant infectious cases in asplenic patients.
Levels of soluble fms-like tyrosine kinase one in first trimester and outcomes of pregnancy: a systematic review
Authors: Jacobs Marni , Nassar Natasha , Roberts Christine L , Hadfield Ruth , Morris Jonathan M , Ashton Anthony W 
Published: June 2011

Abstract
Angiogenic factors are involved in formation of new blood vessels required for placental development and function; and critical for fetal growth and development. Soluble fms-like tyrosine kinase 1(sFlt-1) is an anti-angiogenic protein that inhibits formation of new blood vessels resulting in potential pregnancy complications. The objective of this study was to undertake a systematic review to assess levels of sFlt-1 in early pregnancy and association with adverse pregnancy outcomes. PubMed and Medline databases and reference lists were searched up to July 2010. Inclusion criteria were pregnant women, blood sample taken during first trimester and assessment/reporting of sFlt-1 concentrations and subsequent pregnancy complications. Twelve relevant studies were identified of 71 to 668 women. No pooling of results was undertaken due to variation in sFlt-1 concentrations (range, 166-6,349 pg/ml amongst controls), samples used (serum, plasma), different summary statistics (mean, median, odds ratio) and outcome definitions applied. Levels of sFlt-1 were generally higher among women who developed preeclampsia (11 studies) or gestational hypertension (two studies), but not significantly different to normotensive women in most studies. There was no consistent pattern in association between sFlt-1 concentrations and fetal growth restriction (4 studies); and levels were non-significantly higher for women with postpartum bleeding (1 study) and significantly lower for stillbirths (1 study).This review found no clear evidence of an association between sFlt-1 levels in first trimester and adverse pregnancy outcomes. However, findings were affected by methodological, biological and testing variations between studies; highlighting the need for consistent testing of new biomarkers and reporting of outcome measures.