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991.
Bart ECG de Goeij Matthias Peipp Simone de Haij Edward N van den Brink Christian Kellner Thilo Riedl Rob de Jong Tom Vink Kristin Strumane Wim K Bleeker Paul WHI Parren 《MABS-AUSTIN》2014,6(2):392-402
The human epidermal growth factor receptor (HER)2 provides an excellent target for selective delivery of cytotoxic drugs to tumor cells by antibody-drug conjugates (ADC) as has been clinically validated by ado-trastuzumab emtansine (KadcylaTM). While selecting a suitable antibody for an ADC approach often takes specificity and efficient antibody-target complex internalization into account, the characteristics of the optimal antibody candidate remain poorly understood. We studied a large panel of human HER2 antibodies to identify the characteristics that make them most suitable for an ADC approach. As a model toxin, amenable to in vitro high-throughput screening, we employed Pseudomonas exotoxin A (ETA’) fused to an anti-kappa light chain domain antibody. Cytotoxicity induced by HER2 antibodies, which were thus non-covalently linked to ETA’, was assessed for high and low HER2 expressing tumor cell lines and correlated with internalization and downmodulation of HER2 antibody-target complexes. Our results demonstrate that HER2 antibodies that do not inhibit heterodimerization of HER2 with related ErbB receptors internalize more efficiently and show greater ETA’-mediated cytotoxicity than antibodies that do inhibit such heterodimerization. Moreover, stimulation with ErbB ligand significantly enhanced ADC-mediated tumor kill by antibodies that do not inhibit HER2 heterodimerization. This suggests that the formation of HER2/ErbB-heterodimers enhances ADC internalization and subsequent killing of tumor cells. Our study indicates that selecting HER2 ADCs that allow piggybacking of HER2 onto other ErbB receptors provides an attractive strategy for increasing ADC delivery and tumor cell killing capacity to both high and low HER2 expressing tumor cells. 相似文献
992.
Edwards ML Fagan PK Towers RJ Currie BJ Sriprakash KS 《Microbes and infection / Institut Pasteur》2004,6(10):926-928
Streptococcus pyogenes (group A streptococcus, GAS) is a human-specific pathogen, which employs a large number of adhesins for colonization. Fibronectin-binding proteins (FBPs) play a major role in GAS adhesion to host cells. SfbI, a major streptococcal FBP, has been well studied. A peptide (peptide-MSG) based on this adhesin inhibits fibronectin (Fn)-binding by the pathogen. To test whether this peptide also inhibits adherence of GAS to host cells, adhesion assays were performed with strains possessing different combinations of genes for three distinct FBPs. Peptide-MSG inhibited GAS adherence to human keratinocytes (HaCaT) in a strain dependent manner. There is no consistent pattern between the effect and the ability to express one or more of the FBPs. A single peptide may be insufficient to prevent GAS adherence to host cells. 相似文献
993.
Farnesoid X receptor represses hepatic lipase gene expression 总被引:5,自引:0,他引:5
Sirvent A Verhoeven AJ Jansen H Kosykh V Darteil RJ Hum DW Fruchart JC Staels B 《Journal of lipid research》2004,45(11):2110-2115
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996.
Gwendal Le Martelot Donatella Canella Laura Symul Eugenia Migliavacca Federica Gilardi Robin Liechti Olivier Martin Keith Harshman Mauro Delorenzi Béatrice Desvergne Winship Herr Bart Deplancke Ueli Schibler Jacques Rougemont Nicolas Guex Nouria Hernandez Felix Naef the CycliX consortium 《PLoS biology》2012,10(11)
997.
Jarvis JP Scheinfeldt LB Soi S Lambert C Omberg L Ferwerda B Froment A Bodo JM Beggs W Hoffman G Mezey J Tishkoff SA 《PLoS genetics》2012,8(4):e1002641
African Pygmy groups show a distinctive pattern of phenotypic variation, including short stature, which is thought to reflect past adaptation to a tropical environment. Here, we analyze Illumina 1M SNP array data in three Western Pygmy populations from Cameroon and three neighboring Bantu-speaking agricultural populations with whom they have admixed. We infer genome-wide ancestry, scan for signals of positive selection, and perform targeted genetic association with measured height variation. We identify multiple regions throughout the genome that may have played a role in adaptive evolution, many of which contain loci with roles in growth hormone, insulin, and insulin-like growth factor signaling pathways, as well as immunity and neuroendocrine signaling involved in reproduction and metabolism. The most striking results are found on chromosome 3, which harbors a cluster of selection and association signals between approximately 45 and 60 Mb. This region also includes the positional candidate genes DOCK3, which is known to be associated with height variation in Europeans, and CISH, a negative regulator of cytokine signaling known to inhibit growth hormone-stimulated STAT5 signaling. Finally, pathway analysis for genes near the strongest signals of association with height indicates enrichment for loci involved in insulin and insulin-like growth factor signaling. 相似文献
998.
Stefanie Vandevijvere Wim Coucke Jean Vanderpas Caroline Trumpff Maarten Fauvart Ann Meulemans Sandrine Marie Marie-Fran?oise Vincent Roland Schoos Fran?ois Boemer Timothy Vanwynsberghe Eddy Philips Fran?ois Eyskens Brigitte Wuyts Valbona Selimaj Bart Van Overmeire Christine Kirkpatrick Herman Van Oyen Rodrigo Moreno-Reyes 《PloS one》2012,7(10)
It has been proposed that neonatal thyroid-stimulating hormone (TSH) concentrations are a good indicator of iodine deficiency in the population. A frequency of neonatal TSH concentrations above 5 mU/L below 3% has been proposed as the threshold indicating iodine sufficiency. The objective of the present study was to evaluate feasibility and usefulness of nation-wide neonatal TSH concentration screening results to assess iodine status in Belgium. All newborns born in Belgium during the period 2009–2011 (n = 377713) were included in the study, except those suffering from congenital hypothyroidism and premature neonates. The frequency of neonatal TSH concentrations above 5 mU/L from 2009 to 2011 in Belgium fluctuated between 2.6 and 3.3% in the centres using the same TSH assay. There was a significant inverse association between neonatal TSH level and birth weight. The longer the duration between birth and screening, the lower the TSH level. Neonatal TSH levels were significantly lower in winter than in spring or autumn and significantly lower in spring and summer than in autumn while significantly higher in spring compared to summer. In conclusion, despite that pregnant women in Belgium are mildly iodine deficient, the frequency of neonatal TSH concentrations above 5 mU/L was very low, suggesting that the neonatal TSH threshold proposed for detecting iodine deficiency needs to be re-evaluated. Although neonatal TSH is useful to detect severe iodine deficiency, it should not be recommended presently for the evaluation of iodine status in mildly iodine deficient regions. 相似文献
999.
Patricia Valente Teun Boekhout Melissa Fontes Landell Juliana Crestani Fernando Carlos Pagnocca Lara Dur?es Sette Michel Rodrigo Zambrano Passarini Carlos Augusto Rosa Luciana R. Brand?o Raphael S. Pimenta José Roberto Ribeiro Karina Marques Garcia Ching-Fu Lee Sung-Oui Suh Gábor Péter Dénes Dlauchy Jack W. Fell Gloria Scorzetti Bart Theelen Marilene H. Vainstein 《PloS one》2012,7(10)
Background
Independent surveys across the globe led to the proposal of a new basidiomycetous yeast genus within the Bulleromyces clade of the Tremellales, Bandoniozyma gen. nov., with seven new species.Methodology/Principal Findings
The species were characterized by multiple methods, including the analysis of D1/D2 and ITS nucleotide sequences, and morphological and physiological/biochemical traits. Most species can ferment glucose, which is an unusual trait among basidiomycetous yeasts.Conclusions/Significance
In this study we propose the new yeast genus Bandoniozyma, with seven species Bandoniozyma noutii sp. nov. (type species of genus; CBS 8364T = DBVPG 4489T), Bandoniozyma aquatica sp. nov. (UFMG-DH4.20T = CBS 12527T = ATCC MYA-4876T), Bandoniozyma complexa sp. nov. (CBS 11570T = ATCC MYA-4603T = MA28aT), Bandoniozyma fermentans sp. nov. (CBS 12399T = NU7M71T = BCRC 23267T), Bandoniozyma glucofermentans sp. nov. (CBS 10381T = NRRL Y-48076T = ATCC MYA-4760T = BG 02-7-15-015A-1-1T), Bandoniozyma tunnelae sp. nov. (CBS 8024T = DBVPG 7000T), and Bandoniozyma visegradensis sp. nov. (CBS 12505T = NRRL Y-48783T = NCAIM Y.01952T). 相似文献1000.
Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells 总被引:1,自引:0,他引:1
Easley CA Phillips BT McGuire MM Barringer JM Valli H Hermann BP Simerly CR Rajkovic A Miki T Orwig KE Schatten GP 《Cell reports》2012,2(3):440-446
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been shown to differentiate into primordial germ cells (PGCs) but not into spermatogonia, haploid spermatocytes, or spermatids. Here, we show that hESCs and hiPSCs differentiate directly into advanced male germ cell lineages, including postmeiotic, spermatid-like cells, in?vitro without genetic manipulation. Furthermore, our procedure mirrors spermatogenesis in?vivo by differentiating PSCs into UTF1-, PLZF-, and CDH1-positive spermatogonia-like cells; HIWI- and HILI-positive spermatocyte-like cells; and haploid cells expressing acrosin, transition protein 1, and protamine 1 (proteins that are uniquely found in spermatids and/or sperm). These spermatids show uniparental genomic imprints similar to those of human sperm on two loci: H19 and IGF2. These results demonstrate that male PSCs have the ability to differentiate directly into advanced germ cell lineages and may represent a novel strategy for studying spermatogenesis in?vitro. 相似文献