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11.
Adelphocorisella australis sp. n. is described from north Queensland. This, the first representative of the genus known from Australia, is compared with the two previously described species, both from Japan. 相似文献
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Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab 总被引:6,自引:0,他引:6
Adams CW Allison DE Flagella K Presta L Clarke J Dybdal N McKeever K Sliwkowski MX 《Cancer immunology, immunotherapy : CII》2006,55(6):717-727
Dimerization is essential for activity of human epidermal growth factor receptors (HER1/EGFR, HER2/ErbB2, HER3/ErbB3, and
ErbB4) and mediates intracellular signaling events leading to cancer cell proliferation, survival, and resistance to therapy.
HER2 is the preferred dimerization partner. Activation of HER signaling pathways may be blocked by inhibition of dimer formation
using a monoclonal antibody (MAb) directed against the dimerization domain of HER2. The murine MAb 2C4 that specifically binds
the HER2 dimerization domain was cloned as a chimeric antibody, humanized using a computer-generated model to guide framework
substitutions, and variants were tested as Fabs. Pharmacokinetics and toxicology were evaluated in rodents and cynomolgus
monkeys. Cloning the variable domains of MAb 2C4 into a vector containing human kappa and CH1 domains allowed construction
of a mouse-human chimeric Fab. DNA sequencing of the chimeric clone permitted identification of CDR residues. The full-length
IgG1 of variant F-10 was equivalent in binding to chimeric IgG1 and was designated pertuzumab (rhuMAb 2C4; Omnitarg). Pertuzumab
pharmacokinetics was best described by a two-compartment model with a distribution phase of <1 day, terminal half-life of
~10 days, and volume of distribution of ~40 mL/kg that approximates serum volume. With the exception of diarrhea, pertuzumab
was generally well tolerated in cynomolgus monkeys. Pertuzumab, a recombinant humanized IgG1 MAb, is the first of a new class
of agents known as HER dimerization inhibitors. Inhibition of HER dimerization may be an effective anticancer strategy in
tumors with either normal or elevated expression of HER2. 相似文献
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Zheng J. Lisa Frantz Gretchen Lewis Annette K. Sliwkowski Mark Gao Wei-Qiang 《Brain Cell Biology》1999,28(10-11):901-912
Hair cell loss due to acoustic and ototoxic damage often leads to hearing and balance impairments. Although a spontaneous event in chicks and lower vertebrates, hair cell replacement occurs at a much lower frequency in mammals presumably due to a very low rate of supporting cell proliferation following injury. We report here that heregulin, a member of the neuregulin family, dramatically enhances proliferation of supporting cells in postnatal rat utricular epithelial sheet cultures after gentamicin treatment, as revealed by bromo-deoxyuridine (BrdU) immunocytochemistry. A dose-dependent study shows that the maximal effects of heregulin are achieved at 3 nM. The mitogenic effects of heregulin are confirmed in utricular whole mount cultures. Autoradiography of the utricular whole mount cultures shows that heregulin also enhances the number of tritiated thymidine-labeled cells within the hair cell layer. TaqMan quantitative RT-PCR analysis and immunocytochemistry reveal that heregulin and its binding receptors (ErbB-2, ErbB-3 and ErbB-4) are expressed in the inner ear sensory epithelium. Of several ligands activating various ErbB receptors, including heregulin, neuregulin-3, β-cellulin, heparin binding-epidermal growth factor (HB-EGF), transforming growth factor-α (TGF-α) and EGF, heregulin shows the most potent mitogenic effects on supporting cells. Because neuregulin-3 that signals only through ErbB-4 does not show an effect, these data suggest that activation of the ErbB-2-ErbB-3 heterodimeric complexes, rather than ErbB-4, is critical for the proliferative response in the utricular sensory epithelium. In addition, gentamicin treatment induces an upregulation of heregulin mRNA. Considered together, heregulin may play an important role in hair cell regeneration following ototoxic damage. 相似文献
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Bortezomib is a chemotherapeutic agent used to treat several cancers; however, it exhibits severe side effects in testicular tissue. We investigated the use of agomelatine to prevent testicular tissue damage caused by bortezomib. We used 36 male Sprague-Dawley rats divided randomly into six equal groups: group 1, no treatment control; group 2, agomelatine treatment only; group 3, bortezomib treatment only for 48 h; group 4, bortezomib + agomelatine treatment for 48 h; group 5, bortezomib treatment only for 72 h; and group 6, bortezomib + agomelatine treatment for 72 h. After treatments, the rats were sacrificed and testicular tissue was harvested. Lipid oxidation (LPO) and superoxide dismutase (SOD) levels in the tissues were determined using biochemical methods. Tissue samples also were examined using histopathological and immunohistochemical techniques. The LPO level was increased, while the SOD level was decreased in the bortezomib treated groups. We found that agomelatine treatment normalized LPO and SOD activities in the bortezomib treated groups. In the spermatogonia and Sertoli cells, the staining density of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and caspase 3 were decreased in the bortezomib + agomelatine groups at both 48 and 72 h compared to bortezomib only treated groups. We observed maturation arrest, basal membrane thickening, increase in inflammatory cells and connective tissue, and edema between germ cells in the bortezomib only treated groups. By contrast, normal basal membrane, less edema and more normal maturation were observed in the bortezomib + agomelatine groups at 48 and 72 h. We found that agomelatine reduced the damaging effects of bortezomib. The use of agomelatine to prevent bortezomib induced testicular tissue damage in human patients should be investigated further. 相似文献
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Bianca V Gapp Tomasz Konopka Thomas Penz Vineet Dalal Tilmann Bürckstümmer Christoph Bock Sebastian MB Nijman 《Molecular systems biology》2016,12(8)
Reverse genetic screens have driven gene annotation and target discovery in model organisms. However, many disease‐relevant genotypes and phenotypes cannot be studied in lower organisms. It is therefore essential to overcome technical hurdles associated with large‐scale reverse genetics in human cells. Here, we establish a reverse genetic approach based on highly robust and sensitive multiplexed RNA sequencing of mutant human cells. We conduct 10 parallel screens using a collection of engineered haploid isogenic cell lines with knockouts covering tyrosine kinases and identify known and unexpected effects on signaling pathways. Our study provides proof of concept for a scalable approach to link genotype to phenotype in human cells, which has broad applications. In particular, it clears the way for systematic phenotyping of still poorly characterized human genes and for systematic study of uncharacterized genomic features associated with human disease. 相似文献