Objective-The aim of our study was to investigate the use of targeted contrast-enhanced highfrequency ultrasonography for molecular imaging of vascular endothelial growth factor receptor 2 (VEGFR2) expression on tumor vascular endothelium in murine models of breast cancer.Methods-Highly invasive metastatic (4T1) and nonmetatstatic (67NR) breast cancer cells were implanted in athymic nude mice. Tumors were examined in vivo with targeted contrast-enhanced high-frequency ultrasonography using a scanner with a 40-MHz probe. Randomized boluses of ultrasound contrast agents (UCAs) conjugated with an anti-VEGFR2 monoclonal antibody or an isotype control antibody (immunoglobulin G) were injected into the animals. Sonograms were analyzed by calculation of the normalized video intensity amplitudes caused by backscatter of the bound UCA. After ultrasonography, the tumor samples were harvested for analysis of VEGFR2 expression by immunoblotting and immunocytochemistry.Results-The mean video intensity amplitude caused by backscatter of the retained VEGFR2-targeted UCA was significantly higher than that of the control UCA (mean ± SD: 4T1 tumors, 15 ± 3.5 versus 7 ± 1.6 dB; P < .01; 67NR tumors, 50 ± 12.3 versus 12 ± 2.6 dB; P < .01). There was a significant difference in VEGFR2-targeted UCA retention between 4T1 and 67NR tumors (normalized video intensity amplitudes, 15 ± 3.5 and 50 ± 12.3 dB, respectively; P < .001), and this correlated well with relative VEGFR2 expression in the two tumor types.Conclusions-Targeted contrast-enhanced high-frequency ultrasonography may enable in vivo molecular imaging of VEGFR2 expression on the tumor vascular endothelium and may be used for noninvasive longitudinal evaluation of tumor angiogenesis in preclinical studies.Keywords breast cancer; molecular ultrasonography; vascular endothelial growth factor receptor 2 Noninvasive molecular imaging attempts to map spatial distribution of molecular events or processes. When applied to cancer, molecular imaging may be used not only to identify and locate a tumor but also to visualize the expression and activity of specific molecules and
Germ line DNA directs the development of the next generation and, as such, is profoundly different from somatic cell DNA. Spermatogenic cells obtained from young adult lacI transgenic mice display a lower spontaneous mutant frequency and greater in vitro base excision repair activity than somatic cells and tissues obtained from the same mice. However, spermatogenic cells from old lacI mice display a 10-fold higher mutant frequency. This increased spontaneous mutant frequency occurs coincidentally with decreased in vitro base excision repair activity for germ cell and testicular extracts that in turn corresponds to a decreased abundance of AP endonuclease. To directly test whether a genetic diminution of AP endonuclease results in increased spontaneous mutant frequencies in spermatogenic cell types, AP endonuclease heterozygous (Apex ؉/؊ ) knockout mice were crossed with lacI transgenic mice. Spontaneous mutant frequencies were significantly elevated (approximately twofold) for liver and spleen obtained from 3-month-old Apex ؉/؊ lacI ؉ mice compared to frequencies from Apex ؉/؉ lacI ؉ littermates and were additionally elevated for somatic tissues from 9-monthold mice. Spermatogenic cells from 9-month-old Apex ؉/؊ lacI ؉ mice were significantly elevated twofold compared to levels for 9-month-old Apex ؉/؉ lacI ؉ control mice. These data indicate that diminution of AP endonuclease has a significant effect on spontaneous mutagenesis in somatic and germ line cells.Maintenance of germ cell genetic integrity is fundamental to the development of healthy offspring. However, DNA is constantly exposed to endogenous sources of damage (15). If left unrepaired, DNA damage can lead to errors during replication, thus generating de novo germ line mutations. Such mutations can result in genetic diseases. It has been suggested that most spontaneous germ line mutations occur in male gametes rather than female gametes (11,18,55), and there is a paternal age effect associated with several dominant genetic disorders (8,11,14,19,36,52,55). Studies on germ line mutagenesis were facilitated greatly by the development of mice transgenic for the lacI or lacZ reporter genes. Using these models, a direct assessment of in vivo spontaneous mutant frequencies for male germ cells and somatic cells and tissues is possible. lacI transgenic mice display an approximately 10-fold lower spontaneous mutant frequency (0.6 ϫ 10 Ϫ5 ) for male germ cells than for somatic cells and tissues (4.8 ϫ 10 Ϫ5 ) obtained from young adults (26,47,60). Notably, a 10-fold higher spontaneous mutant frequency was observed for spermatogenic cells obtained from old (28-month-old) mice (2.9 ϫ 10 Ϫ5 to 4.9 ϫ 10 Ϫ5 ) than for young adult (60-day-old) mice (0.4 ϫ 10 Ϫ5 to 0.8 ϫ 10 Ϫ5 ), thereby indicating a paternal age effect in the mouse model (60). The lacI transgenic mice represent the first mouse model used to study mechanisms mediating the paternal age effect.The results demonstrating a lower spontaneous mutant frequency in the male germ line led to questions about how a...
The magnitude of the molecular ultrasonographic signal from a VEGFR2-targeted UCA retained by tissue correlates with VEGFR2 expression. These results validate the use of molecular ultrasonography for in vivo detection and quantification of VEGFR2 expression in this breast cancer model.
BACKGROUND AND PURPOSE:Ischemic injury to the brain is a common complication of SCA. To better understand the neurologic impact of SCA, TBSS were applied to DTI data to investigate white matter injuries in pediatric patients with SCA.
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