Biomedical subjects

Caroline Zeiss

Publications and source records attributed to Caroline Zeiss.

4 recordsLinked to original sources

PubMed2005

Complement factor H polymorphism in age-related macular degeneration.

Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH) is strongly associated with AMD (nominal P value <10(-7)). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.

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PubMed2005

Correlation of tumor phenotype with c-fms proto-oncogene expression in an in vivo intraperitoneal model for experimental human breast cancer metastasis.

Although proto-oncogene expression has been shown to correlate with clinical outcome in breast carcinoma, an experimental model has not been proposed to study this phenomenon in vivo. In addition, the ability to modulate this proto-oncogene in vivo to correlate with phenotypic behavior has not been determined. Utilizing an intraperitoneal model for metastatic spread with BT20 human breast carcinoma cells, clonally expanded cells expressing five fold higher c-fms protein were compared with parent BT20 cells as well as an underexpressing clone using intrasplenic injection following left flank cut-down in female nude and Severe combined immunodeficient (SCID) mice. Athymic BALB/c nude and SCID animals were observed for clinical evidence of tumorigenicity with necropsy performed at either 50 or 80 days unless compromised earlier. Immunohistochemistry (IHC) of the harvested tumors was performed to correlate c-fms expression from its original in vitro culture to the in vivo model. At day 50, differences in primary tumor take and spread to the pelvis were already evident favoring the c-fms over-expression group with IHC of these tumors revealing significantly higher intensity of staining for c-fms, (mean H score of 205 vs. 43 in the over-expression and parent groups, respectively). At day 80, tumor take and spread was comparable; however, tumor size in the over-expression group was significantly larger than the parent and under-expressing group in both the BALB/c and SCID experiments. Modulation of c-fms proto-oncogene expression was also achieved using the anti-glucocorticoid, RU-486, via oral administration to SCID mice with subsequent correlation to IHC staining. This model thus provides tumors of significant size and organ diversity which retain their phenotype early in tumorigenesis allowing an early endpoint to assess efficacy of novel treatments.

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PubMed2004

A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels.

The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex(-/-) mice die by mid-gestation (E14.5) and the cause of their early demise remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2) hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Interestingly, vascular endothelial growth factor A (Vegfa) levels in the hearts of Hhex(-/-) mice were elevated as much as three-fold between E9.5 and E11.5, and treatment of cultured Hhex(-/-) AV explants with truncated soluble Vegfa receptor 1, sFlt-1, an inhibitor of Vegf signaling, completely abolished the excessive epithelial-mesenchymal transformation seen in the absence of Hhex. Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development.

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PubMed2003

Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate.

Low or absent expression of the cyclin-dependent kinase inhibitor p27(Kip1) serves as an excellent malignant marker for prostate and other human cancers. The level of p27(Kip1) is regulated primarily by the ubiquitin E3 ligase SCF(SKP2) through ubiquitin-dependent proteolysis. Expression of the F-box protein SKP2 is inversely correlated with p27 in many cancers. To determine the role of SCF(SKP2) in proliferation and tumorigenesis, we established transgenic mouse lines that specifically expressed SKP2 in the prostate gland. Unscheduled expression of SKP2 promoted marked overproliferation, resulting in hyperplasia, dysplasia, and low-grade carcinoma in the prostate gland. Consistent with its critical role in p27 proteolysis, SKP2 expression caused significant down-regulation of p27 in prostate glands from transgenic animals. Immunohistological staining indicated that SKP2 expression is restricted to the hyperplastic/dysplastic regions and that there is an inverse relationship between SKP2 and p27 expression in the ductal epithelium in transgenic animals. The prostate glands from transgenic mice also exhibited high levels of proliferative and mitotic markers such as Ki67 and cyclin B1. Our data suggest that SKP2 acts as an oncoprotein in the mouse prostate gland, probably through its function as a limiting factor for ubiquitin-dependent degradation of p27.

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