Preferential accumulation within tumors and in vivo imaging by functionalized luminescent dendrimer lanthanide complexes.

We have created a dendrimer complex suitable for preferential accumulation within liver tumors and luminescence imaging by substituting thirty-two naphthalimide fluorophores on the surface of the dendrimer and incorporating eight europium cations within the branches. We demonstrate the utility and performance of this luminescent dendrimer complex to detect hepatic tumors generated via direct subcapsular implantation or via splenic injections of colorectal cancer cells (CC531) into WAG/RijHsd rats. Luminescence imaging of the tumors after injection of the dendrimer complex via hepatic arterial infusion revealed that the dendrimer complex can preferentially accumulate within liver tumors. Further investigation indicated that dendrimer luminescence in hepatic tumors persisted in vivo. Due to the incorporation of lanthanide cations, this luminescence agent presents a strong resistance against photobleaching. These studies show the dendrimer complex has great potential to serve as an innovative accumulation and imaging agent for the detection of metastatic tumors in our rat hepatic model.

Luminescence targeting and imaging using a nanoscale generation 3 dendrimer in an in vivo colorectal metastatic rat model.

Surgery is currently the best approach for treating either primary or metastatic hepatic malignancies. Because only 20% of hepatic cancers are operable in patients, several types of regional therapy (RT) are emerging as alternate treatment modalities. However, RTs can have their own limitations at controlling tumor growth or may lack the ability to detect such metastases. Additional strategies can be implemented to enhance their efficacy. An animal model of hepatic metastases coupled with a gastroduodenal artery (GDA) cannulation technique may provide a site to apply such therapies. In our study, splenic injections were performed with CC531 adenocarcinoma cells, which generated metastatic hepatic tumors in WAG/RijHsd rats. Cannulation of GDA was achieved via a polyethylene catheter. Infusion of generation 3 polyamidoamine 4-amino-1,8-naphthalimide dendrimer containing 8 europium ions (Eu-G3P4A18N) via the GDA resulted in luminescence of the hepatic metastatic nodules. Imaging of the metastatic hepatic nodules was obtained with the help of a cooled charge coupled device (CCD) camera. FROM THE CLINICAL EDITOR: Hepatic malignancies represent a major therapeutic challenge, despite the available surgical and oncologic treatment modalities. In this paper, an animal model of hepatic adenocarcinoma is used in demonstrating successful targeting of spleen metastases with generation 3 polyamidoamine 4-amino-1,8-naphthalimide dendrimer containing 8 europium ions (Eu-G3P4A18N) for luminescence imaging.

Joint effects of smoking history and APOE genotypes in age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) is a leading cause of severe visual impairment in older adults worldwide. Cigarette smoking is one of the most consistently identified environmental risk factors for the disease. Several studies have implicated the apolipoprotein E (APOE) gene as modulating AMD risk. The purpose of this study was to investigate whether APOE genotypes modify the smoking-associated risk of AMD. METHODS: Patients with early- and late-stage AMD (n=377) and a group of unrelated ethnically matched controls of similar age (n=198) were ascertained at two sites in the southeastern United States. Smoking history and APOE genotype distribution in cases and controls were compared by multivariable logistic regression. RESULTS: All measures of smoking history showed a highly significant association with AMD, and odds ratio estimates were consistently higher when only patients with exudative AMD were compared to controls. Main effects of APOE genotypes in the overall analysis did not reach statistical significance. The analysis of exudative AMD patients suggested that the risk increase due to smoking was greatest in carriers of the APOE-2 allele, with genotype-specific odds ratios increasing from 1.9 for APOE-4 carriers (p=0.11) to 2.2 for APOE-3/3 homozygotes (p=0.007) to 4.6 (p=0.001) for APOE-2 carriers, compared to nonsmoking APOE-3/3 individuals. Measures of statistical interaction indicated more than additive, and possibly more than multiplicative, joint effects of APOE and smoking history, however, the interaction was not statistically significant on either scale. CONCLUSIONS: We hypothesize that a history of smoking is a stronger risk factor for exudative AMD in carriers of the APOE-2 allele, compared to carriers of APOE-4 and the most common APOE-3/3 genotype. To further clarify the association of AMD with APOE and smoking history, future studies should consider both factors simultaneously.

A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is a kidney disorder of unknown etiology, and up to 20% of patients on dialysis have been diagnosed with it. Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6). The proline-to-glutamine substitution at position 112, which occurs in a highly conserved region of the protein, enhances TRPC6-mediated calcium signals in response to agonists such as angiotensin II and appears to alter the intracellular distribution of TRPC6 protein. Previous work has emphasized the importance of cytoskeletal and structural proteins in proteinuric kidney diseases. Our findings suggest an alternative mechanism for the pathogenesis of glomerular disease.

Complement factor H variant increases the risk of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in the elderly whose etiology remains largely unknown. Previous studies identified chromosome 1q32 as harboring a susceptibility locus for AMD. We used single-nucleotide polymorphisms to interrogate this region and identified a strongly associated haplotype in two independent data sets. DNA resequencing of the complement factor H gene within this haplotype revealed a common coding variant, Y402H, that significantly increases the risk for AMD with odds ratios between 2.45 and 5.57. This common variant likely explains approximately 43% of AMD in older adults.