Small Drusen and Age-Related Macular Degeneration: The Beaver Dam Eye Study

We tested the hypothesis that large areas of small hard drusen (diameter \u3c63 μm) and intermediate drusen (diameter 63-124 μm) are associated with the incidence of age-related macular degeneration (AMD). Eyes of 3344 older adults with at least 2 consecutive visits spaced 5 years apart over a 20-year period were included. A 6-level severity scale including no drusen, 4 levels of increasing area (from minimal (\u3c2596 μm2) to large (\u3e9086 μm2)) of only small hard drusen, and intermediate drusen was used. The 5-year incidence of AMD was 3% in eyes at the start of the interval with no, minimal, small, and moderate areas of only small drusen and 5% and 25% for eyes with large area of only small drusen and intermediate drusen, respectively. Compared to eyes with a moderate area of small drusen, the odds ratio (OR) of developing AMD in eyes with a large area of only small drusen was 1.8 (p \u3c 0.001). Compared to eyes with large area of only small drusen, eyes with intermediate drusen had an OR of 5.5 (p \u3c 0.001) of developing AMD. Our results are consistent with our hypothesis that large areas of only small drusen are associated with the incidence of AMD

Preclinical Evaluation of Novel Fatty Acid Synthase Inhibitors in Primary Colorectal Cancer Cells and a Patient-Derived Xenograft Model of Colorectal Cancer

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition. CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs. In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC

A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10−109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10−9) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number

A PCR-RFLP Assay for the A716T Mutation in the WFS1 Gene, a Common Cause of Low-Frequency Sensorineural Hearing Loss

Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of hearing loss that affects frequencies at 2,000 Hz and below. Recently, we reported five different heterozygous missense mutations in the Wolfram syndrome gene, WFS1, found to be responsible for LFSNHL in six families. One of the five mutations, A716T, may be a common cause of LFSNHL, as it has been reported in three families to date (Bespalova et al., 2001; Young et al., 2001). We have developed a PCR-based restriction fragment-length polymorphism (RFLP) assay to detect the A716T mutation in a simple, specific test. This method was evaluated with DNA samples from a family in which the A716T mutation was segregating with LFSNHL. This simple assay successfully detected the presence of the A716T mutation in all of the individuals predicted to be affected, based on audiologic results. Therefore, this assay can be routinely used for initial screening of the A716T mutation in patients with LFSNHL, before screening the entire coding region of the WFS1 gene.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63374/1/109065702761403423.pd

Small Drusen and Age-Related Macular Degeneration: The Beaver Dam Eye Study

We tested the hypothesis that large areas of small hard drusen (diameter <63 µm) and intermediate drusen (diameter 63–124 µm) are associated with the incidence of age-related macular degeneration (AMD). Eyes of 3344 older adults with at least two consecutive visits spaced five years apart over a 20-year period were included. A 6-level severity scale, including no drusen, four levels of increasing area (from minimal (<2596 µm²) to large (>9086 µm²)) of only small hard drusen, and intermediate drusen, was used. The five-year incidence of AMD was 3% in eyes at the start of the interval with no, minimal, small, and moderate areas of only small drusen and 5% and 25% for eyes with large area of only small drusen and intermediate drusen, respectively. Compared to eyes with a moderate area of small drusen, the odds ratio (OR) of developing AMD in eyes with a large area of only small drusen was 1.8 (p < 0.001). Compared to eyes with large area of only small drusen, eyes with intermediate drusen had an OR of 5.5 (p < 0.001) of developing AMD. Our results are consistent with our hypothesis that large areas of only small drusen are associated with the incidence of AMD