Student Abstract Competition

Articlehttp://deepblue.lib.umich.edu/bitstream/2027.42/97000/1/UMURJ-Issue07_2010-StudentAbstractCompetition.pd

University of Michigan Undergraduate Research Journal, Issue 7, Winter 2010

Articlehttp://deepblue.lib.umich.edu/bitstream/2027.42/97002/1/UMURJ-Issue07_2010.pd

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Nucleolin Staining May Aid in the Identification of Circulating Prostate Cancer Cells

Circulating tumor cells (CTCs) have great potential as circulating biomarkers for solid malignancies. Currently available assays for CTC detection rely on epithelial markers with somewhat limited sensitivity and specificity. We found that the staining pattern of nucleolin, a common nucleolar protein in proliferative cells, separates CTCs from white blood cells (WBCs) in men with metastatic prostate cancer. Whole peripheral blood from 3 men with metastatic prostate cancer was processed with the AccuCyte CTC system (RareCyte, Seattle, WA). Slides were immunostained with 4',6-diamidino-2-phenylindole (DAPI), anti-pan-cytokeratin, anti-CD45/CD66b/CD11b/CD14/CD34, and anti-nucleolin antibodies and detected using the CyteFinder system. DAPI nucleolin colocalization and staining pattern wavelet entropy were measured with novel image analysis software. A total of 33,718 DAPI-positive cells were analyzed with the novel imaging software, of which 45 (0.13%) were known CTCs based on the established AccuCyte system criteria. Nucleolin staining pattern for segmentable CTCs demonstrated greater wavelet entropy than that of WBCs (median wavelet entropy, 6.86 × 10(7) and 3.03 × 10(6), respectively; P = 2.92 × 10(-22); approximated z statistic = 9.63). Additionally, the total nucleolin staining of CTCs was greater than that of WBCs (median total pixel intensity, 1.20 × 10(5) and 2.55 × 10(4) integrated pixel units, respectively; P = 2.40 × 10(-21); approximated z statistic = 9.41). Prostate cancer CTCs displayed unique nucleolin expression and localization compared to WBCs. This finding has the potential to serve as the basis for a sensitive and specific CTC detection metho

Characterization of Urothelial Cancer Circulating Tumor Cells with a Novel Selection-Free Method

To investigate circulating tumor cells (CTCs) as biomarkers of urothelial carcinoma (UC). The majority of this work to date has utilized the CellSearch test, which has limited sensitivity due to reliance on positive selection for the cell surface protein EpCAM. We used a novel selection-free method to enumerate and characterize CTCs across a range of UC stages. Blood samples from 38 patients (9 controls, 8 non-muscle invasive bladder cancer [NMIBC], 12 muscle-invasive bladder cancer [MIBC] and 9 metastatic UC) were processed with the AccuCyte-CyteFinder system. Slides were stained for the white blood cell (WBC) markers CD45 and CD66b and the epithelial markers EpCAM and pancytokeratin (CK). CTCs were defined as any CK+/WBC- cell. Separately, the more restrictive CellSearch definition was applied, with the additional requirement of EpCAM positivity. The Kruskal-Wallis ANOVA test compared CTC counts by stage. ≥1 CTC was detected in 2/8(25%) patients with NMIBC, 7/12(58%) with MIBC, and 6/9(67%) with metastatic disease. No control had CTCs. Comparing CTC counts between groups, the only statistically significant comparison was between controls and patients with metastatic UC (p=0.009). With EpCAM positivity as a CTC requirement, no CTCs were detected in any NMIBC patient, and only 2(17%) MIBC patients had CTCs. CTCs tended to be larger in metastatic patients. CTCs were detected at all UC stages and exhibited phenotypic diversity of cell size and EpCAM expression. EpCAM negative CTCs that would be missed with the CellSearch test were detected in NMIBC and MIBC patient

Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France

on behalf of Eurocord and Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)International audienceDouble cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years