Charles S., "Interleukin-1 polymorphisms associated with increased risk of gastric cancer" (2000). To evaluate dopaminergic cells of the dorsomedial cluster by tyrosine hydroxylase immunostaining, serial 4-mm sections were cut to include the entire brain. Immunopositive cells at the level of the giant interneuron commissure, posterior to the fan-shaped body, were counted in well oriented frontal sections at 1, 10, 30 and 60 days. At 1 day all control and experimental sections contained four or ®ve cells in the delineated region. At 30 and 60 days all controls showed four or ®ve cells. At 30 and 60 days all a-synucleinexpressing animals (a-synuclein, elav±GAL4 and a-synuclein, Ddc±GAL4 transheterozygotes) showed 0 or 1 tyrosine-hydroxylase-positive cell in the de®ned region. Tyrosinehydroxylase-positive cells outside the dorsomedial cluster were present, and served as internal controls for the immunostaining procedure. At least four, and usually between six and ten brains were examined for wild-type a-synuclein and each mutant a-synuclein. Controls included young and aged¯ies of the genotypes elav±GAL4/+ and Ddc±GAL4/+. We evaluated expression of a-synuclein and b-galactosidase on similar serial section preparations. Quanti®cation was simpli®ed in these experiments because no clear cellbody-associated a-synuclein or b-galactosidase immunoreactivity was observed in the aged a-synuclein transgenic¯ies at the times reported.For histological examination of retinas, heads were ®xed in glutaraldehyde and embedded in epon. Tangential retinal sections were prepared at a thickness of 1 mm and stained with toluidine blue (Fig 4).Standard electron microscopy was performed on brains from 25-day-old experimental (UAS±A30P a-synuclein/elav±GAL4) and control (elav±GAL4/+)¯ies. For immunoelectron microscopy, pre-embedding immunohistochemistry with an Hrp-congugated secondary antibody was performed on 60-day adult brains from experimental (UAS± A30P a-synuclein/elav±GAL4) and control (elav±GAL4/+)¯ies ®xed in 4% paraformaldehyde with 0.5% glutaraldehyde. Tissue was post-®xed in osmium and embedded in epon. Unstained ultrathin sections and ultrathin sections stained with uranyl acetate and lead citrate were examined. Climbing assayThe climbing assay was performed as described 19,20 . Forty¯ies were placed in a plastic vial, and gently tapped to the bottom of the vial. The number of¯ies at the top of the vial was counted after 18 s of climbing. Twenty trials were performed for each time point. The data shown represent results from a cohort of¯ies tested serially over 55 days. The experiment was repeated three times, with independently derived transgenic lines. Similar results were obtained from each experiment. The experiment was carried out under red light (Kodak Safelight Filter 1A). Control¯ies were of the genotype elav±GAL4/+. Experimental animals were of the following genotypes: (1) elav±GAL4/+; UAS±wild-type a-synuclein/+; (2) UAS±A30P a-synuclein/elav±GAL4; and (3) UAS±A53T a-synuclein/elav±GAL4.

Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.

Context Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Since most prior research has concerned kidney recipients, large studies that include recipients of differing organs can inform cancer etiology. Objective Describe the overall pattern of cancer among solid organ transplant recipients. Design Cohort study using linked data from the U.S. Scientific Registry of Transplant Recipients (1987–2008) and 13 state/regional cancer registries. Participants and Setting Solid organ transplant recipients in the U.S. Main Outcome Measure Standardized incidence ratios (SIRs) and excess absolute risks (EARs) assessing relative and absolute cancer risk in transplant recipients compared to the general population. Results Registry linkages yielded data on 175,732 solid organ transplants (58.4% kidney, 21.6% liver, 10.0% heart, 4.0% lung). Overall cancer risk was elevated (N=10,656 cases, incidence 1374.7 per 100,000 person-years; SIR 2.10, 95%CI 2.06–2.14; EAR 719.3, 95%CI 693.3–745.6, per 100,000 person-years). Risk was increased (p<0.001) for 32 different malignancies, some related to known infections (e.g., anal cancer, Kaposi sarcoma) and others unrelated (e.g., melanoma, thyroid and lip cancers). The most common malignancies with elevated risk were non-Hodgkin lymphoma (N=1504, incidence 194.0; SIR 7.54, 95%CI 7.17–7.93; EAR 168.3, 95%CI 158.6–178.4) and cancers of the lung (N=1344, incidence 173.4; SIR 1.97, 95%CI 1.86–2.08; EAR 85.3, 95%CI 76.2–94.8), liver (N=930, incidence 120.0; SIR 11.56, 95%CI 10.83–12.33; EAR 109.6, 95%CI 102.0–117.6), and kidney (N=752, incidence 97.0; SIR 4.65, 95%CI 4.32–4.99; EAR 76.1, 95%CI 69.3–83.3). Lung cancer risk was most elevated in lung recipients (SIR 6.13, 95%CI 5.18–7.21) but also increased among other recipients (SIR 1.46, 95%CI 1.34–1.59 for kidney; 1.95, 1.74–2.19 for liver; 2.67, 2.40–2.95 for heart). Liver cancer was elevated only among liver recipients (SIR 43.83, 95%CI 40.90–46.91), who manifested exceptional risk in the first 6 months (SIR 508.97, 95%CI 474.16–545.66) and continuing two-fold excess for 10–15 years (SIR 2.22, 95%CI 1.57–3.04). Among kidney recipients, kidney cancer was elevated (SIR 6.66, 95%CI 6.12–7.23) and bimodal in onset. Kidney cancer was also increased in liver and heart recipients (SIR 1.80, 95%CI 1.40–2.29, and 2.90, 2.32–3.59, respectively). Conclusions Recipients of a kidney, liver, heart, or lung transplant have an increased risk for diverse infection-related and unrelated cancers, compared with the general population.

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.