A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10 −8 to P=2.7×10 −33 ).Genome-wide association studies (GWAS) provide a powerful approach to identify common disease alleles. We previously conducted a GWAS 1 , based on genotyping of 541, 129 SNPs in 1,854 clinically detected PrCa cases and 1,894 controls (see Figure 1, stage 1). Follow-up genotyping of SNPs exhibiting strong evidence of association (P<10 −6 ), in a further 3,268 cases and 3,366 controls, allowed us to identify SNPs at 7 susceptibility loci associated with the disease at genome-wide levels of significance 1 . Other studies have identified an additional 8 loci [2][3][4][5][6][7][8][9] . These loci, however, explain only a small fraction of the familial risk of PrCa. Moreover, the strength of the associations that have been detected are generally small (perallele odds ratios, OR, 1.1-1.2), and the power of the existing studies to detect many of the susceptibility alleles has been limited. It is highly likely, therefore, that other PrCa predisposition loci exist, and that such loci should be detectable by studies with larger sample sizes.In an attempt to identify further susceptibility loci, we conducted a more extensive follow-up of SNPs showing evidence of association in stage 1 of our GWAS. We designed a panel of 47,120 SNPs, aiming to include all SNPs with a significant association in stage 1 at P-trend (1df)<.05 or P(2df)<.01 (see Online Methods). These SNPs were genotyped using the Illumina iSELECT platform in 3,894 PrCa cases and 4,055 controls from the United Kingdom (UK) and Australia ( Figure 1, stage 2). After quality control (QC) exclusions (as described in Online Methods), we utilised data from 43,671 SNPs in 3,650 PrCa cases and 3,940 controls. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGenotype frequencies in cases and controls were compared using a 1 degree of freedom (df) Cochran-Armitage trend test (for QQ plots see Supplementary Figure 1). There was little evidence of inflation in the test statistics in the UK samples (estimated inflation factor λ=1.08), but there was more marked inflation in those from Australia (λ=1.23; λ=1.19 for stage 2 overall), suggestive of some population substructure. The Australian samples were selected from three studies (MCCS, RFPCS and EOPCS; see Supplementary Note for cohort descriptions), and further analysis revealed that ...

Plasminogen activator inhibitor type 2 (PAI-2) is a serine proteinase inhibitor or serpin that is a major product of macrophages in response to endotoxin and inflammatory cytokines. We have explored the role of PAI-2 in apoptotic cell death initiated by tumor necrosis factor alpha (TNF). HeLa cells stably transfected with PAI-2 cDNA were protected from TNF-induced apoptosis, whereas cells transfected with antisense PAI-2 cDNA, a control gene, or the plasmid vector alone remained susceptible. The level of PAI-2 expressed by different HeLa cell clones was inversely correlated with their sensitivity to TNF. Loss of TNF sensitivity was not a result of loss of TNF receptor binding. In contrast, PAI-2 expression did not confer protection against apoptosis induced by ultraviolet or ionizing radiation. The serine proteinase urokinase-type plasminogen activator was not demonstrated to be the target of PAI-2 action. The P1-Arg amino acid residue of PAI-2 was determined to be required for protection, because cells expressing PAI-2 with an Ala in this position were not protected from TNF-mediated cell death. The results suggest that intracellular PAI-2 might be an important factor in regulating cell death in TNF-mediated inflammatory processes through inhibition of a proteinase involved in TNF-induced apoptosis.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (P=4.0 ×10−8 to P=2.7 ×10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified.

There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed.