HLA-DR4 is associated with insulin-dependent diabetes mellitus (IDDM) in many populations. Many recent studies suggest that the DR4 effect is really due to DQ3.2, an allele of the nearby DQB1 locus. We used T cell clones, MAb, and allelespecific oligonucleotides to test IDDM and control subjects for DR4 subtypes (Dw4, DwlO, Dwl3, and Dw14) and for DR4-associated DQB1 alleles (DQ3.1 and DQ3.2). We find that (a) IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and DwlO, combined relative risk, RR = 6.4) and the DQB1 locus (DQ3.2, RR = 5.9); and (b) there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM. The only IDDM-associated DR4 haplotypes were those carrying the IDDM-associated alleles at both loci (RR = 12.1); haplotypes with Dw4 or 10 but not DQ3.2, or vice versa, had a RR < 1. Alternative explanations include: (a) that susceptibility requires specific allelic products of both DR and DQ loci; (b) that the combination ofcertain DR and DQ alleles marks haplotypes with the true susceptibility allele at a third locus; or (c) that Dw4 and 10 mark haplotypes with an allele at another locus that interacts with DQ3.2. As discussed, this third locus is unlikely to be DQA1 (DQa). The data thus are not easily reconciled with an exclusive effect of HLA-DQ. This information increases our ability to predict IDDM by genetic typing: in the population studied, heterozygotes DR3/IDQ3.2, Dw41 or DR3/[DQ3.2, DwlOj had a relative risk of 38.0 and an absolute risk of I in 15.

We present here first time that Plumbagin (PL), a medicinal plant-derived 1,4-naphthoquinone, inhibits the growth and metastasis of prostate cancer (PCa) in an orthotopic xenograft mouse model. In this study, human PCa PC-3M-luciferase cells (2X106) were injected into the prostate of athymic nude mice. Three days post cell implantation, mice were treated with PL (2 mg/kg body wt. i.p five days in a week) for 8 weeks. Growth and metastasis of PC-3M-luciferase cells was examined weekly by bioluminescence imaging of live mice. PL-treatment significantly (p=0.0008) inhibited the growth of orthotopic xenograft tumors. PCa metastasis into the liver, lungs and lymph nodes was determined by bioluminescence imaging and histopathology. Results demonstrated a significant inhibition of metastasis into liver (p=0.037), but inhibition of metastasis into the lungs (p=0.60) and liver (p=0.27) was not observed to be significant. These results were further confirmed by histopathology of these organs. Results of histopathology demonstrated a significant inhibition of metastasis into lymph nodes (p=0.034) and lungs (p=0.028), and a trend to significance in liver (p=0.075). None of the mice in the PL-treatment group showed PCa metastasis into the liver, but these mice had small metastasis foci into the lymph nodes and lungs. However, control mice had large metastatic foci into the lymph nodes, lungs, and liver. PL-caused inhibition of the growth and metastasis of PC-3M cells accompanies inhibition of the expression of: 1) PKCε, pStat3Tyr705, and pStat3Ser727, 2) Stat3 downstream target genes (survivin and BclxL), 3) proliferative markers Ki-67 and PCNA, 4) metastatic marker MMP9, MMP2, and uPA, and 5) angiogenesis markers CD31 and VEGF. Taken together, these results suggest that PL inhibits tumor growth and metastasis of human PCa PC3-M-luciferase cells, which could be used as a therapeutic agent for the prevention and treatment of human PCa. PL: Plumbagin, PCa: Prostate cancer.

Aims: Pancreatic cancer (PC) is the most aggressive malignant disease, ranking as the fourth most leading cause of cancer-related death among men and women in the United States. In this study, we provide evidence of chemotherapeutic effects of a-mangostin, a dietary antioxidant isolated from the pericarp of Garcinia mangostana L. against human PC. Results: The chemotherapeutic effect of a-mangostin was determined using four human PC cells (PL-45, PANC1, BxPC3, and ASPC1). a-Mangostin resulted in a significant inhibition of PC cells viability without having any effects on normal human pancreatic duct epithelial cells. a-Mangostin showed a dose-dependent increase of apoptosis in PC cells. Also, a-mangostin inhibited the expression levels of pNF-jB/p65Ser552, pStat3Ser727, and pStat3Tyr705. a-Mangostin inhibited DNA binding activity of nuclear factor kappa B (NF-jB) and signal transducer and activator 3 (Stat3). a-Mangostin inhibited the expression levels of matrix metallopeptidase 9 (MMP9), cyclin D1, and gp130; however, increased expression of tissue inhibitor of metalloproteinase 1 (TIMP1) was observed in PC cells. In addition, i.p. administration of a-mangostin (6 mg/kg body weight, 5 days a week) resulted in a significant inhibition of both primary (PL-45) and secondary (ASPC1) human PC cell-derived orthotopic and ectopic xenograft tumors in athymic nude mice. No sign of toxicity was observed in any of the mice administered with a-mangostin. a-Mangostin treatment inhibited the biomarkers of cell proliferation (Ki-67 and proliferating cell nuclear antigen [PCNA]) in the xenograft tumor tissues. Innovation: We present, for the first time, that dietary antioxidant a-mangostin inhibits the growth of PC cells in vitro and in vivo. Conclusion: These results suggest the potential therapeutic efficacy of a-mangostin against human PC. Antioxid. Redox Signal. 21, 682-699.