ABSTRACT
Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.
Subject(s)
Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/metabolism , SOXC Transcription Factors/metabolism , Antineoplastic Combined Chemotherapy Protocols , Binding Sites , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Chromatin Immunoprecipitation , Gene Expression , Gene Expression Regulation, Neoplastic , High-Throughput Nucleotide Sequencing , Humans , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/mortality , Nucleotide Motifs , Prognosis , Protein Binding , SOXC Transcription Factors/genetics , Signal Transduction , Transcription, Genetic , Wnt Proteins/metabolism , Wnt Signaling Pathway , beta Catenin/metabolismABSTRACT
A randomized trial comparing 3 manufacturing consistency lots of a combination hepatitis A/hepatitis B vaccine to each other and to hepatitis A vaccine and hepatitis B vaccine given separately and concurrently was done to evaluate safety, tolerability, and immunogenicity. Healthy volunteers >/=11 years of age were divided into 4 groups. Each of 3 groups received a separate consistency lot of the combination vaccine, and 1 group received separate but concurrent injections of hepatitis A and hepatitis B vaccines. Injections were given at weeks 0 and 24. The combination vaccine was generally well tolerated. The hepatitis A portion of the combination vaccine produced clinically acceptable high seropositivity rates 4 and 52 weeks after the first injection. The hepatitis B portion of the vaccine did not produce clinically acceptable seropositivity rates 4 weeks after the second injection. Lack of antibody production may be attributed, at least in part, to immunologic interference.
Subject(s)
Hepatitis B Antibodies/biosynthesis , Hepatitis B Surface Antigens/immunology , Hepatitis B Vaccines/immunology , Vaccines, Combined/immunology , Viral Hepatitis Vaccines/immunology , Adolescent , Adult , Child , Female , Hepatitis A Vaccines , Hepatitis B Vaccines/administration & dosage , Hepatitis B virus/immunology , Hepatovirus/immunology , Humans , Male , Vaccination , Vaccines, Combined/administration & dosage , Viral Hepatitis Vaccines/administration & dosageABSTRACT
In an open-label, randomised trial, 520 adults of both sexes aged 18-30 years were allocated to receive one of two inactivated hepatitis A vaccines; Vaqta or Havrix, at 0 and 24 weeks. Doses used were 50 or 100 antigen units (U) of Vaqta and 1440 enzyme linked immunosorbent assay U of Havrix given as 1 ml intramuscular injections. For each trial group safety data were available for all subjects and full serological data for more than 80% of randomised volunteers. Local side effects which were mild in most cases were significantly (p < 0.0001) more common with Havrix than with Vaqta, irrespective of dose given. Systemic tolerance was similar for the 3 regimens. From 4 weeks after the first dose, > or =94% of the subjects had seroconverted. The mean antibody titres 4 weeks after the second vaccine dose were 2978, 4346 and 1589 mIU/ml in subjects who were randomised to Vaqta 50 U/dose, Vaqta 100 U/dose and Havrix 1440 U/dose, respectively. The 2 vaccines had similar immunogenicity but local tolerance was better with Vaqta.
