Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

Requirement of p27Kip1 for Restriction Point Control of the Fibroblast Cell Cycle

Abstract: Cells deprived of serum mitogens will either undergo immediate cell cycle arrest or complete mitosis and arrest in the next cell cycle. The transition from mitogen dependence to mitogen independence occurs in the mid- to late G 1 phase of the cell cycle and is called the restriction point. Murine Balb/c-3T3 fibroblasts deprived of serum mitogens accumulated the cyclin-dependent kinase (CDK) inhibitor p27 Kip1 . This was correlated with inactivation of essential G 1 cyclin-CDK complexes and with cell cycle arrest in G 1 . The ability of specific mitogens to allow transit through the restriction point paralleled their ability to down-regulate p27, and antisense inhibition of p27 expression prevented cell cycle arrest in response to mitogen depletion. Therefore, p27 is an essential component of the pathway that connects mitogenic signals to the cell cycle at the restriction point.

Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

Abstract: Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.

Induction of a Striking Systemic Cytokine Cascade prior to Peak Viremia in Acute Human Immunodeficiency Virus Type 1 Infection, in Contrast to More Modest and Delayed Responses in Acute Hepatitis B and C Virus Infections

Abstract: Characterization of the immune responses induced in the initial stages of human immunodeficiency virus type 1 (HIV-1) infection is of critical importance for an understanding of early viral pathogenesis and prophylactic vaccine design. Here, we used sequential plasma samples collected during the eclipse and exponential viral expansion phases from subjects acquiring HIV-1 (or, for comparison, hepatitis B virus [HBV]or hepatitis C virus [HCV]) to determine the nature and kinetics of the earliest systemic elevations in cytokine and chemokine levels in each infection. Plasma viremia was quantitated over time, and levels of 30 cytokines and chemokines were measured using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. The increase in plasma viremia in acute HIV-1 infection was found to be associated with elevations in plasma levels of multiple cytokines and chemokines, including rapid and transient elevations in alpha interferon (IFN-alpha) and interleukin-15 (IL-15) levels; a large increase in inducible protein 10 (IP-10) levels; rapid and more-sustained increases in tumor necrosis factor alpha and monocyte chemotactic protein 1 levels; more slowly initiated elevations in levels of additional proinflammatory factors including IL-6, IL-8, IL-18, and IFN-gamma; and a late-peaking increase in levels of the immunoregulatory cytokine IL-10. Notably, there was comparatively little perturbation in plasma cytokine levels during the same phase of HBV infection and a delayed response of more intermediate magnitude in acute HCV infection, indicating that the rapid activation of a striking systemic cytokine cascade is not a prerequisite for viral clearance (which occurs in a majority of HBV-infected individuals). The intense early cytokine storm in acute HIV-1 infection may have immunopathological consequences, promoting immune activation, viral replication, and CD4(+) T-cell loss.

Fruit and Vegetable Intakes and Prostate Cancer Risk

Abstract: Background: There is extensive and consistent evidence that high fruit and vegetable intakes are associated with decreased risks of many cancers, but results for prostate cancer risk have been inconsistent. We studied the associations of fruit and vegetable intakes with prostate cancer risk in a population-based, case‐control study of men under 65 years of age. Methods: Case participants were 628 men from King County (Seattle area), WA, who were newly diagnosed with prostate cancer. Control participants were 602 men recruited from the same underlying population and frequency matched to case p articipants b y a ge. S elfadministered food-frequency questionnaires were used to assess diet over the 3- to 5-year period before diagnosis or recruitment. Daily nutrient intakes were calculated by use of a nutrient database with recently updated analytic values for carotenoids. Odds ratios for prostate cancer risk associated with foods and nutrients were calculated by use of unconditional logistic regression. Results: No associations were found between fruit intake and prostate cancer risk. The adjusted odds ratio (ORs) for the comparison of 28 or more servings of vegetables per week with fewer than 14 servings per week was 0.65 (95% confidence interval [CI] = 0.45‐0.94), with a two-sided P for trend = .01. For cruciferous vegetable consumption, adjusted for covariates and total vegetable intake, the OR for comparison of three or more servings per week with less than one serving per week was 0.59 (95% CI = 0.39‐0.90), with a two-sided P for trend = .02. The OR for daily intake of 2000 µg or more lutein plus zeaxanthin compared with an intake of less than 800 µg was 0.68 (95% CI = 0.45‐1.00). Conclusion: These results suggest that high consumption of vegetables, particularly cruciferous vegetables, is associated with a reduced risk of prostate cancer. [J Natl Cancer Inst 2000;92:61‐8]