In Kaposi's sarcoma-associated herpesvirus (KSHV), poly(ADP-ribose) polymerase 1 (PARP-1) acts as an inhibitor of lytic replication. Here, we demonstrate that KSHV downregulated PARP-1 upon reactivation. The viral processivity factor of KSHV (PF-8) interacted with PARP-1 and was sufficient to degrade PARP-1 in a proteasome-dependent manner; this effect was conserved in murine gammaherpesvirus 68. PF-8 knockdown in KSHV-infected cells resulted in reduced lytic replication upon reactivation with increased levels of PARP-1, compared to those in control cells. PF-8 overexpression reduced the levels of the poly(ADPribosyl)ated (PARylated) replication and transcription activator (RTA) and further enhanced RTA-mediated transactivation. These results suggest a novel viral mechanism for overcoming the inhibitory effect of a host factor, PARP-1, thereby promoting the lytic replication of gammaherpesvirus. IMPORTANCEGammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors and establish latency mainly in host B lymphocytes. Replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is a central molecular switch for lytic replication, and its expression is tightly regulated by many host and viral factors. In this study, we investigated a viral strategy to overcome the inhibitory effect of poly(ADP-ribose) polymerase 1 (PARP-1) on RTA's activity. PARP-1, an abundant multifunctional nuclear protein, was downregulated during KSHV reactivation. The viral processivity factor of KSHV (PF-8) directly interacted with PARP-1 and was sufficient and necessary to degrade PARP-1 protein in a proteasome-dependent manner. PF-8 reduced the levels of PARylated RTA and further promoted RTA-mediated transactivation. As this was also conserved in another gammaherpesvirus, murine gammaherpesvirus 68, our results suggest a conserved viral modulation of a host inhibitory factor to facilitate its lytic replication. Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and murine gammaherpesvirus 68 (MHV-68), are associated with various malignancies and lymphoproliferative disorders (1, 2). Several cellular factors are known to regulate the lytic replication of gammaherpesvirus, ultimately contributing to viral pathogenesis (3, 4). Poly(ADP-ribose) polymerase 1 (PARP-1) is an abundant nuclear protein that catalyzes the poly(ADP-ribosyl)ation of target proteins acting in DNA repair, cell cycle control, apoptosis, and gene expression (5-7). In KSHV and MHV-68 infections, PARP-1 interacts with the poly(ADP-ribosyl)ate replication and transcription activator (RTA), the molecular switch of lytic replication, thereby repressing lytic viral replication (8-11). PARP-1 is also known to be a component of the viral replication complex, increasing viral genome replication (9, 12). Previously, we showed that open reading frame 49 (ORF49) of MHV-68 interacts with PARP-1, disrupting interactions between RTA and PARP-1 and furthe...

PurposeCaveolin-1 (CAV-1) expression is more associated with basal-like cancers than estrogen receptor- or ErbB-2–expressing breast cancers. However, the biological relevance of different levels of CAV-1 expression according to subtype in the epithelial compartment of breast cancer remains unclear.Materials and MethodsWe investigated whether CAV-1 functions as a tumor suppressor and/or modulator of the cytotoxic activity of docetaxel (DTX) in subtypes of breast cancer using in vitro and xenograft models.ResultsThe levels of CAV-1 expression were closely associated with DTX sensitivity in triple-negative breast cancer cells. In addition, CAV-1 significantly inhibited cell proliferation and modulated DTX-induced apoptosis through cell cycle arrest in the G2/M phase. The mechanisms underlying DTX-induced apoptosis differed in breast cancers according to the levels of CAV-1 expression. DTX robustly enhanced Bcl-2 inactivation by CAV-1 in MDA-MB-231 cells, while p53-mediated cell cycle arrest by DTX was more pronounced in CAV-1–low but p53-functional MCF-7 cells. In parallel with the data from breast cancer cell lines, CAV-1–transfected MCF-7 cells showed higher efficacy of DTX treatment in a xenograft model.ConclusionWe clearly demonstrated cooperative effects between CAV-1 and DTX in mediating apoptosis, suggesting that the levels of CAV-1 expression might be an important indicator for DTX use in breast cancer.

The combination of gemcitabine and carboplatin is effective in elderly patients with advanced transitional cell carcinoma or those unfit for cisplatin-based chemotherapy, with manageable toxicity.

Paraneoplastic leukocytosis was defined as elevated white blood cell (WBC) levels caused by cytokines, likely produced by the tumor itself, without evidence of infection or myeloproliferative disease. We report a case of anaplastic thyroid carcinoma with leukocytosis caused by elevated production of granulocyte colony-stimulating factor (G-CSF) by the carcinoma. Initially, acute pyelonephritis (APN) was diagnosed and treatment for APN was ongoing, but the WBC count steadily increased to 68.8×109/L. She was diagnosed with anaplastic thyroid carcinoma on her neck mass, and the serum concentration of G-CSF was found to be markedly increased at 1,010 pg/mL. In spite of supportive care, the patient's condition rapidly deteriorated and the patient died on day 23 of hospital stay. Leukocytosis without definite evidence of infection could be a paraneoplastic manifestation in patients with malignant tumors, and paraneoplastic leukocytosis may be related to poor prognosis.

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Evidence regarding the association between allergic rhinitis (AR) and physical activity (PA) is conflicting. Previous studies have mostly relied only on self-reported symptoms to define AR, did not classify AR by severity or persistence, and included only children or athletes. The present cross-sectional study evaluated the association between PA and objectively-defined AR and its subtypes in the general adult population using data for 1932 eligible participants aged 19 years or older in the 2010 Korea National Health and Nutrition Examination Survey. Multivariable logistic regression analyses were performed to evaluate the relationship between three types of PA and overall AR, AR subtypes, and rhinoscopy findings showed that moderate-severe AR was positively associated with vigorous (odds ratio [OR] = 3.392, p = 0.002) and moderate (OR = 3.623, p = 0.007) PA compared to mild AR, while persistent AR was associated with vigorous (OR = 3.954, p = 0.004) and moderate (OR = 3.411, p = 0.022) PA compared to intermittent AR. On rhinoscopy, vigorous PA was significantly associated with watery rhinorrhea (OR = 2.203, p = 0.048) but not pale mucosa. Total immunoglobulin E (IgE) and three allergen-specific IgE were not significantly elevated in participants who performed PA. Therefore, regular vigorous PA is associated with subjective and objective aggravation of AR symptoms, which may not necessarily manifest as increased serum IgE levels.

Caveolin-1 is reported to be down-regulated in breast cancers compared with normal mammary tissue. More recent data showed that high caveolin-1 expression is more associated with basaloid cancers than ER and/or PR or HER-2 expressing cancers. Investigatirs have reported that Caveolin-1 promoted resistance to chemotherapy-induced apoptosis in Ewing's sarcoma cells. However, the biologic relevance of caveolin-1 in breast cancer remains unclear. Thus, the aim of this study is to investigate its potential biologic relevance of Caveolin-1 to cell survival after docetaxel chemotherapy, one of the most important drug in breast cancer treatment. In this current study, we first showed that Caveolin-1 protein expression was suppressed in the ER(+) human breast cancer cell lines (MCF-7, T47D, and ZR75-1), but not in triple negative cancer cells (MDA-MB-231 and HS578T) and one of the HER-2 type cell (HCC1954) using Western blot analysis. Better cytotoxic effect of docetaxel was observed in the caveolin-1-expressing triple negative cells and HER-2 type cell than the other caveolin-1-deficient HER-2 type and luminal type of cancer cells. Next, caveolin-1 gene was reintroduced into caveolin-1 deficient luminal type breast cancer cells (MCF-7 and ZR75-1) to investigate its potential modulatory effect on docetaxel-induced cytotoxicity. The cell proliferation and MTT assay showed that the overexpressed caveolin-1 had further modulated docetaxel-induced anti-proliferative and cytotoxic effect in the luminal type cells. The anti-proliferative effect of docetaxel in the caveolin-1 gene over-expressed breast cancer cell lines was accompanied by decreasing cyclin D1 expression and inducing cyclin B1 accumulation, then resulting in cell cycle arrest at G2/M phase in the FACS analysis. In addition, re-introduction of caveolin-1 further increased docetaxel-induced cell death by synergistically inducing p53 expression and subsequent induction of p21, then finally apoptosis of breast cancer cells. These results were verified in the mouse model using SCID mice implated with either Caveolin-1-MCF-7 cells or control MCF-7 cells. When each group of tumor-bearing mice were treated by docetacel, mice with Caveolin-1-MCF-7 tumors showed a signiflcantly smaller tumors than those of control group. These results suggest that caveolin-1 may have a modulating factor for docetaxel activity by inducing p53 expression in breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4895. doi:1538-7445.AM2012-4895

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