Browsing by Subject "Bone Neoplasms"

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    ItemOpen Access
    A novel, non-apoptotic role for Scythe/BAT3: a functional switch between the pro- and anti-proliferative roles of p21 during the cell cycle.
    (2012) Yong, Sheila T.
    Scythe/BAT3 is a member of the BAG protein family whose role in apoptosis, a form of programmed cell death, has been extensively studied. However, since the developmental defects observed in Bat3‐null mouse embryos cannot be explained solely by defects in apoptosis, I investigated whether BAT3 is also involved in regulating cell‐cycle progression. Using a stable‐inducible Bat3‐knockdown cellular system, I demonstrated that reduced BAT3 protein level causes a delay in both the G1/S transition and G2/M progression. Concurrent with these changes in cell‐cycle progression, I observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21. p21 is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Additionally, I observed that the p21 turnover rate was also reduced in Bat3‐knockdown cells released from G2/M synchronization. My findings indicate that in Bat3‐knockdown cells, p21 continues to be synthesized during cell‐cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent cell‐cycle delay. Finally, I showed that BAT3 co‐localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression. My study reveals a novel, non‐apoptoticrole for BAT3 in cell‐cycle regulation. By maintaining low p21 protein level during G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 into S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation, an event that promotes G2/M progression. BAT3 modulates these pro‐ and anti‐proliferative roles of p21 at least in part by regulating the translocation of p21 between the cytoplasm and nucleus of the cells to ensure proper functioning and regulation of p21 in the appropriate intracellular compartments during different cell‐cycle phases.
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    Bone scan positivity in non-metastatic, castrate-resistant prostate cancer: external validation study.
    (International braz j urol : official journal of the Brazilian Society of Urology, 2020-01) Johnston, Ashley W; Longo, Thomas A; Davis, Leah Gerber; Zapata, Daniel; Freedland, Stephen J; Routh, Jonathan C

    Introduction

    Tables predicting the probability of a positive bone scan in men with non-metastatic, castrate-resistant prostate cancer have recently been reported. We performed an external validation study of these bone scan positivity tables.

    Materials and methods

    We performed a retrospective cohort study of patients seen at a tertiary care medical center (1996-2012) to select patients with non-metastatic, castrate-resistant prostate cancer. Abstracted data included demographic, anthropometric, and disease-specific data such as patient race, BMI, PSA kinetics, and primary treatment. Primary outcome was metastasis on bone scan. Multivariable logistic regression was performed using generalized estimating equations to adjust for repeated measures. Risk table performance was assessed using ROC curves.

    Results

    We identified 6.509 patients with prostate cancer who had received hormonal therapy with a post-hormonal therapy PSA ≥2ng/mL, 363 of whom had non-metastatic, castrate-resistant prostate cancer. Of these, 187 patients (356 bone scans) had calculable PSA kinetics and ≥1 bone scan. Median follow-up after castrate-resistant prostate cancer diagnosis was 32 months (IQR: 19-48). There were 227 (64%) negative and 129 (36%) positive bone scans. On multivariable analysis, higher PSA at castrate-resistant prostate cancer (4.67 vs. 4.4ng/mL, OR=0.57, P=0.02), shorter time from castrate-resistant prostate cancer to scan (7.9 vs. 14.6 months, OR=0.97, P=0.006) and higher PSA at scan (OR=2.91, P<0.0001) were significantly predictive of bone scan positivity. The AUC of the previously published risk tables for predicting scan positivity was 0.72.

    Conclusion

    Previously published risk tables predicted bone scan positivity in men with non-metastatic, castrate-resistant prostate cancer with reasonable accuracy.
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    Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer.
    (Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2016-05) Halabi, Susan; Kelly, William Kevin; Ma, Hua; Zhou, Haojin; Solomon, Nicole C; Fizazi, Karim; Tangen, Catherine M; Rosenthal, Mark; Petrylak, Daniel P; Hussain, Maha; Vogelzang, Nicholas J; Thompson, Ian M; Chi, Kim N; de Bono, Johann; Armstrong, Andrew J; Eisenberger, Mario A; Fandi, Abderrahim; Li, Shaoyi; Araujo, John C; Logothetis, Christopher J; Quinn, David I; Morris, Michael J; Higano, Celestia S; Tannock, Ian F; Small, Eric J

    Purpose

    Reports have suggested that metastatic site is an important predictor of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC), but these were based on a limited number of patients. We investigate the impact of site of metastases on OS of a substantial sample of men with mCRPC who received docetaxel chemotherapy in nine phase III trials.

    Patients and methods

    Individual patient data from 8,820 men with mCRPC enrolled onto nine phase III trials were combined. Site of metastases was categorized as lymph node (LN) only, bone with or without LN (with no visceral metastases), any lung metastases (but no liver), and any liver metastases.

    Results

    Most patients had bone with or without LN metastases (72.8%), followed by visceral disease (20.8%) and LN-only disease (6.4%). Men with liver metastases had the worst median OS (13.5 months). Although men with lung metastases had better median OS (19.4 months) compared with men with liver metastases, they had significantly worse median survival duration than men with nonvisceral bone metastases (21.3 months). Men with LN-only disease had a median OS of 31.6 months. The pooled hazard ratios for death in men with lung metastases compared with men with bone with or without LN metastases and in men with any liver metastases compared with men with lung metastases were 1.14 (95% CI, 1.04 to 1.25; P = .007) and 1.52 (95% CI, 1.35 to 1.73; P < .0001), respectively.

    Conclusion

    Specific sites of metastases in men with mCRPC are associated with differential OS, with successive increased lethality for lung and liver metastases compared with bone and nonvisceral involvement. These data may help in treatment decisions, the design of future clinical trials, and understanding the variation in biology of different sites of metastases in men with mCRPC.
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    Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.
    (Molecular cancer therapeutics, 2020-07) Reddy, Gireesh B; Kerr, David L; Spasojevic, Ivan; Tovmasyan, Artak; Hsu, David S; Brigman, Brian E; Somarelli, Jason A; Needham, David; Eward, William C
    Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t 1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2-2 μmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.
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    The oncoprotein DEK affects the outcome of PARP1/2 inhibition during mild replication stress.
    (PloS one, 2019-01) Ganz, Magdalena; Vogel, Christopher; Czada, Christina; Jörke, Vera; Gwosch, Eva Christina; Kleiner, Rebecca; Pierzynska-Mach, Agnieszka; Zanacchi, Francesca Cella; Diaspro, Alberto; Kappes, Ferdinand; Bürkle, Alexander; Ferrando-May, Elisa
    DNA replication stress is a major source of genomic instability and is closely linked to tumor formation and progression. Poly(ADP-ribose)polymerases1/2 (PARP1/2) enzymes are activated in response to replication stress resulting in poly(ADP-ribose) (PAR) synthesis. PARylation plays an important role in the remodelling and repair of impaired replication forks, providing a rationale for targeting highly replicative cancer cells with PARP1/2 inhibitors. The human oncoprotein DEK is a unique, non-histone chromatin architectural protein whose deregulated expression is associated with the development of a wide variety of human cancers. Recently, we showed that DEK is a high-affinity target of PARylation and that it promotes the progression of impaired replication forks. Here, we investigated a potential functional link between PAR and DEK in the context of replication stress. Under conditions of mild replication stress induced either by topoisomerase1 inhibition with camptothecin or nucleotide depletion by hydroxyurea, we found that the effect of acute PARP1/2 inhibition on replication fork progression is dependent on DEK expression. Reducing DEK protein levels also overcomes the restart impairment of stalled forks provoked by blocking PARylation. Non-covalent DEK-PAR interaction via the central PAR-binding domain of DEK is crucial for counteracting PARP1/2 inhibition as shown for the formation of RPA positive foci in hydroxyurea treated cells. Finally, we show by iPOND and super resolved microscopy that DEK is not directly associated with the replisome since it binds to DNA at the stage of chromatin formation. Our report sheds new light on the still enigmatic molecular functions of DEK and suggests that DEK expression levels may influence the sensitivity of cancer cells to PARP1/2 inhibitors.