Chemotherapy-Induced CXC-Chemokine/CXC-Chemokine Receptor Signaling in Metastatic Prostate Cancer Cells Confers Resistance to Oxaliplatin through Potentiation of Nuclear Factor-κB Transcription and Evasion of Apoptosis

Constitutive activation of nuclear factor (NF)-kappa B is linked with the intrinsic resistance of androgen-independent prostate cancer (AIPC) to cytotoxic chemotherapy. Interleukin-8 (CXCL8) is a transcriptional target of NF-kappa B whose expression is elevated in AIPC. This study sought to determine the significance of CXCL8 signaling in regulating the response of AIPC cells to oxaliplatin, a drug whose activity is reportedly sensitive to NF-kappa B activity. Administration of oxaliplatin to PC3 and DU145 cells increased NF-kappa B activity, promoting antiapoptotic gene transcription. In addition, oxaliplatin increased the transcription and secretion of CXCL8 and the related CXC-chemokine CXCL1 and increased the transcription and expression of CXC-chemokine receptors, especially CXC-chemokine receptor (CXCR) 2, which transduces the biological effects of CXCL8 and CXCL1. Stimulation of AIPC cells with CXCL8 potentiated NF-kappa B activation in AIPC cells, increasing the transcription and expression of NF-kappa B-regulated antiapoptotic genes of the Bcl-2 and IAP families. Coadministration of a CXCR2-selective antagonist, AZ10397767 (Bioorg Med Chem Lett 18:798-803, 2008), attenuated oxaliplatin-induced NF-kappa B activation, increased oxaliplatin cytotoxicity, and potentiated oxaliplatin-induced apoptosis in AIPC cells. Pharmacological inhibition of NF-kappa B or RNA interference-mediated suppression of Bcl-2 and survivin was also shown to sensitize AIPC cells to oxaliplatin. Our results further support NF-kappa B activity as an important determinant of cancer cell sensitivity to oxaliplatin and identify the induction of autocrine CXCR2 signaling as a novel mode of resistance to this drug.

Ionic liquids for the nuclear industry: A radiochemical, structural, and electrochemical investigation

The applicability of ionic liquids within the nuclear industry has been investigated. The radiation stability of ionic liquids containing dialkylimidazolium cations has been tested through with alpha, beta and gamma irradiation. The results of these tests suggest that imidazolium salts have stabilities similar to alkylbenzenes and greater than tetrabutylphosphate / odorless kerosene (TBP/OK) mixtures. The oxidative dissolution of uranium dioxide and the anodic dissolution of uranium metal and plutonium metal have been carried out in various ionic liquid media (C) 2002 American Chemical Society.

Formation of Novel Di-Nuclear Lanthanide Luminescent Sm(III), Eu(III) and Tb(III) Triple Stranded Helicates from a C2 Symmetrically 2,6-Dicarboxylic Amide based 1,3-Xylene Ligand in CH3CN

The synthesis of the C2-symmetrical ligand 1 consisting of two naphthalene units connected to two pyridine-2,6-dicarboxamide moieties linked by a xylene spacer and the formation of LnIII-based (Ln1/4 Sm, Eu, Tb, and Lu) dimetallic helicates [Ln2 · 13] in MeCN by means of a metal-directed synthesis is described. By analyzing the metal-induced changes in the absorption and the fluorescence of 1, the formation of the helicates, and the presence of a second species [Ln2 · 12] was confirmed by nonlinear- regression analysis. While significant changes were observed in the photophysical properties of 1, the most dramatic changes were observed in the metal-centred lanthanide emissions, upon excitation of the naphthalene antennae. From the changes in the lanthanide emission, we were able to demonstrate that these helicates were formed in high yields (ca. 90% after the addition of 0.6 equiv. of LnIII), with high binding constants, which matched well with that determined from the changes in the absorption spectra. The formation of the LuIII helicate, [ Lu2 · 13 ] , was also investigated for comparison purposes, as we were unable to obtain accurate binding constants from the changes in the fluorescence emission upon formation of [Sm2 · 13], [Eu2 · 13], and [Tb2 · 13].

Rheological Evaluation of the Isothermal Cure Characteristics of Medical Grade Silicone Elastomers

Silicone elastomer systems have been shown to offer potential for the fabrication of medical devices and sustained release drug delivery devices comprising low molecular weight drugs and protein therapeutics. For drug delivery systems in particular, there is often no clear rationale for selection of the silicone elastomer grade, particularly in respect of optimizing the manufacturing conditions to ensure thermal stability of the active agent and short cycle times. In this study, the cure characteristics of a range of addition-cure and condensation-cure, low-consistency, implant-grade silicone elastomers, either as supplied or loaded with the model protein bovine serum albumin (BSA) and the model hydrophilic excipient glycine, were investigated using oscillatory rheology with a view to better understanding the isothermal cure characteristics. The results demonstrate the influence of elastomer type, cure temperature, protein loading, and glycine loading on isothermal cure properties. By measuring the cure time required to achieve tan delta values representative of early and late-stage cure conditions, a ratio t(1)/t(2) was defined that allowed the cure characteristics of the various systems to be compared. Sustained in vitro release of BSA from glycine-loaded silicone elastomer covered rod devices was also demonstrated over 14 days. (C) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 116: 2320-2327, 2010

The incidence of esophageal cancer and high-grade dysplasia in Barrett's esophagus: A systematic review and meta-analysis

Barrett's esophagus is a well-recognized precursor of esophageal adenocarcinoma. Surveillance of Barrett's esophagus patients is recommended to detect high-grade dysplasia (HGD) or early cancer. Because of wide variation in the published cancer incidence in Barrett's esophagus, the authors undertook a systematic review and meta-analysis of cancer and HGD incidence in Barrett's esophagus. Ovid Medline (Ovid Technologies, Inc., New York, New York) and EMBASE (Elsevier, Amsterdam, the Netherlands) databases were searched for papers published between 1950 and 2006 that reported the cancer/HGD risk in Barrett's esophagus. Where possible, early incident cancers/HGD were excluded, as were patients with HGD at baseline. Forty-seven studies were included in the main analysis, and the pooled estimate for cancer incidence in Barrett's esophagus was 6.1/1,000 person-years, 5.3/1,000 person-years when early incident cancers were excluded, and 4.1/1,000 person-years when both early incident cancer and HGD at baseline were excluded. Corresponding figures for combined HGD/cancer incidence were 10.0 person-years, 9.3 person-years, and 9.1/1,000 person-years. Compared with women, men progressed to cancer at twice the rate. Cancer or HGD/cancer incidences were lower when only high-quality studies were analyzed (3.9/1,000 person-years and 7.7/1,000 person-years, respectively). The pooled estimates of cancer and HGD incidence were low, suggesting that the cost-effectiveness of surveillance is questionable unless it can be targeted to those with the highest cancer risk.

Positive association between nuclear Runx2 and oestrogen-progesterone receptor gene expression characterises a biological subtype of breast cancer

Purpose: The runt-related transcription factor, Runx2 may have an oncogenic role in mediating metastatic events in breast cancer, but whether Runx2 has a role in the early phases of breast cancer development is not clear. We examined the expression of Runx2 and its relationship with oestrogen receptor (ER) and progesterone receptor (PR) in breast cancer cell lines and tissues.

Characterization of Numb expression in astrocytomas

During early neurodevelopment, asymmetric segregation of Numb in mitotic progenitor cells influences the fate of daughter cells, whereby one daughter retains the progenitor phenotype while the other proceeds along a differentiation pathway. Numb has also been reported to function as a tumor suppressor in breast cancers and medulloblastomas. Given its role in maintaining neural progenitor pools in animal models and its reported role as a tumor suppressor, Numb could potentially contribute to astrocytoma oncogenesis. We characterized Numb expression in both human astrocytoma tissue samples and glioblastoma cell lines. We found that Numb is expressed in all grades of astrocytomas, being predominantly cytoplasmic in higher-grade astrocytomas but nuclear in pilocytic astrocytomas. Numb is also present in normal neurons, but not in normal astrocytes. In cultured glioblastoma cells, Numb concentrates in the perinuclear region and process tips. Numb expression in astrocytomas recapitulates that of progenitor cells during neurodevelopment, and suggests a role for Numb in astrocytoma oncogenesis.

An introduction to biological nuclear magnetic resonance spectroscopy

ABSTRACT Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful analytical techniques available to biology. This review is an introduction to the potential of this method and is aimed at readers who have little or no experience in acquiring or analyzing NMR spectra. We focus on spectroscopic applications of the magnetic resonance effect, rather than imaging ones, and explain how various aspects of the NMR phenomenon make it a versatile tool with which to address a number of biological problems. Using detailed examples, we discuss the use of 1H NMR spectroscopy in mixture analysis and metabolomics, the use of 13C NMR spectroscopy in tracking isotopomers and determining the flux through metabolic pathways (‘fluxomics’) and the use of 31P NMR spectroscopy in monitoring ATP generation and intracellular pH homeotasis in vivo. Further examples demonstrate how NMR spectroscopy can be used to probe the physical environment of a cell by measuring diffusion and the tumbling rates of individual metabolites and how it can determine macromolecular structures by measuring the bonds and distances which separate individual atoms. We finish by outlining some of the key challenges which remain in NMR spectroscopy and we highlight how recent advances— such as increased magnet field strengths, cryogenic cooling, microprobes and hyperpolarisation—are opening new avenues for today’s biological NMR spectroscopists.

Endocrine disrupting effects of zearalenone, alpha- and beta-zearalenol at the level of nuclear receptor binding and steroidogenesis.

The mycotoxin zearalenone (ZEN) is a secondary metabolite of fungi which is produced by certain species of the genus Fusarium and can occur in cereals and other plant products. Reporter gene assays incorporating natural steroid receptors and the H295R steroidogenesis assay have been implemented to assess the endocrine disrupting activity of ZEN and its metabolites -zearalenol (-ZOL) and -zearalenol (-ZOL). -ZOL exhibited the strongest estrogenic potency (EC50 0.022 ± 0.001 nM), slightly less potent than 17- estradiol (EC50 0.015 ± 0.002 nM). ZEN was ~70 times less potent than -ZOL and twice as potent as -ZOL. Binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of ZEN, -ZOL or -ZOL. ZEN, -ZOL or -ZOL increased production of progesterone, estradiol, testosterone and cortisol hormones in the H295R steroidogenesis assay, with peak productions at 10 M. At 100 M, cell viability decreased and levels of hormones were significantly reduced except for progesterone. -ZOL increased estradiol concentrations more than -ZOL or ZEN, with a maximum effect at 10 M, with -ZOL (562 ± 59 pg/ml) > -ZOL (494 ± 60 pg/ml) > ZEN (375 ± 43 pg/ml). The results indicate that ZEN and its metabolites can act as potential endocrine disruptors at the level of nuclear receptor signalling and by altering hormone production.