COX-derived prostanoid pathways in gastrointestinal cancer development and progression : novel targets for prevention and intervention

Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE 2, which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA 2 in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD 2 and its metabolite 15d-PGJ2, PGF 1α and PGI 2. Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity.A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field. © 2011 Elsevier B.V.

Generalised gamma bidding model

A generalised gamma bidding model is presented, which incorporates many previous models. The log likelihood equations are provided. Using a new method of testing, variants of the model are fitted to some real data for construction contract auctions to find the best fitting models for groupings of bidders. The results are examined for simplifying assumptions, including all those in the main literature. These indicate no one model to be best for all datasets. However, some models do appear to perform significantly better than others and it is suggested that future research would benefit from a closer examination of these.

PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma

Background Although PPARγ antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARγ ligands induce PPARγ-independent effects. There is a need to better define such effects to permit rational utilization of these agents. Methods We have studied the effects of a range of endogenous and synthetic PPARγ ligands on proliferation, growth arrest (FACS analysis) and apoptosis (caspase-3/7 activation and DNA fragmentation) in multiple prostate carcinoma cell lines (DU145, PC-3 and LNCaP) and in a series of cell lines modelling metastatic transitional cell carcinoma of the bladder (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2). Results 15-deoxy-prostaglandin J2 (15dPGJ2), troglitazone (TGZ) and to a lesser extent ciglitazone exhibited inhibitory effects on cell number; the selective PPARγ antagonist GW9662 did not reverse these effects. Rosiglitazone and pioglitazone had no effect on proliferation. In addition, TGZ induced G0/G1 growth arrest whilst 15dPGJ2 induced apoptosis. Conclusion Troglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARγ-independent.

Development and characterization of a novel, antimicrobial, sterile hydrogel dressing for burn wounds : single-step production with gamma irradiation creates silver nanoparticles and radical polymerization

Patients with burn wounds are susceptible to wound infection and sepsis. This research introduces a novel burn wound dressing that contains silver nanoparticles (SNPs) to treat infection in a 2-acrylamido-2-methylpropane sulfonic acid sodium salt (AMPS-Na(+) ) hydrogel. Silver nitrate was dissolved in AMPS-Na(+) solution and then exposed to gamma irradiation to form SNP-infused hydrogels. The gamma irradiation results in a cross-linked polymeric network of sterile hydrogel dressing and a reduction of silver ions to form SNPs infused in the hydrogel in a one-step process. About 80% of the total silver was released from the hydrogels after 72 h immersion in simulated body fluid solution; therefore, they could be used on wounds for up to 3 days. All the hydrogels were found to be nontoxic to normal human dermal fibroblast cells. The silver-loaded hydrogels had good inhibitory action against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Results from a pilot study on a porcine burn model showed that the 5-mM silver hydrogel was efficient at preventing bacterial colonization of wounds, and the results were comparable to the commercially available silver dressings (Acticoat(TM) , PolyMem Silver(®) ). These results support its use as a potential burn wound dressing.

Gamma tocotrienol targets tyrosine phosphatase SHP2 in mammospheres resulting in cell death through RAS/ERK pathway

Background There is increasing evidence supporting the concept of cancer stem cells (CSCs), which are responsible for the initiation, growth and metastasis of tumors. CSCs are thus considered the target for future cancer therapies. To achieve this goal, identifying potential therapeutic targets for CSCs is essential. Methods We used a natural product of vitamin E, gamma tocotrienol (gamma-T3), to treat mammospheres and spheres from colon and cervical cancers. Western blotting and real-time RT-PCR were employed to identify the gene and protein targets of gamma-T3 in mammospheres. Results We found that mammosphere growth was inhibited in a dose dependent manner, with total inhibition at high doses. Gamma-T3 also inhibited sphere growth in two other human epithelial cancers, colon and cervix. Our results suggested that both Src homology 2 domain-containing phosphatase 1 (SHP1) and 2 (SHP2) were affected by gamma-T3 which was accompanied by a decrease in K- and H-Ras gene expression and phosphorylated ERK protein levels in a dose dependent way. In contrast, expression of self-renewal genes TGF-beta and LIF, as well as ESR signal pathways were not affected by the treatment. These results suggest that gamma-T3 specifically targets SHP2 and the RAS/ERK signaling pathway. Conclusions SHP1 and SHP2 are potential therapeutic targets for breast CSCs and gamma-T3 is a promising natural drug for future breast cancer therapy.

Comparison of human and animal Chlamydia pneumoniae responses to interferon gamma and penicillin treatment

This thesis has made a significant contribution to future chlamydial research by uncovering the chlamydial pathogenic mechanisms which will potentially help in the development of targeted vaccine against the pathogen. This thesis has made important new contributions to our understanding of Chlamydia pneumoniae specific adaptations to stress responses and has provided new perspectives on the survival of this successful pathogen. This thesis has used two well established microbial stressors and has identified major differences in stress responses between human and animal Chlamydia pneumoniae isolates.

Polysaccharopeptide enhanced the anti-cancer effect of gamma-tocotrienol through activation of AMPK

Background Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy. Method We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer. Result We showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo. Conclusion Our results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.

The variation of N-gamma with footing roughness using the method of characteristics

By using the method of characteristics, the effect of footing-soil interface friction angle (delta) on the bearing capacity factor N-gamma was computed for a strip footing. The analysis was performed by employing a curved trapped wedge under the footing base; this wedge joins the footing base at a distance B-t from the footing edge. For a given footing width (B), the value of B-t increases continuously with a decrease in delta. For delta = 0, no trapped wedge exists below the footing base, that is, B-t/B = 0.5. On the contrary, with delta = phi, the point of emergence of the trapped wedge approaches toward the footing edge with an increase in phi. The magnitude of N-gamma increases substantially with an increase in delta/phi. The maximum depth of the plastic zone becomes higher for greater values of delta/phi. The results from the present analysis were found to compare well with those reported in the literature.

IFN-gamma inhibits growth of WISH cells in a cell cycle phase-specific manner

Treatment of WISH (human amnion) cells with interferon-gamma (IFN-gamma) inhibits their growth. Release of the cells from IFN-gamma-mediated growth inhibition led to a rapid and significant increase in DNA synthesis, followed by doubling of cell numbers. The DNA synthesis profile was strikingly similar to that shown by WISH cells released from growth arrest by the G(1)/S phase inhibitor, aphidicolin, This strongly suggested that IFN-gamma treatment leads to growth inhibition of WISH cells at the G(1)/S boundary of the cell cycle. In contrast, IFN-alpha blocked growth of these cells at the G(0)/G(1) boundary.

Ultrafast Solvation Dynamics of an Ion in the gamma-Cyclodextrin Cavity: The Role of Restricted Environment

A detailed study of the solvation dynamics of a charged coumarin dye molecule in gamma-cyclodextrin/water has been carried out by using two different theoretical approaches. The first approach is based on a multishell continuum model (MSCM). This model predicts the time scales of the dynamics rather well, provided an accurate description of the frequency-dependent dielectric function is supplied. The reason for this rather surprising agreement is 2-fold. First, there is a cancellation of errors, second, the two-zone model mimics the heterogeneous microenvironment surrounding the ion rather well. The second approach is based on the molecular hydrodynamics theory (MI-IT). In this molecular approach, the solvation dynamics has been studied by restricting the translational motion of the solvent molecules enclosed within the cavity. The results from the molecular theory are also in good agreement with the experimental results. Our study indicates that, in the present case, the restricted environment affects only the long time decay of the solvation time correlation function. The short time dynamics is still governed by the librational (and/or vibrational) modes present in bulk water.

Gamma-ray luminosity function of gamma-ray bright AGNs

Detection of gamma-ray emissions from a class of active galactic nuclei (viz blazars), has been one of the important findings from the Compton Gamma-Ray Observatory (CGRO). However, their gamma-ray luminosity function has not-been well determined. Few attempts have been made in earlier works, where BL Lacs and Flat Spectrum Radio Quasars (FSRQs) have been considered as a single source class. In this paper, we investigated the evolution and gamma-ray luminosity function of FSRQs and BL Lacs separately. Our investigation indicates no evolution for BL Lacs, however FSRQs show significant evolution. Pure luminosity evolution is assumed for FSRQs and exponential and power law evolution models are examined. Due to the small number of sources, the low luminosity end index of the luminosity function for FSRQs is constrained with an upper limit. BL Lac luminosity function shows no signature of break. As a consistency check, the model source distributions derived from these luminosity functions show no significant departure from the observed source distributions.

Towards the development of a Cavendish banana resistant to race 4 of fusarium wilt: gamma irradiation of micropropagated Dwarf Parfitt (Musa spp., AAA group, Cavendish subgroup)

'Dwarf parfitt', an extra-dwarf Cavendish cultivar with resistance to subtropical race 4 fusarium oxysporum f. sp. cubense 9Foc), was gamma irradiated at a dose of 20 Gy and putative mutants were recovered with improved agronomic characteristics. Further screening of putative mutants for improved yield and fruit size, as well as a degree of resistence to fusarium wilt, led to the selection of a line (DPM25) with improved productivity when grown on soils infested with subtropical race 4 Foc. DPM25 was equal to the industry standard, 'Williams', in every agronomic trait measured and it consistently showed a lower incidence of fusarium wilt. Further improvement of field resistance to race 4 Foc is needed in DPM25 and further cycles of mutation induction and selction is an option discussed.

Contribution from normal and starburst galaxies to the extragalactic gamma-ray background (EGRB)

The extragalactic diffuse emission at gamma-ray energies has interesting cosmological implications since these photons suffer little or no attenuation during their propagation from the site of origin. The emission could originate from either truly diffuse processes or from unresolved point sources such as AGNs, normal galaxies and starburst galaxies. Here, we examine the unresolved point source origin of the extragalactic gamma-ray background emission from normal galaxies and starburst galaxies. gamma-ray emission from normal galaxies is primarily coming from cosmic-ray interactions with interstellar matter and radiation (similar to 90%) along with a small contribution from discrete point sources (similar to 10%). Starburst galaxies are expected to have enhanced supernovae activity which leads to higher cosmic-ray densities, making starburst galaxies sufficiently luminous at gamma-ray energies to be detected by the current gamma-ray mission(Fermi Gamma-ray Space Telescope).

A Radical Cyclization Route To +/-Andirolactone, A Spiro-Gamma-Butyrolactone

Synthesis of Andirolactone (Image ), starting from 4-methyl cyclohex-3-en-1-one (Image ), via the radical cyclisation of the bromoacetal (Image ), is described.