Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer

It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations.

Identification of lactic acid bacteria strains modulating incretin hormone secretion and gene expression in enteroendocrine cells

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released from intestinal enteroendocrine (EE) cells and have well-established glucose-lowering actions. Lactic acid bacteria (LAB) colonise the human intestine, but it is unknown whether LAB and EE cells interact. Acute co-culture of LAB with EE cells showed that certain LAB strains elicit GLP-1 and GIP secretion (13-194-fold) and upregulate their gene expression. LAB-induced incretin hormone secretion did not appear to involve nutrient mechanisms, nor was there any evidence of cytolysis. Instead PCR array studies implicated signalling agents of the toll-like receptor system, e.g. adaptor protein MyD88 was decreased 23-fold and cell surface antigen CD14 was increased 17-fold. Mechanistic studies found that blockade of MyD88 triggered significant GLP-1 secretion. Furthermore, blocking of CD14 completely attenuated LAB-induced secretion. A recent clinical trial clearly shows that LAB have potential for alleviating type 2 diabetes, and further characterisation of this bioactivity is warranted.

UV dosimetry for solar water disinfection (SODIS) carried out in different plastic bottles and bags

Solar water disinfection (SODIS) is a well-established inexpensive means of water disinfection in developing countries, but lacks an indicator to illustrate its end-point. A study of the solar UV dosage required for SODIS, in order to achieve a bacteria concentration below the detection limit for: Escherichia coli, Enterococcus spp. and Clostridium perfringens, in water in PET bottles, PE and PE/EVA bags showed disinfection to be most efficient in PE bags, with a solar UV (290–385 nm) dose of 389 kJ m−2 required. In parallel to the disinfection experiments, a range of polyoxometalate, semiconductor photocatalysis and photodegradable dye-based solar UV dosimeter indicators were tested under the same solar UV irradiation conditions. All three types of dosimeter produced indicators that largely and significantly change colour upon exposure to 389 kJ m−2 solar UV; further indicators are reported which change colour at higher doses and hence would be suitable for the less efficient SODIS containers tested. All indicators tested were robust, easy to use and inexpensive so as not to add significantly to the attractive low cost of SODIS. Furthermore, whilst semiconductor photocatalyst and photodegradable dye based indicators are disposable, one-use systems, the polyoxometalate based indicators recover colour in the dark overnight, allowing them to be reused, and hence further decreasing the cost of using indicators during the implementation of the SODIS method.

The nitric oxide ISO photocatalytic reactor system: Measurement of NOx removal activity and capacity

Although the NO removal-based air-purification ISO method ISO 22197-1:2007 is well established, its preconditioning requirements mean that only the initial activity of the photocatalyst under test is measured owing to the often-reported, gradual alteration of the surface kinetics for NO oxidation by air through the accumulation of surface HNO3. Herein, we compare the photocatalytic NO removal abilities of a number of different, common TiO2 materials, surface-saturated with photogenerated HNO3, with their behaviours observed during the typical 5 h-long ISO standard test. It is found that all the TiO2 materials studied eventually become largely NO to NO2 converters after sufficient exposure to NO under irradiation (>5 h) due to the accumulation of surface HNO3. The UV exposure time, t*, necessary to reach this HNO3 saturated condition is different for each different catalyst. As a consequence, an alternative preconditioning process for the ISO method is proposed which can be used to provide a more realistic measure of the photocatalytic activity of the underlying material and provide a measure of the NOx removing capacity of the photocatalytic material under test.

Absolute magnitudes and slope parameters for 250,000 asteroids observed by Pan-STARRS PS1 - preliminary results

We present the results of a Monte Carlo technique to calculate the absolute magnitudes (H) and slope parameters (G) of about 240,000 asteroids observed by the Pan-STARRS1 telescope during the first 15 months of its 3-year all-sky survey mission. The system's exquisite photometry with photometric errors asteroids rotation period, amplitude and color to derive the most-likely H and G, but its major advantage is in estimating realistic statistical+systematic uncertainties and errors on each parameter. The method was confirmed by comparison with the well-established and accurate results for about 500 asteroids provided by Pravec et al. (2012) and then applied to determining H and G for the Pan-STARRS1 asteroids using both the Muinonen et al. (2010) and Bowell et al. (1989) phase functions. Our results confirm the bias in MPC photometry discovered by ( Jurić et al., 2002).

Kaempferol Exhibits Progestogenic Effects in Ovariectomized Rats

OBJECTIVE: Progesterone (P4) plays a central role in women's health. Synthetic progestins are used clinically in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Unfortunately, synthetic progestins are associated with side effects, including cardiovascular disease and breast cancer. Botanical dietary supplements are widely consumed for the alleviation of a variety of gynecological issues, but very few studies have characterized natural compounds in terms of their ability to bind to and activate progesterone receptors (PR). Kaempferol is a flavonoid that functions as a non-steroidal selective progesterone receptor modulator (SPRM) in vitro. This study investigated the molecular and physiological effects of kaempferol in the ovariectomized rat uteri.

METHODS: Since genistein is a phytoestrogen that was previously demonstrated to increase uterine weight and proliferation, the ability of kaempferol to block genistein action in the uterus was investigated. Analyses of proliferation, steroid receptor expression, and induction of well-established PR-regulated targets Areg and Hand2 were completed using histological analysis and qPCR gene induction experiments. In addition, kaempferol in silico binding analysis was completed for PR. The activation of estrogen and androgen receptor signalling was determined in vitro.

RESULTS: Molecular docking analysis confirmed that kaempferol adopts poses that are consistent with occupying the ligand-binding pocket of PRA. Kaempferol induced expression of PR regulated transcriptional targets in the ovariectomized rat uteri, including Hand2 and Areg. Consistent with progesterone-l ke activity, kaempferol attenuated genistein-induced uterine luminal epithelial proliferation without increasing uterine weight. Kaempferol signalled without down regulating PR expression in vitro and in vivo and without activating estrogen and androgen receptors.

CONCLUSION: Taken together, these data suggest that kaempferol is a unique natural PR modulator that activates PR signaling in vitro and in vivo without triggering PR degradation.

KATNAL1 regulation of sertoli cell microtubule dynamics is essential for spermiogenesis and male fertility

Spermatogenesis is a complex process reliant upon interactions between germ cells (GC) and supporting somatic cells. Testicular Sertoli cells (SC) support GCs during maturation through physical attachment, the provision of nutrients, and protection from immunological attack. This role is facilitated by an active cytoskeleton of parallel microtubule arrays that permit transport of nutrients to GCs, as well as translocation of spermatids through the seminiferous epithelium during maturation. It is well established that chemical perturbation of SC microtubule remodelling leads to premature GC exfoliation demonstrating that microtubule remodelling is an essential component of male fertility, yet the genes responsible for this process remain unknown. Using a random ENU mutagenesis approach, we have identified a novel mouse line displaying male-specific infertility, due to a point mutation in the highly conserved ATPase domain of the novel KATANIN p60-related microtubule severing protein Katanin p60 subunit A-like1 (KATNAL1). We demonstrate that Katnal1 is expressed in testicular Sertoli cells (SC) from 15.5 days post-coitum (dpc) and that, consistent with chemical disruption models, loss of function of KATNAL1 leads to male-specific infertility through disruption of SC microtubule dynamics and premature exfoliation of spermatids from the seminiferous epithelium. The identification of KATNAL1 as an essential regulator of male fertility provides a significant novel entry point into advancing our understanding of how SC microtubule dynamics promotes male fertility. Such information will have resonance both for future treatment of male fertility and the development of non-hormonal male contraceptives.

HD Laser scanning for the evaluation of salt decay laboratory simulations of building limestone

Laboratory salt decay simulations are a well established method to assess the relative durability of stone. There is still, however, very much scope to implement improved monitoring techniques to investigate the changes experienced by the materials during these experiments. Non-destructive techniques have acquired over recent decades a preferential status for monitoring change samples during salt decay tests, as they allow cumulative tests on each sample. The development of HD laser scanning permits detailed mapping of surface changes and, therefore, constitutes an effective technique to monitor non-destructively surface changes in tested samples as an alternative to other monitoring techniques such as traditional weight loss strategies that do not permit any degree of spatial differentiation that can be related, for example, to underlying stone properties.

A spatio-temporal contrast of the predatory impact of an invasive freshwater crustacean

Aim: Impacts of invasive species may vary across invasion gradients, owing to trait-based sorting of individuals through dispersal: those aggregating at invasion fronts may be more aggressive and voracious. We examine, in the field and laboratory, variation in the predatory impacts of an invasive Ponto-Caspian crustacean Hemimysis anomala G.O. Sars, 1907 at two sites along a spatio-temporal gradient of invasion.

Location: Republic of Ireland.

Methods: We used reciprocal transplant field-deployed mesocosms to compare predation rates of invasion front and well-established H. anomala on natural zooplankton assemblages. In the laboratory, we measured the functional response (relationship between predation rate and prey supply) of H. anomala from both sites, for a per capita mechanistic comparison of predation efficiency. We also assessed prey selectivity of H. anomala in the mesocosm experiments to further compare feeding behaviour. Finally, we used a correlative approach to assess the community impact of H. anomala across sites, including a nearby uninvaded site, by comparing zooplankton diversities and densities.

Results: Invasion front H. anomala had higher predation rates than well-established H. anomala at high in situ zooplankton densities. Invasion front H. anomala also had higher functional responses - in particular showing higher 'attack rates' - indicating a heightened ability to locate and capture prey. Prey selectivity was consistent across the spatio-temporal contrast, with positive selection for cladocerans. Zooplankton diversity and density declined with time since H. anomala invasion, both being maximal at the uninvaded site.

Main conclusions: Our study, for the first time, (1) reveals differences in predatory per capita effects and associated behavioural traits between two sites along a spatio-temporal invasion gradient and (2) shows a negative community-level impact of the invasive H. anomala in natural water bodies. Further spatio-temporal comparisons of predatory per capita effects of invaders are needed to assess the generality of these results.

(223)Ra and other bone-targeting radiopharmaceuticals-the translation of radiation biology into clinical practice

Osseous metastases are a source of significant morbidity for patients with a variety of cancers. Radiotherapy is well established as an effective means of palliating symptoms associated with such metastases. The role of external beam radiotherapy is limited where sites of metastases are numerous and widespread. Low linear energy transfer (LET) radionuclides have been utilized to allow targeted delivery of radiotherapy to disparate sites of disease, with evidence of palliative benefit. More recently, the bone targeting, high LET radionuclide (223)Ra has been shown to not only have a palliative effect but also a survival prolonging effect in metastatic, castration-resistant prostate cancer with bone metastases. This article reviews the different radionuclide-based approaches for targeting bone metastases, with an emphasis on (223)Ra, and key elements of the underlying radiobiology of these that will impact their clinical effectiveness. Consideration is given to the remaining unknowns of both the basic radiobiological and applied clinical effects of (223)Ra as targets for future research.

Sustainable concrete: design and testing

Producing concrete with secondary raw materials is an excellent way to contribute to a moresustainable world, provided that this concrete has at least the same performance during itsservice life as concrete made with the primary raw materials it replaces. Secondary rawmaterials for Light Weight (LW) aggregates (rigid polyurethane foams, shredded tire rubberand mixed plastic scraps) have been combined with secondary raw materials for the binder(fly ash, slag and perlite tailings) making sustainable concretes that were investigated fortheir suitability as LW, highly insulating concrete for four different types of applications.Compliance to desired engineering properties (workability, setting time) was not alwaysfeasible: it was mostly the low workability of the mixtures that limited their application.Contrary to well established cements, steering the workability by adding water was not anoption for these binders that rely on alkali-activation. Eight successful mixtures have beentested further. The results have shown that it is possible to produce a non-structuralsustainable concrete with good mechanical and thermal insulation properties.Design of concrete made with novel materials is currently not feasible without extensiveexperimentation as no design rules exist other than empirically derived rules based ontraditional materials. As a radical different approach, a flexible concrete mix design has beendeveloped with which the concrete can be modelled in the fresh and hardened state. Thenumerical concrete mix design method proves a promising tool in designing concrete forperformance demands such as elasticity parameters and thermal conductivity

The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer

It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype. A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many processes including apoptosis. To date, studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast, colon and stomach, with only limited data available on prostate cancer. Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer. The most significant advances have involved the discovery of apoptotic gene targets of methylation, including XAF1, (fragile histidine triad (FHIT ), cellular retinol binding protein 1 (CRBP1), decoy receptor 1(DCR1), decoy receptor 2 (DCR2 ), target of methylation-induced silenceing 1 (TMS1), TNF receptor superfamily, member 6 (FAS), Reprimo (RPRM) and GLI pathogenesis-related 1 (GLIPR1). These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers. We also introduce the concept of an 'apoptotic methylation signature' for prostate cancer and evaluate its potential in a diagnostic, prognostic and therapeutic setting.

The TGF-β-inducible miR-23a cluster attenuates IFN-γ levels and antigen-specific cytotoxicity in human CD8+ T cells

Cytokine secretion and degranulation represent key components of CD8(+) T-cell cytotoxicity. While transcriptional blockade of IFN-γ and inhibition of degranulation by TGF-β are well established, we wondered whether TGF-β could also induce immune-regulatory miRNAs in human CD8(+) T cells. We used miRNA microarrays and high-throughput sequencing in combination with qRT-PCR and found that TGF-β promotes expression of the miR-23a cluster in human CD8(+) T cells. Likewise, TGF-β up-regulated expression of the cluster in CD8(+) T cells from wild-type mice, but not in cells from mice with tissue-specific expression of a dominant-negative TGF-β type II receptor. Reporter gene assays including site mutations confirmed that miR-23a specifically targets the 3'UTR of CD107a/LAMP1 mRNA, whereas the further miRNAs expressed in this cluster-namely, miR-27a and -24-target the 3'UTR of IFN-γ mRNA. Upon modulation of the miR-23a cluster by the respective miRNA antagomirs and mimics, we observed significant changes in IFN-γ expression, but only slight effects on CD107a/LAMP1 expression. Still, overexpression of the cluster attenuated the cytotoxic activity of antigen-specific CD8(+) T cells. These functional data thus reveal that the miR-23a cluster not only is induced by TGF-β, but also exerts a suppressive effect on CD8(+) T-cell effector functions, even in the absence of TGF-β signaling.

Combining Bio- and Chemo-catalysis for the Sustainable Production of Chemicals

The combination of bio- and chemo-catalysis to form a single synthetic route is a powerful methodology for the improvement of chemical synthesis. The extreme methods of biocatalysis (whole cell and isolated enzyme) fulfill very different roles. Biocatalysis by isolated enzymes enables highly efficient chemical transformations of extremely high selectivity and low contamination; however, conditions and substrates are limited to a narrow range. Whole cell biocatalysis enables the conversion of crude substrates, such as those derived from biomass; however, the products tend to be impure and delivered in dilute aqueous solution. Chemocatalysis is a well-established technique, and the addition of chemical catalysis and chemocatalytic methods to biocatalysis enables synthetic chemists to avoid the shortcomings of a biocatalytic step. For example, in enzymatic catalysis the addition of a chemical catalyst can allow the conversion of a racemic alcohol to an enantiopure, instead of racemic, product. In whole cell biocatalysis chemical reagents can assist the separation, transformation, and further isolation of the functionality of interest. The cooperation of bio- and chemocatalysts enables sustainable production of chemicals that would be impossible using biocatalysis alone, while achieving selectivities and using substrates not currently possible with chemocatalysis alone.

Structure and dynamics of aqueous 2-propanol: A THz-TDS, NMR and neutron diffraction study

Aqueous liquid mixtures, in particular, those involving amphiphilic species, play an important role in many physical, chemical and biological processes. Of particular interest are alcohol/water mixtures; however, the structural dynamics of such systems are still not fully understood. Herein, a combination of terahertz time-domain spectroscopy (THz-TDS) and NMR relaxation time analysis has been applied to investigate 2-propanol/water mixtures across the entire composition range; while neutron diffraction studies have been carried out at two specific concentrations. Excellent agreement is seen between the techniques with a maximum in both the relative absorption coefficient and the activation energy to molecular motion occurring at ∼90 mol% H₂O. Furthermore, this is the same value at which well-established excess thermodynamic functions exhibit a maximum/minimum. Additionally, both neutron diffraction and THz-TDS have been used to provide estimates of the size of the hydration shell around 2-propanol in solution. Both methods determine that between 4 and 5 H₂O molecules per 2-propanol are found in the 2-propanol/water clusters at 90 mol% H₂O. Based on the acquired data, a description of the structure of 2-propanol/water across the composition range is presented.