Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance

Prostate cancer (PCa) mortality remains a significant public health problem, as advanced disease has poor survivability due to the development of resistance in response to both standard and novel therapeutic interventions. Therapeutic resistance is a multifaceted problem involving the interplay of a number of biological mechanisms including genetic, signaling, and phenotypic alterations, compounded by the contributions of a tumor microenvironment that supports tumor growth, invasiveness, and metastasis. The androgen receptor (AR) is a primary regulator of prostate cell growth, response and maintenance, and the target of most standard PCa therapies designed to inhibit AR from interacting with androgens, its native ligands. As such, AR remains the main driver of therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). While androgen deprivation therapy (ADT), in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in patients with mCRPC, therapeutic resistance invariably develops, leading to lethal disease. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes and also to the development of biomarker signatures of predictive value. The interconversions between epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) navigate the prostate tumor therapeutic response, and provide a novel targeting platform in overcoming therapeutic resistance. Both microRNA (miRNA)- and long non-coding RNA (lncRNA)-mediated mechanisms have been associated with epigenetic changes in prostate cancer. This review discusses the current evidence-based knowledge of the role of the phenotypic transitions and novel molecular determinants (non-coding RNAs) as contributors to the emergence of therapeutic resistance and metastasis and their integrated predictive value in prostate cancer progression to advanced disease.     

The AFLATOX® Project: Approaching the Development of New Generation,Natural-Based Compounds for the Containment of the Mycotoxigenic Phytopathogen Aspergillus flavus and Aflatoxin Contamination

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox^® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.     

Multicomponent Bioluminescence Imaging with Naphthylamino Luciferins

Bioluminescent tools have been used for decades to image processes in complex tissues and preclinical models. However, few distinct probes are available to probe multicellular interactions. We and others are addressing this limitation by engineering new luciferases that can selectively process synthetic luciferin analogues. In this work, we explored naphthylamino luciferins as orthogonal bioluminescent probes. Three analogues were prepared using an optimized synthetic route. The luciferins were found to be robust emitters with native luciferase in vitro and in cellulo. We further screened the analogues against libraries of luciferase mutants to identify unique enzyme-substrate pairs. The new probes can be used in conjunction with existing bioluminescent tools for multi-component imaging.     

Solvent-free oxidation of benzyl alcohol with oxygen using zeolite-supported Au and Au–Pd catalysts

The oxidation of benzyl alcohol to benzaldehyde has been investigated in the absence of solvent using zeolite-supported Au and Au–Pd catalysts. Three zeolites were investigated, ZSM-5, zeolite β and zeolite Y, and these were contrasted with the titanoslicalite TS-1 and TiO₂ as supports. For the Au catalysts the best results are obtained with zeolite β as the support and the conversions were comparable or better than those observed with TiO₂ in terms of turn over frequencies. However, the selectivities observed with the acidic zeolites were lower than the non-acidic TS-1 and TiO₂. This is due to the subsequent reaction of benzaldehyde via acid catalysed reactions to give benzyl benzoate and its dibenzyl acetal, and, in some cases dibenzylether. Initial catalysts were evaluated with a gold loading of 2 wt% and increasing this to 4 wt% showed the expected increase in activity, indicating that there is scope to improve the performance of these catalysts. The most active catalysts were prepared by impregnation and catalysts prepared by deposition precipitation were considerably less active. Introduction of Pd into the catalyst improved the activity without significantly affecting the selectivity.     

Time and shear dependent rheology of maleated polyethylene and its nanocomposites

Dipole-dipole and/or hydrogen-bonding interactions between the pendant functional groups within maleated high-density polyethylene (PE-g-MAn) establish a physical polymer network, whose formation kinetics and shear-sensitivity are revealed by dynamic oscillatory testing. The pronounced time and shear dependent viscoelastic properties of PE-g-MAn were not observed for a corresponding imide derivative, PE-g-imide, presumably due to weakened functional group associations in the latter material.The melt compounding of PE-g-MAn with onium-ion exchanged montmorillonite clay (NR₄⁺-MM) resulted in a partially exfoliated hybrid nanocomposite structure, whose viscoelastic behaviour differed significantly from that of the unfilled polymer. The presence of dispersed clay platelets altered the extent of functional group associations, thereby changing the dynamics of network formation.     

Brain mass estimation by head circumference and body mass methods in neonatal glycaemic modelling and control

Introduction

Hyperglycaemia is a common complication of stress and prematurity in extremely low-birth-weight infants. Model-based insulin therapy protocols have the ability to safely improve glycaemic control for this group. Estimating non-insulin-mediated brain glucose uptake by the central nervous system in these models is typically done using population-based body weight models, which may not be ideal.

Method

A head circumference-based model that separately treats small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) infants is compared to a body weight model in a retrospective analysis of 48 patients with a median birth weight of 750 g and median gestational age of 25 weeks. Estimated brain mass, model-based insulin sensitivity (S_I) profiles, and projected glycaemic control outcomes are investigated. SGA infants (5) are also analyzed as a separate cohort.

Results

Across the entire cohort, estimated brain mass deviated by a median 10% between models, with a per-patient median difference in S_I of 3.5%. For the SGA group, brain mass deviation was 42%, and per-patient S_I deviation 13.7%. In virtual trials, 87–93% of recommended insulin rates were equal or slightly reduced (Δ < 0.16 mU/h) under the head circumference method, while glycaemic control outcomes showed little change.

Conclusion

The results suggest that body weight methods are not as accurate as head circumference methods. Head circumference-based estimates may offer improved modelling accuracy and a small reduction in insulin administration, particularly for SGA infants.     

Studies of lipoproteins and fatty acids in maternal and cord blood of two racial groups in Trinidad

The high mortality rate from coronary heart disease (CHD) among Indians compared to Negroes in Trinidad led us to test plasma lipid profiles to see whether dietary or genetic factors might be involved. There were no interracial differences in the composition of plasma cholesterol ester fatty acids of the tested women and neonates. This finding suggests that dietary fat does not account for the interracial difference in CHD, nor does the cause appear to be due to genetic differences in lipid profiles, as there was no significant difference between values for plasma triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, apo-I, apo-II, apo B or cholesterol ester fatty acids in the cord blood of each racial group. Blood samples were collected from 69 nonpregnant and 71 postpartum, fasted Negro and Indian women. Also taken were 71 umbilical cord blood samples. The mean triglyceride level was significantly lower in the Negro nonpregnant and postpartum women than in the Indians. HDL cholesterol and apo-I values were lower in the Indian women. There were no significant differences in the total cholesterol and apo B measurements. The triglyceride values for postpartum women were higher than those of the nonpregnant Negroes and Indians (75% and 47%, respectively), whereas the total cholesterol and HDL cholesterol, apo A-I and apo A-II ranged from 9% to 29% higher in the postpartum women. Apo B was about 40% higher postpartum in both ethnic groups. The high CHD rate of Indians in Trinidad cannot be explained by dietary factors, plasma total cholesterol or fatty acid composition. However, the lower level of HDL cholesterol and plasma A-I could play a role in the higher CHD rate in Indians.     

Dynamic behaviour of viologen-activated nanostructured TiO2: correlation between kinetics of charging and coloration

The dynamic response of viologen-activated nanostructured titanium dioxide has been studied by means of electrical and electro-optical measurements. We show that the state of charge of the semiconductor network is the key factor mediating between the electrode potential and colouration of viologen. Theoretically, we relate the electrode potential to the statistics of occupancy of both TiO₂ nanoparticles and oxidized viologen molecules attached to the surface, on the assumption of quasi-equilibrium of Fermi levels in these contacting phases. Experimentally, we determine the statistical function from steady-state measurements (electrochemical impedance spectroscopy) of the capacitance of the semiconductor film. From this understanding we explain the main features that correlate the simultaneous voltammetry and transmittance responses. Finally, the redox process of viologen is resolved separately from the TiO₂ response by means of transmittance data.     

Studies of cyclic and linear poly(dimethyl siloxanes): 5. Diffusion behaviour in dilute solution

The diffusion coefficients of cyclic and linear oligomeric and polymeric dimethyl siloxanes, containing number-average numbers of skeletal bonds in the range $\text{6 <}\text{n}\text{?}{}_{\mathrm{n}}\text{< 650}$, have been measured in toluene solution at 298K. Impermeable diffusion behaviour was observed for all the siloxanes studied, in agreement with previous findings for ethylene oxide and hexamethylene oxide oligomers and polymers. The ratio of the friction coefficients $\text{f}{}_{\mathrm{r}}\text{f}{}_{\mathrm{l}}$ for the ring (r) and linear (l) dimethyl siloxanes was found to be $\text{8}\text{3κ}$ (within the limits of experimental error) over the whole range of molecular weights studied. Values of the expansion factor α_f for the linear poly(dimethyl siloxanes) (obtained from the diffusion measurements) were found to be approximately equal to the corresponding values for α_η (found previously by viscometric studies) for small values of the excluded volume parameter z; and α_f was larger than α_η for large z, as predicted by first-order perturbation theory. Mean-square radii of gyration 〈s²_G〉 were calculated from the diffusion data for both cyclic and linear poly(dimethyl siloxanes) assuming Gaussian statistics, and found to be in good agreement with the corresponding values obtained by neutron scattering. However, the values of 〈s²_G,l〉 for the short chain poly(dimethyl siloxanes) did not agree with the corresponding values of 〈s²_O,l〉, calculated using the rotational isomeric state model of Flory, Crescenzi and Mark. This discrepancy is thought to arise from deviations from Gaussian behaviour, and considerably better agreement between experiment and theory was achieved by using appropriate values of a function ψ_l(x), which relates radii of gyration and impermeable hydrodynamic diffusion radii.     

Role of semiochemicals in mate location by parasitic sea louse,Lepeophtheirus salmonis

The role of olfaction and diffusible pheromones in mate location behavior of sea lice, Lepeophtheirus salmonis, was assessed with Y-tube behavioral bioassays. The pheromone emitting animals were located in a chamber in one arm of a Y-tube arena, with artificial seawater flowing through both arms. Adult male sea lice displayed both activation and directional responses to seawater conditioned with preadult II virgin females, but were only activated by mated adult female conditioned water. Further, when males were given the choice of preadult II virgin females or mated adult females, a significant number of males chose the arm with the preadult II virgin females. Adult males showed activation responses when presented with water conditioned with adult males but were not attracted to them. When presented with adult males, preadult II virgin females showed only directional responses, but not activation responses. Preadult II virgin female conditioned water was extracted using solid-phase extraction (SPE) protocols pioneered for semiochemical isolation. Adult male sea lice showed significant directional responses to the preadult II virgin female SPE extract. Distillation under vacuum was performed on the extract to give a distillate comprising components with a molecular weight range and physical properties comparable to those of compounds utilized as volatile semiochemicals by terrestrial organisms and a residue comprising components with higher molecular weight range comparable to those utilized as involatile semiochemicals. Adult males were found to be both significantly activated and attracted to the distillate, but not to the residue. This research provides evidence that small, lipophilic organic molecules are used by sea lice as sex pheromone signals to locate a member of the opposite sex.