A cytotoxic and cytostatic gold(III) corrole

We have synthesized and characterized a water-soluble gold(III) corrole (1-Au) that is highly toxic to cisplatin-resistant cancer cells. Relative to its 1-Ga analogue, axial ligands bind only weakly to 1-Au, which likely accounts for its lower affinity for human serum albumin (HSA). We suggest that the cytotoxicity of 1-Au may be related to this lower HSA affinity

Fighting Cancer with Corroles

Corroles are exceptionally promising platforms for the development of agents for simultaneous cancer-targeting imaging and therapy. Depending on the element chelated by the corrole, these theranostic agents may be tuned primarily for diagnostic or therapeutic function. Versatile synthetic methodologies allow for the preparation of amphipolar derivatives, which form stable noncovalent conjugates with targeting biomolecules. These conjugates can be engineered for imaging and targeting as well as therapeutic function within one theranostic assembly. In this review, we begin with a brief outline of corrole chemistry that has been uniquely useful in designing corrole-based anticancer agents. Then we turn attention to the early literature regarding corrole anticancer activity, which commenced one year after the first scalable synthesis was reported (1999–2000). In 2001, a major advance was made with the introduction of negatively charged corroles, as these molecules, being amphipolar, form stable conjugates with many proteins. More recently, both cellular uptake and intracellular trafficking of metallocorroles have been documented in experimental investigations employing advanced optical spectroscopic as well as magnetic resonance imaging techniques. Key results from work on both cellular and animal models are reviewed, with emphasis on those that have shed new light on the mechanisms associated with anticancer activity. In closing, we predict a very bright future for corrole anticancer research, as it is experiencing exponential growth, taking full advantage of recently developed imaging and therapeutic modalities

Lanthanides: Applications in Cancer Diagnosis and Therapy

Lanthanide complexes are of increasing importance in cancer diagnosis and therapy, owing to the versatile chemical and magnetic properties of the lanthanide-ion 4f electronic configuration. Following the first implementation of gadolinium(III)-based contrast agents in magnetic resonance imaging in the 1980s, lanthanide-based small molecules and nanomaterials have been investigated as cytotoxic agents and inhibitors, in photodynamic therapy, radiation therapy, drug/gene delivery, biosensing, and bioimaging. As the potential utility of lanthanides in these areas continues to increase, this timely review of current applications will be useful to medicinal chemists and other investigators interested in the latest developments and trends in this emerging field

Imputation of missing expenditure information in standard household income surveys

The aim of this paper is to present a new methodology for dealing with missing expenditure information in standard income surveys. Under given conditions, typical imputation procedures, such as statistical matching or regression-based models, can replicate well in the income survey both the unconditional density of household expenditure and its joint density with a set of socio-demographic variables that the two surveys have in common. However, standard imputation procedures may fail in capturing the overall relation between income and expenditure, especially if the common control variables used for the imputation have a weak correlation with the missing information. The paper suggests a two-step imputation procedure that allows reproducing the joint relation between income and expenditure observed from external sources, while maintaining the advantages of traditional imputation methods. The proposed methodology suits well for any empirical analysis that needs to relate income and consumption, such as the estimation of Engel curves or the evaluation of consumption taxes through micro-simulation models. An empirical application shows the makings of such a technique for the evaluation of the distributive effects of consumption taxes and proves that common imputation methods may produce significantly biased results in terms of policy recommendations when the control variables used for the imputation procedure are weakly correlated with the missing variable

Cell-Penetrating Protein/Corrole Nanoparticles

Recent work has highlighted the potential of metallocorroles as versatile platforms for the development of drugs and imaging agents, since the bioavailability, physicochemical properties and therapeutic activity can be dramatically altered by metal ion substitution and/or functional group replacement. Significant advances in cancer treatment and imaging have been reported based on work with a water-soluble bis-sulfonated gallium corrole in both cellular and rodent-based models. We now show that cytotoxicities increase in the order Ga < Fe < Al < Mn < Sb < Au for bis-sulfonated corroles; and, importantly, that they correlate with metallocorrole affinities for very low density lipoprotein (VLDL), the main carrier of lipophilic drugs. As chemotherapeutic potential is predicted to be enhanced by increased lipophilicity, we have developed a novel method for the preparation of cell-penetrating lipophilic metallocorrole/serum-protein nanoparticles (NPs). Cryo-TEM revealed an average core metallocorrole particle size of 32 nm, with protein tendrils extending from the core (conjugate size is ~100 nm). Optical imaging of DU-145 prostate cancer cells treated with corrole NPs (≤100 nM) revealed fast cellular uptake, very slow release, and distribution into the endoplasmic reticulum (ER) and lysosomes. The physical properties of corrole NPs prepared in combination with transferrin and albumin were alike, but the former were internalized to a greater extent by the transferrin-receptor-rich DU-145 cells. Our method of preparation of corrole/protein NPs may be generalizable to many bioactive hydrophobic molecules to enhance their bioavailability and target affinity

SOD2 immunoexpression predicts lymph node metastasis in penile cancer

BACKGROUND: Superoxide dismutase-2 (SOD2) is considered one of the most important antioxidant enzymes that regulate cellular redox state in normal and tumorigenic cells. Overexpression of this enzyme in lung, gastric, colorectal, breast cancer and cervical cancer malignant tumors has been observed. Its relationship with inguinal lymph node metastasis in penile cancer is unknown. METHODS: SOD2 protein expression levels were determined by immunohistochemistry in 125 usual type squamous cell carcinomas of the penis from a Brazilian cancer center. The casuistic has been characterized by means of descriptive statistics. An exploratory logistic regression has been proposed to evaluate the independent predictive factors of lymph node metastasis. RESULTS: SOD2 expression in more than 50% of cells was observed in 44.8% of primary penile carcinomas of the usual type. This expression pattern was associated with lymph node metastasis both in the uni and multivariate analysis. CONCLUSIONS: Our results indicate that SOD2 expression predicts regional lymph node metastasis. The potential clinical implication of this observation warrants further studies.Dr. Lara Termini (FAPESP 2005/57274-9); Dr. Luisa Lina Villa (FAPESP 2008/57889-1 and CNPq 573799/2008-3)

Influence of Bed Roughness on Flow and Turbulence Structure Around a Partially-Buried, Isolated Freshwater Mussel

The present study uses eddy-resolving numerical simulations to investigate how bed roughness affects flow and turbulence structure around an isolated, partially-buried mussel (Unio elongatulus) aligned with the incoming flow. The rough-bed simulations resolve the flow past the exposed part of a gravel bed, whose surface is obtained from a laboratory experiment that also provides some additional data for validation of the numerical model. Results are also discussed for the limiting case of a horizontal smooth bed. Additionally, the effects of varying the level of burial of the mussel inside the substrate and the discharge through the two mussel siphons are investigated via a set of simulations in which the ratio between the median diameter of the (gravel) particles forming the rough bed, d50, and the height of the exposed part of the mussel, h, varies between 0.10 and 0.22. The increase of the bed roughness is associated with a strong amplification of the turbulence kinetic energy in the near-wake region. Increasing the bed roughness and/or reducing h intensifies the interactions of the eddies generated by the bed particles with the base and tip vortices induced by the active filtering and by the mussel shell, respectively, which, in turn, induces a more rapid dissipation of these vortices. Increasing the bed roughness also reduces the strength of the main downwelling flow region forming in the wake. The strong downwelling near the symmetry plane is the main reason why the symmetric wake shedding mode dominates in the smooth bed simulations with negligible active filtering. By contrast, the anti-symmetric wake shedding mode dominates in the simulations conduced with a high value of the bed roughness. The mean streamwise drag force coefficient for the emerged part of the shell and the dilution of the excurrent siphon jet increase with increasing bed roughness

Identification of hydrodynamic changes in rivers by means of freshwater mussels' behavioural response: An experimental investigation

The present work concerns the interaction between hydraulic processes and biological communities in rivers. In particular, the aim of this study is to investigate the interactions between flow dynamics and the freshwater mussels (FMs) to verify if the mussels' behavioural response to the hydrodynamic stress could be used to monitor natural extreme events in rivers. Although the influence of mussels on the kinematic characteristics of flow at the water–sediment interface was investigated by a certain number of studies, their behavioural response to flow, both in static and dynamic conditions, remains understudied. Laboratory experiments were performed in an artificial flume exposing Unio elongatulus to different values of flow discharge, both in steady and in unsteady conditions either with or without sediment transport. Mussels' behavioural responses were detected by using Hall sensor technology to measure gaping frequency, amplitude and duration, both in static conditions and under the effect of hydrodynamic stresses. Five categories of behavioural response were identified: Normal Activity (NA), Resting (Re), Transition (Tr), Adaptation (Ad) and Avoidance (Av). During NA (standard feeding and moving), FMs presented valve gaping, while during Re valves were kept constantly opened for water filtration. After a variation of flow discharge (ΔQ), FMs promptly reacted showing a transition from their normal behaviour, with constant gaping frequency (below 0.01 Hz), to higher valve gaping frequencies. The mean valves' gaping frequency increased as a function of ΔQ, and the highest values were reached in the presence of sediment transport. The mean valve opening amplitude was less sensitive to ΔQ. Its range of variation was very narrow with the highest values corresponding to the protrusion/retraction of the animals' foot to move or anchor to the substrate. The percentage of mussels responding to the discharge variation (Transition behaviour) increases with ΔQ confirming that mussels' behavioural response represents a promising tool for monitoring the occurrence of hydrodynamic stressors in fluvial systems