SINTESI DI DERIVATI NON STEROIDEI POTENZIALMENTE UTILI NEL TRATTAMENTO DI TUMORI ESTROGENO-DIPENDENTI

In this thesis, I have synthetized novel compound potentially implicated in the genesis and the development of estrogen-dependent diseases. Most of my work has concerned the synthesis of novel salicylaldoximes in an attempt to obtain estrogen receptor (ER) ligands with improved ER-beta selective affinity and agonist properties. The salicylaldoxime template constitutes a novel class of nonsteroidal ER-ligands that is based on a hydrogen-bonded pseudocyclic ring as a bioisosteric replacement of the phenol ring (functional group present in most estrogen receptor ligands). Among several modifications of previously developed salicylaldoximes, the best results were obtained by the simultaneous exchange of the relative positions of the phenol OH and oxime groups together with the insertion of a chloro group in the 6-position of the central scaffold. The resulting compound showed the best affinity (Ki = 0.38 nM) for ER-beta Another part of my thesis was dedicated to the synthesis of a new compound as a nonsteroidal inhibitor of 17beta-Hydroxysteroid Dehydrogenase Type 1 (17beta-HSD1). This enzyme catalyzes the reduction of estrone (E1) to the highly potent ER-agonist estradiol (E2) and, therefore, it is an important target for the treatment of hormone-dependent diseases, because its inhibition leads to a reduction of the endogenous production of E2.. I have developed a thioamido-derivative able to inhibit the enzyme to a certain extent (20% of inhibition at 1 microM concentration), although other non-steroidal analogues, this level of inhibition turned out to unfavourably compare to previously reported 17beta-HSD1 inhibitors

A study of autotrophic communities in two Victoria Land lakes (Continental Antarctica) using photosynthetic pigments

The composition of algal pigments and extracellular polymeric substances (EPS) was determined in microbial mats from two lakes in Victoria Land (Continental Antarctica) with different lithology and environmental features. The aim was to expand knowledge of benthic autotrophic communities in Antarctic lacustrine ecosystems, providing reference data for future assessment of possible changes in environmental conditions and freshwater communities. The results of chemical analyses were supported by microscopy observations. Pigment profiles showed that filamentous cyanobacteria are dominant in both lakes. Samples from the water body at Edmonson Point had greater biodiversity, fewer pigments and lower EPS ratios than those from the lake at Kar Plateau. Differences in mat composition and in pigment and EPS profile between the two lakes are discussed in terms of local environmental conditions such as lithology, ice-cover and UV radiation. The present study suggests that a chemical approach could be useful in the study of benthic communities in Antarctic lakes and their variations in space and time

Detection of IncP replicon-specific regions in DNA from Antarctic microbiota

Abstract Plasmids capable of horizontal transfer contribute to the adaptability of bacteria, as they may provide genes that enable their hosts to cope with different selective pressures. Only limited information is available on plasmids from Antarctic habitats, and up until now surveys have only used traditional methods of endogenous plasmid isolation. The method based on primer systems, designed on the basis of published sequences for plasmids from different incompatibility (Inc) groups, is appropriate to detect the replicon-specific regions of corresponding plasmids in cultured bacteria, or in total community DNA, which share sufficient DNA similarity with reference plasmids at the amplified regions. In this study, we applied broad-host-range plasmid-specific primers to DNA from microbial samples collected at six different locations in Northern Victoria Land (Antarctica). DNA preparations were used as targets for PCR (polymerase chain reaction) amplification with primers for the IncP (trfA2) and IncQ (oriV ) groups. PCR products were Southern blotted and hybridized with PCR-derived probes for trfA2 and oriV regions. This approach detected the occurrence of IncP-specific sequences in eight out of fifteen DNA samples, suggesting a gene-mobilizing capacity within the original habitats

Causal Rule Ensemble: Interpretable Inference of Heterogeneous Treatment Effects

In environmental epidemiology, it is critically important to identify subpopulations that are most vulnerable to the adverse effects of air pollution so we can develop targeted interventions. In recent years, there have been many methodological developments for addressing heterogeneity of treatment effects in causal inference. A common approach is to estimate the conditional average treatment effect (CATE) for a pre-specified covariate set. However, this approach does not provide an easy-to-interpret tool for identifying susceptible subpopulations or discover new subpopulations that are not defined a priori by the researchers. In this paper, we propose a new causal rule ensemble (CRE) method with two features simultaneously: 1) ensuring interpretability by revealing heterogeneous treatment effect structures in terms of decision rules and 2) providing CATE estimates with high statistical precision similar to causal machine learning algorithms. We provide theoretical results that guarantee consistency of the estimated causal effects for the newly discovered causal rules. Furthermore, via simulations, we show that the CRE method has competitive performance on its ability to discover subpopulations and then accurately estimate the causal effects. We also develop a new sensitivity analysis method that examine robustness to unmeasured confounding bias. Lastly, we apply the CRE method to the study of the effects of long-term exposure to air pollution on the 5-year mortality rate of the New England Medicare-enrolled population in United States. Code is available at https://github.com/kwonsang/causal_rule_ensemble

Leaf trapping and retention of particles by holm oak and other common tree species in Mediterranean urban environments

Holm oak (Quercus ilex), a widespread urban street tree in the Mediterranean region, is widely used as biomonitor of persistent atmospheric pollutants, especially particulate-bound metals. By using lab- and field-based experimental approaches, we compared the leaf-level capacity for particles’ capture and retention between Q. ilex and other common Mediterranean urban trees: Quercus cerris, Platanus × hispanica, Tilia cordata and Olea europaea. All applied methods were effective in quantifying particulate capture and retention, although not univocal in ranking species performances. Distinctive morphological features of leaves led to differences in species’ ability to trap and retain particles of different size classes and to accumulate metals after exposure to traffic in an urban street. Overall, P. × hispanica and T. cordata showed the largest capture potential per unit leaf area for most model particles (Na+ and powder particles), and street-level Cu and Pb, while Q. ilex acted intermediately. After wash-off experiments, P. × hispanica leaves had the greatest retention capacity among the tested species and O. europaea the lowest. We concluded that the Platanus planting could be considered in Mediterranean urban environments due to its efficiency in accumulating and retaining airborne particulates; however, with atmospheric pollution being typically higher in winter, the evergreen Q. ilex represents a better year-round choice to mitigate the impact of airborne particulate pollutants

Commentary : missing targets on drugs-related deaths, and a Scottish paradox

The 10-year drug strategy for England and Wales was published in February 2008. It dropped drugs-related deaths (DRDs) as a key performance indicator. Scotland retained a necessary strong focus on DRDs. Scotland's DRDs numbered 1006 in 2000–02 and 1009 in 2003–05. The previous Scottish administration's claim that its number of current injectors had decreased substantially between 2000 and 2003 implied, paradoxically, that their DRD rate would have to have increased. Worse was to come: Scotland's DRDs had increased to 876 in 2006 + 2007. We analyse UK's DRDs by sex and age-group to reveal temporal trends (2000–02 versus 2003–05 versus 2006 + 2007) with different public health and epidemiological implications. We also address the above Scottish paradox and assess, by age-group, how consistent Scotland's 876 DRDs in 2006 + 2007 are with Scottish injectors’ DRD rate in 2003–05 of around 1 per 100 injector-years. Public health success in the UK in reducing DRDs at younger ages should not be overshadowed by the late consequence in terms of older-age DRDs of UK's injector epidemics; in the early 1980s in Scotland, and late 1980s in England and Wales. Targets for reducing DRDs should pay heed to UK's injector epidemics

Heterogeneous Treatment and Spillover Effects under Clustered Network Interference

The bulk of causal inference studies rules out the presence of interference between units. However, in many real-world settings units are interconnected by social, physical or virtual ties and the effect of a treatment can spill from one unit to other connected individuals in the network. In these settings, interference should be taken into account to avoid biased estimates of the treatment effect, but it can also be leveraged to save resources and provide the intervention to a lower percentage of the population where the treatment is more effective and where the effect can spill over to other susceptible individuals. In fact, different people might respond differently not only to the treatment received but also to the treatment received by their network contacts. Understanding the heterogeneity of treatment and spillover effects can help policy-makers in the scale-up phase of the intervention, it can guide the design of targeting strategies with the ultimate goal of making the interventions more cost-effective, and it might even allow generalizing the level of treatment spillover effects in other populations. In this paper, we develop a machine learning method that makes use of tree-based algorithms and an Horvitz-Thompson estimator to assess the heterogeneity of treatment and spillover effects with respect to individual, neighborhood and network characteristics in the context of clustered network interference. We illustrate how the proposed binary tree methodology performs in a Monte Carlo simulation study. Additionally, we provide an application on a randomized experiment aimed at assessing the heterogeneous effects of information sessions on the uptake of a new weather insurance policy in rural China

Macro- and Microplastics in the Antarctic Environment: Ongoing Assessment and Perspectives

The number of scientists and tourists visiting Antarctica is on the rise and, despite the management framework for environmental protection, some coastal areas, particularly in the Antarctic Peninsula region, are affected by plastic contamination. The few data available on the occurrence of microplastics (<5 mm) are difficult to compare, due to the different methodologies used in monitoring studies. However, indications are emerging to guide future research and to implement environmental protocols. In the surface and subsurface waters of the Southern Ocean, plastic debris >300 p.m appears to be scarce and far less abundant than paint chips released from research vessels. Yet, near some coastal scientific stations, the fragmentation and degradation of larger plastic items, as well as microbeads and microfibers released into wastewater from personal care products and laundry, could potentially affect marine organisms. Some studies indicate that, through long-range atmospheric transport, plastic fibers produced on other continents can be deposited in Antarctica. Drifting plastic debris can also cross the Polar Front, with the potential to carry alien fouling organisms into the Southern Ocean. Sea ice dynamics appear to favor the uptake of microplastics by ice algae and Antarctic krill, the key species in the Antarctic marine food web. Euphausia superba apparently has the ability to fragment and expel ingested plastic particles at the nanoscale. However, most Antarctic organisms are endemic species, with unique ecophysiological adaptations to extreme environmental conditions and are likely highly sensitive to cumulative stresses caused by climate change, microplastics and other anthropogenic disturbances. Although there is limited evidence to date that micro- and nanoplastics have direct biological effects, our review aims at raising awareness of the problem and, in order to assess the real potential impact of microplastics in Antarctica, underlines the urgency to fill the methodological gaps for their detection in all environmental matrices, and to equip scientific stations and ships with adequate wastewater treatment plants to reduce the release of microfibers