Computational polypharmacology comes of age

No abstrac

La Vegetazione arbustiva di un settore costiero dell'adriatico centrale italiano

The shrubby vegetation in a coastal sector of italian central adriatic sea. The results of the phytosociological analysis concerning the shrubby vegetation of a sector of the italian adriatic coast, of around 20 Kms, situated in the Rrgional natural park of Conero, are presented. It deals with mountainous coasts of two main lithomorphological typologies: marly-arenaceous and calcareous formations. On the first formation, in correspondence to marly rocks, the new Lonicero etruscae-Cornetum sanguineae association, belonging to the edapho-hygrophilous meso and submediterranean pre-apennine series of the elm (Symphyto bulbosi-Ulmeto minoris sigmetum), develops. On the contrary, on sand stones, constituted by superimposed levels and intercalated to marlstones, develops a xerophilous vegetation which stops at the maquis stadium, referred to the new Coronillo emeroidis-Rhamnetum alaterni association in the new loniceretosum etrusca e sub-association. On the calcareous cliffs of the warmest slopes, a maquis vegetation develops, referred to the same association but in the most thermophilous subassociation viburnetosum tini, colonising partially consolidated screes, which represents an element of the mesomediterranean italian-tyrrhenian and amphiadriatic calcicolous series of the holm-oak (Fraxino orni -Querceto ilicis sigmetum). Finally, on the steep slopes of the compact limestones of the warmest sectors of the South-East side of M. Conero (Valley ofthe Vellare), the new ampelodesmetosum mauritanici sub-association ofthe Coronillo emeroidis-Euphorbietum dendroidis association is described. It differentiates from the latter for the presence of more temperate elements and for the loss of some thermomediterranean species

Parametric design, fabrication and validation of one-way polymeric valves for artificial sphincters

Abstract The design of artificial sphincters requires an accurate dimensioning of dedicated valves, normally made of polymeric materials. This effort is also interesting for developing fluid and pressure regulating solutions related to other biomedical and non-biomedical fields. In this article we focused on the parametric design of polymeric valves, by taking inspiration from commercially exploited solutions used in the food industry and performing appropriate scaling in order to make them suitable for artificial organs and components. In addition, different materials with diverse mechanical properties were considered, focusing on a low-cost fabrication approach. Finite element model analyses were conducted to simulate the behavior of different valve profiles and to predict the valve opening pressure. Simulation results were validated by comparing them with experimental results, obtained by fabricating and testing different valve types. This polymeric valve parametric analysis may be exploited for the design of artificial sphincters, having the potential to tackle urinary incontinence, a disease that affects about 350 million people worldwide

On the integration of in silico drug design methods for drug repurposing

Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A number of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug-target, target-disease, and ultimately drug-disease associations

On the development of B-Raf inhibitors acting through innovative mechanisms

B-Raf is a protein kinase participating to the regulation of many biological processes in cells. Several studies have demonstrated that this protein is frequently upregulated in human cancers, especially when it bears activating mutations. In the last years, few ATP-competitive inhibitors of B-Raf have been marketed for the treatment of melanoma and are currently under clinical evaluation on a variety of other types of cancer. Although the introduction of drugs targeting B-Raf has provided significant advances in cancer treatment, responses to ATP-competitive inhibitors remain limited, mainly due to selectivity issues, side effects, narrow therapeutic windows, and the insurgence of drug resistance. Impressive research efforts have been made so far towards the identification of novel ATP-competitive modulators with improved efficacy against cancers driven by mutant Raf monomers and dimers, some of them showing good promises. However, several limitations could still be envisioned for these compounds, according to literature data. Besides, increased attentions have arisen around approaches based on the design of allosteric modulators, polypharmacology, proteolysis targeting chimeras (PROTACs) and drug repurposing for the targeting of B-Raf proteins. The design of compounds acting through such innovative mechanisms is rather challenging. However, valuable therapeutic opportunities can be envisioned on these drugs, as they act through innovative mechanisms in which limitations typically observed for approved ATP-competitive B-Raf inhibitors are less prone to emerge. In this article, current approaches adopted for the design of non-ATP competitive inhibitors targeting B-Raf are described, discussing also on the possibilities, ligands acting through such innovative mechanisms could provide for the obtainment of more effective therapies

Planning for steerable needles in neurosurgery

The increasing adoption of robotic-assisted surgery has opened up the possibility to control innovative dexterous tools to improve patient outcomes in a minimally invasive way. Steerable needles belong to this category, and their potential has been recognised in various surgical fields, including neurosurgery. However, planning for steerable catheters' insertions might appear counterintuitive even for expert clinicians. Strategies and tools to aid the surgeon in selecting a feasible trajectory to follow and methods to assist them intra-operatively during the insertion process are currently of great interest as they could accelerate steerable needles' translation from research to practical use. However, existing computer-assisted planning (CAP) algorithms are often limited in their ability to meet both operational and kinematic constraints in the context of precise neurosurgery, due to its demanding surgical conditions and highly complex environment. The research contributions in this thesis relate to understanding the existing gap in planning curved insertions for steerable needles and implementing intelligent CAP techniques to use in the context of neurosurgery. Among this thesis contributions showcase (i) the development of a pre-operative CAP for precise neurosurgery applications able to generate optimised paths at a safe distance from brain sensitive structures while meeting steerable needles kinematic constraints; (ii) the development of an intra-operative CAP able to adjust the current insertion path with high stability while compensating for online tissue deformation; (iii) the integration of both methods into a commercial user front-end interface (NeuroInspire, Renishaw plc.) tested during a series of user-controlled needle steering animal trials, demonstrating successful targeting performances. (iv) investigating the use of steerable needles in the context of laser interstitial thermal therapy (LiTT) for maesial temporal lobe epilepsy patients and proposing the first LiTT CAP for steerable needles within this context. The thesis concludes with a discussion of these contributions and suggestions for future work.Open Acces