Combining Gene Expression Profiles and Drug Activity Patterns Analysis: A Relational Clustering Approach

The combined analysis of tissue micro array and drug response datasets has the potential of revealing valuable knowledge about various relations among gene expressions and drug activity patterns in tumor cells. However, the amount and the complexity of biological data needs appropriate data mining models in order to extract interesting patterns and useful information. The ultimate goal of this paper is to define a model which, given the gene expression profile related to a specific tumor tissue, could help in selecting a set of most responsive drugs. This is accomplished through an integrated framework based on a constraint-based clustering algorithm, called Relational K-Means, which groups cell lines using drug response information and taking into account cell-to-cell relationships derived from their gene expression profiles.     

Phase transitions for random walk asymptotics on free products of groups

Suppose we are given finitely generated groups Γ₁,…,Γ_m equipped with irreducible random walks. Thereby we assume that the expansions of the corresponding Green functions at their radii of convergence contain only logarithmic or algebraic terms as singular terms up to sufficiently large order (except for some degenerate cases). We consider transient random walks on the free product Γ₁* … *Γ_m and give a complete classification of the possible asymptotic behaviour of the corresponding n‐step return probabilities. They either inherit a law of the form ?^nδn log n from one of the free factors Γ_i or obey a ?^nδn^?3/2‐law, where ? < 1 is the corresponding spectral radius and δ is the period of the random walk. In addition, we determine the full range of the asymptotic behaviour in the case of nearest neighbour random walks on free products of the form $\mathbb{Z}^{d_1}\ast \ldots \ast \mathbb{Z}^{d_m}Suppose we are given finitely generated groups Γ₁,…,Γ_m equipped with irreducible random walks. Thereby we assume that the expansions of the corresponding Green functions at their radii of convergence contain only logarithmic or algebraic terms as singular terms up to sufficiently large order (except for some degenerate cases). We consider transient random walks on the free product Γ₁* … *Γ_m and give a complete classification of the possible asymptotic behaviour of the corresponding n‐step return probabilities. They either inherit a law of the form ?^nδn log n from one of the free factors Γ_i or obey a ?^nδn^?3/2‐law, where ? < 1 is the corresponding spectral radius and δ is the period of the random walk. In addition, we determine the full range of the asymptotic behaviour in the case of nearest neighbour random walks on free products of the form $\mathbb{Z}^{d_1}\ast \ldots \ast \mathbb{Z}^{d_m}$. Moreover, we characterize the possible phase transitions of the non‐exponential types n log n in the case Γ₁ * Γ₂. © 2011 Wiley Periodicals, Inc. Random Struct. Alg., 2012     

Metastability and exponential approach to equilibrium for low-temperature stochastic Ising models

We present a proof of the exponential convergence to equilibrium of single-spin-flip stochastic dynamics for the two-dimensional Ising ferromagnet in the low-temperature case with not too small external magnetic fieldh uniformly in the volume and in the boundary conditions.     

A higher-order parametric nonlinear reduced-order model for imperfect structures using Neumann expansion

Nonlinear Dynamics - We present an enhanced version of the parametric nonlinear reduced-order model for shape imperfections in structural dynamics we studied in a previous work. In this model, the...     

Patient-specific finite element analysis of popliteal stenting

Nitinol self-expanding stents are used for the endovascular management of peripheral artery diseases of the popliteal artery, which is located behind the knee joint. Unfortunately, the complex kinematics of the artery during the leg flexion leads to severe loading conditions, favouring the mechanical failure of the stent, calling for a specific biomechanical analysis. For this reason, in the present study we reconstruct by medical image analysis the patient-specific popliteal kinematics during leg flexion, which is subsequently exploited to compute the mechanical response of a stent model, virtually implanted in the artery by structural finite element analysis (FEA). The medical image analysis indicates a non-uniform configuration change of the artery during the leg flexion, leading to an increase of the vessel curvature above the knee. The computed mechanical response of the stent reflects the non-uniform configuration change of the artery as after the flexion the average stress is higher in the part of the stent located above the knee. Although the proposed analysis is limited to a case-study, it shows the capability of patient-specific FEA simulations to compute the mechanical response of a stent model subjected to the complex and severe loading conditions of the popliteal artery during leg flexion.     

Achillea moschata Wulfen: From Ethnobotany to Phytochemistry,Morphology, and Biological Activity

A multidisciplinary investigation on Achillea moschata Wulfen (Asteraceae) is outlined herein. This work, part of the European Interreg Italy–Switzerland B-ICE project, originated from an ethnobotanical survey performed in Chiesa in Valmalenco (Sondrio, Lombardy, Northern Italy) in 2019–2021 which highlighted this species’ relevance of use in folk medicine to treat gastrointestinal diseases. In addition, this contribution included analyses of the: (a) phytochemical profile of the aqueous and methanolic extracts of the dried flower heads using LC-MS/MS; (b) morpho-anatomy and histochemistry of the vegetative and reproductive organs through Light, Fluorescence, and Scanning Electron Microscopy; (c) biological activity of the aqueous extract concerning the antioxidant and anti-inflammatory potential through cell-based in vitro models. A total of 31 compounds (5 phenolic acids, 13 flavonols, and 13 flavones) were detected, 28 of which included in both extracts. Covering and secreting trichomes were observed: the biseriate 10-celled glandular trichomes prevailing on the inflorescences represented the main sites of synthesis of the polyphenols and flavonoids detected in the extracts, along with volatile terpenoids. Finally, significant antioxidant and anti-inflammatory activities of the aqueous extract were documented, even at very low concentrations; for the first time, the in vitro tests allowed us to formulate hypotheses about the mechanism of action. This work brings an element of novelty due to the faithful reproduction of the traditional aqueous preparation and the combination of phytochemical and micromorphological research approaches.     

Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFV600E Protein

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF^V600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF^V600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC₅₀ values in the 40–88 nM range. Selected compounds inhibited BRAF^V600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.