Forward precision medicine: Micelles for active targeting driven by peptides

Precision medicine is based on innovative administration methods of active principles. Drug delivery on tissue of interest allows improving the therapeutic index and reducing the side effects. Active targeting by means of drug-encapsulated micelles decorated with targeting bioactive moieties represents a new frontier. Between the bioactive moieties, peptides, for their versatility, easy synthesis and immunogenicity, can be selected to direct a drug toward a considerable number of molecular targets overexpressed on both cancer vasculature and cancer cells. Moreover, short peptide sequences can facilitate cellular intake. This review focuses on micelles achieved by self-assembling or mixing peptide-grafted surfactants or peptide-decorated amphiphilic copolymers. Nanovectors loaded with hydrophobic or hydrophilic cytotoxic drugs or with gene silence sequences and externally functionalized with natural or synthetic peptides are described based on their formulation and in vitro and in vivo behaviors

Fluorescence and Morphology of Self-Assembled Nucleobases and Their Diphenylalanine Hybrid Aggregates

Studies carried out in recent decades have revealed that the ability to self-assemble is a widespread property among biomolecules. Small nucleic acid moieties or very short peptides are able to generate intricate assemblies endowed with remarkable structural and spectroscopic properties. Herein, the structural/spectroscopic characterization of aggregates formed by nucleobases and peptide nucleic acid (PNA)-peptide conjugates are reported. At high concentration, all studied nucleobases form aggregates characterized by previously unreported fluorescence properties. The conjugation of these bases, as PNA derivatives, to the dipeptide Phe-Phe leads to the formation of novel hybrid assemblies, which are characterized by an amyloid-like association of the monomers. Although these compounds share the same basic cross-\u3b2 motif, the nature and number of PNA units have an important impact on both the level of structural order and the intrinsic fluorescence of the self-assembled nanostructure

Peptide-based hydrogels and nanogels for delivery of doxorubicin

Introduction: The clinical use of the antitumoral drug doxorubicin (Dox) is reduced by its dose-limiting toxicity, related to cardiotoxic side effects and myelosuppression. In order to overcome these drawbacks, here we describe the synthesis, the structural characterization and the in vitro cytotoxicity assays of hydrogels (HGs) and nanogels (NGs) based on short peptide sequences loaded with Dox or with its liposomal formulation, Doxil. Methods: Fmoc-FF alone or in combination with (FY)3 or PEG8-(FY)3 peptides, at two different ratios (1/1 and 2/1 v/v), were used for HGs and NGs formulations. HGs were prepared according to the “solvent-switch” method, whereas NGs were obtained through HG submicroni-tion by the top-down methodology in presence of TWEEN®60 and SPAN®60 as stabilizing agents. HGs gelation kinetics were assessed by Circular Dichroism (CD). Stability and size of NGs were studied using Dynamic Light Scattering (DLS) measurements. Cell viability of empty and filled Dox HGs and NGs was evaluated on MDA-MB-231 breast cancer cells. Moreover, cell internalization of the drug was evaluated using immunofluorescence assays. Results: Dox filled hydrogels exhibit a high drug loading content (DLC=0.440), without syneresis after 10 days. Gelation kinetics (20–40 min) and the drug release (16–28%) over time of HGs were found dependent on relative peptide composition. Dox filled NGs exhibit a DLC of 0.137 and a low drug release (20–40%) after 72 h. Empty HGs and NGs show a high cell viability (>95%), whereas Dox loaded ones significantly reduce cell viability after 24 h (49–57%) and 72 h (7–25%) of incubation, respectively. Immunofluorescence assays evidenced a different cell localization for Dox delivered through HGs and NGs with respect to the free drug. Discussion: A modulation of the Dox release can be obtained by changing the ratios of the peptide components. The different cellular localization of the drug loaded into HGs and NGs suggests an alternative internalization mechanism. The high DLC, the low drug release and preliminary in vitro results suggest a potential employment of peptide-based HGs and NGs as drug delivery tools

Ascaridia galli: a report of erratic migration

This paper describes a case of an unusual recovery of adult Ascaridia galli in hen's egg. Several data are available on this occurrence but it appears to be the first case described in Italy. The worm was identified as an adult female, 6.8 cm in length, with three trilobed lips, cervical narrow alae, oesophagus club-shaped without posterior bulb, vulva near the middle of body, with gravid uteri containing a large number of eggs. The presence of Ascaridia galli in hen's eggs cannot be considered as hazard for public health but may be cause of a potential consumer complaint. Moreover it is a sign of presence of ascaridiosis, parasitosis that still produces economic losses in modern poultry production system

Self-supporting hydrogels based on fmoc-derivatized cationic hexapeptides for potential biomedical applications

Peptide-based hydrogels (PHGs) are biocompatible materials suitable for biological, biomedical, and biotechnological applications, such as drug delivery and diagnostic tools for imaging. Recently, a novel class of synthetic hydrogel-forming amphiphilic cationic peptides (referred to as series K), containing an aliphatic region and a Lys residue, was proposed as a scaffold for bioprinting applications. Here, we report the synthesis of six analogues of the series K, in which the acetyl group at the N-terminus is replaced by aromatic portions, such as the Fmoc protecting group or the Fmoc-FF hydrogelator. The tendency of all peptides to self-assemble and to gel in aqueous solution was investigated using a set of biophysical techniques. The structural characterization pointed out that only the Fmoc-derivatives of series K keep their capability to gel. Among them, Fmoc-K3 hydrogel, which is the more rigid one (G’ = 2526 Pa), acts as potential material for tissue engineering, fully supporting cell adhesion, survival, and duplication. These results describe a gelification process, allowed only by the correct balancing among aggregation forces within the peptide sequences (e.g., van der Waals, hydrogen bonding, and π–π stacking)

The Science of Stem Cell Biobanking: Investing in the Future

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Un processo innovativo per la produzione di un piatto tradizionale della Sardegna: il maialetto (Porcheddu) arrosto

Il suinetto arrosto (Porcheddu) è uno dei piatti tradizionali della Sardegna più apprezzati, questo

Shear-Velocity Structure and Dynamics Beneath the Sicily Channel and Surrounding Regions of the Central Mediterranean Inferred From Seismic Surface Waves

The evolution of the Sicily Channel Rift Zone (SCRZ) is thought to accommodate the regional tectonic stresses of the Calabrian subduction system. Much of the observations we have today are either limited to the surface or to the upper crust or deeper from regional seismic tomography, missing important details about the lithospheric structure and dynamics. It is unclear whether the rifting is passive from far-field extensional stresses or active from mantle upwelling beneath. We measure Rayleigh-and Love-wave phase velocities from ambient seismic noise and invert for 3-D shear-velocity and radial anisotropic models. Variations in crustal S-velocities coincide with topographic and tectonic features. The Tyrrhenian Sea has a ∼10 km thin crust, followed by the SCRZ (∼20 km). The thickest crust is beneath the Apennine-Maghrebian Mountains (∼55 km). Areas experiencing extension and intraplate volcanism have positive crustal radial anisotropy (VSH > VSV); areas experiencing compression and subduction-related volcanism have negative anisotropy. The crustal anisotropy across the Channel shows the extent of the extension. Beneath the Tyrrhenian Sea, we find very low sub-Moho S-velocities. In contrast, the SCRZ has a thin mantle lithosphere underlain by a low-velocity zone. The lithosphere-asthenosphere boundary rises from 60 km depth beneath Tunisia to ∼33 km beneath the SCRZ. Negative radial anisotropy in the upper mantle beneath the SCRZ is consistent with vertical mantle flow. We hypothesize a more active mantle upwelling beneath the rift than previously thought from an interplay between poloidal and toroidal fluxes related to the Calabrian slab, which in turn produces uplift at the surface and induces volcanism

Amplified spontaneous emission and gain in highly concentrated Rhodamine-doped peptide derivative

Bioinspired fluorescence, being widely explored for imaging purposes, faces challenges in delivering bright biocompatible sources. While quite a few techniques have been developed to reach this goal, encapsulation of high-quantum yield fluorescent dyes in natural biological forms suggest achieving superior light-emitting characteristics, approaching amplified spontaneous emission and even lasing. Here we compare gain capabilities of highly concentrated Rhodamine B solutions with a newly synthesized biocompatible peptide derivative hybrid polymer/peptide material, RhoB-PEG1300-F6, which contains the fluorescent covalently bound dye. While concentration quenching effects limit the maximal achievable gain of dissolved Rhodamine B, biocompatible conjugation allows elevating amplification coefficients towards moderately high values. In particular, Rhodamine B, anchored to the peptide derivative material, demonstrates gain of 22–23 cm−1 for a 10−2 M solution, while a pure dye solution possesses 25% smaller values at the same concentration. New biocompatible fluorescent agents pave ways to demonstrate lasing in living organisms and can be further introduced to therapeutic applications, if proper solvents are found

po 324 interferon regulatory factor 1 irf1 regulates inflammatory and metabolic phenotypes in pancreatic ductal adenocarcinoma

Introduction Pancreatic Ductal Adenocarcinoma (PDAC) is the most frequent neoplasia of the exocrine pancreas. This tumour is and is characterised by a pervasive heterogeneity, with the coexistence of a range of histological grades, from epithelial-like to mesenchymal-like features. We previously dissected the transcriptional and epigenetic networks underlying PDAC grading. We identified the association of low grade phenotypes with a cell-autonomous interferon-related signature. Therefore, we set out to investigate the sustainment of inflammatory and interferon-related signatures in well-differentiated pancreatic cancer cells, and to determine the role of this network in PDAC biology. Material and methods We used cell-line based models of cancer differentiation, xenografts and human samples. We used CRISPR-Cas9 mediated genome editing to delete the transcription factor IRF1 (Interferon Regulatory Factor 1) in low-grade PDAC cells. RNA-seq, metabolic assays (oxygraphy, steady state metabolomics, fluxomics) and cell biology assays were carried out in IRF1 wt and knock-out cell lines. Data validation in human PDAC samples was carried out by immunohistochemistry. Results and discussions We found that IRF1 is a transcription factor differentially expressed between low- and high-grade PDACs, both in cell lines and in human tumours. IRF1 deletion in low-grade cell lines reduced the expression of genes in the antigen processing and presentation pathways, while its overexpression promoted the expression of the same genes in high-grade cells, where they are normally not expressed. Furthermore, xenografted IRF1-deficient cell lines recruited fewer immune cells in vivo . IRF1 deletion also affected epithelial phenotypes, including growth rate, cell shape, motility and collagen remodelling ability. Alongside, we unveiled a role of IRF1 in the control of the metabolism of low-grade PDAC cells, consisting in the control of mitochondrial respiration and lipogenesis as well as of the overall lipid profile of these cells. Conclusion To conclude, our results provide hints on the regulatory networks controlling cell differentiation in human PDACs. We show that IRF1 acts as a pleiotropic regulator in the low grade component of PDACs, with wide effects on immunological and metabolic features of this cancer population. Our work reinforces the body of knowledge needed for the development of those therapeutic strategies aiming at exploiting immunological or metabolic pitfalls