Association between Immune Checkpoint Inhibitors and Atherosclerotic Cardiovascular Disease Risk: Another Brick in the Wall.

In recent years, immune checkpoint inhibitors have significantly changed the field of oncology, emerging as first-line treatment, either alone or in combination with other regimens, for numerous malignancies, improving overall survival and progression-free survival in these patients. However, immune checkpoint inhibitors might also cause severe or fatal immune-related adverse events, including adverse cardiovascular events. Initially, myocarditis was recognized as the main immune checkpoint inhibitor-related cardiac event, but our knowledge of other potential immune-related cardiovascular adverse events continues to broaden. Recently, preclinical and clinical data seem to support an association between immune checkpoint inhibitors and accelerated atherosclerosis as well as atherosclerotic cardiovascular events such as cardiac ischemic disease, stroke, and peripheral artery disease. In this review, by offering a comprehensive overview of the pivotal role of inflammation in atherosclerosis, we focus on the potential molecular pathways underlying the effects of immune checkpoint inhibitors on cardiovascular diseases. Moreover, we provide an overview of therapeutic strategies for cancer patients undergoing immunotherapy to prevent the development of cardiovascular diseases.

Detection of oligonucleotides by PNA-peptide conjugates recognizing the biarsenical fluorescein complex FlAsH-EDT2.

We report the application of the arsenical complex FlAsH-EDT2 for the identification of oligonucleotide sequences. We designed PNA sequences conjugated to either a tetracysteine motif and to split tetracysteine sequences, that are recognized by FlAsH. The effect of conjugation of the PNA to the tetracysteine peptide and RNA hybridization on the fluorescence of the arsenical complex has been investigated. The reconstitution of the tetracysteine motif, starting from 15-mer PNAs conjugated to split tetracysteine sequences and hybridized to a complementary oligonucleotide was also explored.

Nano-precipitated curcumin loaded particles: effect of carrier size and drug complexation with (2-hydroxypropyl)-ß-cyclodextrin on their biological performances.

In this work, curcumin (CURC)-encapsulating nanoparticles (NPs), made up of an amphiphilic blend of poloxamers and PLGA (PPC NPs) at different polymer concentrations, were prepared by nanoprecipitation. CURC was preliminarily complexed with (2-hydroxypropyl)-ß-cyclodextrin (HPßCD) to improve its loading efficiency. The formation of host-guest complexes of CURC with HPßCD (CD-CURC) was confirmed by means of 1HNMR studies and differential scanning calorimetry (DSC). Nanoprecipitation allowed to obtain NPs with a small size (90-120nm depending on the polymer concentration), a narrow size distribution and stable in water for 30days at 4°C and in RPMI-1640 cell culture medium up to 72h at 37°C. The in vitro release of CD-CURC, sustained up to 5days, was governed mainly by a diffusive mechanism. It was also found that the produced NPs were efficiently internalized by mesothelioma cells (MSTO-211H) in the cytoplasmic space, at an extent strongly dependent on NP size and polydispesity index, therefore pointing at the importance of NP preparation method in improving their uptake.

Structure-Activity Study of the Peptides P5U and Urantide by the Development of Analogues Containing Uncoded Amino Acids at Position†9.

Previous modifications of the peptide sequence of human urotensin-II (U-II) led to the identification of two well-known ligands: P5U and urantide. These derivatives are considered to be the most representative agonist and antagonist, respectively, at the human urotensin receptor (UT). Optimization of P5U and urantide was carried out to stabilize specific conformations that may suggest new elements for discriminating agonist versus antagonist activity. We studied novel derivatives containing uncoded amino acids. In particular, the Tyr(9) residue of both P5U and urantide was replaced with nonaromatic hydrophobic bulky residues, as well as conformationally constrained aromatic moieties to generate eight novel derivatives. These analogues further contributed to determining the influence of such residues on binding affinity for and biological activity at UT. One of these eight peptides was also investigated by NMR spectroscopy and docking studies owing to its peculiar conformational properties and mode of interaction with UT. This structure-activity study is aimed at a more thorough examination of the role of tyrosine in modulating the agonism/antagonism of human U-II.

Chemical modifications in the seed region of miRNAs 221/222 increase the silencing performances in gastrointestinal stromal tumor cells.

Most GastroIntestinal Stromal Tumors (GISTs) are characterized by KIT gene overexpression, which in turn is regulated by levels of microRNA 221 and microRNA 222. GISTs can also be distinguished by their miRNAs expression profile in which miRNAs 221/222 result reduced in comparison with GI normal tissues. In this paper, to restore normal miRNAs levels and to improve the silencing performances of miRNAs 221/222, new miRNA mimics in which guide strands are modified by Phosphorothioate (PS) and/or 2'-O-methyl RNA (2'-OMe) inside and outside the seed region, were synthesized and tested in GIST48 cells. We evaluated the positional effect of the chemical modifications on the miRNAs silencing activity, compared to natural and several commercial miRNA mimics. Our results show that chemically modified miRNAs 221/222 with alternating 2'-OMe-PS and natural nucleotides in the seed region are effective inhibitors of KIT gene expression and exhibit increased stability in rat plasma. Besides, their transfection in GIST 48 cells showed significant effects on different cellular processes in which KIT plays a functional role for tumor development (such as migration, cell proliferation, and apoptosis). Therefore, modified miRNAs 221/222 may provide an alternative therapeutic option for GIST treatment also aimed to overcome drug resistance concerns.

Phase transfer catalyzed enantioselective cyclopropanation of 4-nitro-5-styrylisoxazoles.

Heavily substituted cyclopropane esters were prepared in high yields, complete diastereoselection and high (up to 96%) enantioselectivity. The reaction described herein entailed reacting 4-nitro-5-styrylisoxazoles, a class of cinnamate synthetic equivalent, with 2-bromomalonate esters under the catalysis of 5 mol% of a Cincona derived phase-transfer catalyst. The reaction allowed multi-gram preparation of desired products.