Synthesis and Analysis of the Conformational Preferences of 5-Aminomethyloxazolidine-2,4-dione Scaffolds: First Examples of \u3b22- and \u3b22, 2-Homo-Freidinger Lactam Analogues

Constrained peptidomimetic scaffolds are of considerable interest for the design of therapeutically useful analogues of bioactive peptides. We present the single-step cyclization of (S)- or (R)-\u3b1-hydroxy-\u3b22- or \u3b1-substituted-\u3b1-hydroxy-\u3b22, 2-amino acids already incorporated within oligopeptides to 5-aminomethyl-oxazolidine-2,4-dione (Amo) rings. These scaffolds can be regarded as unprecedented \u3b22- or \u3b22, 2-homo-Freidinger lactam analogues, and can be equipped with a proteinogenic side chain at each residue. In a biomimetic environment, Amo rings act as inducers of extended, semi-bent or folded geometries, depending on the relative stereochemistry and the presence of \u3b1-substituents

Opioid activity profiles of oversimplified peptides lacking in the protonable N-terminus

Recently, we described cyclopeptide opioid agonists containing the D-Trp-Phe sequence. To expand the scope of this atypical pharmacophore, we tested the activity profiles of the linear peptides Ac-Xaa-Phe-Yaa (Xaa = L/D-Trp, D-His/Lys/Arg; Yaa = H, GlyNH2). Ac-D-Trp-PheNH2 appeared to be the minimal binding sequence, while Ac-D-Trp-Phe-GlyNH 2 emerged as the first noncationizable short peptide (partial) agonist with high \u3bc-opioid receptor affinity and selectivity. Conformational analysis suggested that 5 adopts in solution a \u3b2-turn conformation. \ua9 2012 American Chemical Society

In-peptide synthesis of di-oxazolidinone and dehydroamino acid-oxazolidinone motifs as \u3b2-turn inducers

Small and easy-to-do mimetics of \u3b2-turns are of great interest to interfere with protein-protein recognition events mediated by \u3b2-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd 2-Oxd3 or \u394Abu2-Oxd3 (Oxd, oxazolidin-2-one; \u394Abu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained, and \u3c7 dihedral angles, and induced clear \u3b2-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses. \ua9 The Royal Society of Chemistry 2013

In-Peptide Synthesis of Imidazolidin-2-one Scaffolds, Equippable with Proteinogenic or Taggable/Linkable Side Chains, General Promoters of Unusual Secondary Structures

Peptidomimetics containing (S)- or (R)-imidazolidin-2-one-4- carboxylate (Imi) have been obtained by the expedient in-peptide cyclization of (S)- or (R)-\u3b1,\u3b2-diaminopropionic acid (Dap) residues. These Imi scaffolds behave as proline analogues characterized by a flat structure and a transrestricted geometry of the preceding peptide bond and induce well-defined secondary structures in a biomimetic environment. While (S)-Imi peptides adopted a \u3b3\u2032-turn conformation, (R)-Imi induced the contemporary formation of a \u3b3-turn and a rare 11-membered H-bonded structure in the 2\u21924 opposite direction of the sequence, identified as a \u3b5-turn. In order to exploit these Imi scaffolds as general promoters of unusual secondary structures, proteinaceous side chains have been introduced at the N1 position of the five-membered ring, potentially mimicking any residues. Finally, the Imi rings have been equipped with unnatural side chains or with functionalized substituents, which can be utilized as linkers to chemoselectively bind the Imi-peptides onto nanoparticles, biomaterials, or diagnostic probes

Modern role of magnetic resonance and spectroscopy in the imaging of prostate cancer

Recently, a large number of studies have shown that the addition of proton 1H-spectroscopic imaging (1H-MRSI) and dynamic contrast enhanced imaging (DCEMR) to magnetic resonance (MR) could represent a powerful tool for the management of prostate cancer (CaP) in most of its aspects. This combination of MR techniques can substantially sustain the clinical management of patients with CaP at different levels: in particular, (1) in the initial assessment, reducing the need for more extensive biopsies and directing targeted biopsies; (2) in the definition of a biochemical progression after primary therapies, distinguishing between fibrotic reaction and local recurrence from CaP. (C) 2011 Elsevier Inc. All rights reserved

Analysis of Snow Cover in the Sibillini Mountains in Central Italy

Research on solid precipitation and snow cover, especially in mountainous areas, suffers from problems related to the lack of on-site observations and the low reliability of measurements, which is often due to instruments that are not suitable for the environmental conditions. In this context, the study area is the Monti Sibillini National Park, and it is no exception, as it is a mountainous area located in central Italy, where the measurements are scarce and fragmented. The purpose of this research is to provide a characterization of the snow cover with regard to maximum annual snow depth, average snow depth during the snowy period, and days with snow cover on the ground in the Monti Sibillini National Park area, by means of ground weather stations, and also analyzing any trends over the last 30 years. For this research, in order to obtain reliable snow cover data, only data from weather stations equipped with a sonar system and manual weather stations, where the surveyor goes to the site each morning and checks the thickness of the snowpack and records, it were collected. The data were collected from 1 November to 30 April each year for 30 years, from 1991 to 2020; six weather stations were taken into account, while four more were added as of 1 January 2010. The longer period was used to assess possible ongoing trends, which proved to be very heterogeneous in the results, predominantly negative in the case of days with snow cover on the ground, while trends were predominantly positive for maximum annual snow depth and distributed between positive and negative for the average annual snow depth. The shorter period, 2010–2022, on the other hand, ensured the presence of a larger number of weather stations and was used to assess the correlation and presence of clusters between the various weather stations and, consequently, in the study area. Furthermore, in this way, an up-to-date nivometric classification of the study area was obtained (in terms of days with snow on the ground, maximum height of snowpack, and average height of snowpack), filling a gap where there had been no nivometric study in the aforementioned area. The interpolations were processed using geostatistical techniques such as co-kriging with altitude as an independent variable, allowing fairly precise spatialization, analyzing the results of cross-validation. This analysis could be a useful tool for hydrological modeling of the area, as well as having a clear use related to tourism and vegetation, which is extremely influenced by the nivometric variables in its phenology. In addition, this analysis could also be considered a starting point for the calibration of more recent satellite products dedicated to snow cover detection, in order to further improve the compiled climate characterizatio

Value of magnetic resonance spectroscopy imaging and dynamic contrast-enhanced imaging for detecting prostate cancer foci in men with prior negative biopsy

Purpose: This study aimed to prospectively analyze the role of magnetic resonance spectroscopy imaging (MRSI) and dynamic-contrast enhancement magnetic resonance (DCEMR) in the detection of prostate tumor foci in patients with persistently elevated prostate-specific antigen levels (in the range of >= 4 ng/mL to <10 ng/mL) and prior negative random trans-rectal ultrasound (TRUS)-guided biopsy. Experimental Design: This was a prospective randomized single-center study. One hundred and eighty eligible cases were included in the study. Patients in group A were submitted to a second random prostate biopsy, whereas patients in group B were submitted to a (1)H-MRSI-DCEMR examination and samples targeted on suspicious areas were associated to the random biopsy. Results: At the second biopsy, a prostate adenocarcinoma histologic diagnosis was found in 22 of 90 cases (24.4%) in group A and in 41 of 90 cases (45.5%) in group B (P = 0.01). On a patient-by-patient basis, MRSI had 92.3% sensitivity, 88.2% specificity, 85.7% positive predictive value (PPV), 93.7% negative predictive value (NPV), and 90% accuracy; DCEMR had 84.6% sensitivity, 82.3% specificity, 78.5% PPV, 87.5% NPV, and 83.3% accuracy; and the association MRSI plus DCEMR had 92.6% sensitivity, 88.8% specificity, 88.7% PPV, 92.7% NPV, and 90.7% accuracy, for predicting prostate cancer detection. Conclusions: The combination of MRSI and DCEMR showed the potential to guide biopsy to cancer foci in patients with previously negative TRUS biopsy. To avoid a potential bias, represented from having taken more samples in group B (mean of cores, 12.17) than in group A (10 cores), in the future a MRSI/DCEMR directed biopsy could be prospectively compared with a saturation biopsy procedure. Clin Cancer Res; 16(6); 1875-83. (C) 2010 AACR

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

Kappa opioid receptor (KOPr) agonists represent alternative analgesics for their low abuse potential, although relevant adverse effects have limited their clinical use. Functionally selective KOPr agonists may activate, in a pathway-specific manner, G protein-mediated signaling, that produces antinociception, over \u3b2-arrestin 2-dependent induction of p38MAPK, which preferentially contributes to adverse effects. Thus, functionally selective KOPr agonists biased toward G protein-coupled intracellular signaling over \u3b2-arrestin-2-mediated pathways may be considered candidate therapeutics possibly devoid of many of the typical adverse effects elicited by classic KOPr agonists. Nonetheless, the potential utility of functionally selective agonists at opioid receptors is still highly debated; therefore, further studies are necessary to fully understand whether it will be possible to develop more effective and safer analgesics by exploiting functional selectivity at KOPr. In the present study we investigated in vitro functional selectivity and in vivo antinociceptive effects of LOR17, a novel KOPr selective peptidic agonist that we synthesized. LOR17-mediated effects on adenylyl cyclase inhibition, ERK1/2, p38MAPK phosphorylation, and astrocyte cell proliferation were studied in HEK-293 cells expressing hKOPr, U87-MG glioblastoma cells, and primary human astrocytes; biased agonism was investigated via cAMP ELISA and \u3b2-arrestin 2 recruitment assays. Antinociception and antihypersensitivity were assessed in mice via warm-water tail-withdrawal test, intraperitoneal acid-induced writhing, and a model of oxaliplatin-induced neuropathic cold hypersensitivity. Effects of LOR17 on locomotor activity, exploratory activity, and forced-swim behavior were also assayed. We found that LOR17 is a selective, G protein biased KOPr agonist that inhibits adenylyl cyclase and activates early-phase ERK1/2 phosphorylation. Conversely to classic KOPr agonists as U50,488, LOR17 neither induces p38MAPK phosphorylation nor increases KOPr-dependent, p38MAPK-mediated cell proliferation in astrocytes. Moreover, LOR17 counteracts, in a concentration-dependent manner, U50,488-induced p38MAPK phosphorylation and astrocyte cell proliferation. Both U50,488 and LOR17 display potent antinociception in models of acute nociception, whereas LOR17 counteracts oxaliplatin-induced thermal hypersensitivity better than U50,488, and it is effective after single or repeated s.c. administration. LOR17 administered at a dose that fully alleviated oxaliplatin-induced thermal hypersensitivity did not alter motor coordination, locomotor and exploratory activities nor induced pro-depressant-like behavior. LOR17, therefore, may emerge as a novel KOPr agonist displaying functional selectivity toward G protein signaling and eliciting antinociceptive/antihypersensitivity effects in different animal models, including oxaliplatin-induced neuropathy

Prospective comparative trial on nerve-sparing radical prostatectomy using a robot-assisted versus laparoscopic technique: expectation versus satisfaction and impact on surgical margins

Introduction: The aim of this study was to analyze whether differences exist in a population selected for a nerve-sparing (NS) procedure between robot-assisted (RARP) and laparoscopic radical prostatectomy (LRP), and whether they can have an impact on surgical margins (SM) status. Material and methods: This is a single center prospective comparative trial on prostate cancer patients submitted to a RARP-NS or LRP-NS. A self-administered questionnaire on expectations before surgery, and level of satisfaction after surgery was used. Results: A total of 134 cases were included in our analysis. A higher percentage of capsular bulging was found in the RARP group, compared to the LRP group (p = 0.077). At biopsy, the percentage of positive cores and multifocality were higher in the RARP group (p = 0.005). Positive SM (SM+) rate was higher in the RARP, than in LRP group (p = 0.046). On univariable analysis, the risk of SM+ increased 1.95 times using RARP when compared with LRP. On multivariable analysis, the surgical approach did not maintain a significant predictive role in terms of risk for SM+. Expectations before surgery were mainly focused on oncological radicality, however in the RARP group a higher percentage of cases focused on sexual function recovery. Satisfaction after surgery was lower in the RARP than in the LRP group. Conclusions: Comparing LRP-NS with RARP-NS in a high-volume single center, the expectation/satisfaction ratio is in favor of LRP. Worse oncologic preoperative characteristics in the RARP group may influence the higher incidence of SM+. However, the surgical approach does not result as a significant and independent factor able to influence SM positivity

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects