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Introduction Angioleiomyoma is a rare neoplasm that represents ∼ 0.2 % of all head and neck benign tumors and ∼ 2% of total cases of tumors of the sinonasal tract. It was once considered a possible subtype of leiomyoma, but, in the 2020 World Health Organization (WHO) classification of soft tissue tumors, it is accepted as a singular entity. Objective To systematically review the existing literature on angioleiomyoma in the light of the new classification of soft tissue tumors. Data Synthesis The present study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A comprehensive search in the PubMed, Cochrane, Scopus, and Google Scholar databases was performed in January 2022. The search items included the following keywords: nasal angioleiomyoma OR sinonasal angioleiomyoma OR nasal vascular leiomyoma OR sinonasal vascular leiomyoma. A total of 87 patients were evaluated. He age of the patients in the studies ranged from 15 to 88 years (mean age at diagnosis: 55.6 years). The most common site of involvement was the nasal septum (28.4 %), followed by the inferior turbinate (22.5%). The most common symptom was nasal obstruction (66.7%), followed by epistaxis (47.1%). Surgical excision represented the main treatment, and there was recurrence of pathology in only 1 case (0.9%). Conclusion To our knowledge, only 87 cases of sinonasal-tract angioleiomyoma have been previously described. The results of the present review seem to confirm the rarity and the benign nature of this neoplasm, and they seem to confirm the necessity to improve the available data about sinonasal-tract angioleiomyoma. [ABSTRACT FROM AUTHOR]

Abstract: The Polycomb Repressive complex 2 (PRC2) maintains a repressive chromatin state and silences many genes, acting as methylase on histone tails. This enzyme was found overexpressed in many types of cancer. In this work, we have set up a Computer‐Aided Drug Design approach based on the allosteric modulation of PRC2. In order to minimize the possible bias derived from using a single set of coordinates within the protein‐ligand complex, a dynamic workflow was developed. In details, molecular dynamic was used as tool to identify the most significant ligand‐protein interactions from several crystallized protein structures. The identified features were used for the creation of dynamic pharmacophore models and docking grid constraints for the design of new PRC2 allosteric modulators. Our protocol was retrospectively validated using a dataset of active and inactive compounds, and the results were compared to the classic approaches, through ROC curves and enrichment factor. Our approach suggested some important interaction features to be adopted for virtual screening performance improvement. [ABSTRACT FROM AUTHOR]

3,5-Dicarbamoyl-1,4-dihydropyridines were prepared in high yields using a green protocol by reduction of the corresponding pyridinium salts in aqueous buffered sodium dithionite solutions. The pH value is a fundamental parameter for the reduction step and depends on the nature of substituent groups at positions 1, 3, and 5 of the pyridinium salts. These 3,5-dicarbamoyl dihydropyridines show a lower tendency towards oxidation and a higher stability than N-benzyl-3-carbamoyl-1,4-dihydropyridine at low pH values. [ABSTRACT FROM AUTHOR]

Background: In Huntington's disease, expansion of a CAG triplet repeat occurs in exon 1 of the huntingtin gene (HTT), resulting in a protein bearing>35 polyglutamine residues whose N-terminal fragments display a high propensity to misfold and aggregate. Recent data demonstrate that polyglutamine expansion results in conformational changes in the huntingtin protein (HTT), which likely influence its biological and biophysical properties. Developing assays to characterize and measure these conformational changes in isolated proteins and biological samples would advance the testing of novel therapeutic approaches aimed at correcting mutant HTT misfolding. Time-resolved Förster energy transfer (TR-FRET)-based assays represent high-throughput, homogeneous, sensitive immunoassays widely employed for the quantification of proteins of interest. TR-FRET is extremely sensitive to small distances and can therefore provide conformational information based on detection of exposure and relative position of epitopes present on the target protein as recognized by selective antibodies. We have previously reported TR-FRET assays to quantify HTT proteins based on the use of antibodies specific for different amino-terminal HTT epitopes. Here, we investigate the possibility of interrogating HTT protein conformation using these assays. Methodology/Principal Findings: By performing TR-FRET measurements on the same samples (purified recombinant proteins or lysates from cells expressing HTT fragments or full length protein) at different temperatures, we have discovered a temperature-dependent, reversible, polyglutamine-dependent conformational change of wild type and expanded mutant HTT proteins. Circular dichroism spectroscopy confirms the temperature and polyglutamine-dependent change in HTT structure, revealing an effect of polyglutamine length and of temperature on the alpha-helical content of the protein. Conclusions/Significance: The temperature- and polyglutamine-dependent effects observed with TR-FRET on HTT proteins represent a simple, scalable, quantitative and sensitive assay to identify genetic and pharmacological modulators of mutant HTT conformation, and potentially to assess the relevance of conformational changes during onset and progression of Huntington's disease. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the effectiveness of P6 acupressure on vertigo and neurovegetative symptoms, its possible interference with vestibular-ocular reflex (VOR), and its clinical usefulness during acute vertigo. Materials and methods: Two hundred and four patients, either affected by acute vertigo ( n=124) or undergoing labyrinth stimulation ( n=80), were randomly divided in two homogeneous groups: an experimental group A and a placebo group B. Each patient rated severity of vertigo and neurovegetative symptoms on a visuo-analogue scale ranging from 0 to 10, before and after bilateral placement of a P6 device. The latter was placed on the P6 acupressure point (appropriate placement) in Group A patients or on the dorsal part of the carpus (inappropriate placement) in the Group B patients. Furthermore, qualitative and quantitative nystagmus parameters were collected via recorded video-oculoscopy and electronystagmography. Results: Eighty-five percent of Group A patients reported improvement of symptoms, which was significant for neurovegetative symptoms, but not for vertigo. In contrast, only 11% of the Group B patients reported improvement. VOR analysis did not show any significant variation of qualitative and quantitative nystagmus variables. Conclusions: This study demonstrated that the P6 device is effective in improving neurovegetative symptoms in patients affected by spontaneous and provoked vertigo, without any interference with VOR. Given the low cost and lack of side-effects of the P6 device, its routine application is suggested for acute vertigo and during labyrinth stimulation. [ABSTRACT FROM AUTHOR]

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 µM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases. [ABSTRACT FROM AUTHOR]

NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) activation has been linked to several chronic pathologies, including atherosclerosis, type-II diabetes, fibrosis, rheumatoid arthritis, and Alzheimer's disease. Therefore, NLRP3 represents an appealing target for the development of innovative therapeutic approaches. A few companies are currently working on the discovery of selective modulators of NLRP3 inflammasome. Unfortunately, limited structural data are available for this target. To date, MCC950 represents one of the most promising noncovalent NLRP3 inhibitors. Recently, a possible region for the binding of MCC950 to the NLRP3 protein was described but no details were disclosed regarding the key interactions. In this communication, we present an in silico multiple approach as an insight useful for the design of novel NLRP3 inhibitors. In detail, combining different computational techniques, we propose consensus-retrieved protein residues that seem to be essential for the binding process and for the stabilization of the protein–ligand complex. [ABSTRACT FROM AUTHOR]

Introduction  Angioleiomyoma is a rare neoplasm that represents ∼ 0.2 % of all head and neck benign tumors and ∼ 2% of total cases of tumors of the sinonasal tract. It was once considered a possible subtype of leiomyoma, but, in the 2020 World Health Organization (WHO) classification of soft tissue tumors, it is accepted as a singular entity. Objective  To systematically review the existing literature on angioleiomyoma in the light of the new classification of soft tissue tumors. Data Synthesis  The present study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A comprehensive search in the PubMed, Cochrane, Scopus, and Google Scholar databases was performed in January 2022. The search items included the following keywords: nasal angioleiomyoma OR sinonasal angioleiomyoma OR nasal vascular leiomyoma OR sinonasal vascular leiomyoma . A total of 87 patients were evaluated. He age of the patients in the studies ranged from 15 to 88 years (mean age at diagnosis: 55.6 years). The most common site of involvement was the nasal septum (28.4 %), followed by the inferior turbinate (22.5%). The most common symptom was nasal obstruction (66.7%), followed by epistaxis (47.1%). Surgical excision represented the main treatment, and there was recurrence of pathology in only 1 case (0.9%). Conclusion  To our knowledge, only 87 cases of sinonasal-tract angioleiomyoma have been previously described. The results of the present review seem to confirm the rarity and the benign nature of this neoplasm, and they seem to confirm the necessity to improve the available data about sinonasal-tract angioleiomyoma., Competing Interests: Conflict of Interests The authors have no conflict of interests to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit ( https://creativecommons.org/licenses/by/4.0/ ).)

Aberrant epigenetic modifications are involved in cancer development. Jumonji C domain-containing histone lysine demethylases (KDMs) are found mainly up-regulated in breast, prostate, and colon cancer. Currently, growing interest is focusing on the identification and development of new inhibitors able to block the activity of KDMs and thus reduce tumor progression. KDM4A is known to play a role in several cellular physiological processes, and was recently found overexpressed in a number of pathological states, including cancer. In this work, starting from the structure of purpurogallin 9aa , previously identified as a natural KDM4A inhibitor, we synthesized two main sets of compound derivatives in order to improve their inhibitory activity against KDM4A in vitro and in cells, as well as their antitumor action. Based on the hypothetical biogenesis of the 5-oxo-5 H -benzo[7]annulene skeleton of the natural product purpurogallin (Salfeld, 1960; Horner et al., 1961; Dürckheimer and Paulus, 1985; Tanaka et al., 2002; Yanase et al., 2005) the pyrogallol and catechol units were first combined with structural modifications at different positions of the aryl ring using enzyme-mediated oxidative conditions, generating a series of benzotropolone analogs. Two of the synthetic analogs of purpurogallin, 9ac and 9bc , showed an efficient inhibition (50 and 80%) of KDM4A in enzymatic assays and in cells by increasing levels of its specific targets, H3K9me3/2 and H3K36me3. However, these two compounds/derivatives did not induce cell death. We then synthesized a further set of analogs of these two compounds with greater structural diversification. The most potent of these analogs, 9bf , displayed the highest KDM4A inhibitory enzymatic activity in vitro (IC 50 of 10.1 and 24.37 μM) in colon cancer cells, and the strongest antitumor action in several solid and hematological human cancer cell lines with no toxic effect in normal cells. Our findings suggest that further development of this compound and its derivatives may lead to the identification of new therapeutic antitumor agents acting through inhibition of KDM4A., (Copyright © 2020 Souto, Sarno, Nebbioso, Papulino, Álvarez, Lombino, Perricone, Padova, Altucci and de Lera.)

A new series of imidazo[2,1- b ][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l , showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC 50 ) ranging from 5.11 to 10.8 µM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1- b ][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases., Competing Interests: The authors declare no conflict of interest.

In recent years pharmacophore modeling has become increasingly popular due to the development of software solutions and improvement in algorithms that allowed researchers to focus on interactions between protein and ligands instead of technical details of the software. At the same time, progress in computer hardware made molecular dynamics (MD) simulations on regular PC hardware possible. MD simulations are usually used, within the virtual screening process, to take into account the flexibility of the target and studying it in more realistic way. In order to do so, it is customary to use simulations before the virtual screening process and then use them for collecting some specific conformation of the target used. Furthermore, some researchers have demonstrated that the use of multiple crystal structures of the same protein can be valuable to better explore the role of the ligand within the binding pocket and then evaluate the most important interactions that are created during the host-guest recognition process. Findings derived from the MD analysis, especially focused on interactions, can be in fact exploited as features for pharmacophore generation or constraints to be used in the molecular docking as integrated steps of the whole virtual screening process. In this chapter, we will present the recent advances in the field pharmacophore modeling combined with the use of MD, a field well explored by our research group in the last 2 years.

Purpose: There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial., Patients and Methods: A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy., Results: The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin., Conclusion: The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma., (© 2015 by American Society of Clinical Oncology.)

The design and optimization of small molecule inhibitors of the murine double minute clone 2-p53 (p53-MDM2) interaction has attracted a great deal of interest as a way to novel anticancer therapies. Herein we report 3D-QSAR studies of 41 small molecule inhibitors based on the use of molecular interaction fields and docking experiments as part of an approach to generating predictive models of MDM2 affinity and shedding further light on the structural elements of the ligand-target interaction. These studies have yielded predictive models explaining much of the variance of the 41 compound training set and satisfactorily predicting with 75% success an external test set of 36 compounds. Not surprisingly, and in full agreement with previous data, inspection of the 3D-QSAR coefficients reveals that the major driving force for potent inhibition is given by the hydrophobic interaction between the inhibitors and the p53 binding cleft of MDM2. More surprisingly, and challenging previous suggestions, the projection of the 3D-QSAR coefficients back onto the experimental structures of MDM2 provides an intriguing hypothesis concerning an active role played by the N-terminal region of MDM2 in ligand binding.

S100B contributes to cell proliferation by binding the C terminus of p53 and inhibiting its tumor suppressor function. The use of multiple computational approaches to screen fragment libraries targeting the human S100B-p53 interaction site is reported. This in silico screening led to the identification of 280 novel prospective ligands. NMR spectroscopic experiments revealed specific binding at the p53 interaction site for a set of these compounds and confirmed their potential for further rational optimization. The X-ray crystal structure determined for one of the binders revealed key intermolecular interactions, thus paving the way for structure-based ligand optimization.

Poor aqueous solubility is one of the major issues in drug discovery and development, impacting negatively on all aspects of the research and development process. The pharmaceutical industry has realized that solubility issues need to be resolved at the discovery stage. We here present an innovative way to address this problem via a model designed to address the simple question, "Is the compound likely to be sufficiently soluble to provide interpretable data in biological screening assays?" A recursive partitioning (RP) method was applied to a set of 3563 molecules, with in house determined aqueous solubility values. Five models were generated on the basis of a small number of descriptors affording intuitive information regarding structural features influencing solubility. The final model was based on only two descriptors: the molecular weight (MW) and the aromatic proportion (AP). This model provided satisfactory values of accuracy (81%) and precision (75%) for a test set of 1200 compounds, suggesting that the model may add value in compound selection and library design during early drug discovery.

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.

We report here the case of an epithelioid haemangioendothelioma (EHE) arising in the nasal cavity which is, to the best of our knowledge, the first ever described example in the world literature in that particular site. The patient is a 23-year-old male who presented with repeated episodes of epistaxis from the nasal cavity and with a 1.5 cm reddish, polypoid, smooth, spontaneously bleeding nodule in the right middle meatus. This lesion was histologically diagnosed as epithelioid haemangioendothelioma. Immunohistochemically the neoplasm displayed striking positivity for CD31, CD34 and vimentin. A surgical approach was performed by 'facial degloving', removing the right inferior turbinate, the anterior two-thirds of the middle turbinate and the medial wall of the ethmoid bone. After 12 months follow-up the patient is disease-free, without any local or distant recurrence.