Angioleiomyoma of the Sinonasal Tract: A Systematic Review of an Uncommon Clinicopathological Entity.

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.

Angioleiomyoma of the Sinonasal Tract: A Systematic Review of an Uncommon Clinicopathological Entity

Abstract 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.

Dynamic-shared Pharmacophore Approach as Tool to Design New Allosteric PRC2 Inhibitors, Targeting EED Binding Pocket.

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.

Targeting SARS-CoV-2 RBD Interface: a Supervised Computational Data-Driven Approach to Identify Potential Modulators.

Coronavirus disease 2019 (COVID-19) has spread out as a pandemic threat affecting over 2 million people. The infectious process initiates via binding of SARS-CoV-2 Spike (S) glycoprotein to host angiotensin-converting enzyme 2 (ACE2). The interaction is mediated by the receptor-binding domain (RBD) of S glycoprotein, promoting host receptor recognition and binding to ACE2 peptidase domain (PD), thus representing a promising target for therapeutic intervention. Herein, we present a computational study aimed at identifying small molecules potentially able to target RBD. Although targeting PPI remains a challenge in drug discovery, our investigation highlights that interaction between SARS-CoV-2 RBD and ACE2 PD might be prone to small molecule modulation, due to the hydrophilic nature of the bi-molecular recognition process and the presence of druggable hot spots. The fundamental objective is to identify, and provide to the international scientific community, hit molecules potentially suitable to enter the drug discovery process, preclinical validation and development.

A New Family of Jumonji C Domain-Containing KDM Inhibitors Inspired by Natural Product Purpurogallin.

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-5H-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 (IC50 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.

3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1H-Indole Derivatives as New Anticancer Agents in the Treatment of Pancreatic Ductal Adenocarcinoma.

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.

In Silico Insights towards the Identification of NLRP3 Druggable Hot Spots.

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.

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge.

Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calculating some kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognised as vital to the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced allows researchers to optimise small molecules and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.

The Use of Dynamic Pharmacophore in Computer-Aided Hit Discovery: A Case Study.

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.

A Molecular Dynamics-Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Receptor†α.

Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein's active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes. The study was carried out on peroxisome proliferator-activated receptor α (PPARα). Findings derived from the dynamic analysis of interactions were then used as features for pharmacophore generation and constraints for generating the docking grid for use in virtual screening. We found that information derived from short multiple MD simulations using different molecules within the binding pocket of the target can improve the early enrichment of active ligands in the virtual screening process for this receptor. In the end we adopted a consensus scoring based on docking score and pharmacophore alignment to rank our dataset. Our results showed an improvement in virtual screening performance in early recognition when screening was performed with the Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approach.

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours.

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.

Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein-Protein Interaction by a Scaffold-Hopping Approach.

Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.

Polyglutamine- and temperature-dependent conformational rigidity in mutant huntingtin revealed by immunoassays and circular dichroism spectroscopy.

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.

P6 acupressure effectiveness on acute vertiginous patients: a double blind randomized study.

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.

In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors.

Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl-N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents.

Molecular interaction fields and 3D-QSAR studies of p53-MDM2 inhibitors suggest additional features of ligand-target interaction.

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.

Fragmenting the S100B-p53 interaction: combined virtual/biophysical screening approaches to identify ligands.

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.

Voice disorders and posturography: variables to define the success of rehabilitative treatment.

Previous studies have investigated the relationship between muscular tension, body posture, and voice quality. The aim of this paper is to study the postural pattern during voice production in healthy subjects compared with patients affected by voice disorders and in the same patients before and after vocal treatment by means of static posturography. Classic posturographic variables and spectral frequency analysis of body sway have been measured. Posturographic values in patients before vocal treatment and controls were within normal ranges but not homogeneous. Body sway significantly decreased during voice production in patients after voice training. Spectral frequency analysis of body sway showed a significantly decreased body sway at middle frequencies on the anteroposterior (y) plane during voice production after voice training. Our results would suggest that in patients affected by voice disorders rehabilitative treatment may cause an improvement of the body proprioceptive scheme and this improvement might be useful to evaluate the proper (ongoing) treatment.