Showing papers by "University of Perugia published in 2022"

Putative Anticancer Compounds from Plant-Derived Endophytic Fungi: A Review

Abstract: Endophytic fungi are microorganisms that exist almost ubiquitously inside the various tissues of living plants where they act as an important reservoir of diverse bioactive compounds. Recently, endophytic fungi have drawn tremendous attention from researchers; their isolation, culture, purification, and characterization have revealed the presence of around 200 important and diverse compounds including anticancer agents, antibiotics, antifungals, antivirals, immunosuppressants, and antimycotics. Many of these anticancer compounds, such as paclitaxel, camptothecin, vinblastine, vincristine, podophyllotoxin, and their derivatives, are currently being used clinically for the treatment of various cancers (e.g., ovarian, breast, prostate, lung cancers, and leukemias). By increasing the yield of specific compounds with genetic engineering and other biotechnologies, endophytic fungi could be a promising, prolific source of anticancer drugs. In the future, compounds derived from endophytic fungi could increase treatment availability and cost effectiveness. This comprehensive review includes the putative anticancer compounds from plant-derived endophytic fungi discovered from 1990 to 2020 with their source endophytic fungi and host plants as well as their antitumor activity against various cell lines.

Combined effects of singular and exponential nonlinearities in fractional Kirchhoff problems

Abstract: In this paper we establish the existence of at least two (weak) solutions for the following fractional Kirchhoff problem involving singular and exponential nonlinearities \begin{document}$ \begin{cases} M\left(\|u\|^{{n}/{s}}\right)(-\Delta)^s_{n/s}u = \mu u^{-q}+ u^{r-1}\exp( u^{\beta})\quad\text{in } \Omega,\\ u>0\qquad\text{in } \Omega,\\ u = 0\qquad\text{in } \mathbb R^n \setminus{ \Omega}, \end{cases} $\end{document} where \begin{document}$ \Omega $\end{document} is a smooth bounded domain of \begin{document}$ \mathbb R^n $\end{document} , \begin{document}$ n\geq 1 $\end{document} , \begin{document}$ s\in (0,1) $\end{document} , \begin{document}$ \mu>0 $\end{document} is a real parameter, \begin{document}$ \beta and \begin{document}$ q\in (0,1) $\end{document} .The paper covers the so called degenerate Kirchhoff case andthe existence proofs rely on the Nehari manifold techniques.

Diagnostic performance of the Bladder EpiCheck methylation test and photodynamic diagnosis-guided cystoscopy in the surveillance of high-risk non-muscle invasive bladder cancer: A single centre, prospective, blinded clinical trial

Abstract: Currently, bladder cancer (BC) surveillance consists of periodic white light cystoscopy and urinary cytology (UC). However, both diagnostic tools have limitations. Therefore, to improve the management of recurrent BC, novel, innovative diagnostic tests are needed. The primary aim of this study was to determine the diagnostic performance of Bladder EpiCheck (BE) and photodynamic diagnosis (PDD) guided cystoscopy in the surveillance of high-risk BC. A secondary aim was to compare Bladder EpiCheck (BE) and PDD-guided cystoscopy findings with whose of UC to design a diagnostic algorithm that facilitates clinical decision making. PATIENTS AND METHODS: This was a prospective, blinded, single-arm, single-visit cohort study. All patients were under surveillance for high-risk non-muscle-invasive bladder cancer, and underwent cystoscopy with PDD and a BE test. Those who received a histological diagnosis were used as a reference population. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic performance of BE, PDD-guided cystoscopy, and UC for identifying biopsy-confirmed BC lesions. The diagnostic power of the test was assessed by determining the area under the curve (AUC).Forty patients were enrolled. For BE, the AUC was 0.95, and BC recurrence was detected at a sensitivity of 100% and specificity of 90.9%. For PDD, the AUC was 0.51, with a sensitivity and specificity of 61% and 41%, respectively. BE was combined with UC to create a decision-making algorithm capable of reducing the number of follow-up cystoscopies needed.BE is a very accurate diagnostic tool that has the potential to be useful in the surveillance of high-risk BC patients. Especially when combined with UC, it may be used to reduce the number of cystoscopies needed throughout follow-up. Conversely, the use of PDD as a diagnostic tool in such patients should be reconsidered. However, due to the small sample size of this study, a larger prospective clinical trial should be performed to confirm findings.

Combined effects of singular and exponential nonlinearities in fractional Kirchhoff problems

Abstract: <p style='text-indent:20px;'>In this paper we establish the existence of at least two (weak) solutions for the following fractional Kirchhoff problem involving singular and exponential nonlinearities</p><p style='text-indent:20px;'><disp-formula> <label/> <tex-math id="FE1"> \begin{document}$ \begin{cases} M\left(\|u\|^{{n}/{s}}\right)(-\Delta)^s_{n/s}u = \mu u^{-q}+ u^{r-1}\exp( u^{\beta})\quad\text{in } \Omega,\\ u&gt;0\qquad\text{in } \Omega,\\ u = 0\qquad\text{in } \mathbb R^n \setminus{ \Omega}, \end{cases} $\end{document} </tex-math></disp-formula></p><p style='text-indent:20px;'>where <inline-formula><tex-math id="M1">\begin{document}$ \Omega $\end{document}</tex-math></inline-formula> is a smooth bounded domain of <inline-formula><tex-math id="M2">\begin{document}$ \mathbb R^n $\end{document}</tex-math></inline-formula>, <inline-formula><tex-math id="M3">\begin{document}$ n\geq 1 $\end{document}</tex-math></inline-formula>, <inline-formula><tex-math id="M4">\begin{document}$ s\in (0,1) $\end{document}</tex-math></inline-formula>, <inline-formula><tex-math id="M5">\begin{document}$ \mu&gt;0 $\end{document}</tex-math></inline-formula> is a real parameter, <inline-formula><tex-math id="M6">\begin{document}$ \beta &lt;{n/(n-s)} $\end{document}</tex-math></inline-formula> and <inline-formula><tex-math id="M7">\begin{document}$ q\in (0,1) $\end{document}</tex-math></inline-formula>.The paper covers the so called degenerate Kirchhoff case andthe existence proofs rely on the Nehari manifold techniques.</p>

Osteoarthritis: New Insight on Its Pathophysiology

Abstract: Understanding of the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, as well as the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA physiopathology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms as underlying causes of pain chronicity has been characterized. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. To this aim, this review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insights on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.

Stochastic Approach for the Analysis of Demand Induced Transients in Real Water Distribution Systems

Abstract: A stochastic approach for modeling and analysing the transients due to the users’ water consumptions in a real water distribution system is presented. The analysis is based on field measure...

Circulating tumour DNA sequencing to determine therapeutic response and identify tumour heterogeneity in patients with paediatric solid tumours

Abstract: Clinical diagnostic sequencing of circulating tumour DNA (ctDNA) is well advanced for adult patients, but application to paediatric cancer patients lags behind.To address this, we have developed a clinically relevant (67 gene) NGS capture panel and accompanying workflow that enables sensitive and reliable detection of low-frequency genetic variants in cell-free DNA (cfDNA) from children with solid tumours. We combined gene panel sequencing with low pass whole-genome sequencing of the same library to inform on genome-wide copy number changes in the blood.Analytical validity was evaluated using control materials, and the method was found to be highly sensitive (0.96 for SNVs and 0.97 for INDEL), specific (0.82 for SNVs and 0.978 for INDEL), repeatable (>0.93 [95% CI: 0.89-0.95]) and reproducible (>0.87 [95% CI: 0.87-0.95]). Potential for clinical application was demonstrated in 39 childhood cancer patients with a spectrum of solid tumours in which the single nucleotide variants expected from tumour sequencing were detected in cfDNA in 94.4% (17/18) of cases with active extracranial disease. In 13 patients, where serial samples were available, we show a close correlation between events detected in cfDNA and treatment response, demonstrate that cfDNA analysis could be a useful tool to monitor disease progression, and show cfDNA sequencing has the potential to identify targetable variants that were not detected in tumour samples.This is the first pan-cancer DNA sequencing panel that we know to be optimised for cfDNA in children for blood-based molecular diagnostics in paediatric solid tumours.

Effectiveness in Real World of Once Weekly Semaglutide in People with Type 2 Diabetes: Glucagon-Like Peptide Receptor Agonist Naïve or Switchers from Other Glucagon-Like Peptide Receptor Agonists: Results from a Retrospective Observational Study in Umbria

Abstract: To complement results of the SUSTAIN program, this study assessed effectiveness and safety of once weekly subcutaneous semaglutide in people with type 2 diabetes (T2D) managed under routine care.This was a multicenter, observational, retrospective study including all patients treated with semaglutide. Changes in clinical outcomes from baseline to 6 and 12 months were assessed in patients who were glucagon-like peptide receptor agonist (GLP-1RA) naïve or switching from another GLP-1RA. Discontinuation rate was assessed.Overall, 216 patients (mean age 64 years, 65.7% men) were evaluated: 135 (61.5%) naïve and 81 (38.5%) switchers from another GLP-1RA. In the naïve cohort, after 6 months from semaglutide initiation, levels of HbA1c significantly decreased by - 1.31% (p < 0.0001). All obesity indices improved, with mean reductions in body weight of - 3.92 kg, in BMI of - 1.43 kg/m2, and in waist circumference of - 5.03 cm. In the switcher cohort, statistically significant improvements in HbA1c (- 0.78%), body weight (- 2.64 kg), and waist circumference (- 3.03 cm) were obtained after 6 months. Reductions were sustained after 12 months in both cohorts (mean semaglutide dose: 0.86 mg in naïve and 0.96 mg in switcher cohort). Blood pressure and lipid profile mean levels decreased after 12 months from semaglutide initiation in both cohorts. No severe hypoglycemia occurred; 6.5% of patients discontinued semaglutide (2.8% due to gastrointestinal side effects).Effectiveness and tolerability of semaglutide have been confirmed in the real world irrespective of diabetes duration and severity. As expected, more marked reductions in HbA1c and obesity indices were obtained in naïve patients, but it is noteworthy that relevant improvements were also obtained in patients already treated with GLP-1RAs.

The 70‐year search for the voltage‐sensing mechanism of ion channels

Abstract: This retrospective on the voltage-sensing mechanisms and gating models of ion channels begins in 1952 with the charged gating particles postulated by Hodgkin and Huxley, viewed as charges moving across the membrane and controlling its permeability to Na+ and K+ ions. Hodgkin and Huxley postulated that their movement should generate small and fast capacitive currents, which were recorded 20 years later as gating currents. In the early 1980s, several voltage-dependent channels were cloned and found to share a common architecture: four homologous domains or subunits, each displaying six transmembrane α-helical segments, with the fourth segment (S4) displaying four to seven positive charges invariably separated by two non-charged residues. This immediately suggested that this segment was serving as the voltage sensor of the channel (the molecular counterpart of the charged gating particle postulated by Hodgkin and Huxley) and led to the development of the sliding helix model. Twenty years later, the X-ray crystallographic structures of many voltage-dependent channels allowed investigation of their gating by molecular dynamics. Further understanding of how channels gate will benefit greatly from the acquisition of high-resolution structures of each of their relevant functional or structural states. This will allow the application of molecular dynamics and other approaches. It will also be key to investigate the energetics of channel gating, permitting an understanding of the physical and molecular determinants of gating. The use of multiscale hierarchical approaches might finally prove to be a rewarding strategy to overcome the limits of the various single approaches to the study of channel gating.

Development of a multi-method analytical approach based on the combination of synchrotron radiation X-ray micro-analytical techniques and vibrational micro-spectroscopy methods to unveil the causes and mechanism of darkening of “fake-gilded” decorations in a Cimabue painting

Abstract: Redox processes activated by environmental factors have been identified as the main cause of the chromatic alterations of a number of artists’ pigments, including the yellow pigment orpiment (As2S3). Although a general comprehension of the mechanisms has been provided through characterization of degradation compounds of As2S3, experimental evidences to prove how other paint components and how different environmental agents influence the formation pathways of specific secondary compounds are still lacking. Thus, it becomes fundamental to develop a methodological strategy which enable achieving a discrimination among the causes affecting the chemical stability of more heterogenous As2S3-based paints and defining the mechanism through which the alteration establishes and evolves, with the ultimate goal of optimizing the preventive conservation measures of unique masterpieces. In this paper, we propose a comprehensive multi-material and multi-method approach based on the combination of synchrotron radiation X-ray micro-analytical techniques (i.e., X-ray diffraction, X-ray fluorescence and X-ray absorption near edge structure spectroscopy at S K-/Ag L3-/As K-edges) and vibrational micro-spectroscopy methods to unveil the causes and mechanism of darkening of “fake-gilded” decorations in tempera paintings, originally consisting of an unusual mixture of As2S3 and metallic silver (Ag0). Such degradation process is a not yet understood phenomenon threatening a series of Old Master paintings, including those by the Italian painters Cimabue and Pietro Lorenzetti. The high specificity, sensitivity and lateral resolution of the employed analytical methods allowed providing first-time evidence for the presence of black acanthite (α-Ag2S), mimetite [Pb5(AsO4)3Cl] and syngenite [K2Ca(SO4)2∙H2O] as degradation products of the “fake-gilded” decorations in the Maesta by Cimabue (Church of Santa Maria dei Servi, Bologna, Italy). Furthermore, the study of the painting combined with that of tempera paint mock-ups permitted to explore and define the environmental agents and internal factors causing the darkening, by proving that: (i)Ag0 and moisture are key-factors for triggering the transformation of As2S3 to α-Ag2S and As-oxides; (ii)S2--ions arising from the degradation of As2S3 are the main responsible for the formation of α-Ag2S; (iii)light exposure strengthens the tendency of the paint components towards alteration. Based on our findings, we finally propose a degradation mechanism of As2S3/Ag0-based tempera paints.

Amniotic fluid stem cell‐derived extracellular vesicles are independent metabolic units capable of modulating inflammasome activation in THP‐1 cells

Abstract: An immunoregulatory role of stem cells, often mediated by their secretome, has been claimed by several studies. Stem cell-derived extracellular vesicles (EVs) are crucial components of the secretome. EVs, a heterogeneous group of membranous vesicles released by many cell types into the extracellular space, are now considered as an additional mechanism for intercellular communication. In this study, we aimed at investigating whether human amniotic stem cell-derived extracellular vesicles (HASC-EVs) were able to interfere with inflammasome activation in the THP-1 cell line. Two subsets of HASC-EVs were collected by sequential centrifugation, namely HASC-P10 and HASC-P100. We demonstrated that HASC-EVs were neither internalized into nor undertake a direct interaction with THP-1 cells. We showed that HASC-P10 and P100 were able to intrinsically produce ATP, which was further converted to adenosine by 5'-nucleotidase (CD73) and ectonucleoside triphosphate diphosphohydrolase-1 (CD39). We found that THP-1 cells conditioned with both types of HASC-EVs failed to activate the NLRP3/caspase-1/inflammasome platform in response to LPS and ATP treatment by a mechanism involving A2a adenosine receptor activation. These results support a role for HASC-EVs as independent metabolic units capable of modifying the cellular functions, leading to anti-inflammatory effects in monocytic cells.