Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization

Background Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition. Methods Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel2) and TERRA (TERRA2). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~ 257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations. Results Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2/TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed. Conclusions Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s. General significance The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio

Impact of agrochemicals on non-target species: Calathus fuscipes Goeze 1777 (Coleoptera: Carabidae) as model

Carabid beetles are important in the biological control of arable crop pests. Agricultural practices can produce over time a delayed toxic effect at the organismal and population levels and can compromise the survival on these species. In this research, we quantified the cumulative sublethal effect on body size, Malpighian tubules and immune responses in Calathus fuscipes adults living in the potato field and exposed to lambda-cyhalothrin and cymoxanil-based commercial formulates. Reductions of morphological parameters such as body, pronotum and elytron in both males and females from the potato field indicated that the pre-imaginal stages (larvae and pupae) suffer the sublethal effects of exposure to the larvicide control action of lambda-cyhalothrin. Ultrastructural alterations recorded in Malpighian tubules at the level of plasma membrane, mitochondria and nucleus indicated the reduction of the detoxification capability. The basal phenoloxidase and lysozyme-like enzyme activities have measured as markers of immune competence. Spectrophometric analyses showed that the chronic exposure in field causes an increase of basal phenoloxidase enzyme activity, while the lytic activity of haemolymph was not affected. As a result, the use of larvicides and fungicides have a harmful effect on beneficial species such C. fuscipes living in the soil of potato fields. These morphological and physiological results recorded at the organismal level can provide useful information of effects at the population and community levels to preserve the biodiversity of agroecosystem

Endovascular Abdominal Aortic Aneurysm Repair With Ovation Alto Stent Graft: Protocol for the ALTAIR (ALTo endogrAft Italian Registry) Study

Background: Since 2010, the Ovation Abdominal Stent Graft System has offered an innovative sealing option for abdominal aortic aneurysm (AAA) by including a sealing ring filled with polymer 13 mm from the renal arteries. In August 2020, the redesigned Ovation Alto, with a sealing ring 6 mm closer to the top of the fabric, received CE Mark approval. Objective: This registry study aims to evaluate intraoperative, perioperative, and postoperative results in patients treated by the Alto stent graft (Endologix Inc.) for elective AAA repair in a multicentric consecutive experience. Methods: All consecutive eligible patients submitted to endovascular aneurysm repair (EVAR) by Alto Endovascular AAA implantation will be included in this analysis. Patients will be submitted to EVAR procedures based on their own preferences, anatomical features, and operators experience. An estimated number of 300 patients submitted to EVAR with Alto stent graft should be enrolled. It is estimated that the inclusion period will be 24 months. The follow-up period is set to be 5 years. Full data sets and cross-sectional images of contrast-enhanced computed tomography scan performed before EVAR, at the first postoperative month, at 24 or 36 months, and at 5-year follow-up interval will be reported in the central database for a centralized core laboratory review of morphological changes. The primary endpoint of the study is to evaluate the technical and clinical success of EVAR with the Alto stent graft in short- (90-day), mid- (1-year), and long-term (5-year) follow-up periods. The following secondary endpoints will be also addressed: operative time; intraoperative radiation exposure; contrast medium usage; AAA sac shrinkage at 12-month and 5-year follow-up; any potential role of patients' baseline characteristics, valuated on preoperative computed tomography angiographic study, and of device configuration (number of component) in the primary endpoint. Results: The study is currently in the recruitment phase and the final patient is expected to be treated by the end of 2023 and then followed up for 5 years. A total of 300 patients will be recruited. Analyses will focus on primary and secondary endpoints. Updated results will be shared at 1- and 3-5-year follow-ups. Conclusions: The results from this registry study could validate the safety and effectiveness of the new design of the Ovation Alto Stent Graft. The technical modifications to the endograft could allow for accommodation of a more comprehensive range of anatomies on-label

Evaluation of the application of italian national guidelines for prevention and management of dental injuries in developmental age

Background: The objective of this study is to evaluate the application of National guidelines for prevention and clinical management of traumatic dental injuries (NGPCMTDI) in developmental age published by the Italian Ministry of Health. Methods: In the present retrospective and multicenter study, 246 patients who underwent dental injury were selected to assess the management of the traumatic event compiled with the protocol provided by the National guidelines. Each health worker involved completed a form related to the dental injury in order to standardize the collected data. Two reference centers have been identified for data collection. Analyses for comparisons between groups were performed using the X2 test for categorical variables or by Fisher exact test as appropriate. Statistical significance was assumed at p < 0.05. Results: Evaluating the distribution by age we concluded that: 27.24% of the enrolled patients were aged 1-5 years, 51.63% 6-10 years, and 19.92% 11-17 years. The dental injuries occurred in 10.16% of the situations at home, 50.81% at school, 28.86% during recreation, and 9.35% at the gym. The deciduous dentition is involved in 34.96% of the traumas while the permanent dentition is involved in 69.51%. Conclusion: From the present study it emerged that the National guidelines are not uniformly applied

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

Background/Aims: Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes. Methods: By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1. Results: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability. Conclusion: Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy

Endovascular Aneurysm Repair Using Anaconda Repositionable Aortic Stent Graft Assisted Exclusively by Intravascular Ultrasound Imaging

Arteriography with contrast medium (CM) injection is normally employed to visualise the lowest renal artery during endovascular aneurysm repair (EVAR). Intravascular ultrasound (IVUS) has been proposed as an alternative, real-time imaging diagnostic technique to arteriography. In this study, we evaluated the feasibility of EVAR using Anaconda repositionable aortic stent graft (Vascutek) assisted by IVUS (Volcano Visions, Philips) during intraluminal navigation without CM. From January 2016 to December 2017, 25 patients with infrarenal abdominal aortic aneurysms, identified through anatomical inclusion criteria, underwent EVAR. All of the patients had an arteriogram at the end of the EVAR procedure to confirm aortic stent graft patency and to exclude type 1 endoleaks. The primary objective was the technical and clinical success of this CM-free aortic stent graft delivery procedure. At the end of the period, 150 target vessels were evaluated. IVUS versus angio-CT sensitivity and specificity rate were 97.3% and 100%, respectively. The primary technical success was obtained in 88% of the cases. Three patients (12%) needed CM injection to complete the procedure and there were no cases of type 1 endoleak. Primary clinical success was 100%. During follow-up at a mean of 20 months, none of the patients died or had complications. We conclude that a full EVAR procedure is feasible using only IVUS navigation and repositionable aortic stent graft without CM injection in anatomically selected cases

Blood biomarkers from the emergency department disclose severe omicron covid-19-associated outcomes

Background: Since its outbreak, Coronavirus disease 2019 (COVID-19), a life-threatening respiratory illness, has rapidly become a public health emergency with a devastating social impact. Lately, the Omicron strain is considered the main variant of concern. Routine blood biomarkers are, indeed, essential for stratifying patients at risk of severe outcomes, and a huge amount of data is available in the literature, mainly for the previous variants. However, only a few studies are available on early routine biochemical blood biomarkers for Omicron-afflicted patients. Thus, the aim and novelty of this study were to identify routine blood biomarkers detected at the emergency room for the early prediction of severe morbidity and/or mortality. Methods: 449 COVID-19 patients from Sapienza University Hospital of Rome were divided into four groups: (1) the emergency group (patients with mild forms who were quickly discharged); (2) the hospital ward group (patients that after the admission in the emergency department were hospitalized in a COVID-19 ward); (3) the intensive care unit (ICU) group (patients that after the admission in the emergency department required intensive assistance); (4) the deceased group (patients that after the admission in the emergency department had a fatal outcome). Results: ANOVA and ROC data showed that high-sensitivity troponin-T (TnT), fibrinogen, glycemia, C-reactive protein, lactate dehydrogenase, albumin, D-dimer myoglobin, and ferritin for both men and women may predict lethal outcomes already at the level of the emergency department. Conclusions: Compared to previous Delta COVID-19 parallel emergency patterns of prediction, Omicron-induced changes in TnT may be considered other early predictors of severe outcomes

Validation of PARADISE 24 and Development of PARADISE-EDEN 36 in Patients with Dementia

Dementia was one of the conditions focused on in an EU (European Union) project called “PARADISE” (Psychosocial fActors Relevant to brAin DISorders in Europe) that later produced a measure called PARADISE 24, developed within the biopsychosocial model proposed in the International Classification of Functioning Disability and Health (ICF). The aims of this study are to validate PARADISE 24 on a wider sample of patients with mild to moderate dementia to expand PARADISE 24 by defining a more specific scale for dementia, by adding 18 questions specifically selected for dementia, which eventually should be reduced to 12. We enrolled 123 persons with dementia, recruited between July 2017 and July 2019 in home care and long-term care facilities, in Italy, and 80 participants were recruited in Warsaw between January and July 2012 as part of a previous cross-sectional study. The interviews with the patient and/or family were conducted by health professionals alone or as a team by using the Paradise data collection protocol. The psychometric analysis with the Rasch analysis has shown that PARADISE 24 and the selection of 18 additional condition-specific items can be expected to have good measurement properties to assess the functional state in persons with dementia

Developing a competence framework for nurses in pharmaceutical care: A Delphi study

Background: Nurses play an important role in pharmaceutical care. They are involved in: detecting clinical change; communicating/discussing pharmacotherapy with patients, their advocates, and other healthcare professionals; proposing and implementing medication-related interventions; and ensuring follow-up of patients and medication regimens. To date, a framework of nurses' competences on knowledge, skills, and attitudes as to interprofessional pharmaceutical care tasks is missing. Objectives: To reach agreement with experts about nurses' competences for tasks in interprofessional pharmaceutical care. Methods: A two-phase study starting with a scoping review followed by five Delphi rounds was performed. Competences extracted from the literature were assessed by an expert panel on relevance by using the RAND/UCLA method. The experts (n = 22) involved were healthcare professionals, nurse researchers, and educators from 14 European countries with a specific interest in nurses' roles in interprofessional pharmaceutical care. Descriptive statistics supported the data analysis. Results: The expert panel reached consensus on the relevance of 60 competences for 22 nursing tasks. 41 competences were related to 15 generic nursing tasks and 33 competences were related to seven specific nursing tasks. Conclusions: This study resulted in a competence framework for competency-based nurse education. Future research should focus on imbedding these competences in nurse education. A structured instrument should be developed to assess students' readiness to achieve competence in interprofessional pharmaceutical care in clinical practice.The research was supported by the Erasmus+ Programme of the European Union (grant number 2018–1-BE02-KA203–046861) and MDMJ accountants, an accountancy service in Belgium that financially supported the Belgian authors, without any conflicts of interest