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This case report illustrates a nonsurgical treatment plan using a miniscrew-assisted rapid palatal expander (MARPE) in a 50-year-old patient with maxillary transverse deficiency. The MARPE appliance consisted of a conventional Hyrax expander anchored to 4 orthodontic miniscrews. The exact locations of the miniscrews were determined with virtual planning software. Cone-beam computed tomography (CBCT) scans were superimposed on the maxillary digital model, and 3-dimensional-printed surgical guides were used to accurately position the mini-implants. A slow expansion protocol was used, and the appliance was held in place during the entire treatment (almost 20 months). Pretreatment, postexpansion, and posttreatment CBCT scans show the parallel expansion obtained without dental torque compensation or bite opening. The posttreatment scan showed that a long period is required to complete the midpalatal suture mineralization. MARPE has proven effective in correcting transverse discrepancies, even in adults. However, posttreatment CBCT imaging showed incomplete ossification of the midpalatal suture, demonstrating that the retention period should be extended in some adult patients. [ABSTRACT FROM AUTHOR]

Biological soft tissues and polymers used in biomedical applications (e.g. in the cardiovascular area) are hyperelastic incompressible materials that commonly operate under multi-axial large deformation fields. Their characterisation requires biaxial tensile testing. Due to the typically small sample size, the gripping of the specimens commonly relies on rakes or sutures, where the specimen is punctured at the edges of the gauge area. This approach necessitates of an apron, excess of material around the gauge region. This work analyses the apron influence on the estimated mechanical response of biaxial tests performed by using a rakes gripping system, with the aim of verifying the test accuracy and propose improved solutions. In order to isolate the effect of the apron, avoiding the influence of anisotropy and inhomogeneity typical of most soft tissues, homogeneous and isotropic hyperplastic samples made from a uniform sheet of casted silicone were tested. The stress-strain response of specimens with different apron sizes/shapes was measured experimentally by means of biaxial testing and digital image correlation. Tests were replicated numerically, to interpret the experimental findings. The apron surrounding the gauge area acts as an additional annular constraint which stiffens the system, resulting in a significant overestimate in the stress values. This error can be avoided by introducing specific cuts in the apron. The study quantifies, for the first time, the correlation between the apron size/shape and the experimental stress overestimation, proposing a research protocol which, although identified on homogeneous hyperelastic materials, can be useful in providing more accurate characterisation of both, synthetic polymers and soft tissues. • Current Biaxial tests, crucial to characterise hyperelastic materials, are inaccurate. • The necessary presence of an apron affects the determined material response. • This work analyses and quantifies the error introduced by the apron. • A new procedure to eliminate the error due to the apron is presented. [ABSTRACT FROM AUTHOR]

Highlights • We investigated coherent eddies and exchange processes in a large amplitude meandering flume with vegetated bed. • We verified that mass and momentum transport between vegetation the overflow is controlled by the coherent turbulent motion. • A different contribution from turbulence to the exchange mechanism has been observed for h/kv > 2 and for h/kv < 2. • In the central region of the apex section (2 < h/kv < 5) the vertical turbulent transport exchange is more significant than streamwise transport. • In the inner-bank region (h/kv < 2) the turbulent vertical transport becomes less important compared to the streamwise transport. Abstract Aquatic plants in rivers interact with flow and exert an important role in maintaining suitable habitat and ecological equilibrium. Understanding turbulence structure in the presence of vegetation is important with respect to environmental processes, such as sediment transport and mixing of transported quantities. Literature indicates that mass and momentum exchanges in the presence of vegetation are strongly influenced by the sequence of coherent structures which form between vegetated and non-vegetated zones. In the present paper we investigate turbulence structure and coherent motion in high-curvature channels with submerged vegetation. The analysis is performed with the aid of detailed experimental data collected in a meandering flume of large amplitude. Results essentially highlight that the contribution of turbulence to lateral diffusion and to streamwise and vertical transport may be significantly influenced by the relative submergence h/kv. The dominant mechanism of exchange obtained for h/kv < 2 is different from that obtained for h/kv > 2. Quadrant analysis has been also applied to investigate the occurrence of turbulent events and the associated exchange mechanism. In particular, at the apex section, it has been found that ejection events dominate in the outer bank region and, as literature indicates, this could cause the suspension of sediment in the flow that is transported downstream. In the central region the motion is especially characterized by high-speed fluid directed towards the bed, influencing the transport process significantly. [ABSTRACT FROM AUTHOR]

Mussels ( Mytilus galloprovincialis ) were transplanted from a reference site (Syracuse harbour) to an impacted site (Augusta Bay) from January to July 2013 to assess the biochemical response of caged mussels to high trace element and polycyclic aromatic hydrocarbon (PAH) contamination, using lipid and fatty acid (FA) biomarkers. Sediment and mussels were analysed to assess contaminant bioavailability in the study sites and bioaccumulation in mussel tissue. Trace elements (As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, V, Zn) and PAHs were significantly higher in mussels from Augusta than in those from Syracuse, mirroring the different environmental contamination. The biological impact quotient (BIQs), which indicates the potential biological impact of mussel-accumulated contaminants, reflected the highest contaminant concentrations found in Augusta and their temporal trend, which increased from the start of the experiment to 3–4 months after transplanting, followed by a decrease, as indication of mussel detoxification processes. Lower condition index (CI) and phospholipids (PL), as well as higher total (TL) and neutral lipids (NL) in mussels from Augusta, indicated the occurrence of a physiological and biochemical stress response to pollutant exposure and accumulation. Differences in FA composition, especially polyunsaturated (PUFA), essential (EFA) and non-methylene interrupted dienoic (NMID) FAs between the study sites revealed the occurrence of stress-induced lipid peroxidation, followed by compensatory/adaptive processes in Augusta mussels. The marked increase in bacterial biomarkers, mainly cyclopropyl (CY) FAs, reflecting the greater bioaccumulation of chemicals in the Augusta mussels, may be the result of bacterial infections or symbiosis with bacteria involved in detoxification processes. [ABSTRACT FROM AUTHOR]

Fish species have attracted considerable interest in studies assessing biological responses to environmental contaminants. In this study, the attention has been focussed on fishbone of selected fish species from a highly polluted marine area, Augusta Bay (Italy, Central Mediterranean) to evaluate if toxicant elements had an effect on the mineralogical structure of bones, although macroscopic deformations were not evident. In particular, an attempt was made to evaluate if bone mineral features, such as crystallinity, mineral maturity and carbonate/phosphate mineral content, determined by XR-Diffraction and FT-IR Spectroscopy, suffered negative effects due to trace element levels in fishbone, detected by ICP-OES. Results confirmed the reliability of the use of diffractometric and spectroscopic techniques to assess the degree of crystallinity and the mineral maturity in fishbone. In addition, in highly polluted areas, Hg and Cr contamination induced a process of premature aging of fishbone, altering its biochemical and mineral contents. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to analyze the cost-effectiveness outcomes of video-assisted thoracic surgery (VATS) in the treatment of primary spontaneous pneumothorax (PSP), comparing the minimally invasive procedure with pleural drainage (PD). Methods: Between July 2006 and October 2012, we treated 122 patients with a first episode of PSP by VATS (61 patients) or pleural drainage (61 patients). We established the relationship between costs and quality-adjusted life (QAL) for both techniques. Results: The total cost per patient of minimally invasive procedure was more advantageous than that of chest tube (€2,422.96 vs €4,855.12). The QAL expectancy of VATS was longer than that of PD (57.00 vs 40.80 at 60 months). The QAL year of VATS (.32 at 1st year and .25 at 5th year) was better than that of PD. Incremental cost-effectiveness ratio of VATS versus PD was between €7,600.00 (1st year) and €10,045.00 (5th year), remaining well below the threshold of acceptability. Conclusion: VATS as the first-line treatment for PSP allowed low morbidity, short hospitalization, and excellent quality of life. [ABSTRACT FROM AUTHOR]

Verbal working memory plays a crucial role in supporting the learning process over the school years. In this study, we investigated the role of the acoustic conditions of school classrooms, specifically reverberation time and babble noise, on second-graders' verbal working memory. A sample of twenty-five second-graders was administered a validated verbal working memory task in two different acoustic conditions, with a time frame of 1 month: Poor acoustic quality (long reverberation time [Long RT] and babble) versus Adequate acoustic quality (short reverberation time [Short RT] and babble). Results showed that the same children were able to remember fewer words and less accurately on the task in a classroom with longer reverberation time and babble compared to one with shorter reverberation time and babble. Moreover, children omitted more words in the recall task in the Poor acoustic quality condition than in the Adequate acoustic quality condition. The results suggested that primary school children's verbal working memory processing is sensitive to variations in the classroom acoustic conditions. These findings offer a research contribution about the importance of adopting a contextual view on cognitive development and insights for the implementation of school interventions in terms of metacognitive work on learning to listen and classroom design. • Primary school children's verbal working memory processing is sensitive to variations in the classroom acoustic conditions. • Results provide support of adopting contextual view on cognitive functioning and development. [ABSTRACT FROM AUTHOR]

Abstract: The distribution of rare earth elements and yttrium (REEs+ Y) has been investigated in box-core sediments recovered from four stations in the Sicilian coastal zone seawards of Augusta, one of the most industrialized and contaminated areas in the Mediterranean region. Shale-like REE patterns and low Y/Ho ratios (close to the chondritic ratio) suggest a dominant terrigenous (geogenic) source for REE. Slight enrichment of LREE over the HREE is interpreted as due to preferential adsorptive transfer of LREE from seawater to sediment particles. Samples from offshore cores exhibit slightly positive Gd and negative Ce anomalies. It is here hypothesized that main drivers of anthropogenic Gd flux towards the offshore are dredged contaminated materials that, recovered from the Augusta Bay, have been repeatedly discharged offshore. Consistent with the redox-chemistry of Ce, these anomalous sedimentary inputs induce a decrease of O2 concentration in the sediment, which in turn triggers Ce regeneration. [Copyright &y& Elsevier]

[Display omitted] • Uniaxial tension tests on nitinol plates strongly depart from the uniaxial idealisation. • Results from tension test on nitinol plates can be affected by major inaccuracy. • DIC technique can help to ensure the reliability of tension tests. • Geometrical explanation of Lüders bands formation. Thanks to its unique behaviour characterised by a superelastic response, Nitinol has now become the material of preference in a number of critical applications, especially in the area of medical implants. However, the reversible phase transformation producing its exceptional comportment is also responsible for a number of phenomena that make its mechanical characterisation particularly complex, by hindering the assumptions at the very basis of common uniaxial tensile testing. This necessarily reduces the level of safety and design optimization of current applications, which rely on incorrect mechanical parameters. In this study, the spurious effects introduced by the unconventional material behaviour during uniaxial tensile testing are analysed by means of digital image correlation (DIC), identifying the onset of undesirable material inhomogeneities and bending moments that are dependent on the test setup and strongly limit the reliability of standard characterisation. Hence, a more accurate and systematic testing approach, exploiting the ability of DIC to analyse the local mechanical response at specific regions of the test specimen, is presented and discussed. [ABSTRACT FROM AUTHOR]

Abstract: Total Hg concentrations have been measured for five box-core sediments collected seawards of the Augusta industrial area (SE Sicily). In more coastal sediments, upcore increasing Hg concentrations, exceeding the Hg background concentration estimated for the Strait of Sicily, indicate Hg contamination over time due to the industrial area development. Strong correlation between total organic C (TOC) and Hg concentrations was found only for core BX2, that displays organic C to total N (C/N) ratios indicative of autochthonous organic matter. For other sediments, high Hg enrichment factors with respect to TOC indicate, in addition to Hg trapping by TOC, other factors as responsible for Hg accumulation. In the presence of some contribution of detrital organic matter, Hg is mainly adsorbed onto the mineral component of the bottom sediments probably because TOC is saturated by Hg excess. Contaminant impact affected also the open sea environment. Main drivers of Hg flux towards the offshore were dredged materials, which repeatedly discharged sediment, resulting in substantial increases in TOC contents and high C/N ratios. Consistent with the geochemistry of recent turbidites, these anomalous sedimentary inputs induced sediment redox environment modifications, constrained by Mn peaks, which affected Hg distribution. [Copyright &y& Elsevier]

Pristine and functionalized carbon nanotube (CNT) webs were introduced at the interlaminar region of two different thin-ply carbon fibre reinforced polymer systems (NTPT 402 prepreg, and TeXtreme/SE84LV). The Mode I interlaminar fracture toughness (ILFT) for the NTPT 402 material was substantially lower. In contrast when SE84LV resin was used, the resistance curves were virtually unchanged and with no depreciation in the steady state value of the ILFT. This demonstrates that a careful choice of the resin is essential to permit the embedding of CNT webs in thin-ply laminates without compromising structural performance and opens a new way towards the development of multifunctional thin-ply structures. [ABSTRACT FROM AUTHOR]

High sediment contamination in the coastal area of Priolo Bay, adjacent to the highly-polluted Augusta Harbour, poses serious risks for the benthic communities inhabiting the area. Nevertheless, the transfer of trace elements and consequent bioaccumulation in the biota is an overlooked issue. This study aimed to assess the transfer and bioaccumulation patterns of As, Cd, Ni and Hg to the dominant macroalgae and benthic invertebrates of Priolo Bay. Results revealed different patterns among trace elements (TEs), not driven by sediment contamination but rather by element-specific behaviour coupled with sediment physicochemical properties. Specifically, As accumulated in macroalgae but not in invertebrates, indicating bioavailability of dissolved As only, and a lack of effective trophic transfer. Ni was confined to surface sediment and transfer to biota was not highlighted. Cd and Hg showed the highest concentrations in invertebrates and bioaccumulated especially in filter feeders and carnivores, revealing the importance of suspended particulate and diet as transfer pathways. Total organic carbon (TOC), fine-grained sediments and redox potential were the most important sediment features in shaping the sediment contamination spatial patterns as well as those of TE transfer and bioaccumulation. In particular, As and Cd transfer to macroalgae, and especially Hg bioaccumulation in benthic invertebrates was controlled by sediment properties, resulting in limited transfer and accumulation in the most contaminated stations. [ABSTRACT FROM AUTHOR]

Two field campaigns were conducted in the tidal and estuarine reach of the Sông Hậu distributary of the Mekong River to explore the dynamics of sand transport and export to the coastal ocean. This study examines variations in suspended sand concentration and net flux of suspended and bedload sand with respect to changes in discharge between the October 2014 high discharge and March 2015 low discharge season. Isokinetic measurements of suspended sand were used to calibrate a larger dataset of LISST profiles to report suspended sand mass concentrations. During the high discharge season, ebb and flood currents are a primary control on suspended sand concentrations. Ebb tidal flows are more capable of sand transport than flooding flows, due to river discharge augmenting tidal currents. Sand in suspension is primarily derived locally from bed material sand. Bedform transport estimates were limited, but suggest that bedload sand transport is less than 10% of net suspended sand flux. Very low concentrations of suspended sand sediment are found during the low discharge season. These low concentrations are likely caused by (1) a reduction in maximum ebb tide shear stresses associated with less freshwater input, and (2) mud mantling in the bed associated with upstream migration of estuarine circulation, that inhibits local sourcing (resuspension) of bed sand. Results of the observational study were used to calibrate a numerical model of annual sand flux to the ocean from all distributaries of the Mekong River. Annual sand export is estimated at 6.5 ± 1.6 Mt yr −1 . The Định An subdistributary accounts for 32% of this total while the smaller Trần Đề subdistributary accounts for only 9%. [ABSTRACT FROM AUTHOR]

International and national oncology societies had released recommendations in favor of COVID-19 vaccination in cancer patients. In the context of the national vaccination campaign targeting the so called extremely vulnerable, we aimed to assess the safety and efficacy of the mRNA vaccines in a cohort of 623 patients. Between March 26 and April 04, 2021, the Pfizer and BioNTech BNT162b2 mRNA and the Moderna mRNA-1273 vaccines were given as a two-dose prime-boost regimen. Starting on September 25th 2021 a third dose was offered to patients in whom a suboptimal immunogenicity with COVID-19 vaccination could be expected. Safety assessments were performed by phone call 7 days after each dose. Electronic health records were accessed to review demographic information, disease history, treatment detail, and outcome events of participants patients'. No toxicities were reported in 63.7%, 54%, and in 48.7% patients with cancer after each dose. Mild-to-moderate pain at the injection site was the most commonly adverse event. After the second dose, 46% of the 610 patients reported toxicity, with more systemic side-effects observed. Fever was reported in 45% of patients, with a temperature ≥ 38 °C in 21.4% of them. Of the 335 patients receiving a third vaccine dose, 51% reported toxicity, with 13% of patients reporting more than one effect. Logistic regression analysis reported mixed results, with limited variables or categories reporting a significant odd ratio. The type of vaccine reported a significant value at first dose (OR = 0.12; CI 0.52, 0.26; p = 0.00). Thirty-four cases of COVID-19 infection were reported with only one patient requiring a short-term hospitalization for monitoring. The safety profile of the mRNA vaccines does not raise any specific concerns and support prioritization of vaccination for cancer patients. • COVID-19 vaccination is recommended in patients with cancer. • We observed a first dose-refusal rate of 4.5%. • No safety concerns have emerged in our cohort of patients. • After two-dose prime-boost vaccination 6 cases of COVID-19 infection were reported. [ABSTRACT FROM AUTHOR]

Abstract: It has been proposed that retinoblastoma is ‘caused’ by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic alterations. Retinoblastoma remains probably the only cancer in which the rather simplistic ‘two hit’ mutational model is still considered of value, although cancer is known to be associated with genomic and microsatellite instability, defects of the DNA mismatch repair system, alterations of DNA methylation and hystone acethylation/deacethylation, and aneuploidy. Moreover, as it is shown herein, the predictions made by the ‘two hit’ model, are not fulfilled by the clinical and epidemiological data reported so far. Moreover, while the role of mutational events in cancer has been largely questioned in the more recent literature, no serious effort has been done to investigate the role of epigenetic alterations and aneuploidy in retinoblastoma. Through the analysis of the specialised literature and a set of original epidemiological and biological data concerning retinoblastoma, the authors illustrate the evidences arguing against the ‘two hit’ hypothesis and propose that epigenetic factors and aneuploidy play central roles in the disease. [Copyright &y& Elsevier]

Focuses on a study which investigated wether pRB deficiency could drive perpetual aneuploidy in normal human and mouse fibroblasts after mitotic checkpoint challenge by microtubule-destabilizing drugs. Materials and methods; Results; Discussion.

Abstract European Union (EU) and United States (US) regulations implement different food safety standards, particularly relating to the presence of Listeria monocytogenes in certain ready-to-eat (RTE) meat products. Compared to EU, the US adopt different procedures and methods, and establish zero tolerance limits to ensure consumers protection from Listeria monocytogenes in RTE products. A complete equivalence evaluation of the EU and US food inspection and certification systems has not been carried out yet. This study was funded by the Italian Central Competent Authority in the field of food safety (Ministry of Health) and included a total of 164 Italian establishments, 81 authorized for export of pork meat products to US ("US establishments") and 83 only authorized for EU internal trade ("EU establishments"). Establishments were stratified according to production volume, type of RTE products manufactured, presentation and processing, in order to include two homogeneous groups (US and EU). Sampling was carried out by NAS (Carabinieri Corps for the prevention of the adulteration of beverages and foodstuffs) without any given notice. Sampling, detection and identification of Listeria monocytogenes and Salmonella spp. took place according to US Food Safety and Inspection Service (FSIS) directives and procedures. All 1124 samples tested negative for Salmonella spp., while 5 samples tested positive for Listeria monocytogenes. Among the latter, 4 samples were collected in 3 US establishments (US products prevalence 4/556 = 0.72%, 95% CL: 0.29–1.83%; US establishments prevalence 3/81 = 3.70%, 95% CL: 1.34–10.32%) and 1 was collected in a EU establishment (EU products prevalence 1/568 = 0.18%, 95% CL: 0.04–0.98%; EU establishment prevalence 1/83 = 1.20%, 95% CL: 0.29–0.46%). Bilateral Fisher's exact test showed no differences between EU and US products and establishments prevalence (P = 0.213 and P = 0.364, respectively), corroborating the existence of equivalent Listeria monocytogenes and Salmonella spp. contamination in the products under these two control systems. Highlights • US and EU apply different food safety standards in RTE meat products. • US adopt different methods than EU and zero tolerance for L. monocytogenes. • In Italy, only establishments that apply FSIS regulations can export to US. • US-export and EU-internal market authorized establishments were compared. • No differences were found in L. monocytogenes and Salmonella contaminations. [ABSTRACT FROM AUTHOR]

Abstract Nonsense mutations in the CFTR gene prematurely terminate translation of the CFTR mRNA leading to the production of a truncated protein that lacks normal function causing a more severe form of the cystic fibrosis (CF) disease. About 10% of patients affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by Translational Readthrough Inducing Drugs (TRIDs) such as PTC124. In this context we aimed to compare the activity of PTC124 with analogues differing in the heteroatoms position in the central heterocyclic core. By a validated protocol consisting of computational screening, synthesis and biological tests we identified a new small molecule (NV2445) with 1,3,4-oxadiazole core showing a high readthrough activity. Moreover, we evaluated the CFTR functionality after NV2445 treatment in CF model systems and in cells expressing a nonsense- CFTR-mRNA. Finally, we studied the supramolecular interactions between TRIDs and CFTR-mRNA to assess the biological target/mechanism and compared the predicted ADME properties of NV2445 and PTC124. Graphical abstract Image 1 Highlights • Nonsense mutations originate premature termination codons (PTC) in the mRNA. • PTC are responsible for the production of a not-functional truncated protein. • Translational readthrough inducing drugs (TRIDs) rescue protein production. • CFTR production and functionality can be restored by TRIDs. • Oxadiazoles are small non-toxic molecules with readthrough activity. [ABSTRACT FROM AUTHOR]

This paper presents a five-phase switched reluctance motor designed to satisfy the requirements of flap actuators in medium size aircrafts, a real example of the more electric aircraft trend. In normal conditions the machine operates with two phases conducting simultaneously but it is designed to satisfy the load specifications also with one or two phases open as consequence of fault remedial strategies. A finiteelement study, aiming to predict both the healthy and faulty-mode performance, is presented. The mean torque vs. current capability and the torque ripple are investigated and optimum commutation angles are evaluated in static conditions. Experimental tests on the motor prototype are included, which confirm its capability to satisfy the planned degraded modes of operation and validate the design. [ABSTRACT FROM AUTHOR]

Because of the growing need for efficient energy production systems, energy policies promoted in recent years have also involved complex structures, like airports. This paper proposes the implementation of an energy management system for a very energy-consuming structure, composed of different power plants and many energy consumers: the Leonardo da Vinci International Airport of Rome. In this study, the examination of historical data related to airport electric power, thermal energy and fuel consumption is discussed, starting with the analysis of the production energy plants, mainly based on a combined heat and power system. Furthermore, pioneering solutions are proposed, not only to cover airport energy requirements, but also to test the safety and reliability of innovative load management systems. For this reason, the choice of the Leonardo da Vinci management company, oriented to install a smart storage in order to manage the bidirectional energy flows by consumers and producers, is justified. Such innovative energy procurement systems are examined, with the goal of achieving greater penetration of renewable sources: mini and micro wind power plants and high concentrator photovoltaic plants. [ABSTRACT FROM AUTHOR]

Ataluren, also known as PTC124, is a 5-(fluorophenyl)-1,2,4-oxadiazolyl-benzoic acid suggested to suppress nonsense mutations by readthrough of premature stop codons in the mRNA. Potential interaction of PTC124 with mRNA has been recently studied by molecular dynamics simulations highlighting the importance of H-bonding and stacking π−π interactions. A series of non-acidic analogues of PTC124 were selected from a large database via a ligand-based virtual screening approach. Eight of them were synthesized and tested for their readthrough activity using the Fluc reporter harboring the UGA premature stop codon. The most active compound was further tested for suppression of the UGA nonsense mutation in the bronchial epithelial IB3.1 cell line carrying the W1282X mutation in the CFTR gene. [ABSTRACT FROM AUTHOR]

Premature stop codons are the result of nonsense mutations occurring within the coding sequence of a gene. These mutations lead to the synthesis of a truncated protein and are responsible for several genetic diseases. A potential pharmacological approach to treat these diseases is to promote the translational readthrough of premature stop codons by small molecules aiming to restore the full-length protein. The compound PTC124 (Ataluren) was reported to promote the readthrough of the premature UGA stop codon, although its activity was questioned. The potential interaction of PTC124 with mutated mRNA was recently suggested by molecular dynamics (MD) studies highlighting the importance of H-bonding and stacking π–π interactions. To improve the readthrough activity we changed the fluorine number and position in the PTC124 fluoroaryl moiety. The readthrough ability of these PTC124 derivatives was tested in human cells harboring reporter plasmids with premature stop codons in H2BGFP and FLuc genes as well as in cystic fibrosis (CF) IB3.1 cells with a nonsense mutation. Maintaining low toxicity, three of these molecules showed higher efficacy than PTC124 in the readthrough of the UGA premature stop codon and in recovering the expression of the CFTR protein in IB3.1 cells from cystic fibrosis patient. Molecular dynamics simulations performed with mutated CFTR mRNA fragments and active or inactive derivatives are in agreement with the suggested interaction of PTC124 with mRNA. [ABSTRACT FROM AUTHOR]

Abstract: Alterations in the number and/or morphology of centrosomes are frequently observed in human tumours. However, it is still debated if a direct link between supernumerary centrosomes and tumorigenesis exists and if centrosome amplification could directly cause aneuploidy. Here, we report that hydroxyurea treatment induced centrosome amplification in both human fibroblasts expressing the HPV16 -E6-E7 oncoproteins, which act principally by targeting p53 and pRB, respectively, and in conditional pRB deficient mouse fibroblasts. Following hydroxyurea removal both normal and p53 deficient human fibroblasts arrested. On the contrary pRB deficient fibroblasts entered the cell cycle generating aneuploid cells. Also the majority of conditional Rb deficient MEFs showed supernumerary centrosomes and aneuploid cells which increased over time. Finally, our results suggest that pRB dysfunction both in human and murine fibroblasts transiently arrested in G1/S by hydroxyurea allows centrosomes amplification, in the absence of DNA synthesis, that in turn could drive aneuploidy. [Copyright &y& Elsevier]

[Display omitted] • Nanocomposites based on HNTs/pyrazolo[3,4- d ]pyrimidine derivatives were developed. • Kinetic release was performed in physiological pH conditions. • Their antitumoral activity was evaluated on three cancer cell lines. • Cell cycle was investigated, showing cells arrested in the G1 phase. • Molecular dynamics studies showed an interaction with the active site of CDK2. Uncontrolled cell proliferation is a hallmark of cancer as a result of rapid and deregulated progression through the cell cycle. The inhibition of cyclin-dependent kinases (CDKs) activities is a promising therapeutic strategy to block cell cycle of tumor cells. In this work we reported a new example of nanocomposites based on halloysite nanotubes (HNTs)/pyrazolo[3,4- d ]pyrimidine derivatives (Si306 and Si113) as anticancer agents and CDK inhibitors. HNTs/Si306 and HNTs/Si113 nanocomposites were synthesized and characterized. The release kinetics were also investigated. Antitumoral activity was evaluated on three cancer cell lines (HeLa, MDA-MB-231 and HCT116) and the effects on cell cycle arrest in HCT116 cells were evaluated. Finally, molecular dynamics simulations were performed of the complexes between Si113 or Si306 and the active site of both CDK 1 and 2. [ABSTRACT FROM AUTHOR]

In this paper the innovative approach of nano into micro dry powders (NiM) was applied to incorporate into mannitol or mannitol/cysteamine micromatrices ivacaftor-loaded nanoparticles for pulmonary delivery in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing loaded with ivacaftor at 15.5% w/w were produced. The nanoparticles were incorporated into microparticles to obtain NiM that were fully characterized in terms of size, morphology, interactions with artificial Cf mucus (CF-AM) as well as for aerodynamic behaviour. Finally the activity of ivacaftor-containing NiM was evaluated by in vitro preliminary experiments. NiM at matrix composed by a mixture of mannitol:cysteamine showed greater ability to reduce CF-AM viscosity whereas that based on just mannitol showed better aerodynamic properties with a FPF of about 25%. All produced NiM showed very good cytocompatibility and the released ivacaftor was able to restore the chroride transport in vitro. [ABSTRACT FROM AUTHOR]