Edge-Grafted Molecular Junctions between Graphene Nanoplatelets: Applied Chemistry to Enhance Heat Transfer in Nanomaterials

The edge-functionalization of graphene nanoplatelets (GnP) was carried out exploiting diazonium chemistry, aiming at the synthesis of edge decorated nanoparticles to be used as building blocks in the preparation of engineered nanostructured materials for enhanced heat transfer. Indeed, both phenol functionalized and dianiline-bridged GnP (GnP-OH and E-GnP, respectively) were assembled in nanopapers exploiting the formation of non-covalent and covalent molecular junctions, respectively. Molecular dynamics allowed to estimate the thermal conductance for the two different types of molecular junction, suggesting a factor 6 between conductance of covalent vs. non-covalent junctions. Furthermore, the chemical functionalization was observed to drive the self-organization of the nanoflakes into the nanopapers, leading to a 20% enhancement of the thermal conductivity for GnP-OH and E-GnP while the cross plane thermal conductivity was boosted by 150% in the case of E-GnP. The application of chemical functionalization to the engineering of contact resistance in nanoparticles network was therefore validated as a fascinating route for the enhancement of heat exchange efficiency on nanoparticle networks, with great potential impact in low-temperature heat exchange and recovery application

Multitarget antioxidant NO-donor organic nitrates: a novel ap-proach to overcome nitrates tolerance, an ex vivo study

Chronic use of glyceryl trinitrate (GTN) is limited by serious side effects, such as tolerance and endothelial dysfunction of coronary and resistance arteries. Although GTN is used as a drug since more than 130 years, the mechanisms of the vasodilatory effects and of tolerance development to organic nitrates are still incompletely elucidated. New synthesized organic nitrates with and without antioxidant properties were characterized for their ex vivo tolerance profile, in order to investigate the oxidative stress hypothesis of nitrate tolerance. The organic nitrates studied showed different vasodilation and tolerance profiles, probably due to the ability or inability of the compounds to interact with the aldehyde dehydrogenase-2 enzyme (ALDH-2) involved in bioactivation. Furthermore, nitrooxy derivatives endowed with antioxidant properties did not determine the onset of tolerance, even if bioactivated by ALDH-2. The results of this study could be further evidence of the involvement of ALDH-2 in the development of nitrate tolerance. Moreover, the behavior of organic nitrates with antioxidant properties supports the hypothesis of the involvement of ROS in inactivating ALDH-2

Plasma from pre-pubertal obese children impairs insulin stimulated Nitric Oxide (NO) bioavailability in endothelial cells: Role of ER stress.

Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation

Incidence and phenotypes of childhood-onset genetic epilepsies:a prospective population-based national cohort

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy

Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFV600E Protein

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF(V600E) mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF(V600E) has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC(50) values in the 40–88 nM range. Selected compounds inhibited BRAF(V600E) signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior

Real-world use of adjunctive perampanel for focal-onset seizures in Italy: A mirroring clinical practice study of perampanel in adults and adolescents (AMPA)

Objective: The AMPA study (Study 501; NCT04257604) was a multicenter, prospective, 12-month observational study in Italy that evaluated the effectiveness and safety of adjunctive perampanel in patients with focal-onset seizures (FOS), with or without focal to bilateral tonic–clonic seizures (FBTCS). Methods: Patients aged ≥12 years with insufficiently controlled FOS, with or without FBTCS, receiving 1–3 anti-seizure medications (ASMs) were prescribed adjunctive perampanel per the approved indication. The primary endpoint was the median percent change in total seizure frequency per 28 days from baseline at Month 6. Baseline seizure frequency per 28 days was calculated using seizure diaries and/or medical records of seizures occurring in the 8 weeks prior to the baseline visit while patients were receiving 1–3 ASMs. Treatment-emergent adverse events (TEAEs), including serious TEAEs, were monitored for up to 12 months. Results: Of the 240 patients enrolled in the study, 234 were included in the Full and Safety Analysis Sets. Median age (minimum, maximum) was 36.0 years (12, 84) and 51.3% (n = 120/234) were female. The majority of patients (77.8% [n = 182/234]) received ≥2 concomitant ASMs at baseline, with the most common being carbamazepine (33.8% [n = 79/234]). The median percent reduction in total seizure frequency per 28 days from baseline (95% confidence interval) was 55.4% (46.7%–66.7%) at Month 6. Overall, the retention rate was 57.3% (n = 134/234) following 12 months of treatment. During the study, the overall incidence of TEAEs was 56.4% (n = 132/234), with the most frequently reported TEAE being dizziness/vertigo (21.8% [n = 51/234]). Serious TEAEs were experienced by 6.0% (n = 14/234) of patients and no deaths were reported during the 12-month treatment period. Significance: Data from the AMPA study suggest that adjunctive perampanel is associated with improvement in seizure control and with good retention rates and tolerability in a real-world clinical setting. These findings further support the use of adjunctive perampanel as a suitable treatment option for adolescent and adult patients with epilepsy. Plain Language Summary: Our study looked at teenage and adult patients with epilepsy in Italy who took the study drug, called perampanel, as well as the epilepsy treatments they had already been prescribed. After 12 months, 134 out of 234 patients were still using perampanel. Patients taking perampanel had fewer seizures than they did before they started taking perampanel. Side effects occurred in 132 patients (most commonly dizziness/vertigo, irritability, and sleepiness) and caused 45 of them to withdraw from the study. Perampanel was a suitable treatment option for teenage and adult patients with epilepsy