Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas

BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or cold, with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10 RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically cold tumors to hot. (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.)

Mechanical Behavior of a Novel Nanocomposite Polysulphone - Carbon Nanotubes Membrane for Water Treatment

Nowadays, global fresh water shortage is becoming the most serious problem affecting the economic and social development. Water treatment including seawater desalination and wastewater treatment is the main technology for producing fresh water. Membrane technology is favored over other approaches for water treatment due to its promising high efficiency, ease of operation, chemicals free, energy and space saving. Membrane filtration for water treatment has increased significantly in the past few decades with the enhanced membrane quality and decreased membrane costs. In addition to high permeate flux and high contaminant rejection, membranes for water treatment require good mechanical durability and good chemical and fouling resistances. Thus, investigation of the mechanical behavior of water treatment membranes with underlying deformation mechanisms is critical not only for membrane structure design but also for their reliability and lifetime prediction. Compared to ceramic and metallic membranes, polymer membranes with smaller pore size and higher efficiency for particle removal are widely used in seawater desalination with a high applied pressure. However, polymer membranes are mechanically weaker and have lower thermal and chemical stability compared to inorganic membranes. Blending of polymers with inorganic fillers is an effective method to introduce advanced properties to polymer based membranes to meet the requirements of many practical applications. The reinforced polymeric membranes with inorganic fillers can provide desirable mechanical strength as well as mechanical stability. Carbon nanotubes (CNTs) have received considerable attention from academic and industries over the last twenty years. In addition to their excellent electrical and thermal properties, CNTs exhibit outstanding mechanical characteristics due to its instinct mechanical strength and high aspect ratio. For the application of water treatment membranes, CNTs could be the excellent channels for water to go through and therefore, CNTs have proven to be excellent fillers in polymer membranes improving the permeability and rejection properties. In literature, it is reported that the mechanical strength of the polymer membranes was improved with the embedding of CNTs due to reinforcement effect of the more rigid CNTs. The mechanical responses of polymer_CNTs composites depended on the interfacial adhesion between the CNTs and the membrane-based polymer as well as the dispersion and distribution of the CNTs within the polymer matrix. In this study, a vertical chemical vapor deposition reactor was designed in order to synthesize CNTs of high aspect ratio using continues injection atomization. Bundles of high purity (99%) and high quality CNTs were produced by this system. The produced CNTs had diameters ranging from 20 to 50 nm and lengths ranging from 300 to 500 micron (corresponded aspect ratios ranging from 6000 to 25000). A novel polysulphone (PSF) based nanocomposite membrane incorporated with the produced high aspect ratio CNTs was then casted via phase inversion method, at a wide range of CNTs loading (0-5 wt. %), in polysulphone-dimethylformamide solutions using the Philos casting system. The poly(vinylpyrrolidone) was used as pore-forming additive. To demonstrate the effect of nanocomposite morphology on the mechanical behavior of the prepared membranes, a set of control samples consisted of PSF membranes embedded with commercial CNTs at the same CNTs loading, were casted at the same conditions. The commercial CNTs had a lengths of 1 ?m to 10 ?m and outer diameters of 10 nm to 20 nm (corresponded aspect ratios ranging from 50 to 1000), with purity >95% and BET surface area of 156 m2/g. The effects of CNTs content and aspect ratio on morphological, water transport and mechanical properties of the prepared PSF-based porous membranes were investigated. The surface and cross-section morphologies of PSF/CNTs porous membranes were examined using scanning electron microscopy (SEM). The orientation, dispersion and distribution of CNTs within polymer membranes were evaluated for the membrane samples with different CNTs content and CNTs aspect ratio. The average membrane pore size was evaluated by using SEM image analysis software. Uniaxial tensile behavior of the membranes was characterized by means of a universal material testing machine under different testing conditions. Wet specimens were carefully cut from the casted membranes by using a razor blade. Elastic, plastic and failure behaviors of the membranes are analyzed with the impacts of CNTs content and aspect ratio. The macroscopic mechanical behaviors of the membranes are correlated with their strain induced microstructure evolution by using SEM. In this, pore shape evolution, pore and CNTs orientations, neighboring pore interaction, interface between the CNTs and PSF matrix and the failure behavior of the deformed porous membranes were analyzed. The macroscopic stress-strain responses of the membranes were correlated with the microstructure of the studied nanocomposites membranes to provide a better understanding of materials' processing-microstructure-properties relationship.qscienc

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

\ua9 2023, The Author(s).BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m−2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485

Imports and isotopes: a modern baseline study for interpreting Iron Age and Roman trade in fallow deer antlers

The European Fallow deer (Dama dama dama) became extinct in the British Isles and most of continental Europe at the time of the Last Glacial Maximum, with the species becoming restricted to an Anatolian refugium (Masseti et al. 2008). Human-mediated reintroductions resulted in fallow populations in Rhodes, Sicily, Mallorca, Iberia and other parts of western Europe (Sykes et al. 2013). Eventually, the species was brought to Britain by the Romans during the 1st century AD, with a breeding population being established at Fishbourne Roman Palace (Sykes et al. 2011). The human influence on the present-day distribution of the species makes it particularly interesting from a zooarchaeological perspective. This paper describes my MSc research, as part of the AHRC-funded project Dama International: Fallow Deer and European Society 6000 BC–AD 1600, looking at antlers from Iron Age and Roman sites in Britain for evidence of trade in body parts and whether this can be elucidated by a parallel stable isotope study of modern fallow antlers of known provenance

Essential Oil Composition, Antioxidant, Cytotoxic and Antiviral Activities of Teucrium pseudochamaepitys Growing Spontaneously in Tunisia

The chemical composition, antioxidant, cytotoxic and antiviral activities of the essential oil obtained by hydrodistillation from the aerial parts of Teucrium pseudochamaepitys (Lamiaceae) collected from Zaghouan province of Tunisia are reported. The essential oil was analyzed by gas chromatography equipped with a flame ionization detector (GC-FID) and gas chromatography coupled with mass spectrometry (GC/MS). Thirty-one compounds were identified representing 88.6% of the total essential oil. Hexadecanoic acid was found to be the most abundant component (26.1%) followed by caryophyllene oxide (6.3%), myristicin (4.9%) and α-cubebene (3.9%). The antioxidant capacity of the oil was measured on the basis of the scavenging activity to the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH). The IC50 value of the oil was evaluated as 0.77 mg·mL−1. In addition, the essential oil was found to possess moderate cytotoxic effects on the HEp-2 cell line (50% cytotoxic concentration (CC50) = 653.6 µg·mL−1). The potential antiviral effect was tested against Coxsackievirus B (CV-B), a significant human and mouse pathogen that causes pediatric central nervous system disease, commonly with acute syndromes. The reduction of viral infectivity by the essential oil was measured using a cytopathic (CPE) reduction assay

Do Islamic fundamental weighted indices outperform their conventional counterparts? An empirical investigation during the crises in the MENA region

This paper investigates the performance of Islamic fundamental weighted (FW) portfolios compared to that of non-Islamic counterparts, to examine whether Shari'ah-compliant stocks can protect investors during crises in the Middle East and North Africa region. Portfolios' performance is assessed using several risk-adjusted performance measures including more robust measures in the context of recently developed multi-factor models. The study's findings suggest that the performance of Islamic and non-Islamic FW portfolios depends on the performance measures used and on the periods under analysis. Both Islamic and non-Islamic FW portfolios underperform against the cap-weighted benchmark. Furthermore, the Islamic portfolios underperform compared to their non-Islamic counterparts during the period of the global financial crisis, while they perform similarly to their non-Islamic counterparts during the Arab Spring period. Based on these results, we conclude that Islamic FW portfolios do not seem to protect investors from losses during crises.This work was carried out within the funding with COMPETE reference no POCI-01-0145-FEDER006683, with the FCT/MEC's (Fundacaopara a Ciencia e a Tecnologia, I.P.) financial support through national funding and by the ERDF through the Operational Programme on "Competitiveness and Internationalization COMPETE 2020 under the PT2020 Partnership Agreement"