Evaluation of perampanel as monotherapy for focal seizures: Experience from open-label extension studies

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic–clonic seizures in patients with epilepsy aged ≥ 12 years. Perampanel was recently approved for monotherapy use for focal seizures in the U.S.A. Anti-seizure drug monotherapy may be preferable to polytherapy, which is generally associated with increased toxicity, non-compliance, and cost. Here, we report cases where patients had converted to perampanel monotherapy during open-label extension (OLEx) portions of 9 Phase II and III studies. Of 2245 patients who enrolled in the OLEx studies, we identified 7 patients with drug-resistant focal seizures who discontinued all non-perampanel anti-seizure drugs and were maintained on perampanel monotherapy for ≥ 91 days until the end of data cut-off. Patients received perampanel monotherapy for up to 1099 days (157 weeks), most at a modal dose of 12 mg. Seizure data were available for 6 patients, of whom 5 had a ≥ 90% reduction in overall seizure frequency between baseline and their last 13-week period of monotherapy (3 were seizure-free). Perampanel monotherapy was generally well tolerated and the safety profile during perampanel monotherapy was consistent with clinical and post-marketing experience in the adjunctive setting. This analysis included a small proportion of patients with highly drug-resistant focal seizures who converted to monotherapy during OLEx studies. While these limited data are encouraging in suggesting that perampanel might be useful as a monotherapy, further studies are required to explore outcomes in a less drug-resistant population, where a larger proportion of patients might benefit from monotherapy. © 2017 The Author

Chemical aspects related to using recycled geopolymers as aggregates

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Despite extensive research into sustainability of geopolymers, end-of-life aspects have been largely overlooked. A recycling scenario is examined in this study. This requires an investigation of alkali leaching potential from a geopolymeric matrix. To study the feasibility of geopolymer cement (GPC) recycling, the migration of alkalis was evaluated for the first time on a microstructural level through energy dispersive X-ray (EDX) scanning electron microscopy (SEM) elemental mapping and leaching tests. Macroscale impacts were assessed through an investigation of Portland cement (PC) mortar properties affected by alkali concentration. Leaching tests indicated that alkalis immediately become available in aqueous environments, but the majority remain chemically or physically bound in the matrix. This type of leaching accelerates the initial setting of PC paste. Elemental mapping and EDX/SEM analysis showed a complex paste-aggregate interfacial transition zone. Exchange of calcium and sodium, revealed by the maps, resulted in the migration of sodium into the PC paste and the formation of additional calcium-silicon-based phases in the geopolymeric matrix. Strength values of mortars with 25% and 50% recycled aggregates (RA) showed negligible differences compared with the reference sample. Screening tests indicated a low potential for GPC RA inducing alkali-silica reaction. Transport of GPC RA alkalis and the underlying mechanisms were observed. This transport phenomenon was found to have minor effects on the properties of the PC mortar, indicating that recycling of geopolymers is a viable reuse practice.Peer reviewedFinal Published versio

Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

Càncer d'ovaris; Biomarcadors tumoralsCáncer de ovarios; Biomarcadores tumoralesOvarian cancer; Tumour biomarkersARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity

final safety tolerability and seizure outcomes in patients with focal epilepsy treated with adjunctive perampanel for up to 4 years in an open label extension of phase iii randomized trials study 307

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Predation stress causes excessive aggression in female mice with partial genetic inactivation of Tryptophan hydroxylase-2: evidence for altered myelination-related processes

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2-/-) mice. In heterozygous male mice (Tph2+/-), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2+/- mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2+/- females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2+/- mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior.The authors’ animal work reported here was supported by Deutsche Forschungsgemeinschaft (DFG:CRC TRR58A1/A5), the European Union’s Seventh Framework Programme (FP7/2007–2013) under Grant No. 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNice) (to K.-P.L. and T.S.) and Grant No. 101007642 (PhytoAPP) (to D.C.A. and T.S.), and Swiss-Russian Cooperation grant RPG Russia 2020 (to S.W. and K.-P.L.). Molecular data analysis was supported by RAS N0520-2019-0031 (to E.S. and T.S.).info:eu-repo/semantics/publishedVersio

Predation Stress Causes Excessive Aggression in Female Mice with Partial Genetic Inactivation of Tryptophan Hydroxylase-2: Evidence for Altered Myelination-Related Processes

The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2-/-) mice. In heterozygous male mice (Tph2+/-), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2+/- mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2+/- females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2+/- mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior. Keywords: 5-HT receptors; female aggression; glycogen synthase kinase-3 β (GSK-3β); myelination; predation stress; tryptophan hydroxylase-2 (Tph2)

A bidirectional study of the association between insomnia, high-sensitivity C-reactive protein, and comorbid low back pain and lower limb pain

Objectives - To examine the possible bidirectional association between insomnia and comorbid chronic low back pain (LBP) and lower limb pain and to explore whether high-sensitivity C-reactive protein (hsCRP) amplifies these associations. Methods - We calculated adjusted risk ratios (RR) with 95% confidence intervals (CI) for the development of insomnia and mild-to-severe chronic LBP and lower limb pain at 11 years follow-up in participants aged ≥32 years and with hsCRP ≤10 mg/L at baseline in 2007–2008: 3,714 without chronic LBP or lower limb pain (sample 1) and 7,892 without insomnia (sample 2). Results - Compared to participants without chronic pain, participants with comorbid chronic LBP and lower limb pain had a RR of insomnia of 1.37 (95% CI 1.12–1.66). Compared with participants without insomnia, participants with insomnia did not have an increased risk of comorbid chronic LBP and lower limb pain (RR: 1.06, 95% CI 0.76–1.46); however, participants with insomnia had a RR of chronic LBP of 1.20 (95% CI 1.02–1.42). There was no strong amplifying effect of elevated hsCRP (3.00–10.0 mg/L) on these associations. Conclusions - These findings suggest that elevated hsCRP does not amplify the associations between insomnia and mild-to-severe chronic LBP and lower limb pain. Further research using data on the temporal relation between insomnia, chronic pain, and inflammatory responses are required to fully understand the causal pathways

Integrated Omics Reveals the Orchestrating Role of Calycosin in Danggui Buxue Tang, a Herbal Formula Containing Angelicae Sinensis Radix and Astragali Radix, in Inducing Osteoblastic Differentiation and Proliferation

Systems biology unravels the black box of signaling pathway of cells; but which has not been extensively applied to reveal the mechanistic synergy of a herbal formula. The therapeutic efficacies of a herbal formula having multi-target, multi-function and multi-pathway are the niches of traditional Chinese medicine (TCM). Here, we reported an integrated omics approach, coupled with the knockout of an active compound, to measure the regulation of cellular signaling, as to reveal the landscape in cultured rat osteoblasts having synergistic pharmacological efficacy of Danggui Buxue Tang (DBT), a Chinese herbal formula containing Angelicae Sinensis Radix and Astragali Radix. The changes in signaling pathways responsible for energy metabolism, RNA metabolism and protein metabolism showed distinct features between DBT and calycosin-depleted DBT. Here, our results show that calycosin within DBT can orchestrate the osteoblastic functions and signaling pathways of the entire herbal formula. This finding reveals the harmony of herbal medicine in pharmacological functions, as well as the design of drug/herbal medicine formulation. The integration of systems biology can provide novel and essential insights into the synergistic property of a herbal formula, which is a key in modernizing TCM