Pediatric TAFRO syndrome: A multi-institution case series illustrating clinical challenges and excellent outcomes.

A rare lymphoproliferative disorder involving thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), renal dysfunction (R), and organomegaly (O), called TAFRO syndrome, was first reported in 2010. Considered a variant of idiopathic multicentric Castleman's disease, the recent discovery and rarity of this syndrome pose challenges to diagnosis and management. Herein, we review three pediatric cases, including an infant, that illustrate the heterogeneity of TAFRO syndrome. Despite differences in presentation and treatment responses, all patients experienced excellent outcomes. This multi-institutional case series highlights the need to work toward earlier diagnosis and improved long-term management recommendations for patients with TAFRO syndrome.

Pharmacological inhibition of ENT1 enhances the impact of specific dietary fats on energy metabolism gene expression.

Medium chain fatty acids are commonly consumed as part of diets for endurance sports and as medical treatment in ketogenic diets where these diets regulate energy metabolism and increase adenosine levels. However, the role of the equilibrative nucleoside transporter 1 (ENT1), which is responsible for adenosine transport across membranes in this process, is not well understood. Here, we investigate ENT1 activity in controlling the effects of two dietary medium chain fatty acids (decanoic and octanoic acid), employing the tractable model system Dictyostelium. We show that genetic ablation of three ENT1 orthologues unexpectedly improves cell proliferation specifically following decanoic acid treatment. This effect is not caused by increased adenosine levels triggered by both fatty acids in the presence of ENT1 activity. Instead, we show that decanoic acid increases expression of energy-related genes relevant for fatty acid ß-oxidation, and that pharmacological inhibition of ENT1 activity leads to an enhanced effect of decanoic acid to increase expression of tricarboxylicacid cycle and oxidative phosphorylation components. Importantly, similar transcriptional changes have been shown in the rat hippocampus during ketogenic diet treatment. We validated these changes by showing enhanced mitochondria load and reduced lipid droplets. Thus, our data show that ENT1 regulates the medium chain fatty acid-induced increase in cellular adenosine levels and the decanoic acid-induced expression of important metabolic enzymes in energy provision, identifying a key role for ENT1 proteins in metabolic effects of medium chain fatty acids.

Illness Trajectories After Revascularization in Patients With Peripheral Artery Disease: A Unified Approach to Understanding the Risk of Major Amputation and Death.

BACKGROUND: The aim of this study was to investigate the illness trajectories of patients with peripheral artery disease (PAD) after revascularization and estimate the independent risks of major amputation and death (from any cause) and their interaction. METHODS: Data from Hospital Episode Statistics Admitted Patient Care were used to identify patients (≥50 years of age) who underwent lower limb revascularization for PAD in England from April 2013 to March 2020. A Markov illness-death model was developed to describe patterns of survival after the initial lower limb revascularization, if and when patients experienced major amputation, and survival after amputation. The model was also used to investigate the association between patient characteristics and these illness trajectories. We also analyzed the relative contribution of deaths after amputation to overall mortality and how the risk of mortality after amputation was related to the time from the index revascularization to amputation. RESULTS: The study analyzed 94 690 patients undergoing lower limb revascularization for PAD from 2013 to 2020. The majority were men (65.6%), and the median age was 72 years (interquartile range, 64-79). One-third (34.8%) of patients had nonelective revascularization, whereas others had elective procedures. For nonelective patients, the amputation rate was 15.2% (95% CI, 14.4-16.0) and 19.9% (19.0-20.8) at 1 and 5 years after revascularization, respectively. For elective patients, the corresponding amputation rate was 2.7% (95% CI, 2.4-3.1) and 5.3% (4.9-5.8). Overall, the risk of major amputation was higher among patients who were younger, had tissue loss, diabetes, greater frailty, nonelective revascularization, and more distal procedures. The mortality rate at 5 years after revascularization was 64.3% (95% CI, 63.2-65.5) for nonelective patients and 33.0% (32.0-34.1) for elective patients. After major amputation, patients were at an increased risk of mortality if they underwent major amputation within 6 months after the index revascularization. CONCLUSIONS: The illness-death model provides an integrated framework to understand patient outcomes after lower limb revascularization for PAD. Although mortality increased with age, the study highlights patients <60 years of age were at increased risk of major amputation, particularly after nonelective revascularization.

Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma.

Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system Dictyostelium discoideum and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In D. discoideum, T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn-) or MIOS (mios-). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the D. discoideum mios- cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified.

Functional mechanism study of the allelochemical myrigalone A identifies a group of ultrapotent inhibitors of ethylene biosynthesis in plants.

Allelochemicals represent a class of natural products released by plants as root, leaf, and fruit exudates that interfere with the growth and survival of neighboring plants. Understanding how allelochemicals function to regulate plant responses may provide valuable new approaches to better control plant function. One such allelochemical, Myrigalone A (MyA) produced by Myrica gale, inhibits seed germination and seedling growth through an unknown mechanism. Here, we investigate MyA using the tractable model Dictyostelium discoideum and reveal that its activity depends on the conserved homolog of the plant ethylene synthesis protein 1-aminocyclopropane-1-carboxylic acid oxidase (ACO). Furthermore, in silico modeling predicts the direct binding of MyA to ACO within the catalytic pocket. In D. discoideum, ablation of ACO mimics the MyA-dependent developmental delay, which is partially restored by exogenous ethylene, and MyA reduces ethylene production. In Arabidopsis thaliana, MyA treatment delays seed germination, and this effect is rescued by exogenous ethylene. It also mimics the effect of established ACO inhibitors on root and hypocotyl extension, blocks ethylene-dependent root hair production, and reduces ethylene production. Finally, in silico binding analyses identify a range of highly potent ethylene inhibitors that block ethylene-dependent response and reduce ethylene production in Arabidopsis. Thus, we demonstrate a molecular mechanism by which the allelochemical MyA reduces ethylene biosynthesis and identify a range of ultrapotent inhibitors of ethylene-regulated responses.

A phase 1/2 study of pepinemab in children, adolescents, or young adults with recurrent or refractory solid tumors: A children's oncology group consortium report (ADVL1614).

PURPOSE: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma. EXPERIMENTAL DESIGN: Pepinemab was administered intravenously on Days 1 and 15 of a 28-day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2-stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood. RESULTS: Pepinemab (20 mg/kg) was well tolerated and no dose-limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults. CONCLUSIONS: Pepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response. CLINICAL TRIAL REGISTRY: This trial is registered as NCT03320330 at Clinicaltrials.gov. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Concerted adoption as an emerging strategy for digital transformation of healthcare-lessons from Australia, Canada, and England.

OBJECTIVES: With an increasing focus on the digitalization of health and care settings, there is significant scope to learn from international approaches to promote concerted adoption of electronic health records. MATERIALS AND METHODS: We review three large-scale initiatives from Australia, Canada, and England, and extract common lessons for future health and social care transformation strategy. RESULTS: We discuss how, despite differences in contexts, concerted adoption enables sharing of experience and learning to streamline the digital transformation of health and care. DISCUSSION AND CONCLUSION: Concerted adoption can be accelerated through building communities of expertise and partnerships promoting knowledge transfer and circulation of expertise; commonalities in geographical and cultural contexts; and commonalities in technological systems.

The Impact of Pre-Operative Anaemia on One Year Amputation Free Survival and Re-Admissions in Patients Undergoing Vascular Surgery for Peripheral Arterial Disease: a National Vascular Registry Study.

OBJECTIVE: Anaemia is common among patients undergoing surgery, but its association with post-operative outcomes in patients with peripheral arterial disease (PAD) is unclear. The aim of this observational population based study was to examine the association between pre-operative anaemia and one year outcomes after surgical revascularisation for PAD. METHODS: This study used data from the National Vascular Registry, linked with an administrative database (Hospital Episode Statistics), to identify patients who underwent open surgical lower limb revascularisation for PAD in English NHS hospitals between January 2016 and December 2019. The primary outcome was one year amputation free survival. Secondary outcomes were one year re-admission rate, 30 day re-intervention rate, 30 day ipsilateral major amputation rate and 30 day death. Flexible parametric survival analysis and generalised linear regression were performed to assess the effect of anaemia on one year outcomes. RESULTS: The analysis included 13 641 patients, 57.9% of whom had no anaemia, 23.8% mild, and 18.3% moderate or severe anaemia. At one year follow up, 80.6% of patients were alive and amputation free. The risk of one year amputation or death was elevated in patients with mild anaemia (adjusted HR 1.3; 95% CI 1.15 - 1.41) and moderate or severe anaemia (aHR 1.5; 1.33 - 1.67). Patients with moderate or severe anaemia experienced more re-admissions over one year (adjusted IRR 1.31; 1.26 - 1.37) and had higher odds of 30 day re-interventions (aOR 1.22; 1.04 - 1.45), 30 day ipsilateral major amputation (aOR 1.53; 1.17 - 2.01), and 30 day death (aOR 1.39; 1.03 - 1.88) compared with patients with no anaemia. CONCLUSION: Pre-operative anaemia is associated with lower one year amputation free survival and higher one year re-admission rates following surgical revascularisation in patients with PAD. Research is required to evaluate whether interventions to correct anaemia improve outcomes after lower limb revascularisation.

Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth.

Glioblastomas are a highly aggressive cancer type which respond poorly to current pharmaceutical treatments, thus novel therapeutic approaches need to be investigated. One such approach involves the use of the bioactive natural product Tanshinone IIA (T2A) derived from the Chinese herb Danshen, where mechanistic insight for this anti-cancer agent is needed to validate its use. Here, we employ a tractable model system, Dictyostelium discoideum, to provide this insight. T2A potently inhibits cellular proliferation of Dictyostelium, suggesting molecular targets in this model. We show that T2A rapidly reduces phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB) activity, but surprisingly, the downstream complex mechanistic target of rapamycin complex 1 (mTORC1) is only inhibited following chronic treatment. Investigating regulators of mTORC1, including PKB, tuberous sclerosis complex (TSC), and AMP-activated protein kinase (AMPK), suggests these enzymes were not responsible for this effect, implicating an additional molecular mechanism of T2A. We identify this mechanism as the increased expression of sestrin, a negative regulator of mTORC1. We further show that combinatory treatment using a PI3K inhibitor and T2A gives rise to a synergistic inhibition of cell proliferation. We then translate our findings to human and mouse-derived glioblastoma cell lines, where both a PI3K inhibitor (Paxalisib) and T2A reduces glioblastoma proliferation in monolayer cultures and in spheroid expansion, with combinatory treatment significantly enhancing this effect. Thus, we propose a new approach for cancer treatment, including glioblastomas, through combinatory treatment with PI3K inhibitors and T2A.

Editor's Choice - Outcomes of Surgery for Patients with Peripheral Arterial Disease During the COVID-19 Pandemic in the United Kingdom: A Population Based Study.

OBJECTIVE: There is limited information on changes in the patterns of care and outcomes for patients who had vascular procedures after the first wave of the COVID-19 pandemic. The aim of this population based study was to examine the patterns of care and outcomes for vascular lower limb procedures in the UK during the COVID-19 pandemic. METHODS: Lower limb revascularisations and major amputations performed from January 2019 to April 2021 in the UK and entered in the National Vascular Registry were included in the study. The primary outcome was in hospital post-operative death and secondary outcomes were complications and re-interventions. The study was divided into Pre-pandemic (1 January 2019 - 29 February 2020), Wave 1 (1 March - 30 June 2020), Respite (1 July - 31 October 2020), Wave 2/3 (1 November 2020 - 30 April 2021). RESULTS: The study included 36 938 procedures (7 245 major amputations, 16 712 endovascular, 12 981 open revascularisations), with 15 501 procedures after March 2020, a 27.7% reduction compared with pre-pandemic. The proportion of open surgical procedures performed under general anaesthetic was lower in Wave 1 and after compared with pre-pandemic (76.7% vs. 81.9%, p < .001). Only 4.6% of patients in the cohort had SARS-CoV-2 infection (n = 708), but their in hospital post-operative mortality rate was 25.0% (n = 177), six times higher than patients without SARS-CoV-2 (adjusted odds ratio 5.88; 95% CI 4.80 - 7.21, p < .001). The in hospital mortality rate was higher during the pandemic than pre-pandemic after elective open and endovascular revascularisation (respectively 1.6% vs. 1.1%, p = .033, and 0.9% vs. 0.5%, p = .005) and after major amputations (10.4% during Wave 2/3 vs. 7.7% pre-pandemic, p = .022). CONCLUSION: There was excess post-operative mortality rate for patients undergoing lower limb vascular procedures during the pandemic, which was associated with SARS-CoV-2 infections. Further research should be conducted on long term outcomes of patients operated on during the COVID-19 pandemic period.

Anti-emetic effects of thalidomide: Evidence, mechanism of action, and future directions.

The rationale for using thalidomide (THD) as a treatment for nausea and vomiting during pregnancy in the late 1950s appears to have been based on its sedative or hypnotic properties. In contrast to contemporaneous studies on the anti-emetic activity of phenothiazines, we were unable to identify publications reporting preclinical or clinical evaluation of THD as an anti-emetic. Our survey of the literature revealed a clinical study in 1965 showing THD reduced vomiting in cancer chemotherapy which was substantiated by similar studies from 2000, particularly showing efficacy in the delayed phase of chemotherapy-induced nausea and vomiting. To identify the mechanism(s) potentially involved in thalidomide's anti-emetic activity we reviewed its pharmacology in the light of nausea and vomiting mechanisms and their pharmacology with a particular emphasis on chemotherapy and pregnancy. The process identified the following potential mechanisms: reduced secretion of Growth Differentiation Factor 15, suppression of inflammation/prostaglandin production, downregulation of cytotoxic drug induced upregulation of iNOS, and modulation of BK (KCa1.1) channels and GABAA/glutamate transmission at critical points in the emetic pathways (nucleus tractus solitarius, area postrema). We propose ways to investigate these hypothesized mechanisms and discuss the associated challenges (e.g., objective quantification of nausea) in addition to some of the more general aspects of developing novel drugs to treat nausea and vomiting.

CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.

The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML) and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G-fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, folate receptor α (FOLR1), and demonstrated their preclinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.

Neutropenia in pediatric solid organ transplant.

Neutropenia is generally defined as an absolute neutrophil count in the circulation of less than 1500/mm3 and occurs in up to 25%-30% of pediatric solid organ transplant recipients (SOT) within the first year after transplantation. In the SOT population, neutropenia is most often a result of drug-induced bone marrow suppression but can also be secondary to viral infection, nutritional deficiencies, lymphoproliferative infiltrate, and inherited causes. Outcomes for patients with neutropenia vary by degree of neutropenia and type of solid organ transplant. Management of neutropenia should begin by addressing the underlying cause, including reducing or removing medications when appropriate, treating infections, and addressing nutrient deficiencies; however, consultation with an experienced pediatric hematologist and use of granulocyte colony-stimulating factor (G-CSF) may be helpful in some cases. Overall, data on clinical outcomes for G-CSF use remain limited, but observational studies may support its use in patients with infections or severe neutropenia.

If You Can See It, You Can Be It: Perceptions of Diversity in Surgery Among Under-Represented Minority High School Students.

PURPOSE: Increasing racial and ethnic diversity in the surgical workforce is essential to improving outcomes for marginalized communities. To address the persistent shortage of under-represented minority (URM) surgeons, this study assessed the impact of providing early exposure to the field of surgery on URM high school students' perceptions of pursuing surgical careers. METHODS: The Association of Women Surgeons organized a pilot 3-hour "Day in the Life" virtual event geared toward URM high school students involving suturing/knot-tying, case conferences, and mentoring activities. RESULTS: Pre- and post-event survey results from 65 participants showed that students became more familiar with surgery (p < 0.001) and perceived the field as more diverse (p = 0.017). Over 70% felt capable of becoming surgeons themselves and over 80% were interested in learning more and gaining mentorship. CONCLUSIONS: Our programming provides a model for future initiatives aimed at strengthening the pipeline of URM surgeons.

Compatibility of intravenous acetaminophen with morphine, fentanyl and ketamine in acute pediatric pain setting.

BACKGROUND: Intravenous acetaminophen and opioid analgesics are routinely given concurrently to children after major surgery, where intravenous access can be limited. There is limited information about the compatibility of acetaminophen with opioid analgesics and ketamine in concentrations commonly used in pediatric setting. AIMS: We aimed to determine the physical and chemical compatibility in mixtures of intravenous acetaminophen 10 mg/mL with morphine (0.025, 0.05, 0.1, 0.2, 1, and 2 mg/ml), fentanyl (0.5, 0.75, 1, 1.5, 2, and 5 mcg/ml) and ketamine (0.01, 0.1, 0.5, 1, 1.5, and 3 mg/ml). METHODS: Acetaminophen was mixed with all 18 solutions and was examined at time 0, 15, 30, and 60 min. In Phase one of the study, we used a colorimetric method to assess preliminary feasibility and acetaminophen recovery. In Phase two study, we used high-performance liquid chromatography to evaluate the recovery of all components of the mixtures. RESULTS: All solutions tested, for both acetaminophen and the three analgesics, had more than 90% of the drug recovery, up to 60 min after mixing. CONCLUSION: Our data demonstrated the stability of acetaminophen, in combination with fentanyl, morphine, and ketamine at clinical concentrations used in acute pediatric pain setting.

Social Deprivation and the Association With Survival Following Fenestrated Endovascular Aneurysm Repair.

BACKGROUND: Social deprivation is associated with poor clinical outcomes. It is known to have an impact on length of stay and post-operative mortality across a number of other surgical specialties. This study evaluates the impact of social deprivation on outcomes following fenestrated endovascular aneurysm repair (FEVAR). METHODS: All elective FEVARs performed between 2010 and 2018 at a tertiary vascular center were analyzed. Deprivation (index of multiple deprivation [IMD]) data was sourced from the English indices of deprivation 2019, by postcode. Primary outcome was overall survival by Kaplan-Meier. Secondary outcomes included length of hospital stay (LOS) and complications. Cox-proportional hazard analyses were conducted. RESULTS: Some 132 FEVAR patients were followed-up for 3.7 (SD 2.2) years. Fifty-seven patients lived in areas with high levels of deprivation (IMD 1-3), 34 in areas with moderate deprivation (IMD 4-6) and 41 in areas with the lowest level (IMD 7-10) of deprivation. Groups were comparable for Age, BMI, AAA diameter and co-morbidity. A higher proportion of patients from deprived areas had renal failure (15% [26.3%] vs. 9% [11.8%] P = 0.019) but no overall difference in procedure time was observed (200 min [155-250] vs. 180 min [145-240] P = 0.412). Kaplan-Meier analysis demonstrated significantly poorer survival for patients living in areas with high levels of deprivation (IMD 1-3) (P = 0.03). Mortality was comparable for IMD 4-6 and 7-10 groups. Patients from the most deprived areas had longer hospital stay (6 days [4-9] vs. 5 [3-7] P = 0.005) and higher all-cause complication rates (21 [36.8%] vs. 14 [18.4%] P = 0.02). Decreasing IMD was associated with worse survival (HR -0.85 [0.75-0.97] [P = 0.02]). CONCLUSIONS: Social deprivation was associated with increased mortality, length of stay and all-cause complication rates in patients undergoing FEVAR for complex abdominal aortic aneurysm (AAA). These results may help direct preoptimization measures to improve outcomes in higher risk sub-groups.

Structural basis of AMPA receptor inhibition by trans-4-butylcyclohexane carboxylic acid.

BACKGROUND AND PURPOSE: AMPA receptors, which shape excitatory postsynaptic currents and are directly involved in overactivation of synaptic function during seizures, represent a well-accepted target for anti-epileptic drugs. Trans-4-butylcyclohexane carboxylic acid (4-BCCA) has emerged as a new promising anti-epileptic drug in several in vitro and in vivo seizure models, but the mechanism of its action remained unknown. The purpose of this study is to characterize structure and dynamics of 4-BCCA interaction with AMPA receptors. EXPERIMENTAL APPROACH: We studied the molecular mechanism of AMPA receptor inhibition by 4-BCCA using a combination of X-ray crystallography, mutagenesis, electrophysiological assays, and molecular dynamics simulations. KEY RESULTS: We identified 4-BCCA binding sites in the transmembrane domain (TMD) of AMPA receptor, at the lateral portals formed by transmembrane segments M1-M4. At this binding site, 4-BCCA is very dynamic, assumes multiple poses, and can enter the ion channel pore. CONCLUSION AND IMPLICATIONS: 4-BCCA represents a low-affinity inhibitor of AMPA receptors that acts at the TMD sites distinct from non-competitive inhibitors, such as the anti-epileptic drug perampanel and the ion channel blockers. Further studies might examine the possibsility of synergistic use of these inhibitors in treatment of epilepsy and a wide range of neurological disorders and gliomas. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.