A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The patho- mechanisms of rare epilepsies are, however, increasingly understood, which poten- tially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epi- lepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), au- toimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was gener- ated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were pre- sent in most responding centers for TSC (87%), Dravet syndrome (85%), and auto- immune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppres- sive therapies in autoimmune encephalitis. Screening for comorbidities was rou- tinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential partici- pants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers

Cognitive Profile of Zonisamide and Valproic Acid in the Treatment of Idiopathic Generalized Epilepsy: A Comparative Observational Study

Introduction: Calls for an alternative to valproic acid (VPA) as drug of choice for idiopathic generalized epilepsies (IGEs) have intensified since the recent International League Against Epilepsy recommendation that the drug should not be administered to women of childbearing age. Zonisamide (ZNS), a third-generation antiepileptic drug, has proven effective in generalized seizures and could be considered an alternative to VPA in this population.Objectives: The present study was designed to examine possible differences in cognitive profile between ZNS and VPA as monotherapy in patients with IGE in real-life settings.Methods: We conducted a comparative, descriptive, observational, retrospective cohort study in two groups of patients diagnosed with IGE treated with ZNS C200 mg/day or VPA C1000 mg/day as stable monotherapy for at least the previous 6 months. We used specific neuropsychological tests for short-and long-term mnemonic functions, working memory, visuospatial speed, attention and processing speed, verbal fluency, executive functions, visual perception, abstraction, anxiety, depression, and apathy.Results: We included 16 patients in the study: eight in the VPA and eight in the ZNS group. Significantly superior mean scores were obtained by the VPA group in working memory (Forward Digits test) and by the ZNS group in execution time for the Rey-Osterrieth complex figure test. No statistically significant differences were found between the groups in the remaining tests.Conclusion: Zonisamide as monotherapy has a similar cognitive profile to that of VPA in patients with IGE. The final treatment selection setting should be individualized. ZNS may be a reasonable alternative to VPA in some cases in this population

Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.

Clinical studies report that viral infections promote acute or chronic bacterial infections at multiple host sites. These viral-bacterial co-infections are widely linked to more severe clinical outcomes. In experimental models in vitro and in vivo, virus-induced interferon responses can augment host susceptibility to secondary bacterial infection. Here, we used a cell-based screen to assess 389 interferon-stimulated genes (ISGs) for their ability to induce chronic Pseudomonas aeruginosa infection. We identified and validated five ISGs that were sufficient to promote bacterial infection. Furthermore, we dissected the mechanism of action of hexokinase 2 (HK2), a gene involved in the induction of aerobic glycolysis, commonly known as the Warburg effect. We report that HK2 upregulation mediates the induction of Warburg effect and secretion of L-lactate, which enhances chronic P. aeruginosa infection. These findings elucidate how the antiviral immune response renders the host susceptible to secondary bacterial infection, revealing potential strategies for viral-bacterial co-infection treatment

Efficient phenanthrene, helicene, and azahelicene syntheses

Homolytic aromatic substitution reactions are used for the efficient regioselective synthesis of helicenes, phenanthrenes, and azahelicenes. The use of halo and alkoxy substituents to control the stereochemical outcome of this approach and X-ray studies of the resulting helicenes are described (see structure; red O, gray C)

RUNX1c Regulates Hematopoietic Differentiation of Human Pluripotent Stem Cells Possibly in Cooperation with Proinflammatory Signaling.

Runt-related transcription factor 1 (Runx1) is a master hematopoietic transcription factor essential for hematopoietic stem cell (HSC) emergence. Runx1-deficient mice die during early embryogenesis due to the inability to establish definitive hematopoiesis. Here, we have used human pluripotent stem cells (hPSCs) as model to study the role of RUNX1 in human embryonic hematopoiesis. Although the three RUNX1 isoforms a, b, and c were induced in CD45+ hematopoietic cells, RUNX1c was the only isoform induced in hematoendothelial progenitors (HEPs)/hemogenic endothelium. Constitutive expression of RUNX1c in human embryonic stem cells enhanced the appearance of HEPs, including hemogenic (CD43+) HEPs and promoted subsequent differentiation into blood cells. Conversely, specific deletion of RUNX1c dramatically reduced the generation of hematopoietic cells from HEPs, indicating that RUNX1c is a master regulator of human hematopoietic development. Gene expression profiling of HEPs revealed a RUNX1c-induced proinflammatory molecular signature, supporting previous studies demonstrating proinflammatory signaling as a regulator of HSC emergence. Collectively, RUNX1c orchestrates hematopoietic specification of hPSCs, possibly in cooperation with proinflammatory signaling. Stem Cells 2017;35:2253-2266

Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines

Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings.SCOPUS: re.jinfo:eu-repo/semantics/publishe