Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition.

Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy.

Risk of malignancies in patients with inflammatory bowel disease who used thiopurines as compared with other indications: a territory-wide study.

AIMS: Thiopurines are believed to increase cancer risks, but data from Asian patients are sparse. We determined the risks of malignancies in thiopurine users with inflammatory bowel disease (IBD) or other indications from Hong Kong. METHODS: All patients who had received thiopurines between 2005 and 2009 in Hong Kong were identified from local electronic healthcare database. Patients were followed from the start date of thiopurines until death or end of study in 2017. We excluded patients with baseline malignancy. Standardized incidence ratios (SIR) and the corresponding 95% confidence intervals (CI) of all malignancies were computed against matched local general population from the cancer registry. Patients in the same diagnosis category but not exposed to thiopurines were included as controls. RESULTS: There were 7452 thiopurines users (median age 47.0 years), including 595 IBD patients, with a median follow-up of 11.2 years. Of them, 684 (9.2%) developed malignancies with an overall SIR of 2.30 (95% CI 2.13-2.48). The SIR in IBD patients who used thiopurines was 2.37 (95% CI 1.71-3.18) as compared with non-users (SIR 1.35, 95% CI 1.05-1.72). Highest risk of malignancies was observed in post-transplant patients (SIR 3.83, 95% CI 3.34-4.35), and lower risks were seen in patients with rheumatological diseases (SIR 1.46, 95% CI 1.02-2.02). CONCLUSION: IBD patients in Hong Kong who used thiopurines had 2.37-fold increase in risk of malignancies than the general population, which was higher than non-users and different from thiopurine users for other indications.

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

Zafirlukast antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance.

ATP-binding cassette (ABC) transporters are present in the majority of human tumors and are involved in multidrug resistance (MDR). Therefore, compounds that inhibit the function of ABC transporters may improve the efficacy of anticancer agents. Previous research has shown that zafirlukast is a reversal drug for multidrug resistance protein (MRP) 1-mediated MDR. In the present study, we assessed whether zafirlukast could be a reversal agent for other ABC transporter-mediated MDR. Using the MTT assay, we found that zafirlukast enhanced the cytotoxicity of several anticancer drugs that are substrates of breast cancer resistance proteins (BCRP/ABCG2), including mitoxantrone and SN-38. Furthermore, zafirlukast could partially reverse P-glycoprotein-mediated (P-gp/ABCB1) and MRP7 (ABCC10)-mediated MDR at nontoxic doses. Studies on [(3)H]-mitoxantrone accumulation and efflux have shown that zafirlukast increases the intracellular accumulation of [(3)H]-mitoxantrone by directly inhibiting ABCG2-mediated drug efflux. Western blot analysis indicated that zafirlukast did not alter the expression of ABCG2. In addition, a docking model predicted the binding conformation of zafirlukast within the transmembrane region of homology-modeled human ABCG2. Our findings suggest a possible strategy to potentially enhance the activity of anticancer drugs using a clinically approved drug with known side effects and drug-drug interactions.