The contribution of Na1.6 to the efficacy of voltage-gated sodium channel inhibitors in wild type and Na1.6 gain-of-function (GOF) mouse seizure control.

Background And Purpose: Inhibitors of voltage-gated sodium channels (Nas) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na channels as a means of informing the development of improved antiseizure drugs.

Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na1.

Autologous human preclinical modeling of melanoma interpatient clinical responses to immunotherapeutics.

Background: Despite recent advances in immunotherapy, a substantial population of late-stage melanoma patients still fail to achieve sustained clinical benefit. Lack of translational preclinical models continues to be a major challenge in the field of immunotherapy; thus, more optimized translational models could strongly influence clinical trial development. To address this unmet need, we designed a preclinical model reflecting the heterogeneity in melanoma patients' clinical responses that can be used to evaluate novel immunotherapies and synergistic combinatorial treatment strategies.

Potassium channelopathies associated with epilepsy-related syndromes and directions for therapeutic intervention.

A number of mutations to members of several CNS potassium (K) channel families have been identified which result in rare forms of neonatal onset epilepsy, or syndromes of which one prominent characteristic is a form of epilepsy. Benign Familial Neonatal Convulsions or Seizures (BFNC or BFNS), also referred to as Self-Limited Familial Neonatal Epilepsy (SeLNE), results from mutations in 2 members of the K7 family (KCNQ) of K channels; while generally self-resolving by about 15 weeks of age, these mutations significantly increase the probability of generalized seizure disorders in the adult, in some cases they result in more severe developmental syndromes. Epilepsy of Infancy with Migrating Focal Seizures (EIMSF), or Migrating Partial Seizures of Infancy (MMPSI), is a rare severe form of epilepsy linked primarily to gain of function mutations in a member of the sodium-dependent K channel family, KCNT1 or SLACK.

Nemvaleukin alfa, a novel engineered IL-2 fusion protein, drives antitumor immunity and inhibits tumor growth in small cell lung cancer.

Background: Small cell lung cancer (SCLC) is a deadly disease with a 5-year survival of less than 7%. The addition of immunotherapy to chemotherapy was recently approved as first-line treatment; however, the improved clinical benefit is modest, highlighting an urgent need for new treatment strategies. Nemvaleukin alfa, a novel engineered interleukin-2 fusion protein currently in phase I-III studies, is designed to selectively expand cytotoxic natural killer (NK) cells and CD8 T cells.

Cardiovascular effects of GLP-1 receptor agonism.

Glucagon-like peptide-1 (GLP-1) receptor agonists are extensively used in type 2 diabetic patients for the effective control of hyperglycemia. It is now clear from outcomes trials that this class of drugs offers important additional benefits to these patients due to reducing the risk of developing major adverse cardiac events (MACE). This risk reduction is, in part, due to effective glycemic control in patients; however, the various outcomes trials, further validated by subsequent meta-analysis of the outcomes trials, suggest that the risk reduction in MACE is also dependent on glycemic-independent mechanisms operant in cardiovascular tissues.