MicroRNA-187 inhibits pentylenetetrazol-induced neuronal apoptosis and alleviates development of epilepsy in epileptic rats by regulating SPRY1 expression

Purpose: To explore the role of microRNA-187 on the pathological process of epilepsy. Methods: The seizure score of epileptic rats was evaluated according to Racine’s scale. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression levels of microRNA-187 (miR-187). Western blot technique was conducted to assess the expression levels of caspase 3, B-cell lymphoma-2 (BCL-2), and poly (ADP-ribose) polymerase (PARP)] and activation of phosphatase and tensin homolog (PTEN)/PI3K/AKT cascade. Caspase 3 colorimetric assay kit was employed to evaluate the activity of caspase 3. Dual-luciferase reporter gene system was used to explore the regulating mechanisms of miR-187 and protein sprouty homolog 1 gene (SPRY1). Results: The results showed that miR-187 was aberrantly downregulated in the hippocampus regions of pentylenetetrazol (PTZ)-treated rats compared to normal rats (p < 0.05). Furthermore, PTZ promoted caspase 3-dependent neuronal apoptosis by increasing the expression of pro-apoptosis protein PARP and decreasing the expression levels of BCL-2 in rats. On the other hand, overexpression of miR-187 downregulated SPRY1 as well as PTEN (p < 0.05), thereby activating the downstream PI3K/AKT signaling pathway. Notably, the effects of upregulated miR-187 on neuronal apoptosis and epilepsy development in PTZ-induced rats was reversed by the concomitant overexpression of SPRY1 (p < 0.05). Conclusion: The results of this research show that overexpressed miR-187 alleviates the development of PTZ-induced neuronal apoptosis and epilepsy in epileptic rat models by regulating SPRY1 expression. These findings can hopefully be beneficial for the discovery of new therapeutic strategies for epilepsy treatment

Case report: Deep molecular remissions post two separate CD19-targeted chimeric antigen receptor T-cell therapies do not prevent disease from relapsing in Philadelphia chromosome-positive acute lymphoblastic leukemia

Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) is an aggressive B-cell malignancy. The management of a relapsed Ph+ ALL patient is challenging. Currently, either allogeneic stem cell transplant (allo-SCT) or CD19-targeted chimeric antigen receptor T-cell (CAR T-cell) are usually employed as salvage modalities for a relapsed patient. However, there are few reports concerning cases that had both allo-SCT and multiple CAR T-cell therapies, and the optimal management of such patients is unclear. Here, we report a relapsed Ph+ ALL male who was first salvaged with autologous CAR T-cell therapy, followed by allo-SCT. Unfortunately, he had a second relapse even with complete molecular remission (CMR) response after the first CAR T and allo-SCT. This patient was then successfully salvaged by a second CAR T-cell product that is donor-derived. However, even with a CMR response once again following the second CAR T-cell therapy and prophylactic donor lymphocyte infusion, he experienced a molecular relapse; ponatinib was employed as the subsequent salvage treatment. He achieved a CMR response following ponatinib and was still in remission at the last follow-up. No ABL kinase mutation was detected during the whole course of the disease. This case indicated that a repeated CD19-targeted CAR T-cell treatment is feasible and may be effective in a relapsed Ph+ ALL patient that had previous CAR T-cell and allo-SCT, even though both CAR T-cell have the same construction. However, even with a deep response after each CAR T-cell therapy and allo-SCT, there is still a very small amount of undetectable leukemic cells. The optimal management of Ph+ ALL patients who have a deep response after a second CAR T-cell therapy deserves further exploration