Background. Electrical stimulation of damaged peripheral nerve may aid regeneration. Objective. The purpose of this study was to determine whether 1 mA of percutaneous electrical stimulation at 1, 2, 20, or 200 Hz augments regeneration between the proximal and distal nerve stumps. Methods. A10-mm gap was made in rat sciatic nerve by suturing the stumps into silicone rubber tubes. A control group received no stimulation. Starting 1 week after transection, electrical stimulation was applied between the cathode placed at the distal stump and the anode at the proximal stump every other day for 6 weeks. Results. Higher frequency stimulation led to less regeneration compared to lower frequencies. Quantitative histology of the successfully regenerated nerves revealed that the groups receiving electrical treatment, especially at 2 Hz, had a more mature structure with a smaller cross-sectional area, more myelinated fibers, higher axon density, and higher ratio of blood vessel to total nerve area compared with the controls. Electrophysiology showed significantly shorter latency, longer duration, and faster conduction velocity. Conclusion. Electrical stimulation can have either a positive or negative impact on peripheral nerve regeneration. Clinical trials that combine stimulation with rehabilitation must determine the parameters that are most likely to be safe and effective.

Background: The tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins, and microRNAs. Results: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Coculture of GAMs (and GAM-derived exosomes) and GBM cell lines increased GBM cells’ resistance against temozolomide (TMZ) by upregulating the prosurvival gene programmed cell death protein 4 (PDCD4) and stemness markers SRY (sex determining region y)-box 2 (Sox2), signal transducer and activator of transcription 3 (STAT3), Nestin, and miR-21-5p and increasing the M2 cytokines interleukin 6 (IL-6) and transforming growth factor beta 1(TGF-β1) secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed a markedly reduced ability to secret M2 cytokines and reduced miR-21-enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which the tumor suppressor PDCD4 was targeted. We subsequently established patient-derived xenograft (PDX) models where mice bore patient GBM and GAMs. Treatment with pacritinib and the combination of pacritinib and TMZ appeared to significantly reduce the tumorigenesis of GBM/GAM PDX mice as well as overcome TMZ resistance and M2 polarization of GAMs. Conclusion: In summation, we showed the potential of pacritinib alone or in combination with TMZ to suppress GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in clinical settings.

Background. The timing of electrical stimulation (ES) after peripheral nerve transection may enhance axonal regeneration and functional recovery. Objective. The authors examined whether percutaneous ES at 1 mA and 2 Hz affects regeneration between the proximal and distal nerve stumps. Methods. Four groups of adult rats were subjected to sciatic nerve section followed by repair using silicone rubber conduits across a 10-mm gap. All groups received ES for 15 minutes every other day for 2 weeks. Stimulation was initiated on day 1 following the nerve repair for group A, day 8 for group B, and day 15 for group C. The control group D received no ES. Results. At 6 weeks after surgery in groups B and C, histological evaluations showed a significantly higher number of regenerated myelinated fibers in the sciatic nerve, and the electrophysiological results showed higher levels of reinnervation with relatively larger mean values of amplitudes, durations, and areas of compound muscle action potentials compared with A and D. Conclusion. A short delay in the onset of ES may improve the recovery of a severe peripheral nerve injury, which should be considered as a way of augmenting rehabilitative approaches.