Irreversible electroporation (IRE) is an emerging focal therapy which is demonstrating utility in the treatment of unresectable tumors where thermal ablation techniques are contraindicated. IRE uses ultra-short duration, high-intensity monopolar pulsed electric fields to permanently disrupt cell membranes within a well-defined volume. Though preliminary clinical results for IRE are promising, implementing IRE can be challenging due to the heterogeneous nature of tumor tissue and the unintended induction of muscle contractions. High-frequency IRE (H-FIRE), a new treatment modality which replaces the monopolar IRE pulses with a burst of bipolar pulses, has the potential to resolve these clinical challenges. We explored the pulse-duration space between 250 ns and 100 μs and determined the lethal electric field intensity for specific H-FIRE protocols using a 3D tumor mimic. Murine tumors were exposed to 120 bursts, each energized for 100 μs, containing individual pulses 1, 2, or 5 μs in duration. Tumor growth was significantly inhibited and all protocols were able to achieve complete regressions. The H-FIRE protocol substantially reduces muscle contractions and the therapy can be delivered without the need for a neuromuscular blockade. This work shows the potential for H-FIRE to be used as a focal therapy and merits its investigation in larger pre-clinical models.

Pericytes are multifunctional cells wrapped around endothelial cells via cytoplasmic processes that extend along the abluminal surface of the endothelium. The interactions between endothelial cells and pericytes of the blood–brain barrier are necessary for proper formation, development, stabilization, and maintenance of the blood–brain barrier. Blood–brain barrier pericytes regulate paracellular flow between cells, transendothelial fluid transport, maintain optimal chemical composition of the surrounding microenvironment, and protect endothelial cells from potential harmful substances. Thus, dysfunction or loss of blood–brain barrier pericytes is an important factor in the pathogenesis of several diseases that are associated with microvascular instability. Importantly, recent research indicates that blood–brain barrier pericytes can be a target of HIV-1 infection able to support productive HIV-1 replication. In addition, blood–brain barrier pericytes are prone to establish a latent infection, which can be reactivated by a mixture of histone deacetylase inhibitors in combination with TNF. HIV-1 infection of blood–brain barrier pericytes has been confirmed in a mouse model of HIV-1 infection and in human post-mortem samples of HIV-1-infected brains. Overall, recent evidence indicates that blood–brain barrier pericytes can be a previously unrecognized HIV-1 target and reservoir in the brain.

Radiation therapy, the most commonly used for the treatment of brain tumors, has been shown to be of major significance in tu-mor control and survival rate of brain tumor patients. About 200,000 patients with brain tumor are treated with either partial large field or whole brain radiation every year in the United States. The use of radiation therapy for treatment of brain tumors, however, may lead to devastating functional deficits in brain several months to years after treatment. In particular, whole brain radiation therapy results in a significant reduction in learning and memory in brain tumor patients as long-term consequences of treatment. Although a number of in vitro and in vivo studies have demonstrated the pathogenesis of radiation-mediated brain injury, the cel-lular and molecular mechanisms by which radiation induces damage to normal tissue in brain remain largely unknown. Therefore, this review focuses on the pathophysiological mechanisms of whole brain radiation-induced cognitive impairment and the iden-tification of novel therapeutic targets. Specifically, we review the current knowledge about the effects of whole brain radiation on pro-oxidative and pro-inflammatory pathways, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) system and extracellular matrix (ECM), and physiological angiogenesis in brain. These studies may provide a foundation for defin-ing a new cellular and molecular basis related to the etiology of cognitive impairment that occurs among patients in response to whole brain radiation therapy. It may also lead to new opportunities for therapeutic interventions for brain tumor patients who are undergoing whole brain radiation therapy.

Despite successful control of viremia by combined antiretroviral therapy, brain infection and its resulting neurocognitive impairment remain a prevalent comorbidity in HIV infected individuals. HIV invades the brain early in the course of infection via penetration through the blood-brain barrier (BBB). While the impact of HIV on BBB astrocytes and endothelial cells is relatively well studied, the role of pericytes in BBB regulation during HIV infection remains unclear; however, it is known that a selective population of pericytes is prone to infection. In the present study, we hypothesize that injury signals are propagated from infected pericytes to neighboring cells via gap junction (GJ)-mediated intercellular communication. Among a variety of studied GJ proteins, HIV infection of human brain pericytes specifically increased expression of connexin 43 as determined by immunoblotting and immunostaining. This effect was confirmed in the brains of mice infected with EcoHIV, a mouse-specific HIV strain. In addition, HIV infection enhanced functional GJ-mediated intercellular communication in pericytes. The importance of this process was confirmed in experiments in which inhibition of GJs by carbenoxolone attenuated HIV infection. In addition to GJs, an extracellular ATP release assay revealed that HIV may also play a role in opening of connexin (Cx)-containing hemichannels (HCs). Overall, these findings indicate an important role of GJs in the propagation of HIV infection in human brain pericytes that may contribute to BBB dysfunction in brain infection and the pathogenesis of NeuroAIDS.