Medical hypotheses
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Although promising treatments are currently in development to slow disease progression and increase patient survival, cancer remains the second leading cause of death in the United States. Cancer treatment modalities commonly include chemoradiation and therapies that target components of aberrantly activated signaling pathways. However, treatment resistance is a common occurrence and recent evidence indicates that the existence of cancer stem cells (CSCs) may underlie the limited efficacy and inability of current treatments to effectuate a cure. ⋯ TSCM cells, compared to TCM cells, exhibit stem cell properties that more closely match those of ESCs and ASCs, including self-renewal and differentiation into all memory T cell subsets. It is our hypothesis that activation of AMPK, a master regulator of cellular metabolism that plays a critical role in T cell activation and differentiation of ESCs and ASCs, will lead to both T cell activation-induced latent HIV-1 reactivation, facilitating virus destruction, as well as "activation", differentiation, and/or apoptosis of CSCs, thus inhibiting tumorigenesis. We also propose the novel observation that compounds that have been shown to both facilitate latent HIV-1 reactivation and promote CSC differentiation/apoptosis (e.g. bryostatin-1, JQ1, metformin, butyrate, etc.) likely do so through a common mechanism of AMPK activation.
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Chronic pain after spinal cord injury (SCI) is a form of central neuropathic pain that is debilitating and often refractory to current pharmacological treatments. Neurostimulation pain therapies, such as epidural spinal cord stimulation, have only moderate success in reducing SCI pain. The pathogenesis of SCI pain may involve a state of central neuronal hyperexcitability, especially in the spinal cord dorsal horn, that develops after injury. ⋯ Our hypothesis can be readily tested in preclinical models of SCI pain by using a combination of in vivo electrophysiological (neuronal activity) and animal behavioral (pain response) approaches. Since ISMS electrodes stimulate the spinal structures directly, we expect that the effective stimulus intensity and energy consumption can be lower than that for epidural spinal cord stimulation. The proposed hypothesis may provide insights and rationales for developing a novel neurostimulation pain therapy by directly inhibiting the pain generators in the spinal cord, and ISMS may be an alternative strategy to treat SCI pain.