ABSTRACT
INTRODUCTION: Complementary and alternative medicine (CAM) are highly used among those diagnosed with glioma. Further research is warranted, however, as it remains important to clearly delineate CAM practices that are unproven, disproven, or promising for future research and implementation. METHODS: A systematic review was conducted to identify all articles that investigated the effect of any CAM therapy on survival of patients with newly diagnosed or recurrent glioma. RESULTS: Eighteen papers and 4 abstracts pertaining to the effects of ketogenic diet (4), antioxidants (3), hyperbaric oxygen (4), cannabinoids (2), carbogen and nicotinamide (3), mistletoe extract (2), hypocupremia and penicillamine (1), and overall CAM use (3) on overall and progression-free survival in patients with low- and high-grade glioma were identified (Levels of Evidence I-IV). Ketogenic diets, hyperbaric oxygen therapy, and cannabinoids appear to be safe and well tolerated by patients; preliminary studies demonstrate tumor response and increased progression-free survival and overall survival when combined with standard of care therapies. Antioxidant usage exhibit mixed results perhaps associated with glioma grade with greater effect on low-grade gliomas; vitamin D intake was associated with prolonged survival. Conversely, carbogen breathing and hypocupremia were found to have no effect on the survival of patients with glioma, with associated significant toxicity. Most modalities under the CAM umbrella have not been appropriately studied and require further investigation. CONCLUSIONS: Despite widespread use, Level I or II evidence for CAM for the treatment of glioma is lacking, representing future research directions to optimally counsel and treat glioma patients.
Subject(s)
Brain Neoplasms/therapy , Complementary Therapies/methods , Glioma/therapy , Complementary Therapies/adverse effects , Humans , Treatment OutcomeABSTRACT
The unfolded protein response (UPR) maintains protein-folding homeostasis in the endoplasmic reticulum (ER) and has been implicated as both beneficial and detrimental to flavivirus infection. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a sensor of the UPR, is commonly associated with antiviral effects during mosquito-borne flavivirus (MBFV) infection, but its relation to tick-borne flavivirus (TBFV) infection remains largely unexplored. In this study, we identified changes in UPR and autophagic activity during Langat virus (LGTV) infection. LGTV robustly activated UPR and altered autophagic flux. Knockdown of endogenous PERK in human cells resulted in increased LGTV replication, but not that of closely related Powassan virus (POWV). Finally, on examining changes in protein levels of components associated with UPR and autophagy in the absence of PERK, we could show that LGTV-infected cells induced UPR but did not lead to expression of C/EBP homologous protein (CHOP), an important downstream transcription factor of multiple stress pathways. From these data, we hypothesize that LGTV can antagonize other kinases that target eukaryotic initiation factor 2α (eIF2α), but not PERK, implicating PERK as a potential mediator of intrinsic immunity. This effect was not apparent for POWV, a more pathogenic TBFV, suggesting it may be better equipped to mitigate the antiviral effects of PERK.
Subject(s)
Encephalitis Viruses, Tick-Borne/physiology , Encephalitis, Tick-Borne/metabolism , Encephalitis, Tick-Borne/virology , Signal Transduction , Unfolded Protein Response , Virus Replication , eIF-2 Kinase/metabolism , Autophagy , Biomarkers , Cell Line , Cell Survival , Clustered Regularly Interspaced Short Palindromic Repeats , Fluorescent Antibody Technique , Gene Knockdown Techniques , Gene Targeting , Humans , Transcription Factor CHOP/genetics , Transcription Factor CHOP/metabolismABSTRACT
Tick-borne flaviviruses have a global distribution and cause significant human disease, including encephalitis and hemorrhagic fever, and often result in neurologic sequelae. There are two distinct properties that determine the neuropathogenesis of a virus. The ability to invade the central nervous system (CNS) is referred to as the neuroinvasiveness of the agent, while the ability to infect and damage cells within the CNS is referred to as its neurovirulence. Examination of laboratory variants, cDNA clones, natural isolates with varying pathogenicity, and virally encoded immune evasion strategies have contributed extensively to our understanding of these properties. Here we will review the major viral determinants of virulence that contribute to pathogenesis and influence both neuroinvasiveness and neurovirulence properties of tick-borne flaviviruses, focusing particularly on the envelope protein (E), nonstructural protein 5 (NS5), and the 3′ untranslated region (UTR).
