Diagnostic utility of diagnostic investigations to identify neuropathic pain in low back-related leg pain: protocol for a systematic review.

INTRODUCTION: Neuropathic pain in low back-related leg pain has gained increasing interest in contemporary research. Identification of neuropathic pain in low back-related leg pain is essential to inform precision management. Diagnostic investigations are commonly used to identify neuropathic pain in low back-related leg pain; yet the diagnostic utility of these investigations is unknown. This systematic review aims to investigate the diagnostic utility of diagnostic investigations to identify neuropathic pain in low back-related leg pain. METHODS AND ANALYSIS: This protocol has been designed and reported in accordance with the Cochrane Handbook for Diagnostic Test Accuracy studies, Centre for Reviews and Dissemination and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols checklist, respectively. The search strategy will involve two independent reviewers searching electronic databases (CINAHL, EMBASE, MEDLINE, Web of Science, Cochrane Library, AMED, Pedro), key journals (Spine, The Clinical Journal of Pain, PAIN, European Journal of Pain, The Journal of Pain, Musculoskeletal Science and Practice) and grey literature (British National Bibliography for report literature, OpenGrey, EThOS) from inception to 31 July 2023 to identify studies. Studies evaluating the diagnostic accuracy of diagnostic investigation to identify neuropathic pain in patients with low back-related leg pain will be eligible, studies not written in English will be excluded. The reviewers will extract the data from included studies, assess risk of bias (Quality Assessment of Diagnostic Accuracy Studies 2) and determine confidence in findings (Grading of Recommendations, Assessment, Development and Evaluation guidelines). Methodological heterogeneity will be assessed to determine if a meta-analysis is possible. If pooling of data is not possible then a narrative synthesis will be done. ETHICS AND DISSEMINATION: Ethical approval is not required. Findings will be published in a peer-reviewed journal, presented at relevant conferences and shared with the Patient Partner Advisor Group at Western University, Canada. PROSPERO REGISTRATION NUMBER: CRD42023438222.

Enhancement of arsenic trioxide cytotoxicity by dietary isothiocyanates in human leukemic cells via a reactive oxygen species-dependent mechanism.

Although clearly effective in acute promyelocytic leukemia (APL), arsenic trioxide (ATO) demonstrates little clinical benefit as a single agent in the treatment of non-APL hematological malignancies. We screened a library of 2000 marketed drugs and naturally occurring compounds to identify agents that potentiate the cytotoxic effects of ATO in leukemic cells. Here, we report the identification of three isothiocyanates (sulforaphane, erysolin and erucin) found in cruciferous vegetables as enhancers of ATO cytotoxicity. Both erysolin and sulforaphane significantly enhanced ATO-mediated cytotoxicity and apoptosis in a panel of leukemic cell lines; erucin activity was variable among cell types. Cellular exposure to sulforaphane in combination with ATO resulted in a dramatic increase in levels of reactive oxygen species (ROS) compared to treatment with either agent alone. Sulforaphane, alone or with ATO, decreased intracellular glutathione (GSH) content. Furthermore, addition of the free radical scavenger N-acetyl-l-cysteine (NAC) rescued cells from ATO/isothiocyanate-mediated cytotoxicity. Our data suggest that isothiocyanates enhance the cytotoxic effects of ATO through a ROS-dependent mechanism. Combinatorial treatment with isothiocyanates and ATO might provide a promising therapeutic approach for a variety of myeloid malignancies.

Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism.

PURPOSE: Current standard chemotherapeutic regimens for malignant melanoma are unsatisfactory. Although in vitro studies of arsenic trioxide (ATO) have demonstrated promise against melanoma, recent phase II clinical trials have failed to show any significant clinical benefit when used as a single agent. To enhance the efficacy of ATO in the treatment of melanoma, we sought to identify compounds that potentiate the cytotoxic effects of ATO in melanoma cells. Through a screen of 2,000 marketed drugs and naturally occurring compounds, a variety of antibiotic inhibitors of mitochondrial protein translation were identified. METHODS: The mechanism of action for the most effective agent identified, thiostrepton, was examined in a panel of melanoma cells. Effects of combinatorial ATO and thiostrepton treatment on cytotoxicity, apoptosis, mitochondrial protein content, and reactive oxygen species (ROS) were assessed. RESULTS: Thiostrepton (1 microM) sensitized three out of five melanoma cell lines to ATO-mediated growth inhibition. Treatment with thiostrepton resulted in reduced levels of the mitochondrial-encoded protein cytochrome oxidase I (COX1). Exposure to thiostrepton in combination with ATO resulted in increased levels of cleaved poly (ADP-ribose) polymerase and cellular ROS. The growth inhibitory and pro-apototic effects of addition of the ATO/thiostrepton combination were reversed by the free radical scavenger N-acetyl-L-cysteine. CONCLUSIONS: Our data suggest that thiostrepton enhances the cytotoxic effects of ATO through a ROS-dependent mechanism. Co-administration of oxidative stress-inducing drugs such as thiostrepton in order to enhance the efficacy of ATO in the treatment of melanoma warrants further investigation.