RESUMO
Objective: To evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS). Materials & methods: This was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-one veterans with fibromyalgia were randomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST with auricular PENFS (STâ¯+â¯PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2â¯weeks post-treatment.â Clinical pain and physical function were also assessed at these timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness. Results: Both the STâ¯+â¯PENFS and ST groups reported a decrease in pain with treatment. Volumetric: Cortical thickness significantly decreased in the left middle posterior cingulate (pâ¯=â¯0.018) and increased in the left cuneus (pâ¯=â¯0.014) following STâ¯+â¯PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (pâ¯=â¯0.02) inversely correlated with pain scores. STâ¯+â¯PENFS group right hemisphere posterior dorsal cingulate size significantly (pâ¯=â¯0.044) positively correlated with pain scores. GABA: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (pâ¯=â¯0.083) using a linear mixed effects model. Conclusions: Results suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.
RESUMO
PURPOSE: Exploitation of altered glycosylation in cancer is a major goal for the design of new cancer therapy. Here, we designed a novel secreted chimeric signal peptide-Galectin-3 conjugate (sGal-3) and investigated its ability to induce cancer-specific cell death by targeting aberrantly N-glycosylated cell surface receptors on cancer cells. EXPERIMENTAL DESIGN: sGal-3 was genetically engineered from Gal-3 by extending its N-terminus with a noncleavable signal peptide from tissue plasminogen activator. sGal-3 killing ability was tested on normal and tumor cells in vitro and its antitumor activity was evaluated in subcutaneous lung cancer and orthotopic malignant glioma models. The mechanism of killing was investigated through assays detecting sGal-3 interaction with specific glycans on the surface of tumor cells and the elicited downstream proapoptotic signaling. RESULTS: We found sGal-3 preferentially binds to ß1 integrin on the surface of tumor cells due to aberrant N-glycosylation resulting from cancer-associated upregulation of several glycosyltransferases. This interaction induces potent cancer-specific death by triggering an oncoglycan-ß1/calpain/caspase-9 proapoptotic signaling cascade. sGal-3 could reduce the growth of subcutaneous lung cancers and malignant gliomas in brain, leading to increased animal survival. CONCLUSIONS: We demonstrate that sGal-3 kills aberrantly glycosylated tumor cells and antagonizes tumor growth through a novel integrin ß1-dependent cell-extrinsic apoptotic pathway. These findings provide proof-of-principle that aberrant N-oncoglycans represent valid cancer targets and support further translation of the chimeric sGal-3 peptide conjugate for cancer therapy.