Heparan sulfate proteoglycans (HSPGs) are important modulators for optimizing signal transduction of many pathways, including the Wnt pathways. We demonstrate that HSPG glycosaminoglycan levels increased with increasing metastatic potential of melanoma cells. Previous studies have demonstrated that Wnt5A increases the invasiveness of melanoma cells. We further demonstrate that HSPGs potentiate Wnt5A signaling, since enzymatic removal of the HSPG backbone resulted in a decrease in cellular Wnt5A levels, an increase in secreted Wnt5A in cell media, a decrease in downstream signaling, and ultimately, a decrease in invasiveness. Specifically, syndecan 1 and syndecan 4 expression correlated to Wnt5A expression and melanoma malignancy. Knockdown of syndecan 1 or 4 caused decreases in cell invasion, which could be restored by treating the cells with recombinant Wnt5A. These data indicate that syndecan 1 and 4 correlate to increased metastatic potential in melanoma patients and are an important component of the Wnt5A autocrine signaling loop, the activation of which leads to increased metastasis of melanoma.
Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Dexmedetomidine is a central alpha-2 agonist commonly used on intubated patients. It is increasingly being used off-label in non-intubated agitated patients. We sought to determine the overall clinical course, adverse effects, and need for subsequent mechanical ventilation in toxicology patients after treatment with dexmedetomidine. Methods This was a retrospective cohort study conducted by chart review of electronic records from the Virginia Poison Control Center from January 1, 2019 to February 4, 2022. Inclusion criteria consisted of all poison center cases where dexmedetomidine was used. The primary outcome was the presence or absence of clinical improvement following dexmedetomidine use. Secondary outcomes included adverse effects, subsequent intubation, or death. Results During this study period, there were 220 cases in which dexmedetomidine was used to treat agitation. After exclusions, 70 cases were analyzed. The categories included antimuscarinic (n= 19), polysubstance (n= 16), sedative withdrawal (n = 10), unknown agitation (n= 7), sympathomimetic (n =5), baclofen withdrawal (n= 3), unknown ingestion (n = 3), sedative/hypnotic (n= 2), antipsychotic (n = 2), hallucinogenic (n= 2), and opioid withdrawal (n= 1). Clinical improvement occurred in 62 of 70 patients (89%). There were no deaths. A total of four patients were intubated after starting dexmedetomidine, two for refractory agitation and two for hypoxia after aspiration. Conclusion Global clinical improvement was observed in the agitated toxicology patients administered dexmedetomidine. There was one case of intubation secondary to oversedation. Dexmedetomidine could be a useful adjunctive treatment for agitated toxicologic patients but should be studied further before routinely used.
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