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INTRODUCTION: Abdominal pain frequently co-occurs with pain in other body sites. Chronic overlapping pain conditions (COPCs) represent a group of widespread pain diagnoses. Our study characterized how patterns of somatic pain distribution are associated with COPCs and aimed to characterize predictors of widespread pain among patients with chronic abdominal pain. METHODS: This retrospective cohort study included adults presenting to a tertiary pain clinic, reporting abdominal pain at their initial visit, and with a follow-up visit at 12 months. Body maps divided patients into localized, intermediate, and widespread pain distribution patterns. Diagnostic and psychosocial measures were assessed across groups at the initial and follow-up visits. We analyzed the association of baseline diagnoses and demographics and time-varying changes in psychosocial measures from initial to follow-up visit with changes in pain distribution over time with alternating logistic regression (ALR). RESULTS: Among 258 patients, most were female (91.5%) and reported widespread pain (61.5%). Those with widespread pain at baseline reported elevated anger and 60.0% of patients remained in the same pain category at follow-up. Multivariable ALR demonstrated higher pain interference (AOR 1.06, 95% CI 1.02-1.10, P = 0.002), higher anxiety (AOR 1.05, 95% CI 1.01-1.09, P = 0.01), more than one COPC at initial visit (AOR 2.85, 95% CI 1.59-5.11, P = 0.0005), and initial visit widespread pain categorization (AOR 4.18, 95% CI 2.20-8.00, P < 0.0001) were associated with an increased risk of widespread pain at the follow-up visit. CONCLUSION: Most patients with abdominal pain report additional pain locations at multiple other body sites, and non-localized pain persists 12 months after pain treatment. Screening for widespread pain and COPC at the initial visit may identify patients at higher risk for persistent or new-onset widespread pain, and interventions to reduce pain interference and anxiety may promote reversal of widespread pain.
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Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels.
