Pharmacology & therapeutics
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The power of a placebo to effect clinically meaningful neurobiological change comparable to pharmacological therapies has been demonstrated, although the mechanisms are not fully understood. Predicting placebo responsiveness has only recently received more attention, but psychological disposition, contextual and biological factors are now known to dramatically affect a person's susceptibility to the placebo effect. The placebo effect depends upon expectancies that can be modified in a number of ways, including conditioning through explicit or implicit learned associations. ⋯ We include evidence for detrimental effects arising from seemingly inert interventions, termed the 'nocebo effect.' Neuroimaging has critically advanced the study of the placebo effect and provides some of the strongest evidence for the mechanisms of this phenomenon prevalent across an array of human health-related circumstances. This review specifically focuses on mechanisms of the placebo effect in the three conditions that have most significantly demonstrated this effect and for which a plausible physiological basis can be identified: pain, PD and depression. Other neurological and psychiatric diseases reviewed include multiple sclerosis, Huntington's disease, Alzheimer's disease, schizophrenia and epilepsy.
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Neutrophilic inflammation persists in COPD despite best current therapies and it is particularly resistant to inhaled glucocorticosteroids. Persistent neutrophil activation not only contributes to matrix breakdown, but can maintain inflammation through the release of endogenous damage associated molecule patterns (DAMPs). Inhibiting excessive neutrophilic inflammation is challenging as many pathogen recognition receptors can initiate migration and the targeting of downstream signaling molecules may compromise essential host defense mechanisms. ⋯ SAA not only initiates lung inflammation via ALX/FPR2 but can allosterically modify this receptor so that it no longer transduces pro-resolving signals from endogenous lipoxins that would otherwise promote tissue healing. We propose that there is an imbalance in endogenous and microbial ALX/FPR2 receptor agonists in the inflamed COPD lung environment that oppose protective anti-inflammatory and pro-resolution pathways. These insights open the possibility of targeting ALX/FPR2 receptors using synthetic agonists to resolve persistent neutrophilic inflammation without compromising essential host defense mechanisms.
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In the United States, prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in males and the second leading cause of cancer-related death for men. The prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR), a hormone activated transcription factor. ⋯ The finding that constitutively active AR splice variants that lack the hormone binding domain are frequently expressed in CRPC highlights the need to develop therapies that target other portions of AR. In this review, the role of AR in normal prostate, in PCa, and particularly the mechanisms for its reactivation subsequent to ADT are summarized. In addition, recent clinical trials and novel approaches to target AR are discussed.