Local Amplification of Platelet Function by 8-Epi Prostaglandin F2α Is Not Mediated by Thromboxane Receptor Isoforms

8-epi-Prostaglandin (PG) F2alpha may be formed by cyclooxygenases 1 and 2 or by a free radical catalyzed process as an isoprostane. Concentrations of 8-epi-PGF2alpha in the range 1 nM to 1 microM induce a dose-dependent increase in platelet shape change, in calcium release from intracellular stores [Ca2+]iand in inositol phosphates; it also causes irreversible platelet aggregation, dependent on thromboxane generation, when incubated with subthreshold concentrations of ADP, thrombin, collagen, and arachidonic acid. Much higher concentrations of 8-epi-PGF2alpha (10-20 microM) alone induce weak, reversible aggregation. Although these effects are prevented by pharmacological thromboxane receptor antagonists, they are unlikely to be mediated by thromboxane receptors. Thus, 8-epi-PGF2alpha does not compete for binding at the stably expressed placental or endothelial isoforms of the thromboxane receptor or for binding of thromboxane ligands to human platelets. Furthermore, the response to 8-epi PGF2alpha exhibits structural specificity versus 8-epi PGF3alpha and PGF2alpha. Concentrations in the range that evoke its effects on platelets do not desensitize the aggregation response stimulated by thromboxane or PGH2 analogs. Unlike primary prostaglandins, which are rapidly metabolized to inactive products, 8-epi PGF2alpha circulates in plasma. However, the systemic concentrations found in healthy volunteers (median 48 pmol/liter) and in patients with hepatic cirrhosis (median 147 pmol/liter), a syndrome of oxidant stress in vivo, fall well below those which modulate platelet function. 8-Epi PGF2alpha may amplify the response to platelet agonists in syndromes where oxidant stress and platelet activation coincide. Despite blockade by thromboxane antagonists, 8-epi PGF2alpha does not activate either of the thromboxane receptor isoforms described in platelets. Activation of a distinct receptor would be consistent with the enzymatic formation of 8-epi PGF2alpha by cyclooxygenases. However, incidental activation of such a receptor by systemic concentrations of 8-epi PGF2alpha is unlikely to occur, even in syndromes of excessive free radical generation in vivo

Telehealth Delivery of a Multi-Disciplinary Rehabilitation Programme for Upper Gastro-Intestinal Cancer: ReStOre@Home Feasibility Study

Advances in diagnosis and the treatment for upper gastro-intestinal (UGI) cancers have led to improved survival rates and, consequently, to a larger population of survivors of many types of UGI cancer [1,2]. Progress in survivorship care for UGI cancer remains poor, and many survivors experience ongoing negative physical and psychosocial impacts of treatment, which can have profound and long-term impacts on physical function and quality of life (QOL) [3,4]. At one year post-op, 40% of survivors report poor physical function, and significant reductions in walking distance, cardiorespiratory fitness and muscle strength are observed, along with a high prevalence of fatigue (41%), sarcopenia (35%) and dyspnoea (20%) [5–7]. Nutritional compromise in UGI cancer survivors is frequently reported, with eating restrictions are observed in 49% at 1 year post-surgery and malabsorption in 73% at two years post-op [6,8]. This can lead to significant reductions in fat-free body mass and skeletal muscle [8]. From a psychosocial perspective, anxiety (36%), fear of recurrence (29%) and high rates of sleep difficulties (51%) are reported. An integrated, multi-disciplinary specialist rehabilitation approach focusing on patient-centred outcomes is indicated to address the substantial, complex, multi-dimensional rehabilitation needs of UGI cancer survivors and to enable them to achieve the best possible quality of life and to reintegrate into family, social and working life [9–12]

Prostanoids in health and disease

Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease. Journal of Lipid Research. 2009;50:S423-S428.The prostanoids are a family of lipid mediators generated by the action of cyclooxygenase on a 20-carbon unsaturated fatty acid, arachidonic acid. Prostanoids are generated widely in response to diverse stimuli and, acting in a paracrine or autocrine manner, play important roles in normal physiology and disease. This review summarizes the current knowledge on prostanoid generation and the roles of individual mediators, their biosynthetic pathways, and their receptors in health and disease

COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer

Garg R, Blando JM, Perez CJ, et al. COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer. Oncogene. 2018;37(34):4735-4749.The pro-oncogenic kinase PKCε is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE2 production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCε, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation, as well as angiogenesis in a mouse model of prostate-specific PKCε expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-κB pathway and its target gene COX2 as PKCε effectors, and highlight the potential of PKCε as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer