Patients with resected stage III melanoma have a heterogeneous prognosis with an especially high risk of relapse for patients with stage IIIB, IIIC and IIID according to the 2018 classification in ...AJCC Cancer Staging Manual, 8
th
edition (AJCC-8). Ipilimumab was the first immune checkpoint inhibitor (ICI) to show prolonged overall survival (OS) but at the cost of high toxicity. Pembrolizumab and nivolumab are inhibitors of programmed cell death 1 (PD-1) and showed prolonged relapse-free survival (RFS) in patients with resected stage III melanoma at high risk of relapse compared to placebo and ipilimumab, respectively.
The aim of this article is to review the mechanisms of action, pharmacokinetics and safety data of pembrolizumab in resected stage III melanoma and to compare its safety profile to other immune checkpoint inhibitors for the same indication.
Pembrolizumab as adjuvant therapy of resected stage III melanoma showed an acceptable safety profile, which is comparable to that in advanced melanoma. However, it caused one death. There is uncertainty about its benefits in AJCC-8 stage IIIA melanoma patients. Additionally, caution is required since OS and long-term safety data are not available yet.
Stimulation of phosphatidylinositol 3′-kinase (PI3K) and protein kinase B (PKB) is implicated in the regulation of protein synthesis in various cells. One mechanism involves PI3K/PKB-dependent ...phosphorylation of 4E-BP1, which dissociates from eIF4E, allowing initiation of translation from the 7-methylGTP cap of mRNAs. We examined the effects of insulin and H2O2 on this pathway in neonatal cardiac myocytes. Cardiac myocyte protein synthesis was increased by insulin, but was inhibited by H2O2. PI3K inhibitors attenuated basal levels of protein synthesis and inhibited the insulin-induced increase in protein synthesis. Insulin or H2O2 increased the phosphorylation (activation) of PKB through PI3K, but, whereas insulin induced a sustained response, the response to H2O2 was transient. 4E-BP1 was phosphorylated in unstimulated cells, and 4E-BP1 phosphorylation was increased by insulin. H2O2 stimulated dephosphorylation of 4E-BP1 by increasing protein phosphatase (PP1/PP2A) activity. This increased the association of 4E-BP1 with eIF4E, consistent with H2O2 inhibition of protein synthesis. The effects of H2O2 were sufficient to override the stimulation of protein synthesis and 4E-BP1 phosphorylation induced by insulin. These results indicate that PI3K and PKB are important regulators of protein synthesis in cardiac myocytes, but other factors, including phosphatase activity, modulate the overall response. (Circ Res. 2000;86:1252-1258.)
Synthesizing two key texts from Frédéric Pham's groundbreaking research in algebraic geometry, this essential introduction to the singularities of integrals focuses on topological and geometrical ...aspects before moving on to explain the analytical approach.
Full text
Available for:
FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
