ABSTRACT
Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.
Subject(s)
Crizotinib , Kidney Diseases, Cystic , Humans , Crizotinib/adverse effects , Kidney Diseases, Cystic/chemically induced , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/drug therapy , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Oncogene Proteins, Fusion/genetics , Adenocarcinoma of Lung/drug therapy , Antineoplastic Agents/adverse effectsABSTRACT
Kv2.1 as a voltage-gated potassium (Kv) channel subunit has a pivotal role in the regulation of glucose-stimulated insulin secretion (GSIS) and pancreatic ß-cell apoptosis, and is believed to be a promising target for anti-diabetic drug discovery, although the mechanism underlying the Kv2.1-mediated ß-cell apoptosis is obscure. Here, the small molecular compound, ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (SP6616) was discovered to be a new Kv2.1 inhibitor. It was effective in both promoting GSIS and protecting ß cells from apoptosis. Evaluation of SP6616 on either high-fat diet combined with streptozocin-induced type 2 diabetic mice or db/db mice further verified its efficacy in the amelioration of ß-cell dysfunction and glucose homeostasis. SP6616 treatment efficiently increased serum insulin level, restored ß-cell mass, decreased fasting blood glucose and glycated hemoglobin levels, and improved oral glucose tolerance. Mechanism study indicated that the promotion of SP6616 on ß-cell survival was tightly linked to its regulation against both protein kinases C (PKC)/extracellular-regulated protein kinases 1/2 (Erk1/2) and calmodulin(CaM)/phosphatidylinositol 3-kinase(PI3K)/serine/threonine-specific protein kinase (Akt) signaling pathways. To our knowledge, this may be the first report on the underlying pathway responsible for the Kv2.1-mediated ß-cell protection. In addition, our study has also highlighted the potential of SP6616 in the treatment of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Insulin-Secreting Cells/drug effects , Potassium Channel Blockers/pharmacology , Pyrimidines/pharmacology , Shab Potassium Channels/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Thiazoles/pharmacology , Animals , CHO Cells , Calmodulin/antagonists & inhibitors , Calmodulin/genetics , Calmodulin/metabolism , Cell Line , Cell Survival/drug effects , Cricetulus , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Drug Discovery , Gene Expression Regulation , Glucose Tolerance Test , Hypoglycemic Agents/chemistry , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Male , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Phosphatidylinositol 3-Kinase/genetics , Phosphatidylinositol 3-Kinase/metabolism , Phosphoinositide-3 Kinase Inhibitors , Potassium Channel Blockers/chemistry , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/genetics , Protein Kinase C/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/chemistry , Shab Potassium Channels/genetics , Shab Potassium Channels/metabolism , Signal Transduction , Small Molecule Libraries/chemistry , Streptozocin , Thiazoles/chemistryABSTRACT
OBJECTIVE: To elucidate the association of fat-mass and obesity-associated gene (FTO) rs9939609 polymorphism with obesity among children and adolescents. METHODS: A literature search was conducted in PubMed, MEDLINE, Springer, and Google scholar to identify eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used for four models: co-dominant model (AA vs. TT, AT vs. TT), dominant model (AA + AT vs. TT), recessive model (AA vs. AT + TT), and allelic model (A vs. T). Subgroup analyses stratified by ethnicity (Caucasian, others) and participants (children, children and adolescents) were assessed under allelic model. The heterogeneity and publication bias were examined. RESULTS: This meta-analysis included 12 eligible studies consisting 5,000 cases and 9,853 controls. The results revealed that FTO rs9939609 polymorphism was significantly associated with the increased risk of obesity in co-dominant model (AA vs. TT: OR = 1.91, 95% CI: 1.47-2.48, p < 0.01; AT vs. TT: OR = 1.18, 95% CI: 1.02-1.38, p = 0.03), dominant model (AA + AT vs. TT: OR = 1.47, 95% CI: 1.35-1.59, p < 0.01), recessive model (AA vs. AT + TT: OR = 1.79, 95% CI: 1.47-2.17, p < 0.01), and allelic model (A vs. T: OR = 1.39, 95% CI: 1.22-1.58, p < 0.01). Similar results were obtained for the subgroup analyses stratified by ethnicity and participants under allelic model. CONCLUSIONS: FTO rs9939609 polymorphism is associated with the increased risk of obesity among children and adolescents, especially the homozygous carriers.