ABSTRACT
The number of people with diabetes is expected to reach 592 million in the year 2035. Diabetic foot lesions are responsible for more hospitalizations than any other complication of diabetes. The aims of this study were to examine for the first time a new biocompatible and biodegradable tridimensional collagen-based matrix, GBT013, in humans for diabetic foot ulcer wound healing and to evaluate its ease of use to better define a protocol for a future clinical trial. Seven adult patients with a diabetic foot ulcer of grade 1A to 3D (University of Texas Diabetic Wound Classification) were treated using GBT013, a new collagen-based advance dressing and were monitored in two specialized foot care units for a maximum of 9 weeks. Five of seven wounds achieved complete healing in 4 to 7 weeks. Nonhealed ulcers showed a significant reduction of the wound surface (>44%). GBT013 was well tolerated and displayed positive wound healing outcomes as a new treatment strategy of chronic foot ulcers in diabetic patients.
Subject(s)
Benzamides/therapeutic use , Melanoma/drug therapy , Melanoma/genetics , Piperazines/therapeutic use , Proto-Oncogene Proteins c-kit/genetics , Pyrimidines/therapeutic use , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Aged , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Humans , Imatinib Mesylate , Melanoma/metabolism , Point Mutation , Proto-Oncogene Proteins c-kit/metabolism , Signal Transduction/genetics , Skin Neoplasms/metabolismABSTRACT
Selection for targeted therapies in melanoma is currently based on the search for mutations in selected genes. We aimed at evaluating the interest of signalling and chemosensitivity studies in addition to genotyping for assessing the best suitable treatment in an individual patient. We extracted genomic DNA and melanoma cells from tumor tissue of a skin metastasis of a 17-year-old woman with stage IV melanoma progressing despite three successive lines of treatment. Despite the absence of mutation in BRAF, NRAS cKIT, the MAPK pathway was activated and a significant response to sorafenib, a mitogen-activated protein kinase (MAPK)/RAF inhibitor, was found in signalling and chemosensitivity assays. A treatment combining sorafenib and dacarbazine produced a partial response for 9 months, with marked necrosis in some lesions. Chemosensitivity assays and signalling pathway studies could be of great value in addition to genotyping for assessing the most appropriate treatment in melanoma.
Subject(s)
Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Molecular Targeted Therapy/methods , Mutation/genetics , Precision Medicine/methods , Signal Transduction/drug effects , Adolescent , Antineoplastic Agents/pharmacology , Benzenesulfonates/pharmacology , Benzenesulfonates/therapeutic use , Butadienes/pharmacology , Cell Survival/drug effects , Dacarbazine/pharmacology , Dacarbazine/therapeutic use , Drug Therapy, Combination/methods , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Fatal Outcome , Female , Genes, ras/genetics , Humans , Melanoma/genetics , Melanoma/metabolism , Melanoma/pathology , Niacinamide/analogs & derivatives , Nitriles/pharmacology , Nitrosourea Compounds/pharmacology , Organophosphorus Compounds/pharmacology , Phenylurea Compounds , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-kit/genetics , Pyridines/pharmacology , Pyridines/therapeutic use , Sorafenib , Treatment OutcomeABSTRACT
AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated by an increased AMP/ATP ratio. AMPK is now well recognized to induce glucose uptake in skeletal muscle and heart. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) is phosphorylated to form the AMP analog ZMP, which activates AMPK. Its effects on glucose transport appear to be tissue specific. The purpose of our study was to examine the effect of AICAR on insulin-induced glucose uptake in adult rat ventricular cardiomyocytes. We studied isolated adult rat ventricular cardiomyocytes treated or not with the AMPK activators AICAR and metformin and, subsequently, with insulin or not. Insulin action was investigated by determining deoxyglucose uptake, insulin receptor substrate-1- or -2-associated phosphatidylinositol 3-kinase activity and protein kinase B (PKB) cascade using antibodies to PKB, glycogen synthase kinase-3, and Akt substrate of 160 kDa. Intracellular pH was evaluated using the fluorescent pH-sensitive dye 2',7'-bis (2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and Na(+)/H(+) exchanger 1 (NHE1) activity was assessed using the NH(4)(+) prepulse method. Our key findings are as follows. AICAR and metformin enhance insulin signaling downstream of PKB. Metformin potentiates insulin-induced glucose uptake, but surprisingly, AICAR inhibits both basal and insulin-induced glucose uptake. Moreover, we found that AICAR decreases intracellular pH, via inhibition of NHE1. In conclusion, AMPK potentiates insulin signaling downstream of PKB in isolated cardiac myocytes, consistent with findings in the heart in vivo. Furthermore, AICAR inhibits basal and insulin-induced glucose uptake in isolated cardiac myocytes via the inhibition of NHE1 and the subsequent reduction of intracellular pH. Importantly, AICAR exerts these effects in a manner independent of AMPK activation.
