RESUMEN
Multiple myeloma (MM) is a hematologic cancer characterized by malignant proliferation of plasma cells and their precursors. Immunosuppressive CD4+CD25+Foxp3+ regulatory T (Treg) cells are increased in the peripheral blood of patients with MM. On the basis of this finding, we sought to evaluate the ex vivo effect of CD4+CD25+Foxp3+ Treg cells on the anti-tumor effect of the proteosome inhibitor bortezomib on MM cells. We collected peripheral blood and bone marrow aspiration samples from 20 patients with newly diagnosed MM and isolated CD4+CD25+Foxp3+ Treg cells from peripheral blood mononuclear cells. The bone marrow mononuclear cells were cultivated in RPMI at 37°C and 5% CO2 for 72 hours. The LD50 doses of bortezomib, isolated Treg cells, and their combination were added. After 24 hours, the viability of CD138+ myeloma cells was evaluated by WST-1. We compared the anti-tumor effect of bortezomib alone and in combination with Treg expansion and statistically analyzed the measured differences with respect to the clinical parameters of the patients. Treg cells had varied effects on bortezomib, increasing, decreasing, or not changing its anti-tumor effect. The increased in vitro anti-tumor effect of bortezomib after Treg cell expansion was correlated in patients who did not develop bortezomib resistance in vivo (p = 0.022). These patients with in vivo non-bortezomib-resistant MM also responded to Treg expansion with decreased cell viability (p = 0.024). Our data indicate that the ex vivo expansion of Treg cells increased the cytotoxic effect of bortezomib in clinically sensitive cases.
Asunto(s)
Antineoplásicos/farmacología , Bortezomib/farmacología , Mieloma Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Anciano , Anciano de 80 o más Años , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antígenos de Superficie/metabolismo , Biomarcadores , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Estadificación de Neoplasias , Sindecano-1/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
AIMS: Wounds in patients with hyperglycemia show impaired healing. Plasminogen activation is crucial in several overlapping phases of wound healing process. In this study, we aimed i) to compare acute wound fluid in patients with hyperglycemia and normoglycemia, ii) to focus on the elements of plasminogen activation in the wound fluid, and iii) to determine if the acute wound fluid characteristics are associated with surgical site infections. METHODS: In a cohort of 54 patients, a closed suction drain was placed in the wound above the anterior abdominal wall fascia under the skin in order to collect postoperative acute wound fluid samples for 3 following days after colorectal surgery. Patients were classified as normoglycemic (n=25) or hyperglycemic (n=29; 17 with type 2 diabetes and 12 with stress induced hyperglycemia). Surgical site infection was defined according to the Centers for Disease Control criteria. The levels of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAr), plasminogen activator inhibitor-1 (PAI-1), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and fibroblast growth factor-1 (FGF-1) were measured in the wound fluid. RESULTS: Compared to normoglycemic subjects, patients with hyperglycemia had significantly lower levels of uPA and uPAr in the wound fluid despite similar or even higher circulating levels. There was no significant difference in IL-1ß, TNF-α, PAI-1 and FGF-1 levels. In the whole study population, the wound fluid levels of uPA and uPAr were negatively correlated with circulating glucose levels. No difference was detected in the wound fluid characteristics of patients with and without surgical site infection. CONCLUSION: Patients with hyperglycemia exhibit decreased levels of uPA and uPAr in the wound fluid, suggesting a local failure in plasminogen activation at the wound site.