RESUMO
Acute myeloid leukemias are a group of hematological malignancies characterized by a poor prognosis for survival. The discovery of oncogenic mutations in the FMS-like tyrosine kinase 3 (FLT3) gene has led to the development of tyrosine kinase inhibitors such as quizartinib. However, achieving complete remission in patients remains challenging because these new tyrosine kinase inhibitors (TKIs) are unable to completely eradicate all leukemic cells. Residual leukemic cells persist during quizartinib treatment, leading to the rapid emergence of drug-resistant leukemia. Given that mitochondrial oxidative metabolism promotes the survival of leukemic cells after exposure to multiple anticancer drugs, we characterized the metabolism of leukemic cells that persisted during quizartinib treatment and developed metabolic strategies to eradicate them. In our study, employing biochemical and metabolomics approaches, we confirmed that the survival of leukemic cells treated with FLT3 inhibitors critically depends on maintaining mitochondrial metabolism, specifically through glutamine oxidation. We uncovered a synergistic interaction between the FLT3 inhibitor quizartinib and L-asparaginase, operating through antimetabolic mechanisms. Utilizing various models of persistent leukemia, we demonstrated that leukemic cells resistant to quizartinib are susceptible to L-asparaginase. This combined therapeutic strategy shows promise in reducing the development of resistance to FLT3 inhibitors, offering a potential strategy to enhance treatment outcomes.
RESUMO
Autologous fat grafting is the gold standard for treatment in patients with soft-tissue defects. However, the technique has a major limitation of unpredictable fat resorption due to insufficient blood supply in the initial phase after transplantation. To overcome this problem, we investigated the capability of a medical-grade poly L-lactide-co-poly ε-caprolactone (PLCL) scaffold to support adipose tissue and vascular regeneration. Deploying FDM 3D-printing, we produced a bioresorbable porous scaffold with interconnected pore networks to facilitate nutrient and oxygen diffusion. The compressive modulus of printed scaffold mimicked the mechanical properties of native adipose tissue. In vitro assays demonstrated that PLCL scaffolds or their degradation products supported differentiation of preadipocytes into viable mature adipocytes under appropriate induction. Interestingly, the chorioallantoic membrane assay revealed vascular invasion inside the porous scaffold, which represented a guiding structure for ingrowing blood vessels. Then, lipoaspirate-seeded scaffolds were transplanted subcutaneously into the dorsal region of immunocompetent rats (n = 16) for 1 or 2 months. The volume of adipose tissue was maintained inside the scaffold over time. Histomorphometric evaluation discovered small- and normal-sized perilipin+ adipocytes (no hypertrophy) classically organized into lobular structures inside the scaffold. Adipose tissue was surrounded by discrete layers of fibrous connective tissue associated with CD68+ macrophage patches around the scaffold filaments. Adipocyte viability, assessed via TUNEL staining, was sustained by the presence of a high number of CD31-positive vessels inside the scaffold, confirming the CAM results. Overall, our study provides proof that 3D-printed PLCL scaffolds can be used to improve fat graft volume preservation and vascularization, paving the way for new therapeutic options for soft-tissue defects.
RESUMO
La exposición a factores de riesgo psicosociales presentes en el lugar de trabajo constituye un tema prioritario para la salud ocupacional. El OBJETIVO del estudio es estimar la asociación entre factores de riesgo psicosocial presentes en el trabajo, y autopercepción de salud y siniestralidad laboral, en conductores de vehículos de transporte de carga y pasajeros, urbanos e interurbanos, de empresas afiliadas a la Asociación Chilena de Seguridad. Se aplicaron 4 cuestionarios a una muestra de 356 conductores de 4 empresas de transporte, en que 100% fue hombre con una edad promedio de 45,4 ± 9,7 años; el 70,8% transporta pasajeros, con jornadas de 11,4 horas/día. Todas las dimensiones de ISTAS-21 resultaron con promedios inferiores a la referencia salvo "trabajo activo y desarrollo de habilidades". El 93,8% se reportó como "sin alteraciones de salud mental". Se demostraron asociaciones estadísticamente significativas entre dimensiones del ISTAS 21 con, GHQ-12 y participación en accidentes de tránsito (sólo compensaciones), aun después de ajustar por variables de confusión. Esto permitió el diseño de intervenciones, consensuadas con las empresas, a fin de controlar/eliminar estas exposiciones para mejorar la salud y calidad de vida de los trabajadores y reducir las enfermedades profesionales y accidentes del trabajo relacionados.
Exposure to psychosocial risk factors present in the workplace is a priority topic for occupational health. The AIM of the study is to estimate the association between psychosocial risk factors present at work, and self-rated health and occupational accidents in drivers of passenger and freight transport, urban and intercity, of companies affiliated with the Chilean Safety Association. Four questionnaires were applied to a sample of 356 drivers from 4 Transport companies, in which 100% were male with a average age of 45,4 ± 9,7 years; 70,8% carry passengers, with working days of 11,4 hours / day. All dimensions of ISTAS-21 resulted with lower averages to the reference except for "active job and skill development." 93,8% was reported as "no mental health disorders". Statistically significant associations between dimensions of ISTAS 21, GHQ-12 and involvement in traffic accidents (just compensation), even after adjusting for confounding variables were demonstrated. This allowed the design of interventions, agreed with the companies, in order to control/eliminate these exposures to improve the health and quality of life of workers and reduce occupational diseases and work-related accidents.