Ultrasound and Microbubbles Increase the Uptake of Platinum in Murine Orthotopic Pancreatic Tumors.

OBJECTIVE: Currently available cytotoxic treatments have limited effect on pancreatic ductal adenocarcinoma (PDAC) because desmoplastic stroma limits drug delivery. Efforts have been made to overcome these barriers by drug targeting the tumor microenvironment. Results so far are promising, but without clinical impact. Our aim was to investigate whether ultrasound and microbubbles could improve the uptake and therapeutic response of conventional chemotherapy. METHODS: Orthotopic pancreatic tumors growing in mice were treated with commercially available FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin and calcium folinate) and SonoVue microbubbles combined with focused ultrasound. Tumor uptake of platinum (Pt) was measured by inductively coupled plasma mass spectroscopy (ICP-MS), and tumor volumes were measured by ultrasound imaging. DISCUSSION: Uptake of Pt, the active ingredient of oxaliplatin, was significantly increased after ultrasound treatment of orthotopic PDAC tumors. Multiple injections with FOLFIRONOX increased the amount of Pt in tumors. However, the enhanced accumulation did not improve therapeutic response. Increased uptake of Pt confirms that ultrasound and microbubbles have potential in clinical practice with existing drugs. CONCLUSION: The lack of therapeutic response, despite increased uptake in tumor tissue, emphasizes the importance of studying how to overcome stromal barriers.

Validation of a training protocol for marcha contests of the mangalarga marchador breed / Validação de um protocolo de treinamento para provas de marcha da raça mangalarga marchador

The Mangalarga Marchador breed is functionally evaluated through marcha contests. The present research aimed to verify the efficacy of a training protocol for conditioning Mangalarga Marchador horses for marcha contests. Eight mares were used in a completely randomized block split-plot design, where each animal was a block, the physical tests (T I, T II, T III, T IV and T V) every 21 days of training were the plots, and the time of evaluation and collection of samples inside each test were the split-plots. The mares were trained for 84 days for one hour a day, five days a week, with rest on Saturdays and Sundays. On Mondays, Wednesdays, and Fridays, the animals warmed up in an oval track by walking for 10 minutes and then marching for a period established individually through a marcha test. Next, the animals were led in walk gait until an hour of exercise was completed. On Tuesdays and Thursdays, the animals were trained outdoors for one hour only walking. The tests consisted of successive 10 minutes stages at marcha, which was interrupted when heart rate reached 150 beats per minute and lactate levels were greater than 4 mmol/L, or after 70 min of the test. Marcha duration, heart rate and blood concentrations of lactate were evaluated. The results were submitted to an analysis of variance and the averages were compared by Fisher's test at 5% probability. From zero at nine weeks of training, marcha duration increased progressively (p < 0.05), but there was no difference (p >0.05) between nine and 12 weeks of training. The training protocol used was appropriate to condition Mangalarga Marchador equines to compete in marcha contests following the rules of Brazilian Association of Mangalarga Marchador Breeders.

A raça Mangalarga Marchador é avaliada funcionalmente através das provas de marcha. O presente estudo objetivou verificar a eficácia de um protocolo de treinamento para condicionar equinos Mangalarga Marchador visando participação em provas de marcha. Foram utilizadas oito éguas em delineamento de blocos ao acaso com esquema de parcelas subdivididas, onde cada animal constituiu um bloco, as parcelas foram representadas pelos testes físicos (T I, T II, T III, T IV e T V) realizados a cada 21 dias do treinamento e as subparcelas foram constituídas pelos tempos de avaliação e coletas de amostras em cada teste. As éguas foram treinadas durante 84 dias, uma hora por dia, cinco dias por semana, com descanso aos sábados e domingos. Nas segundas, quartas e sextas-feiras, os animais realizavam 10 minutos de aquecimento ao passo em uma pista oval, em seguida marchavam por um tempo individual de marcha, estabelecido em um teste prévio. Depois, caminhavam até completar uma hora de exercício. Na terças e quintas-feiras eram montadas ao passo por uma hora. Os testes foram formados por etapas sucessivas de 10 minutos de marcha, sendo interrompido quando a frequência cardíaca atingia 150 batimentos por minuto e a concentração de lactato era maior que 4mmol/L ou a prova atingisse 70 minutos de duração. Avaliou-se o tempo de marcha, frequência cardíaca e concentração sanguínea de lactato. Os resultados foram submetidos à análise de variância e as médias comparadas pelo teste de Fisher a 5% de probabilidade. De zero a nove semanas de treinamento, o tempo de marcha aumentou progressivamente (p < 0,05), mas não houve diferença (p > 0,05) entre nove e doze semanas de treinamento. O protocolo de treinamento adotado foi adequado para condicionar equinos Mangalarga Marchador para competir em uma prova de marcha realizada de acordo com a regulamentação da Associação Brasileira de Criadores do Cavalo Mangalarga Marchador.