RESUMO
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.
Assuntos
Neoplasias de Mama Triplo Negativas/genética , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos SCID , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
El páncreas anular (PA) es una anomalía congénita infrecuente. Se caracteriza por la presencia de tejido pancreático ectópico alrededor del duodeno y puede estar asociado a obstrucción duodenal. Se presenta un paciente con cuadro de dolor abdominal y vómitos de 12 días de evolución. El laboratorio mostró elevación de lipasa en sangre. La tomografia computarizada de abdomen evidenció estómago y primera porción duodenal distendidos, en relación con una imagen en anillo de 5 cm de diámetro ubicada entre la cabeza del páncreas y la segunda porción del duodeno, sugestiva de PA. Ante la mala respuesta al tratamiento médico con reposo digestivo, sonda nasogástrica y nutrición parenteral, se decide conducta quirúrgica confirmando el diagnóstico de obstrucción duodenal por un PA. Se realiza gastroyeyunostomía en Y de Roux con buena evolución posquirúrgica. El PA puede manifestarse clínicamente como una obstrucción duodenal. Los casos con mala respuesta al tratamiento conservador requieren conducta quirúrgica para confirmar el diagnóstico y resolver la oclusión.
Annular pancreas (AP) is a rare congenital anomaly, characterized by ectopic pancreatic tissue surroun-ding the duodenum, that may associate with duodenal obstructon. We present a patent complaining of 12 days of abdominal pain and vomitis. Blood testis showed hyper-lipasemia. Computed tomography scan demonstrated stomach and frst duodenal porton distended in relaton to a 5 cm diameter image resembling a ring between the pancreatic head and the second porton of the duodenum, a well known characteristic of AP. Following a lack of clinical response to medical treatment, surgery was performed confirming a duodenal obstructon due to AP. Roux-en-Y gastrojejunostomy was done, with good postoperative outicome. Annular pancreas may present as a duodenal obstructon. For these cases, we suggest surgical treatment to confirm diagnosis and resolve the obstructon in cases with negative clinical response to conservative treatment.
RESUMO
El Tumor Desmolde o Fibromatosis Mesentérica es una enfermedad infrecuente en la que se reconocen 2 formas: una esporádica y otra asociada a poliposis familiar adenomatosa. De etiología desconocida, su diagnóstico preoperatorio es dificultoso y el tratamiento de elección es quirúrgico. Se pone en consideración un caso de esta entidad en un varón joven, que se presentó con dolor abdominal y fiebre. Se realizó cirugía resectiva agresiva, otorgándose el alta a los 18 días de la intervención.
Desmoid tumor or mesenteric fibromatosis is an uncommon disease with to variants: a sporadic form and one associated to familial adenomatous polyposis. Surgery is the treatment of choice. We report a 45 years old male presenting with abdominal pain and fever. An abdominal ultrasound informed the presence of a mass in the periumblical area. An Abdominal CAT sean showed a 13 cm diameter solid mass located in the left upper quadrant. The patient was operated and that mass is excised, requiring also a hemicolectomy, excision of the fourth portion of the duodenum and cholecystectomy. The pathology report of the excised tumor informs a mesenteric fibromatosis. The patient was discharged at the 18th postoperative day.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Fibromatose Abdominal/cirurgia , Fibromatose Abdominal/complicações , Mesentério , Neoplasias Peritoneais/cirurgia , Dor Abdominal/etiologia , Fibroma , Resultado do TratamentoRESUMO
La paniculitis mesentérica es una enfermedad inflamatoria del tejido adiposo del mesenterio, de presentación infrecuente y que se caracteriza, por el engrasamiento, endurecimiento y nodularidad del mismo. Se pone en consideración un caso clínico en un varón joven, con una forma de presentación poco común que requirió de laparotomía exploradora para realizar el diagnóstico y tratamiento.
We report a 28 years old obese male presenting with abdominal pain of increasing intensity lasting 15 days. In the last days, diarrhea and fever appeared. On abdominal examination a 8 cm painful mass was palpated. An abdominal ultrasound showed an anechoic mass in the epigastrium. An abdominal CAT sean showed an inflammatory mass that involves the small bowel. The patient is subjected to a percutaneous needle aspiration, obtaining 50 mi of a purulent fluid. Due to persistence of fever, the patient was operated finding an inflammation that involved the mesentery and the great omentum and covering abscess. The pathologic study of the surgical piece reported a unspecific nodular mesenteric panniculitis.