Assuntos
Fibrose Cística/cirurgia , Farmacorresistência Bacteriana , Transplante de Pulmão/efeitos adversos , Micobacteriófagos/genética , Infecções por Mycobacterium não Tuberculosas/terapia , Mycobacterium abscessus/virologia , Terapia por Fagos , Ferida Cirúrgica/microbiologia , Adolescente , Feminino , Engenharia Genética , Humanos , Infecções por Mycobacterium não Tuberculosas/etiologiaRESUMO
INTRODUCTION: PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown. EXPERIMENTAL DESIGN: We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models. RESULTS: We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1-wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment. CONCLUSIONS: Our data suggest that in both BRCA1-mutant and BRCA1-wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi. Clin Cancer Res; 23(2); 514-22. ©2016 AACR.
Assuntos
Proteína BRCA1/genética , Resistencia a Medicamentos Antineoplásicos/genética , Rad51 Recombinase/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Proteína BRCA2/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inferior dislocation (luxatio erecta) is the most uncommon form of dislocation of the glenohumeral joint. The chance that a person endures the specific direction of forces to dislocate both shoulders simultaneously makes bilateral luxatio erecta even more uncommon. In this article, we report the case of a man who sustained bilateral luxatio erecta when he jumped from a falling scaffold and tried grabbing onto another structure.
Assuntos
Vértebras Lombares/lesões , Luxação do Ombro/diagnóstico por imagem , Fraturas da Coluna Vertebral/diagnóstico por imagem , Vértebras Torácicas/lesões , Fixação de Fratura , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Modalidades de Fisioterapia , Luxação do Ombro/complicações , Luxação do Ombro/terapia , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/terapia , Vértebras Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
The location of a sound is derived computationally from acoustical cues rather than being inherent in the topography of the input signal, as in vision. Since Lord Rayleigh, the descriptions of that representation have swung between "labeled line" and "opponent process" models. Employing a simple variant of a two-point separation judgment using concurrent speech sounds, we found that spatial discrimination thresholds changed nonmonotonically as a function of the overall separation. Rather than increasing with separation, spatial discrimination thresholds first declined as two-point separation increased before reaching a turning point and increasing thereafter with further separation. This "dipper" function, with a minimum at 6 ° of separation, was seen for regions around the midline as well as for more lateral regions (30 and 45 °). The discrimination thresholds for the binaural localization cues were linear over the same range, so these cannot explain the shape of these functions. These data and a simple computational model indicate that the perception of auditory space involves a local code or multichannel mapping emerging subsequent to the binaural cue coding.