RESUMO
Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at advanced tumor stages with chemotherapy as the only treatment option. Transcriptomic analysis has defined a classical and basallike PDAC subtype, which are regulated by epigenetic modification. The present study aimed to determine if druginduced epigenetic reprogramming of pancreatic cancer cells affects PDAC subtype identity and chemosensitivity. Classical and basallike PDAC cell lines PaTuS, Capan1, Capan2, Colo357, PaTuT, PANC1 and MIAPaCa2, were treated for a short (up to 96 h) and long (up to 30 weeks) period with histone acetyltransferase (HAT) and histone deacetylase (HDAC) inhibitors. The cells were analyzed using gene expression approaches, immunoblot analysis, and various cell assays to assess cell characteristics, such as proliferation, colony formation, cell migration and sensitivity to chemotherapeutic drugs. Classical and basallike PDAC cell lines showed pronounced epigenetic regulation of subtypespecific genes through acetylation of lysine 27 on Histone H3 (H3K27ac). Moreover, classical cell lines revealed a significantly decreased expression of HDAC2 and increased total levels of H3K27ac in comparison with the basallike cell lines. Following HAT inhibitor treatment, classical cell lines exhibited a loss of epithelial marker gene expression, decreased chemotherapy response gene score and increased cell migration in vitro, indicating a tumorpromoting phenotype. HDAC inhibitor treatment, however, exerted minimal reprogramming effects in both subtypes. Epigenetic reprogramming of classical and basallike tumor cells did not have a major impact on gemcitabine response, although the gemcitabine transporter gene SLC29A1 (solute carrier family 29 member 1) was epigenetically regulated.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Histonas/genética , Histonas/metabolismo , Gencitabina , Epigênese Genética , Acetilação , Linhagem Celular Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão GênicaRESUMO
Objective To evaluate the post-operative outcomes of patients with obstructive sleep apnea (OSA) given intraoperative ketamine. Design: case-control study A total of 574 patients (287 received ketamine and 287 were matched controls) diagnosed with OSA and body mass index (BMI) > 30 who received general anesthesia were included in this study. Patients given intraoperative ketamine were matched (1:1) with those who did not receive ketamine for age, gender, BMI, ethnicity, anesthesia time, intraoperative fentanyl dose, ketamine dose, and surgery type. A sub-analysis was performed based on the dose of ketamine administered and also on the surgery type. Measured outcomes include post-operative pain scores, post-operative opioid requirements, respiratory status, oxygen use, and duration post-operatively. Results Intraoperative ketamine use did not decrease pain scores or post-operative opioid use when compared with the control (no intraoperative ketamine) group. Patients who received high-dose ketamine had significantly higher post-operative pain scores (p=0.048) while in the post-anesthesia care unit (PACU) and required supplemental oxygen for a longer period of time (p = 0.030), pain scores were not significant for patients who underwent orthopedic/spine procedures (p = 0.074), and high-dose ketamine group patients who underwent orthopedic/spine surgery required significantly more opioids in the PACU (p = 0.031). Among patients who received low-dose ketamine, those who underwent head, ear, nose, and throat surgery required significantly more opioids in PACU (p = 0.022). Conclusions Low-dose intraoperative ketamine did not decrease pain scores or post-operative opioid use significantly and did not improve standard respiratory recovery parameters for OSA patients after surgery. Neither low- nor high-dose ketamine demonstrated the anticipated benefits of low pain scores and reduced post-operative opioid use. These outcomes will differ depending on the surgery type and dose of ketamine used.
RESUMO
Neuroleptic malignant syndrome (NMS) in the absence of an elevated creatine kinase is atypical and more difficult to diagnose. We present a patient with NMS significant risk factors who developed atypical NMS 6 days after a liver transplant. Symptoms of hyperthermia, altered mental status, dyskinesia, and autonomic instability (hypertension and tachycardia) coincided with promethazine administration, with rapid progression to fulminant NMS with lead pipe rigidity after a single injection of intramuscular ziprasidone. Rapid diagnosis and management resulted in full patient recovery. Differential diagnoses for NMS are discussed and a treatment algorithm is proposed.
Assuntos
Síndrome Maligna Neuroléptica/diagnóstico , Algoritmos , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Maligna Neuroléptica/etiologia , Síndrome Maligna Neuroléptica/terapiaRESUMO
Canine distemper virus (CDV) infection induces multifocal demyelination in the central nervous system (CNS). It is thought that the resident macrophages of the CNS, the microglia, as well as invading monocytes associated with the inflammatory reaction may play a central role in the demyelinating process. To evaluate changes in peripheral monocytes in CDV infection their immunophenotype was characterized by flow cytometry during the course of an experimental CDV infection in dogs. The highest number of CDV-infected monocytes was found in dogs developing demyelinating lesions. In CD18, CD45, CD44, and CD14 neither up- nor down-regulation was observed. Marked up-regulation occurred in a number of surface molecules including CD1c, B7-1 and B7-2, MHC I, and CD11b. Peak expression was found at 4-5 weeks post-infection (PI), regardless of clinical outcome. All these molecules play an important role in the host's immune response, notably antigen presentation and cell adhesion. These results demonstrate that CDV infection in vivo may enhance several macrophage functions. This could lead to more effective clearance of the virus but may also increase demyelination through a bystander effect in animals that accumulated significant amounts of CDV in the CNS.
Assuntos
Vírus da Cinomose Canina/imunologia , Cinomose/imunologia , Imunofenotipagem/veterinária , Monócitos/imunologia , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Temperatura Corporal , Cães , Feminino , Regulação da Expressão Gênica , Masculino , Organismos Livres de Patógenos Específicos , Fatores de TempoRESUMO
Microglia cells are the principal immune effector elements of the brain responding to any pathological event. To elucidate the possible role of microglia in initial non-inflammatory demyelination in canine distemper virus (CDV) infection, microglia from experimentally CDV infected dogs were isolated ex vivo by density gradient centrifugation and characterized immunophenotypically and functionally using flow cytometry. Results from dogs with demyelinating lesions were compared to results from recovered dogs and two healthy controls. CDV antigen could be detected in microglia of dogs with histopathologically confirmed demyelination. Microglia of these dogs showed marked upregulation of the surface molecules CD18, CD11b, CD11c, CD1c, MHC class I and MHC class II and a tendency for increased expression intensity of ICAM-1 (CD54), B7-1 (CD80), B7-2 (CD86), whereas no increased expression was found for CD44 and CD45. Functionally, microglia exhibited distinctly enhanced phagocytosis and generation of reactive oxygen species (ROS). It was concluded that in CDV infection, there is a clear association between microglial activation and demyelination. This strongly suggests that microglia contribute to acute myelin destruction in distemper.