RESUMO
BACKGROUND: The Affordable Care Act provides health care coverage to an increasing segment of the population at Medicaid reimbursement rates. Health care systems currently offset lower Medicaid reimbursement through higher payers. The ability to "cost shift" will be diminished as the Medicaid population increases. STUDY DESIGN: A financial cost and revenue analysis of outpatient laparoscopic cholecystectomy at our institution was performed. Cost was defined as actual expense to the health care institution. Fixed and variable costs were identified to calculate a break-even point. Time spent from check in to dismissal was based on historic averages. When actual costs could not be pinpointed, estimates from industry experts were used. Reimbursement included surgeon and anesthesia professional fees and facility fees. RESULTS: A total of 501 laparoscopic cholecystectomies were performed at the main operating room facility in 2012. Annual fixed costs were $252,637. Variable costs were $1,860/case. Personnel and single-use equipment made the largest contribution to variable costs. Reimbursement for professional and facility fees totaled $2,444/case. The break-even point occurred at 454 cases. Based on historic volume, the break-even point for the calendar year would occur on November 27. CONCLUSIONS: Our analysis demonstrates that laparoscopic cholecystectomy can be performed with a positive margin at Medicaid reimbursement rates with sufficient volume. The minimal margin, however, could substantially limit the ability of lower-volume hospitals to provide these services and negatively impact access to care in this patient population.
Assuntos
Procedimentos Cirúrgicos Ambulatórios/economia , Colecistectomia Laparoscópica/economia , Custos Hospitalares/estatística & dados numéricos , Hospitais com Alto Volume de Atendimentos , Medicaid/economia , Humanos , Estados UnidosRESUMO
Neuroendocrine carcinoma of the thymus, previously termed thymic carcinoid, is a rare clinical entity. Rarer still are such cases presenting with endocrinopathies. We report a case of thymic neuroendocrine carcinoma presenting with ectopic adrenocorticotroic hormone production and resultant Cushing's syndrome.
Assuntos
Hormônio Adrenocorticotrópico/biossíntese , Carcinoma Neuroendócrino/complicações , Carcinoma Neuroendócrino/metabolismo , Síndrome de Cushing/etiologia , Neoplasias do Timo/complicações , Neoplasias do Timo/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The Surgical Safety Checklist (SSC) has been introduced as an effective tool for reducing perioperative mortality and complications. Although reported completion rates are high, objective compliance is not well defined. The purpose of this retrospective analysis is to determine SSC compliance as measured by accuracy and completion, and factors that can affect compliance. STUDY DESIGN: In September 2010, our institution implemented an adaptation of the World Health Organization's SSC in an effort to improve patient safety and outcomes. A tool was developed for objective evaluation of overall compliance (maximum score 40) that was an aggregate score of completion and accuracy (20 each). Random samples of SSCs were analyzed at specific, predefined, time points throughout the first year after implementation. Procedure start time, operative time, and case complexity were assessed to determine association with compliance. RESULTS: A total of 671 SSCs were analyzed. The participation rate improved from 33% (95 of 285) at week 1 to 94% (249 of 265) at 1 year (p < 0.0001, chi-square test). Mean overall compliance score was 27.7 (± 5.4 SD) of 40 possible points (69.3% ± 13.5% of total possible score; n = 671) and did not change over time. Although completion scores were high (16.9 ± 2.7 out of 20 [84.5% ± 13.6%]), accuracy was poor (10.8 ± 3.4 out of 20 [54.1% ± 16.9%]). Overall compliance score was significantly associated with case start-time (p < 0.05), and operative time and case complexity showed no association. CONCLUSIONS: Our data indicate that although implementation of an SSC results in a high level of overall participation and completion, accuracy remained poor. Identification of barriers to effective use is needed, as improper checklist use can adversely affect patient safety.
Assuntos
Lista de Checagem/normas , Fidelidade a Diretrizes , Segurança do Paciente , Procedimentos Cirúrgicos Operatórios/normas , Humanos , Estudos RetrospectivosRESUMO
Fibrous dysplasia may involve the ribs or thoracic spine and cause progressive asphyxiation. We present a 41-year-old man with polyostotic fibrous dysplasia who was admitted to the hospital with progressive shortness of breath requiring initiation of supplemental oxygen. Pulmonary function test results revealed severely limited function with forced expiratory volume in 1 second (FEV1) of 14% predicted and diffusion capacity of 17%. As a lifesaving effort, the patient was offered resection, decortication, and chest wall reconstruction, after which the lung reexpanded. At 6 months, his FEV1 was 49% and his diffusion capacity was 56%. He no longer required supplemental oxygen and now exercises daily.
Assuntos
Displasia Fibrosa Poliostótica/diagnóstico por imagem , Displasia Fibrosa Poliostótica/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Insuficiência Respiratória/diagnóstico , Toracotomia/métodos , Adulto , Dispneia/diagnóstico , Dispneia/etiologia , Displasia Fibrosa Poliostótica/patologia , Seguimentos , Humanos , Masculino , Cuidados Pré-Operatórios , Doenças Raras , Testes de Função Respiratória , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Costelas/cirurgia , Índice de Gravidade de Doença , Parede Torácica/cirurgia , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
INTRODUCTION: The World Health Organization Surgical Safety Checklist (SSC) has been shown to decrease surgical site infections (SSI). The Surgical Care Improvement Project (SCIP) SSI reduction bundle (SCIP Inf) contains elements to improve SSI rates. We wanted to determine if integration of SCIP measures within our SSC would improve SCIP performance and patient outcomes for SSI. METHODS: An integrated SSC that included perioperative SCIP Inf measures (antibiotic selection, antibiotic timing, and temperature management) was implemented. We compared SCIP Inf compliance and patient outcomes for 1-y before and 1-y after SSC implementation. Outcomes included number of patients with initial post-anesthesia care unit temperature <98.6°F and SSI rates according to our National Surgical Quality Improvement Program data. RESULTS: Implementation of a SCIP integrated SSC resulted in a significant improvement in antibiotic infusion timing (92.7% [670/723] versus 95.4% [557/584]; P < 0.05), antibiotic selection (96.2% [707/735] versus 98.7% [584/592]; P < 0.01), and temperature management (93.8% [723/771] versus 97.7% [693/709]; P < 0.001). Furthermore, we found a significant reduction in number of patients with initial post-anesthesia care unit temperature <98.6°F from 9.7% (982/10,126) to 6.9% (671/9676) (P < 0.001). Institutional SSI rates decreased from 3.13% (104/3319) to 2.96% (107/3616), but was not significant (P = 0.72). SSI rates according to specialty service were similar for all groups except colorectal surgery (24.1% [19/79] versus 11.5% [12/104]; P < 0.05). CONCLUSION: Implementation of an integrated SSC can improve compliance of SSI reduction strategies such as SCIP Inf performance and maintenance of normothermia. This did not, however, correlate with an improvement in overall SSI at our institution. Further investigation is required to determine other factors that may influence SSI at an institutional level.
Assuntos
Lista de Checagem/normas , Avaliação de Processos e Resultados em Cuidados de Saúde , Garantia da Qualidade dos Cuidados de Saúde , Melhoria de Qualidade , Infecção da Ferida Cirúrgica/prevenção & controle , Centros Médicos Acadêmicos/normas , Antibacterianos/uso terapêutico , Seguimentos , Pesquisas sobre Atenção à Saúde , Mortalidade Hospitalar , Humanos , Hipotermia/mortalidade , Salas Cirúrgicas , Assistência Perioperatória/normas , Fatores de Risco , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/mortalidade , TemperaturaRESUMO
Hemorrhagic shock (HS)-induced microvascular hyperpermeability poses a serious challenge in the management of trauma patients. Microvascular hyperpermeability occurs mainly because of the disruption of endothelial cell adherens junctions, where the "intrinsic" apoptotic signaling plays a regulatory role. The purpose of this study was to understand the role of the "extrinsic" apoptotic signaling molecules, particularly Fas-Fas ligand interaction in microvascular endothelial barrier integrity. Rat lung microvascular endothelial cells (RLMECs) were exposed to HS serum in the presence or absence of the Fas ligand inhibitor, FasFc. The effect of HS serum on Fas receptor and Fas ligand expression on RLMECs was determined by flow cytometry. Endothelial cell permeability was determined by monolayer permeability assay and the barrier integrity by ß-catenin immunofluorescence. Mitochondrial reactive oxygen species formation was determined using dihydrorhodamine 123 probe by fluorescent microscopy. Mitochondrial transmembrane potential was studied by fluorescent microscopy as well as flow cytometry. Caspase 3 enzyme activity was assayed fluorometrically. Rat lung microvascular endothelial cells exposed to HS serum showed increase in Fas receptor and Fas ligand expression levels. FasFc treatment showed protection against HS serum-induced disruption of the adherens junctions and monolayer hyperpermeability (P < 0.05) in the endothelial cells. Pretreatment with FasFc also decreased HS serum-induced increase in mitochondrial reactive oxygen species formation, restored HS serum-induced drop in mitochondrial transmembrane potential, and reduced HS serum-induced caspase 3 activity in RLMECs. These findings open new avenues for drug development to manage HS-induced microvascular hyperpermeability by targeting the Fas-Fas ligand-mediated pathway.
Assuntos
Apoptose/fisiologia , Permeabilidade Capilar/fisiologia , Proteína Ligante Fas/antagonistas & inibidores , Pulmão/metabolismo , Choque Hemorrágico/metabolismo , Receptor fas/antagonistas & inibidores , Animais , Caspase 3/metabolismo , Inibidores de Caspase/farmacologia , Comunicação Celular/fisiologia , Endotélio Vascular/metabolismo , Pulmão/citologia , Masculino , Microvasos/enzimologia , Microvasos/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survival protein in a variety of cell lineages and is critically regulated via ubiquitination. METHODS: The Mcl-1, Bcl-xL and USP9X expression patterns in human lung and colon adenocarcinomas were evaluated via immunohistochemistry. Interaction between USP9X and Mcl-1 was demonstrated by immunoprecipitation-western blotting. The protein expression profiles of Mcl-1, Bcl-xL and USP9X in multiple cancer cell lines were determined by western blotting. Annexin-V staining and cleaved PARP western blotting were used to assay for apoptosis. The cellular toxicities after various treatments were measured via the XTT assay. RESULTS: In our current analysis of colon and lung cancer samples, we demonstrate that Mcl-1 and Bcl-xL are overexpressed and also co-exist in many tumors and that the expression levels of both genes correlate with the clinical staging. The downregulation of Mcl-1 or Bcl-xL via RNAi was found to increase the sensitivity of the tumor cells to chemotherapy. Furthermore, our analyses revealed that USP9X expression correlates with that of Mcl-1 in human cancer tissue samples. We additionally found that the USP9X inhibitor WP1130 promotes Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies. Moreover, the combination of WP1130 and ABT-737, a well-documented Bcl-xL inhibitor, demonstrated a chemotherapeutic synergy and promoted apoptosis in different tumor cells. CONCLUSION: Mcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. USP9X inhibition increases tumor cell sensitivity to various chemotherapeutic agents including Bcl-2/Bcl-xL inhibitors.
Assuntos
Adenocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ubiquitina Tiolesterase/biossíntese , Proteína bcl-X/biossíntese , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Western Blotting , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Imuno-Histoquímica , Imunoprecipitação , Neoplasias Pulmonares/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Proto-Oncogênicas c-bcl-2/análise , Ubiquitina Tiolesterase/análise , Proteína bcl-X/análiseRESUMO
Malignant mesothelioma is a rare, highly aggressive cancer arising from mesothelial cells that line the pleural cavities. Approximately 80% of mesothelioma cases can be directly attributed to asbestos exposure. Additional suspected causes or co-carcinogens include other mineral fibres, simian virus 40 (SV40) and radiation. A mesothelioma epidemic in Turkey has demonstrated a probable genetic predisposition to mineral fibre carcinogenesis and studies of human tissues and animal models of mesothelioma have demonstrated genetic and epigenetic events that contribute to the multistep process of mineral fibre carcinogenesis. Several growth factors and their receptors have a significant role in the oncogenesis, progression and resistance to therapy of mesothelioma. Epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF) have been shown as targets for therapy based on promising preclinical data. However, clinical trials of tyrosine kinase inhibitors in mesothelioma have been disappointing. Bcl-XL is an important antiapoptotic member of the Bcl-2 family and is overexpressed in several solid tumours, including mesothelioma. Reduction of Bcl-XL expression in mesothelioma induces apoptosis and engenders sensitisation to cytotoxic chemotherapeutic agents. Pharmacological inhibitors of antiapoptotic Bcl-2 family members continue to undergo refinement and have shown promise in mesothelioma.
Assuntos
Mesotelioma/genética , Mesotelioma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Mesotelioma/tratamento farmacológico , Mesotelioma/etiologia , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMO
By conducting a structure-activity relationship study of the backbone of a series of oligoamide-foldamer-based α-helix mimetics of the Bak BH3 helix, we have identified especially potent inhibitors of Bcl-x(L). The most potent compound has a K(i) value of 94 nM in vitro, and single-digit micromolar IC(50) values against the proliferation of several Bcl-x(L)-overexpressing cancer cell lines.
Assuntos
Antineoplásicos/síntese química , Benzamidas/síntese química , Materiais Biomiméticos/síntese química , Ácidos Picolínicos/síntese química , Proteína bcl-X/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Sítios de Ligação , Materiais Biomiméticos/farmacologia , Linhagem Celular Tumoral , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fragmentos de Peptídeos/química , Ácidos Picolínicos/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Termodinâmica , Proteína Killer-Antagonista Homóloga a bcl-2/química , Proteína bcl-X/químicaRESUMO
BACKGROUND: A fall in the postpneumonectomy fluid level is considered a sign of bronchopleural fistula (BPF) requiring surgical intervention. We have discovered however that in rare asymptomatic patients, this event may not require aggressive surgical treatment. METHODS: After seeing a case of benign emptying of the postpneumonectomy space (BEPS), we surveyed 28 surgeons to determine its incidence and characteristics. RESULTS: Forty-four cases of BEPS were reported by 23 survey respondents. Among 7 fully documented cases from 4 institutions, we defined the following criteria: the patient must be asymptomatic (no fever, white cell count elevation, or fluid expectoration), negative culture results if fluid sampled (patient not receiving antibiotics), no BPF at bronchoscopy or ventilation scintigraphy scan (or both), and recovery without drainage, or retrospective assessment that the intervention was unnecessary. BEPS occurred between 5 days and 152 days after pneumonectomy (6 cases right pneumonectomy and 1 case left pneumonectomy). Four patients underwent no treatment, 1 patient underwent thoracoscopic exploration (sterile) and closure after antibiotic irrigation, 1 patient underwent thoracoscopic exploration alone, and 1 patient underwent open window thoracostomy (sterile) with eventual closure. In all 7 patients (except the patient who underwent the open window procedure) the space refilled within 8 weeks; no patient experienced a subsequent empyema/BPF. Four patients who met the initial criteria for BEPS went on to experience empyema. The incidence of BEPS appears related to pneumonectomy volume, particularly extrapleural pneumonectomy. Using surgeon volume assumptions, the incidence of BEPS is 0.65%. CONCLUSIONS: To our knowledge, BEPS is a previously unreported occurrence. We hypothesize that it results from postoperative intrapleural pressure shifts, with or without a microscopic BPF, that drive fluid out of the pleural space while failing to cause contamination. Awareness of BEPS' existence may allow surgeons to safely avoid open drainage procedures occasionally in patients who experience an asymptomatic fall in fluid level.
Assuntos
Fístula Brônquica/cirurgia , Drenagem/métodos , Neoplasias Pulmonares/cirurgia , Derrame Pleural/cirurgia , Pneumonectomia/efeitos adversos , Adolescente , Adulto , Idoso , Fístula Brônquica/epidemiologia , Fístula Brônquica/etiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Derrame Pleural/epidemiologia , Derrame Pleural/etiologia , Complicações Pós-Operatórias , Estudos Retrospectivos , Inquéritos e Questionários , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Although a rare entity, chondrosarcoma is the most common malignant tumor of the chest wall. Most patients present with an enlarging, painful anterior chest wall mass arising from the costochondrosternal junction. CT scan with intravenous contrast is the gold standard radiographic study for diagnosis and operative planning. Contrary to previous dictum, resection may be performed in an appropriate surgical candidate based on imaging characteristics or image-guided percutaneous biopsy results; incisional biopsy is rarely required. The keys to successful treatment are early recognition and radical excision with adequate margins, as chondrosarcoma is relatively resistant to radiotherapy and conventional cytotoxic chemotherapy. Overall survival is excellent in most surgical series from experienced centers. Complete excision with widely negative microscopic margins at the initial operation is of the utmost importance, as local recurrence portends systemic metastasis and eventual tumor-related mortality. This paper summarizes data from relevant surgical series and thereupon draws conclusions regarding preoperative, intraoperative, and postoperative management of thoracic chondrosarcoma.
RESUMO
Academic surgery is a microcosm of the greater academic medical enterprise-albeit with some admitted idiosyncrasies. Most of the issues and challenges are common to other areas of academic practice, but the means by which academic surgeons meet these challenges will be different. Along with continuous process improvement, future innovation is imperative in virtually all areas. Some specific solutions to challenges in clinical care that academic surgeons should pursue include promoting both evidenced-based and more uniform, quality surgical clinical care; incorporating more efficiency into the clinical care environment; continuing to develop minimally invasive technology and techniques; and implementing the use of prospective clinical databases in real time. Goals of surgical education should include using simulation technology, standardizing technical evaluation techniques, incorporating more basic science, and focusing more on professionalism. Lastly, the surgical research enterprise needs restructuring (including a new process for making decisions regarding who receives resources), strategies to improve extramural funding, and new approaches for selecting foci for surgical research efforts that build on differentiated strengths related to surgical practice.
Assuntos
Centros Médicos Acadêmicos , Cirurgia Geral/educação , Cirurgia Geral/tendências , Simulação por Computador , Eficiência Organizacional , Medicina Baseada em Evidências , Previsões , Humanos , Internato e Residência/tendências , Relações Interpessoais , Procedimentos Cirúrgicos Minimamente Invasivos , Admissão e Escalonamento de Pessoal , Garantia da Qualidade dos Cuidados de Saúde , Pesquisa/tendências , Ciência/educação , Estados Unidos , Carga de TrabalhoRESUMO
BACKGROUND: Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy. RESULTS: The present study reports the development of I-45-BTZ-R, a bortezomib-resistant cell line, from the bortezomib-sensitive mesothelioma cell line I-45. I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin, 5-fluorouracil, and doxorubicin. Moreover, the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit beta5 (PSMB5) as compared to parental I-45 cells. I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity, but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib. Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response (UPR) in the bortezomib-adapted cells, while higher doses induced UPR with concomitant cell death, as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum (ER) stress-related pro-apoptotic protein CHOP. In addition, bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53, Mcl-1S, and noxa in the bortezomib-adapted cells. CONCLUSION: These results suggest that UPR evasion, together with reduced pro-apoptotic gene induction, accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Mesotelioma/metabolismo , Pirazinas/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Western Blotting , Bortezomib , Linhagem Celular Tumoral , Separação Celular , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Humanos , Mesotelioma/genética , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , TransfecçãoRESUMO
BACKGROUND: Mitochondria-mediated apoptotic signaling contributes to microvascular hyperpermeability. We hypothesized that cyclosporine A (CsA), which protects mitochondrial transition pores, would attenuate hyperpermeability independent of its calcineurin inhibitory property. METHODS: Hyperpermeability was induced in microvascular endothelial cell monolayers using proapoptotic BAK or active caspase-3 after CsA or a specific calcineurin inhibitor, calcineurin autoinhibitory peptide (CIP), treatment. Permeability was measured based on fluorescein isothiocyanate-albumin flux across the monolayers. Mitochondrial transmembrane potential (MTP) was determined using 5,5',6,6'-tetrachoro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide. Mitochondrial release of cytochrome c was measured using an enzyme-linked immunosorbent assay and caspase-3 activity fluorometrically. RESULTS: CsA-attenuated (10 nmol/L) but not CIP-attenuated (100 mumol/L) BAK induced hyperpermeability (P < .05), CsA- but not CIP-attenuated BAK induced a decrease in MTP and an increase in cytochrome c levels and caspase-3 activity (P < .05). CsA and CIP were ineffective against caspase-3-induced hyperpermeability. CONCLUSIONS: CsA attenuated hyperpermeability by protecting MTP, thus preventing mitochondria-mediated apoptotic signaling. The protective effect of CsA is independent of calcineurin inhibition.
Assuntos
Calcineurina/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Ciclosporina/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Pulmão/irrigação sanguínea , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Inibidores de Caspase , Citocromos c/metabolismo , Microcirculação , Mitocôndrias/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Vascular hyperpermeability is a clinical complication associated with hemorrhagic shock (HS) and occurs mainly because of the disruption of the adherens junctional complex. The objective of this study was to understand the role of 17beta-estradiol in HS-induced hyperpermeability particularly focusing on estrogen receptors. In male Sprague-Dawley rats, HS was induced by withdrawing blood to reduce the mean arterial pressure to 40 mmHg for 1 hour followed by 1 hour of resuscitation to 90 mmHg. The study groups were 17beta-estradiol, tamoxifen, fulvestrant plus 17beta-estradiol, propyl pyrazole triol plus 17beta-estradiol, and diarylpropionitrile plus 17beta-estradiol. Intravital microscopy was used to study changes in mesenteric postcapillary venules. Mitochondrial reactive oxygen species formation was studied in vivo using dihydrorhodamine 123. The mitochondrial transmembrane potential was studied using the fluorescent cationic probe 5,5',6,6'tetrachloro-1,1',3,3'tetraethylbenzimidazolyl carbocyanine iodide (JC-1). The mesenteric microvasculature was analyzed for cytochrome c levels by enzyme-linked immunosorbent assay and caspase-3 activity by a fluorometric assay. Our results demonstrated that 17beta-estradiol attenuated HS-induced hyperpermeability. Fulvestrant reversed this protective effect (P < 0.05). Tamoxifen 5 mg/kg attenuated HS-induced hyperpermeability, whereas 10 mg/kg induced permeability (P < 0.05). Both alpha and beta estrogen receptor agonists inhibited HS-induced hyperpermeability (P < 0.05). 17beta-Estradiol decreased HS-induced reactive oxygen species formation and restored mitochondrial transmembrane potential. 17beta-Estradiol decreased both cytosolic cytochrome c level and activation of caspase-3 (P < 0.05). These findings suggest that 17beta-estradiol protects the microvasculature after HS, and that this protection may be mediated through the alpha and beta estrogen receptors.
Assuntos
Síndrome de Vazamento Capilar/prevenção & controle , Permeabilidade Capilar/efeitos dos fármacos , Estradiol/uso terapêutico , Receptor alfa de Estrogênio/fisiologia , Receptor beta de Estrogênio/fisiologia , Choque Hemorrágico/fisiopatologia , Animais , Síndrome de Vazamento Capilar/etiologia , Relação Dose-Resposta a Droga , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/toxicidade , Moduladores de Receptor Estrogênico/administração & dosagem , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Moduladores de Receptor Estrogênico/toxicidade , Receptor alfa de Estrogênio/agonistas , Receptor beta de Estrogênio/agonistas , Fulvestranto , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mesentério/irrigação sanguínea , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Fenóis , Propionatos/administração & dosagem , Propionatos/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Choque Hemorrágico/complicações , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Tamoxifeno/toxicidade , Vênulas/ultraestruturaRESUMO
Bcl-xl and the hepatocyte growth factor (HGF) receptor c-Met are both highly expressed in mesotheliomas, where they protect cells from apoptosis and can confer resistance to conventional therapeutic agents. In our current study, we investigate a model for the transcriptional control of Bcl-xl that involves ETS transcription factors and the HGF/Met axis. In addition, the effects of activated c-Met on the phosphorylation of the ETS family transcriptional factors were examined. The transient expression of ETS-2 and PU.1 cDNAs in mesothelioma cell lines resulted in an increase in the promoter activity of Bcl-xl and consequently in its mRNA and protein expression levels, whereas the transcriptional repressor Tel suppressed Bcl-xl transcription. The activation of the HGF/Met axis led to rapid phosphorylation of ETS family transcription factors in mesothelioma cells through the mitogen-activated protein kinase pathway and via nuclear accumulation of ETS-2 and PU.1. A chromatin immunoprecipitation assay further demonstrated that the activation of c-Met enhanced the binding of ETS transcriptional factors to the Bcl-x promoter. Finally, we determined the Bcl-xl and phosphorylated c-Met expression levels in mesothelioma patient samples; these data suggest a strong correlation between Bcl-xl and phosphorylated c-Met levels. Taken together, these findings support a role for c-Met as an inhibitor of apoptosis and an activator of Bcl-xl.
Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Mesotelioma/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteína bcl-X/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Mesotelioma/patologia , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-ets-2/genética , Proteína Proto-Oncogênica c-ets-2/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-met/genética , Transativadores/genética , Transativadores/metabolismo , Regulação para Cima , Proteína bcl-X/genéticaRESUMO
The objective of this review is to determine the outcome of patients with sarcomas involving the main pulmonary artery, pulmonic valve, or right ventricular outflow tract. Survival data were analyzed using an aggregate series derived from the published literature in conjunction with a current series. Median survival was 36.5 +/- 20.2 months for patients undergoing an attempt at curative resection compared with 11 +/- 3 months for those undergoing incomplete resection. Median survival was 24.7 +/- 8.5 months for patients undergoing multimodality treatment compared with 8.0 +/- 1.7 months for patients having single-modality therapy. A complete review of diagnosis, evaluation, treatment, and surveillance of primary pulmonary artery sarcomas follows.
Assuntos
Artéria Pulmonar , Sarcoma , Neoplasias Vasculares , Adulto , Idoso , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma/diagnóstico , Sarcoma/terapia , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/terapia , Adulto JovemRESUMO
BACKGROUND: Previous work from our laboratory demonstrated the involvement of "intrinsic" mitochondrial apoptotic signaling in vascular hyperpermeability. The objective of this study was to determine if 17beta-estradiol, a known inhibitor of apoptosis, would attenuate microvascular endothelial cell hyperpermeability. METHODS: Rat lung microvascular endothelial cell monolayers were treated with 17beta-estradiol or estrogen-receptor antagonist ICI 182780 after transfection with BAK peptide (5 microg/mL). Fluorescein isothiocyanate (FITC)-albumin was used to determine the change in permeability. Mitochondrial reactive oxygen species (ROS) formation and transmembrane potential were determined using 123 dihydrorhodamine and JC-1, respectively. Cytosolic cytochrome c levels and caspase-3 activity were determined using enzyme-linked immunosorbent assay and fluorometric assay respectively. RESULTS: 17beta-estradiol (10 nm) attenuated BAK-induced hyperpermeability (P < .05), ROS formation, cytochrome c release, and caspase-3 activation. The estrogen receptor antagonist ICI 182780 blocked the protective effect of 17beta-estradiol on hyperpermeability (P < .05). CONCLUSIONS: 17beta-estradiol attenuates BAK-induced hyperpermeability in rat lung microvascular endothelial cells by way of an estrogen-receptor mediated pathway.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Células Endoteliais/efeitos dos fármacos , Estradiol/farmacologia , Doenças Vasculares/prevenção & controle , Animais , Células Cultivadas , Pulmão/irrigação sanguínea , RatosRESUMO
BACKGROUND: Aprotinin has been used to decrease blood loss with complicated cardiac surgery but has not been investigated in extrapleural pneumonectomy, an operation that does not use cardiopulmonary bypass. In this prospective, randomized, placebo-controlled, double-blind trial, the authors investigated whether aprotinin decreased blood loss in patients who underwent this operation. METHODS: After appropriate statistical design and institutional review board approval, eligible patients who were scheduled for extrapleural pneumonectomy were randomized to receive either aprotinin or placebo during the operation. Blood loss and survival data were obtained from electronic medical records and surgical databases. RESULTS: Of 20 patients who were enrolled, 16 patients met criteria for blood loss analysis. Four patients were excluded from the blood loss analysis: Three patients were inoperable because of tumor spread and underwent limited surgery, and 1 patient died intraoperatively because of acute, massive hemorrhage. The mean blood loss was 769 mL with aprotinin versus 1832 mL with placebo (P = .05; Wilcoxon test). All 20 patients were included in survival analyses. All 9 patients who received placebo died. In contrast, 7 of 11 patients who received aprotinin remained alive at the time of the current report. Kaplan-Meier survival curves differed significantly between the 2 groups (P = .0004). A Bayesian multivariate survival analysis of 18 patients who had complete data available on 8 prognostic variables indicated a posterior probability of .99 that aprotinin was beneficial. CONCLUSIONS: Aprotinin decreased blood loss. After accounting for covariate effects, there was a significant comparative benefit with aprotinin in postoperative survival. This finding was unexpected and could not be considered conclusive because of the small size of the current study. A confirmatory study may be warranted.
Assuntos
Aprotinina/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Hemostáticos/uso terapêutico , Mesotelioma/mortalidade , Neoplasias Pleurais/mortalidade , Pneumonectomia , Idoso , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Metástase Linfática , Masculino , Mesotelioma/secundário , Mesotelioma/cirurgia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Neoplasias Pleurais/cirurgia , Cuidados Pós-Operatórios , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
Bcl-xL functions as a dominant regulator of apoptotic cell death and is implicated in chemotherapeutic resistance of malignant pleural mesothelioma (MPM). Mesothelioma cell lines demonstrate increasing levels of Bcl-xL as resistant clones are selected in vitro. Moreover, upon introduction of antisense oligonucleotides specific to Bcl-xL mRNA, MPM cells are sensitized to chemotherapeutic agents. Here we describe the therapeutic effects of a novel combination therapy, Bcl-xL antisense oligonucleotide (ASO 15999) and cisplatin, on mesothelioma cell lines in vitro and in vivo; in addition, efficacy of ASO 15999 in decreasing tumor load as well as its effect on survival in an animal model. Finally, we initiated preliminary toxicity studies involved with intraperitoneal (IP) injections of ASO 15999 into mice. This novel combination, with doses of cisplatin four times below established IC(50) levels, significantly decreased viability of MPM cell lines after 48 hr. The growth of established mouse flank human tumor xenografts was reduced with intra-tumor administration of ASO 15999. Local spread and development of IP xenografts was reduced with treatments of ASO alone, and survival of mice afflicted with these xenografts was prolonged after administration of ASO alone and ASO 15999 + cisplatin combination therapy. These findings suggest that ASO 15999 sensitizes MPM cell lines to the toxic effects of cisplatin. ASO 15999 induced reduction of Bcl-xL is effective in slowing the progression of human mesothelioma cell lines both in vitro and in vivo. More notably, the combination of Bcl-xL ASO and cisplatin extends survival in an orthotopic tumor xenograft model.