RESUMO
Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain-containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1ß-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.
Assuntos
Senescência Celular/imunologia , Lamina Tipo B/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Senescência Celular/genética , Humanos , Lamina Tipo B/genética , Oxirredução , Doença Pulmonar Obstrutiva Crônica/patologia , Células Tumorais CultivadasRESUMO
Tumor progression is the main cause of death in patients with breast cancer. Accumulating evidence suggests that dual-specificity tyrosine-regulated kinase 2 (DYRK2) functions as a tumor suppressor by regulating cell survival, differentiation, proliferation and apoptosis. However, little is known about the mechanisms of transcriptional regulation by DYRK2 in cancer progression, particularly with respect to cancer proliferation and invasion. Here, using a comprehensive expression profiling approach, we show that cyclin-dependent kinase 14 (CDK14) is a target of DYRK2. We found that reduced DYRK2 expression increases CDK14 expression, which promotes cancer cell proliferation and invasion in vitro, in addition to tumorigenicity in vivo. CDK14 and DYRK2 expression inversely correlated in human breast cancer tissues. We further identified androgen receptor (AR) as a candidate of DYRK2-dependent transcription factors regulating CDK14. Taken together, our findings suggest a mechanism by which DYRK2 controls CDK14 expression to regulate tumor cell proliferation and invasion in breast cancer. Targeting of this pathway may be a promising therapeutic strategy for treating breast cancer.
Assuntos
Neoplasias da Mama/patologia , Quinases Ciclina-Dependentes/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Regulação para Cima , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Quinases Ciclina-Dependentes/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Quinases DyrkRESUMO
Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition-mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.
Assuntos
Fibrose Pulmonar Idiopática/patologia , Mitofagia/fisiologia , Miofibroblastos/patologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Western Blotting , Diferenciação Celular/fisiologia , Imunofluorescência , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologiaRESUMO
PURPOSE: Skin-sparing mastectomy (SSM) enables a radical cure of breast cancer while overcoming the cosmetic issues related to surgery. We review our experience of performing SSMs and assess whether preservation of the nipple-areola complex (NAC) could have been an option for some patients who underwent SSM. METHODS: The subjects of this retrospective study were women who underwent SSM that utilized four incision types; namely, the so-called tennis racket incision, a periareolar and midaxillary incision, an areola-sparing and midaxillary incision, and a small transverse elliptical incision. We assessed whether preservation of the NAC would have been an option in SSM, based on histologic examination of three serial cut surfaces of the specimen around the nipple, ruling out the option when evidence of the malignant lesion/s was found in at least one of the following locations: in the nipple, within a 1-cm radius from the base of the nipple, or within 1 cm from the surface of the NAC. RESULTS: We performed 193 SSMs. The cumulative 10-year local disease-free survival rate was 98%, with 89% of patients reporting levels of satisfaction with the reconstructed breast, of excellent, very good, or good. We evaluated that 70 of the 193 procedures could have been performed as nipple-sparing mastectomy (NSM). CONCLUSIONS: The outcomes of SSM in this series were excellent and NSM might have been an option for about one-third of the patients.
Assuntos
Neoplasias da Mama/cirurgia , Mastectomia/métodos , Mamilos/cirurgia , Tratamentos com Preservação do Órgão/métodos , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Mamoplastia/métodos , Mastectomia/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Pulmonary cryptococcosis is difficult to distinguish from lung cancer clinically, and is often diagnosed by surgery. A 72-year-old woman, who underwent distal pancreatectomy and splenectomy for pancreatic carcinoma. Four months after surgery, a tumor shadow was detected in the left lung as a groundglass nodule (GGN)of 12 mm in diameter, which was found to change to 15 mm with increased density by the computed tomography(CT)scan after 2 months. The nodule showed positive accumulation of fluorodeoxyglucose(FDG)by positron emission tomography(PET), and was suspected of malignant tumor. She underwent a partial resection of the left lung under thoracoscopy.
Assuntos
Criptococose/diagnóstico por imagem , Pneumopatias Fúngicas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Idoso , Diagnóstico Diferencial , Feminino , Fluordesoxiglucose F18 , Humanos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios XRESUMO
Elastofibroma is a relatively rare tumor that occurs commonly at the apex of scapula in elderly people. We report a case of elastofibroma of a female in her seventies. She visited our hospital with complaints of painful mass in her back, which was increasing in size. On the magnetic resonance imaging (MRI),the T1 and the T2-weighted images showed the same signal intensity as the muscle between the right scapula and the intercostal muscles. The internal fat component was cord-like, with high signal intensity. Based on the site of the tumor and characteristic findings on imaging, it was diagnosed as elastofibroma and resection was performed. Pathological findings revealed bundle-like proliferation of fibrous and spherical hyaline substances, together with collagen fibers. The hyaline substance stained in black on Elastica van Gieson staining and was confirmed to be elastic fiber. Thus, it was diagnosed as elastofibroma. The patient is on regular follow-up, with no recurrence after surgery.
Assuntos
Músculos do Dorso , Fibroma , Neoplasias Musculares , Idoso , Músculos do Dorso/diagnóstico por imagem , Músculos do Dorso/patologia , Tecido Elástico/diagnóstico por imagem , Tecido Elástico/patologia , Feminino , Fibroma/diagnóstico por imagem , Fibroma/patologia , Humanos , Imageamento por Ressonância Magnética , Neoplasias Musculares/diagnóstico por imagem , Neoplasias Musculares/patologia , EscápulaRESUMO
The patient was a 74-year-old man who had undergone surgery for rectal cancer 9 years before and had developed left lung metastasis(S3)3 years and 4 months prior to admission. He had received video assisted left lung wedge resection. He presented with a growing nodular lesion close to the remaining left lung margin and elevated serum carcinoembryonic antigen(CEA)levels, and underwent open extended segmentectomy. The chest drain tube was removed on 3rd post-operative day, but he developed left pneumothorax on 4th post-operative day and a computed tomography(CT)scan revealed a cystic lesion 5.0 cm in size at the base of his left lung. Revision surgery was performed on 8th post-operative day. A pulmonary cyst on the diaphragmatic surface of the lung(S10)was found and location of the air leak was confirmed in the same area. Following wedge resection of the cyst-containing region, the leak ceased completely. Rapid manifestation of a newly formed pulmonary cyst during the acute post-operative period is rare.
Assuntos
Cistos/cirurgia , Pneumopatias/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/efeitos adversos , Pneumotórax/etiologia , Complicações Pós-Operatórias/cirurgia , Idoso , Antígeno Carcinoembrionário/sangue , Tubos Torácicos , Cistos/diagnóstico por imagem , Humanos , Pulmão , Pneumopatias/diagnóstico por imagem , Pneumopatias/etiologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Masculino , Pneumonectomia/métodos , Complicações Pós-Operatórias/diagnóstico por imagem , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-ß (TGF-ß)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-ß. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.
Assuntos
Antioxidantes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Piridonas/farmacologia , Animais , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Bleomicina , Células Cultivadas , Modelos Animais de Doenças , Humanos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transfecção , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: This study evaluated the feasibility of thoracoscopic thymectomy (TT) for the treatment of early- and advanced-stage thymoma and compared patient outcomes with those following open thymectomy (OT). METHODS: A retrospective review was conducted for 140 patients who underwent TT or OT for Masaoka stage I-IV thymoma between 1996 and 2014. RESULTS: TT was performed in 88 patients and OT in 52 patients. The postoperative hospital stay was significantly shorter in the TT group than in the OT group (4 and 13 days, respectively; P < 0.0001). WHO types B3-C were identified in Masaoka stage III-IV disease with high frequency. There was a significant relationship between Masaoka stage and WHO type (P < 0.05); the numbers of advanced-stage thymoma progressively increased in WHO type B3-C. Eight patients in each group had recurrent disease, with greater recurrence for WHO types B3-C and stage III-IV tumors. Five-year disease-free survival (DFS) was not different between groups (P = 0.3906); however, survival for patients with stage III-IV thymomas (47 %) was significantly worse than that for patients with stage I and II tumors (97.5 and 94.1 %, respectively; P < 0.0001). Based on multivariate analysis, both Masaoka stage and WHO type were significant predictors of thymoma patient survival. CONCLUSIONS: These results demonstrate the safety and substantially decreased invasiveness of TT for thymoma. The oncological results were comparable between the TT and OT groups. Furthermore, Masaoka stage III-IV and WHO B3-C were revealed as independent prognostic factors for DFS.
Assuntos
Complicações Pós-Operatórias/epidemiologia , Toracoscopia/métodos , Timectomia/métodos , Timoma/cirurgia , Neoplasias do Timo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica , Transfusão de Sangue , Intervalo Livre de Doença , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Toracotomia , Timoma/patologia , Carga Tumoral , Adulto JovemRESUMO
A clinical implication of programmed cell death 1 ligand 1 (PD-L1) expression in lung adenocarcinoma has not been well established. We evaluated PD-L1 expression immunohistochemically on 296 surgically resected lung adenocarcinomas to investigate a clinical implication of PD-L1 expression especially in terms of smoking history and epidermal growth-factor receptor (EGFR) mutation status. Patients were classified into high- and low-PD-L1 expression groups. The high-expression group (n = 107) showed a significantly higher proportion of smokers and poor differentiation compared with the low-expression group (n = 189). Survival analysis showed that the prognosis of the high-expression group was worse in overall survival than that of the low-expression group (3-year overall survival 85 vs. 94%, P = 0.005). Stratified survival analyses showed that the prognoses of the high-expression group were worse than those of the low-expression group in both strata of smokers and wild-type EGFR (P = 0.009 and P = 0.007, respectively). We found that high PD-L1 expression was a poor prognostic factor in the smokers or the patients with wild-type EGFR, whereas it was not the case in those who never smoked or those with EGFR mutation, implying the importance of adenocarcinoma driver mutations and etiology.
Assuntos
Adenocarcinoma/patologia , Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/análise , Neoplasias Pulmonares/patologia , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Adulto , Idoso , Antígeno B7-H1/análise , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fumar/efeitos adversos , Análise Serial de TecidosRESUMO
BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci (FF) is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis (IPF) pathogenesis, and transforming growth factor (TGF)-ß plays a key regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS) has been proposed to be involved in the mechanism for TGF-ß-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMP-activated protein kinase (AMPK), which regulates not only energy homeostasis but also stress responses, including ROS. Therefore, we sought to investigate the inhibitory role of metformin in lung fibrosis development via modulating TGF-ß signaling. METHODS: TGF-ß-induced myofibroblast differentiation in lung fibroblasts (LF) was used for in vitro models. The anti-fibrotic role of metfromin was examined in a bleomycin (BLM)-induced lung fibrosis model. RESULTS: We found that TGF-ß-induced myofibroblast differentiation was clearly inhibited by metformin treatment in LF. Metformin-mediated activation of AMPK was responsible for inhibiting TGF-ß-induced NOX4 expression. NOX4 knockdown and N-acetylcysteine (NAC) treatment illustrated that NOX4-derived ROS generation was critical for TGF-ß-induced SMAD phosphorylation and myofibroblast differentiation. BLM treatment induced development of lung fibrosis with concomitantly enhanced NOX4 expression and SMAD phosphorylation, which was efficiently inhibited by metformin. Increased NOX4 expression levels were also observed in FF of IPF lungs and LF isolated from IPF patients. CONCLUSIONS: These findings suggest that metformin can be a promising anti-fibrotic modality of treatment for IPF affected by TGF-ß.
Assuntos
Fibrose Pulmonar Idiopática/prevenção & controle , Pulmão/efeitos dos fármacos , Metformina/farmacologia , Miofibroblastos/efeitos dos fármacos , NADPH Oxidase 4/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Bleomicina , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Pulmão/enzimologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Miofibroblastos/enzimologia , Miofibroblastos/patologia , NADPH Oxidase 4/genética , Fosforilação , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Proteínas Smad/metabolismo , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Cigarette smoke (CS)-induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated ß-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.
Assuntos
Autofagia/fisiologia , Brônquios/patologia , Senescência Celular/fisiologia , Células Epiteliais/patologia , Fator de Crescimento Insulin-Like I/fisiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Sirtuínas/fisiologia , Fumaça/efeitos adversos , Acetilação , Proteína 5 Relacionada à Autofagia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Volume Expiratório Forçado , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/fisiologia , Mutação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/fisiologia , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Serina-Treonina Quinases TOR/fisiologia , Nicotiana , Capacidade VitalRESUMO
PURPOSE: Skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR) has become popular as an effective procedure for patients with early breast cancer. We herein report an overview of the four types of skin incisions used for SSM. METHODS: The records of 111 consecutive breast cancer patients, who received SSM and IBR from 2003 to 2012, were reviewed retrospectively. Four types of skin incisions were used. Type A was the so-called tennis racquet incision, type B was a periareolar incision and mid-axillary incision, type C was the so-called areola-sparing with mid-axillary incision and type D was a small transverse elliptical incision and transverse axillary incision. RESULTS: Twenty-six type A, 59 type B, 20 type C and six type D incisions were made. The average blood loss and average length of the operation during SSM were not significantly different between the four approaches. The average areolar diameter was 35 mm for type A, B and D incisions, and 45 mm for type C. There was a need for postoperative nipple-areolar complex plasty (NAC-P) in 75 % of the cases following type A, B and D incisions, and 35 % of the cases treated using type C incisions. CONCLUSION: The type C incision is superior with regard to the cost and cosmetic outcomes, because fewer of these patients request postoperative NAC-P.
Assuntos
Neoplasias da Mama/cirurgia , Mamoplastia/métodos , Mastectomia Subcutânea/métodos , Adulto , Idoso , Análise Custo-Benefício , Feminino , Humanos , Mamoplastia/economia , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated ß-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development.
Assuntos
Brônquios/patologia , Senescência Celular/efeitos dos fármacos , Células Epiteliais/patologia , Mitocôndrias/patologia , Nicotiana/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Western Blotting , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Células Cultivadas , Dinaminas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , GTP Fosfo-Hidrolases/antagonistas & inibidores , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Técnicas Imunoenzimáticas , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , RNA Interferente Pequeno/genéticaRESUMO
Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF.
Assuntos
Autofagia , Fibrose Pulmonar Idiopática/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Diferenciação Celular/fisiologia , Senescência Celular/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Células Epiteliais/patologia , Células Epiteliais/fisiologia , Humanos , Miofibroblastos/citologia , Proteína Sequestossoma-1 , Tunicamicina/farmacologia , Ubiquitina/biossínteseRESUMO
This study aimed to investigate bronchiolar catalase expression and its relationship with smoking and/or chronic obstructive pulmonary disease (COPD) in humans and to determine the dynamic change of bronchiolar catalase expression in response to cigarette smoke in mice. Lung tissue was obtained from 36 subjects undergoing surgery for peripheral tumours, consisting of life-long nonsmokers and smokers with or without COPD. Male C57BL/6 mice were subjected to cigarette smoke exposure for up to 3 months followed by a 28-day cessation period. We quantified bronchiolar catalase mRNA using laser capture microdissection and quantitative reverse transcription-polymerase chain reaction. C22 club cells (Clara cells) in culture were exposed to cigarette smoke extract and monitored for viability when catalase expression was decreased by siRNA. Catalase was decreased at mRNA and protein levels in bronchiolar epithelium in smokers with COPD. In mice, bronchiolar catalase is temporarily upregulated at 1 day after cigarette smoke exposure but is downregulated by repeated cigarette smoke exposure, and is not restored long after withdrawal once emphysema is developed. Decreasing catalase expression in C22 cells resulted in greater cigarette smoke extract-induced cell death. Bronchiolar catalase reduction is associated with COPD. Regulation of catalase depends on the duration of cigarette smoke exposure, and plays a critical role for protection against cigarette smoke-induced cell damage.
Assuntos
Brônquios/enzimologia , Catalase/metabolismo , Epitélio/enzimologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumar/efeitos adversos , Idoso , Animais , Modelos Animais de Doenças , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Pulmão/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredução , Estresse Oxidativo , RNA Mensageiro/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure. METHODS: Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM. RESULTS: The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure. CONCLUSIONS: These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Regulação da Expressão Gênica , Macrófagos Alveolares/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/genética , Proteínas Reguladoras de Apoptose/genética , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Feminino , Células HEK293 , Humanos , Lectinas Tipo C/biossíntese , Lectinas Tipo C/genética , Macrófagos Alveolares/patologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Células U937RESUMO
TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8-dependent mechanisms. However, insulin efficiently inhibited TLR3/polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.
Assuntos
Apoptose/imunologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Insulina/fisiologia , Sistema de Sinalização das MAP Quinases/imunologia , Fosfatidilinositol 3-Quinase/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Mucosa Respiratória/imunologia , Receptor 3 Toll-Like/antagonistas & inibidores , Brônquios/enzimologia , Brônquios/imunologia , Brônquios/patologia , Células Cultivadas , Humanos , Mucosa Respiratória/enzimologia , Mucosa Respiratória/patologia , Receptor 3 Toll-Like/fisiologiaRESUMO
We describe the benefits of simulating an anatomical lung segmentectomy using multidetector computed tomography bronchography and angiography (tailor-made virtual lung). Preoperative determination of the anatomical intersegmental plane is possible by visualizing the segmental bronchi and pulmonary vein branches. This advanced technique could be useful during thoracoscopic anatomical segmentectomy for lung cancer.
Assuntos
Simulação por Computador , Pulmão/cirurgia , Modelos Anatômicos , Pneumonectomia/métodos , Cirurgia Assistida por Computador , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios X , Humanos , Imageamento Tridimensional , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Seleção de Pacientes , Valor Preditivo dos Testes , Cuidados Pré-Operatórios , Interpretação de Imagem Radiográfica Assistida por Computador , Software , Resultado do TratamentoRESUMO
Spin-contrast-variation (SCV) small-angle neutron scattering (SANS) is a technique to determine the nanostructure of composite materials from the scattering of polarized neutrons that changes with proton polarization of samples. The SCV-SANS enabled us to determine structure of nanoice crystals that were generated in rapidly frozen sugar solutions by separating the overlapped signals from the nanoice crystals and frozen amorphous solutions. In the frozen glucose solution, we found that the nanoice crystals formed a planar structure with a radius larger than several tens of nanometers and a thickness of 2.5 ± 0.5 nm, which was close to the critical nucleation size of ice crystals in supercooled water. This result suggests that the glucose molecules were preferentially bound to a specific face of nanoice crystals and then blocked the crystal growth perpendicular to that face.