RESUMO
The orphan nuclear receptor Nur77 (also known as TR3 or nerve growth factor-induced clone B NGFI-B) functions as a nuclear transcription factor in the regulation of target gene expression and plays a critical role in the regulation of differentiation, proliferation, apoptosis, and survival of many different cell types. Recent studies demonstrate that Nur77 also involves many important physiological and pathological processes including cancer, inflammation and immunity, cardiovascular diseases, and bone diseases. Our previous studies showed that cardiac glycosides could induce the expression of Nur77 protein and its translocation from the nucleus to the cytoplasm and subsequent targeting to mitochondria, leading to apoptosis of cancer cells. In order to probe the Nur77 protein inducting pathway, we designed and synthesized a series of novel biotinylated cardiac glycosides from ß-Antiarin and α-Antiarin, two typical cardiac glycosides from the plant of Antiaris toxicaria. The induction of Nur77 protein expression of these biotinylated cardiac glycosides and their inhibitory effects on NIH-H460 cancer cell proliferation were evaluated. Results displayed that some biotinylated cardiac glycosides could significantly induce the expression of Nur77 protein comparable with their parent compounds ß-Antiarin and α-Antiarin. Also, their streptavidin binding activities were evaluated. Among them, biotinylated cardiac glycosides P4b and P5a exhibited significant effect on the induction of Nur77 expression along with high binding capacity with streptavidin, suggesting that they can be used as probes for probing Nur77 protein inducting pathway.
Assuntos
Biotina/química , Glicosídeos Cardíacos/química , Glicosídeos Cardíacos/síntese química , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/química , Animais , Glicosídeos Cardíacos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Sondas MolecularesRESUMO
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint and DNA repair by homologous recombination (HR). However, the biochemical mechanism underlying the transition from DSB sensing to resection remains unclear. Using Xenopus egg extracts and human cells, we show that the tumor suppressor protein CtIP plays a critical role in this transition. We find that CtIP translocates to DSBs, a process dependent on the DSB sensor complex Mre11-Rad50-NBS1, the kinase activity of ATM, and a direct DNA-binding motif in CtIP, and then promotes DSB resection. Thus, CtIP facilitates the transition from DSB sensing to processing: it does so by binding to the DNA at DSBs after DSB sensing and ATM activation and then promoting DNA resection, leading to checkpoint activation and HR.
Assuntos
Proteínas de Transporte/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas Nucleares/metabolismo , Sequência de Aminoácidos , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Reparo do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endodesoxirribonucleases , Ativação Enzimática , Humanos , Dados de Sequência Molecular , Proteínas Nucleares/genética , Oócitos/citologia , Oócitos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Recombinação Genética , Alinhamento de Sequência , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Xenopus laevisRESUMO
ATR and Chk1 are two key protein kinases in the replication checkpoint. Activation of ATR-Chk1 has been extensively investigated, but checkpoint termination and replication fork restart are less well understood. Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. The protein levels of Chk1 and Fbx6 showed an inverse correlation in both cultured cancer cells and in human breast tumor tissues. Further, we show that low levels of Fbx6 and consequent impairment of replication stress-induced Chk1 degradation are associated with cancer cell resistance to the chemotherapeutic agent, camptothecin. We propose that Fbx6-dependent Chk1 degradation contributes to S phase checkpoint termination and that a defect in this mechanism might increase tumor cell resistance to certain anticancer drugs.
Assuntos
Dano ao DNA , Replicação do DNA , Neoplasias/enzimologia , Proteínas Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Ligases SKP Culina F-Box/metabolismo , Estresse Fisiológico , Antineoplásicos Fitogênicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia , Camptotecina/farmacologia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática , Humanos , Lisina , Neoplasias/genética , Neoplasias/patologia , Fosforilação , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Interferência de RNA , Proteínas Ligases SKP Culina F-Box/genética , Fatores de Tempo , UbiquitinaçãoRESUMO
For traditional ferroelectric field-effect transistors (FeFETs), enhancing the polarization domain of bulk ferroelectric materials is essential to improve device performance. However, there has been limited investigation into the enhancement of polarization field in two-dimensional (2D) ferroelectric material such as CuInP2S6 (CIPS). In this study, similar to bulk ferroelectric materials, CIPS exhibited enhanced polarization field upon application of external cyclic voltage. Moreover, unlike traditional ferroelectric materials, the polarization enhancement of CIPS is not due to redistribution of the defect but rather originates from a mechanism: the long-distance migration of Cu ions. We termed this mechanism the "wake-up-like effect". After incorporating the wake-up-like effect into the graphene/CIPS/WSe2 FeFET device, we successfully increased the hysteresis window and enhanced the current on/off ratio by 4 orders of magnitude. Moreover, the FeFET yielded remarkable achievements, such as multilevel nonvolatile memory with 21 distinct conductance levels, a high on/off ratio exceeding 106, a long retention time exceeding 103 s, and neuromorphic computing with 93% accuracy at recognizing handwritten digits. Introducing the wake-up-like effect to 2D CIPS may pave the way for innovative approaches to achieve advanced multilevel nonvolatile memory and neuromorphic computing capabilities for next-generation micro-nanoelectronic devices.
RESUMO
OBJECTIVE: To observe the effects of Yiqi Huayu Recipe, a Chinese compound herbal medicine, on apoptosis of dorsal root ganglion (DRG) neurons and expression of caspase-3 in rats after lumbar nerve root compression injury. METHODS: A total of 40 male Sprague-Dawley rats were randomly allocated into 4 groups: control group, untreated group, Methylcobal group and Yiqi Huayu Recipe group. Surgery was performed on rats of untreated group, Methylcobal group and Yiqi Huayu Recipe group to place a micro-silica gel on right L4 DRG, while control group received skin and paravertebral muscle incision only. Rats in Methylcobal group and Yiqi Huayu Recipe group were given Methylcobal by intramuscular injection and Yiqi Huayu Recipe intragastrically respectively. Rats in control group and untreated group received saline intragastrically as equal amount as Yiqi Huayu Recipe group. The compressed nerve roots were harvested at the 10th day after treatment. Apoptosis of DRG neurons was detected by terminal deoxynucleotidyl transferase-mediated nick-end labeling. Caspase-3 activity and mRNA expression in compressed nerve roots were detected with spectrophotography and real-time polymerase chain reaction respectively. RESULTS: Apoptosis of DRG neurons was significantly increased in the rat model. The apoptosis index of untreated group was higher than that of control group (P<0.01). Yiqi Huayu Recipe and Methylcobal could reduce the apoptosis of DRG neurons, and both groups showed a lower apoptosis index than untreated group (P<0.01). Caspase-3 activity and its gene expression were significantly increased in untreated group. The levels of caspase-3 activity and its gene expression in untreated group were higher than those in control group (P<0.05 or P<0.01). Yiqi Huayu Recipe and Methylcobal could reduce the overexpression of caspase-3 mRNA, and statistically significant differences were found between the untreated group and Yiqi Huayu Recipe group or Methylcobal group (P<0.01). CONCLUSION: Lumbar nerve root compression results in overexpression of caspase-3 in nerve root tissue and increase of DRG neuron apoptosis. Yiqi Huayu Recipe can inhibit the overexpression of caspase-3 and alleviate the apoptosis of DRG neurons after nerve injury.
Assuntos
Apoptose , Caspase 3/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Neurônios/efeitos dos fármacos , Radiculopatia/metabolismo , Animais , Gânglios Espinais/citologia , Masculino , Radiculopatia/patologia , Ratos , Ratos Sprague-Dawley , Compressão da Medula Espinal/metabolismo , Compressão da Medula Espinal/patologiaRESUMO
BACKGROUND: The purpose of this study is to evaluate the effect and safety of Huangqi-Guizhi-Wuwu Decoction (HGWD) and Erxian Decoction (EXD) in the treatment of frozen shoulder (FS). METHODS: We will compressively search potential randomized controlled trials from electronic databases of MEDLINE, EMBASE, Cochrane Library, CINAHL, PsycINFO, Web of Science, Allied and Complementary Medicine Database, Google Scholar, and China National Knowledge Infrastructure. We will search all of them from inception of each electronic database up to the present without language limitations. Two researchers will conduct selection of study, data extraction, and study quality evaluation independently. Study quality will be identified using Cochrane risk of bias tool. Statistical analysis will be performed using RevMan 5.3 software. RESULTS: This study will summarize high quality evidence of randomized controlled trials on exploring the effect and safety of HGWD and EXD in the treatment of FS. CONCLUSIONS: The results of this study will provide helpful evidence of the effect and safety of HGWD and EXD in the treatment of FS to facilitate the clinical practice and guideline development. STUDY REGISTRATION NUMBER: INPLASY202040070.
Assuntos
Bursite/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Avaliação da Deficiência , Humanos , Metanálise como Assunto , Medição da Dor , Qualidade de Vida , Projetos de Pesquisa , Revisões Sistemáticas como AssuntoRESUMO
The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation in vitro and in vivo, decreased the IC50 values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.
Assuntos
Adenocarcinoma de Pulmão/genética , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Glutationa Peroxidase/genética , Neoplasias Pulmonares/genética , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metabolismo Energético , Feminino , Regulação Neoplásica da Expressão Gênica , Glutationa Peroxidase/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Estresse Oxidativo , PrognósticoRESUMO
We have previously discovered that HDAC6 regulates the DNA damage response (DDR) via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6's ubiquitin E3 ligase activity. Here, we have reported HDAC6's second potential E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo and in vitro. Specifically, HDAC6 interacts with Chk1 via the DAC1 domain, which contains its ubiquitin E3 ligase activity. During the cell cycle, Chk1 protein levels fluctuate, peaking at the G2 phase, subsequently resolving via the ubiquitin-proteasome pathway, and thereby allowing cells to progress to the M phase. However, in HDAC6 knockdown non-small cell lung cancer (NSCLC) cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), and this enhanced Chk1 activity leads to preferential G2 arrest in HDAC6 knockdown cells accompanied by a reduction in colony formation capacity and viability. Depletion or pharmacological inhibition of Chk1 in HDAC6 knockdown cells reverses this radiosensitive phenotype, suggesting that the radiosensitivity of HDAC6 knockdown cells is dependent on increased Chk1 kinase activity. Overall, our results highlight a novel mechanism of Chk1 regulation at the post-translational level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting HDAC6's E3 ligase activity.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Quinase 1 do Ponto de Checagem/metabolismo , Desacetilase 6 de Histona/metabolismo , Neoplasias Pulmonares/genética , Tolerância a Radiação/fisiologia , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , TransfecçãoRESUMO
OBJECTIVE: To investigate the impact of intracellular interaction between fibroblasts and colorectal cancer cells on the expression of insulin growth factor binding protein7 (IGFBP7). METHODS: Colorectal cancer cells SW480 were cultured with or without fibroblasts HELF cells in RPMI 1640 medium for 0 h, 48 h, 7 2 h and 96 h, respectively. By RT-PCR and immunohistochemical staining methods,the expression of IGFBP7 was detected in mono-and co-cultured cells. RESULT: When SW480 cells were co-cultured with HELF cells, IGFBP7 expression in SW480 cells was significantly upregulated. Furthermore, IGFBP7 was induced in HELF cells both at mRNA and protein levels, which did not express when cells were mono-cultured. CONCLUSION: Fibroblasts-colorectal cancer cells interaction induces the expression of IGFBP7, which indicates tumor-stroma interactions may play an important role in colorectal cancer development.
Assuntos
Comunicação Celular , Neoplasias Colorretais/patologia , Fibroblastos/citologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Feto , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
AIM: To evaluate the association between X-ray cross-complementing gene 1 (XRCC1) genetic polymorphism Arg399Gln and gastric cancer risk by means of meta-analysis. METHODS: We searched PubMed and NCBI up to June 1, 2008. A total of 16 clinical trials and reports were identified, but only 8 trials qualified under our selection criteria. Statistical analysis was performed with the software program Review Manage, version 4.2.8. RESULTS: Of the 8 case-control studies selected for this meta-analysis, a total of 1334 gastric cancer cases and 2194 controls were included. For Arg399Gln, the Gln/Gln genotype carriers did not have a decreased cancer risk compared with those individuals with the Arg/Arg genotype (OR = 0.92, 95% CI, 0.71-1.19; P = 0.51). Similarly, no associations were found in the recessive and dominant modeling (Gln/Gln vs Arg/Gln + Arg/Arg: OR = 0.96; 95% CI, 0.77-1.19; P = 0.70 and Gln/Gln + Arg/Gln vs Arg/Arg: OR = 0.90, 95% CI, 0.77-1.05; P = 0.18). CONCLUSION: No association is found between the XRCC1 polymorphism Arg399Gln and gastric cancer risk.
Assuntos
Proteínas de Ligação a DNA/genética , Polimorfismo Genético/genética , Neoplasias Gástricas/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Genótipo , Humanos , Fatores de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
The Epstein-Barr virus (EBV) is a common virus in humans and the most common causative agent of Infectious Mononucleosis. EBV primary infection has recently risen in some countries and children below 2 years of age are highly susceptible. The clinical manifestations in children with EB virus infection involve multiple systems, causing severe illness, meaning attention should be paid during diagnosis and treatment. Objective: This single institution based retrospective study was carried out with the aim of estimating the overall prevalence of EBV infection and identifying high-risk age group among children. Methods: This study include total 253 patients under 15 years of age found to be positive for EBV DNA by PCR who were admitted to the Pediatrics Department of Renmin Hospital,(Shiyan, China) during a 4-year period from 2014 to 2017. Patients were divided into three groups; 0-<4years, 4-<6years and 6-<15years. We then calculated the percentage and prevalence of EBV DNA-positive cases. Results: The yearly EBV prevalence rate was 4.99 per 1000 admissions in 2014, 6.97 per 1000 admissions in 2015, 10.42 per 1000 admissions in 2016, and 12.16 per 1000 admissions in 2017. Out of 253 EBV-positive cases, those under 4 years had the highest rate of EBV infection (74.7%). The rate drops to 11.06% in the 4-6 years group, and was 14.22% in the 6-15 years group. Those between 6 months and 1 year are those at the highest risk. Conclusion: The rate of hospital admission of children due to EBV infection is increasing day by day. Children under 4 years of age are highly susceptible to infection and children of age between 6 months and 1 year are the high-risk group for EBV infection.
Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4 , Adolescente , Fatores Etários , Criança , Pré-Escolar , China/epidemiologia , DNA Viral , Infecções por Vírus Epstein-Barr/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Mononucleose Infecciosa/diagnóstico , Mononucleose Infecciosa/epidemiologia , Mononucleose Infecciosa/virologia , Masculino , Admissão do Paciente , Reação em Cadeia da Polimerase , Vigilância da População , Prevalência , Estudos RetrospectivosRESUMO
Fulminant myocarditis is a life-threatening clinical condition. It is the inflammation of myocardium leading to acute heart failure, cardiogenic shock and cardiac arrhythmias. Incidence of fulminant myocarditis is low and mortality is high. Most grievous complications of fulminant myocarditis is mainly cardiac arrhythmias; if there is delay on active management of the patient, it may be fatal. Here, we describe a case of III° atrioventricular block due to fulminant myocarditis that was managed with non-invasive transcutaneous cardiac pacing in the absence of ECMO. The non-invasive transcutaneous pacemaker is a safe, effective and convenient device to revert arrhythmias.
RESUMO
Cardiac glycosides exhibit significant anticancer effects and the glycosyl substitution at C3 position of digoxigenin is pivotal for their biological activity. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and explore more potent anticancer agents, a series of C3-O-neoglycosides and C3-MeON-neoglycosides of digoxigenin were synthesized by the Koenigs-Knorr and neoglycosylation method, respectively. In addition, digoxigenin bisdigitoxoside and monodigitoxoside were prepared from digoxin by sodium periodate (NaIO4) oxidation and 6-aminocaproic acid hydrolysis. The SAR analysis revealed that C3-O-neoglycosides of digoxigenin exhibited stronger cytotoxicity and induction of Nur77 expression of tumor cells than C3-MeON-neoglycosides. Also, 3ß-O-glycosides exhibited stronger anticancer effects than 3α-O-glycosides. Among them, 3ß-O-(ß-l-fucopyranosyl)-digoxigenin (3i) showed the highest activity on induction of Nur77 expression and translocation from the nucleus to cytoplasm, leading to cancer cell apoptosis.
Assuntos
Antineoplásicos/farmacologia , Digoxigenina/farmacologia , Glicosídeos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Digoxigenina/síntese química , Digoxigenina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/síntese química , Glicosídeos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
OBJECTIVE: To investigate the expression of extracellular matrix metalloproteinase inducer gene (EMMPRIN) regulated by the interactions between fibroblasts and colon cancer cells, and to study its role in the invasion and metastasis of colon cancer. METHODS: Colon cancer cells (SW480) were co-cultured with fibroblasts (HELF) in RPMI 1640 media for 0, 12, 24 and 48 hours. The expression of EMMPRIN in SW480 cells and HELF cells was documented by RT-PCR and immunocytochemistry. RESULTS: The mRNA and protein expressions of EMMPRIN in SW480 cells were remarkably increased by the co-culturing with HELF cells. Although without the endogenous expression, HELF cells began to express EMMPRIN in a time-dependent manner after being co-cultured with SW480 cells. CONCLUSIONS: Intercellular interactions between colon cancer cells and fibroblasts not only up-regulate the EMMPRIN expression in SW480 cells, but also induce its expression in HELF cells. Such interactions may play a crucial role in the invasion and metastasis of colon cancer.
Assuntos
Basigina/biossíntese , Neoplasias do Colo/metabolismo , Fibroblastos/metabolismo , Basigina/genética , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Neoplasias do Colo/patologia , Fibroblastos/citologia , Humanos , Pulmão/citologia , RNA Mensageiro/metabolismoRESUMO
Bronchial foreign body obstruction is common in all clinical settings. Obstruction of the airway due to foreign bodies and foreign body aspiration are major causes of childhood mortality and morbidity, which are a big challenge to manage. Occasionally, bronchial obstruction may be due to mucus plugs or other endogenous factors. Here we describe a case of bronchial obstruction caused by mucus plug formation that was managed conservatively in a one-year old boy. The patient was suffering from a cough and noisy breathing for 2 days prior to coming to our hospital, when he experienced sudden onset of difficulty in breathing and a severe cough. At the time of presentation his vital sign readings were:- HR 186 bpm, RR 46/min, BP 78/40 MmHg, temp 36.9°C and SPO2 68%. He was given oxygen immediately and nebulization was started. Chest CT scan was performed that suggested the presence of a right bronchial foreign body with right sided obstructive emphysema. The patient was stable with oxygenation and nebulization with ipratropium bromide, albuterol, normal saline and budesonide before the CT scan. Therefore, we conclude that symptoms resembling foreign body obstruction are not always aspirated or inhaled, and sometimes secreted sputum forms a plug, which mimics the symptoms of foreign body obstruction.
RESUMO
RATIONALE: Preoperative localization of small pulmonary nodules is essential for precise resection, besides, the optimal treatment for pulmonary nodules is controversial and the prognosis without surgery is uncertain. PATIENT CONCERNS: Herein we present a patient with compromised pulmonary function harboring synchronous triple ground-glass nodules located separately in different pulmonary lobes. DIAGNOSES: The pathological diagnosis of the nodules were chronic inflammation, inflammatory pseudotumor and atypical adenomatous hyperplasia, respectively. INTERVENTIONS: The patient underwent single-stage, non-intubated thoracoscopic pulmonary wedge resection after computed tomography-guided coil labeling of the nodules. OUTCOMES: The postoperative recovery was encouragingly fast without obvious complications. LESSONS: Non-intubated thoracoscopic pulmonary wedge resection is feasible for patients with compromised lung function, meanwhile, preoperative coil labeling of small nodules is reliable.
Assuntos
Pneumopatias/cirurgia , Nódulos Pulmonares Múltiplos/cirurgia , Humanos , Pneumopatias/patologia , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/patologia , Toracoscopia/métodosRESUMO
Accumulated evidence suggests that connexin43 (Cx43) serves as a tumor-suppressing gene. We have previously shownA. B. that Cx43 suppressed the G(1)-S phase cell cycle transition via increasing the level of p27 (Zhang, Y. W., et al., Oncogene, 20: 4138-4149, 2001). Here we report that Cx43 inhibited expression of Skp2, the human F-box protein that regulates p27 ubiquitination. This reduction was attributed to an increased degradation of Skp2. The Cx43 antisense oligonucleotide blocked this inhibitory effect of Cx43 on Skp2 expression and led to p27 down-regulation. In contrast, the antisense oligonucleotide of Skp2 induced a further increase in the level of p27. However, ectopic expression of Skp2 reversed the Cx43-induced Skp2 reduction, p27 accumulation, and cell proliferation inhibition. Cx43 increased p27 expression only in the SKP2 +/+ mouse embryo fibroblasts (MEFs), but not in the SKP2 -/- MEFs, indicating that Skp2 plays a critical role in the Cx43-induced p27 up-regulation. We also show that both Skp2 and p27 are required for Cx43 to inhibit cell proliferation, in that Cx43 hardly inhibited cell proliferation of the SKP2 -/- and p27 -/- MEFs, whereas it clearly did both in the SKP2 +/- and in the p27 +/- MEFs. Our findings suggest a new route for Cx43 to inhibit tumor growth by linking it with the key cell cycle regulators.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Conexina 43/fisiologia , Animais , Células COS , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Divisão Celular/fisiologia , Chlorocebus aethiops , Conexina 43/genética , Inibidor de Quinase Dependente de Ciclina p27 , Células HeLa , Humanos , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Ratos , Proteínas Quinases Associadas a Fase S , Transfecção , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genéticaRESUMO
Previous studies have established the role of phosphorylated form of insulin-like growth factor type 1 receptor (p-IGF1R) as a good candidate for tumor biomarker. The aims of this study were to investigate p-IGF1R expression status in gastric cancer (GC) specimens and to clarify its clinical significance. A total of 78 GC patients treated with radical resection were enrolled in this study. Immunohistochemistry was used to detect p-IGF1R and phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression in paired tumor and adjacent normal tissues. Results showed a higher level of p-IGF1R protein expression in tumor tissues than that in normal tissues, and the rate of p-IGF1R protein high/moderate expression in GC and normal tissues was 52.6% (41/78) and 6.4% (5/78), respectively (p < 0.001). In contrast, PTEN protein expression was downregulated in GC, as compared with normal tissues (negative/low expression 49/78 vs. 8/78, p < 0.001). Moreover, PTEN protein downregulation was consistent with p-IGF1R upregulation. Overexpression of p-IGF1R protein was associated with lymph metastasis, clinical stage, and adverse 3-year progression-free survival (PFS). Survival analysis and Cox proportional hazards model revealed that p-IGF1R overexpression was an independent factor in predicting PFS for GC patients, apart from lymph metastasis. In conclusion, p-IGF1R is highly expressed in GC, which may be a novel biomarker to predict the clinical outcome of GC patients.
Assuntos
Povo Asiático , Biomarcadores Tumorais/biossíntese , PTEN Fosfo-Hidrolase/biossíntese , Receptores de Somatomedina/biossíntese , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Fosforilação/fisiologia , Valor Preditivo dos Testes , Prognóstico , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Neoplasias Gástricas/genéticaRESUMO
DNA methylation plays a critical role during the development of acquired chemoresistance. The aim of this study was to identify candidate DNA methylation drivers of cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). The A549/DDP cell line was established by continuous exposure of A549 cells to increasing concentrations of DDP. Gene expression and methylation profiling were determined by high-throughput microarrays. Relationship of methylation status and DDP response was validated in primary tumor cell culture and the Cancer Genome Atlas (TCGA) samples. Cell proliferation, apoptosis, cell cycle, and response to DDP were determined in vitro and in vivo. A total of 372 genes showed hypermethylation and downregulation in A549/DDP cells, and these genes were involved in most fundamental biological processes. Ten candidate genes (S100P, GDA, WISP2, LOXL1, TIMP4, ICAM1, CLMP, HSP8, GAS1, BMP2) were selected, and exhibited varying degrees of association with DDP resistance. Low dose combination of 5-aza-2'-deoxycytidine (5-Aza-dC) and trichostatin A (TSA) reversed drug resistance of A549/DDP cells in vitro and in vivo, along with demethylation and restoration of expression of candidate genes (GAS1, TIMP4, ICAM1 and WISP2). Forced expression of GAS1 in A549/DDP cells by gene transfection contributed to increased sensitivity to DDP, proliferation inhibition, cell cycle arrest, apoptosis enhancement, and in vivo growth retardation. Together, our study demonstrated that a panel of candidate genes downregulated by DNA methylation induced DDP resistance in NSCLC, and showed that epigenetic therapy resensitized cells to DDP.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/farmacologia , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/genética , RNA Mensageiro/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Decitabina , Epigênese Genética , Proteínas Ligadas por GPI/metabolismo , Perfilação da Expressão Gênica/métodos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Neoplasias Pulmonares/patologiaRESUMO
The RUNX3 gene has been shown to function as a tumor suppressor gene implicated in various cancers, but its association with tumor chemoresistance has not been fully understood. Here, we investigated the effect of epigenetic downregulation of RUNX3 in docetaxel resistance of human lung adenocarcinoma and its possible molecular mechanisms. RUNX3 was found to be downregulated by hypermethylation in docetaxel-resistant lung adenocarcinoma cells. Its overexpression could resensitize cells to docetaxel both in vitro and in vivo by growth inhibition, enhancement of apoptosis and G1 phase arrest. Conversely, knockdown of RUNX3 could lead to the decreased sensitivity of parental human lung adenocarcinoma cells to docetaxel by enhancing proliferative capacity. Furthermore, we showed that overexpression of RUNX3 could inactivate the AKT/GSK3ß/ß-catenin signaling pathway in the docetaxel-resistant cells. Importantly, co-transfection of RUNX3 and constitutively active Akt1 could reverse the effects of RUNX3 overexpression, while treatment with the MK-2206 (AKT inhibitor) mimicked the effects of RUNX3 overexpression in docetaxel-resistant human lung adenocarcinoma cells. Immunohistochemical analysis revealed that decreased RUNX3 expression was correlated with high expression of Akt1 and decreased sensitivity of patients to docetaxel-based chemotherapy. Taken together, our results suggest that epigenetic downregulation of RUNX3 can induce docetaxel resistance in human lung adenocarcinoma cells by activating AKT signaling and increasing expression of RUNX3 may represent a promising strategy for reversing docetaxel resistance in the future.