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1.
BMC Bioinformatics ; 21(Suppl 14): 368, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998690

RESUMO

BACKGROUND: Lung cancer is the leading cause of the largest number of deaths worldwide and lung adenocarcinoma is the most common form of lung cancer. In order to understand the molecular basis of lung adenocarcinoma, integrative analysis have been performed by using genomics, transcriptomics, epigenomics, proteomics and clinical data. Besides, molecular prognostic signatures have been generated for lung adenocarcinoma by using gene expression levels in tumor samples. However, we need signatures including different types of molecular data, even cohort or patient-based biomarkers which are the candidates of molecular targeting. RESULTS: We built an R pipeline to carry out an integrated meta-analysis of the genomic alterations including single-nucleotide variations and the copy number variations, transcriptomics variations through RNA-seq and clinical data of patients with lung adenocarcinoma in The Cancer Genome Atlas project. We integrated significant genes including single-nucleotide variations or the copy number variations, differentially expressed genes and those in active subnetworks to construct a prognosis signature. Cox proportional hazards model with Lasso penalty and LOOCV was used to identify best gene signature among different gene categories. We determined a 12-gene signature (BCHE, CCNA1, CYP24A1, DEPTOR, MASP2, MGLL, MYO1A, PODXL2, RAPGEF3, SGK2, TNNI2, ZBTB16) for prognostic risk prediction based on overall survival time of the patients with lung adenocarcinoma. The patients in both training and test data were clustered into high-risk and low-risk groups by using risk scores of the patients calculated based on selected gene signature. The overall survival probability of these risk groups was highly significantly different for both training and test datasets. CONCLUSIONS: This 12-gene signature could predict the prognostic risk of the patients with lung adenocarcinoma in TCGA and they are potential predictors for the survival-based risk clustering of the patients with lung adenocarcinoma. These genes can be used to cluster patients based on molecular nature and the best candidates of drugs for the patient clusters can be proposed. These genes also have a high potential for targeted cancer therapy of patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/patologia , Genômica/métodos , Neoplasias Pulmonares/patologia , Transcriptoma , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Área Sob a Curva , Análise por Conglomerados , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Mapas de Interação de Proteínas/genética , Curva ROC , Fatores de Risco , Taxa de Sobrevida
2.
Carbohydr Polym ; 250: 116800, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33049807

RESUMO

Chitosan, as a biodegradable and biocompatible polymer, is characterized by anti-microbial and anti-cancer properties. It lately has received a widespread interest for use as the pulmonary particulate backbone materials of drug carrier for the treatment of infectious disease and cancer. The success of chitosan as pulmonary particulate drug carrier is a critical interplay of their mucoadhesive, permeation enhancement and site/cell-specific attributes. In the case of nanocarriers, various microencapsulation and micro-nano blending systems have been devised to equip them with an appropriate aerodynamic character to enable efficient pulmonary aerosolization and inhalation. The late COVID-19 infection is met with acute respiratory distress syndrome and cancer. Chitosan and its derivatives are found useful in combating HCoV and cancer as a function of their molecular weight, substituent type and its degree of substitution. The interest in chitosan is expected to rise in the next decade from the perspectives of drug delivery in combination with its therapeutic performance.


Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Quitosana/análogos & derivados , Portadores de Fármacos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Betacoronavirus/isolamento & purificação , Materiais Biocompatíveis/química , Sobrevivência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Neoplasias Pulmonares/patologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia
3.
Nat Commun ; 11(1): 4913, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004813

RESUMO

Reprograming of proline metabolism is critical for tumor growth. Here we show that PINCH-1 is highly expressed in lung adenocarcinoma and promotes proline synthesis through regulation of mitochondrial dynamics. Knockout (KO) of PINCH-1 increases dynamin-related protein 1 (DRP1) expression and mitochondrial fragmentation, which suppresses kindlin-2 mitochondrial translocation and interaction with pyrroline-5-carboxylate reductase 1 (PYCR1), resulting in inhibition of proline synthesis and cell proliferation. Depletion of DRP1 reverses PINCH-1 deficiency-induced defects on mitochondrial dynamics, proline synthesis and cell proliferation. Furthermore, overexpression of PYCR1 in PINCH-1 KO cells restores proline synthesis and cell proliferation, and suppresses DRP1 expression and mitochondrial fragmentation. Finally, ablation of PINCH-1 from lung adenocarcinoma in mouse increases DRP1 expression and inhibits PYCR1 expression, proline synthesis, fibrosis and tumor growth. Our results identify a signaling axis consisting of PINCH-1, DRP1 and PYCR1 that regulates mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for alleviation of tumor growth.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma de Pulmão/patologia , Proteínas com Domínio LIM/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proliferação de Células/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Dinaminas/metabolismo , Feminino , Técnicas de Inativação de Genes , Humanos , Proteínas com Domínio LIM/genética , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Proteínas Musculares/metabolismo , Proteínas de Neoplasias/metabolismo , Prolina/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirrolina Carboxilato Redutases/metabolismo , Análise de Sobrevida
4.
Medicine (Baltimore) ; 99(40): e22483, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019442

RESUMO

INTRODUCTION: Epithelial-myoepithelial carcinoma (EMC) is a rare, low-grade malignancy that occurs primarily in the parotid gland and is most common in women aged 60 to 70 years. Cases of parotid EMC have been reported previously. Furthermore, some studies have suggested an increased risk of salivary gland tumors with secondary primary malignancies. There have been few reports of parotid EMC with other primary tumors. PATIENT CONCERNS: A 62-year-old Chinese man visited the hospital with a complaint of a mass on his left cheek that had persisted for 20 years. Routine pulmonary computed tomography showed a local ground glass shadow in the lower lobe of the right lung. DIAGNOSIS: The pathological diagnosis of lung was right lower lobe lung adenocarcinoma (pT1N0). Immunohistochemistry analysis showed that cytokeratin (CK)-7, NapsinA, and thyroid transcription factor-1 tested positive, while CK5/6, P40, and ALKD5F3 tested negative. The pathological diagnosis of left parotid gland: EMC. On immunohistochemistry staining, the outer cells expressed myoepithelial markers, such as CK5/6, P63, smooth muscle actin, while the inner cells expressed glandular epithelial markers, such as low-molecular-weight CK7 and CK8. INTERVENTIONS: The patient underwent resection of the lung and parotid tumors, and received preventive radiotherapy in the parotid gland area. OUTCOMES: The patient is in good condition. No symptom recurrence, distant metastatic spread or significant toxicity occurred during or after the treatment. The patient remains under regular surveillance. CONCLUSION: We report a rare case of parotid EMC with a second primary lung adenocarcinoma. This case is the third case of primary lung cancer associated with parotid EMC reported to date and the first to be reported in nearly 30 years.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Mioepitelioma/patologia , Segunda Neoplasia Primária/patologia , Neoplasias Parotídeas/patologia , Adenocarcinoma de Pulmão/cirurgia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mioepitelioma/radioterapia , Mioepitelioma/cirurgia , Segunda Neoplasia Primária/radioterapia , Segunda Neoplasia Primária/cirurgia , Neoplasias Parotídeas/radioterapia , Neoplasias Parotídeas/cirurgia
5.
Medicine (Baltimore) ; 99(40): e22637, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019486

RESUMO

INTRODUCTION: Small cell lung cancer (SCLC) is an aggressive malignancy that progresses rapidly and easily relapses. To the best of our knowledge, advances have been minimal for decades and the first-line treatment is still platinum-etoposide and radiotherapy. However, elderly patients with severe renal failure who suffer from SCLC usually show more serious drug-related side effects. A large proportion of them cannot tolerate the standard treatment, and their prognosis is poorer compared with that of younger patients. Presently, oral etoposide capsules may be accepted as a replaceable option. We report the case of a male patient with SCLC on hemodialysis who was successfully treated with concurrent oral etoposide monotherapy and radiotherapy and achieved excellent outcomes. PATIENT'S CONCERNS: A 63-year-old man with severe renal failure was diagnosed with SCLC. PRIMARY DIAGNOSES: SCLC was diagnosed using transbronchial biopsy. INTERVENTIONS: He received concomitant single-agent oral etoposide (6 cycles) and local radiotherapy. Etoposide 100 mg once daily combined with thoracic radiation treatment (2 Gy/f, total DT: 50 Gy/25 f), was subsequently followed by prophylactic cranial irradiation plus anlotinib. OUTCOMES: The patient achieved complete response after 1 cycle and the subsequent treatment was effective without any kidney damage and other severe side effects. CONCLUSION: Though etoposide capsule is an old drug, its use should be considered in SCLC patients with renal insufficiency undergoing hemodialysis. However, treatment guidelines and research data for such patients are still lacking and further studies are needed. Although recent research focuses mainly on new drugs, some old drugs like etoposide which can bring unexpected positive effects should not be neglected.


Assuntos
Etoposídeo/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/radioterapia , Inibidores da Topoisomerase II/uso terapêutico , Administração Oral , Terapia Combinada , Irradiação Craniana/métodos , Etoposídeo/administração & dosagem , Humanos , Indóis/uso terapêutico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Quinolinas/uso terapêutico , Diálise Renal/métodos , Insuficiência Renal/terapia , Inibidores da Topoisomerase II/administração & dosagem , Resultado do Tratamento
6.
Arch. prev. riesgos labor. (Ed. impr.) ; 23(3): 357-362, jul.-sept. 2020. ilus
Artigo em Espanhol | IBECS | ID: ibc-194121

RESUMO

Navarra cuenta con el primer y más exhaustivo Registro de trabajadores expuestos laboralmente a amianto de España. Desde 1996 son remitidos por los Servicios de Prevención y pasan al Servicio Navarro de Salud_Osasunbidea para la vigilancia de patología neumológica relacionada, al jubilarse. Actualmente constan 2858 trabajadores, 395 mujeres y 2463 hombres. La práctica totalidad ya no ocupan puestos de riesgo. Durante años ha ayudado al reconocimiento de la contingencia profesional de los daños. Paradógicamente, en este caso, un trabajador fallecido por cáncer de pulmón con patología intersticial previa, un resultado negativo de necropsia, 425CF (cuerpos ferruginosos)/gr de tejido seco de pulmón se utilizó como argumento para rechazar el origen profesional. Es necesario considerar que un resultado positivo confirma exposición pasada pero uno negativo, si era crisotilo, no la descarta, dada la baja persistencia en tejidos. Una historia laboral detallada y, cuando existan, los Registros han de ser el principal argumento causal


Navarra has the first and most exhaustive Record of workers exposed to asbestos in Spain. Since 1996, referred by the Prevention Services and transferred to the Servicio Navarro de Salud_Osasunbidea for related pulmonary pathology surveillance upon retirement. There are currently 2,858 workers, 395 women and 2,463 men. Almost no longer occupy positions of risk. For years it has helped to recognize the professional contingency of damages.Paradoxically, in this case, a worker who died of lung cancer with previous interstitial pathology, a negative result of an autopsy, 425ferruginous bodies/gr dry lung tissue was used to deny the professional origin. It is necessary to consider that a positive result confirms past exposure but the negative one should not be evaluated when it was chrysotile, given the low temporal persistence in tissues. A reliable work history and, when they exist, the Records must be the main causal argument


Assuntos
Humanos , Masculino , Feminino , Asbestos/efeitos adversos , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Autopsia
7.
Eur J Cancer ; 138: 109-112, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32871524
9.
Medicine (Baltimore) ; 99(33): e21600, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872014

RESUMO

INTRODUCTION: Apatinib is a novel anti-angiogenic agent that targets vascular endothelial growth factor receptor-2, and is effective in patients with advanced lung cancer who are refractory to first-line chemotherapy. However, there are limited reports on concurrent apatinib therapy with iodine-125 radioactive seeds brachytherapy in elderly patients with advanced lung cancer. PATIENT CONCERNS: We describe the first reported case of a 70-year-old woman with advanced lung cancer (T3N3M1, stage IV) who received concurrent apatinib and iodine-125 radioactive seeds brachytherapy after the failure of platinum-based doublet chemotherapy DIAGNOSIS:: The patient was diagnosed with left lower lung cancer with mediastinal lymph node metastasis by chest computed tomography. INTERVENTIONS: Initially, apatinib alone was used as second-line cancer therapy. Subsequently, the patient received concurrent apatinib and iodine-125 radioactive seeds brachytherapy. OUTCOMES: The patient achieved partial response shortly after undergoing treatment with only apatinib. During the treatment, the tumor continued to respond to apatinib therapy, and the lung metastases were diminished eventually. However, a chest computed tomography scan showed a large cavity in the lung tumor. Thereafter, the patient received concurrent apatinib and iodine-125 radioactive seeds brachytherapy. Unfortunately, she died due to pulmonary infection. CONCLUSION: Apatinib alone may be a good second-line therapy for advanced lung cancer patients who are refractory to platinum-based doublet chemotherapy. However, its potential benefits, especially as combination therapy, need further investigation by future prospective clinical studies. Elderly patients with advanced lung cancer may benefit from concurrent apatinib with iodine-125 radioactive seeds brachytherapy when chemotherapy is not tolerated or effective. Further studies are needed to investigate the clinical outcomes and toxicities associated with concurrent apatinib and radiation therapy in patients with advanced lung cancer.


Assuntos
Braquiterapia/métodos , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/métodos , Neoplasias Pulmonares/terapia , Piridinas/uso terapêutico , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Radioisótopos do Iodo/administração & dosagem , Neoplasias Pulmonares/patologia , Metástase Linfática , Estadiamento de Neoplasias , Piridinas/administração & dosagem
10.
Medicine (Baltimore) ; 99(33): e21628, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872023

RESUMO

RATIONABLE: Large cell neuroendocrine carcinoma of the lung is rare, especially in the area of the foramen magnum. No previous studies have reported metastatic large cell neuroendocrine lung cancer to the foramen magnum. This paper will be the first time to report this special case. PATIENT CONCERNS: A case of a 37-year-old woman presented with headache that had developed 20 days previously. Imaging examination revealed a circular abnormal signal at the posterior margin of the foramen magnum. DIAGNOSES: The patient we report was diagnosed with a metastatic intracranial tumor. INTERVENTIONS: The patient underwent occipital craniotomy. Pathological results showed metastatic neuroendocrine carcinoma of the brain. Whole body PET-CT examination showed that fusiform soft tissue shadows could be seen near the hilum of the lower lobe of the left lung. OUTCOMES: The final bronchoscopy pathological results showed the large cell neuroendocrine carcinoma of the lung. The patient underwent further chemotherapy and radiotherapy in the oncology department. LESSONS: Diagnosis and treatment of large cell neuroendocrine carcinoma of the lung are difficult. The prognosis is poorer, and effective treatment is urgently needed.


Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Neuroendócrino/patologia , Forame Magno/patologia , Neoplasias Pulmonares/patologia , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/terapia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
11.
Lancet Oncol ; 21(9): 1213-1223, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888453

RESUMO

BACKGROUND: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. METHODS: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. FINDINGS: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. INTERPRETATION: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/administração & dosagem , Neoplasias Pleurais/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália/epidemiologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Cisplatino/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Pemetrexede/efeitos adversos , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão
12.
J Cancer Res Clin Oncol ; 146(11): 2731-2741, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892231

RESUMO

PURPOSE: Purinergic P2X7 receptor (P2X7R) is a gated ion channel for which adenosine triphosphate (ATP) is a ligand. Activated P2X7R is widely expressed in a variety of immune cells and tissues and is involved in a variety of physiological and pathological processes. Studies have confirmed that P2X7R is involved in the regulation of tumor cell growth, stimulating cell proliferation or inducing apoptosis. Recent studies have found that P2X7R is abnormally expressed in lung cancer and is closely related to the carcinogenesis and development of lung cancer. In this paper, we comprehensively describe the structure, function, and genetic polymorphisms of P2X7R. In particular, the role and therapeutic potential of P2X7R in lung cancer are discussed to provide new targets and new strategies for the treatment and prognosis of clinical lung cancer. METHODS: The relevant literature on P2X7R and lung cancer from PubMed databases is reviewed in this article. RESULTS: P2X7R regulates the function of lung cancer cells by activating multiple intracellular signaling pathways (such as the JNK, Rho, HMGB1 and EMT pathways), thereby affecting cell survival, growth, invasion, and metastasis and patient prognosis. Targeting P2X7R with inhibitors effectively suppresses the growth and metastasis of lung cancer cells. CONCLUSION: In summary, P2X7R is expected to become a potential target for the treatment of lung cancer, and more clinical research is needed in the future to explore the effectiveness of P2X7R antagonists as treatments.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/fisiologia , Animais , Humanos
13.
Medicine (Baltimore) ; 99(36): e21453, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32898994

RESUMO

To analyze the relationship between pathologic subtype and lymph node metastasis for lung adenocarcinomas of ≤3 cm diameter.We retrospectively studied 384 patients with operable lung adenocarcinomas of ≤3 cm diameter that had been radically resected by lobectomy or anatomic segmentectomy with systematic nodal dissection, at the Fujian Medical University Union Hospital between March 2014 and March 2016.Lymph node metastasis pN1 + pN2 (pN+) was found in 2 of 104 (1.9%) patients with tumor diameter ≤1.0 cm, 12 of 159 (7.5%) patients with tumor diameter >1.0 cm but ≤2.0 cm, and 35 of 121 (28.9%) patients with tumor size >2.0 cm but ≤3.0 cm (P < .01). Lymph node metastasis pN+ was found in 19 of 53 (35.8%) patients with visceral invasion pleural (VIP) and 30 of 331 (9.0%) patients without VIP (P < .05). It was also found in 16 of 51 (31.3%) patients with high serum CEA concentrations and 28 of 297 (9.4%) patients with normal concentrations (P < .05). In a multivariate analysis, tumor diameter, VIP, high serum CEA concentration, and pathologic subtype were significant risk factors. The prevalences of lymph node metastasis pN+ were: 0.0% (0/2), 0.0% (0/89), 3.2% (1/31), 16.2% (34/209), 7.7% (1/13), 46.7% (7/15), 100% (4/4), and 11.8% (2/17) for adenocarcinoma in situ (AIS); minimally invasive adenocarcinoma (MIA); predominantly lepidic (LEP), acinar (ACI), papillary, solid (SOL), and micropapillary (MIP) tumors; and variants of invasive adenocarcinoma, respectively (P < .05). For predominant SOL and MIP tumors, the prevalences of lymph node involvement were significantly higher than for the other subtypes.We have shown that lymph node metastasis in patients with tumor diameter ≤3 cm differs according to lung adenocarcinoma subtype. AIS and MIA were not associated with lymph node metastasis; therefore, systematic nodal dissection may be unnecessary. The prevalence of lymph node metastasis rate was low for LEP, suggesting that systemic lymph node sampling is sufficient. In contrast, for other pathologic subtypes, including SOL and MIP, systematic lymph node dissection should be performed.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Metástase Linfática/patologia , Adenocarcinoma de Pulmão/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
Medicine (Baltimore) ; 99(36): e22128, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899099

RESUMO

RATIONALE: Brain metastasis (BM) is a serious complication in non-small cell lung cancer (NSCLC) patients. Pemetrexed is one of the preferred agents in nonsquamous NSCLC with BM; however, the traditional chemotherapy demonstrated limited efficacy partly due to drug resistance and the blood-brain barrier. PATIENT CONCERNS: A 52-year-old male non-smoker was admitted for irritating cough, chest distress, and back pain. DIAGNOSES: Epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative primary lung adenocarcinoma with an asymptomatic solitary BM (cTxNxM1b, IVA). INTERVENTIONS: Pemetrexed (500 mg/m of body surface area) and carboplatin (area under the curve of 5) were firstly administered every 3 weeks for 3 cycles, followed by pemetrexed/carboplatin plus anlotinib (12 mg daily; 2 weeks on and 1 week off) for another 3 cycles. Then maintenance anlotinib monotherapy was continued for a year, without unacceptable adverse events. OUTCOMES: The BM was slightly enlarged after 3 cycles of pemetrexed/carboplatin; however, a complete remission was achieved after the combination therapy. His intracranial progression-free survival was more than 2 years. LESSONS: Pemetrexed/carboplatin plus anlotinib could be considered for the treatment of epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative lung adenocarcinoma with BM. Further well-designed trials are warranted to verify this occasional finding.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico/metabolismo , Carboplatina/uso terapêutico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Quinolinas/uso terapêutico
15.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
16.
Nat Commun ; 11(1): 4527, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913197

RESUMO

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Evolução Clonal , Variações do Número de Cópias de DNA , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Cultura Primária de Células , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA-Seq , Estudos Retrospectivos , Esferoides Celulares , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Proteína Supressora de Tumor p53/genética , Microtomografia por Raio-X
17.
Anticancer Res ; 40(9): 4807-4818, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878769

RESUMO

The microbiome is extremely important for human health; more recently its role in the context of cancer became clear. Microbial effects range from enhancing cancer immunity and cancer therapy efficacy, to promoting cancer progression and inhibiting treatment efficacy. These broad implications led researchers to investigate these specific interactions, as well as how modification of the microbiome can improve cancer survival and treatment efficacy. While these interactions are better established for cancers such as gastric cancer, they are far less understood in others. As non-small cell lung cancer (NSCLC) makes up the majority of lung cancer cases, and is among the top causes of cancer deaths worldwide, understanding the mechanisms by which the microbiome may impact progression and treatment is crucial to improve patient survival and treatment response. A literature review was conducted to reveal the crosslink between human microbiome and lung cancer. This includes immune priming, induction of pro- or anti-tumor response, and the local effects of intra-tumoral microbiota. Overall, this is a complex multifactorial relationship, and there are broad implications as to how this knowledge can improve cancer treatment. Solutions include manipulation of the microbiome using probiotics, bacterial vaccines and antibiotics. Bacteria biomarkers may also be used as a diagnostic tool.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/microbiologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/terapia , Microbiota/fisiologia , Antibacterianos/uso terapêutico , Antineoplásicos/uso terapêutico , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunomodulação , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Microbiota/efeitos dos fármacos , Resultado do Tratamento
18.
Anticancer Res ; 40(9): 4937-4946, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878782

RESUMO

BACKGROUND/AIM: ALK inhibitors like Crizotinib, Ceritinib and Alectinib are targeted therapies used in patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC). Since in this tumor entity radiotherapy is employed sequentially or concomitantly, potential synergistic effects were investigated, which may support the hypothesis of induced radiosensitization by using ALK inhibitors. MATERIALS AND METHODS: Two cell lines expressing wild-type (WT) or echinoderm microtubule-associated protein-like 4 (EML4)-ALK were treated with ALK inhibitors, followed by irradiation. Cell survival, cell death, cell cycle and phosphorylation of H2A histone family, member X (H2AX) were examined. RESULTS: Combined treatment with ALK-inhibitors plus 10 Gy-irradiation led to effects similar to those of sole radiotherapy, but was more effective than sole drug treatment. CONCLUSION: There is no clear evidence of sensitization to radiation by treating EML4-ALK mutated cells with ALK inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/efeitos da radiação , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/patologia , Mutação
19.
Anticancer Res ; 40(9): 4947-4960, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878783

RESUMO

BACKGROUND/AIM: This study aimed to investigate the anticancer effects and potential mechanisms of sclareol in a human small cell lung carcinoma (SCLC) cell line. MATERIALS AND METHODS: Cell viability was determined by the MTT assay. Cell cycle, apoptosis and caspase activity were evaluated by flow cytometry. Cell cycle and DNA damage related protein expression was determined by western blotting. In vivo evaluation of sclareol was carried out in xenografted tumor mice models. RESULTS: Sclareol significantly reduced cell viability, induced G1 phase arrest and subsequently triggered apoptosis in H1688 cells. In addition, this sclareol-induced growth arrest was associated with DNA damage as indicated by phosphorylation of H2AX, activation of ATR and Chk1. Moreover, in vivo evaluation of sclareol showed that it could inhibit tumor weight and volume in a H1688 xenograft model. CONCLUSION: Sclareol might be a novel and effective therapeutic agent for the treatment of SCLC patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Diterpenos/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Anticancer Res ; 40(9): 4989-4999, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878787

RESUMO

BACKGROUND/AIM: Epithelial to mesenchymal transition (EMT) is a cellular process that facilitates cancer metastasis. Therefore, therapeutic approaches that target EMT have garnered increasing attention. The present study aimed to examine the in vitro effects of ephemeranthol A on cell death, migration, and EMT of lung cancer cells. MATERIALS AND METHODS: Ephemeranthol A was isolated from Dendrobium infundibulum. Non-small cell lung cancer cells H460 were treated with ephemeranthol A and apoptosis was evaluated by Hoechst 33342 staining. Anoikis resistance was determined by soft agar assay. Wound healing assay was performed to test the migration. The regulatory proteins of apoptosis and cell motility were determined by western blot. RESULTS: Treatment with ephemeranthol A resulted in a concentration-dependent cell apoptosis. At non-toxic concentrations, the compound could inhibit anchorage-independent growth of the cancer cells, as indicated by the decreased colony size and number. Ephemeranthol A also exhibited an inhibitory effect on migration. We further found that ephemeranthol A exerts its antimetastatic effects via inhibition of EMT, as indicated by the markedly decrease of N-cadherin, vimentin, and Slug. Furthermore, the compound suppressed the activation of focal adhesion kinase (FAK) and protein kinase B (Akt) proteins, which are key regulators of cell migration. As for the anticancer activity, ephemeranthol A induced apoptosis by decreasing Bcl-2 followed by the activation of caspase 3 and caspase 9. CONCLUSION: The pro-apoptotic and anti-migratory effects of ephemeranthol A on human lung cancer cells support its use for the development of novel anticancer therapies.


Assuntos
Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Neoplasias Pulmonares/patologia , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dendrobium/química , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Estrutura Molecular , Fenantrenos/química
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