RESUMO
Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Gefitinibe , Indóis , Neoplasias Pulmonares , Mutação , Inibidores de Proteínas Quinases , Quinolinas , Humanos , Gefitinibe/administração & dosagem , Gefitinibe/efeitos adversos , Gefitinibe/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Indóis/administração & dosagem , Indóis/uso terapêutico , Indóis/efeitos adversos , Masculino , Feminino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Pessoa de Meia-Idade , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Idoso de 80 Anos ou maisRESUMO
Using nanobubbles as geometrical confinements, we create a thin water film (â¼10 nm) in a graphene liquid cell and investigate the evolution of its instability at the nanoscale under transmission electron microscopy. The breakdown of the water films, resulting in the subsequent formation and growth of nanodroplets, is visualized and generalized into different modes. We identified distinct droplet formation and growth modes by analyzing the dynamic processes involving 61 droplets and 110 liquid bridges within 31 Graphene Liquid Cells (GLCs). Droplet formation is influenced by their positions in GLCs, taking on a semicircular shape at the edge and a circular shape in the middle. Growth modes include liquid mass transfer driven by Plateau-Rayleigh instability and merging processes in and out-of-plane of the graphene interface. Droplet growth can lead to the formation of liquid bridges for which we obtain multiview projections. Data analysis reveals the general dynamics of liquid bridges, including drawing liquids from neighboring residual water films, merging with surrounding droplets, and merging with other liquid bridges. Our experimental observations provide insights into fluid transport at the nanoscale.
RESUMO
Heterogeneity is a fundamental feature of human tumors and plays a major role in drug resistance and disease progression. In the present study, we selected single-cell-derived cell lines (SCDCLs) derived from Lewis lung carcinoma (LLC1) cells to investigate tumorigenesis and heterogeneity. SCDCLs were generated using limiting dilution. Five SCDCLs were subcutaneously injected into wild-type C57BL/6N mice; however, they displayed significant differences in tumor growth. Subclone SCC1 grew the fastest in vivo, whereas it grew slower in vitro. The growth pattern of SCC2 was the opposite to that of SCC1. Genetic differences in these two subclones showed marked differences in cell adhesion and proliferation. Pathway enrichment results indicate that signal transduction and immune system responses were the most significantly altered functional categories in SCC2 cells compared to those in SCC1 cells in vitro. The number and activation of CD3+ and CD8+ T cells and NK cells in the tumor tissue of tumor-bearing mice inoculated with SCC2 were significantly higher, whereas those of myeloid cells were significantly lower, than those in the SCC1 and LLC1 groups. Our results suggest that the in vivo growth of two subclones derived from LLC1 was determined by the tumor microenvironment rather than their intrinsic proliferative cell characteristics.
RESUMO
The aim of the study was to investigate the sensitivity of AHH-1 human lymphoblastoid cells to radiation and its relevance to intracellular events, specifically alteration in cellular energy-producing systems. AHH-1 human lymphoblastoid cells were irradiated with 6 Gy of gamma radiation, and then were collected at the indicated time points. Parallel studies were conducted to assess the effects of radiation on the cell proliferation and apoptotic index. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production were monitored. A marked decrease of cell viability was observed as early as 12 h postirradiation and fraction of apoptotic cells was highest at 24 h. Intracellular ROS generation measured with 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) appeared to be highest as early as 30 min postirradiation and resumed to normal level at 6 h. Unexpectedly, the fluorescence intensity of Rhodamine 123 for measuring MMP did not change during the first 3h after radiation and exhibited an aberrant increase at 6 h. The results suggest that AHH-1 cells are sensitive to radiation-induced apoptosis and ROS generation is an early phase in the apoptosis process. Moreover, the results might cast doubts on those studies using Rhodamine 123 which hypothesized that the fall in MMP is one of the early events of apoptosis.
Assuntos
Apoptose/efeitos da radiação , Caspases/metabolismo , Raios gama , Linfócitos/metabolismo , Potencial da Membrana Mitocondrial/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Humanos , Linfócitos/citologia , Linfócitos/efeitos da radiação , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiaçãoRESUMO
AIM: To investigate the changes of lymphocyte subpopulations, especially CD4(+)CD25(+) T regulatory cells in Smad3(-/-) mice. METHODS: Hematological changes and changes of lymphocyte subpopulations were detected in Smad3(-/-) mice using cell counter and flow cytometry, respectively, and compared to their littermate controls. RESULTS: The numbers of neutrophils and lymphocytes in peripheral blood were significantly increased in Smad3(-/-) mice compared to littermate controls. CD19(+) expressing cells in blood and spleen, and CD8(+) T cells in thymus were all markedly decreased in Smad3(-/-) mice. More important, Smad3(-/-) mice had an increased population of CD4(+)CD25(+) T cells in peripheral lymphoid tissues, including thymus, spleen, and lymph nodes. CONCLUSION: These observations suggest that the changes of lymphocyte subpopulations might play a role in susceptibility to inflammation of Smad3(-/-) mice.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteína Smad3/deficiência , Animais , Inflamação/etiologia , Contagem de Leucócitos , Camundongos , Camundongos Knockout , Neutrófilos/imunologia , Receptores de Interleucina-2/metabolismo , Proteína Smad3/genética , Proteína Smad3/fisiologia , Subpopulações de Linfócitos T/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Bcl-xL belongs to a family of proteins which inhibit apoptosis in a number of stimuli including ionizing radiation. To better understand the effects and mechanisms of Bcl-xL on the apoptosis of lymphocytes and provide experimental basis to treat immune injury induced by radiation, we used normal human lymphoblastoid AHH-1 cells that were engineered to overexpress Bcl-xL proteins. Our results showed that overexpressed Bcl-xL reduced time-dependent increase of apoptosis induced by ionizing radiation. Reactive oxygen species (ROS) generation and Bax protein expression in the transfected AHH1-Bcl-xL cells were also lower compared to parental AHH-1 cells. Unexpectedly, the fluorescence intensity of Rhodomine 123 (Rh 123) for measuring mitochondrial membrane potential (MMP) did not change at all detected time points. These results possess a vital significance for insights into a new strategy for gene therapy of radiation-induced immune injury.
Assuntos
Apoptose/efeitos da radiação , Raios gama , Linfócitos/fisiologia , Proteína bcl-X/metabolismo , Morte Celular/efeitos da radiação , Linhagem Celular , Relação Dose-Resposta à Radiação , Humanos , Linfócitos/efeitos da radiação , Potenciais da Membrana , Membranas Mitocondriais/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transfecção , Proteína X Associada a bcl-2/metabolismoAssuntos
Embolectomia , Embolia Pulmonar/terapia , Terapia Trombolítica , Doença Aguda , Adulto , Humanos , MasculinoRESUMO
Apoptosis or programmed cell death is an active form of cell death which is essential for tissue homeostasis. Many proteins are involved in the molecular signal transduction of apoptosis. The caspase enzymes, a family of specific cysteine proteases, play a central role in cell death machinery. In this review, we mainly discuss the current understanding of several pathways to activate caspases and some key proteins related to these pathways.