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1.
BMC Cancer ; 21(1): 141, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557782

RESUMO

BACKGROUND: Lung carcinoid is a rare malignant tumor with poor survival. The current study established a nomogram model for predicting cancer-specific survival (CSS) in patients with lung carcinoid tumors. METHODS: A total of 1956 patients diagnosed with primary lung carcinoid tumors were extracted from the Surveillance, Epidemiology, and End Results database. The specific predictors of CSS for lung carcinoid tumors were identified and integrated to build a nomogram. Validation of the nomogram was conducted using parameters concordance index (C-index), calibration plots, decision curve analyses (DCAs), and the receiver operating characteristic (ROC) curve. RESULTS: Age at diagnosis, grade, histological type, N stage, M stage, surgery of the primary site, radiation of the primary site, and tumor size were independent prognostic factors of CSS. High discriminative accuracy of the nomogram model was shown in the training cohort (C-index = 0.873), which was also testified in the internal validation cohort (C-index = 0.861). In both cohorts, the calibration plots showed good concordance between the predicted and observed CSS at 3, 5, and 10 years. The DCA showed great potential for clinical application. The ROC curve showed superior survival predictive ability of the nomogram model (area under the curve = 0.868). CONCLUSIONS: We developed a practical nomogram that provided independent predictions of CSS for patients with lung carcinoid tumors. This nomogram may have the potential to assist clinicians in prognostic evaluations or developing individualized therapies for patients with this neoplasm.

2.
Transl Lung Cancer Res ; 9(5): 1952-1962, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209615

RESUMO

Background: T790M relative allele frequency (RAF) in plasma, calculated by the ratio of T790M to epidermal growth factor receptor (EGFR)-sensitizing mutation allele frequencies (AF), is associated with osimertinib response in patients with progressive non-small cell lung cancer (NSCLC) post 1st generation EGFR-tyrosine kinase inhibitor (TKI) treatment. However, which subgroup of patients carry concurrent resistance mechanisms and have poor responsiveness to osimertinib remains unknown. Methods: Matched re-biopsy tissue and plasma samples obtained from 32 patients who had progression following 1st generation EGFR-TKI treatment were genotyped using next-generation sequencing (NGS) to investigate which subgroup of patients, classified by plasma position 790 (T790M) RAF, were more likely to carry concurrent resistance mechanisms. In another independent cohort, consisting of 21 T790M-positive patients, we validated whether these patients had a poor response to osimertinib treatment. Results: In the discovery cohort, patients with T790M RAF less than 20% were more likely to harbor concurrent resistance mechanisms (P=0.018), such as MET or ERBB2 amplification, and small cell lung cancer transformation. In the validation cohort, we found that patients with low T790M RAF (<20%) had significantly lower objective response rates (ORRs) (0 vs. 68.8%, P=0.03) and disease control rates (DCRs) (60% vs. 100%, P=0.048) in response to osimertinib compared to patients with high T790M RAF. Conclusions: In patients with progressive NSCLC post 1st generation EGFR-TKI treatment, plasma T790M RAFs of less than 20% can be used to identify patients who carry concurrent resistance mechanisms, and can predict a poorer response to osimertinib. Trial registration: This study was registered on http://www.chictr.org.cn (registration number: ChiCTR-DDD-16007900).

3.
Scand J Trauma Resusc Emerg Med ; 28(1): 106, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109234

RESUMO

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) is a global public health emergency. Here, we developed and validated a practical model based on the data from a multi-center cohort in China for early identification and prediction of which patients will be admitted to the intensive care unit (ICU). METHODS: Data of 1087 patients with laboratory-confirmed COVID-19 were collected from 49 sites between January 2 and February 28, 2020, in Sichuan and Wuhan. Patients were randomly categorized into the training and validation cohorts (7:3). The least absolute shrinkage and selection operator and logistic regression analyzes were used to develop the nomogram. The performance of the nomogram was evaluated for the C-index, calibration, discrimination, and clinical usefulness. Further, the nomogram was externally validated in a different cohort. RESULTS: The individualized prediction nomogram included 6 predictors: age, respiratory rate, systolic blood pressure, smoking status, fever, and chronic kidney disease. The model demonstrated a high discriminative ability in the training cohort (C-index = 0.829), which was confirmed in the external validation cohort (C-index = 0.776). In addition, the calibration plots confirmed good concordance for predicting the risk of ICU admission. Decision curve analysis revealed that the prediction nomogram was clinically useful. CONCLUSION: We established an early prediction model incorporating clinical characteristics that could be quickly obtained on hospital admission, even in community health centers. This model can be conveniently used to predict the individual risk for ICU admission of patients with COVID-19 and optimize the use of limited resources.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Hospitalização , Unidades de Terapia Intensiva , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Adulto , Idoso , China , Infecções por Coronavirus/diagnóstico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Nomogramas , Pandemias , Pneumonia Viral/diagnóstico , Estudos Retrospectivos , Medição de Risco
4.
Int J Biol Sci ; 16(15): 2951-2963, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061808

RESUMO

Previous studies have demonstrated that the antitumor potential of IU1 (a pharmacological compound), which was mediated by selective inhibition of proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). However, the underlying molecular mechanisms remain elusive. It has been well established that mdm2 (Murine double minute 2) gene was amplified and/or overexpressed in a variety of human neoplasms, including cervical cancer. Furthermore, MDM2 is critical to cervical cancer development and progression. Relatively studies have reported that USP15 and USP7 stabilized MDM2 protein levels by removing its ubiquitin chain. In the current study, we studied the cell proliferation status after IU1 treatment and the USP14-MDM2 protein interaction in cervical cancer cells. This study experimentally revealed that IU1 treatment reduced MDM2 protein expression in HeLa cervical cancer cells, along with the activation of autophagy-lysosomal protein degradation and promotion of ubiquitin-proteasome system (UPS) function, thereby blocked G0/G1 to S phase transition, decreased cell growth and triggered cell apoptosis. Thus, these results indicate that IU1 treatment simultaneously targets two major intracellular protein degradation systems, ubiquitin-proteasome and autophagy-lysosome systems, which leads to MDM2 degradation and contributes to the antitumor effect of IU1.

5.
J Wound Care ; 29(9): 510-517, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32924816

RESUMO

OBJECTIVE: Necrotising soft-tissue infection is a rare but life-threatening infectious disease with high morbidity and mortality. It is typically caused by toxin-producing bacteria and characterised clinically by a very rapid progression of the disease with significant local tissue destruction. In this study, we intend to explore effective wound management to control the invasive infection and to decrease the high mortality. METHOD: This retrospective analysis explored the wound management and mortality in patients with necrotising soft-tissue infection. Extensive debridement, vacuum sealing drainage (VSD) with normal saline instillation combined with broad-spectrum or sensitive antibiotics, and supportive therapies were used. RESULTS: All 17 patients included in the analysis survived. The microbiology of 11 patients was found to be polymicrobial. Of the patients, 14 were discharged with completely healed wounds and three were transferred to a local hospital after the systemic and invasive wound infection was controlled. CONCLUSION: Our experiences revealed the outstanding effect of VSD with instillation in removing the debris of necrotising tissue on the wound bed, in the continual and complete drainage of wound exudates, and in prompting wound healing.

6.
Sci Rep ; 10(1): 12817, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732990

RESUMO

The prognostic factors for survival among patients with secondary osteosarcoma remain unclear. The aim of this study was to develop a practical nomogram for predicting cancer-specific survival (CSS) in patients with osteosarcoma as a secondary malignancy. The surveillance, epidemiology, and end results database was used for the identification of osteosarcoma cases. The total sample comprised 5860 cases of primary osteosarcoma and 268 cases of secondary osteosarcoma during the period from 1973 to 2015. The CSS and overall survival (OS) of primary and secondary osteosarcomas were analyzed. The predictors of CSS for secondary osteosarcoma were identified and integrated to build a nomogram. Validation of the nomogram was performed using concordance index (C-index) and calibration plots. The results indicated that patients with secondary osteosarcoma had poorer CSS and OS than patients with primary osteosarcoma. The nomogram model exhibited high discriminative accuracy in the training cohort (C-index = 0.826), which was confirmed in the internal validation cohort (C-index = 0.791). In addition, the calibration plots confirmed good concordance for prediction of CSS at 3, 5, and 10 years. In conclusion, we developed a practical nomogram that provided individual predictions of CSS for patients with secondary osteosarcoma. This nomogram may help clinicians with prognostic evaluations and with the development of individualized therapies for this aggressive disease.

7.
PLoS One ; 15(5): e0233328, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421703

RESUMO

BACKGROUND: Since December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan and spread across the globe. The objective of this study is to build and validate a practical nomogram for estimating the risk of severe COVID-19. METHODS: A cohort of 366 patients with laboratory-confirmed COVID-19 was used to develop a prediction model using data collected from 47 locations in Sichuan province from January 2020 to February 2020. The primary outcome was the development of severe COVID-19 during hospitalization. The least absolute shrinkage and selection operator (LASSO) regression model was used to reduce data size and select relevant features. Multivariable logistic regression analysis was applied to build a prediction model incorporating the selected features. The performance of the nomogram regarding the C-index, calibration, discrimination, and clinical usefulness was assessed. Internal validation was assessed by bootstrapping. RESULTS: The median age of the cohort was 43 years. Severe patients were older than mild patients by a median of 6 years. Fever, cough, and dyspnea were more common in severe patients. The individualized prediction nomogram included seven predictors: body temperature at admission, cough, dyspnea, hypertension, cardiovascular disease, chronic liver disease, and chronic kidney disease. The model had good discrimination with an area under the curve of 0.862, C-index of 0.863 (95% confidence interval, 0.801-0.925), and good calibration. A high C-index value of 0.839 was reached in the interval validation. Decision curve analysis showed that the prediction nomogram was clinically useful. CONCLUSION: We established an early warning model incorporating clinical characteristics that could be quickly obtained on admission. This model can be used to help predict severe COVID-19 and identify patients at risk of developing severe disease.


Assuntos
Infecções por Coronavirus/diagnóstico , Nomogramas , Pneumonia Viral/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Betacoronavirus , China , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
8.
Breast Cancer ; 27(3): 363-371, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31728872

RESUMO

BACKGROUND: Breast cancer has become a dangerous killer for the female, which seriously threatened women's life, leading to huge pressures to society. The present study assessed the mechanism underlying the involvement of bone marrow tyrosine kinase on chromosome X (BMX) in breast cancer development. METHODS: The expression of BMX was examined by qPCR and immunohistochemistry. The effect of BMX on cell proliferation and migration was detected by Clone formation assay and Transwell assay. In vitro study, the correlation of BMX with Wnt/ß-catenin pathway was explored by western blot and TOP/FOP flash assay. RESULTS: In the present study, we found that BMX was up-regulated in breast cancer, which was associated with the tumor differentiation and TNM stage. Oncogenic BMX enhanced the ability of breast cancer cell proliferation and migration. Furthermore, BMX could up-regulate the protein expression levels of p-ß-catenin (Y142), p-ß-catenin(Y654) and inhibit the expression level of p-ß-catenin (S33/37), thus activating Wnt/ß-catenin pathway in MCF-7 and MDA-MB-231 cells. In addition, we revealed that BMX promoted GSK3ß phosphorylation, which suppressed the degradation of ß-catenin. CONCLUSIONS: In this study, we identified that BMX-activated Wnt/ß-catenin signaling pathway, playing an oncogenic role in breast cancer, suggesting that BMX could become a potential treatment target of breast cancer.

9.
Oncogene ; 39(11): 2258-2274, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31831834

RESUMO

Previous studies have shown that the main function of VASP is to regulate the cytoskeleton and play an important role in promoting tumor cell metastasis. In this study, we first reveal that VASP is located in the nucleus of breast cancer cells and elucidate a Wnt/ß-catenin/VASP positive feedback loop. We identify that VASP is a target gene of Wnt/ß-catenin signaling pathway, and activation of Wnt/ß-catenin signaling pathway can significantly upregulate VASP protein expression, while upregulated VASP protein can in turn promote translocation of ß-catenin and DVL3 proteins into the nucleus. In the nucleus, VASP, DVL3, ß-catenin, and TCF4 can form VASP/DVL3/ß-catenin/TCF4 protein complex, activating Wnt/ß-catenin signaling pathway, and promoting the expression of target genes VASP, c-myc, and cyclin D1. Thus, our study reveals that there is a Wnt/ß-catenin/VASP malignant positive feedback loop in breast cancer, which promotes the proliferation and migration of breast cancer cells, and breaking this positive feedback loop may provide new strategy for breast cancer treatment.

10.
Int J Biol Sci ; 15(12): 2733-2749, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754343

RESUMO

Breast cancer is one of the most common malignant tumors worldwide. Metastasis remains the leading cause of death in breast cancer patients. Research on the mechanism of breast cancer metastasis has become a core issue in breast cancer research. Our previous series of studies have shown that VASP, as a key oncogene, plays an important role in the development of various tumors such as breast cancer. In this study, we find that miR-638 can target to inhibit VASP expression, and Lin28 acts as an RNA-binding protein to regulate the processing of miR-638, which inhibits its maturation and promotes the expression of VASP. In addition, we also find that CREB1 acts as a transcription factor that binds to the promoter of Lin28 gene and activates the Lin28/miR-638/VASP pathway. Furthermore, CREB1 can also directly bind to the promoter of VASP, and activate VASP expression, forming a CREB/Lin28/miR-638/VASP interactive network, which plays an important role in promoting cell proliferation and migration in breast cancer. Our study explained the mechanism of CREB1/Lin28/miR-638/VASP network promoting the development of breast cancer, which further elucidated the mechanism of VASP as a key oncogene, and also provided a theoretical basis for expanding new approaches to tumor biotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias da Mama/genética , Moléculas de Adesão Celular/genética , Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Fator de Crescimento Epidérmico/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Neoplasias Experimentais , Fosfoproteínas/genética , Prognóstico , Mapas de Interação de Proteínas , Proteínas de Ligação a RNA/genética , Cicatrização
11.
PLoS One ; 14(9): e0223275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31560723

RESUMO

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is a rare and typically aggressive malignancy with poor prognosis. This study developed a nomogram model to predict the overall survival (OS) of patients with LCNEC. METHODS: LCNEC patients were identified from the Surveillance, Epidemiology, and End Results database between 2004-2014. Univariate and multivariate Cox regression models were used to determine demographic and clinicopathological features associated with OS. A nomogram model was generated to predict OS and its performance was assessed by Harrell's concordance index (C-index), calibration plots, and subgroup analysis by risk scores. RESULTS: Of 3048 eligible patients with LCNEC, 2138 were randomly grouped into the training set and 910 into the validation set. Age at diagnosis, gender, tumor stage, N stage, tumor size, and surgery of primary site were independent prognostic factors of OS. C-index values of the nomogram were 0.75 (95% CI, 0.74-0.76) and 0.76 (95% CI, 0.74-0.77) in the training and validation sets, respectively. In both cohorts, the calibration plots showed good concordance between the predicted and observed OS at 3 and 5 years. Kaplan-Meier curves revealed significant differences in OS in patients stratified by nomogram-based risk score, and patients with a higher-than-median risk score had poorer OS. CONCLUSION: This is the first nomogram developed and validated in a large population-based cohort for predicting OS in patients with LCNEC, and it shows favorable discrimination and calibration abilities. Use of this proposed nomogram has the potential to improve prediction of survival risk, and lead to individualized clinical decisions for LCNEC.


Assuntos
Carcinoma de Células Grandes/mortalidade , Carcinoma Neuroendócrino/mortalidade , Neoplasias Pulmonares/mortalidade , Nomogramas , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Tomada de Decisão Clínica/métodos , Técnicas de Apoio para a Decisão , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Curva ROC , Medição de Risco , Fatores de Risco , Programa de SEER/estatística & dados numéricos
12.
Pathol Res Pract ; 215(10): 152573, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31399258

RESUMO

The development of breast cancer is still a relatively unclear biological process, and there is currently no consensus on the occurrence of breast cancer and the process of tumor metastases. This study was to reveal a correlation between TRIM63 and the development of breast cancer. In this study, we found that the expression of TRIM63 was significantly increased in breast cancer tissues and closely related to pathological differentiation and TNM stage of breast cancer. Overexpression of TRIM63 could significantly promote proliferation and migration of breast cancer cells, while TRIM63 knockdown significantly inhibited the proliferation and migration of breast cancer cells. In addition, TRIM63 could activate Wnt/ß-catenin signaling pathway in breast cancer cells. Further study found that TRIM63 could regulate ß-catenin degradation by promoting GSK3ß phosphorylation. Our study revealed that TRIM63, as an oncogene, involved in breast cancer progression by activating the Wnt/ß-catenin signaling pathway, suggesting that the potential applicability of TRIM63 as a target for breast cancer treatment.


Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica , Proteínas Musculares/metabolismo , Invasividade Neoplásica/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Via de Sinalização Wnt/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Proteínas Musculares/genética , Invasividade Neoplásica/patologia , Fosforilação , RNA Interferente Pequeno , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , beta Catenina
13.
Pathol Res Pract ; 215(10): 152575, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387807

RESUMO

The important role of LncRNA in the development of breast cancer is attracting more and more attention. In the previous study, we found that the expression level of LncRNA SNHG6 in breast cancer tissues and cells was significantly increased, but its mechanism in the development of breast cancer was still unclear. Our study found that knockdown of SNHG6 significantly inhibited the proliferation, migration and invasion of breast cancer cells MCF-7 and MDA-MB-231 cells. Further study showed that knockdown of SNHG6 significantly inhibited the expression level of VASP. More importantly, SNHG6 and VASP both can bind directly to miR-26a, suggesting that SNHG6 could act as a ceRNA to sponge miR-26a, thereby promoting the expression of VASP, which leading to activated proliferation, migration and invasion of breast cancer cells. Taken together, this study revealed the important role of the SNHG6/miR-26a/VASP regulatory network in the development of breast cancer, and provided a reference for exploring new pathogenesis and biomarkers of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Invasividade Neoplásica/genética , Fosfoproteínas/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Inativação Gênica , Humanos , Invasividade Neoplásica/patologia , RNA Longo não Codificante/genética
14.
DNA Cell Biol ; 38(9): 933-944, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31361540

RESUMO

Interstitial lung disease (ILD) is the main reason of death in patients with systemic sclerosis (SSc). The potential microRNA (miRNA)-messenger RNA (mRNA) interaction networks of SSc-ILD from a systematic biological perspective are unclear. To characterize differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DEGs) likely related to SSc-ILD, we downloaded the miRNA microarray dataset (GSE81923) and mRNA datasets (GSE76808 and GSE81292) from the Gene Expression Omnibus database. Comprehensive bioinformatic analyses were conducted to predict target genes for DE-miRNAs and generate an miRNA-hub gene network with SSc-ILD. In total, 26 DE-miRNAs were detected in SSc-ILD, among which 2 were upregulated and 24 were downregulated. Additionally, 178 common DEGs (55 upregulated and 123 downregulated) were identified. miRNAs were primarily enriched in pathways involving inflammation and regulation of fibroblasts. The hub genes identified were MMP7, IER2, HBEGF, CCL4, NFKBIA, JUNB, LIF, SERPINE1, FOSL1, and NAMPT. We discovered the miRNA-mediated regulatory network in SSc-ILD using an integrated bioinformatic analysis. The findings provide novel insight and expand our comprehension of the molecular mechanisms participating in the pathogenesis of SSc-ILD, along with identification of new potential diagnostic biomarkers.


Assuntos
Redes Reguladoras de Genes , Fibrose Pulmonar Idiopática/genética , MicroRNAs/genética , Escleroderma Sistêmico/genética , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/metabolismo
15.
Mol Med Rep ; 20(2): 1943-1951, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257464

RESUMO

Saikosaponin b2 (SSb2) can be extracted from Bupleurum spp. roots (Radix Bupleuri), which belongs to the Umbelliferae family. The current study aimed to explore the effects of SSb2 on proliferation of breast cancer cells and to identify the mechanism by which SSb2 affects breast cancer cell migration. mRNA expression levels of STAT3 and vasodilator­stimulated phosphoprotein (VASP) were determined and increased expression was observed in 16 breast cancer tissues compared with the paracancerous tissues. MTT, wound healing, colony formation assays and western blot suggested that SSb2 inhibited MCF­7 proliferation and migration. It was further identified by western blot analysis that SSb2 treatment reduced levels of phosphorylated STAT3, VASP, matrix metallopeptidase (MMP) 2 and MMP9 in MCF­7 compared with the untreated cells. In addition, it was demonstrated that inhibition of STAT3 phosphorylation decreased VASP expression levels and induction of STAT3 phosphorylation increased VASP levels. Furthermore, it was observed that the treatment of Kunming mice with SSb2 at 30 mg/kg/day for 30 days induced no obvious changes in the liver or kidney tissues, as determined by haematoxylin and eosin staining. In conclusion, these results indicated that SSb2 may be a potential antitumor drug for the treatment of breast cancer, which acts by suppressing proliferation and migration by downregulating the STAT3 signalling pathway and inhibiting the expression of VASP, MMP2 and MMP9 expression.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Moléculas de Adesão Celular/genética , Proteínas dos Microfilamentos/genética , Ácido Oleanólico/análogos & derivados , Fosfoproteínas/genética , Fator de Transcrição STAT3/genética , Saponinas/farmacologia , Adolescente , Adulto , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Camundongos , Pessoa de Meia-Idade , Ácido Oleanólico/farmacologia , Adulto Jovem
16.
Clin Lung Cancer ; 20(4): 313-321, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31155475

RESUMO

BACKGROUND: This analysis was performed to describe the outcome of very elderly (≥ 80 years) patients with small-cell lung cancer (SCLC) as there is no published data regarding these patients. MATERIALS AND METHODS: One hundred forty-six very elderly patients with SCLC were identified from the Institutional Lung Cancer Database ranging in age from 80 to 92 years (median, 82 years). Of these, 47 (32%) patients had limited-stage SCLC (L-SCLC), and 99 (68%) had extensive-stage SCLC (E-SCLC). All were Caucasian, and the majority (64%) were female. Sixty-seven (46%) patients had Zubrod performance status (PS) of 0 to 1. RESULTS: Of the 146 patients, 44 (30%) received no therapy, 65 (45%) received chemotherapy alone, 27 (19%) received chemotherapy plus local therapy (thoracic radiotherapy [TRT] or surgery), and 10 (7%) received local therapy alone. The median survival was 5.4 months. On univariable analysis, age (P = .019), stage (L-SCLC vs. E-SCLC; P = .0002), PS (P < .0001), and treatment option (P < .0001) were associated with survival. On multivariable analysis, stage (P = .011), PS (P = .029), and treatment option (P < .0001) maintained significance. For entire cohort, the median survival was 1.3 months without active therapy, 6 months with local therapy alone, 7.2 months with chemotherapy alone, and 14.4 months with chemotherapy plus local therapy (P < .0001, univariable and multivariable). Similar survival findings in response to treatment were found when the L-SCLC and E-SCLC cohorts were separately analyzed. CONCLUSIONS: The survival of very elderly patients with SCLC was associated with stage (L-SCLC vs. E-SCLC), PS, and treatment option. Very elderly patients with SCLC often have limited functional reserve required to tolerate aggressive multimodality therapy but appeared to benefit from it. Geriatric assessments, careful monitoring, and extra support are warranted in elderly patients. Care should be individualized based on the desires and needs of each patient.


Assuntos
Neoplasias Pulmonares/epidemiologia , Carcinoma de Pequenas Células do Pulmão/epidemiologia , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Estadiamento de Neoplasias , Pneumonectomia , Radioterapia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/terapia , Análise de Sobrevida , Resultado do Tratamento
17.
Biomed Res Int ; 2019: 3235021, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011573

RESUMO

Background: Breast cancer (BC) is one of the most common malignant tumors in women around the world. Atorvastatin (ATO) was found to be associated with a decreased risk of recurrence and mortality in cancer. But the exact mechanism of its carcinostatic effects is unclear. The expression level of Ras homolog family member B (RhoB) in breast cancer cells was found to be upregulated after being treated with ATO. Thus, we conjecture that altered expression of RhoB induced by ATO may be decisive for the migration and progression of breast cancer. Methods: The effects of ATO on breast tumor cells in vivo and in vitro were detected by clone formation assay, CCK-8 assay, flow cytometry, wound healing, transwell assays, tumor xenograft model, and immunohistochemistry. Distribution of RhoB in different breast cancer tissues and its influence on prognosis were analyzed using the data from TCGA or GEO databases. The relationship between RhoB and PTEN/AKT pathway was detected by Western blotting and RT-qPCR. Results: ATO inhibits proliferation, invasion, EMT, and PTEN/AKT pathway and promotes apoptosis in breast tumor cells. In addition, ATO inhibits the volume and weight of breast tumor in tumor-bearing mice and upregulated RhoB in tumor tissues. The expression of RhoB in mRNA and protein level was upregulated in statin-treated breast cancer cells and downregulated in cancer tissues. Low expression of RhoB links with poor prognosis in patients with breast cancer (HR = 0.74[0.66-0.83], p =7e-8, log-rank test). Further research found that RhoB inhibits the proliferation, invasion, EMT, and PTEN/AKT signal pathway in breast tumor cells. Conclusions: The exact mechanism of ATO's carcinostatic effects in breast cancer is related to downregulating PTEN/AKT pathway via promoting RhoB. Our study also demonstrates the potential applicability of RhoB as a therapeutic target for breast cancer.


Assuntos
Atorvastatina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Proteína rhoB de Ligação ao GTP/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/genética , Prognóstico , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
Oncol Rep ; 41(4): 2418-2430, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816548

RESUMO

Lung cancer is the leading cause of cancer­associated mortality worldwide. Tumor necrosis factor α (TNF­α) is an important cytokine in the tumor microenvironment that serves a function in the balance of cell survival and cell death pathways. Our previous studies indicated that hypoxia­inducible factor 1α (HIF­1α) acts downstream of TNF­α in MCF­7 luminal breast cancer cells. However, whether vasodilator­stimulated phosphoprotein (VASP) is implicated in the direct regulation of HIF­1α in response to TNF­α in lung cancer remains unknown. In vitro studies were performed using A549 and H226 lung carcinoma cells and in vivo studies of tumor xenograft models were performed to investigate the effects of TNF­α. The results demonstrated that TNF­α decreased VASP expression by upregulating the expression of HIF­1α to inhibit A549 cell proliferation and adhesion. Inhibition of transplanted tumor growth was associated with downregulation of VASP expression in nude mice. Bioinformatics analysis indicated that expression levels of VASP or HIF­1α lead to differential outcomes of overall survival in lung carcinoma. These results suggest that the HIF­1α/VASP signaling pathway serves an important function in the regulation of TNF­α­induced suppression of A549 cell proliferation and xenograft growth. This may improve our understanding of the antitumor effect of TNF­α.


Assuntos
Adenocarcinoma de Pulmão/patologia , Moléculas de Adesão Celular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/patologia , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cancer Med ; 8(4): 1679-1693, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30806044

RESUMO

Breast cancer is one of the most common malignant tumors among women worldwide. About 70-75% of primary breast cancers belong to estrogen receptor (ER)-positive breast cancer. In the development of ER-positive breast cancer, abnormal activation of the ERα pathway plays an important role and is also a key point leading to the failure of clinical endocrine therapy. In this study, we found that the small molecule peptide chlorotoxin (CTX) can significantly inhibit the proliferation, migration and invasion of breast cancer cells. In in vitro study, CTX inhibits the expression of ERα in breast cancer cells. Further studies showed that CTX can directly bind to ERα and change the protein secondary structure of its LBD domain, thereby inhibiting the ERα signaling pathway. In addition, we also found that vasodilator stimulated phosphoprotein (VASP) is a target gene of ERα signaling pathway, and CTX can inhibit breast cancer cell proliferation, migration, and invasion through ERα/VASP signaling pathway. In in vivo study, CTX significantly inhibits growth of ER overexpressing breast tumor and, more importantly, based on the mechanism of CTX interacting with ERα, we found that CTX can target ER overexpressing breast tumors in vivo. Our study reveals a new mechanism of CTX anti-ER-positive breast cancer, which also provides an important reference for the study of CTX anti-ER-related tumors.


Assuntos
Moléculas de Adesão Celular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Venenos de Escorpião/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Charibdotoxina/química , Charibdotoxina/isolamento & purificação , Charibdotoxina/farmacologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Fosfoproteínas/química , Fosfoproteínas/genética , Ligação Proteica , Venenos de Escorpião/química , Venenos de Escorpião/isolamento & purificação
20.
Menopause ; 26(3): 306-310, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30153217

RESUMO

OBJECTIVE: More than 5,000 premenopausal women are diagnosed with lung cancer annually in the United States. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. METHODS: Premenopausal women diagnosed with lung cancer under age 50 were surveyed at diagnosis and annually thereafter about their menstrual status as a part of the Mayo Clinic Epidemiology and Genetics of Lung Cancer Research Program. Types of lung cancer-directed treatments were recorded, and frequencies of self-reported menopause at each survey were calculated. RESULTS: A cohort of 182 premenopausal women were included in this study, with average age at lung cancer diagnosis 43 years (SD 6). Among the 85 patients who received chemotherapy, 64% self-reported that they had become menopausal within a year of diagnosis. Platinum salts were universally included in these chemotherapy regimens, and the majority of these women also received taxanes within 1 year of diagnosis. Only 15% of the 94 patients who did not receive systemic therapy within 1 year of diagnosis experienced self-reported menopause. Three patients received targeted therapy alone, two of whom remained premenopausal at the final qualifying survey, completed a median of 3 years after diagnosis. CONCLUSIONS: Chemotherapy for lung cancer patients appears to increase risk of early loss of menses in survivors.


Assuntos
Amenorreia/induzido quimicamente , Antineoplásicos/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Sistema de Registros , Inquéritos e Questionários
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