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1.
Heart ; 106(3): 213-220, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31704783

RESUMO

OBJECTIVE: To comprehensively examine the potential impacts of prenatal experience of the Chinese Great Famine on chronic disease risks in the middle age. METHODS: This study included 92 284 participants aged 39-51 years from China Kadoorie Biobank born around the famine period and without major chronic diseases at baseline. We categorised participants into non-famine births (born between 1 October 1956 and 30 September 1958, and 1 October 1962 and 30 September 1964) and famine births (born between 1 October 1959 and 30 September 1961). The outcomes were incident cardiovascular disease, cancer and respiratory system disease. Cox regression was used to estimate adjusted HR and 95% CI for famine exposure. Subgroup analyses were performed according to baseline characteristics. RESULTS: During a median 10.1 years of follow-up, we identified 4626 incident ischaemic heart disease (IHD) cases, 7332 cerebrovascular disease cases, 3111 cancer cases and 16 081 respiratory system disease cases. In the whole population, prenatal famine exposure was not statistically associated with the risks of developing any chronic diseases in adulthood. However, for urban participants, compared with non-famine births, famine births had a higher risk of cerebrovascular disease (HR 1.18; 95% CI 1.09 to 1.28); such association was not shown for rural participants (p for interaction <0.001). Also, we observed the associations of prenatal famine exposure with IHD (HR 1.15; 95% CI 1.05 to 1.26) and cerebrovascular disease (HR 1.13; 95% CI 1.05 to 1.21) in participants with lower physical activity level, but not in those with higher ones (all p for interaction=0.003). CONCLUSION: Our findings indicate that prenatal exposure to the Chinese famine might be associated with an increased cardiovascular risk and such risk may be modified by adult lifestyle.

2.
Anticancer Drugs ; 31(1): 44-54, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31503013

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitors therapy, such as gefitinib, have proven to be effective for lung adenocarcinoma with epidermal growth factor receptor-sensitive mutations. However, drug resistance remains inevitable and the underlying mechanisms are still elusive and poorly understood. In order to explore the mechanisms underlying tyrosine kinase inhibitors resistance, we used long non-coding RNA microarray analysis and found that long non-coding RNA H19 was highly expressed in gefitinib-resistant cell lines. In addition, knockdown of long non-coding RNA H19 was found to be able to decrease cell proliferation, half maximal inhibitory concentration (IC50) of gefitinib, migration and invasion. Mechanistically, we demonstrated that long non-coding RNA H19 positively regulated dimethylarginine dimethylaminohydrolase-1 expression via sponging miR-148b-3p. Furthermore, overexpression or inactivation of miR-148b-3p could enhance or reverse the inhibitory effect of long non-coding RNA H19 inhibition in lung adenocarcinoma cells, respectively. High expression of either long non-coding RNA H19 or dimethylarginine dimethylaminohydrolase-1 was associated with poorer overall survival in patients with lung adenocarcinoma, while high expression of miR-148b was associated with better overall survival. Overall, our data revealed that long non-coding RNA H19 confers resistance to gefitinib via miR-148b/dimethylarginine dimethylaminohydrolase-1 axis in lung adenocarcinoma, which offers a new insight into the epidermal growth factor receptor tyrosine kinase inhibitors therapy resistance.

3.
J Exp Clin Cancer Res ; 38(1): 481, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801598

RESUMO

BACKGROUND: Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are beneficial to lung adenocarcinoma patients with sensitive EGFR mutations, resistance to these inhibitors induces a cancer stem cell (CSC) phenotype. Here, we clarify the function and molecular mechanism of shisa3 as a suppressor that can reverse EGFR-TKI resistance and inhibit CSC properties. METHODS: The suppresser genes involved in EGFR-TKI resistance were identified and validated by transcriptome sequencing, quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Biological function analyses, cell half maximal inhibitory concentration (IC50), self-renewal, and migration and invasion capacities, were detected by CCK8, sphere formation and Transwell assays. Tumorigenesis and therapeutic effects were investigated in nonobese diabetic/severe combined immunodeficiency (nod-scid) mice. The underlying mechanisms were explored by Western blot and immunoprecipitation analyses. RESULTS: We found that low expression of shisa3 was related to EGFR-TKI resistance in lung adenocarcinoma patients. Ectopic overexpression of shisa3 inhibited CSC properties and the cell cycle in the lung adenocarcinoma cells resistant to gefitinib/osimertinib. In contrast, suppression of shisa3 promoted CSC phenotypes and the cell cycle in the cells sensitive to EGFR-TKIs. For TKI-resistant PC9/ER tumors in nod-scid mice, overexpressed shisa3 had a significant inhibitory effect. In addition, we verified that shisa3 inhibited EGFR-TKI resistance by interacting with FGFR1/3 to regulate AKT/mTOR signaling. Furthermore, combinational administration of inhibitors of FGFR/AKT/mTOR and cell cycle signaling could overcome EGFR-TKI resistance associated with shisa3-mediated CSC capacities in vivo. CONCLUSION: Taken together, shisa3 was identified as a brake to EGFR-TKI resistance and CSC characteristics, probably through the FGFR/AKT/mTOR and cell cycle pathways, indicating that shisa3 and concomitant inhibition of its regulated signaling may be a promising therapeutic strategy for reversing EGFR-TKI resistance.

4.
BMJ Open ; 9(4): e027696, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967410

RESUMO

OBJECTIVES: Chronic hepatitis B virus (HBV) infection is associated with a higher risk of liver diseases. Substantial uncertainty remains, however, about the associations of HBV infection with mortality from extrahepatic causes, especially from subtypes of cardiovascular diseases. We prospectively examined the association of chronic HBV infection with total and cause-specific mortality. DESIGN: Population-based prospective cohort study. SETTING: China Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008. PARTICIPANTS: 475 801 participants 30-79 years of age without reporting major chronic diseases at baseline were enrolled. Hepatitis B surface antigen (HBsAg) was tested using an on-site rapid test strip at baseline. PRIMARY AND SECONDARY OUTCOME MEASURES: Total and cause-specific mortality. RESULTS: A total of 35 822 deaths were recorded during ~10 years of follow-up. In multivariable-adjusted analyses, compared with HBsAg-negative participants, HBsAg-positive participants had an increased risk of total mortality (HR=2.01, 95% CI: 1.91 to 2.12), which was higher in men (HR=2.16, 95% CI: 2.01 to 2.31) than in women (HR=1.74, 95% CI: 1.60 to 1.90). Presence of HBsAg was associated with increased mortality from liver cancer (1339 deaths, HR=13.95, 95% CI: 12.46 to 15.62), infections (410 deaths, HR=10.30, 95% CI: 8.21 to 12.94), digestive diseases (688 deaths, HR=6.83, 95% CI: 5.49 to 8.50), intracerebral haemorrhage (4077 deaths, HR=1.38, 95% CI: 1.14 to 1.68) and ischaemic heart diseases (4624 deaths, HR=1.31, 95% CI: 1.09 to 1.58). The positive association between HBsAg status and risk of death was stronger in participants younger than 50 years, smokers, physically active or non-hypertensive participants. CONCLUSIONS: Among Chinese adults, chronic HBV infection was associated with increased mortality from a range of hepatic and extrahepatic diseases.

5.
Cancer Manag Res ; 11: 1299-1308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799956

RESUMO

Purpose: The role of neoadjuvant chemotherapy and subsequent adjuvant therapy in the treatment of patients with locally advanced esophageal squamous cell carcinomas (ESCC) is not well established. Patients and methods: We retrospectively reviewed 228 patients with locally advanced ESCC receiving esophagectomy following neoadjuvant chemotherapy from January 2007 through December 2016. The probabilities of disease-free survival (DFS) and overall survival (OS) were estimated by means of the Kaplan-Meier method and were compared with the use of the log-rank test. Univariate and multivariate analyses of predictors of DFS and OS were performed using a Cox proportional-hazards model. Propensity score matching analysis was performed for further analysis regarding the benefit of adjuvant therapy. Results: The pathological complete response of neoadjuvant chemotherapy was achieved in 13 of 228 patients (5.7%). With a median follow-up of 59.6 months, the median DFS and OS were 35.4 and 45.4 months, respectively. The multivariate Cox model determined chemotherapy regimens (P=0.003) and ypT category (P=0.006) were significant independent predictors of DFS; and chemotherapy regimens (P=0.001), ypT category (P<0.001), and ypN category (P=0.013) were significant independent predictors of OS. Furthermore, patients who received adjuvant therapy seemed to be associated with poorer survival (both DFS and OS) compared with those who did not in full cohort (P=0.001 and P=0.184, respectively) and matched cohort (P=0.251 and P=0.374, respectively). Conclusion: Surgery following neoadjuvant chemotherapy was applicable. Chemotherapy regimens and ypT category were significant independent predictors of both DFS and OS and ypN category was also a significant independent predictor of OS. However, these patients did not seem to benefit from subsequent adjuvant therapy. The necessity of adjuvant therapy requires further investigation.

6.
Cancer Lett ; 442: 53-67, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391781

RESUMO

The study sought to explore novel genetic aberration driving squamous cell lung carcinoma (LUSC). The whole exome (WES), whole genome (WGS) and target region (TS) sequencings and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from LUSC primary tumors and corresponding patient-derived xenografts (PDXs). Seven genes (FGFR2, GRM1,PIK3CG, PIK3CA,ZFHX4, CSMD3, GRM8) with high frequencies of both single nucleotide variants (SNVs) and copy number variants (CNVs), and two genes (CLDN1 and RIT1) only with CNVs were identified by bioinformatics analysis. The functions of these candidates were validated through CRISPR-Cas9 system in primary PDX cells. Furthermore, we focused on the genetic and functional analysis of Metabotropic glutamate receptor 8 (GRM8), whose transcriptional activation was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway. The SNV identified in GRM8, A112G, activated downstream signaling pathway and induced cell proliferation, which could be reversed by cAMP stimulator and MEK inhibitor. In conclusion, the components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer carrying GRM8 activating variants.


Assuntos
Sistemas CRISPR-Cas , Carcinoma de Células Escamosas/genética , Edição de Genes/métodos , Neoplasias Pulmonares/genética , Receptores de Glutamato Metabotrópico/genética , Sequenciamento Completo do Exoma , Animais , Antineoplásicos/uso terapêutico , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , AMP Cíclico/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Mutação , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais , Ativação Transcricional , Carga Tumoral , Células Tumorais Cultivadas
7.
BMC Med ; 16(1): 93, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29909773

RESUMO

BACKGROUND: Existing evidence remains inconclusive as to the association between chronic hepatitis B virus (HBV) infection and the risk of chronic kidney disease (CKD). We prospectively examined the association between chronic HBV infection and CKD risk, and the joint associations of HBV infection with established risk factors of several lifestyle factors and prevalent diseases on CKD risk. METHODS: Participants from the China Kadoorie Biobank were enrolled during 2004-2008 and followed up until 31 December 2015. After excluding participants with previously diagnosed CKD, cancer, heart disease, and stroke at baseline, the present study included 469,459 participants. Hepatitis B surface antigen (HBsAg) was qualitatively tested at baseline. Incident CKD cases were identified mainly through the health insurance system and disease and death registries. RESULTS: During a median follow-up of 9.1 years (4.2 million person-years), we documented 4555 incident cases of CKD. Cox regression yielded multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with HBsAg-negative participants, the multivariable-adjusted HR (95% CI) for CKD was 1.37 (1.18, 1.60) for HBsAg-positive participants. The association was stronger in men (HR = 1.77; 95% CI: 1.43, 2.20) than in women (HR = 1.10; 95% CI: 0.88, 1.36). HBsAg-positive participants, with or without hepatitis or cirrhosis, whether or not under treatment, all showed increased risk of developing CKD. We observed positive additive interactions of HBsAg positivity with smoking, physical inactivity, or diabetes on CKD risk. Compared with HBsAg-negative participants who were nonsmokers, more physically active, or did not have diabetes at baseline, the greatest CKD risk for HBsAg-positive participants was for those who were smokers (HR = 1.85; 95% CI: 1.44, 2.38), physically inactive (HR = 1.91; 95% CI: 1.52, 2.40), or diabetic (HR = 6.11; 95% CI: 4.47, 8.36). CONCLUSIONS: In countries with a high endemicity of HBV infection, kidney damage associated with chronic HBV infection should be a non-negligible concern. Our findings also highlight the importance of health advice on quitting smoking, increasing physical activity, improving glucose control, and early screening for CKD in people with chronic HBV infection.


Assuntos
Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Insuficiência Renal Crônica/etiologia , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Estudos de Coortes , Feminino , Hepatite B Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Insuficiência Renal Crônica/patologia , Fatores de Risco
8.
Heart ; 104(21): 1756-1763, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29785957

RESUMO

OBJECTIVE: To examine the associations between egg consumption and cardiovascular disease (CVD), ischaemic heart disease (IHD), major coronary events (MCE), haemorrhagic stroke as well as ischaemic stroke. METHODS: During 2004-2008, over 0.5 million adults aged 30-79 years were recruited from 10 diverse survey sites in China. Participants were asked about the frequency of egg consumption and were followed up via linkages to multiple registries and active investigation. Among 461 213 participants free of prior cancer, CVD and diabetes, a total of 83 977 CVD incident cases and 9985 CVD deaths were documented, as well as 5103 MCE. Stratified Cox regression was performed to yield adjusted hazard ratios for CVD endpoints associated with egg consumption. RESULTS: At baseline, 13.1% of participants reported daily consumption (usual amount 0.76 egg/day) and 9.1% reported never or very rare consumption (usual amount 0.29 egg/day). Compared with non-consumers, daily egg consumption was associated with lower risk of CVD (HR 0.89, 95% CI 0.87 to 0.92). Corresponding multivariate-adjusted HRs (95% CI) for IHD, MCE, haemorrhagic stroke and ischaemic stroke were 0.88 (0.84 to 0.93), 0.86 (0.76 to 0.97), 0.74 (0.67 to 0.82) and 0.90 (0.85 to 0.95), respectively. There were significant dose-response relationships of egg consumption with morbidity of all CVD endpoints (P for linear trend <0.05). Daily consumers also had an 18% lower risk of CVD death and a 28% lower risk of haemorrhagic stroke death compared to non-consumers. CONCLUSION: Among Chinese adults, a moderate level of egg consumption (up to <1 egg/day) was significantly associated with lower risk of CVD, largely independent of other risk factors.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Ovos/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Adulto , Fatores Etários , Idoso , China , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Comportamento de Redução do Risco , Fatores Sexuais , Análise de Sobrevida
9.
Theranostics ; 8(21): 5890-5902, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30613269

RESUMO

Activation of c-Met plays a critical role in tumorigenesis, migration and invasion in lung cancer. Here, we explored the therapeutic efficacy of a novel small-molecule c-Met inhibitor (BPI-9016M) in lung adenocarcinoma and investigated the underlying molecular mechanisms. Method: BPI-9016M, a c-Met tyrosine kinase receptor inhibitor, was used to treat patient-derived xenografts (PDX) from lung adenocarcinoma in NOD/SCID mice. Immunohistochemistry and Western blot analysis were used to determine the expression of c-Met and its downstream signaling molecules. CCK8, wound healing, and trans-well assays were used to analyze cell proliferation, spreading, migration and invasion. RNA sequencing and quantitative real-time PCR (qPCR) was used to screen and validate the expression of downstream genes in lung adenocarcinoma cells treated with BPI-9016M. Luciferase reporter assay was used to detect the interaction between miRNA and the targeted gene. Results: BPI-9016M significantly suppressed growth in three out of four lung adenocarcinoma PDX models, particularly in the tumors with high expression of c-Met. In lung adenocarcinoma cell lines, BPI-9016M treatment resulted in increased miR203, which reduced migration and invasion and also repressed Dickkopf-related protein 1 (DKK1) expression. Forced overexpression of DKK1 or down-regulation of miR203 reversed the inhibitory effect of BPI-9016M on migration and invasion. C-Met was verified to positively and negatively associate with DKK1 and miR203, respectively. High expression of c-Met/DKK1 or low expression of miR203 related to poor outcome of lung adenocarcinoma patients. Furthermore, we observed significantly enhanced tumor cell growth inhibition upon combining BPI-9016M treatment with miR203 mimics or DKK1 siRNA. Conclusion: Our data indicated that BPI-9016M is an effective agent against lung adenocarcinoma, particularly in tumors with c-Met activation, and likely functions through upregulation of miR203 leading to reduced DKK1 expression.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Adenocarcinoma de Pulmão/patologia , Animais , Western Blotting , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos SCID , Transplante de Neoplasias , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Resultado do Tratamento
10.
Diabetologia ; 60(5): 836-842, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28064359

RESUMO

AIMS/HYPOTHESIS: Season of birth as a surrogate for potential environmental exposure during fetal development and early postnatal life has shown an inconsistent association with adult type 2 diabetes in white populations living in high-latitude regions. The present study aimed to examine the association between birth seasonality and risk of adult type 2 diabetes in Chinese individuals living across wide regions of low latitude and lower to middle latitude. METHODS: Participants from the China Kadoorie Biobank were enrolled during 2004-2008 and followed up until 31 December 2013. After excluding participants with cancer, heart disease, stroke and diabetes at baseline, the present study included 189,153 men and 272,058 women aged 30-79 years. We used multivariable Cox proportional hazards model to estimate the HR and 95% CI. RESULTS: During a median follow-up of 7.2 years (3.3 million person-years), we documented 8784 incident cases of type 2 diabetes. In the whole cohort, compared with summer-born participants, the adjusted HRs (95% CIs) were 1.09 (1.02, 1.16), 1.08 (1.02, 1.15) and 1.09 (1.02, 1.15) for those who were born in Spring, Autumn and Winter, respectively. The association was consistent in both men and women and across subgroups defined by residence and lifestyle factors later in life. CONCLUSIONS/INTERPRETATION: In this large prospective study, participants born in summer had a lower risk of adult type 2 diabetes compared with other seasons of birth, suggesting exposures in early life with some degree of seasonal variation might influence the risk of adult diabetes.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Estações do Ano , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Circunferência da Cintura/fisiologia
11.
World J Surg Oncol ; 15(1): 34, 2017 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-28129775

RESUMO

BACKGROUND: Considering neoadjuvant chemotherapy (NAC) prior to surgery could shrink and reduce the primary tumor and distant micro-metastases to reduce the high relapses rates, NAC has been an accepted therapeutic management for patients with non-small cell lung cancer (NSCLC). CMTM1_v17 is highly expressed in human testis tissues and solid tumor tissues but relatively low expression was obtained in the corresponding normal tissues. This study aims to investigate the significance of CMTM1_v17 in NSCLC and its association with platinum-based NAC efficacy. METHODS: 31 pairs of tumor tissues before and after NAC and 78 resected tumor tissues after NAC were utilized for immunohistochemistry (IHC) staining of CMTM1_v17 protein. The correlation between CMTM1_v17 expression and chemotherapy efficacy was analyzed. The prognostic value of CMTM1_v17 index for disease-free survival (DFS) and overall survival (OS) was analyzed using Kaplan-Meier survival and multivariable Cox regression. RESULTS: CMTM1_v17 expression was related to treatment effect and outcome in tumor tissues after NAC not before NAC from 31 cases of NSCLC. We identified that high CMTM1_v17 expression was associated with low objective remission rate (ORR) (P = 0.008) and poor prognosis (the median OS: 35.1 months vs 65.6 months, P = 0.0045; the median DFS: 17.27 months vs 35.54 months, P = 0.0207) in the 31 patients. Next, we detected CMTM1_v17 expression to confirm correlation between this protein status and clinical characteristics in 78 NSCLC patients with NAC treatment. The upregulation of CMTM1_v17 had a higher SD rate (P = 0.007) and worse outcome (the median OS: 41.0 months vs 80.6 months, P = 0.0028; the median DFS: 33.4 vs 64.8 months, P = 0.0032). COX multivariate analysis indicated that CMTM1_v17 is an independent prognostic risk factor on patients who have received NAC (OS: HR = 3.642, P = 0.002; DFS:HR = 3.094, P = 0.002). CONCLUSIONS: CMTM1_v17 expression is significantly associated with chemoresistance and poor prognosis of the early stage NSCLC patients who have received NAC.


Assuntos
Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Proteínas com Domínio MARVEL/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
12.
Heart ; 103(10): 783-789, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28077466

RESUMO

OBJECTIVE: To prospectively examine the association between tea consumption and the risk of ischaemic heart disease (IHD). METHODS: Prospective study using the China Kadoorie Biobank; participants from 10 areas across China were enrolled during 2004-2008 and followed up until 31 December 2013. After excluding participants with cancer, heart disease and stroke at baseline, the present study included 199 293 men and 288 082 women aged 30-79 years at baseline. Information on IHD incidence was collected through disease registries and the new national health insurance databases. RESULTS: During a median follow-up of 7.2 years, we documented 24 665 (7.19 cases/1000 person-years) incident IHD cases and 3959 (1.13 cases/1000 person-years) major coronary events (MCEs). Tea consumption was associated with reduced risk of IHD and MCE. In the whole cohort, compared with participants who never consumed tea during the past 12 months, the multivariable-adjusted HRs and 95% CIs for less than daily and daily tea consumers were 0.97 (0.94 to 1.00) and 0.92 (0.88 to 0.95) for IHD, 0.92 (0.85 to 1.00) and 0.90 (0.82 to 0.99) for MCE. No linear trends in the HRs across the amount of tea were observed in daily consumers for IHD and MCE (PLinear >0.05). The inverse association between tea consumption and IHD was stronger in rural (PInteraction 0.006 for IHD, <0.001 for MCE), non-obese (PInteraction 0.012 for MCE) and non-diabetes participants (PInteraction 0.004 for IHD). CONCLUSIONS: In this large prospective study, daily tea consumption was associated with a reduced risk of IHD.


Assuntos
Isquemia Miocárdica/epidemiologia , Medição de Risco/métodos , Chá , Adulto , Idoso , China/epidemiologia , Comportamento de Ingestão de Líquido , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , População Rural , Fatores de Tempo , População Urbana
13.
Med Sci Monit ; 22: 4017-4025, 2016 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-27784882

RESUMO

BACKGROUND The immune checkpoint of programmed cell death ligand 1 (PD-L1) commonly expressed in solid cancers, and the blockade of this molecule show promising results in advanced cancers, including lung cancer. The relevance of PD-L1 to patient-derived xenograft (PDX) formation and clinicopathological characteristics in early stage lung cancer have not been fully elucidated. MATERIAL AND METHODS Cell counting kit-8 and flow cytometry were carried out to examine proliferation and apoptosis in PC9 and H520 cells transfected with siRNAs. Nod-scid mice were used to establish PDX. Immunohistochemistry was done to investigate PD-L1 expression in tumor tissues. RESULTS PD-L1 was detected in lung cancer cell lines and 45.45% of primary tumor tissues from a cohort of 209 lung cancer patients. Cell growth was restrained and apoptosis was induced when PD-L1 was inhibited in PC9 and H520 cells. In addition, we successfully established 16 PDX models from tissues from 43 cases of primary lung cancer. Higher PD-L1 expression rates (75%) was observed in primary tumors with PDX formation compared to protein expression rate (44.44%) in tumors without PDX formation. Consistently, a 1.9-fold increase of PDX formation frequency was identified in the PD-L1 positive tumors than in the PD-L1 negative tumors. Moreover, PD-L1 was found to be related to smoking, histological type, and pathological stage. Importantly, PD-L1 overexpression was associated with shorter overall survival (OS) of lung cancer patients. CONCLUSIONS This study suggests that overexpression of PD-L1 could induce PDX formation and is related to poor outcome for the lung cancer patients.


Assuntos
Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Transplante Heterólogo/métodos , Animais , Apoptose/fisiologia , Biomarcadores Tumorais/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Receptores ErbB/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Estudos Retrospectivos
14.
Int J Oncol ; 48(6): 2349-58, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27035162

RESUMO

Acquired resistance to standard chemotherapy causes treatment failure in patients with local advanced and advanced non-small lung cancer (NSCLC). Cancer stem cells (CSCs) are a small subpopulation within cancer that is thought to be resistant to conventional chemotherapy. The Notch pathway is one of the most intensively studied for putative therapeutic targets of CSCs in solid tumors. In our study, suppression of Notch3 decreased colony and sphere formation of stem-like property in lung cancer cells. In addition, Notch3 expression was demonstrated to be upregulated in the patients with chemoresistance and related to poor prognosis of NSCLC patients. Our results also showed that CSC markers ALDH1A1 and CD44 were highly expressed in NSCLC patients with chemoresistance and these two markers were positively correlated with Notch3 expression in lung cancer specimens from TCGA database. Furthermore, the lung cancer cells with drug resistance were shown to be associated with activation of autophagy. All the data support a crucial role of Notch3 in the increase of stem-like property in NSCLC cells that might be associated with upregulation of ALDH1A1 and CD44 and activation of autophagy.


Assuntos
Aldeído Desidrogenase/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores de Hialuronatos/biossíntese , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Receptor Notch3/antagonistas & inibidores , Células A549 , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Receptor Notch3/metabolismo , Retinal Desidrogenase
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