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Eur J Clin Pharmacol ; 76(2): 139-147, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31748819


PURPOSE: The aim of this study was to explore the relationship between proton pump inhibitors use and the risk of dementia. METHODS: A comprehensive literature search was conducted in English and Chinese databases from origination to December 2018. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with a random-effects model. Subgroup analyses and sensitivity analyses were also conducted. Cochran's Q test and the I2 statistic were used to evaluate the heterogeneity. Publication bias was assessed by Begg's test and Egger's test. RESULTS: Six studies were included, which contained a total of 166,146 participants. The overall result demonstrated a significant increase in dementia risk with proton pump inhibitors use (HR = 1.29, 95% CI = 1.12-1.49). In subgroup analyses, a significant association was detected between proton pump inhibitors use and the risk of dementia in Europe (HR = 1.46, 95% CI = 1.23-1.73) and among participants aged ≥ 65 years (HR = 1.39, 95% CI = 1.17-1.65). For the factor follow-up time ≥ 5 years, the pooled HR was 1.28 (95% CI = 1.12-1.46), demonstrating a 1.28-fold increase in the risk of dementia among proton pump inhibitors users. In the case of regional impact, participants from Europe showed an overall pooled HR estimate of 1.46 (95% CI = 1.23-1.73). There was no evidence of publication bias. CONCLUSIONS: The overall result of this meta-analysis supports the hypothesis that proton pump inhibitors increase the risk of dementia. Furthermore, high-quality cohort studies are needed to confirm these findings.

J Clin Periodontol ; 47(2): 134-147, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31697412


OBJECTIVE: To evaluate the association between periodontitis and the incidence and mortality of gastrointestinal cancer. METHOD: A comprehensive literature search was conducted to identify all relevant studies published prior to April 2019 according to the established inclusion criteria. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with a random-effects model. RESULTS: We identified 10 studies with 26 estimates of the relationship between periodontitis and gastrointestinal cancer. The HR for the incidence of gastrointestinal cancer in periodontitis was 1.23 (95% CI: 1.10-1.37). Subgroup analyses showed that periodontitis was associated with an increased risk of gastrointestinal cancers in prospective cohort studies and high-quality studies, North American individuals, and individuals 18 years or older, as well as when the dental status was self-reported and when the study was adjusted for smoking. A meta-analysis of nine reports demonstrated that periodontitis was associated with increased mortality from gastrointestinal cancer (HR = 1.59, 95% CI: 1.16-2.16). Additionally, periodontitis was associated with mortality from pancreatic cancer (HR = 2.20, 95% CI: 1.44-3.37); thus, periodontitis may be a risk factor for pancreatic cancer. CONCLUSION: Our meta-analysis demonstrated that periodontitis may be a risk factor for gastrointestinal cancers. Additional prospective cohort studies are warranted to confirm these findings.

Blood Adv ; 2(19): 2478-2490, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30266823


Infant B-cell acute lymphoblastic leukemias (B-ALLs) that harbor MLL-AF4 rearrangements are associated with a poor prognosis. One important obstacle to progress for this patient population is the lack of immunocompetent models that faithfully recapitulate the short latency and aggressiveness of this disease. Recent whole-genome sequencing of MLL-AF4 B-ALL samples revealed a high frequency of activating RAS mutations; however, single-agent targeting of downstream effectors of the RAS pathway in these mutated MLL-r B-ALLs has demonstrated limited and nondurable antileukemic effects. Here, we demonstrate that the expression of activating mutant N-Ras G12D cooperates with Mll-Af4 to generate a highly aggressive serially transplantable B-ALL in mice. We used our novel mouse model to test the sensitivity of Mll-Af4/N-Ras G12D leukemia to small molecule inhibitors and found potent and synergistic preclinical efficacy of dual targeting of the Mek and Atr pathways in mouse- and patient-derived xenografts with both mutations in vivo, suggesting this combination as an attractive therapeutic opportunity that might be used to treat patients with these mutations. Our studies indicate that this mouse model of Mll-Af4/N-Ras B-ALL is a powerful tool to explore the molecular and genetic pathogenesis of this disease subtype, as well as a preclinical discovery platform for novel therapeutic strategies.

Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Genes ras , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Ativação Transcricional , Animais , Apoptose/genética , Ciclo Celular/genética , Modelos Animais de Doenças , Progressão da Doença , Expressão Gênica , Vetores Genéticos/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Inibidores de Proteínas Quinases/farmacologia , Retroviridae/genética , Transdução de Sinais
Oncotarget ; 7(25): 37740-37754, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27192115


WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription. However, the oncogenic effect of WDR5 in leukemia remains largely unknown. Here, we found WDR5 expression is increased in leukemia patients. High expression of WDR5 is associated with high risk leukemia; Patients with WDR5 and MLL1 high expression have poor complete remission rate. We further identified the global genomic binding of WDR5 in leukemic cells and found the genomic co-localization of WDR5 binding with H3K4me3 enrichment. Moreover, WDR5 knockdown by shRNA suppresses cell proliferation, induces apoptosis, inhibits the expression of WDR5 targets, and blocks the H3K4me3 enrichment on the promoter of its targets. We also observed the positive correlation of WDR5 expression with these targets in the cohort study of leukemia patients. Our data reveal that WDR5 may have oncogenic effect and WDR5-mediated H3K4 methylation plays an important role in leukemogenesis.

Regulação Leucêmica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Adulto , Idoso , Apoptose , Carcinogênese , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Regiões Promotoras Genéticas , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Indução de Remissão , Transcrição Genética , Adulto Jovem
Biochem Biophys Res Commun ; 460(3): 759-65, 2015 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-25817730


Adenosine, a metabolite of ATP, ubiquitously exists in a wide range of organs and tissues. We previously reported that adenosine was implicated in apoptosis in many cancer cells by extrinsic and/or intrinsic pathways. Here, we found that adenosine suppresses the cell growth by induction of apoptosis of human colonic cancer cells through a novel mechanism. Adenosine suppresses the cell growth of human SW620 and SW480 colon cells in an adenosine transporter and adenosine kinase dependent manner. Moreover, the cell growth suppression is induced by apoptosis through activation of caspase-3 and PARP, and accumulation of ROS in cells. Importantly, we found that adenosine increases the expression of TNFR1 and RIPK1 and the phosphorylation of p38. Knockdown of TNFR1 or RIPK1 impairs the activation of p38, blocks the cleavage of PARP, and provides partially, yet significantly protection from cell death, including reducing the ROS generation in the colon cancer cells. These results indicate that a TNFR1/RIPK1/P38 axis is present in adenosine-induced apoptosis of colonic cancer cells. This axis triggers apoptosis and plays crucial roles in relay of the death signaling. Our study also provides additional experimental evidence for adenosine as a potent therapeutic drug in cancer therapy.

Adenosina/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Neoplasias do Colo/enzimologia , Neoplasias do Colo/metabolismo , Humanos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo