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INTRODUCTION: Early gastric cancer with current Helicobacter pylori infection (HpC-EGC) is common, but it is still unclear whether H. pylori eradication therapy (Hp-ET) or endoscopic submucosal dissection (ESD) should be performed first. We evaluated Hp-ETs short-term effects on horizontal boundary delineations of HpC-EGC in ESD. METHODS: Prospectively enrolled HpC-EGC patients were randomly assigned to eradication or control groups. Operation scopes of HpC-EGC lesions were delineated with marking dots at 5 mm out of the endoscopic demarcation line by an independent endoscopist, unaware of eradication status, before formal circumferential incision. As representatives, precise delineation rate, the shortest distance of all marking dots to the pathological demarcation line in all slices of one intact resected specimen (Dmin), and negative marking dot specimen rate were examined. RESULTS: Twenty-three HpC-EGC patients (25 lesions) were allocated to eradication group and 26 patients (27 lesions) were allocated to the control group with similar eradication success rates and all were differentiated type. With improving background mucosa inflammation after Hp-ET and similar gastritis-like epithelium rates, 10 lesions (40.0%) in the eradication group were of precise delineation compared to control group with 2 lesions (7.4%) (relative risk = 5.40, 95% CI 1.31-22.28). Dmin of eradication and control groups were 4.17 ± 2.52 mm and 2.67 ± 2.30 mm (p = 0.029), accompanied by 4 (14.8%) and none (0.0%) specimens that exhibited positive marking dots (p = 0.11), respectively. CONCLUSION: For HpC-EGC patients, administrating eradication medication before ESD is beneficial for the precise delineation of lesions and reducing the risk of positive horizontal resection margins.
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Resección Endoscópica de la Mucosa , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Mucosa Gástrica/cirugía , Mucosa Gástrica/patologíaRESUMEN
Our previous works have indicated that extracellular ATP is an important prometastasis factor. However, the molecular mechanism involved needs to be further studied. We demonstrated that extracellular ATP treatment could upregulate the expression of connective tissue growth factor (CTGF) in both triple-negative breast cancer (TNBC) cells and endothelial cells (ECs). Extracellular ATP stimulated the migration of TNBC cells and ECs, and angiogenesis of ECs via the P2Y2--YAP-CTGF axis. Furthermore, we demonstrated that adenosine triphosphate (ATP) stimulated TNBC cell adhesion to ECs and transmigration through the EC layer via CTGF by upregulation of integrin ß1 on TNBC cells and VCAM-1 on ECs. Both apyrase (ATP-diphosphohydrolase) and CTGF shRNA treatments could inhibit the metastasis of inoculated tumors to lung and liver in a mouse model, and these treated tumors had fewer blood vessels. Collectively, our data indicated that extracellular ATP promotes tumor angiogenesis and the interactions between TNBC cells and ECs through upregulation of CTGF, thereby stimulating TNBC metastasis. The pleiotropic effects of ATP in angiogenesis and cell adhesion suggest that extracellular ATP or CTGF could be an effective target for TNBC therapy.
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Adenosina Trifosfato , Factor de Crecimiento del Tejido Conjuntivo , Neoplasias de la Mama Triple Negativas , Adenosina Trifosfato/metabolismo , Animales , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Células Endoteliales/metabolismo , Humanos , Ratones , Neovascularización Patológica/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Regulación hacia ArribaRESUMEN
PURPOSE: This study aimed to investigate whether genetic polymorphisms in TGFB1 contribute to breast cancer (BC) susceptibility, and explore the mechanism of action. METHODS: A total of 7 tagging SNPs (tSNPs) were genotyped in 1161 BC cases and 1337 age-matched controls among Chinese Han population. Bioinformatics analysis was used to predict functional SNP closely linked to tSNPs. Luciferase gene reporter assay was performed to determine the effect of genetic variants on promoter activity. DNA pull-down assay and mass spectrometry were used to identify the differentially binding proteins to genetic variants. RESULTS: Genotyping analysis showed that rs1800469 (C>T) in the 5' regulatory region of TGFB1 was associated with reduced BC risk. Bioinformatics analysis predicted that rs11466313 (-2389_-2391 Del/AGG) in the 5' regulatory region of TGFB1, was closely linked to tSNP rs1800469 and could be functional. The genotyping of rs11466313 by PCR-SSCP showed that rs11466313 also conferred decreased BC risk. Luciferase assays demonstrated that rs11466313 minor allele reduced over ninefold of promoter activity compared with its major allele (p < 0.001). DNA pull-down assay and mass spectrometry revealed that rs11466313 minor allele lost the binding ability with FAM98B and HSP90B. Knocking down FAM98B but not HSP90B, the enhanced promoter activity driven by TGFB1 rs11466313 major allele was attenuated. CONCLUSIONS: This study elucidates the impact of functional polymorphism rs11466313 in the regulatory region of TGFB1 on breast cancer susceptibility and gene expression, and could be helpful for future research to determine the value of this TGFB1 variant in the clinical setting.
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Neoplasias de la Mama , Alelos , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Extracellular ATP has been shown to play an important role in invasion and the epithelial-mesenchymal transition (EMT) process in breast cancer; however, the mechanism is unclear. Here, by using a cDNA microarray, we demonstrated that extracellular ATP could stimulate hypoxia-inducible factor (HIF) signaling and upregulate hypoxia-inducible factor 1/2α (HIF-1/2α) expression. After knocking down HIF-1/2α using siRNA, we found that ATP-driven invasion and EMT were significantly attenuated via HIF2A-siRNA in breast cancer cells. By using ChIP assays, we revealed that the biological function of extracellular ATP in invasion and EMT process depended on HIF-2α direct targets, among which lysyl oxidase-like 2 (LOXL2) and matrix metalloproteinase-9 (MMP-9) mediated ATP-driven invasion, and E-cadherin and Snail mediated ATP-driven EMT, respectively. In addition, using silver staining and mass spectrometry, we found that phosphoglycerate kinase 1 (PGK1) could interact with HIF-2α and mediate ATP-driven HIF-2α upregulation. Furthermore, we demonstrated that expressions of HIF-2α and its target proteins could be regulated via ATP by AKT-PGK1 pathway. Using a Balb/c mice model, we illustrated the function of HIF-2α in promoting tumor growth and metastasis in vivo. Moreover, by exploring online databases, we found that molecules involved in ATP-HIF-2α signaling were highly expressed in human breast carcinoma tissues and were associated with poor prognosis. Altogether, these findings suggest that extracellular ATP could promote breast carcinoma invasion and EMT via HIF-2α signaling, which may be a potential target for future anti-metastasis therapy.
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Adenosina Trifosfato/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Transición Epitelial-Mesenquimal/fisiología , Hipoxia/patología , Invasividad Neoplásica/patología , Aminoácido Oxidorreductasas/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Células MCF-7 , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
OBJECTIVE: Yiqifumai injection is a compound Chinese medicine used to treat microcirculatory disturbance-related diseases clinically. Our previous study proved that Yiqifumai injection pretreatment inhibited lipopolysaccharide-induced venular albumin leakage in rat mesentery. This study aimed to investigate whether Yiqifumai injection attenuated cerebral microvascular hyperpermeability and corresponding contribution of its main ingredients. METHODS: Rats were challenged by lipopolysaccharide infusion (5 mg/kg/h) for 90 minutes. Yiqifumai injection (160 mg/kg/h), Rb1 (5 mg/kg/h), Sch (2.5 mg/kg/h), and Rb1 (5 mg/kg/h) + Sch (2.5 mg/kg/h) were infused 30 minutes before (pretreatment) or after (post-treatment) lipopolysaccharide administration. RESULTS: Both pretreatment and post-treatment with Yiqifumai injection attenuated cerebral venular albumin leakage during lipopolysaccharide infusion and cerebrovascular hyperpermeability at 72 hours after lipopolysaccharide infusion. Yiqifumai injection restrained the decreased junction protein expression, adenosine triphosphate content, and mitochondria complex I, II, IV, and V activities. Moreover, Yiqifumai injection inhibited toll-like receptor-4 expression, Src phosphorylation, and caveolin-1 expression. Its main ingredients Rb1 and Sch alone worked differently, with Rb1 being more effective for enhancing energy metabolism, while Sch attenuating toll-like receptor-4 expression and Src activation. CONCLUSION: Yiqifumai injection exerts a protective and ameliorated effect on cerebral microvascular hyperpermeability, which is more effective than any of its ingredients, possibly due to the interaction of its main ingredients through a multi-pathway mode.
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Permeabilidad Capilar/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Lipopolisacáridos/toxicidad , Microcirculación/efectos de los fármacos , Animales , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND: Conventional endoscopy and endoscopic ultrasonography (EUS) are used to estimate the invasion depth of early-stage gastric cancers (EGCs), but estimates made by either technique are often inaccurate. We developed a model to determine the invasion depth of EGCs using conventional endoscopy and EUS findings, with pathology results as the reference. METHODS: We performed a retrospective study of 195 patients (205 lesions) diagnosed with gastric cancers who underwent endoscopy and EUS followed by resection. Based on pathology analyses, lesions (n = 205) were assigned to categories of: mucosa invasion or minute invasion into the submucosal layer less than 500 µm from the muscularis mucosae (M-SM1) or penetration of 500 µm or more (≥SM2). The lesions were randomly assigned to derivation (138 lesions) and validation sets (67 lesions). A depth predictive model was proposed in the derivation set using multivariate logistic regression analyses. The discriminative power of this model was assessed in both sets. RESULTS: Remarkable redness (OR 5.42; 95% CI 1.32-22.29), abrupt cutting of converging folds (OR 8.58; 95% CI 1.65-44.72), lesions location in the upper third of the stomach (OR 10.26; 95% CI 2.19-48.09), and deep invasion based on EUS findings (OR 16.53; 95% CI 4.48-61.15) significantly associated with ≥SM2 invasion. A model that incorporated these 4 variables discriminated between M-SM1 and ≥SM2 lesions with the area under the ROC curve of 0.865 in the derivation set and 0.797 in the validation set. In the derivation set, a cut-off score of 8 identified lesions as ≥SM2 with 54% sensitivity and 97% specificity. The model correctly predicted the invasion depth 89.86% of lesions; it overestimated the depth of 2.17% of lesions. CONCLUSIONS: We developed a model to identify EGCs with invasion depth ≥SM2 based on endoscopy and EUS findings. This model might reduce overestimation of gastric tumor depth and prevent unnecessary gastrectomy.
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Endosonografía , Mucosa Gástrica/patología , Gastroscopía , Modelos Estadísticos , Invasividad Neoplásica , Neoplasias Gástricas/patología , Detección Precoz del Cáncer , Femenino , Mucosa Gástrica/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/cirugíaRESUMEN
Extracellular adenosine 5'-triphosphate (ATP), secreted by living cancer cells or released by necrotic tumor cells, plays an important role in tumor invasion and metastasis. Our previous study demonstrated that ATP treatment in vitro could promote invasion in human prostate cancer cells via P2Y2, a preferred receptor for ATP, by enhancing EMT process. However, the pro-invasion mechanisms of ATP and P2Y2 are still poorly studied in breast cancer. In this study, we found that P2Y2 was highly expressed in breast cancer cells and associated with human breast cancer metastasis. ATP could promote the in vitro invasion of breast cancer cells and enhance the expression of ß-catenin as well as its downstream target genes CD44, c-Myc and cyclin D1, while P2Y2 knockdown attenuated above ATP-driven events in vitro and in vivo. Furthermore, iCRT14, a ß-catenin/TCF complex inhibitor, could also suppress ATP-driven migration and invasion in vitro. These results suggest that ATP promoted breast cancer cell invasion via P2Y2-ß-catenin axis. Thus blockade of the ATP-P2Y2-ß-catenin axis could suppress the invasive and metastatic potential of breast cancer cells and may serve as potential targets for therapeutic interventions of breast cancer.
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Adenosina Trifosfato/metabolismo , Neoplasias de la Mama/patología , Invasividad Neoplásica/patología , Receptores Purinérgicos P2Y2/metabolismo , Transducción de Señal/fisiología , beta Catenina/metabolismo , Animales , Western Blotting , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/fisiología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator that catalyzes the trimethylation of H3K27 and is modulated by post-translational modifications (PTMs). However, the precise regulation of EZH2 PTMs remains elusive. We, herein, report that EZH2 is acetylated by acetyltransferase P300/CBP-associated factor (PCAF) and is deacetylated by deacetylase SIRT1. We identified that PCAF interacts with and acetylates EZH2 mainly at lysine 348 (K348). Mechanistically, K348 acetylation decreases EZH2 phosphorylation at T345 and T487 and increases EZH2 stability without disrupting the formation of polycomb repressive complex 2 (PRC2). Functionally, EZH2 K348 acetylation enhances its capacity in suppression of the target genes and promotes lung cancer cell migration and invasion. Further, elevated EZH2 K348 acetylation in lung adenocarcinoma patients predicts a poor prognosis. Our findings define a new mechanism underlying EZH2 modulation by linking EZH2 acetylation to its phosphorylation that stabilizes EZH2 and promotes lung adenocarcinoma progression.
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Adenocarcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Acetilación , Adenocarcinoma/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Proteína Potenciadora del Homólogo Zeste 2 , Silenciador del Gen , Células HEK293 , Humanos , Neoplasias Pulmonares/patología , Espectrometría de Masas , Metástasis de la Neoplasia , Complejo Represivo Polycomb 2/genética , Estabilidad Proteica , Sirtuina 1/metabolismoRESUMEN
OBJECTIVE: To investigate the clinical characteristics and outcome of patients with undiagnosed fever of unknown origin (FUO). METHODS: To retrospectively review the clinic data of patients discharged with FUO from the Department of General Internal Medicine, Peking Union Medical College Hospital during 2004 to 2008. Medical records and phone call follow-up data were collected until 2014. RESULTS: Among 758 in-patients diagnosed with FUO, 70 patients still discharged with FUO were enrolled in this study, including 23 males and 47 females. There were 14 missing patients. Finally, definite diagnoses were made in 20 patients by clinical reassessments, empirical therapy or repeated biopsies, in whom 3 patients dying from underlying diseases. A total of 36 patients did not get final diagnoses, while fever was relieved in 23 patients, including 10 treated with corticosteroids or non-steroid anti-inflammatory drugs (NSAIDs) from 1 month to 12 months due to suspected connective tissue diseases. Another 3 patients still had episodic fever. Seven patients died shortly after discharge. There were 3 dying in the long-term follow-up. The overall FUO-related mortality was 18.6%. Mortality was correlated with the number of dysfunctional organs, especially cytopenia, coagulation dysfunction, bleeding events, respiratory damage and acute renal failure with OR 2.1, 9.9, 3.3 and 6.6 (P < 0.05) respectively. CONCLUSIONS: Close follow-up, intermittent clinical reassessments, repeated biopsies will contribute to the diagnosis of patients discharged with FUO. Empirical therapy with corticosteroids, NSAIDs or anti-tubercular drugs in selected patients may be safe and effective. Mortality rates increased with impaired organs, especially the hematological, respiratory and renal systems.
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Fiebre de Origen Desconocido/epidemiología , Lesión Renal Aguda , Beijing , Coagulación Sanguínea , Enfermedades del Tejido Conjuntivo , Femenino , Estudios de Seguimiento , Glucocorticoides , Hospitales , Humanos , Masculino , Alta del Paciente , Estudios RetrospectivosRESUMEN
Kindlin-2 is an adaptor protein that contributes to renal tubulointerstitial fibrosis (TIF). Epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells was regarded as one of the key events in TIF. To determine whether kindlin-2 is involved in the EMT process, we investigated its regulation of EMT in human kidney tubular epithelial cells (TECs) and explored the underlying mechanism. In this study, we found that overexpression of kindlin-2 suppressed epithelial marker E-cadherin and increased the expression of fibronectin and the myofibroblast marker α-smooth muscle actin (SMA). Kindlin-2 significantly activated ERK1/2 and Akt, and inhibition of ERK1/2 or Akt reversed kindlin-2-induced EMT in human kidney TECs. Mechanistically, kindlin-2 interacted with Ras and son of sevenless (Sos)-1. Furthermore, overexpression of kindlin-2 increased Ras activation through recruiting Sos-1. Treatment with a Ras inhibitor markedly repressed kindlin-2-induced ERK1/2 and Akt activation, leading to restraint of EMT. We further demonstrated that knockdown of kindlin-2 inhibited EGF-induced Ras-Sos-1 interaction, resulting in reduction of Ras activation and suppression of EMT stimulated by EGF. Importantly, we found that depletion of kindlin-2 significantly inhibited activation of ERK1/2 and Akt signaling in mice with unilateral ureteral obstruction. We conclude that kindlin-2, through activating Ras and the downstream ERK1/2 and Akt signaling pathways, plays an important role in regulating renal tubular EMT and could be a potential therapeutic target for the treatment of fibrotic kidney diseases.
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Proteínas del Citoesqueleto/fisiología , Genes ras/fisiología , Túbulos Renales/fisiología , Proteínas Musculares/fisiología , Transducción de Señal/fisiología , Animales , Western Blotting , Células Cultivadas , Proteínas del Citoesqueleto/genética , Células Epiteliales/fisiología , Transición Epitelial-Mesenquimal/fisiología , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Inmunoprecipitación , Túbulos Renales/citología , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Proteínas Musculares/genética , Nefritis Intersticial/fisiopatología , Proteína Oncogénica v-akt/fisiología , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína SOS1/genética , Transfección , Obstrucción Ureteral/fisiopatologíaRESUMEN
Kindlin-2 has been known to promote most cancer progression through regulation of multiple signaling pathways. However, a novel tumor suppressive role of Kindlin-2 was identified in serous epithelial ovarian cancer progression, which sharply contrasts to the tumor promoting roles for Kindlin-2 in most other cancers. While we demonstrated that Kindlin-2 was highly expressed in control tissues, a drastic low expression of Kindlin-2 was found in the tumor tissues of serous epithelial ovarian cancer, especially in the high-grade serous epithelial ovarian cancer. Importantly, Kindlin-2 inhibited serous epithelial ovarian cancer cell peritoneal dissemination in a mouse model. For clinical relevance, low Kindlin-2 expression correlated with higher tumor grade and older patients. Intriguingly, decreased Kindlin-2 expression predicts poor overall and progression-free survivals in serous epithelial ovarian cancer patients. Mechanistically, Kindlin-2 induced a mesenchymal to epithelial transition in serous epithelial ovarian cancer cells, at least in part, by up-regulation of estrogen receptor α which was recruited to the promoter of E-cadherin and thereby enhanced the transcription of E-cadherin. Collectively, we concluded that inadequate Kindlin-2 is an independent risk factor for serous epithelial ovarian cancer patients.
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Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Animales , Cadherinas/genética , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Movimiento Celular , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Cistadenoma Seroso/genética , Cistadenoma Seroso/metabolismo , Cistadenoma Seroso/patología , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Expresión Génica , Xenoinjertos , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/secundario , Pronóstico , Regiones Promotoras Genéticas , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Kindlin 2, as a focal adhesion protein, controls integrin activation. However, the association of Kindlin 2 with cancer-related signalling pathways is unknown. Here we identified a new direct interaction between Kindlin 2 and the active ß-catenin. Importantly, Kindlin 2 forms a tripartite complex with ß-catenin and TCF4. Mechanistically, Kindlin 2 selectively strengthens the occupancy of ß-catenin on the Wnt target gene Axin2 and enhances Axin2 gene expression. Functionally, the ß-catenin-Axin2-Snail cascade is required for Kindlin 2-induced tumour cell invasion. Our data indicate that Kindlin 2 is a new regulator of Wnt signalling, providing a mechanistic insight into the role of Kindlin 2 in cancer progression.
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Proteínas de la Membrana/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Transcripción Genética , Vía de Señalización Wnt/genética , beta Catenina/metabolismo , Proteína Axina/metabolismo , Western Blotting , Línea Celular , Transición Epitelial-Mesenquimal/genética , Humanos , Invasividad Neoplásica , Unión Proteica/genética , Estabilidad ProteicaRESUMEN
BACKGROUND: The high-risk strategy has been proven effective in preventing cardiovascular disease; however, the population benefits from these interventions remain unknown. This study aims to assess, at the population level, the effects of an evidence-based high cardiovascular risk management program delivered by village doctors in rural China. METHODS: The study will employ a cluster-randomized controlled trial in which a total of 120 villages in five northern provinces of China, will be assigned to either intervention (60 villages) or control (60 villages). Village doctors in intervention villages will be trained to implement a simple evidence-based management program designed to identify, treat and follow-up as many as possible individuals at high-risk of cardiovascular disease in the village. The intervention will also include performance feedback as well as a performance-based incentive payment scheme and will last for 2 years. We will draw two different (independent) random samples, before and after the intervention, 20 men aged≥50 years and 20 women aged≥60 years from each village in each sample and a total of 9,600 participants from 2 samples to measure the study outcomes at the population level. The primary outcome will be the pre-post difference in mean systolic blood pressure, analyzed with a generalized estimating equations extension of linear regression model to account for cluster effect. Secondary outcomes will include monthly clinic visits, provision of lifestyle advice, use of antihypertensive medications and use of aspirin. Process and economic evaluations will also be conducted. DISCUSSION: This trial will be the first implementation trial in the world to evaluate the population impact of the high-risk strategy in prevention and control of cardiovascular disease. The results are expected to provide important information (effectiveness, cost-effectiveness, feasibility and acceptability) to guide policy making for rural China as well as other resource-limited countries. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT01259700). Date of initial registration is December 13, 2010.
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Enfermedades Cardiovasculares/terapia , Agentes Comunitarios de Salud/educación , Médicos Generales/educación , Presión Sanguínea , Cardiología/educación , Enfermedades Cardiovasculares/diagnóstico , China , Análisis Costo-Beneficio , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Población RuralRESUMEN
Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that there appeared to be two instances of overlapping data panels comparing between the cell migration and invasion assay data shown in Figs. 4 and 6 on p. 143 and 145, respectively, such that data which were intended to represent the results from differently performed experiments had apparently been derived from the same original sources. In addition, the authors themselves realized that incorrect western blotting data for Snail protein in Fig. 10A on p. 147 had been included in the figure. The authors were able to reexamine their original data files, and realized that the affected data panels in these figures had inadvertently been incorporated into them incorrectly. The revised versions of Figs. 4, 6, and 10, featuring the correct data for the 'NC / Control' panels in Fig. 4B and C and the 'siRNA2 / ATP 12 h' panels in Fig. 4A and B, a replacement data panel for the 'siRNA1 / Control' experiment in Fig. 6, and the correct western blotting data for Snail protein in Fig. 10A (together with a revised histogram for the MCF7 cell line relating to Fig. 10A) are shown on the next three pages. The authors wish to emphasize that the errors made in compiling these figures did not affect the overall conclusions reported in the paper, and they are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this corrigendum. All the authors agree to the publication of this corrigendum, and also apologize to the readership for any inconvenience caused. [Oncology Reports 39: 138150, 2018; DOI: 10.3892/or.2017.6081].
RESUMEN
Kindlin 2, as a focal adhesion protein, controls integrin activation and regulates Wnt signaling in an integrin-binding independent manner. However, the association of Kindlin 2 with cancer-related microRNAs is unknown. Here, we report that Kindlin 2 markedly downregulates the expression of miR-200 family by inducing CpG island hypermethylation. Mechanistically, Kindlin 2 forms a complex with DNMT3A in the cell nucleus and the two proteins co-occupy the promoter of miRNA-200b. Functionally, repression of miR-200b is required for Kindlin 2-induced breast cancer cell invasion and tumor formation. Our data indicate that Kindlin 2 plays a novel role in epigenetic repression of miR-200 family, a mechanism that promotes breast cancer invasion.
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Neoplasias de la Mama/patología , Silenciador del Gen , Proteínas de la Membrana/fisiología , MicroARNs/genética , Proteínas de Neoplasias/fisiología , Animales , Línea Celular Tumoral , Islas de CpG , ADN (Citosina-5-)-Metiltransferasas/fisiología , Metilación de ADN , ADN Metiltransferasa 3A , Femenino , Humanos , Ratones , Ratones SCID , Invasividad NeoplásicaRESUMEN
Centrosome aberrations have been suggested to cause chromosomal instability and aneuploidy, and eventually promote cancer development. The Centrobin and Nek2 proteins interact with each other and both are involved in centrosome duplication and chromosome segregation. This study aimed to investigate whether genetic polymorphisms in these two genes may affect breast cancer susceptibility in Chinese Han population using a haplotype-based analysis. Five single nucleotide polymorphisms (SNPs) in centrobin and four SNPs in Nek2 were genotyped in 1,215 cases of infiltrating ductal breast cancer and 1,215 age-matched cancer-free controls from Chinese Han population. The results showed that CATCG haplotype of centrobin was strongly associated with decreased breast cancer risk (adjusted OR = 0.14, 95 % CI = 0.09-0.22), which was mainly driven by the C allele of SNP rs11650083 (A>C, located in exon 12, resulting in Pro578Gln). None of the individual SNPs in Nek2 was associated with breast cancer risk. However, haplotype GTAT of Nek2 was associated with increased risk of breast cancer (adjusted OR = 1.56, 95 % CI = 1.18-2.06) and its risk was significantly elevated among women with both family history of cancer and a longer menarche-first full-term pregnancy (FFTP) interval (>11 years) (adjusted OR = 5.31, 95 % CI = 1.97-14.32). Furthermore, women harboring both at-risk haplotype GTAT of Nek2 and protective haplotype CATCG of centrobin were linked with decreased breast cancer risk, suggesting that the association between genetic variants of Nek2 and increased breast cancer risk was modified by genetic variants of centrobin. Our results indicate that genetic polymorphisms of centrobin and Nek2 are related to breast cancer susceptibility in Chinese Han women.
Asunto(s)
Neoplasias de la Mama , Proteínas de Ciclo Celular/genética , Estudios de Asociación Genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Alelos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , China , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Quinasas Relacionadas con NIMA , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Centrosome defects can result in aneuploidy and genomic instability, and have important implications for breast cancer development. The Aurora-A and BRCA1 proteins interact and both are strongly involved in centrosome regulation. Genetic variants in these two genes may have an effect on breast cancer development. Here, we report a comprehensive single nucleotide polymorphism (SNP) and haplotype-tagging association study on these two genes in 1334 breast cancer cases and 1568 unaffected controls among the Chinese Han population. Apart from a missense SNP, rs2273535 (Phe31Ile), and a probable risk SNP, rs2064863, six htSNPs were analysed in three high-LD blocks of AURKA spanning from 10 kb upstream to 2 kb downstream of AURKA. For BRCA1, six htSNPs were analysed in a large high-LD region covering 98 kb (10 kb was extended to each end of BRCA1). The results showed that four SNPs in AURKA (data in recessive model, rs2273535: OR = 2.19, 95% CI = 1.03-4.66, p = 0.0422; rs2298016: OR = 0.38, 95% CI = 0.18-0.82, p = 0.0141; rs6024836: OR = 1.54, 95% CI = 1.18-2.00, p = 0.0014; rs10485805: OR = 0.68, 95% CI = 0.47-0.98, p = 0.0380) and one SNP in BRCA1 (rs3737559, dominant model OR = 1.35, 95% CI = 1.11-1.64, p = 0.0030) were associated with breast cancer susceptibility. After correction for multiple comparisons (FDR = 0.05), only rs6024836 and rs3737559 remained significant. Two haplotypes (CC of block 2, OR = 20.74, 95% CI = 4.35-98.88, p = 0.0001; GG of block 3, OR = 1.32, 95% CI = 1.12-1.56, p = 0.0010) and one diplotype (AG-GG of block 3, OR = 1.63, 95% CI = 1.18-2.26, p = 0.0031) within AURKA showed strong associations with breast cancer risk. One haplotype of BRCA1 (CTGTTG, OR = 1.30, 95% CI = 1.06-1.59, p = 0.0118) was also associated with breast cancer risk. However, women harbouring both at-risk genotypes of Aurora-A and BRCA1 were at a slightly increased risk compared with those harbouring either at-risk variant alone. Common genetic variants in the AURKA and BRCA1 genes may contribute to breast cancer development.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Pueblo Asiatico , Aurora Quinasa A , Aurora Quinasas , Neoplasias de la Mama/etnología , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/etnología , Carcinoma Ductal de Mama/patología , Estudios de Casos y Controles , China/etnología , Femenino , HumanosRESUMEN
OBJECTIVE: To evaluate the application of traditional cytomorphology, telomerase activity analysis and immunocytochemistry in cytopathologic diagnosis of pleural effusion and bronchoalveolar lavage samples. METHODS: A total of 123 agar-paraffin double-embedded pleural effusion and bronchoalveolar lavage fluid samples were enrolled into study. The cytomorphologic features were reviewed and correlated with immunocytochemical findings and telomerase activity. RESULTS: Telomerase activity was detected in 53 specimens using the real-time telomeric repeat amplification protocol. Amongst the cases studied, 39 samples (31.7%) contained overtly malignant cells while 20 cases (16.0%) were equivocal by conventional cytology. After verification by immunocytochemistry and clinical follow-up data, the diagnostic accuracy of telomerase activity and cytology was 87.0% and 82.1%, respectively. The sensitivity (97.6%) and specificity (100.0%) of cytology examination, when combined with telomerase activity analysis, were greater than those of cytology examination or telomerase activity analysis alone. CONCLUSIONS: Telomerase activity analysis can be used as an adjunctive investigative tool in cytology assessment of pleural effusion and bronchoalveolar lavage samples. The diagnostic accuracy can be further improved with the application of immunocytochemistry on agar-paraffin double-embedded cell block tissues.
Asunto(s)
Neoplasias de la Mama/diagnóstico , Líquido del Lavado Bronquioalveolar/química , Neoplasias Pulmonares/diagnóstico , Derrame Pleural/enzimología , Telomerasa/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Derrame Pleural/diagnóstico , Derrame Pleural/patología , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/enzimología , Derrame Pleural Maligno/patología , Sensibilidad y EspecificidadRESUMEN
We have previously demonstrated that extracellular adenosine 5'-triphosphate (ATP) promotes breast cancer cell chemoresistance. However, the underlying mechanism remains unclear. Using a cDNA microarray, we demonstrated that extracellular ATP can stimulate hypoxia-inducible factor (HIF) signaling. In this study, we report that hypoxia-inducible factor 1α (HIF-1α) was upregulated after ATP treatment and mediated the ATP-driven chemoresistance process. We aimed to investigate the mechanisms and identify potential clinically relevant targets that are involved. Using mass spectrometry, we found that aldolase A (ALDOA) interacts with HIF-1α and increases HIF-1α expression. We then demonstrated that STAT3-ALDOA mediates ATP-HIF-1α signaling and upregulates the HIF-1 target genes adrenomedullin (ADM) and phosphoinositide-dependent kinase-1 (PDK1). Moreover, we show that PI3K/AKT acts upstream of HIF-1α in ATP signaling and contributes to chemoresistance in breast cancer cells. In addition, HIF-1α-knockdown or treatment with direct HIF inhibitors combined with the ATP hydrolase apyrase in MDA-MB-231 cells induced enhanced drug sensitivity in nude BALB/c mice. We then used in vitro spheroid formation assays to demonstrate the significance of ATP-HIF-1α in mediating chemoresistance. Furthermore, considering that indirect HIF inhibitors are effective in clinical cancer therapy, we treated tumor-bearing BALB/c mice with STAT3 and PI3K/AKT inhibitors and found that the dual-targeting strategy sensitized breast cancer to cisplatin. Finally, using breast cancer tissue microarrays, we found that ATP-HIF-1α signaling is associated with cancer progression, poor prognosis, and resistance to chemotherapy. Taken together, we suggest that HIF-1α signaling is vital in ATP-driven chemoresistance and may serve as a potential target for breast cancer therapies.
Asunto(s)
Neoplasias de la Mama , Adenosina Trifosfato/metabolismo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Humanos , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: Endoscopic biopsy can underestimate gastric malignancies as low-grade intraepithelial neoplasia (LGIN). Definitively diagnosed LGIN would progress. This study aimed to evaluate predictive factors to identify malignancies misdiagnosed as LGIN by biopsy and LGIN at high risk of progression. METHODS: The clinical records of patients diagnosed with gastric LGIN by endoscopic biopsy who underwent at least two endoscopies during the first year of follow-up between 2007 and 2017 were retrospectively collected. Three endoscopists reviewed photographs of the initial endoscopy, described lesion characteristics, and made endoscopic diagnoses. Logistic regression was used to analyze predictors to identify malignancies underestimated as LGIN. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of these predictors. Patient clinical outcomes of follow-up >1 year were collected. Kaplan-Meier estimates with log-rank tests and Cox proportional hazards regression were used to analyze predictors of progression. RESULTS: Overall, 48 of 182 (26.4%) patients were proven to have malignancies. A single lesion, a large lesion size, and marked intestinal metaplasia (IM) were independent predictors of initially misdiagnosed malignancies. The area under the curve of these predictors was 0.871, with a sensitivity of 68.7% and specificity of 92.5%. Twelve of 98 patients (12.2%) progressed during the 33-month median follow-up period. A whitish appearance, irregular margins, marked IM, and histological diagnosis of LGIN more than twice within the first year were predictors for progression. CONCLUSIONS: Lesions diagnosed as LGIN by biopsy with marked IM and other predictors above should be prudently treated for high potential to be malignancies or progress. Endoscopic follow-up with repeated biopsies within the first year is recommended.