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1.
J Mol Biol ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31821812

RESUMO

Prion diseases, such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, are fatal neurodegenerative diseases that affect many mammals including humans and are caused by the misfolding of prion protein (PrP). A naturally occurring protective polymorphism G127V in human PrP has recently been found to significantly attenuate prion diseases, but the mechanism has remained elusive. We herein report that the hydrophobic chain introduced in G127V significantly inhibits amyloid fibril formation by human PrP, highlighting the protective effect of the G127V polymorphism. We further introduce an amino acid with a different hydrophobic chain (Ile) at the same position and find that G127I has similar protective effects as G127V. Moreover, we show that these two neutralizing mutations, G127V and G127I, significantly decrease the human PrP cytotoxicity resulting from PrP fibril formation, mitochondrial damage, and elevated reactive oxygen species production enhanced by a strong prion-prone peptide PrP 106-126. These findings elucidate the molecular basis for a natural protective polymorphism in PrP and will enable the development of novel therapeutic strategies against prion diseases.

2.
Int J Biol Sci ; 15(9): 1977-1992, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523198

RESUMO

Background: Currently, there are no molecular biomarkers for the early detection of non-small-cell lung cancer (NSCLC). This study focused on identifying RNAs found on tumor-educated blood platelets (TEPs) for detecting stage I NSCLC. Methods: Platelet RNAs, isolated from the blood of 9 patients with NSCLC (stages I and II) and 8 healthy controls, were analyzed using RNA-seq. ITGA2B was selected as a candidate marker. Two different Polymerase Chain Reactions (PCR) were used to measure ITGA2B in platelet samples from healthy controls (n = 150), patients with NSCLC (n = 243), and patients with benign pulmonary nodules (n = 141) in two cohorts. Results: Platelet ITGA2B levels were significantly higher (p < 0.001) in patients with NSCLC than in all controls. The diagnostic accuracy of ITGA2B was area under the curve (AUC) of 0.922 [95% confidence interval (CI), 0.892-0.952], sensitivity of 92.8%, and specificity of 78.6% in the test cohort and 0.888, 91.2%, and 56.5% in the validation cohort for NSCLC by quantitative real time PCR (q-PCR). Furthermore, ITGA2B maintained diagnostic accuracy for patients with NSCLC using Droplet Digital PCR (ddPCR) and the other type of internal control, Ribosomal Protein L32 (RPL32) [ddPCR: 0.967 (0.929-1.000) and RPL32: 0.847(0.773-0.920)]. A nomogram incorporating ITGA2B, carcinoembryonic antigen (CEA) and stage could predict the overall survival (C-index = 0.756). Conclusions: TEP ITGA2B is a promising marker to improve identification of patients with stage I NSCLC and differentiate malignant from benign lung nodules.

3.
Int J Cancer ; 145(10): 2873-2883, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31044420

RESUMO

We analyzed the number of circulating tumor cells (CTCs) and Epstein-Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The levels of CTCs and EBV DNA were measured at baseline and after first-line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non-mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first-line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first-line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first-line chemotherapy was associated with significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first-line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first-line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.

4.
World J Gastroenterol ; 25(17): 2099-2109, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31114136

RESUMO

BACKGROUND: The methylated septin 9 (mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test. However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer (CRC) in Chinese patients is still unknown. AIM: To improve the understanding of diagnostic and prognostic factors, serum mSEPT9 was detected in Chinese CRC patients. METHODS: A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal, was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control (UICC) stages, distant metastasis (M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas (TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier univariate analysis. RESULTS: In Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages (I-IV), primary tumor categories (T1-T4), regional node categories (N0-N2), and distant metastasis categories (M0-M1). The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies. CONCLUSION: MSEPT9 analysis may add valuable information to current tumor staging. Serum mSEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Septinas/metabolismo , Adenoma/sangue , Adenoma/diagnóstico , Adenoma/cirurgia , Idoso , China , Neoplasias Colorretais/sangue , Neoplasias Colorretais/cirurgia , Biologia Computacional , Metilação de DNA , Detecção Precoce de Câncer , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos
5.
Cancer Res Treat ; 51(1): 378-390, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29807404

RESUMO

PURPOSE: The purpose of this study was to identify novel plasma biomarkers for distinguishing nasopharyngeal carcinoma (NPC) patients from healthy individuals who have positive Epstein-Barr virus (EBV) viral capsid antigen (VCA-IgA). Materials and Methods: One hundred seventy-four plasma cytokines were analyzed by a Cytokine Array in eight healthy individuals with positive EBV VCA-IgA and eight patients with NPC. Real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry were employed to detect the expression levels of macrophage migration inhibitory factor (MIF) and CC chemokine ligand 3 (CCL3) in NPC cell lines and tumor tissues. Plasma MIF and CCL3 were measured by ELISA in 138 NPC patients, 127 EBV VCA-IgA negative (VN) and 100 EBV VCA-IgA positive healthy donors (VP). Plasma EBV VCA-IgA was determined by immunoenzymatic techniques. RESULTS: Thirty-four of the 174 cytokines varied significantly between the VP and NPC group. Plasma MIF and CCL3 were significantly elevated in NPC patients compared with VN and VP. Combination of MIF and CCL3 could be used for the differential diagnosis of NPC from VN cohort (area under the curve [AUC], 0.913; sensitivity, 90.00%; specificity, 80.30%), and combination of MIF, CCL3, and VCA-IgA could be used for the differential diagnosis of NPC from VP cohort (AUC, 0.920; sensitivity, 90.00%; specificity, 84.00%), from (VN+VP) cohort (AUC, 0.961; sensitivity, 90.00%; specificity, 92.00%). Overexpressions of MIF and CCL3 were observed in NPC plasma, NPC cell lines and NPC tissues. CONCLUSION: Plasma MIF, CCL3, and VCA-IgA combination significantly improves the diagnostic specificity of NPC in high-risk individuals.


Assuntos
Antígenos Virais/imunologia , Proteínas do Capsídeo/imunologia , Quimiocina CCL3/sangue , Infecções por Vírus Epstein-Barr/diagnóstico , Imunoglobulina A/sangue , Oxirredutases Intramoleculares/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/metabolismo , Sensibilidade e Especificidade , Regulação para Cima , Adulto Jovem
6.
J Exp Clin Cancer Res ; 37(1): 288, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30482227

RESUMO

BACKGROUND: Drugs that inhibit the MEK/ERK pathway have therapeutic benefit in bladder cancer treatment but responses vary with patients, for reasons that are still not very clear. Interferon-α (IFN-α) is also used as a therapeutic agent for bladder cancer treatment but the response rate is low. It was found that IFN-α could enhance the cytotoxic effect of MEK inhibition. However, the potential mechanisms of that are still unclear. Understanding of the cross-talk between the IFN-α and MEK/ERK pathway will help enhance the efficacy of IFN-α or MEK inhibitors on bladder cancer. METHODS: Immunoprecipitation and pull-down assay were used to reveal the formation of signaling complex. The protein expressions were detected by western blot and immunohistochemistry. The cAMP level, Phosphodiesterase 4D (PDE4D) activity and Prostaglandin E2 (PGE2) concentration in cells, serum and tissues were detected by enzyme-linked immunosorbent assay. The role of PDE4D in bladder tumorigenesis in vivo was examined by the xenograft model. Tissue microarray chips were used to investigate the prognostic roles of PDE4D and tumor progression locus 2 (TPL2) in bladder cancer patients. RESULTS: IFN-α down-regulated the cyclooxygenase-2 (COX-2) expression in bladder cancer cells through the inhibition of TPL2/NF-κB pathway; IFN-α also inhibited COX-2 expression by suppressing cAMP signaling through TPL2-ERK mediated PDE4D activity. Reduction of the intracellular cAMP level by PDE4D potentiated the antitumor effect of IFN-α against bladder cancer in vitro and in vivo. Further analysis of clinical samples indicated that low PDE4D expression and high level of TPL2 phosphorylation were correlated to the development and poor prognosis in bladder cancer patients. CONCLUSIONS: Our data reveal that IFN-α can exert its antitumor effect through a non-canonical JAK-STAT pathway in the bladder cancer cells with low activity of IFN pathway, and the TPL2 inhibition is another function of IFN-α in the context of bladder cancer therapy. The antitumor effects of IFN-α and MEK inhibition also depend on the PDE4D-mediated cAMP level in bladder cancer cells. Suppression of the TPL2 phosphorylation and intracellular cAMP level may be possible therapeutic strategies for enhancing the effectiveness of IFN-α and MEK inhibitors in bladder cancer treatment.


Assuntos
Antivirais/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Interferon-alfa/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Aminopiridinas/farmacologia , Animais , Antivirais/farmacologia , Benzamidas/farmacologia , AMP Cíclico/metabolismo , Ciclo-Oxigenase 2/biossíntese , Ciclopropanos/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
7.
BMC Cancer ; 18(1): 9, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29295705

RESUMO

BACKGROUND: To investigate the predictive value of chemokine CCL27 for identifying early stage nasopharyngeal carcinoma (NPC) patients within a population seropositive for Epstein-Barr virus (EBV) capsid antigen-specific IgA (VCA-IgA). METHODS: CCL27 in plasma samples from 104 NPC patients, 112 VCA-IgA-positive healthy donors, and 140 VCA-IgA-negative normal subjects was measured by ELISA. Expression of CCL27 in nasopharyngeal tissue from 20 VCA-IgA-positive healthy donors and 20 NPC patients was examined by immunohistochemical staining. RESULTS: Levels of CCL27 in the plasma of VCA-IgA-positive healthy donors (607.33 ± 218.81 pg/ml) were significantly higher than the levels in all NPC patients (437.09 ± 217.74, P = < 0.0001) and in the subset of patients with early stage NPC (463.85 ± 226.17, P = 0.0126). Plasma CCL27 levels were significantly lower in the VCA-IgA-negative normal subjects (358.22 ± 133.15 pg/ml) than in either the VCA-IgA-positive healthy donors (P < 0.0001) or the NPC patients (P = 0.0113). CCL27 protein was detected in 16 of 20 (80%) nasopharyngeal tissue samples from VCA-IgA-positive healthy donors and in 3 of 20 (15%) tumor tissue samples from NPC patients. There was no relationship between CCL27 levels and VCA-IgA titers or plasma EBV DNA content. Receiver operating characteristic (ROC) curves demonstrated that plasma CCL27 levels had a sensitivity of 67.00%, a specificity of 73.10%, and an area under the ROC of 0.725 (95% confidence interval [CI]: 0.657-0.793) for distinguishing between NPC patients and VCA-IgA-positive healthy donors. Further analysis showed that CCL27 levels could distinguish between early stage NPC patients and VCA-IgA-positive healthy donors with an area under the ROC of 0.712 (95% CI: 0.560-0.865), a sensitivity of 59.80%, and a specificity of 84.60%. CONCLUSIONS: Chemokine CCL27 could successfully identify NPC patients within a VCA-IgA-positive population.


Assuntos
Anticorpos Antivirais/sangue , Biomarcadores Tumorais/sangue , Proteínas do Capsídeo/imunologia , Carcinoma/diagnóstico , Quimiocina CCL27/sangue , Infecções por Vírus Epstein-Barr/complicações , Imunoglobulina A/sangue , Neoplasias Nasofaríngeas/diagnóstico , Adulto , Idoso , Área Sob a Curva , Proteínas do Capsídeo/sangue , Carcinoma/sangue , Carcinoma/virologia , Estudos de Casos e Controles , Infecções por Vírus Epstein-Barr/virologia , Feminino , Seguimentos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/virologia , Prognóstico , Taxa de Sobrevida
8.
World J Gastroenterol ; 23(43): 7693-7704, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29209110

RESUMO

AIM: To identify whether chitinase 3-like 1 (CHI3L1) serves as a suitable biomarker for the prognosis of esophageal squamous cell carcinoma (ESCC) and to analyze this protein's cellular source. METHODS: An ELISA was conducted to detect the concentration of CHI3L1 in the serum of 150 ESCC patients diagnosed between January 2001 and February 2005. The prognostic relevance of CHI3L1 was evaluated by a Kaplan-Meier and Cox regression analysis. The immunohistochemistry was reanalyzed, and fluorescent staining was utilized to explore the cellular origins of CHI3L1. We stimulated monocyte-derived macrophages (MDMs) with either IL-6 or the supernatant of the ESCC cell line Eca-109 and later investigated the level of CHI3L1 by qPCR and ELISA. RESULTS: The level of serum CHI3L1 was higher in older patients (≥ 60) than in patients under the age of 60 (P = 0.001). The patients with higher levels of CHI3L1 had a significantly shorter overall survival, whereas the traditional markers, carcinoembryonic antigen and squamous cell carcinoma antigen, were less effective (P > 0.05). A multivariate Cox analysis (P = 0.001) indicated that CHI3L1 was an independent prognostic factor for ESCC patients. Peritumoral macrophages in ESCC exhibited high levels of CHI3L1. Interleukin-6 (IL-6) and the supernatant of Eca-109 containing IL-6 stimulated MDMs to secrete CHI3L1. The serum concentration of CHI3L1 in the ESCC patients showed a weak correlation with the laboratory inflammatory parameters neutrophil (NEU, P = 0.045), neutrophil/lymphocyte rate (NLR, P = 0.016), and C-reactive protein (CRP, P < 0.001). CONCLUSION: Our study first established a connection between the pretreated CHI3L1 and patients with ESCC, and the serum CHI3L1 was primarily secreted by ESCC-surrounded macrophages.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Proteína 1 Semelhante à Quitinase-3/sangue , Neoplasias Esofágicas/sangue , Macrófagos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proteína 1 Semelhante à Quitinase-3/metabolismo , Ensaio de Imunoadsorção Enzimática , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Esôfago/citologia , Esôfago/patologia , Feminino , Humanos , Imuno-Histoquímica , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Microambiente Tumoral
9.
J Cancer ; 8(10): 1833-1842, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28819381

RESUMO

Background: Although various inflammation-based indexes in esophageal carcinoma have been documented, but the prognostic value of the albumin-to-globulin ratio(AGR) and its correlation with fibrinogen in resectable ESCC remain unknown. Methods: The levels of pre-treatment serum common acute phase proteins (including CRP, albumin and fribrinogen) were retrospectively analyzed in 447 patients with ESCC who underwent surgical resection at our department. The prognostic value was explored by univariate and multivariate cox hazard analysis. The correlation between AGR and acute phase proteins were also analyzed. Results: Patients with decreased levels of AGR and increased CRP had significantly lower 5-year survival rates than those with higher AGR, not only in the whole ESCC cohort but also in the subgroups stratified according to the disease T, N classifications, and metastasis, whereas the other acute phase proteins were not independent prognostic factors for ESCC. In addition, a lower AGR level was observed more often in patients with a high fibrinogen level than in those with a low fibrinogen level. Spearman's rank correlation analysis revealed that the AGR level presented a negative correlation with the fibrinogen level (r =-0.317, p<0.001). Conclusions: The 5-year survival was shorter in resectable ESCC patients exhibiting decreased pre-treatment AGR and increased CRP. Thus, the serum AGR and CRP may be a clinical prognostic factor for resectable ESCC patients. In addition, a negative correlation was present between the levels of AGR and fibrinogen, the common indexes of acute phase reactants.

10.
J Cancer ; 8(11): 2079-2087, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28819409

RESUMO

Aims: The levels of coagulation system tests have been studied in various cancers. In this study, our aim is to evaluate the prognostic value of pretreatment plasma coagulation tests in hepatocellular carcinoma (HCC) patients. Patient and methods: A retrospective study was performed in 539 patients with HCC, and follow-up period was at least 60 months until recurrence or death. The prognostic significance of coagulation system tests (prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen) were determined by univariate and multivariate Cox hazard models. Then, according to the results of the multivariate analyses, we proposed the coagulation-Based Stage, which combined the independent risk factors (prothrombin time and fibrinogen). Results: Coagulation system tests including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fbg) were analyzed. Patients with prolonged PT (≥12.1 sec) levels had significantly poor overall survival (OS) and disease-free survival (DFS), not only in the entire cohort (HR: 1.661, 95%CI: 1.125-2.451, p=0.011 vs. HR: 1.660, 95%CI: 1.125-2.451, p=0.011), but also in the subgroups stratified by pathological stage (stage I-II and stage III-IV). Additionally, high Fbg (≥2.83 g/L) levels experienced significantly decreased OS and DFS (HR: 2.158, 95%CI: 1.427-3.263, p<0.001 vs. HR: 2.161, 95%CI: 1.429-3.267, p<0.001), not only in the entire cohort but also in the subgroups stratified by pathological stage (stage I-II and stage III-IV). All the patients were then stratified (based on combined PT and Fbg) into three groups, The OS for HCC patients were (41.37±17.76), (31.83±19.84) and (18.68±18.41) months, and the DFS for HCC patients were (41.15±17.88), (31.65±19.81) and (18.66±18.39) months. Conclusions: Our findings suggest that the combination of plasma PT and Fbg levels should be evaluated as the valuable predictor of survival in patients with HCC.

11.
J Cancer ; 8(12): 2346-2355, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28819439

RESUMO

Serum tumor markers for the diagnosis of esophageal squamous cell carcinoma (ESCC) have low sensitivity. This study aims to identify new serum markers for ESCC diagnosis from RNA sequencing (RNA-seq) data. RNA-seq was performed using six pairs of ESCC and matched normal tissues. The candidates for ESCC were screened from the differentially expressed genes. The candidates were analyzed by ELISA from the serum of a test group and a validation group. Real-time PCR, Western blotting and immunohistochemistry were used to detect the expression of the candidates in tumor cell lines and tumor tissues. Ten genes were selected from the RNA-seq data. Serum levels of ADAM12, CHI3L1, MMP13 and SPP1 were significantly higher in the ESCC patients than in the healthy controls. A diagnostic model combining CHI3L1, MMP13, and SPP1 was established. The area under the curve (AUC) values for serum CHI3L1, MMP13, and SPP1 and the diagnostic model for discriminating ESCC patients from controls were 0.732, 0.881, 0.661 and 0.928, respectively. In the validation cohort, the AUC values were 0.753, 0.789, 0.696 and 0.843, respectively. Moreover, the AUC of the model for classifying patients with early ESCC was 0.918 in the test group and 0.857 in the validation group. Overexpression of CHI3L1, MMP13 and SPP1 was observed in the tumor cell lines and tissues. The diagnostic model composed of CHI3L1, MMP13 and SPP1 discriminates ESCC patients with high sensitivity. Our data highlight the potential of this diagnostic model for the noninvasive diagnosis of ESCC.

12.
Int J Cancer ; 141(1): 152-159, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28369849

RESUMO

Several non-hepatocellular cancers were linked with hepatitis B virus (HBV) infection. This study was aimed to quantify the potential associations between HBV infection and multiple non-hepatocellular cancers. Continuous cases, including 5,715 non-cancer and 40,963 cancer cases diagnosed from 2008 to 2014 in Sun Yat-sen University Cancer Center were analyzed. HBV DNA and hepatitis B core antigen (HBcAg) were examed in gastric cancer tissues by polymerase chain reaction and immunohistochemical staining. After adjusting for age, sex, year of diagnosis, smoking, drinking and family history of cancer, significant associations were found between serum HBsAg and frequently reported HBV-related non-hepatocellular cancers, including non-Hodgkin's lymphoma, cholangiocarcinoma and pancreatic cancer [adjusted odds ratio (AOR) and 95% confidence interval (CI): 1.89 (1.65-2.16)], as well as total other non-hepatocellular cancers [AOR and 95% CI: 1.12 (1.03-1.22)]. The median ages at diagnosis, all-cause death and cancer-specific death of serum HBsAg positive cancer patients were all significantly younger than those with serum HBsAg negative. HBV DNA was detected in 12.4% (34/275) gastric cancer tissues and HBcAg was most commonly detected in lymphocytes. This was the first report that HBV infection had a modest but significant nonspecific association with total non-hepatocellular cancers. Median age at diagnosis and death was significantly younger in serum HBsAg positive cancer patients. The underlying mechanism needs further investigation.


Assuntos
Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/patogenicidade , Hepatite B/virologia , Neoplasias Hepáticas/virologia , Adulto , Fatores Etários , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Hepatite B/complicações , Hepatite B/genética , Hepatite B/patologia , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/isolamento & purificação , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Medição de Risco
13.
Biomed Res Int ; 2017: 3083267, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28424782

RESUMO

Background. The pretreatment albumin and globulin ratio (AGR) was an inflammation-associated factor which was related to the overall survival in various malignancies. The aim of this study was to evaluate the prognostic value of AGR in patients with gastric cancer. Method. This retrospective study included 862 cases pathologically diagnosed with gastric cancer. All patients were randomly divided into the testing group (431 cases) and validation group (431 cases). The relationships of AGR with clinicopathologic characteristics and prognosis were analyzed by Kaplan-Meier and Cox regression methods. Results. In the testing group, the median overall survival was 26.90 months and the cutoff value of AGR was 1.50 based on R language. Kaplan-Meier analysis showed that lower AGR was correlated with poorer overall survival. Multivariate analysis demonstrated that AGR was an independent prognostic factor for overall survival (HR: 0.584, 95% CI = 0.351-0.973, and p = 0.039). In the validation group, the median overall survival was 24.10 months. Lower AGR (≤1.50) also had a significantly poorer overall survival by Kaplan-Meier analysis. According to multivariate analysis, the AGR was also confirmed to be an independent prognostic factor for overall survival (HR: 0.578, 95% CI = 0.373-0.897, and p = 0.015). Conclusions. Our study suggested that the pretreatment AGR could be a prognostic biomarker for overall survival in patients with gastric cancer.


Assuntos
Globulinas/metabolismo , Cuidados Pré-Operatórios , Albumina Sérica/metabolismo , Neoplasias Gástricas/sangue , Neoplasias Gástricas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Reprodutibilidade dos Testes , Neoplasias Gástricas/patologia
14.
Oncotarget ; 8(69): 113734-113748, 2017 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-29371942

RESUMO

Type I interferons (IFN-α/ß) have broad and potent immunoregulatory and antiproliferative activities, which are negatively regulated by Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2). Inhibition of SHP2 by small molecules may be a new strategy to enhance the effcacy of type I IFNs. Using an in vitro screening assay for new inhibitors of SHP2 phosphatase, we found that quercetin was a potent inhibitor of SHP2. Computational modeling showed that quercetin exhibited an orientation favorable to nucleophilic attack in the phosphatase domain of SHP2. Quercetin enhanced the phosphorylation of signal transducer and activator of transcription proteins 1 (STAT1) and promoted endogenous IFN-α-regulated gene expression. Furthermore, quercetin also sensitized the antiproliferative effect of IFN-α on hepatocellular carcinoma HepG2 and Huh7 cells. The overexpression of SHP2 attenuated the effect of quercetin on IFN-α-stimulated STAT1 phosphorylation and antiproliferative effect, whereas the inhibition of SHP2 promoted the effect of quercetin on IFN-α-induced STAT1 phosphorylation and antiproliferative effect. The results suggested that quercetin potentiated the inhibitory effect of IFN-α on cancer cell proliferation through activation of JAK/STAT pathway signaling by inhibiting SHP2. Quercetin warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-α/ß.

15.
Int J Mol Sci ; 17(11)2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27854304

RESUMO

Recent studies have indicated that inflammation-based prognostic scores, such as the Glasgow Prognostic Score (GPS), modified GPS (mGPS) and C-reactive protein/Albumin (CRP/Alb) ratio, platelet-lymphocyte ratio (PLR), and neutrophil-lymphocyte ratio (NLR), have been reported to have prognostic value in patients with many types of cancer, including nasopharyngeal carcinoma (NPC). In this study, we proposed a novel inflammation-based stage, named I stage, for patients with NPC. A retrospective study of 409 newly-diagnosed cases of NPC was conducted. The prognostic factors (GPS, mGPS, CRP/Alb ratios, PLR, and NLR) were evaluated using univariate and multivariate analyses. Then, according to the results of the multivariate analyses, we proposed a I stage combination of independent risk factors (CRP/Alb ratio and PLR). The I stage was calculated as follows: patients with high levels of CRP/Alb ratio (>0.03) and PLR (>146.2) were defined as I2; patients with one or no abnormal values were defined as I1 or I0, respectively. The relationships between the I stage and clinicopathological variables and overall survival (OS) were evaluated. In addition, the discriminatory ability of the I stage with other inflammation-based prognostic scores was assessed using the AUCs (areas under the curves) analyzed by receiver operating characteristics (ROC) curves. The p value of <0.05 was considered to be significant. A total of 409 patients with NPC were enrolled in this study. Multivariate analyses revealed that only the CRP/Alb ratio (Hazard ratio (HR) = 2.093; 95% Confidence interval (CI): 1.222-3.587; p = 0.007) and PLR (HR: 2.003; 95% CI: 1.177-3.410; p = 0.010) were independent prognostic factors in patients with NPC. The five-year overall survival rates for patients with I0, I1, and I2 were 92.1% ± 2.9%, 83.3% ± 2.6%, and 63.1% ± 4.6%, respectively (p < 0.001). The I stage had a higher area under the curve value (0.670) compared with other systemic inflammation-based prognostic scores (p < 0.001). The I stage is a novel and useful predictive factor for OS in patients with NPC.


Assuntos
Plaquetas/patologia , Proteína C-Reativa/metabolismo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/mortalidade , Neutrófilos/patologia , Albumina Sérica/metabolismo , Adulto , Idoso , Área Sob a Curva , Biomarcadores/sangue , Carcinoma , Contagem de Células , Feminino , Escala de Resultado de Glasgow , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
16.
Sci Rep ; 6: 33440, 2016 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-27678333

RESUMO

Fusobacterium nucleatum (F. nucleatum, Fn) is associated with the colorectal cancer (CRC). Fn-infection could induce significant levels of serum Fn-specific antibodies in human and mice. The objective of this study was to identify Fn-infection that elicit a humoral response in patients with CRC and evaluate the diagnostic performance of serum anti-Fn antibodies. In this work, we showed the mean absorbance value of anti-Fn-IgA and -IgG in the CRC group were significantly higher than those in the benign colon disease group and healthy control group (P < 0.001). The sensitivity and specificity of ELISA for the detection of anti-Fn-IgA were 36.43% and 92.71% based on the optimal cut-off. The combination of anti-Fn-IgA and carcino-embryonic antigen (CEA) was better for diagnosing CRC (Sen: 53.10%, Spe: 96.41%; AUC = 0.848). Furthermore, combining anti-Fn-IgA with CEA and carbohydrate antigen 19-9 (CA19-9) (Sen: 40.00%, Spe: 94.22%; AUC = 0.743) had the better ability to classify CRC patients with stages I-II. These results suggested that Fn-infection elicited high level of serum anti-Fn antibodies in CRC patients, and serum anti-Fn-IgA level may be a potential diagnosing biomarker for CRC. Serum anti-Fn-IgA in combination with CEA and CA19-9 increases the sensitivity of detecting early CRC.

17.
Int J Mol Sci ; 17(9)2016 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-27598151

RESUMO

The purpose of this work is to analyze preoperative serum aspartate aminotransferase (AST) levels and their effect on the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical operation. These analyses were performed retrospectively in patients with NSCLC followed by surgery; participants were recruited between January 2004 and January 2008. All clinical information and laboratory results were collected from medical records. We explored the association between preoperative serum AST and recurrence-free survival (RFS), and the overall survival (OS) of NSCLC patients. Kaplan-Meier analysis and Cox multivariate analysis, stratified by the AST median value, were used to evaluate the prognostic effect. A chi-squared test was performed to compare clinical characteristics in different subgroups. A p-value of ≤0.05 was considered to be statistically significant. A total of 231 patients were enrolled. The median RFS and OS were 22 and 59 months, respectively. The AST levels were divided into two groups, using a cut-off value of 19 U/L: High AST (>19 U/L), n = 113 vs. low AST (≤19 U/L), n = 118. Multivariate analysis indicated that preoperative serum AST > 19 U/L (hazard ratio (HR) = 0.685, 95% confidence interval (CI): 0.493-0.994, p = 0.046 for RFS, HR = 0.646, 95% CI: 0.438-0.954, p = 0.028 for OS) was an independent prognostic factor for both RFS and OS. High preoperative serum AST levels may serve as a valuable marker to predict the prognosis of NSCLC after operation.


Assuntos
Aspartato Aminotransferases/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Análise de Sobrevida
18.
Oncotarget ; 7(28): 42978-42987, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27304186

RESUMO

PURPOSE: We aimed to assess the prognostic value of pretreatment high density lipoprotein cholesterol (HDL-C) levels in patients with nasopharyngeal carcinoma (NPC) and investigate the possible biological effects of these lipoproteins on NPC cells in vitro. EXPERIMENTAL DESIGN: We examined the prognostic value of pretreatment HDL-C levels in 2443 patients with non-metastatic NPC from three independent institutions. The Cox proportional hazard model and log-rank test were used to analyze the correlation between HDL-C levels and overall survival (OS). Cell growth, colony formation, and apoptotic assays were used to determine the biological functions of HDL on NPC cells in vitro. All of the statistical tests were two-sided. RESULTS: OS was decreased in patients with high pretreatment HDL-C levels compared with those with low HDL-C levels (P < 0.05). Similarly, a decreased OS was noted in advanced stage (stage III-IV), NPC patients with high pretreatment HDL-C levels (P < 0.01). Multivariate analyses indicated that HDL-C was an independent prognostic factor associated with shorter OS in training cohorts. These findings were confirmed in both independent validation cohorts (P < 0.01). In vitro experiments demonstrated that HDL could increase cell proliferation, invasion, and colony formation, which were largely dependent on the expression of its receptor SR-B1. Finally, HDL could enhance chemoresistance by protecting cancer cells from apoptosis. CONCLUSIONS: Pretreatment HDL-C is a poor prognostic factor for patients with NPC. This effect may be associated with the ability of HDL to enhance proliferation, colony formation, migration, and chemoresistance in NPC cells.


Assuntos
Biomarcadores Tumorais/sangue , HDL-Colesterol/sangue , Neoplasias Nasofaríngeas/sangue , Adulto , Linhagem Celular Tumoral , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Nasofaríngeas/diagnóstico , Valor Preditivo dos Testes , Prognóstico , Curva ROC
19.
Clin Lab ; 62(4): 553-61, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27215073

RESUMO

BACKGROUND: Assessment of immunoglobulin A (IgA) antibody responses to Epstein-Barr virus (EBV) antigen is important for the early diagnosis of nasopharyngeal carcinoma (NPC). EBV glycoprotein gp42 has been shown to play an essential role in membrane fusion with B cells. The aim of the present study was to assess whether the antibodies to EBV glycoprotein gp42 in serum could be a novel marker for diagnosis of NPC. METHODS: EBV glycoprotein gp42 expressed in the recombinant baculovirus system was used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to gp42 in serum. The blood samples were obtained from 406 participants (n = 208 patients with NPC and 198 healthy controls). Receiver operating characteristics (ROC) was used to calculate diagnostic accuracy. RESULTS: The ROC curves showed that IgA-gp42 ELISA had a sensitivity of 76.4%, specificity of 78.3% and an area under the curve (AUC) of 0.856 (95% CI, 0.82 - 0.891) to diagnose NPC. Furthermore, gp42 maintained diag- nostic capacity in NPC patients who were IgA-viral capsid antigen (VCA) negative (87.5%, 64.1% and 0.844 [95% CI, 0.776 - 0.912]). Combining gp42 and VCA improved the diagnostic capacity compared with the individual tests (89.9%, 94.4% and 0.973 [95% CI, 0.959 - 0.9871). CONCLUSIONS: The EBV glycoprotein complex gp42 acts as a novel biomarker for diagnosis of NPC and improves identification of patients with VCA-negative NPC.


Assuntos
Anticorpos Antivirais/sangue , Glicoproteínas/imunologia , Neoplasias Nasofaríngeas/diagnóstico , Proteínas Virais/imunologia , Adulto , Biomarcadores , Proteínas do Capsídeo/análise , Carcinoma , Feminino , Humanos , Imunoglobulina A/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/virologia , Curva ROC
20.
Oncotarget ; 7(13): 16372-83, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-27093005

RESUMO

To determine whether measuring antibodies against Epstein-Barr virus (EBV) glycoprotein gH/gL in serum could improve diagnostic accuracy in nasopharyngeal carcinoma (NPC) cases, gH/gL expressed in a recombinant baculovirus system was used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies in two independent cohorts. Binary logistic regression analyses were performed using results from a training cohort (n = 406) to establish diagnostic mathematical models, which were validated in a second independent cohort (n = 279). Levels of serum gH/gL antibodies were higher in NPC patients than in healthy controls (p < 0.001). In the training cohort, the IgA-gH/gL ELISA had a sensitivity of 83.7%, specificity of 82.3% and area under the curve (AUC) of 0.893 (95% CI, 0.862-0.924) for NPC diagnosis. Furthermore, gH/gL maintained diagnostic capacity in IgA-VCA negative NPC patients (sensitivity = 78.1%, specificity = 82.3%, AUC = 0.879 [95% CI, 0.820 - 0.937]). Combining gH/gL and viral capsid antigen (VCA) detection improved diagnostic capacity as compared to individual tests alone in both the training cohort (sensitivity = 88.5%, specificity = 97%, AUC = 0.98 [95% CI, 0.97 - 0.991]), and validation cohort (sensitivity = 91.2%, specificity = 96.5%, AUC = 0.97 [95% CI, 0.951-0.988]). These findings suggest that EBV gH/gL detection complements VCA detection in the diagnosis of NPC and aids in the identification of patients with VCA-negative NPC.


Assuntos
Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Proteínas do Capsídeo/imunologia , Carcinoma/imunologia , Imunoglobulina A/imunologia , Neoplasias Nasofaríngeas/imunologia , Adulto , Animais , Anticorpos Antivirais/sangue , Carcinoma/sangue , Carcinoma/diagnóstico , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Chaperonas Moleculares/imunologia , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/diagnóstico , Sensibilidade e Especificidade , Células Sf9 , Spodoptera , Proteínas do Envelope Viral/imunologia , Proteínas Virais/imunologia
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